IMPROVE THE MANUFACTURABILITY AND DISSOLUTION
PERFORMANCE OF DRUGS THROUGH SPHERICAL
CRYSTALLIZATION
A DISSERTATION
SUBMITTED TO THE FACULTY OF
UNIVERSITY OF MINNESOTA
BY
Hongbo Chen
IN PARTIAL FULFILLMENT OF THE REQUIREMENTS
FOR THE DEGREE OF
DOCTOR OF PHILOSOPHY
Changquan Calvin Sun, Advisor
July 2020
© Hongbo Chen, July 2020
i
Acknowledgements
I would like to thank my adviser, Dr. Changquan Calvin Sun, for his unlimited support,
careful guidance, unceasing encouragement, and lasting friendship during my study in the
Department of Pharmaceutics at UMN in the past five years. His passion in research
inspires me and sets a role model for me to learn and improve myself. I’m grateful to have
him to be my advisor.
I want to express my thanks to my committee members, Dr. Raj Suryanarayanan, Dr.
Timothy S. Wiedmann, and Dr. Aktham Aburub, for giving me constructive suggestions
on my research and reviewing my thesis critically. I want to thank Dr. Wiedmann for
reviewing my manuscript drafts critically and providing me with valuable comments. I am
grateful to Dr. Sury for granting me access to instruments in his lab to conduct part of my
research. I am especially thankful to Dr. Aburub for his constructive comments,
suggestions, guidance, and help on my research projects.
My thanks also go to Sun lab members, especially Shubhajit, Chenguang and Manish for
their help, suggestion and discussion on my research, Shao-yu, Wei-jhe, Jiangnan, Shenye,
Kunlin, Yiwang, Amy, Gerrit, Joan, Sibo, Zhongyang, Ling, Zhengxuan, Cosima, Xin,
Shuyu, Hiro, Mingjun, Shan, Hongliang, Yuebin, and Jun for their accompany. My
gratitude also extends to Katie, Amanda, Davin, Kelsey, Krutika, Navpreet, Jayesh, and
Yafan in our department. I also want to thank my collaborators, Dr. Mahanthappa, Dr.
Haynes, Hongyun, Hyunho, and Bo for their contributions on my research projects.
ii
I am grateful to have my girlfriend Jiali, for her company, support, and love during my
study at UMN in the past five years. Because of you, my life is fruitful. Finally, I would
like to thank my family. Thanks for your financial and spiritual support throughout my life
and encouragement on my choice of career.
iii
Dedicated to my family
iv
Abstract
Spherical crystallization, a particle engineering technique, has been commonly
used to modify the size and shape of particles to enhance the micromeritics properties of a
powder and facilitate tablet formulation development. By identifying the key factors
affecting the generation of spherical agglomerates and the underlying mechanism,
spherical agglomerates with optimal size, shape and density can be obtained, presenting
excellent flowability, tabletability and dissolution. The goals of this thesis work include:
(i) prepare and evaluate the properties of the spherical agglomerates of drugs using the two
main methods including spherical agglomeration (SA) and quasi-emulsion solvent
diffusion (QESD) , (ii) explore high drug loading direct compression tablet formulations
enabled by the spherical crystallization technique, (iii) develop a spherical cocrystallization
technique to simultaneously improve the manufacturability and dissolution of drugs, and
(iv) reduce the punch sticking propensity via a polymer assisted QESD method.
To successfully prepare the spherical agglomerates, it is crucial to select a solvent
system-based phase diagram. Spherical agglomerates of a model API, ferulic acid (FA),
via a QESD process presented exceptional flowability and tabletability. Such spherical FA
crystals enabled the development of a direct compression tablet formulation containing 99%
of the API. Spherical griseofulvin agglomerates prepared by a SA process, exhibited not
only good flowability but also excellent tabletability. The unexpected profoundly
improved tabletability was attributed to a micro porous structure of primary crystals, due
to an in-situ solvation and desolvation during the SA process, which enhanced the plasticity
of the agglomerates. For low water-soluble drugs, spherical crystallization of more soluble
cocrystals, i.e., spherical cocrystallization, is an enabling technology to simultaneously
v
improve the manufacturability and dissolution and enable the development of high drug
loading tablet formulation. Moreover, spherical agglomerates of celecoxib obtained via a
polymer assisted QESD process not only showed substantially improved tabletability and
flowability but also significantly reduced punch-sticking propensity. A thin layer of
polymer coating onto the agglomerates surface, confirmed by SEM and XPS analysis,
explains the reduced punch sticking propensity due to the physical barrier of polymer
between the drug and punch.
vi
Table of Contents
Acknowledgements .............................................................................................................. i
Dedication .......................................................................................................................... iii
Abstract .............................................................................................................................. iv
Table of Contents ............................................................................................................... vi
List of Tables ................................................................................................................... xiv
List of Figures .................................................................................................................. xvi
Chapter 1: Introduction ....................................................................................................1
1.1 Background ....................................................................................................................2
1.2 Literature review ............................................................................................................3
1.2.1 Spherical agglomeration (SA) ......................................................................4
1.2.1.1 Selection of a bridging liquid ...............................................................6
1.2.1.2 Phase diagram .......................................................................................7
1.2.2 Quasi-emulsion solvent diffusion (QESD) ................................................10
1.2.3 Powder property .........................................................................................11
1.2.3.1 Micromeritic property ........................................................................11
1.2.3.2 Flowability ..........................................................................................12
1.2.3.3 Tabletability ........................................................................................13
1.2.3.4 Punch sticking ....................................................................................14
1.2.3.5 Dissolution ..........................................................................................15
1.2.4 Continuous manufacturing .........................................................................16
vii
1.2.5 Spherical cocrystallization .........................................................................17
1.3 Objective and hypothesis .............................................................................................18
1.4 Reference .....................................................................................................................24
Chapter 2: Direct compression tablet containing 99% active ingredient – a tale of
spherical crystallization ...................................................................................................31
2.1 Synopsis ......................................................................................................................32
2.2 Introduction .................................................................................................................32
2.3 Methods........................................................................................................................34
2.3.1 Preparation of the QESD FA .....................................................................34
2.3.2 Powder X-ray Diffractometry (PXRD) ......................................................35
2.3.3 Thermogravimetry Analysis (TGA) ..........................................................35
2.3.4 Scanning electron microscopy (SEM) .......................................................35
2.3.5 Particle size distribution (PSD) ..................................................................35
2.3.6 Flowability measurement ...........................................................................36
2.3.7 Direct Compression of Powders ................................................................36
2.3.8 Tablet disintegration ..................................................................................37
2.3.9 Assessment of Tablet Tensile Strength ......................................................37
2.3.10 Friability .....................................................................................................37
2.3.11 Determination of HPMC in QESD FA ......................................................38
2.3.12 Dissolution performance ............................................................................38
2.4 Results and discussion .................................................................................................38
2.4.1 Flowability of as-received FA ...................................................................38
2.4.2 QESD preparation and micromeritic property ...........................................39
viii
2.4.3 Powder flowability and tabletability ..........................................................39
2.4.4 Formulation development ..........................................................................40
2.5 Conclusion ...................................................................................................................42
2.6 References ....................................................................................................................53
Chapter 3: Profoundly improved plasticity and tabletability of griseofulvin by in-
situ solvation and desolvation during spherical crystallization ...................................56
3.1 Synopsis .......................................................................................................................57
3.2 Introduction ..................................................................................................................57
3.3 Materials and methods .................................................................................................59
3.3.1 Materials .......................................................................................................59
3.3.2 Spherical crystallization ................................................................................59
3.3.2.1 Construction of ternary phase diagram ..........................................59
3.3.2.2 Preparation of spherical agglomerates of GSF ..............................60
3.3.3 Powder X-ray Diffractometry (PXRD) .........................................................60
3.3.4 Single Crystal X-ray Diffractometry ............................................................61
3.3.5 Thermal Analyses .........................................................................................61
3.3.6 Powder Flowability .......................................................................................62
3.3.7 Powder tabletability ......................................................................................62
3.3.8 Scanning electron microscopy (SEM) ..........................................................63
3.3.9 In-die Heckel analysis ...................................................................................63
3.3.10 Out-of-die Kuentz–Leuenberger (KL) equation .........................................64
3.3.11 Energy framework of crystal structures ......................................................65
3.4 Results and discussion .................................................................................................65
ix
3.4.1 Ternary Phase Diagram.................................................................................65
3.4.2 Particulate properties ....................................................................................66
3.4.3 Powder flowability and tabletability .............................................................66
3.4.4 Role of plasticity in the improved tabletability of GSF agglomerates..........68
3.4.5 Origin of superior plasticity of GSF SA .......................................................69
3.5 Conclusion ...................................................................................................................71
3.6 References ....................................................................................................................84
Chapter 4: Spherical cocrystallization - an enabling technology for the development
of high dose direct compression tablets of poorly soluble drugs .................................88
4.1 Synopsis .......................................................................................................................89
4.2 Introduction ..................................................................................................................89
4.3 Materials and methods .................................................................................................91
4.3.1 Materials .......................................................................................................91
4.3.2 Preparation of spherical GSF-Acs cocrystal hydrate ....................................92
4.3.3 Powder X-ray Diffractometry (PXRD) .........................................................93
4.3.4 Thermal Analyses .........................................................................................93
4.3.5 Scanning electron microscopy (SEM) ..........................................................93
4.3.6 Contact angle measurement ..........................................................................94
4.3.7 Energy framework and topologic analysis of crystal structures ...................94
4.3.8 Formulation and Tablet Compression ...........................................................95
4.3.9 Powder Flowability .......................................................................................96
4.3.10 Expedited Friability ....................................................................................96
4.3.11 Artificial Stomach-Duodenum Dissolution (ASD) .....................................97
x
4.4 Results and discussion .................................................................................................98
4.4.1 Characterization ............................................................................................98
4.4.2 Formulation development ...........................................................................101
4.5 Conclusions ................................................................................................................104
4.6 References ..................................................................................................................120
Chapter 5: Simultaneously improving the manufacturability and dissolution of
indomethacin by a novel quasi-emulsion solvent diffusion based spherical
cocrystallization strategy ...............................................................................................124
5.1 Synopsis .....................................................................................................................125
5.2 Introduction ................................................................................................................125
5.3 Materials and methods ...............................................................................................128
5.3.1 Materials .....................................................................................................128
5.3.2 Preparation of IMC-SAC cocrystal powders ..............................................129
5.3.2.1 Fine IMC-SAC cocrystal by anti-solvent (AS) method ...............129
5.3.2.2 IMC-SAC spherical cocrystal agglomerates by QESD-CC method
..................................................................................................................129
5.3.3 Particle size distribution (PSD) ...................................................................130
5.3.4 Specific surface area (SSA) measurement ..................................................130
5.3.5 HPMC content determination via size-exclusion chromatography (SEC) .130
5.3.6 Powder X-ray Diffractometry (PXRD) .......................................................132
5.3.7 Thermal Analyses .......................................................................................132
5.3.8 Scanning electron microscopy (SEM) ........................................................133
xi
5.3.9 Computational methods ..............................................................................133
5.3.9.1 Energy framework and topologic analysis of crystal structures ..133
5.3.9.2 Drug – Polymer Intermolecular Interaction .................................134
5.3.10 Preparation of formulated powders ...........................................................134
5.3.11 Powder Flowability ...................................................................................135
5.3.12 Powder Compaction ..................................................................................135
5.3.13 Expedited Friability ..................................................................................136
5.3.14 Dissolution performance ...........................................................................136
5.3.15 Solution 1H Nuclear Magnetic Resonance (NMR) Spectroscopy ............137
5.3.16 Statistical Analysis ....................................................................................137
5.4 Results and discussion ...............................................................................................137
5.4.1 Micromeritic properties ..............................................................................137
5.4.2 Phase purity .................................................................................................139
5.4.3 Flowability and tabletability of various IMC forms ...................................139
5.4.4 Formulation development ...........................................................................141
5.4.5 Dissolution ..................................................................................................143
5.4.6 Drug-polymer molecular interaction...........................................................143
5.4.7 Formation mechanism of spherical cocrystal agglomerates .......................145
5.5 Conclusion .................................................................................................................146
5.6 References ..................................................................................................................170
Chapter 6: Reduction of punch-sticking propensity of celecoxib by spherical
crystallization via polymer assisted quasi-emulsion solvent diffusion ......................174
6.1 Synopsis .....................................................................................................................175
xii
6.2 Introduction ................................................................................................................175
6.3 Materials and methods ...............................................................................................177
6.3.1 Materials .....................................................................................................177
6.3.2 Polymer Screening for Quasi-Emulsion Solvent Diffusion (QESD) ..........177
6.3.3 QESD Spherical Agglomerate Growth Kinetics.........................................178
6.3.4 Particle Size Distribution ............................................................................178
6.3.5 Powder X-ray Diffractometry (PXRD) .......................................................179
6.3.6 Thermal Analyses .......................................................................................179
6.3.7 True density measurement ..........................................................................180
6.3.8 Powder Flowability, Tabletability, and Punch Sticking Assessment .........180
6.3.9 Compressibility and Compactibility Analyses............................................182
6.3.10 Scanning Electron Microscopy (SEM) .....................................................182
6.3.11 X-ray Photoelectron Spectroscopy (XPS) ................................................183
6.3.12 HPMC Content Determination .................................................................183
6.3.13 1H NMR Spectroscopy ..............................................................................184
6.4 Results and discussion ...............................................................................................184
6.4.1 Polymer Screening and Granule Growth Process .......................................185
6.4.2 Sticking propensity reduction by CEL-QESD ............................................186
6.4.3 Solid form and residual solvent ..................................................................187
6.4.4 Manufacturability of CEL Powders ............................................................187
6.4.5 Polymer Coating on CEL-QESD ................................................................189
6.4.6 Interactions between CEL and polymers ....................................................190
6.5 Conclusions ................................................................................................................192
xiii
6.6 References ..................................................................................................................206
Chapter 7: Research summary and future work ........................................................209
Bibliography ...................................................................................................................216
xiv
List of Tables
2.1 Powder and tablet design criteria .................................................................................43
3.1 Plasticity parameters of as received GSF and GSF SA from in-die and out-of-die data
analyses. .............................................................................................................................76
3.2 Intermolecular interaction energies estimated using B3LYP+D2/6+31G(d,p) dispersion
corrected DFT model. Both the total energy (E(tot)) and electrostatic (E(ele)), polarization
(E(pol)), dispersion (E(dis)), and exchange repulsion (E(rep)) components of the energy are
listed. R indicated the distance between centers of mass of the pair of molecules. .... 82-83
4.1 Formulation Composition of GSF-containing tablet using different powder forms. 105
4.2 Intermolecular interaction energies estimated using B3LYP+D2/6+31G(d,p) dispersion
corrected DFT model. Both the total energy (E(tot)) and electrostatic (E(ele)), polarization
(E(pol)), dispersion (E(dis)), and exchange repulsion (E(rep)) components of the energy
are listed. R indicated the distance between centers of mass of the pair of molecules. . 113-
114
4.3 Simulated pharmacokinetic parameters of various GSF-containing tablets (n =3) ...118
4.4 Summary of various GSF tablet formulations in meeting key criteria (meeting– Y, not
meeting – N) ....................................................................................................................119
5.1 N2 physisorption isotherms of QESD-CC and AS ............................................ 147-150
5.2 Intermolecular interaction energies estimated using B3LYP+D2/6+31G(d,p) dispersion
corrected DFT model. Both the total energy (E(tot)) and electrostatic (E(ele)), polarization
(E(pol)), dispersion (E(dis)), and exchange repulsion (E(rep)) components of the energy
are listed. R indicated the distance between centers of mass of the pair of molecules .. 152-
153
5.3 Formulation composition of IMC-containing tablets using different IMC forms .....155
xv
6.1 Elemental composition of sample surfaces ................................................................204
xvi
List of Figures
1.1 Schematic over the capillary conditions between two crystals ....................................21
1.2 Phase diagrams of solvent systems containing (a) three solvents and (b) two solvents
in SA method (M: miscible, I: immiscible) .......................................................................22
1.3 Processes for spherical crystallization via the quasi-emulsion solvent diffusion method
............................................................................................................................................23
2.1 Flowability of mixtures between lactose 316 and as-received FA powder. The
flowability of Avicel PH102 is used as the minimum flowability for high speed tableting.
............................................................................................................................................44
2.2 TGA profile of QESD FA. ...........................................................................................45
2.3 PXRD patterns of FA, pure QESD, as-received, and calculated. ................................46
2.4 Particle size distribution of QESD and as-received FA powders. ...............................47
2.5 SEM images of FA particles: (a) QESD powder (low magnification), (b) QESD powder
(high magnification), (c) as-received powder (low magnification), and (d) as-received
powder (high magnification). .............................................................................................48
2.6 Manufacturability of pure as-received and QESD FA powders (a) tabletability and (b)
flowability. .........................................................................................................................49
2.7 (a) Tablet disintegration time as a function of crospovidone concentration in mixtures
with QESD FA (at 60 MPa compaction pressure), (b) tablet ejection force profiles with and
without 0.25% magnesium stearate. ..................................................................................50
2.8 Properties of QESD based FA formulation (a) tabletability, (b) flowability, (c) friability,
and (d) tablet dissolution in 6.8 pH buffer (in comparison to a formulation using as-received
FA). ....................................................................................................................................51
2.9 Manufacturability of formulated as-received and QESD FA powders (99% loading) (a)
tabletability and (b) flowability. ........................................................................................52
xvii
3.1 Ternary phase diagram of GSF in water-DMF-DCM solvents system. ......................72
3.2 Microscopic images of GSF (a) as-received and (b) SA. ............................................73
3.3 TGA profiles of GSF SA and as-received GSF. ..........................................................74
3.4 (a) Flowability profiles of as-received GSF, GSF SA and Avicel PH102 (n=1); (b)
tabletability profiles of as-received GSF, GSF SA and GSF SA milled (n=3). ................75
3.5 (a) Tabletability, (b) compactibility, (c) compressibility, and (d) hardness profiles of
GSF (80%) and Avicel PH102 (20%) mixture. .................................................................77
3.6 (a) PXRD patterns of calculated GSF Form I, as-received GSF, GSF SA, calculated
GSF-DCM and GSF SA before drying; (b) DSC profiles of as-received GSF and GSF SA.
............................................................................................................................................78
3.7 SEM images at (x10,000 magnification) of GSF (a) as-received crystals, (b) SA, and
tablet fracture surface of (c) GSF-Avicel mixture, and (d) GSF SA-Avicel mixture. .......79
3.8 SEM image at (x20,000 magnification) of GSF SA. ...................................................80
3.9 Energy framework of (a) GSF Form I and (b) GSF-DCM solvate. The (c) desolvated
GSF-DCM with large void is also shown for comparison. The energy threshold for the
energy framework is set at −22 kJ/mol. .............................................................................81
4.1 SEM images of a) GSF, b) GSF-Acs, c) GSF-Acs/SA and d) GSF-Acs/HPC. .........106
4.2 Microscopy images of (a) GSF-Acs/HPC and (b) GSF-Acs/SA. ..............................107
4.3 Particle size distribution of GSF-Acs/SA and GSF-Acs/HPC powders. ...................108
4.4 PXRD patterns of Acs-H, GSF, GSF-Acs/HPC, GSF-Acs/SA, GSF-Acs, and calculated
GSF-Acs. ..........................................................................................................................109
4.5 Thermal behavior of GSF-Acs, GSF-Acs/SA, and GSF-Acs/HPC characterized by
differential scanning calorimetry. ....................................................................................110
4.6 Tabletability profiles of pure GSF, GSF-Acs, GSF-Acs/SA, and GSF-Acs/HPC.....111
xviii
4.7 Energy frameworks of a) GSF, and b) GSF-Acs, both viewed into a axis of
corresponding unit cell. The interaction energy threshold was set at −5 kJ/mol. ............112
4.8 Manufacturability of formulated GSF, GSF-Acs, GSF-Acs/SA, and GSF-Acs/HPC, (a)
tabletability and (b) friability. ..........................................................................................115
4.9 Flowability plots of formulated GSF, GSF-Acs, GSF-Acs/SA and GSF-Acs/HPC..116
4.10 (a) ASD duodenum concentration profiles for formulated GSF, GSF-Acs, GSF-
Acs/SA and GSF-Acs/HPC tablets prepared at 250 MPa, (b) wettability of GSF-Acs/HPC,
GSF-Acs/SA and GSF-Acs. .............................................................................................117
5.1 Correlation between the actual measured HPMC concentration by the SEC method.
..........................................................................................................................................151
5.2 Chemical structures of (a) IMC, (b) SAC and (c) HPMC. Hydrogen atoms that
participated in the intermolecular interactions responsible for QESD-CC to form are
marked..............................................................................................................................154
5.3 Optical microscopy images of particles prepared with aqueous solutions of HPMC in
different concentrations from 0% to 0.5% (scale bar = 500 µm) ....................................156
5.4 Particle size distribution of as-received IMC, AS and QESD-CC, indicating that the
QESD-CC yields highly spherical particles with a relatively narrower size distribution 157
5.5 Optical microscopy images of particles (a) with and (b) without 0.5% HPMC in the
crystallization medium (scale bar = 500 µm) ..................................................................158
5.6 PXRD patterns of calculated IMC-SAC, AS, QESD-CC), as-received IMC, and as-
received SAC ...................................................................................................................159
5.7 DSC profiles of as received IMC, AS, and QESD-CC. .............................................160
5.8 TGA profiles of as received IMC, AS and QESD-CC. .............................................161
5.9 SEM images of AS (a and b) and QESD-CC (c and d) powders at low (x 50) and high
(x 20,000) magnifications. Images e) and f) show the hollow structure of QESD-CC
particles. ...........................................................................................................................162
xix
5.10 Powder properties of as-received IMC, AS, and QESD-CC powders, a) flowability
and b) tabletability. ..........................................................................................................163
5.11 Energy frameworks of (a) IMC and (b) IMC-SAC with a likely slip layer shaded in
pink. The thickness of each cylinder (in blue) represents the relative strength of
intermolecular interaction. The energy threshold for the energy framework is set at −10
kJ/mol. ..............................................................................................................................164
5.12 Performance of tablet formulations based on as-received IMC, AS, and QESD-CC,
(a) flowability, (b) tabletability, c) tablet friability, and d) tablet dissolution. ................165
5.13 Partial 1H NMR spectra of (a) 2 mg/mL IMC-SAC, 2 mg/mL IMC-SAC with 0.5
mg/mL HPMC and 8 mg/mL IMC-SAC, (b) 0.5 mg/mL HPMC with and without 2 mg/mL
of IMC-SAC, and c) Intermolecular hydrogen bonding interactions in IMC-SAC cocrystal.
..........................................................................................................................................166
5.14 Partial 1H NMR spectra of (a) 2 mg/mL SAC, 8 mg/mL SAC and 2 mg/mL SAC with
0.5 mg/mL HPMC, and (b) 0.5 mg/mL HPMC and 2 mg/mL SAC with 0.5 mg/mL HPMC.
..........................................................................................................................................167
5.15 Optimized geometric complexes between IMC-SAC and three HPMC monomer units
with different substituents: a) -H, b) -CH3, c) -CH2CH(OH)CH3. .................................168
5.16 Formation process of QESD-CC particles ...............................................................169
6.1 Chemical structures of (a) the model API CEL, and commonly used polymeric
stabilizers (b) HPMC, (c) HPC, and (d) PVP. .................................................................193
6.2 Micrographs of agglomerates prepared by QESD method in the absence and presence
of various polymers..........................................................................................................194
6.3 Time-dependent growth of CEL spherical agglomerates in various aqueous polymer
solutions assessed by a polarized light microscopy: a) HPMC, b) HPC, and c) PVP. All
scale bars are 500 µm. ......................................................................................................195
6.4 Punch sticking propensity of CEL after compaction at 50 MPa: a) as-received CEL,
and CEL-QESD prepared from different concentrations of HPMC solutions b) 0.1%, c)
xx
0.3%, d) 0.5%. (e) Quantitative sticking propensity assessment using formulated CEL
powders (79.5% (w/w) Avicel PH102, 20% CEL, and 0.5% MgSt). ..............................196
6.5 Thermal behavior of CEL as-received and CEL QESD (from a 0.5% HPMC solution)
a) differential scanning calorimetry, b) thermogravimetric analysis of as-received and
CEL-QESD samples, and c) PXRD patterns for calculated, as-received, and CEL-QESD
samples. ............................................................................................................................197
6.6 a) Flowability (at 1 kPa pre-shear normal stress) and b) Tabletability of CEL-QESD as
compared to as-received CEL. .........................................................................................198
6.7 a) particle size distributions of as-received CEL and CEL-QESD powders, b) HPMC
content in solid CEL-QESD plotted as a function of the HPMC solution concentration (n
= 3). ..................................................................................................................................199
6.8 Compaction properties of as-received CEL and CEL-QESD formulations consisting of
79.5 wt% Avicel PH102, 20 wt% CEL powder, and 0.5 wt% MgSt: a) tabletability and b)
compactibility. .................................................................................................................200
6.9 Compressibility plot of 20% (w/w) as-received CEL and CEL-QESD formulations in
79.5% Avicel PH102 and 0.5% Magnesium stearate. .....................................................201
6.10 SEM images of CEL-QESD (top row) and as-received CEL (bottom row) at low (left
column) and high (right column) magnifications. ...........................................................202
6.11 X-ray photoelectron spectral analysis of the particle surface elemental compositions
of as-received CEL and CEL-QESD, (a) powder, and (b) tablets. ..................................203
6.12 1D 1H NMR spectra of CEL (3 mg/mL) with different polymer additives (3 mg/mL)
in DMSO-d6 over the chemical shift ranges a) 7.80-7.90 ppm, b) 7.40-7.60 ppm, c)
7.12-7.28 ppm, and d) 2.20-2.40 ppm. The numbering of the resonances corresponds
to that given in Figure 6.1. ...............................................................................................205
1
Chapter 1
Introduction
2
1.1 Background
The tablet, one of the most preferred dosage form for the oral drug delivery, has
advantages over others dosage forms, including low manufacturing cost, long shelf life
because of both good physical and chemical stability, and high patient compliance.1, 2 A
successful tablet formulation should meet requirements on several properties, such as flow3,
4, tableting5, 6 and dissolution7, 8, in order to be manufactured in large scale and be
adequately absorbed in the gastrointestinal (GI) tract.
More than 70% active pharmaceutical ingredients (APIs) in the development
pipeline show poor solubility9, and many APIs frequently exhibit poor manufacturability
(e.g., flowability, tabletability)2, 10, posing major challenges in tablet formulation
development. Typically, functional excipients are blended with the API to achieve desired
manufacturability and dissolution properties.11 However, the incorporation of large
amounts of excipients results in large tablet size, which may cause poorer patient
compliance due to difficulty with swallowing, especially when the required drug dose is
high.2 Therefore, enhancing the properties of APIs to reduce the amount of excipients
required for making a high quality tablet is an attractive approach.
Spherical crystallization is a technique that can agglomerate small primary crystals
into large spherical agglomerates to improve flow, tableting and dissolution performance
of APIs.12-15 Based on the formation mechanism of spherical agglomerates, spherical
crystallization is mainly divided into two methods: spherical agglomeration (SA) and
quasi-emulsion solvent diffusion (QESD)16-18. Such spherical agglomerates usually
present excellent flowability owing to their more spherical shape and large particle size.19
In addition, the small primary crystals that form large spherical agglomerates may exhibit
3
improved tabletability if large spherical agglomerates fracture into small crystals during
tablet compression, because of the larger bonding area of small primary crystals20.
Moreover, previous studies have shown that spherical agglomerates incorporated with
water-soluble polymers such as HPC13, 14, 21 and HPMC22 exhibit enhanced dissolution
because of the improved wettability of the API. However, spherical crystallization can
sometimes also reduce dissolution.16
The objective of this thesis is to improve the manufacturability and dissolution
performance of drugs through spherical crystallization technique. When the properties of
API are profoundly improved, amounts of excipients required for a successful tablet
formulation can be significantly reduced. Consequently, a high drug loading direct
compression tablet formulation can be developed. This thesis work focuses on the
following topics:
a) Developing high drug loading direct compression tablet formulation of soluble
APIs by spherical crystallization
b) High dose direct compression tablets of poorly soluble APIs by spherical
cocrystallization
c) Solid form transition during spherical crystallization process and its impact on
the mechanical property of APIs
d) Reducing punch sticking propensity of APIs by spherical crystallization based
on the QESD method
1.2 Literature review
4
As a well-established particle engineering technique, spherical crystallization
modifies the size and shape of the API crystals to improve the micromeritic properties.12
Three common methods of spherical crystallization are SA, QESD and ammonia diffusion
(AD). Since the AD method is only applicable for the APIs that are soluble in ammonia
water,23 in this thesis work, we only focus on the two main methods SA and QESD. With
a clear understanding of both methods, we can develop suitable strategies for optimizing
properties of spherical agglomerates through effective process design and control.
1.2.1 Spherical agglomeration (SA)
The SA method was firstly developed by Kawashima et al., where needle-shape
salicylic acid was successfully transformed into large spherical agglomerates, presenting
better micromeritic property than the starting material.12 During the SA, a bridging liquid
is used to preferentially wet and agglomerate primary crystals into spherical agglomerates
under suitable hydrodynamics (agitation). This method consists of two steps:
crystallization and agglomeration, and depending on the order of introducing the bridging
liquid, these two processes can start simultaneously or separately.18, 24 Pena et al. studied
the impact of the order of introducing the liquids, including poor solvent, good solvent and
bridging liquid, into the system on the formation mechanisms of spherical agglomerates.25
In the first scenario, the API solution in a good solvent is first mixed with a bridging liquid,
which is then gradually fed into the poor solvent to form droplets containing bridging liquid
and good solvent. This is followed by API precipitation in the droplets due to the solvent
counter diffusion. Finally, the bridging liquid on the surface of crystals coalesces small
agglomerates into large and spherical agglomerates. In the second scenario, the bridging
5
liquid is introduced after the generation of small primary crystals, which may be produced
by milling, cooling or anti-solvent, and the bridging liquid functions as a binder to
agglomerate the small crystals. The bridging liquid is crucial in the SA process in both
scenarios.
To be effective, a bridging liquid should have a high interfacial tension with the
crystallization medium in addition to good wettability with the solid.26 From a mechanistic
viewpoint, the crystals clustered together because of surface tension and capillary force
associated with liquid-liquid interface between the water-rich bulk solution (Liquid 2) and
the bridging liquid (Liquid 1) in the aggregates (Fig. 1).27 Adequate wettability of the
bridging liquid on the crystal surfaces is a prerequisite for developing a capillary force
between two particles, which pulls the two particles together. In such a situation, a
meniscus forms between the liquids, i.e., the contact angle becomes less than 90o (Figure
1.1), which leads to a lower pressure on the liquid 1 side than the liquid 2 side. This pressure
difference pull the two particles together and can be calculated using Eq. 1.128.
∆𝑃 = 𝐶1−𝑝
𝑝
𝛾
𝐷cos 𝜃 Eq. (1.1)
where C is a constant depending on the specific surface area of the particles, p is
the porosity of the agglomerate, D is the mean diameter of the agglomerate, γ is the
interfacial tension between the liquids (water and bridging liquid) and θ is the contact angle.
In addition, the amount of bridging liquid introduced to generate the spherical
agglomerates must be well controlled during spherical agglomeration process because the
volume ratio between the bridging liquid and solid particle, BSR, plays a key role in
determining the property of spherical agglomerates. Too low and too high values of BSR
6
lead to insufficient agglomeration and past-like solids, respectively.29 Therefore,
preliminary study to determine the optimal BSR and accurate control of bridge liquid
amount during processing is required to robustly produce spherical agglomerates in large
scale.
1.2.1.1 Selection of a bridging liquid
A suitable bridging liquid is partially miscible or immiscible with the mixture of
good and poor solvent, since a separate phase of bridging liquid is required to wet the
primary crystals and drives the formation of spherical agglomerates. Additionally, the
bridging liquid must wet the solid. Hence, contact angle determination between liquid and
solid can guide the selection of a suitable bridging liquid. A liquid with a lower contact
angle indicates better wettability. Gonza et al.29 proposed and validated a method for
selecting the best bridging liquid based on a Washburn’s test where capillary rise of liquids
in a granular medium was used to determine contact angle. However, wettability is not the
only criterion for selecting a good bridging liquid. Other properties of the bridging liquid
such as viscosity, polarity and the interfacial tension between the bridging liquid rich phase
(liquid 1) and poor solvent rich phase (liquid 2) also influence the formation of spherical
agglomerates. 26
Another commonly used method to select the bridging liquid is the solubility
measurement. Jitkar et al.30 selected the bridging liquid for etodolac by determination the
solubility of API in various solvents. A moderate solubility of the API in the bridging
liquid is preferred. When the solubility of API in the bridging liquid is high, a small amount
of bridging liquid can dissolve the API crystals completely. Therefore, the rate of feeding
7
bridging liquid into the suspension and efficiency of mixing influence agglomeration of
particles, which makes the process less reproducible and difficult to scale up. When the
solubility is too low, the bridging liquid usually does not wet the API particle readily. A
very low solubility also effectively eliminates the possibility of solid bridge formation upon
drying of the bridging liquid. Spherical agglomerates are usually too fragile to be used in
subsequent steps to manufacture tablets.
An efficient approach to screen for a suitable bridging liquid is to calculate the
adhesion free energy between the liquid and API crystal using a mathematic model or
computational tool 31. A negative adhesion value indicates the attraction between the
crystal and liquid so that wetting can occur. Chen et al.32 applied the Lifshitz-van der Waals
acid-base approach to calculate the adhesion free energy, through which a solvent system
for cefotaxime sodium and benzoic acid was successfully selected. Pagire et al.33 predicted
the dominant surface of the API crystal based on the calculated growth morphologies and
calculated the heats of adsorption of various solvents onto the dominant crystal faces. The
solvent with high heats of adsorption was selected and successfully used as the bridging
liquid to form spherical agglomerates.
1.2.1.2 Phase diagram
Ternary phase diagram of poor solvent, good solvent, and bridging liquid can be
used to guide the spherical agglomeration process development (Figure 1.2a). Spherical
agglomeration can only occur in the immiscible region, where free bridging liquid is
available. If the crystallization of API is induced by mixing the good solvent and the poor
solvent before a bridging liquid is added, the starting point of solvent system during the
8
SA process lies somewhere on the line between the good and poor solvents in the ternary
phase diagram. As the bridging liquid is gradually introduced into the solvent system, the
composition of solvent system initially enters the miscible region and then enters the
immiscible region, where free bridging liquid is available. The boundary between the
miscible and immiscible zone is used to calculate the BSRmin. When the amount of
bridging liquid exceeds a certain amount a paste-like product form. This composition
marks the maximum BSR for a given SA process (BSRmax). Therefore, spherical
agglomerates can be produced only between BSRmin and BSRmax (the shaded region in
Figure 1.2). Understandably, a larger difference between BSRmin and BSRmax, i.e., wider
shaded area in Figure 1.2, corresponds to a more robust SA process. This is another
criterion that can be used to select a suitable bridging liquid. To construct the ternary phase
diagram, poor and good solvents at different volume ratios are mixed and maintained at a
preset temperature, followed by introducing the bridging liquid into the solvent system
carefully with a pipette or a microsyringe and the mixture was shaken vigorously by hand.
When the phase separation occurs, a small droplet of bridging liquid can be observed, and
the volume of bridging liquid is noted. A die indicator, such as methylene blue in the
solvent system may help to mark the formation of a separate phase of bridging liquid.
Finally, the phase separation points of each mixture are connected, where the upper and
lower side of the phase separation line implies miscible and immiscible regions,
respectively.34
In a two solvents system, consisting a poor solvent and a bridging liquid, the binary
phase diagram is relevant (Figure 1.2b). In this process, the primary crystals are produced
by milling or cooling instead of an anti-solvent method. Therefore, a good solvent is not
9
required to produce fine API crystals. Similar to that in the ternary phase diagram, when
the bridging liquid is gradually added into the poor solvent, the solvent composition moves
into the miscible region initially, and then the immiscible region when the amount of
bridging liquid exceeds its solubility in the poor solvent. Again, an excessive amount of
bridging liquid causes paste-like product. Spherical agglomerates can be generated only
in the shaded zone in Figure 1.2b.
It should be mentioned that not the entire shaded area (between BSRmin and BSRmax)
is suitable for producing high quality spherical agglomerates. In the shaded area near the
miscible region, most of solid suspended in the medium are small primary crystals because
of the insufficient amount of bridging liquid to enable complete agglomeration. In the
shaded area on near the immiscible region, particles may be too large to be used for
manufacturing pharmaceutical products. An optimal amount of bridging liquid for SA,
corresponding to BSRopt, depends on the API property and processing parameters, such as
solvent addition rate and mixing intensity.
Key processing parameters that influence the quality of spherical agglomerates
include agitation speed, agitation time, BSR value and temperature. Previous studies have
shown that increasing the agitation speed could reduce the particle size significantly due to
enhanced shear force of agitated liquid on the particle, breaking down the large particles
into smaller ones.18 Increasing the value of BSR could enlarge the particles since more
bridging liquid is available.35, 36 Agitation time may or may not influence the particle size
depending on the amount of bridging liquid introduced during the SA process. Morishima
et al.18 showed that, in the SA method, the size of spherical agglomerates was independent
of the agglomeration time when BSR value is low, while strong correlation between the
10
agitation time and agglomerate size was observed when BSR exceeds a critical value. In
addition, the longer agitation time can lower the porosity of the particles since the particles
have more collisions with other particles and the wall of vessel, which strengths the
particles.35 The influence of processing temperature on the spherical agglomerates is
complex. Kawashima et al.37 found that the size of salicylic acid spherical agglomerates
decreased with increasing temperature below a critical temperature of 10 oC, but the size
increased with increasing temperature above 10 oC. The different trends were attributed to
the competition between the amount of crystals precipitated out, induced by the anti-
solvent process, and the solubility of the bridging liquid in the existing medium. This is
because that the solubility of bridging liquid and salicylic acid in the crystallization
medium increased with temperature at different rates.
1.2.2 Quasi-emulsion solvent diffusion (QESD)
QESD is another agglomeration method of spherical crystallization technique
developed by Kawashima et al.38 Different from the SA method, QESD normally involves
two miscible solvents, good solvent and poor solvent (Figure 1.3), which represent
dispersed and continuous phase, respectively. When a solution of an API in a good solvent
is mixed with a poor solvent under agitation, instead of immediate crystallization in SA
method, transient emulsions form. In some cases, emulsifiers are required to stabilize the
emulsions.39, 40 Crystallization of API crystals occurs when the solvent composition
changes due to the good solvent diffusing out the droplets while the poor solvent diffusing
in.41
11
Since the supersaturation level of API at the droplet surface is the highest,
crystallization initiates from the surface of emulsion and then the crystals gradually grow
inward until all the API inside of the emulsion is consumed,18 which may lead to the
spherical agglomerates with a hollow structure.39 Therefore, the size of the resulting
spherical agglomerates is defined by the size of emulsion, which can be influenced by the
agitation speed and concentration of emulsifier.18, 34 Residual good solvent in the droplets
acted as a bridging liquid to agglomerate the precipitated crystals.42
Agitation speed and polymer concentration are the two most important process
parameters that affect the quality of spherical agglomerates by QESD. As shown by
Morishima et al.18, the diameter of the microspheres produced by QESD is mainly
determined by the size of droplet in the initial state, where a higher agitation speed led to
smaller microspheres. The concentration of polymer can influence the size18, 39 and
smoothness38 of microspheres. When other parameters were the same, a higher
concentration of HPMC led to smaller microspheres with higher sphericity because HPMC
on the emulsion surface during QESD prevents the coalescence of droplets. The agitation
time has little impact on the property of microspheres. The size of droplet increases slightly
at the beginning when the two phases are mixed together due to the coalescence of small
droplets. The size of droplet remains constant regardless of the duration of agitation.18
1.2.3 Powder property
1.2.3.1 Micromeritic property
Particle size and shape influence not only the downstream processes, such as
filtration and drying, but also bulk powder properties, such as bulk and tapped density,
12
flowability, and tabletability.43, 44 Usually large and spherical particles with a high bulk
density are preferred. However, very large spherical particle can lead to segregation
problems when mixed with other excipients. Hence, the size of spherical agglomerates
needs to be controlled within a suitable range for pharmaceutical manufacturing.
1.2.3.2 Flowability
During high speed tablet manufacturing, adequate flow property of a formulation
is required for consistent powder filling, which is critical to reduce the weight variation of
tablets and maintain content uniformity.45 The flowability of a powder is affected by
particle size distribution, particle shape, chemical composition of particles, moisture, and
temperature.19, 46, 47 In general, large and more spherical particles exhibit better flowability
than small and irregular particles. The spherical agglomerates of APIs such as salicylic
acid48, ibuprofen38, acebutolol hydrochloride42, bucillamine49, clopidogrel hydrogen
sulfate50, etodolac30, albendazole13 and lactose51, generated by SA or QESD processes,
showed improved flowability over the starting material as indicated by lower angle of
repose, determined by a fixed funnel method. However, an objective criterion for adequate
flow property is needed to evaluate whether or not the improvement is sufficient. A grade
of microcrystalline cellulose, Avicel PH102, was shown to lie near the borderline between
acceptable and unacceptable flowability regions during high speed tableting. 4 Therefore,
one task required to carry out in the development of a spherical crystallization process is
to compare the flowability of spherical agglomerates to Avicel PH102. Spherical
agglomerates with flow property poorer than Avicel PH102 likely exhibit flow problems
13
and further improvement in the flowability is recommended, especially if a direct
compression formulation is sought.
1.2.3.3 Tabletability
Tabletability, the ability of a powder to form a tablet upon compression, is another
important property of a powder in the pharmaceutical research.20, 52 It is represented by a
plot of the tablet tensile strength as a function of compaction pressure. Adequate tablet
tensile strength is required for a tablet to withstand the stresses during shipping and
handling to remain intact. Based on the bonding area (BA)-bonding strength (BS) model,20
the total interparticular area and strength of bonding over a unit area determine the strength
of a tablet. BA and BS can be assessed using compressibility and compactibility plots,
respectively.
Because BS is mainly determined by the functional groups on the surface of crystals,
the particle size and shape modifications through spherical agglomeration is expected to
modify BS but not BA, similar to wet or dry granulation.53-55 In absence of extensive
fragmentation, larger particles reduce the surface area available for bonding among
particles. Therefore, the observation of improved tableting performance analysis of
spherical agglomerates generated by SA method 56, 57 suggested unique mechanism(s) that
leads to stronger tablets. Martino et al.58 observed the vertical cross section of a tablet under
SEM and found that the large spherical agglomerates had fragmented into small particles
during tablet compaction. This corresponds to larger SA than that predicted from the size
of agglomerates. Similar observations were made on naproxen21 and ascorbic acid.59 The
14
agglomerates of ibuprofen38 and acebutolol hydrochloride42 generated by the QESD
method also showed improved tableting performance. Different from the SA method, in a
QESD process, a suitable polymer is introduced to stabilize the emulsion, and this polymer
may coat onto the surface of the spherical agglomerates after the QESD process, which can
potentially influence the tableting performance of a powder. Polymer coating on the sand
to form particles with a core/shell structure could dramatically improve the tabletability of
sand due to the formation of an extensive strong 3D bonding network in the tablet by
compaction.6
1.2.3.4 Punch sticking
The sticking of API onto punches during compression is one of the common
problems that must be overcome for successful tablet manufacturing.60 Punch sticking is
detrimental to not only the aesthetics but also the quality of a tablet due to poor content
uniformity. 61 Powder may accumulate on the punch surface as the compaction process
proceeds, which eventually weakens the tablets and leads to a failed batch.62, 63
Previous approaches to mitigate the punch sticking propensity have been
extensively explored by applying both crystal and particle engineering techniques,
including salt formation61, mixing with excipients64, dry granulation65. Similar to the dry
granulation process,66 which reduces the punch sticking propensity due to the enlarged
particle size, spherical crystallization has the potential to reduce the punch sticking.
However, this has not been investigated to address the punch sticking problem.
15
1.2.3.5 Dissolution
Besides the manufacturability (e.g., flowability and tabletability) discussed above,
dissolution is another property that is crucial for a successful formulation since it
determines the bioavailability of a drug.67, 68 This is particularly important when
considering that over 70% of APIs under development have low water solubility,69, 70
which implies slow dissolution of an API from a tablet in the GI tract. If not properly
addressed, such slow dissolution can significantly influence the absorption, and
consequently bioavailability, of the API.
Factors that can affect the dissolution include solubility, particle size, solid form
stability, use of precipitation inhibitor (polymer/surfactant).71 For low solubility APIs, i.e.,
BCS II and IV drugs, 72 more soluble solid forms, such as cocrystals, salts and amorphous
solids are commonly explored to improve the dissolution.73-75 Particle size influences
dissolution because it affects the area of an API in contact with the medium.76 However,
smaller particles tend to exhibit poor flowability. In practice, an API is milled or
micronized to increase area for faster dissolution but micronized API is then granulated
with excipients to ensure adequate flow property for successful tablet manufacturing. A
disintegrant is also usually incorporated in a tablet formulation to promote the dispersion
of API in the medium.77 If a more soluble solid form is selected to develop a tablet
formulation, the stability of the soluble solid form both in solid state and during dissolution
should be maintained, by preventing the crystallization of the less soluble crystal form, to
maintain the desired fast dissolution.
16
Spherical crystallization can lead to variations in solid form of the API, depending
on the solvents and rate of crystallization during this process. Kawashima et al.78 found
that when indomethacin and epirizole were agglomerated together, different solvent
systems could produce different polymorphs combinations, which further influenced the
dissolution of the API. Similarly, Varshosaz et al.79 observed enhanced dissolution of
spherical agglomerates than untreated powder because of particle solid form change of
simvastatin from crystalline into amorphous in the spherical agglomerates. The
incorporation of a water-soluble polymer or surfactant in the spherical agglomerates
improved the dissolution of tolbutamide22 and etodolac30 , due to enhanced wettability.
1.2.4 Continuous manufacturing
Scaling up a spherical crystallization process, from the lab scale to the commercial
scale, requires full understanding of the key process parameters.80 The batch manufacturing
is the main method in the productions of pharmaceuticals for a long time. However, batch
to batch variation is a concern. Continuous manufacturing has received much attention in
the pharmaceutical industry because of its efficiency, economy, better quality control, and
easiness to scale-up.81, 82, 83
For successful spherical crystallization, several parameters, such as agitation speed,
agitation time, temperature, and feeding speed of bridging liquid, must be well controlled.
These parameters invariably change upon scaling up during the batch manufacturing.
Therefore, scale up of spherical crystallization is complex, which presents a major
challenge in the product development process. In this regard, continuous a spherical
17
crystallization process is favored since the agglomerates are generated and monitored in
real-time and process parameters can be adjusted on the fly as needed. Additionally, a
continuous manufacturing process only needs a small volume of material to run, which
makes optimization and control an much easier and robust effort.84
Because of these benefits, continuous spherical crystallization has been explored in
pharmaceutical field. Pena et al.80 developed a two-stage continuous mixed suspension
mixed product removal (MSMPR) system, where the nucleation/growth and agglomeration
of crystals are decoupled, for the continuous manufacturing of the spherical agglomerates
with desired properties. This continuous MSMPR process allows to tailor both the
properties of primary crystals and generated agglomerates in a SA process to achieve good
biopharmaceutical (e.g., dissolution) and processing (e.g., filtering, drying) performance.
Similarly, Tahara et al.85 applied this continuous MSMPR system to manufacture the
spherical agglomerates of albuterol sulfate. Different from Pena’s work, Tahara et al.
applied the QESD method during the continuous manufacturing. One benefit of using the
QESD method for continuous manufacturing is the easy solvent recycling, where 90% of
the mother liquor was reused during the continuous spherical crystallization,85 making it to
a greener manufacturing process. Moreover, the continuous QESD process, together with
an effective purification process by agglomerating with a complexing agent, can be used
for the impurity separation. This was demonstrated using a model drug, fenofibrate.86
1.2.5 Spherical cocrystallization
18
Spherical cocrystallization, which combines spherical crystallization and
cocrystallization, was firstly applied on the stabilization and spheroidization of ammonium
nitrate to produce smokeless and easy packing cocrystal agglomerates.87 Pagire et al.
applied this technique to prepare spherical carbamazepine-saccharin cocrystals.33 Spherical
cocrystallization was further carried out to control the cocrystal stoichiometry and particle
size.88 Despite the development of the spherical cocrystallization process, properties of the
spherical cocrystal agglomerates and their applications in tablet formulation are very
limited.
1.3 Objective and hypothesis
The overarching goal of this thesis work is to enable the development of high drug
loading direct compression tablet formulations by engineering APIs to improve
manufacturability (e.g., flowability, tabletabillity) and dissolution of drugs, through
applying the spherical crystallization technique.
Chapter 2 aims to develop an extremely high drug loading formulation using the
spherical crystallization of a water-soluble API. The main challenges with developing a
high drug loading tablet formulation, i.e., the manufacturability and dissolution deficiency
of the API, can be overcome by API engineering.
Hypothesis: API agglomerates produced through a spherical crystallization
process show significantly improved manufacturability (e.g., flowability, tabletability),
which enables the development of an extremely high drug loading direct compression
formulation for a water soluble API.
19
Chapter 3 reports an in-situ solid form transition during the SA process, through
which the free-flowing spherical agglomerates exhibits a micro porous structure. This
unique structure leads to an improved plasticity of API bulk solid and, consequently, better
tabletability.
In Chapter 4 and 5, we aim to simultaneously improve the manufacturability and
dissolution of BCS Class II drugs by the spherical cocrystallization technique. Previous
efforts that showed improved dissolution performance of spherical agglomerates were
attributed to the transformation into a more soluble solid form or the incorporation of
polymer that increases the wettability of API. However, the stability of the more soluble
solid form is a concern, which requires extensive investigations before they can be
developed into a formulation. On the other hand, the low degree of enhancement in
dissolution by the improved wettability makes it not very effective to address dissolution
problems of poorly soluble drugs. Both issues can be addressed using the spherical
cocrystallization technique.
Hypothesis: spherical cocrystallization technique can take the advantages of both
spherical crystallization and cocrystallization, and therefore, the generated spherical
cocrystal agglomerates that possess appropriate pharmaceutical properties to enable the
development of high drug loading direct compression tablet formulations.
The spherical cocrystallization technique in Chpater 4 and 5 is based on SA and
QESD method, respectively. Spherical cocrystallization based on SA method can be
developed only if the cocrystal is stable in the complex solvent system and can be bound
by a bridging liquid to form the spherical agglomerates. On the other hand, to develop the
20
spherical cocrystallization based on QESD method, the cocrystal must form through an
anti-solvent process and a suitable polymer may be required to stabilize the emulsion.
In Chapter 6, we investigate the mitigation of API punch sticking by a QESD
method. Based on the mechanism of a QESD process, we examine the effectiveness of a
polymer assisted QESD method to reduce the punch sticking of a highly sticky API.
Hypothesis: While functioning as a stabilizer of the emulsions during the QESD
process, a polymer can also coat the surface of solid spherical agglomerates. Such polymer
coating is an effective physical barrier to prevent the direct contact between the API and
punch during tablet compaction, which consequently mitigates the punch sticking problem.
21
Figure 1.1. Schematic over the capillary conditions between two crystals
22
Figure 1.2. Phase diagrams of solvent systems containing (a) three solvents and (b) two
solvents in SA method (M: miscible, I: immiscible)
a) b)
23
Figure 1.3. Processes for spherical crystallization via the quasi-emulsion solvent diffusion
method.
24
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30
87. Lee, T.; Chen, J. W.; Lee, H. L.; Lin, T. Y.; Tsai, Y. C.; Cheng, S.-L.; Lee, S.-W.;
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13455.
31
Chapter 2
Direct compression tablet containing 99% active ingredient – a
tale of spherical crystallization
32
2.1 Synopsis
Direct compression (DC) is the easiest and most cost-effective process for tablet
manufacturing, since it only involves blending and compression. However, active
pharmaceutical ingredients (API) generally exhibit poor mechanical and micromeritic
properties, which necessitate dilution and the use of high percentage of excipients to enable
a robust DC manufacturing process. Consequently, drug loading in DC tablets is usually
low (typically < 30%, w/w). In this study, spherical crystallization by the quasi-emulsion
solvent diffusion method was used to engineer a poorly flowing model compound, ferulic
acid (FA), to attain superior mechanical properties, particle size distribution, and
morphology. The engineered FA particles enabled the successful development of DC
tablets containing 99% FA, which is in sharp contrast to the maximum 10% FA loading
using as-received FA. The record high API loading in this work illustrates the potential for
spherical crystallization to overcome low drug loading when developing a tablet product
using the DC manufacturing process.
2.2 Introduction
Tablets account for nearly 80% of all marketed dosage forms ,1 due to economical
and stability advantages than other dosage forms. Among the tablet manufacturing
processes, direct compression (DC) is the simplest, and hence, most desirable due to many
advantages, including significantly higher manufacturing efficiency and physical and
chemical stability. 2-4 3, 5
33
Other than very potent drugs, a high drug loading in a tablet formulation can
improve patient compliance by reducing tablet size. Furthermore, it also reduces the risk
of an inhomogeneous blend or non-uniform active pharmaceutical ingredient (API) content
in finished tablets. However, API loading in most DC tablet formulations does not exceed
30 % due to the poor processability.1, 2, 5, 6 Both powder flowability and tabletability are
critical to ensure the manufacturability of a DC tablet formulation.1, 7, 8 Powders consisting
of large particles and spherical shape are expected to exhibit good flowability and packing
properties.3, 9 However, large API particle size can potentially lead to slow drug release,
and a spherical shape is rarely achieved in traditional crystallization. A small particle size
of the API maybe required to provide adequate dissolution, but this can lead to a poor
flowability.10 Poor flowability of API, in turn, limits the maximum achievable API loading
in a DC formulation.
Spherical crystallization is a promising method to produce good flowability and
tableting performance,11-13 where fine crystals are generated and then agglomerated to form
spherical structures.14 Recent papers on lactose,15 albendazole,12 etodolac16 etc have
showed the improved mechanical properties of spherical crystals with larger particle size,
and the improved fragmentation and plasticity are the main mechanism. Spherical
crystallization can be achieved by quasi-emulsion solvent diffusion (QESD), spherical
agglomeration, and ammonia diffusion methods as well as crystallo-co-agglomeration.17-19
In this work, the QESD method was applied to engineer a model API, ferulic acid (FA), to
attain improved bulk powder properties for developing a high API loading tablet. FA is a
natural phenolic phytochemical proposed for use as a medicament for treating disorders,
including Alzheimer’s disease,20 cancer,21 cardiovascular diseases,22 diabetes mellitus23
34
and skin disease.24 The aim of this work was to develop a DC tablet containing a maximum
API loading by forming free-flowing spherical particles consisting of fine FA crystals.13
A successful formulation must ensure that the tablets meet requirements for
acceptable manufacturability, quality, and biopharmaceutical performance. As such, tablet
formulations are typically evaluated against established criteria for key critical
manufacturing parameter and tablet properties, including tabletability, flowability,
friability, disintegration time, tablet ejection force, and dissolution performance (Table 2.1).
If any is not met, the formulation is excluded, and a new formulation is designed and
evaluated to address identified deficiencies. This process is repeated until an optimized
formulation is identified. However, in contrast to empirical screening, we adopted a much
more efficient and material sparing development process, guided by the materials science
tetrahedron.25 In addition, we used predictive tools to characterize powder
manufacturability, e.g., compaction simulator for tabletability and shear cell for flowability
(see Supporting Information for details).
2.3 Methods
2.3.1 Preparation of the QESD FA
A quantity of 25 g ferulic acid was dissolved in 250 ml acetone at room temperature. The
FA solution was directly poured into 2 L 0.1% (w/v) HPMC (K15M) aqueous solution
stirred at 300 rpm by an overhead digital stirrer. After 1 h agitation, the QESD FA was
collected and dried at 60 °C in an oven.
35
2.3.2 Powder X-ray Diffractometry (PXRD)
A powder X-ray diffractometer with Cu Kα radiation (1.54059 Å) was used to characterize
powders. Samples were scanned between 5 to 35° 2θ with a step size of 0.02° and a dwell
time of 1 s/step. The tube voltage and amperage were set at 40 kV and 40 mA, respectively.
The diffraction pattern of the QESD powder was compared to the original powder or the
calculated pattern from the single crystal structure (CCDC refcode: GASVOL02).
2.3.3 Thermogravimetry Analysis (TGA)
Approximately 2 mg of QESD FA was heated in an open aluminum pan from room
temperature to 300oC at 10oC/min under dry nitrogen purge (40 mL/min) on a
thermogravimetric analyzer (Model Q50; TA Instruments, New Castle, DE).
2.3.4 Scanning electron microscopy (SEM)
Particles were sprinkled onto carbon tapes adhered to a SEM stub. The samples were
sputter-coated with a thin layer of platinum (~ 75 Å thickness), using an ion-beams sputter
(IBS/TM200S; VCR Group Inc., San Clemente, CA). The particle morphology and surface
features were evaluated under a scanning electron microscope (JEOL 6500F; JEOL Ltd.,
Tokyo, Japan).
2.3.5 Particle size distribution (PSD)
36
The particle size distribution of as-received and QESD FA powders were analyzed by sieve
analysis. Nine standard sieves (U.S.A. Standard Test Sieve) were used. The weight
retained on different sieves were measured after 10 min sieving interval. Sieve fractions
were calculated accordingly.
2.3.6 Flowability measurement
Powder flowability was measured using a ring shear cell tester (RST-XS; Dietmar Schulze,
Wolfenbüttel, Germany), with a 10 mL cell at 1 kPa preshear normal stresses. The normal
stresses for shear testing were 0.252, 0.4, 0.55, 0.7 and 0.85 kPa. The measurements were
made in triplicate, and the unconfined yield strength (fc) and major principal stress (σn)
were obtained from each yield locus by drawing Mohr’s circles. Flowability index (ffc) was
calculated using Eq. (1):
𝑓𝑓c =𝜎𝑛
𝑓c (1)
2.3.7 Direct Compression of Powders
A compaction simulator (Presster; Metropolitan Computing Corporation, NJ) simulating a
Korsch XL100 (10 stations) press at a speed corresponding to 25 ms dwell time (49,300
tablets/h) using 10.0 mm round flat-faced punch-die sets were used to prepare tablets with
compaction pressures ranging from 25 to 300 MPa. Tablet weight was maintained at 300
mg throughout this study.
37
2.3.8 Tablet disintegration
A disintegration tester (DJ-1; Tianjin Guoming Medical Equipment CO., LTD) was used
to measure the disintegration time (DT) of the tablets compressed at 60 MPa for different
formulations. Tablets were immersed into a beaker containing 900 mL phosphate buffer,
and the temperature was kept at 37°C. DT was recorded for three tablets.
2.3.9 Assessment of Tablet Tensile Strength
Tablets were broken diametrically on a texture analyzer (Texture Technologies Corp.,
Surrey, UK) at a test speed of 0.01 mm/s. Tablet tensile strength, σ, was determined from
equation 2.26
𝜎 =2𝐹
𝜋𝑑ℎ (2)
Where F, d, and h are the breaking force, diameter, and thickness of the tablet, respectively.
2.3.10 Friability
An expedited friability method27 was applied to determine the friability performance of the
formulated powders. Coded tablets prepared under different compaction pressures were
weighted and loaded into a friabilator (Model F2, Pharma Alliance Group Inc., Santa
Clarita, CA) at 25 rpm for 4 min. The final weight of each tablet was noted, and percentage
weight loss of each tablet was plotted against compaction pressure. The compaction
pressure corresponding to 0.8% tablet weight loss was identified from the friability plot.
38
2.3.11 Determination of HPMC in QESD FA
About 500 mg of QESD FA was dissolved in 10 ml DMF. The concentrated FA solution
was diluted with distilled water. The UV absorbance was measured at 315 nm, and the
amount of FA was determined from an appropriate standard curve. The amount of HPMC
was calculated from mass balance.
2.3.12 Dissolution performance
The dissolution performance of the tablets was studied with 500 mL of a pH 6.8 potassium
phosphate buffer. The concentration of dissolved FA was monitored in real-time by a UV
dip probe at 360 nm.
2.4 Results and discussion
2.4.1 Flowability of as-received FA
The as-received FA exhibits poor flowability (Figure 2.1). Therefore, a free-
flowing grade of lactose, Lactose 316,28 was used as a filler to address this deficiency.
Flowability decreases rapidly with increasing percent of FA in the mixture (Figure 2.1).
The maximum achievable loading of as-received FA was only 10% in order to meet the
minimum requirement for powder flowability (Figure 2.1, Table 2.1). To develop a high
loading FA tablet, the QESD method was used to overcome poor flowability.
39
2.4.2 QESD preparation and micromeritic property
During the QESD process, one part of a solution of FA in acetone (100 mg/mL)
was introduced to eight parts of an aqueous solution of HPMC (1 mg/mL) under agitation.
HPMC was used to stabilize the transient emulsion.29, 30 Counter-diffusion between acetone
and water phases leads to the crystallization of FA within the emulsion to eventually obtain
relatively spherical agglomerates.19 The amount of HPMC in the dried QESD powder was
0.75 ± 0.64% (n = 3). Powder X-ray diffraction patterns of the as-received and the QESD
powders were identical and conformed to that calculated from FA single crystal structure
(Figure 2.2).31 The moisture and residual solvent were negligible (Figure 2.3).
The QESD powder had a narrow particle size distribution (most between 125-250
μm, Figure 2.4) and an approximately spherical morphology (Figure 2.5a). These micro-
porous particles consisted of bundles of small needle-like primary crystals (Figure 2.5b),
which likely arose from the high degree of supersaturation and fast precipitation of FA
during the QESD process. This hierarch particle structure of QESD particles is very distinct
compared to the as-received FA crystals, which are needles with a broad size distribution
(most higher than 500 μm, Figure 2.5c, Figure 2.4) and rough surfaces (Figure 2.5d). The
larger and more round QESD particles are expected to exhibit improved flowability over
the as-received FA.9
2.4.3 Powder flowability and tabletability
Tabletability and flowability of the QESD powder of FA are both significantly
better than the as-received FA (Figures 2.6a and 2.6b). Tablet tensile strength of ~6 MPa
40
can be reached with the QESD powder, which is approximately twice that of the as-
received FA (~3 MPa). The enhanced tabletability is attributed to the smaller primary
crystals in QESD powder that favors stronger tablets by affording larger interparticulate
bonding area.32 The flowability of QESD powder is also significantly better as measured
by flowability index (ffc), as expected from its spherical morphology and large particle
size.9 In fact, compared to the expected minimum flowability for high speed tableting
exhibited by Avicel PH102, the flowability of the as-received FA powder is much worse,
while that of the QESD powder is significantly better. The fact that the QESD powder
already meets the minimum requirements for tabletability and flowability (Table 2.1)33, 34
suggests suitability for developing a higher loading tablet formulation that will still meet
the design criteria.
2.4.4 Formulation development
Compacting the QESD powder alone at 60 MPa resulted in tablets that meet the
tensile strength requirement of 2 MPa (Figure 2.6a). However, the disintegration time (>30
min) is longer than the requirement of < 15 min for an immediate release tablet (Table
2.1).35 To determine the amount of a disintegrant, crospovidone, that sufficiently shortens
disintegration time to 15 min, different QESD - crospovidone mixtures were compressed
at 60 MPa to obtain tablets for disintegration time determination. Addition of 0.75 %
crospovidone was sufficient to lower the disintegartion time to about 10 min (Figure 2.7a).
However, when neat QESD powder was compressed, the tablet ejection force was too high
(Figure 2.7b). Therefore, 0.25 % magnesium stearate was added to reduce tablet ejection
force. Consequtnly, ejection forces below 400 N over the entire range of pressure were
41
observed (Figure 2.7b). Thus, 0.25% magnesium stearate was adequate for lubricating the
formulation (Table 2.1). At this point, a formulation containing 99% of FA satisfies the
requirements of short disintegration time and low ejection force as well.
The suitability of the 99% FA loading formulation for manufacturing under realistic
conditions was further examined by assessing tabletability, flowability, friability, and
dissolution. Tablets with tensile strength of 2 and 7 MPa could be made at 60 and 250 MPa,
respectively (Figure 2.8a), which confirms the excellent tabletability of this formulation.
The much higher ffc compared to Avicel PH102 indicates excellent flowability (Figure
2.8b). At a speed corresponding to 49,300 tablets/h (25 ms dwell time), the relative
standard deviation of tablet weight was 2.1% (average tablet weight was 301.8 mg) with
no tablet outside 7.5% of the average weight. This meets the requirement for acceptable
tablet weight variation (Table 2.1).36 Using an expedited method,37 the friability profile of
formulated QESD tablets revealed that a compaction pressure of 30 MPa was sufficient to
guarantee less than 0.8 % weight loss (Figure 2.8c). Tablet friability was about 0.4% at 60
MPa, which is well within the requirement for friability (Table 2.1).38 Finally, the
dissolution performance of FA QESD formulations in a pH 6.8 phosphate buffer is
essentially the same as a control tablet containing 99% as-received FA.More than 80% of
FA was released within 1 h (Figure 2.8d), which meets the USP dissolution requirement
for botanical dosage forms (75% release in 60 min).39 Thus, the improved
manufacturability afforded by QESD process does not sacrifice dissolution performance of
FA. Not surprisingly, this formulated QESD FA exhibited both superior tabletability and
flowability over a formulation containing 99% as-received FA (Figure 2.9a and 2.9b). In
the event that challenges are encountered during manufacturing at the commercial scale,
42
such as punch sticking,40, 41 there is plenty of formulation space to appropriately address
them while still keeping a very high loading of FA.
2.5 Conclusion
In summary, by using spherical crystallization based on the quasi-emulsion solvent
diffusion method, a DC tablet formulation containing 99% of the API, ferulic acid was
developed. The resulting tablet met all critical quality attributes. This work highlights the
potential for spherical crystallization to significantly increase drug loading in DC tablet
formulations, when needed.
43
Table 2.1. Powder and tablet design criteria.
Properties Requirement reference
Tablet weight
variation
Out of 20 tablets, ≤ 2 tablets differ from the average weight
by more than 7.5%, and no tablet differs in weight by more
than 15%
36
Tablet friability For a batch of tablets (unit weight less than 650 mg)
weighing approximately 6.5 g, mean weight loss ≤ 1.0%
38
Tensile strength ≥ 2 MPa 33
Flowability Better than Avicel PH102 34
Tablet disintegration 15 min, unless otherwise specified in the individual
monograph a
35
Dissolution Varies
Ejection force ≤ 600 N b
a For uncoated tablets except soluble tablets, dispersible tablets, effervescent tablets and tablets for
use in the mouth) b Based on experience
44
Figure 2.1. Flowability of mixtures between lactose 316 and as-received FA powder. The
flowability of Avicel PH102 is used as the minimum flowability for high speed tableting.
45
Figure 2.2. TGA profile of QESD FA.
46
Figure 2.3. PXRD patterns of FA, pure QESD, as-received, and calculated
47
Figure 2.4. Particle size distribution of QESD and as-received FA powders.
48
Figure 2.5. SEM images of FA particles: (a) QESD powder (low magnification), (b) QESD
powder (high magnification), (c) as-received powder (low magnification), and (d) as-
received powder (high magnification).
49
Figure 2.6. Manufacturability of pure as-received and QESD FA powders (a) tabletability
and (b) flowability.
a) b)
50
Figure 2.7. (a) Tablet disintegration time as a function of crospovidone concentration in
mixtures with QESD FA (at 60 MPa compaction pressure), (b) tablet ejection force profiles
with and without 0.25% magnesium stearate.
a) b)
51
Figure 2.8. Properties of QESD based FA formulation (a) tabletability, (b) flowability, (c)
friability, and (d) tablet dissolution in 6.8 pH buffer (in comparison to a formulation using
as-received FA).
a) b)
c) d)
52
Figure 2.9. Manufacturability of formulated as-received and QESD FA powders (99%
loading) (a) tabletability and (b) flowability.
a) b)
53
2.6 References
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for the direct compression of tablets. Pharm Sci Technolo Today 2000, 3, 58-63.
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characterization: Visualization of the critical drug loading affecting the processability of a
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pharmaceutical ingredient powder blends and tablets at high drug loading via dry particle coating.
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4. Capece, M.; Huang, Z.; Davé, R. Insight into a novel strategy for the design of tablet
formulations intended for direct compression. J. Pharm. Sci. 2017, 106, 1608-1617.
5. Martinello, T.; Kaneko, T. M.; Velasco, M. V. R.; Taqueda, M. E. S.; Consiglieri, V. O.
Optimization of poorly compactable drug tablets manufactured by direct compression using the
mixture experimental design. Int. J. Pharm. 2006, 322, 87-95.
6. Cai, L.; Farber, L.; Zhang, D.; Li, F.; Farabaugh, J. A new methodology for high drug
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8. Chattoraj, S.; Sun, C. C. Crystal and particle engineering strategies for improving powder
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using a ring shear tester. J. Pharm. Sci. 2008, 97, 4030-4039.
10. Geldart, D. Types of gas fluidization. Powder Technol. 1973, 7, 285-292.
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aceclofenac and paracetamol spherical crystals and their tableting properties. Powder Technol.
2015, 274, 446-454.
12. Thakur, A.; Thipparaboina, R.; Kumar, D.; Sai Gouthami, K.; Shastri, N. R. Crystal
engineered albendazole with improved dissolution and material attributes. CrystEngComm 2016,
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13. Fadke, J.; Desai, J.; Thakkar, H. Formulation development of spherical crystal
agglomerates of itraconazole for preparation of directly compressible tablets with enhanced
bioavailability. AAPS PharmSciTech 2015, 16, 1434-1444.
14. Yoshiaki Kawashima, M. O. Spherical crystallization direct spherical agglomeration of
salicylic acid crystals during crystallization. Science 1982, 216, 1127-1128.
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enhanced mechanical properties. Int. J. Pharm. 2017, 516, 247-257.
16. Jitkar, S.; Thipparaboina, R.; Chavan, R. B.; Shastri, N. R. Spherical agglomeration of
platy crystals: Curious case of etodolac. Cryst. Growth Des. 2016, 16, 4034-4042.
17. Kovačič, B.; Vrečer, F.; Planinšek, O. Spherical crystallization of drugs. Acta Pharm 2012,
62, 1-14.
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18. Leon, R. A. L.; Wan, W. Y.; Badruddoza, A. Z. M.; Hatton, T. A.; Khan, S. A.
Simultaneous spherical crystallization and co-formulation of drug(s) and excipient from
microfluidic double emulsions. Cryst. Growth Des. 2014, 14, 140-146.
19. Yoshiaki Kawashima, T. N. Preparation of controlled-release microspheres of ibuprofen
with acrylic polymers by a novel quasi-emulsion solvent diffusion method. J. Pharm. Sci. 1988,
78, 68-72.
20. Sgarbossa, A.; Giacomazza, D.; Di Carlo, M. Ferulic acid: A hope for alzheimer’s disease
therapy from plants. Nutrients 2015, 7, 5764-5782.
21. Janicke, B.; Hegardt, C.; Krogh, M.; Onning, G.; Akesson, B.; Cirenajwis, H. M.; Oredsson,
S. M. The antiproliferative effect of dietary fiber phenolic compounds ferulic acid and p-coumaric
acid on the cell cycle of caco-2 cells. Nutr. Cancer 2011, 63, 611-22.
22. Pagidipati, N. J.; Gaziano, T. A. Estimating deaths from cardiovascular disease: A review
of global methodologies of mortality measurement. Circulation 2013, 127, 749-56.
23. Prabhakar, P. K.; Prasad, R.; Ali, S.; Doble, M. Synergistic interaction of ferulic acid with
commercial hypoglycemic drugs in streptozotocin induced diabetic rats. Phytomedicine 2013, 20,
488-494.
24. Saija, A.; Tomaino, A.; Trombetta, D.; De Pasquale, A.; Uccella, N.; Barbuzzi, T.; Paolino,
D.; Bonina, F. In vitro and in vivo evaluation of caffeic and ferulic acids as topical photoprotective
agents. Int. J. Pharm. 2000, 199, 39-47.
25. Sun, C. C. Materials science tetrahedron--a useful tool for pharmaceutical research and
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26. Fell, J. T.; Newton, J. M. Determination of tablet strength by the diametral-compression
test. J. Pharm. Sci. 1970, 59, 688-691.
27. Osei-Yeboah, F.; Sun, C. C. Validation and applications of an expedited tablet friability
method. Int J Pharm 2015, 484, 146-55.
28. Paul, S.; Chang, S.-Y.; Dun, J.; Sun, W.-J.; Wang, K.; Tajarobi, P.; Boissier, C.; Sun, C.
C. Comparative analyses of flow and compaction properties of diverse mannitol and lactose grades.
Int. J. Pharm. 2018, 546, 39-49.
29. Kawashima, K. M. a. Y. Micromeritic characteristics and agglomeration mechanisms in
the spherical crystallization of bucillamine by the spherical agglomeration and the emulsion solvent
diffusion methods. Powder Technol. 1993, 76, 57-64.
30. Cui, F.; Yang, M.; Jiang, Y.; Cun, D.; Lin, W.; Fan, Y.; Kawashima, Y. Design of
sustained-release nitrendipine microspheres having solid dispersion structure by quasi-emulsion
solvent diffusion method. J. Control. Release 2003, 91, 375-384.
31. Kumar, N.; Pruthi, V. Structural elucidation and molecular docking of ferulic acid from
parthenium hysterophorus possessing cox-2 inhibition activity. 3 Biotech 2015, 5, 541-551.
32. Sun, C. C. Decoding powder tabletability: Roles of particle adhesion and plasticity. J
Adhes Sci Technol. 2011, 25, 483-499.
33. Sun, C. C.; Hou, H.; Gao, P.; Ma, C.; Medina, C.; Alvarez, F. J.; Hou, H.; Gao, P.
Development of a high drug load tablet formulation based on assessment of powder
manufacturability: Moving towards quality by design. J. Pharm. Sci. 2009, 98, 239-247.
34. Sun, C. C. Setting the bar for powder flow properties in successful high speed tableting.
Powder Technol. 2010, 201, 106-108.
55
35. WHO. Revision of monograph of tablets. 2011, Document QAS/09.324/Final.
36. USP. Usp41(online), general chapters. Weight variation of dietary supplements-tablet.
Rockville: United states pharmacopoeial convention. 2018.
37. Osei-Yeboah, F.; Sun, C. C. Validation and applications of an expedited tablet friability
method. Int. J. Pharm. 2015, 484, 146-155.
38. USP. Usp41(online), general chapters. Tablet friability. Rockville: United states
pharmacopoeial convention. 2018.
39. USP. Usp34 (online), general chapter. Disintegration and dissolution of dietary
supplements. Rockville: United states pharmacopoeial convention. 2011.
40. Paul, S.; Taylor, L. J.; Murphy, B.; Krzyzaniak, J.; Dawson, N.; Mullarney, M. P.; Meenan,
P.; Sun, C. C. Mechanism and kinetics of punch sticking of pharmaceuticals. J. Pharm. Sci. 2017,
106, 151-158.
41. Paul, S.; Sun, C. C. Modulating sticking propensity of pharmaceuticals through excipient
selection in a direct compression tablet formulation. Pharm. Res. 2018, 35, 113.
56
Chapter 3
Profoundly improved plasticity and tabletability of griseofulvin
by in-situ solvation and desolvation during spherical
crystallization
57
3.1 Synopsis
Griseofulvin (GSF) is a high dose drug exhibiting poor flowability and tabletability,
which makes formulating a high drug loading tablet challenging. In using spherical
crystallization to improve flowability, the spherical agglomerates (SA) of GSF were found
to have profoundly improved tabletability over the as-received GSF. An improved
plasticity of GSF SA was observed despite its identical crystal structure and larger particle
size when compared to the as-received GSF. Tracking solid forms during the process
revealed the formation of a GSF solvate with dichloromethane, the bridging liquid for
spherical agglomeration. With subsequent desolvation during drying, nanoporous GSF
crystals were obtained, which could be plastically deformed more easily and exhibited
much improved tabletability.
3.2 Introduction
Successful tablet manufacturing requires the powder blends to meet several criteria,
including adequate tabletability, flowability, uniformity, and free from sticking to
punches.1, 2 Particle engineering and crystal engineering are two effective approaches to
overcome inherent problematic physical or mechanical properties and, thereby, enable
successful tablet development.3-5 Common methods to improve powder flowability and
tabletability of active pharmaceutical ingredients (API) have recently been summarized.6
Methods to improve flowability include making spherical granules,7, 8 increasing size,3
reducing surface roughness,9 reducing cohesion by nano-coating,10 and changing surface
chemistry.11 Methods to improve tabletability, such as surface polymer coating,12 size
reduction,13 increasing roughness,14 cocrystallization,15 and crystal hydration,16 mainly rely
58
on increasing bonding area among particles.17 Typically, flowability enhancement by size
enlargement and surface smoothing by granulation also leads to deteriorated tabletability.18
In comparison to common granulation methods, spherical crystallization (SC)
stands out as an efficient way to simultaneously improve flowability and tabletability.19-21
SC is a method that transforms fine crystals into compact spherical agglomerates (SA).22
Such spherical crystal agglomerates exhibit good flowability because of the large size and
spherical shape.8, 23, 24 While a systematic investigation remains incomplete, the improved
tabletability by SC, is commonly attributed to the enhanced interparticle contacts due to
fragmentation of agglomerates,21, 25 smaller primary crystals19 and easier plastic
deformation.26 Spherical agglomerates are commonly produced by either spherical
agglomeration22 or quasi-emulsion solvent diffusion (QESD)27. In the spherical
agglomeration, three solvents, good solvent, poor solvent, and bridging liquid, are used.
During this process, the API is dissolved in a good solvent, followed by adding the drug
solution to a miscible poor solvent to induce immediate precipitation of fine API crystals.
Then, a bridging liquid is added to facilitate agglomeration of primary fine API crystals
into large spherical agglomerates through the surface tension effect.28 The polarity of
solvents is important in the SA process. The good and poor solvents should have similar
polarity and they are miscible. When they mix through molecular diffusion, API
precipitates out because of the reduced interactions with the good solvent due to the affinity
between the poor and good solvent molecules. The faster the mixing between good and
poor solvents, the faster the crystallization and finer primary crystals, which will
subsequently form agglomerates by the bridging liquid. In general, the polarity of the
bridging liquid should be different from the poor solvent, and hence they are immiscible.
59
This ensures that the bridging liquid is available for collecting small API crystals into
agglomerates.29
Griseofulvin (GSF), an antifungal drug with dose as large as 1 g, is marketed as
high drug loading tablets (up to 500 mg per tablet). Pure GSF shows poor powder
flowability and tabletability. In an effort to improve flowability of GSF by spherical
agglomeration to enable the development of a high dose tablet,1 we surprisingly found
simultaneously and profoundly improved tabletability; the mechanism of which was
investigated.
3.3 Materials and methods
3.3.1 Materials
Griseofulvin was obtained from GSK Glaxo laboratories, London, UK.
Microcrystalline cellulose (Avicel PH102; FMC Biopolymers, Newark, DE),
dimethylformamide (DMF, Sigma-Aldrich, St. Louis, MO), dichloromethane (DCM,
Fisher Scientific, Fair Lawn, NJ), ultrapure deionized water (0.066 μS/cm, Thermo
Scientific, USA) were used as received. All crystallization experiments were performed
using glass beakers.
3.3.2 Spherical crystallization
3.3.2.1 Construction of ternary phase diagram
DMF, water, and DCM were used as the good solvent, poor solvent and bridging
liquid for preparing spherical GSF crystals using the spherical agglomeration method from
60
a preliminary screening study. A ternary phase diagram was constructed to identify the
agglomeration zone by the following process.30 DMF and DCM were cooled to 0 oC in an
ice-bath and then combined in volume ratios of 1:9, 2:8, 3:7, 4:6, 5:5, 4:6, 7:3, 8:2, and 9:1.
A 5 mL aliquot of each was transferred to a screw capped vial, and water was added
dropwise with intermittent mixing. When the clear mixed solvents became turbid, the
volume of water was noted. To obtain the agglomeration zone on the phase diagram, 1 g
of GSF was dissolved in 7 ml of DMF. The DMF solution was poured into water with
DMF:water volume ratios of 7:17.5, 7:30, 7:40, 7:60 and 7:80, where the API precipitated.
Then, DCM was added dropwise until a paste-like product was observed, and the volume
of DCM was noted. A ternary phase diagram, including agglomeration zone, miscible and
immiscible regions, was then constructed.
3.3.2.2 Preparation of spherical agglomerates of GSF
To prepare spherical agglomerates of GSF, 9 g of GSF was dissolved in 60 mL of
DMF at 120 oC to obtain a clear solution. The solution was poured into 270 mL of water
in a 500 mL glass beaker, which was immersed in an ice bath and agitated with an overhead
stirrer at 600 rpm. After 5 min agitation, DCM was added dropwise until fine crystals were
transformed into large agglomerates. The system was agitated for another hour, and the
agglomerates were collected and dried in a 60 oC oven for 4 hours.
3.3.3 Powder X-ray Diffractometry (PXRD)
A powder X-ray diffractometer (PANalytical X'pert pro, Westborough, MA) with
Cu Kα radiation (1.54059 Å) was used to characterize powders. Samples were scanned
61
between 5 to 35° 2θ with a step size of 0.02° and a dwell time of 1 s/step. The tube voltage
and amperage were set at 40 kV and 40 mA, respectively. The diffraction patterns of the
powders were compared to the original powder and the calculated PXRD pattern from the
single crystal structure of GSF (CCDC refcode: GRISFL06).31
3.3.4 Single Crystal X-ray Diffractometry
Single crystal X-ray diffraction experiment was carried out on a Bruker-AXS
Venture Photon-II diffractometer (Bruker AXS Inc., Madison, Wisconsin) equipped with
a Photon-II (CMOS) detector. The data collection was performed using Mo Kα radiation
at 100 K. A suite of software from Bruker, including APEX3, SADABS, SAINT and
XPREP was used to analyze the collected data. The crystal structure was solved and refined
using Bruker ShelXle. Direct-methods solution was applied to place non-hydrogen atoms
from the E-map. All non-hydrogen atoms were refined with anisotropic displacement
parameters. Hydrogen atoms that involved in hydrogen bonding were located from the
residual peaks in the Fourier map, otherwise were generated geometrically.
3.3.5 Thermal Analyses
Powder samples (3−5 mg) were loaded into hermetic aluminum pans and heated
from 30 to 240 °C at a heating rate of 10 °C/min on a differential scanning calorimeter
(Q1000, TA Instruments, New Castle, DE) under a continuous nitrogen purge at a flow
rate of 50 mL/min. DSC cell parameter was calibrated with indium for heat flow and
indium and cyclohexane for temperature. To measure any volatile content in a solid, a
62
thermogravimetry analyzer (Q500, TA Instruments, New Castle, DE) was applied to
analyze the samples (3∼10 mg) placed in an open aluminum pan. The samples were heated
from room temperature to 300 °C at 10 °C/min under 25 mL/ min nitrogen purge.
3.3.6 Powder Flowability
Powder flowability was measured using a ring shear cell tester (RST-XS; Dietmar
Schulze, Wolfenbüttel, Germany), with a 10 mL cell at 1 and 3 kPa pre-shear normal
stresses. The unconfined yield strength (fc) and major principal stress (σn) were obtained
from each yield locus by drawing Mohr’s circles. Flowability index (ffc) was calculated
using Eq. (1):
𝑓𝑓c =𝜎𝑛
𝑓c (1)
3.3.7 Powder tabletability
A universal material test machine (model 1485, Zwick/Roell, Germany) was used
to prepare tablets with compaction pressure ranging from 25 to 350 MPa at speed of 4
mm/min. The punch tip and die wall was lubricated using magnesium stearate. Tablets
were relaxed under ambient environment for at least 24 h before being broken diametrically
using a texture analyzer (TA-XT2i; Texture Technologies Corporation, Scarsdale, NY).
Tablet tensile strength was calculated from the breaking force and tablet dimensions
following the standard procedure.32
True density of powders was measured using a helium pycnometer (Quantachrome
Instruments, Ultrapycnometer 1000e, Byonton Beach, FL). The sample cell was filled with
accurately weighed powders (1-2g). The measurement was stopped when the coefficient
63
of volume variation of the last five consecutive measurements was below 0.005%.
Otherwise, the experiment terminates automatically at a maximum of 100 measurements.
The mean and standard deviation of the last five measurements were reported.
3.3.8 Scanning electron microscopy (SEM)
An ion-beams sputter (IBS/TM200S; VCR Group Inc., San Clemente, CA) was
used to was sputter-coated a thin layer platinum (thickness ~ 75 Å) onto the samples.
Scanning electron microscopy (JEOL 6500F; JEOL Ltd., Tokyo, Japan) operated at SEI
mode with an acceleration voltage of 5kV was used to evaluate particle morphology and
surface feathers and a high vacuum (10-4-10-5 Pa) was maintained during the imaging
process.
3.3.9 In-die Heckel analysis
A universal material test machine (model 1485, Zwick/Roell, Germany) was used
to prepare tablets (about 200mg) with compaction pressure 300 MPa at speed of 4 mm/min
(n=3). The force and normal strain during the compression are exported. Both GSF SA and
as-received were analyzed using the Heckel equation,33 Eq. (2):
− ln(1 − 𝐷) = 𝐾𝑃 + 𝐴 (2)
where P is the compaction pressure, K is the slope of the linear portion of the Heckel plot,
and A is the y-axis intercept of the linear portion. D is the relative density calculated using
Eq. (3)
64
D =tablet density
true density (3)
The reciprocal of K, which is termed mean yield pressure (Py), is a parameter that can be
used to quantify plasticity of the powder. A lower Py indicates higher plasticity of a powder.
The measurement was triplicated.
3.3.10 Out-of-die Kuentz–Leuenberger (KL) equation
The Kuentz–Leuenberger (KL) equation, Eq. (4)34 was applied to obtain the
plasticity parameter, 1/C, by fitting tablet porosity – pressure data. A lower 1/C value
indicates higher plasticity of the powder. The parameter, εc, describes the critical powder
porosity at which the powder starts to gain rigidity or strength.
𝑃 =1
𝐶[𝜀 − 𝜀𝑐 − 𝜀𝑐𝑙𝑛(
𝜀
𝜀𝑐) (4)
Out-of-die Hardness determination by macroindentation
A spherical stainless indenter (3.18 mm in diameter), attached to a texture analyzer
(TA-XT2i, Texture Technologies Corp., NY), was used to indent the cylindrical tablet at
the center of a flat face. During loading, the indenter was moved downward at a speed of
0.01 mm/min, and the indenting force was set around 60% of the breaking force of the
tablet prepared at the same compaction pressure and maintained for 3 min. The indented
area was measured using a calibrated digital microscope (×200 magnification, Dino-Lite
Pro AM413MT; AnMo Electronics Corporation, Taiwan). A three-point method was used
to identify the circular indented area and the projected area, A, was calculated using
DinoCapture software (V2.0 AnMo Electronics Corporation, Taiwan). To more accurately
65
determine the indented area, the contrast between the indent and surrounding flat tablet
surface was enhanced by gently rubbing the tablet face against a piece of graphite-coated
paper. Tablet hardness, H, was calculated using Eq. (5):
𝐻 =𝐹
𝐴 (5)
H0, hardness at zero porosity, was obtained by extrapolating the function to zero porosity.
3.3.11 Energy framework of crystal structures
The pairwise intermolecular interaction energy was estimated using CrystalExplorer and
Gaussian09W with experimental geometry of GSF Form I.35-38 The hydrogen positions
were normalized to standard neutron diffraction values before calculation using the
B3LYP-D2/6-31G(d,p) electron densities model. The total intermolecular interaction
energy for a given molecule is the sum of the electrostatic, polarization, dispersion, and
exchange-repulsion components with scale factors of 1.057, 0.740, 0.871, and 0.618,
respectively. Intermolecular interaction between two molecules was ignored, when the
closest atom - atom distance was more than 3.8 Å. The interaction energies were
graphically presented as a framework by connecting centers of mass of molecules with
cylinder thickness proportional to the total intermolecular interaction energies, where
interaction energies below -5 kJ/mol were omitted for clarity.
3.4 Results and discussion
3.4.1 Ternary Phase Diagram
66
The ternary phase diagram (Figure 3.1) pertaining to SA of GSF in this work
revealed a distinct agglomeration zone for producing spherical agglomerates (shaded
region). This zone is in the immiscible region neighboring the miscible zone, where free
bridging liquid (DCM) was available to collect small primary GSF crystals into large SA.
No agglomerates were obtained in the miscible zone. Outside the shaded area in the
immiscible zone, a paste-like product was formed because of excess amount of bridging
liquid.
3.4.2 Particulate properties
The microscopic images and particle size analysis revealed the particle shape and
size after the spherical agglomeration process. The as-received GSF consisted of irregular
crystals with size ranging 1 - 10 µm, while the agglomerates were round with size ranging
300 - 600 µm (Figure 3.2). Moreover, no weight loss was detected for SA before 153 oC
(boiling point of DMF) by thermal gravimetric analysis (Figure 3.3), indicating negligible
residual solvent.
3.4.3 Powder flowability and tabletability
The flowability of the powder is an important powder property in tablet
manufacturing. At normal stresses of 1 and 3 kPa, the ffC values of GSF SA were similar
to those of Avicel PH102 (Figure 3.4a), which suggests their adequate flowability for high
speed tableting.39 The flow property of the as-received GSF, on the other hand, was much
67
poorer than that of Avicel PH102 (Figure 3.4a). The much improved flowability of the GSF
SA is a consequence of the large size and round shape.23
Similar to a previous study,40 intact tablets of as-received GSF could not be
obtained, due to lamination, over the entire pressure range between 25 and 350 MPa. The
problematic tabletability of GSF is attributed to minimal plasticity due to a lack of active
slip planes in its crystal structure.40 Surprisingly, the GSF SA exhibited excellent
tabletability with the highest tensile strength around 5 MPa at ~300 MPa (Figure 3.4b).
The profoundly improved tabletability could not be explained by any changes in solid state
form, because the GSF SA were phase pure GSF Form I, the same as the as-received GSF.
Another commonly cited mechanism to explain improved tabletability of spherical
agglomerates is extensive fracture of agglomerates during compaction,21, 25 which exposes
fresh surfaces for developing a network of interparticle bonding. This mechanism is
reasonable for lubricated powders where coating of particles by poorly bonding lubricant
weakens bonding strength. In that case, generation of particle surfaces free from such
deleterious effect by fragmentation improves tablet tensile strength through higher bonding
strength according to the bonding area – bonding strength model.17, 18, 41 However, this
explanation is not appropriate, because GSF powders were not mixed with any lubricant.
The external lubrication of tooling could not have affected interparticulate bonding strength.
In addition, fragmentation of agglomerates during compaction unlikely reduced GSF to the
size of as-received GSF, which is very small (1 - 10 µm). Thus, larger bonding area due
to smaller particle also does not explain the improved tabletability. To verify this point,
GSF SA were milled and then compressed. The milled GSF SA exhibited similar
tabletability profile as the un-milled agglomerates (Figure 3.4b). Hence, in-situ particle
68
fragmentation can be excluded as a main mechanism to the profoundly increased
tabletability. Therefore, a different mechanism must have caused significantly larger
interparticulate bonding area, which led to the striking improvement in tabletability.
3.4.4 Role of plasticity in the improved tabletability of GSF agglomerates
To seek an explanation for the improved tabletability, the plasticity of the different
GSF powders was assessed by Heckel analysis of in-die compressibility data. A lower
value of the plasticity parameter, Py, from such an analysis indicates higher plasticity of
the material. Results show that the Py followed the order of: GSF SA ≈ GSF SA milled <
as-received GSF (Table 3.1), which corresponded well with the order of tabletability: GSF
SA ≈ GSF SA milled > as-received GSF. This data supports the premise that the improved
tabletability of GSF SA resulted from increased plasticity. The Py values of all three
materials are higher than that of Avicel PH102, a commonly used plastic excipient with a
Py value of ~ 62 MPa, 42 and exhibiting excellent tabletability.18 However, the higher
plasticity of agglomerated GSF cannot be attributed to a change in particle size, since the
Py of the milled GSF agglomerates is the same as that of un-milled agglomerates.
To further verify the different plasticity between the two powders using out-of-die
data, physical mixtures of GSF (80%) and Avicel PH102 (20%) were studied. Avicel P102
was used, because pure as-received GSF could not be compressed into intact tablets. The
tabletability of the mixture containing GSF SA outperformed that containing as-received
GSF (Figure 3.5a). Although the relative order in tabletability of the mixture and pure GSF
did not change, the tabletability difference between the two mixtures was much smaller
than that between pure GSF powders. The tensile strength extrapolated to zero porosity,
69
which is a parameter to infer apparent bonding strength, was lower for the mixture
containing GSF SA. Thus, the better tabletability of the GSF SA mixture was not due to
higher bonding strength between the particles (Figure 3.5b). However, at the same
compaction pressure, tablets of the mixture containing GSF SA exhibited significantly
lower porosity (Figure 3.5c), indicating higher plasticity. In fact, the plasticity parameter,
1/C, from the KL analysis of the mixture containing GSF SA was lower than the mixture
containing the as-received GSF (Table 3.1), confirming the higher plasticity of SA.
The hardness at zero porosity, H0, is also a measure of plasticity of the powder,
where a lower H0 value relates to a higher plasticity.43 By this measure, the mixture
containing GSF SA was also more plastic because of its lower H0 (Figure 3.5d, Table 3.1).
Therefore, results from all complementary methods confirm the higher plasticity of the
GSF SA. The higher plasticity, in turn, leads to larger bonding area and higher tabletability
for the mixture containing GSF SA.
3.4.5 Origin of superior plasticity of GSF SA
At this point, the underlying reason for the superior plasticity remained elusive.
Because GSF SA had a crystal structure identical to the as-received GSF, as shown by the
nearly identical PXRD patterns (Figure 3.6a) and DSC thermograms (Figure 3.6b).
However, scanning electronic microscope (SEM) images revealed intriguing
difference in the structures of the two powders, where many nanopores with opening size
of ~500 nm were clearly observed in GSF SA but absent in the as-received GSF (Figures
70
3.7 and 3.8). These nanopores can collapse during compression to make particles more
deformable, which leads to larger interparticulate contact area in the tablet.
The collapse of nanopores after compaction was verified by observing GSF
agglomerate crystals exposed to the fracture surface of a tablet prepared at 250 MPa
(mixture containing 20% Avicel PH102) after breaking diametrically (Figure 3.7). It is
interesting to note that small nanosized particles also appeared on the tablet fracture surface
of the GSF SA (Figure 3.7). These nanosized particles indicate possible fragmentation of
the porous GSF crystals, either during compaction or during tablet breaking. In contrast,
no obvious changes to the as-received GSF crystals were observed (Figure 3.7). Thus, the
as-received GSF crystals undergo largely reversible, elastic deformation during
compaction, which correlates to its extremely poor tabletability (Figure 3.4b).
The origin of the nanopores in GSF SA is attributed to the solvation and desolvation
process during the spherical agglomeration process. The formation of a DCM solvate is
confirmed by the PXRD patterns of the fresh prepared GSF SA, which matched the
calculated pattern of GSF-DCM solvate (Figure 3.6a).44 While the GSF molecules are
closely packed in GSF Form I (Figure 3.9a), they form a hexagonal reticular structure
fortified through a series of C-H...O (3.347, 3.348, 3.484, 3.476, 3.478 Å) and C-H...π (3.664
Å) interactions. The voids in the solvate are filled by DCM molecules, which interact with
GSF through C-H...O (3.284, 3.361, 3.364 Å) weak hydrogen bonds (Figure 3.9b). The
weak interaction strength between DCM and GSF is consistent with the observed relatively
facile desolvation process, which goes to completion at 60 oC in 4 h (Table 3.2). The open
structure of the desolvated GSF-DCM crystal, with 18.6% of void by volume, is unstable
(Figure 3.9c), as suggested by the calculated large lattice energy difference (~20 kcal/mol)
71
between GSF Form I (-94.24 kcal/mol) and GSF anhydrous (-73.98 kcal/mol). Driven by
such a large energy difference, fast spontaneous collapse of the desolvated structure to
Form I is expected, which induced cracks and generated nanopores in GSF crystals. A
similar mechanism was previously reported for acetaminophen, which also led to
significantly improved tabletability.45-47 Although we only studied DCM solvate of GSF in
this work, it is likely that the solvation -desolvation of other GSF solvates, such as GSF-
chloroform, GSF-benzene, GSF dioxane,44, 48-50 can achieve a similar effect. This is being
investigated in our laboratory.
3.5 Conclusion
The spherical GSF Form I agglomerates, prepared by the spherical crystallization
process, exhibited not only good flowability as expected but also surprisingly excellent
tabletability without a change in the solid form. The latter is attributed to the in-situ
formation of a DCM solvate and subsequent desolvation during drying, which generates
nanopores and makes the GSF crystals more deformable by collapse of pores during
compaction. Such superior deformability leads to large interparticular bonding area and
stronger tablets. This mechanism for enhancing crystal plasticity may be useful to improve
tabletability of other poorly compressible APIs that can form a solvate or hydrate.
72
Figure 3.1. Ternary phase diagram of GSF in water-DMF-DCM solvents system.
73
Figure 3.2. Microscopic images of GSF (a) as-received and (b) SA.
(b) (a)
74
Figure 3.3. TGA profiles of GSF SA and as-received GSF.
75
Figure 3.4. (a) Flowability profiles of as-received GSF, GSF SA and Avicel PH102 (n=1);
(b) tabletability profiles of as-received GSF, GSF SA and GSF SA milled (n=3).
a) b)
76
Table 3.1. Plasticity parameters of as received GSF and GSF SA from in-die and out-of-
die data analyses.
Sample name As-received GSF GSF SA GSF SA milled
Py (MPa), n=3 143.0 ±5.3 107.9 ±1.3 106.4 ±2.3
1/C (MPa) a 450.0 ± 208.5 (R2=0.98) 143.4 ± 38.4 (R2=0.99) --
H0 (MPa) a 435 ± 21 (R2=0.98) 333 ± 18 (R2=0.98) --
a Parameters were derived for mixtures containing 20% Avicel PH102
77
Figure 3.5. (a) Tabletability, (b) compactibility, (c) compressibility, and (d) hardness
profiles of GSF (80%) and Avicel PH102 (20%) mixture.
c) d)
a) b)
78
Figure 3.6. (a) PXRD patterns of calculated GSF Form I, as-received GSF, GSF SA,
calculated GSF-DCM and GSF SA before drying; (b) DSC profiles of as-received GSF and
GSF SA.
b
) a)
79
Figure 3.7. SEM images at (x10,000 magnification) of GSF (a) as-received crystals, (b)
SA, and tablet fracture surface of (c) GSF-Avicel mixture, and (d) GSF SA-Avicel mixture.
(a) (b)
(c) (d)
80
Figure 3.8. SEM image at (x20,000 magnification) of GSF SA.
81
Figure 3.9. Energy framework of (a) GSF Form I and (b) GSF-DCM solvate. The (c)
desolvated GSF-DCM with large void is also shown for comparison. The energy threshold
for the energy framework is set at −22 kJ/mol.
a) b)
c)
82
Table 3.2. Intermolecular interaction energies estimated using B3LYP+D2/6+31G(d,p)
dispersion corrected DFT model. Both the total energy (E(tot)) and electrostatic (E(ele)),
polarization (E(pol)), dispersion (E(dis)), and exchange repulsion (E(rep)) components of the
energy are listed. R indicated the distance between centers of mass of the pair of molecules.
Symop R E_ele E_pol E_dis E_rep E_tot
- 6.41 -9.4 -1.3 -42.9 28.8 -30.5
x, y, z 8.50 -1.7 -4.2 -16.3 19.5 -7.0
x, y, z 13.93 -6.6 -1.8 -3.1 1.5 -10.0
- 8.02 -18.0 -4.7 -46.9 37.4 -40.3
- 7.08 -1.4 -0.9 -10.2 5.7 -7.5
- 4.73 -6.9 -1.3 -19.7 21.3 -12.3
- 8.08 -16.9 -4.6 -30.1 18.3 -36.2
- 7.37 -1.4 -0.1 -6.4 4.7 -4.2
x, y, z 11.67 -11.9 -4.4 -10.6 8.8 -19.5
- 8.53 -15.4 -4.0 -34.0 20.1 -36.4
- 8.93 0.7 -0.4 -3.8 2.7 -1.2
- 11.96 -0.9 -2.3 -6.1 2.3 -6.5
- 8.34 -12.4 -4.0 -8.2 12.2 -15.7
- 5.89 -8.4 -2.9 -14.4 11.8 -16.2
- 7.70 -20.0 -6.2 -37.8 30.3 -40.0
- 6.93 -2.5 -0.8 -7.4 7.9 -4.8
- 7.37 -1.4 -0.1 -6.4 4.7 -4.2
- 6.93 -2.5 -0.8 -7.4 7.9 -4.8
- 7.79 -8.7 -1.2 -7.7 4.9 -13.9
- 6.14 -2.0 -0.6 -10.0 4.5 -8.6
- 9.19 3.4 -0.6 -3.0 0.8 1.0
- 8.72 -2.9 -0.4 -4.6 3.1 -5.5
- 7.08 -1.4 -0.9 -10.2 5.7 -7.5
- 8.93 0.7 -0.4 -3.8 2.7 -1.2
- 8.34 -12.4 -4.0 -8.2 12.2 -15.7
83
- 6.86 0.9 -0.6 -4.6 1.8 -2.4
- 6.00 -3.4 -0.1 -3.1 11.1 0.5
- 5.72 -2.5 -0.2 -4.7 6.7 -2.8
x, y, z 8.50 1.0 -3.8 -15.9 16.4 -5.5
x, y, z 11.67 -18.0 -6.7 -16.7 17.7 -27.6
- 6.86 0.9 -0.6 -4.6 1.8 -2.4
- 8.80 -1.8 -0.3 -3.6 1.9 -4.1
- 6.14 -2.0 -0.6 -10.0 4.5 -8.6
- 5.20 -6.2 -0.9 -16.6 19.0 -10.0
- 8.72 -2.9 -0.4 -4.6 3.1 -5.5
- 7.79 -8.7 -1.2 -7.7 4.9 -13.9
- 5.72 -13.0 -4.0 -17.6 15.2 -22.6
- 9.19 3.4 -0.6 -3.0 0.8 1.0
- 5.72 -13.0 -4.0 -17.6 15.2 -22.6
- 5.20 -6.2 -0.9 -16.6 19.0 -10.0
- 5.89 -8.4 -2.9 -14.4 11.8 -16.2
- 4.73 -6.9 -1.3 -19.7 21.3 -12.3
- 8.80 -1.8 -0.3 -3.6 1.9 -4.1
84
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88
Chapter 4
Spherical cocrystallization - an enabling technology for the
development of high dose direct compression tablets of poorly
soluble drugs
89
4.1 Synopsis
Spherical cocrystallization (SCC), an integrated crystal and particle engineering
approach, was successfully applied to generate spherical cocrystal agglomerates (SCA)
between a poorly soluble drug, griseofulvin (GSF) and acesulfame (Acs). The SCC process
consists of two steps: 1) GSF-Acs cocrystal formation by reaction crystallization in a slurry,
2) agglomeration by adding a bridging liquid. The obtained SCA exhibited superior
mechanical and powder properties over GSF. Inclusion of a small amount (<1%) HPC in
the agglomerates improved both the tabletability and dissolution performance. Using the
SCA, a high GSF loading (55.7%) direct compression tablet formulation was successfully
developed, which exhibited much improved manufacturability and drug release property
over GSF based tablet formulation.
4.2 Introduction
The successful development of pharmaceutical tablets using the much-preferred
direct compression (DC) process needs to overcome several challenges, depending on dose
and physicochemical properties of the active pharmaceutical ingredient (API). When the
API dose is low (< 5 mg), content uniformity (CU) is a key challenge.1 When the API dose
is high (> 100 mg), manufacturability is a key challenge.2, 3 The CU challenge for low dose
drugs can be very effectively addressed using a versatile platform DC tablet formulation
employing particle engineering that involves forming a drug – carrier composite.4 However,
an effective strategy for solving the manufacturability challenge facing the development of
high dose APIs by the DC process is lacking. Additionally, APIs exhibiting solubility
90
limiting bioavailability is approximately 80-90% of the new chemical entities in
pharmaceutical pipeline.5 For such APIs, solubility in gastric and intestinal fluids must be
sufficiently high to achieve adequate bioavailability if permeability does not limit API
absorption. For a given solid form of an API, a common practice to alleviate solubility
limiting bioavailability is API size reduction, which can enhance dissolution rate by the
virtue of larger API surface area.6, 7 However, smaller API particles correspond to poorer
flowability,8 which deteriorates flowability of the blend if the same API loading is used in
the tablet formulation. Hence, manufacturability problems may be encountered depending
on the dose and flowability of the size-reduced API powder. One way to address such flow
related manufacturability problems is to use lower API loading by using a larger tablet.
However, larger tablets are generally undesirable because of the lower patient compliance.9
An alternative approach to improve API bioavailability is the use of soluble solid
form, such as amorphous solid, cocrystal, and salts.10 Among these solid forms, cocrystal
is attractive because it exhibits better physical stability than amorphous solids during
storage and it is applicable to non-ionizable APIs that are not amenable to salt formation.11
However, the presence of coformer in cocrystal necessarily increases the loading in the
formulation for the same API amount. This presents an additional challenge for high dose
APIs if the more soluble cocrystal does not exhibit desired flow or tableting properties,
which likely dominate manufacturability of the blend.2, 12
Spherical crystallization is a process that directly transforms fine crystals into
compact spherical agglomerates during the crystallization process.13-16 For a given crystal
form, spherical crystallization has been found effective in improving powder flowability,
packability, compressibility, and tabletability on study such as lactose,17 albendazole,14
91
tolbutamide,18 acebutolol hydrochloride19 and etodolac20. In favorable cases, DC tablet
formulation containing as high as 99% API could be attained by using spherical
agglomerates.21
It would be reasonable to expect that spherical cocrystallization (SCC), which
combines spherical crystallization and cocrystallization, can simultaneously improve
manufacturability and dissolution performance of drugs to enable the development of DC
tablet formulations of high dose APIs. In this sense, SCC is a true integrated API crystal
and particle engineering strategy that can be potentially very useful to pharmaceutical
tablet development and manufacturing. SCC was firstly reported on the energetic material
ammonium nitrate to produce smokeless and easy packing cocrystal agglomerates.22
Similarly, it was applied to generate carbamazepine/saccharin cocrystal agglomerates.23
Moreover, it can be used to control the cocrystal stoichiometry and particle size.24
Surprisingly, SCC has not been explored to improve the manufacturing and dissolution
performance of poorly soluble APIs in high dose tablets. The goal of this work was to fill
this knowledge gap using a high dose model drug, griseofulvin (GSF), which is challenging
to formulate by DC process because of its poor powder flowability and tabletability in
addition to low solubility (10 μg·ml-1 at 37 oC).25
4.3 Materials and methods
4.3.1 Materials
Griseofulvin (GSF; Glaxo Laboratories, London, UK), Acesulfame potassium
(Acs-K, Tokyo Chemical Industry Co., Ltd., Japan), fumed silica (CAB-O-Sil, M5-P,
92
Cabot Corporation, Boston, MA), microcrystalline cellulose (Avicel PH105; FMC
Biopolymers, Newark, DE), croscarmellose sodium (CCM-Na, SD-711, FMC Biopolymer,
Philadelphia, PA), magnesium stearate (MgSt, Mallinckrodt Inc., St. Louis, MO),
Hydroxypropylcellulose (HPC, EF Pharm, Ashland., Wilmington, DE), and
dimethylformamide (DMF, Sigma-Aldrich, St. Louis, MO)were received from respective
manufacturers and were used as received.
4.3.2 Preparation of spherical GSF-Acs cocrystal hydrate
A mixture of 0.01 mol of GSF and 0.01 mol of Acs-K was suspended in 70 mL of
methanol and water (2:8, v/v) mixture. Concentrated hydrochloric acid (1 mL) was added
to convert the Acs-K into acesulfame free acid (Acs-H) completely. The suspension was
agitated overnight. This reaction crystallization led to phase pure fine GSF-Acs crystals,
which was a monohydrate.25
The suspension was cooled to 0 oC in an ice-bath and stirred at 500 rpm using an
overhead mixer. Under stirring, DCM was added dropwise into the suspension until the
initially turbid medium became clear, which corresponded to the elimination of fine
crystals from the suspension. Then, the agitation was continued for 1h before filtration and
drying at 60 oC for 4 hr. In some batches, HPC (35 mg) was added to the vessel before
DCM was added to improve wettability of agglomerates.26 Subsequent steps were the same
as the process without HPC. DCM was a bridging liquid that facilitated the agglomeration
of fine GSF crystals.
93
4.3.3 Powder X-ray Diffractometry (PXRD)
A powder X-ray diffractometer with Cu Kα radiation (1.54059 Å) was used to
characterize crystallographic properties of samples. Samples were scanned between 5 to
35° 2θ with a step size of 0.02° and a dwell time of 1 s/step. The X-ray tube voltage and
amperage were 40 kV and 40 mA, respectively. A theoretical PXRD pattern of GSF-Acs
was calculated from the single crystal structure (CCDC refcode: GEPJIW).25
4.3.4 Thermal Analyses
Powder samples (3−5 mg) were loaded into hermetically sealed aluminum pans
(Tzero) and heated from 30 to 200 °C at a rate of 10 °C/min using a differential scanning
calorimeter (Q2000, TA Instruments, New Castle, DE). The sample was purged with
nitrogen at a flow rate of 50 mL/min. The instrument was equipped with a refrigerated
cooling system. The temperature and cell constant were calibrated using high purity indium.
4.3.5 Scanning electron microscopy (SEM)
A thin layer platinum (thickness ~ 75 Å) was sputter-coated onto the samples,
which were mounted onto carbon tapes, using an ion-beam sputter (IBS/TM200S; VCR
Group Inc., San Clemente, CA). The particle morphology and surface features were
evaluated by scanning electron microscopy (JEOL 6500F; JEOL Ltd., Tokyo, Japan),
operated at SEI mode with an acceleration voltage of 5kV. A high vacuum (10-4-10-5 Pa)
was maintained during the imaging process.
94
4.3.6 Contact angle measurement
Tablets, prepared by compressing powders at 300 MPa, were used for contact angle
measurements using the sessile drop method on a goniometer (MAC-3, Kyowa Interface
Science Co. Ltd., Japan). A drop of distilled water (∼2 μL) was gently placed on the surface
of the tablet using a syringe dispenser. The image of the water drop was recorded from the
side every 67 ms for 60 s using a high-speed camera. The angle between the sample surface
and the tangent line at the edge of the drop was determined using image analysis software,
FAMAS3.72 (Kyowa Interface Science Co. Ltd., Japan). Three measurements were made
at different locations on each tablet, and the mean and standard deviations were calculated.
4.3.7 Energy framework and topologic analysis of crystal structures
The pairwise intermolecular interaction energy was estimated using
CrystalExplorer and Gaussian09W with experimental geometry of GSF-Acs monohydrate
and GSF (Form I, CSD refcode: GRISFL06).27-29 The hydrogen positions were normalized
to standard neutron diffraction values before calculation using the B3LYP-D2/6-31G(d,p)
electron densities model. The total intermolecular interaction energy for a given molecule
is the sum of the electrostatic, polarization, dispersion, and exchange-repulsion
components with scale factors of 1.057, 0.740, 0.871, and 0.618, respectively.
Intermolecular interaction between two molecules is ignored when the closest atom - atom
distance was more than 3.8 Å. The interaction energies were graphically presented as a
framework by connecting centers of mass of molecules with cylinder thickness
95
proportional to the total intermolecular interaction energies, where interaction energies less
than -5 kJ/mol were omitted for clarity. The crystal packing topology was analyzed using
a python program.30
4.3.8 Formulation and Tablet Compression
MCC (Avicel PH105) was used as a tablet binder because of its excellent
tabletability.31 However, the flowability of Avicel PH105 is poor. Thus, it was coated with
nano silica particles using a dry comilling process to improve its flowability before mixing
with API.32 Briefly, 50 g of Avicel PH105 and colloidal silica (1.0% loading) were
geometrically mixed and passed through a sieve (150 µm opening). The powder mixture
was then placed in the Comil chamber and passed through a stainless-steel screen (round
holes of 0.9905 mm, or “0.039”, diameter; part number: 7B039R03125) with an impeller
speed of 2200 rpm. The process was repeated 40 times to ensure uniform distribution of
silica particles onto Avicel PH105 particles. API and all other excipients (Table 4.1),
totaling 5 g, were added to a 30 mL plastic bottle, which was manually rotated diagonally
to allow particles slide and mix for 15 min (approximately 900 turns).
A universal material test machine (model 1485, Zwick/Roell, Germany) was used
to prepare tablets with compaction pressure ranging from 25 to 350 MPa at a speed of 4
mm/min. The punch tip and die wall were coated with a 5% (w/v) magnesium stearate
suspension in ethanol and then dried with a fan. Tablets were relaxed under ambient
environment for at least 24 h before being broken diametrically using a texture analyzer
(TA-XT2i; Texture Technologies Corporation, Scarsdale, NY). Tablet tensile strength was
96
calculated from the breaking force (F) and tablet thickness (h) and diameter (d) using
equation (1).33 Tablet flashing was carefully removed to improve accuracy of measured
tablet thickness.34
𝜎 =2𝐹
𝜋𝑑ℎ (1)
4.3.9 Powder Flowability
Powder flowability was measured using a ring shear cell tester (RST-XS; Dietmar
Schulze, Wolfenbüttel, Germany), with a 10 mL cell at 1 and 3 kPa pre-shear normal
stresses. A yield locus was obtained by conducting shear test under different normal
stresses, from which the unconfined yield strength (fc) and major principal stress (σn) were
obtained by drawing Mohr’s circles. The flowability index (ffc) was calculated using Eq.
(2):
𝑓𝑓c =𝜎𝑛
𝑓c (2)
4.3.10 Expedited Friability
An expedited friability method was applied to determine the ability of compressed
tablets to resist wearing and abrasion.35 Coded tablets prepared under different pressures
were weighted, coded, and loaded into a friabilator (Model F2, Pharma Alliance Group
Inc., Santa Clarita, CA) at 25 rpm for 4 min. The final weight of each tablet was used to
calculate percent weight loss, which was plotted against compaction pressure to construct
97
a friability plot. The compaction pressure corresponding to 0.8% tablet weight loss was
identified from the friability plot.35
4.3.11 Artificial Stomach-Duodenum Dissolution (ASD)
Although the griseofulvin is non-ionizable, the coformer of acesulfame (pKa=2.0)
shows strong acidity nature. Therefore, the solubility of griseofulvin - acesufulame
cocrystal is expected to be pH-dependent. Dissolution results in the single chamber
apparatus, such as USP method, may not reflect the real condition and result in wrong
conclusion. Thus, using ASD apparatus with two chambers (pH 1.2 and 6.8) is a more
reliable approach.
The ASD apparatus consisted of two jacketed beakers that were connected using a
short tubing, mimicking stomach chamber and duodenum chamber, respectively. The
temperature was kept at 37 °C by circulating water. Fluid flow from stomach chamber to
duodenum chamber was regulated by a programmed peristaltic pump (Masterflex L/S
Easy-Load II pump, Cole-Parmer, Vernon Hills, IL).36
To simulate human physiological conditions in the fasted state, 0.1 N HCl (pH =
1.2) was prepared for gastric liquid in stomach and 0.1 M sodium phosphate buffer (pH =
6.8) for the duodenum. The initial volume of the stomach chamber was 250 mL, which was
emptied to 50 mL, following a first-order kinetics with a half-life of 15 min to simulate
stomach empty process. Throughout the entire experiment, the fluid volume in the
duodenum chamber was maintained at 30 mL, achieved by setting a vacuum line at a
calibrated height. In addition, the two chambers were infused with fresh gastric or duodenal
98
secretion liquid at 2 mL/min to mimic in vivo secretion processes. A fiber optic UV/Vis
probe was used to monitor the drug concentration. Mixing was achieved by an overhead
paddle stirrer in the stomach chamber and a magnetic stirrer in the duodenum chamber.
Prior to each experiment, calibration of all pumps and spectrometers were performed. All
fluids used in the experiment were degassed to avoid the generation of bubbles that may
interfere the data collection using the UV dip probe.
The drug concentration−time profile in the duodenum was analyzed, using the non-
compartmental method (PKsolver 2.0) to determine the peak plasma concentration (Cmax),
time to reach Cmax (Tmax), and area under the plasma concentration−time curve (AUC).37
4.4 Results and discussion
4.4.1 Characterization
The as-received GSF crystals were 1-5 µm in size and with irregular shape (Figure
4.1a). The GSF-Acs cocrystals (GSF-Acs) from reaction crystallization were prism shape
with size ranging 1 - 10 µm. The primary crystals in the cocrystal agglomerates without
HPC (GSF-Acs/SA) and with HPC (GSF-Acs/HPC) were comparable to those in the GSF-
Acs, indicating that the addition of DCM and HPC did not significantly influence the
property of the primary GSF crystals (Figure 4.1). This is understandable since the
cocrystal forming process was identical in all cases. The subsequent introduction of
bridging liquid and HPC affects, at most, attrition and ripening of these primary crystals.
99
The size of the GSF-Acs/HPC was much smaller compared to that of the GSF-
Acs/SA (Figure 4.2 & Figure 4.3). The smaller size of GSF-Acs/HPC is attributed to the
impact on the agglomeration process by changes in surface tension between bridging liquid
and bulk medium or medium viscosity by the introduction of HPC. Although smaller, the
GSF-Acs/HPC agglomerates were more spherical than GSF-Acs/SA (Figure 4.2a & 4.2b).
Similar effect of HPC on size and shape of spherical agglomeration was reported for
etodolac.38
PXRD patterns of the GSF-Acs, GSF-Acs/SA, and GSF-Acs/HPC all matched well
with the calculated pattern from the GSF-Acs crystal structure (Figure 4.4). The slight
shift of some peaks to higher 2θ values in the calculated PXRD pattern is attributed to the
thermal expansion of crystal lattice since the crystal structure used for calculating PXRD
pattern was solved at 100 K while the experimental PXRD patterns were obtained at ~298
K. The largest 2θ shift (~0.5o) observed in 27.2o and 28.3o is attribute the ease of crystal
thermal expansion along the (0 6 0) and (0 6 1) planes. This is consistent with the fact that
absence of strong interlayer hydrogen bonds interaction between the (0 2 0). Moreover,
characteristic peaks of the starting materials were absent in the experimental PXRD
patterns, confirming their phase purity. DSC thermograms of the three different GSF-Acs
powders (Figure 4.5) were all similar to the reported data with two endotherms between
130-160 oC and 170-190 oC, respectively.25 Collectively, the phase purity of all three GSF-
Acs powders was confirmed.
The tabletability, i.e., tensile strength vs. compaction pressure, of the as-received
GSF was very poor as no intact tablets could be prepared due to lamination (Figure 4.6).
The fine GSF-Acs showed slightly improved tabletability with a maximum tensile strength
100
of ~ 0.4 MPa at 100 MPa compaction pressure (Figure 4.6). Intact tablets were so weak
that very gentle handling was required when measuring their breaking strength. Extensive
tablet lamination still occurred when the compaction pressure was higher than 150 MPa.
The tableting performance of the GSF-Acs/SA was similar to GSF-Acs, except lamination
was observed earlier at 100 MPa compaction pressure. The GSF-Acs/HPC exhibited much
better tabletability compared to GSF-Acs and GSF-Acs/SA. In fact, the highest tensile
strength of GSF-Acs/HPC was 2.5 MPa at a compaction pressure of 150 MPa. The similar
tableting performance of GSF-Acs and GSF-Acs/SA indicated that extensive fracture of
the agglomerates had occurred, which eliminated the potential effect on tabletability by the
larger agglomerate size and microstructure of the SA. HPC is a good tablet binder.39, 40 The
improved tabletability of GSF-Acs/HPC at such a low level of HPC (< 1%) indicated
uniform coating of GSF-Acs crystals by HPC.38 Such polymer distribution is effective in
attaining an extensive three dimensional bonding network in the tablet with increased inter-
particular bonding area.41, 42
It has been demonstrated the solid forms with excellent compaction properties
usually display active slip/cleavage planes with lower interlayer interaction energy and
smooth plane topology, which facilitate plastic deformation.43 However, clear
identification of the active slip planes in both GSF and GSF-Acs is challenging by
visualization of crystal structures.44 While GSF showed no strong hydrogen bonds in its
structure and the GSF-Acs exhibited three-dimensional hydrogen bonds network, neither
shows visually clear molecular layers that can serve as active slip planes. The energy
framework of both crystal structures suggested an absence of crystallographic planes that
can serve as active slip planes with much weaker interlayer interactions (Figure 4.7, also
101
see Table 4.2 for detailed intermolecular interaction energies). Additionally, all the
interlayer distances computed by topology analysis are negative, implying interlocking
between possible molecular layers, which hindered the slip among them. For example, the
most likely slip planes based on topology analysis, (0 1 1) for GSF and (1 -1 1) for GSF-
Acs, had interplanar overlapping of-3.80 Å and -1.72 Å, respectively. Thus, neither GSF
(Form I) nor GSF-Acs exhibits crystal structure that promotes plasticity, which is essential
for forming strong tablets. This is consistent with the very poor tabletability of both
crystals (Figure 4.6).
4.4.2 Formulation development
A successful formulation for tablet product development needs to meet several
criteria: (1) adequate blend flowability for smooth and reproducible hopper emptying and
die filling, which are critical for sustaining high speed tableting, (2) adequate mechanical
strength of the tablet (tabletability), (3) low friability, and (4) adequate dissolution
performance. For APIs exhibiting poor tabletability that still need to be delivered in high
doses, such as GSF, the use of tablet binders with excellent tabletability is necessary to
assure adequate tabletability of the final formulation. Avicel PH105 was chosen in this
work because of its excellent tabletability.31 The 70% loading of GSF-Acs (corresponding
to 55.7% GSF) was used (Table 4.1), since lamination was observed when cocrystal
loading was 80%.
All formulations exhibited good tabletability, where tablet tensile strength could
reach 2 MPa 45 at a compaction pressure above 120 MPa. The tabletability of formulations
102
containing GSF-Acs, GSF-Acs/SA, or GSF-Acs/HPC was similar, which was lower than
the formulation containing GSF (Figure 4.8a). Based on the friability plots (Figure 4.8b),
all formulations met the minimum friability requirement of < 0.8% when the compaction
pressure was higher than 250 MPa.35 The GSF formulation exhibited the best friability,
which required no more than 150 MPa in order to attain < 0.8% friability (Figure 4.8b).
The superior tabletability and friability of the GSF formulation is reasonable because it
contained about 60% higher amount of highly compressible Avicel PH105 than other three
formulations (Table 4.1). Therefore, it is expected that both tabletability and friability of
this formulation is better.46 It is interesting to note that the tabletability of the formulation
containing GSF-Acs/HPC was the same as other two GSF-Acs containing formulations,
despite the significantly better tabletability of GSF-Acs/HPC (Figure 4.6). This highlights
the difficulty in accurately predicting tabletability of a mixture from constitutive
components and the need for mechanistic investigation into compaction behavior of
mixtures.47, 48
Another important property of a successful tablet formulation is the flowability.
Only GSF-Acs/HPC and GSF-Acs/SA formulations exhibited flowability better than that
desired for high speed tableting, marked by Avicel PH102 (Figure 4.9).49 The differences
in flowability are attributed to the different particle sizes and shapes of the API powders
used in these formulations. Both GSF-Acs and GSF consisted of small elongated crystals
(Figure 4.1), while both GSF-Acs/SA and GSF-Acs/HPC consisted of large and more
round agglomerates (Figure 4.2).8
Having verified the acceptable manufacturability of both formulations containing
GSF-Acs agglomerates, we then assessed the dissolution performance of formulated tablets
103
using the ASD apparatus. All three cocrystal formulations released GSF more rapidly than
the formulation of GSF. Both the AUC and Cmax followed the order of GSF-Acs/HPC >
GSF-Acs >> GSF-Acs/SA > GSF (Figure 4.10a, Table 4.3). The enhanced dissolution
performance of the cocrystal formulations compared to that of GSF may be attributed to
the approximately 3 fold higher solubility of GSF-Acs than GSF.25 The time to reach Cmax,
i.e., Tmax, is longer for formulation that exhibited higher Cmax, which is reasonable.
To further understand the different dissolution performance of the three cocrystal
formulations, wettability of the pure APIs was assessed using contact angle measurement.
Contact angle of GSF could not be determined using this method because it did not form
intact tablets. However, it is expected to be high given its significantly lower aqueous
solubility. Contact angle of pure cocrystal samples follow the order of GSF-Acs/SA> GSF-
Acs > GSF-Acs/HPC (Figure 4.10b). Thus, GSF-Acs/HPC exhibited better wettability than
GSF-Acs/SA and GSF-Acs. The better wettability of GSF-Acs/HPC is consistent with the
better dissolution of the GSF-Acs/HPC tablet, despite its much larger size of GSF-
Acs/HPC than GSF-Acs. This suggests that wetting is a key step in the dissolution of GSF-
Acs from tablet. The effect of surface area of API on dissolution is shown by the
significantly faster dissolution from tablet containing GSF-Acs than that containing GSF-
Acs/SA (Figure 4.10a), although wettability of pure API powders was only slightly
different (Figure 4.10b). Thus, the overall effect of both faster wetting and larger API size
of GSF-Acs/HPC led to dissolution performance of its tablet comparable to that of GSF-
Acs tablet (larger surface area and intermediate wetting), both were significantly better
than GSF (poor wetting and large area) and GSF-Acs/SA (small surface area and
intermediate wetting) formulations.
104
The overall performance of each formulation considering manufacturability and
dissolution is summarized in Table 4.4. Only the GSF-Acs/HPC formulation exhibited
acceptable manufacturability and significantly improved dissolution performance. Both the
GSF and GSF-Acs formulation suffered poor flowability due to the small size and poor
flowability of API. Thus, they are unfit for commercial tablet manufacturing. The GSF-
Acs/SA formulation exhibited good manufacturability but only marginal improvement in
dissolution. Therefore, only the use of GSF-Acs/HPC successfully enabled a high dose DC
tablet formulation of GSF, which was both manufacturable and fast releasing.
4.5 Conclusions
In this work, an integrated crystal and particle engineering approach, spherical
cocrystallization (SCC), was used to prepare GSF-Acs spherical agglomerates exhibiting
both improved manufacturability and dissolution performance. Such spherical cocrystal
agglomerates enabled the development of a high GSF loading (55.7%) direct compression
tablet formulation suitable for manufacturing of GSF tablets with enhanced dissolution
performance. The simultaneous improvement of tablet manufacturability and dissolution
by SCC is a powerful approach that may have broad applicability to enable the successful
development of high dose tablets of other poorly soluble drugs.
105
Table 4.1. Formulation Composition of GSF-containing tablet using different powder
forms
Components (%) Function GSF GSF-Acs GSF-Acs/SA GSF-Acs/HPC
GSF or GSF-Acs Active 55.7 70 70 70
Silica coated MCC
PH105 Dry binder 38.8 24.5 24.5 24.5
CCS-Na Disintegrate 5 5 5 5
Magnesium stearate Lubricant 0.5 0.5 0.5 0.5
Total 100 100 100 100
106
Figure 4.1. SEM images of a) GSF, b) GSF-Acs, c) GSF-Acs/SA and d) GSF-Acs/HPC.
a) b)
c)
107
Figure 4.2. Microscopy images of (a) GSF-Acs/HPC and (b) GSF-Acs/SA.
(a) (b)
108
Figure 4.3. Particle size distribution of GSF-Acs/SA and GSF-Acs/HPC powders.
109
Figure 4.4. PXRD patterns of Acs-H, GSF, GSF-Acs/HPC, GSF-Acs/SA, GSF-Acs, and
calculated GSF-Acs.
110
Figure 4.5. Thermal behavior of GSF-Acs, GSF-Acs/SA, and GSF-Acs/HPC
characterized by differential scanning calorimetry.
111
Figure 4.6. Tabletability profiles of pure GSF, GSF-Acs, GSF-Acs/SA, and GSF-Acs/HPC.
112
Figure 4.7. Energy frameworks of a) GSF, and b) GSF-Acs, both viewed into a axis of
corresponding unit cell. The interaction energy threshold was set at −5 kJ/mol.
a) b)
113
Table 4.2. Intermolecular interaction energies estimated using B3LYP+D2/6+31G(d,p)
dispersion corrected DFT model. Both the total energy (E(tot)) and electrostatic (E(ele)),
polarization (E(pol)), dispersion (E(dis)), and exchange repulsion (E(rep)) components of the
energy are listed. R indicated the distance between centers of mass of the pair of molecules.
Sym. Op. R Eele Epol Edis Erep Etot
GSF (form I)
x, y, z 8.90 -3.1 -1.6 -19.8 8.2 -16.7
-y, x, z+1/4 6.75 -9.2 -2.3 -32.1 23.6 -24.8
x, y, z 8.90 -2.2 -2.3 -11.0 11.6 -6.5
-y, x, z+1/4 7.00 -30.3 -12.0 -59.1 47.8 -62.9
y, -x, z+3/4 9.59 1.8 -2.7 -20.3 11.8 -10.6
-y, x, z+1/4 9.77 -11.6 -7.0 -23.7 18.0 -27.0
-x, -y, z+1/2 10.47 -11.2 -4.4 -19.3 13.6 -23.5
GSF-Acs cocrystal
- 7.76 -38.7 -9.6 -5.6 47.1 -23.8
- 6.00 2.2 -1.1 -4.1 2.1 -0.7
- 6.71 0.1 -0.2 -0.8 0.0 -0.7
- 7.50 -41.0 -9.8 -6.9 46.2 -28.1
- 7.36 2.4 -0.7 -3.0 1.3 0.3
- 7.35 4.2 -0.5 -2.1 0.2 2.4
- 4.37 -10.6 -2.2 -4.9 4.1 -14.6
- 4.45 -96.9 -24.3 -7.6 107.9 -60.5
- 7.97 -8.3 -3.4 -9.3 2.8 -17.6
- 6.07 -17.8 -4.0 -39.2 26.1 -39.8
- 10.37 0.2 -0.4 -1.5 0.0 -1.5
x, y, z 8.71 4.4 -0.7 -2.3 0.4 2.4
- 4.45 -96.9 -24.3 -7.6 107.9 -60.5
- 7.66 -9.3 -5.4 -18.1 15.1 -20.2
- 7.25 -2.1 -1.6 -4.7 1.1 -6.7
- 7.61 -19.6 -4.8 -20.7 19.4 -30.3
114
- 5.55 -25.7 -8.7 -58.2 47.3 -55.0
- 4.37 -10.6 -2.2 -4.9 4.1 -14.6
x, y, z 13.62 -8.5 -2.9 -4.6 5.6 -11.7
x, y, z 8.71 -1.1 -3.7 -14.6 13.6 -8.2
- 8.29 2.9 -1.6 -17.5 7.5 -8.7
- 7.72 -20.1 -5.9 -34.7 26.9 -39.2
- 8.14 -16.2 -3.9 -26.5 13.2 -35.0
x, y, z 11.53 -12.2 -4.6 -10.9 11.3 -18.8
-x, y+1/2, -z 11.13 -0.1 -0.5 -5.4 2.0 -4.0
- 8.85 -16.1 -4.0 -29.3 16.8 -35.1
- 7.84 -20.6 -5.3 -54.7 43.7 -46.3
- 7.25 -2.1 -1.6 -4.7 1.1 -6.7
- 7.66 -9.3 -5.4 -18.1 15.1 -20.2
- 7.50 -41.0 -9.8 -6.9 46.2 -28.1
- 6.84 -1.2 -1.1 -25.7 13.8 -16.0
- 5.55 -25.7 -8.7 -58.2 47.3 -55.0
- 10.37 0.2 -0.4 -1.5 0.0 -1.5
- 7.36 2.4 -0.7 -3.0 1.3 0.3
- 7.35 4.2 -0.5 -2.1 0.2 2.4
x, y, z 8.71 0.6 -3.8 -14.5 15.2 -5.3
x, y, z 11.53 -16.4 -6.6 -18.4 17.9 -27.2
-x, y+1/2, -z 11.52 -0.1 -0.4 -3.8 0.5 -3.3
- 7.61 -19.6 -4.8 -20.7 19.4 -30.3
- 6.07 -17.8 -4.0 -39.2 26.1 -39.8
- 6.00 2.2 -1.1 -4.1 2.1 -0.7
- 7.97 -8.3 -3.4 -9.3 2.8 -17.6
- 7.76 -38.7 -9.6 -5.6 47.1 -23.8
- 6.71 0.1 -0.2 -0.8 0.0 -0.7
115
Figure 4.8. Manufacturability of formulated GSF, GSF-Acs, GSF-Acs/SA, and GSF-
Acs/HPC, (a) tabletability and (b) friability.
a) b)
116
Figure 4.9. Flowability plots of formulated GSF, GSF-Acs, GSF-Acs/SA and GSF-
Acs/HPC.
117
Figure 4.10. (a) ASD duodenum concentration profiles for formulated GSF, GSF-Acs,
GSF-Acs/SA and GSF-Acs/HPC tablets prepared at 250 MPa, (b) wettability of GSF-
Acs/HPC, GSF-Acs/SA and GSF-Acs.
b) a)
118
Table 4.3. Simulated pharmacokinetic parameters of various GSF-containing tablets (n =3)
GSF GSF-Acs GSF-Acs/SA GSF-Acs/HPC
Tmax (min) 20 ± 0.0 20 ± 0.0 25 ± 7.1 23 ± 4.2
Cmax (μg/ml) 15.3 ± 0.2 47.9 ± 1.6 21.1 ± 0.8 51.5 ± 3.4
AUC0-t
(μg/ml min) 1394 ± 55 3255 ± 152 1910 ±264 3697 ± 297
119
Table 4.4. Summary of various GSF tablet formulations in meeting key criteria (meeting–
Y, not meeting – N)
Formulation Tabletability
(≥ 2 MPa)
Friability
(≤ 0.8%)
Flowability
(better than
Avicel PH102)
Dissolution Overall
GSF Y Y N N N
GSF-Acs Y Y N Y N
GSF-Acs/SA Y Y Y N N
GSF-Acs/HPC Y Y Y Y Y
120
4.6 References
1. Sun, W.-J.; Aburub, A.; Sun, C. C. Particle engineering for enabling a formulation
platform suitable for manufacturing low-dose tablets by direct compression. J. Pharm. Sci.
2017, 106, 1772-1777.
2. Cai, L.; Farber, L.; Zhang, D.; Li, F.; Farabaugh, J. A new methodology for high
drug loading wet granulation formulation development. Int. J. Pharm. 2013, 441, 790-800.
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Chapter 5
A Novel Quasi-Emulsion Solvent Diffusion-based Spherical
Cocrystallization Strategy for Simultaneously Improving the
Manufacturability and Dissolution of Indomethacin
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5.1 Synopsis
Successful development of tablet formulations of many active pharmaceutical
ingredients (APIs) is challenged by their poor manufacturability (e.g., flowability,
tabletability) and dissolution characteristics. Here, we report a novel quasi-emulsion
solvent diffusion cocrystallization (QESD-CC) method as an integrated crystal and particle
engineering approach for successful generation of spherical cocrystal agglomerates of the
poorly soluble drug indomethacin (IMC) and the sweet co-crystallization agent saccharin
(SAC). The QESD-CC process consists of two distinct steps: 1) formation of a transient
emulsion containing solvated IMC and SAC, and 2) subsequent precipitation of IMC-SAC
cocrystals from the emulsion as hollow spherical particles. Solution 1H NMR analyses and
computational modeling studies indicated that hydroxypropyl methylcellulose (HPMC)
preferentially interacts with the SAC molecules through hydrogen bonds, thus driving the
polymer to form a shell that stabilizes the transient emulsion droplets and coats the
resulting particles. Spherical QESD-CC particles exhibited excellent flowability, while the
HPMC coating and micro-size primary crystals led to excellent tabletability. Outstanding
manufacturability and high cocrystal solubility thus enabled the successful development of
a high drug loading tablet formulation comprising 46.3 wt% IMC.
5.2 Introduction
Tablet manufacturing by direct compression (DC) processes is attractive to the
pharmaceutical industry because of its cost effectiveness. DC tableting is particularly
suitable for continuous manufacturing due to its procedural simplicity.1 For typical active
pharmaceutical ingredients (APIs) with doses ≥ 100 mg, high API-loaded tablet
formulations are preferred to reduce tablet size, making them easier to swallow and thus
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enhancing patient compliance. However, a DC tablet formulation typically does not contain
more than 30 wt% API due to its common and undesirable physical properties, including
poor powder flowability, poor tabletability, and poor water solubility, which requires the
use of large amounts of solubilizing excipients to enable adequate therapeutic absorption.2-
4 APIs exhibiting both poor powder properties and low solubility present a major challenge
for developing a DC tablet formulation.
Spherical crystallization is an established technique for improving micromeritic
properties (e.g., particle size, shape, bulk density) of drugs by agglomerating the small
primary crystals into large and spherical agglomerates, mainly by spherical agglomeration
(SA)5-7 and quasi-emulsion solvent diffusion (QESD) techniques.8, 9 In fact, spherical
crystallization of water-soluble ferulic acid enabled the development of a DC tablet
formulation containing a record high 99% API.3 However, spherical crystallization often
detrimentally impacts the rate of drug release of poorly soluble APIs because this process
reduces the exposed surface area available for dissolution.10
The problem of slow dissolution of poorly soluble APIs may be addressed by the
use of solubilizing excipient(s) in tablet formulations. However, this approach invariably
leads to large tablets due to the significant amounts of solubilizing excipient required.
Another effective approach is to use a soluble solid form of the poorly soluble API, such
as an amorphous solid dispersion (ASD),11 a salt,12 or a cocrystal.13 Among these options,
ASD requires the use of a large amount of excipient as a matrix to maintain adequate
physical stability against crystallization14 as well as a high dissolution rate of the API.15, 16
Salt formation is applicable only to ionizable APIs and is limited by the availability of
pharmaceutically acceptable counterions.17 In comparison to ASD and salt formation,
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cocrystals exhibit unique advantages for enhancing dissolution of poorly soluble APIs
because they are physically stable in solid state, applicable to non-ionizable molecules, and
the number of pharmaceutically acceptable co-formers is substantial.17, 18 However, the use
of these more soluble solid form aggravates the manufacturability problem for developing
a high dose DC tablet formulation because the weight percentage of any of these solid
forms is invariably higher than that of the parent API. To ensure acceptable
manufacturability, micromeritic properties of the new API solid form cannot be poor in
order to maintain a high API loading in the tablet.
Spherical cocrystallization has the potential to simultaneously improve both tablet
manufacturability and dissolution performance.19, 20 Although earlier work successfully
demonstrated, that spherical cocrystallization of griseofulvin (GSF) with the co-former
Acesulfame (Acs) profoundly improves flowability and dissolution characteristics, the
tableting performance of spherical GSF-Acs cocrystal agglomerates remained poor, which
limited GSF loadings in each tablet.19 The reason for the poor tabletability of GSF-Acs
was the large average size of the primary crystals in the spherical agglomerates, which led
to small interparticle bonding areas and consequently weak tablets.21 The large size of
primary cocrystals was attributed to the use of a slurry cocrystallization process, which
allowed large cocrystals to grow. Hence, an improved SCC process that can produce
spherical cocrystal agglomerates consisting of fine primary crystals has the potential to
enable the development of high dose DC tablets through simultaneously improve the
flowability, tabletability, and dissolution of APIs. To attain this goal, we developed a novel
integrated crystal and particle engineering approach called quasi-emulsion solvent
diffusion cocrystallization (QESD-CC). In contrast to slurry cocrystallization, we
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hypothesized that QESD-CC would yield large and spherical particles consisting of much
smaller primary cocrystals due to the high degree of emulsion supersaturation during
QESD, 22 leading to better tabletability and flowability while retaining a high dissolution
rate. A successful QESD-CC process requires the following two conditions: 1) formation
of sufficiently stable transient emulsions of co-formers; 2) raction between API and co-
former reaction to form a cocrystal upon solvent counter-diffusion. In this work, we chose
indomethacin (IMC)-saccharin (SAC) cocrystal to test the feasibility of QESD-CC because
IMC-SAC cocrystal could be prepared by anti-solvent (AS) precipitation.23 We also used
HPMC as the emulsion stabilizer because of its successful use in other QESD processes.
Since the IMC-SAC cocrystal exhibits much higher solubility than neat IMC (13 times
greater in water and 13-65 times higher at pH 1-3),24 it can likely improve the dissolution
of IMC.
5.3 Materials and methods
5.3.1 Materials
Indomethacin (γ-IMC, Tokyo Chemical Industry, Tokyo, JP) and saccharin (SAC,
Carbosynth Limited, Berkshire, UK), were chosen as the model API and co-former,
respectively. Microcrystalline cellulose (Avicel PH102, FMC, Philadelphia, PA), HPMC
(K100M, MW 1,000 kg/mol, Ashland Specialty Ingredients, Wilmington, DE),
croscarmellose sodium (CCM-Na, SD-711, FMC Biopolymer, Philadelphia, PA),
magnesium stearate (MgSt, Mallinckrodt Inc., St. Louis, MO), dimethylformamide (Fisher
Scientific, Hampton, NH), methanol (Fisher Scientific, Hampton, NH) and ultrapure
deionized water (0.066 μS/cm, Thermo Scientific, USA) were used as received. The
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chemical structures of IMC, SAC, and HPMC are shown in Figure 5.2. All crystallization
experiments were performed in glass beakers.
5.3.2 Preparation of IMC-SAC cocrystal powders
5.3.2.1 Fine IMC-SAC cocrystal by anti-solvent (AS) method
Based on a literature study,24 an excess amount of SAC was required to account for
the large solubility difference between IMC and SAC to ensure phase purity of the
produced cocrystal powder. Therefore, 5 mmol of IMC and 15 mmol of SAC were co-
dissolved in 140 mL of methanol. The methanol solution was then poured into 140 mL of
water and mixed with a magnetic stirring bar under ambient conditions for 30 min to
produce fine IMC-SAC cocrystals (AS). The resulting suspension was filtered and dried at
60 °C overnight. The yield of this process was ~ 70%. A small amount of this powder was
dispersed onto a glass slide for analysis under a polarized light microscope (Eclipse E200;
Nikon, Tokyo, Japan).
5.3.2.2 IMC-SAC spherical cocrystal agglomerates by QESD-CC method
A solution of 4 mmol of IMC and 5 mmol of SAC in 6 mL of DMF was poured (in ≤10
s) in into 40 mL of distilled water or 0.01%, 0.1%, or 0.5% (w/v) HPMC aqueous solution.
A HPMC solution at ≥1% concentration was not attempted because they were too viscous
for effective mixing. Our preliminary work also suggested that DMF to water ratios
significantly deviating from 6:40 tended to cause phase impurity and amount adjustment
130
of SAC was also required to attain phase purity of the cocrystal powders. The suspension
was agitated at 300 rpm using an overhead stirrer for 3 h at room temperature (23.5 oC) to
ensure complete transformation into IMC-SAC. Agitation speed at 300 rpm was used
because it generated spherical agglomerates with a suitable particle size distribution (200-
500 μm). The produced solid particles were filtered and dried, without solvent wash, at
60 °C overnight to yield a powder, hereafter referred as QESD-CC. A small amount of this
powder was dispersed on a glass slide for imaging by polarized light microscopy.
5.3.3 Particle size distribution (PSD)
The particle size of as-received IMC, AS, and QESD-CC powders was determined
using a particle size analyzer (Microtrac SIA, Montgomeryville, PA). Approximately 25
mg of each powder was suspended in Isopar G Fluid (∼5 mL). The as-received IMC and
AS samples were sonicated for 30 s to fully disperse particles. Both IMC-SAC and polymer
HPMC exhibited negligible solubility in this medium. The suspension was added into a
sample delivery controller (SDC, Montgomeryville, PA) and circulated through the closed
system. A high-speed camera captured images of particles in focus. Using the Microtrac
Flex image analysis software provided with the instrument, the diameter of a circle with an
area equivalent to the projected area of individual particles was determined. The volume
of the particle was calculated assuming a spherical shape to determine the volume
distribution of a powder.
5.3.4 Specific surface area (SSA) measurement
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Nitrogen adsorption-desorption isotherms for each sample were obtained using a
surface area analyzer (Micromeritics ASAP 2020, Norcross, GA) at 77 K. Before each
measurement, 0.5–1.0 g of accurately weighed sample was placed into a glass tube and
degassed under a vacuum of 15 µm Hg at 27 °C for at least 24 hrs. The amount of the
adsorbed nitrogen at different partial pressures of nitrogen in helium carrier gas was
measured at a temperature of 77.35 K. The data is shown in Table 5.1. The Brunauer–
Emmett–Teller (BET) equation25 was used to fit the data and calculate the sample surface
area. All measurements were made in triplicate.
5.3.5 HPMC content determination via size-exclusion chromatography (SEC)
HPMC concentrations were determined by size exclusion chromatography (SEC)
with refractive index detection.26 SEC measurements were carried out on an Agilent 1260
liquid chromatograph equipped with one guard column and three separating CATSEC
columns with pore sizes of 1000, 300 and 100 Å, operating in 0.1 M Na2SO4(aq) containing
1 wt% acetic acid at an eluent flow rate of 0.4 mL/min at 22 °C. Analyte detection relied
on a Wyatt Optilab T-rEX refractive index (RI) detector and a Wyatt Dawn Heleos II multi-
angle static light scattering detector. The peak area from RI detector signal that corresponds
to HPMC elution was used to determine the HPMC concentration in the ASTRA software.
We determined the refractive index increment (dn/dc) of HPMC as 0.1165 mL/g using a
pure HPMC (K100M) solution with 0.81 mg/mL concentration, assuming 100% mass
recovery. We checked the validity of our analysis by measuring the concentrations of
HPMC solutions from 0.45–1.04 mg/mL and the obtained values agreed within 99.9%
(Figure 5.1). On this basis, we then quantified the amount of HMPC in the QESD-CC
132
powders by dissolving ~0.65 g QESD-CC sample in 5 mL of HPLC grade tetrahydrofuran
(THF) to precipitate the THF-insoluble HPMC. The precipitate was isolated by
centrifugation (11 644 g, 10 min), after which the supernatant THF solution containing
IMC and SAC was carefully decanted. The isolated HPMC was re-dispersed in 5 mL THF
to wash away residual IMC and SAC by sonication for 10 min, and it was again isolated
by centrifugation. The polymer was then dried under vacuum to remove residual THF. The
isolated HPMC from the QESD-CC samples was dissolved in 5 mL SEC eluent and the
concentration determined from the aforementioned calibration curve. The reported HPMC
content in QESD-CC was determined as the average of three independent measurements.
5.3.6 Powder X-ray Diffractometry (PXRD)
The crystallographic properties of samples were characterized by powder X-ray
diffractometer with Cu Kα radiation (1.54059 Å). Samples were scanned over the range 5
≤ 2θ ≤ 35° with a step size of 0.02° and a dwell time of 1 s/step. The divergence and anti-
scattering slits on the incident beam path were 1/16 and 1/8 degree, respectively, and the
antiscattering slit on the diffracted beam path was 5.5 mm (X’Celerator). The X-ray tube
voltage and amperage were 45 kV and 40 mA, respectively. A theoretical PXRD pattern
of IMC-SAC was calculated from the single crystal structure (CCDC refcode: UFERED).27
5.3.7 Thermal Analyses
Powder samples (~ 5 mg) were loaded into hermetic aluminum pans and heated
from 30 to 190 °C at a heating rate of 10 °C/min on a differential scanning calorimeter
133
(Q1000, TA Instruments, New Castle, DE) under a continuous helium purge at a flow rate
of 25 mL/min. DSC heat flow was calibrated with the enthalpy of melting of indium, and
the temperature was calibrated with the melting transitions of indium and cyclohexane. To
determine the volatile content, each sample (~ 5 mg) was placed in an open aluminum pan
and analyzed on a thermogravimetry analyzer (Q500, TA Instruments, New Castle, DE).
All samples were heated from room temperature to 300 °C at 10 °C/min under 25 mL/ min
nitrogen purge.
5.3.8 Scanning electron microscopy (SEM)
Samples were mounted onto stubs with carbon tape. A thin layer platinum
(thickness ~ 75 Å) was coated onto the samples using an ion-beam sputter (IBS/TM200S;
VCR Group Inc., San Clemente, CA). The particle morphology and surface features were
evaluated by scanning electron microscopy (JEOL 6500F; JEOL Ltd., Tokyo, Japan),
operated in SEI mode with an accelerating voltage of 5 kV under high vacuum (10-4-10-5
Pa).
5.3.9 Computational methods
5.3.9.1 Energy framework and topological analyses of crystal structures
Pairwise intermolecular interaction energies were estimated using CrystalExplorer
and Gaussian09 from the experimental geometries of the IMC-SAC cocrystal and IMC (γ
form, CSD refcode: INDMET).28, 29 The hydrogen positions were normalized to standard
neutron diffraction values prior to calculation using the CE-B3LYP electron densities
134
model. The data is shown in Table 5.2. The total intermolecular interaction energy for a
given molecule is the sum of the electrostatic, polarization, dispersion, and exchange-
repulsion components with scale factors of 1.057, 0.740, 0.871, and 0.618, respectively.30
Intermolecular interaction between two molecules is ignored when the closest interatomic
distance was > 3.8 Å. Interaction energies were visualized as a framework by connecting
centers of mass of molecules with cylinder thicknesses proportional to the total
intermolecular interaction energies, where interaction energies weaker than -10 kJ/mol
were omitted for clarity. The crystal packing topology was analyzed using a Python
program.31
5.3.9.2 Drug–Polymer Intermolecular Interaction
To characterize the molecular interactions between IMC-SAC and HPMC,
optimization of their complexation was performed in Gaussian16 using DFT hybrid
functional M06 level of theory and 6-31(d, p) basis sets.32, 33 To reduce the computational
cost, three different monomer units bearing different substituents (R = H, CH3, or
CH2CH(OH)CH3 in Figure 5.2) of HPMC were used. The IMC-SAC complex was from
the reported structure (UFERED). Structure optimization was carried out without any
constraints and local minima energies were confirmed through vibrational frequency
calculations. The final optimized complexes were used to identify the possible
intermolecular hydrogen bond formation.
5.3.10 Preparation of formulated powders
135
Different powder forms of IMC and all other excipients (Table 5.3), totaling
approximately 5 g, were added to a 30 mL plastic bottle, which was manually rotated about
the long axis at an angle of 45o to the horizon for 15 min (approximately 900 turns). A
tablet formulation containing 46.3 wt% IMC in the same matrix was also prepared as a
control. Avicel PH102 was used as the dry binder in all three formulations due to its high
plasticity, acceptable flowability, and excellent tabletability.34, 35 CCM-Na and MgSt
functioned as a tablet super-disintegrant and a lubricant, respectively.
5.3.11 Powder Flowability
Powder flowability was measured in triplicate using a ring shear tester (RST-XS;
Dietmar Schulze, Wolfenbüttel, Germany), with a 10 mL cell at a 1 kPa pre-shear normal
stress. A yield locus was obtained by plotting maximum shear stress as a function of normal
stress (0.25, 0.40, 0.55, 0.70, and 0.85 kPa), from which unconfined yield strength (fc) and
major principal stress (σn) were obtained by drawing Mohr’s circles. The flowability index
was calculated as ffc = 𝜎𝑛
𝑓c .36, 37
5.3.12 Powder Compaction
A universal material test machine (Model 1485, Zwick/Roell, Germany) was used
to prepare tablets at compaction pressures ranging from 25–350 MPa at a tableting speed
of 4 mm/min. The punch tip and die wall were lubricated using a 5% (w/v) suspension of
MgSt in ethanol, which was air-dried with a fan for ∼1 min to complete dryness. Tablets
were relaxed under ambient environment for at least 24 h before being diametrically broken
using a texture analyzer (TA-XT2i; Texture Technologies Corporation, Scarsdale, NY).
136
Tablet tensile strength was calculated from the breaking force and tablet dimensions
following the standard procedure.38
5.3.13 Expedited Friability
Tablet friability was determined by an expedited method to quantify the ability of
compressed tablets to resist wearing and abrasion.39 Coded tablets prepared under different
pressures were weighed, individually coded, and loaded into a friabilator (Model F2,
Pharma Alliance Group Inc., Santa Clarita, CA), which rotated at 25 rpm for 4 min. The
initial and final weight of each tablet was used to calculate percent weight loss, which was
plotted against compaction pressure. The compaction pressure corresponding to 0.8%
tablet weight loss was identified from the friability plot.
5.3.14 Dissolution performance
Tablet dissolution performance was determined in 250 mL pH 2.0 HCl(aq) at 37 ±
0.5 °C, which was paddle stirred at 50 rpm. Tablets were prepared at 200 MPa, each
containing ~50 mg of IMC. Aliquots of the medium (3 mL) were taken at predetermined
time points of 1, 3, 5, 10, 20, 30, 40, 50 and 60 min and passed through a filter membrane
with a pore size of 0.45 μm. The IMC concentration was determined using a UV/Vis
spectrophotometer (DU 500, Beckman Instruments, Fullerton, CA) at = 327 nm to avoid
the interference from SAC using a calibration curve with appropriate background
correction.
137
5.3.15 Solution 1H Nuclear Magnetic Resonance (NMR) Spectroscopy
1H NMR spectra were acquired on a Bruker Advance III HD 400 MHz spectrometer
in DMSO-d6 and referenced to the residual solvent resonance at δ 2.50 ppm. The pulse
repetition delay was set at 10 s in the acquisition spectra for HPMC-containing samples.
Anhydrous DMSO-d6 solvent was distilled from activated molecular sieves and stored in
an argon filled glovebox with [H2O] < 1 ppm. All NMR samples were prepared and sealed
in the glovebox to avoid water uptake during the characterization.
Statistical Analysis
To assess statistical significance, the two-way analysis of variance (ANOVA) was
performed. Difference between two data sets was deemed significant when p < 0.05.
5.4 Results and discussion
5.4.1 Micromeritic properties
For the IMC-SAC system, phase purity of the cocrystal was affected by both the
solvent ratio and relative amount of IMC and SAC. Hence, preliminary work was required
to identify suitable process parameters, i.e., 4 mmol of IMC and 5 mmol of SAC in 6 mL
of DMF poured into 40 mL of distilled water, to ensure phase purity. The use of HPMC
during spherical crystallization significantly affected particle morphology, whereby a
higher HPMC concentration led to larger size aggregates with more spherical shapes
(Figure 5.3), but excessively high HPMC concentrations led to process difficulties due to
138
high viscosity. Therefore 0.5% (w/v) HPMC in the crystallization medium was used in the
following studies. The resulting QESD-CC particles were highly spherical with a narrower
particle size distribution than both as-received IMC and IMC-SAC prepared by the AS
process (Figure 5.4). In contrast, irregular IMC-SAC crystals were obtained when no
HPMC was present in the crystallization medium (Figure 5.5). The effect of added HPMC
is ascribed to its ability to stabilize the emulsions formed on mixing the drug solution with
water. In the absence of HPMC, the emulsions were unstable and easily broke down under
agitation, resulting in the production of fine individual crystals. Similar observations have
been reported with celecoxib,40 ketoprofen,41 and bucillamine42.
The SEM images revealed that primary IMC-SAC crystals prepared by the AS
process consisted of both small and large micro-size crystals (Figures 5.9a, b). This is
consistent with the broad PSD observed by laser scattering (Figure 5.4). Although large
spherical agglomerates were present in the QESD-CC powder (Figure 5.4c), primary
crystals in AS powder were much larger than those obtained by QESD-CC (Figure 5.9d).
The broad PSD of AS powder was attributed to the preparation method, wherein a methanol
co-solution of IMC and SAC was poured (in ≤ 10 s) into an equal volume of water. In this
process, the water to methanol volume ratio is initially high, leading to a high degree of
supersaturation of the IMC-SAC and instant precipitation of small micro-size crystals
precipitate quickly. With continuous addition of methanol, the degree of supersaturation is
lower than that at the beginning of the process because the more methanol-rich solvent can
dissolve more IMC and SAC. Therefore Consequently, precipitation occurs more slowly,
and the resulting crystals grow to larger sizes. However, during the QESD-CC process, the
primary crystals were small (~ 1 µm) because the fast counter-diffusion between DMF and
139
water (v/v = 6: 40) led to a high degree of supersaturation of IMC-SAC inside the emulsion
droplets. Hence, fast nucleation limits the growth of individual primary crystals. The
smaller size of primary IMC-SAC crystals in the QESD-CC powder corresponds well with
the specific surface area (1.06 ±0.02 m2/g) that was approximately 2 times of that of IMC-
SAC via anti-solvent (0.59 ±0.09 m2/g). The spherical IMC-SAC particles obtained by
QESD-CC appeared hollow with openings visible at the surface (Figure 5.9c, e). This
hollow structure was confirmed by cutting a spherical cocrystal agglomerate to reveal the
interior (Figure 5.9f).
5.4.2 Phase purity
The PXRD patterns of both AS and QESD-CC powders matched well with that
calculated for IMC-SAC (Figure 5.6). This, along with the absence of characteristic peaks
of individual crystals of IMC and SAC (Figure 5.6), indicates the formation of phase pure
IMC-SAC cocrystals. The DSC thermograms of AS and QESD-CC powders (Figure 5.7)
also corresponded well with the reported profiles of IMC-SAC.27 The TGA profiles showed
negligible weight loss on increasing the temperature to 153 °C (the boiling point of DMF),
indicating the absence of any residual solvent in IMC-SAC prepared by both methods
(Figure 5.8). The amount of HPMC in QESD-CC powder prepared from a 0.5% HPMC
solution was 0.67 0.01% (n = 3).
5.4.3 Flowability and tabletability of various IMC forms
Both adequate flowability and tabletability of APIs are required for successfully
manufacturing a high drug loading tablet by the DC process. The flow property of a powder
140
is determined by gravity and adhesion, where gravity favors powder flow while adhesion
hinders it.43, 44 In general, larger and more spherical particles with smoother surfaces
exhibit better flowability.45 Given the larger size and more spherical shape of the QESD-
CC particles as compared to those of AS and as-received IMC powders (Figure 5.4), the
flowability of QESD-CC powder was significantly better than other forms of IMC in this
study, as shown by the significantly higher ffc (p < 0.05) (Figure 5.10a). Importantly, the
flowability of the QESD-CC powder was significantly better than the Avicel PH102, which
marks the minimum acceptable powder flowability for high speed tableting.34 Hence, the
flowability of the QESD-CC powder does not require further improvement by
incorporating an excipient to sustain tablet manufacturing.
Both as-received IMC and AS powders showed poor tableting behavior (Figure
5.10b), which indicates inadequate plastic deformation that is required to develop
sufficiently large bonding areas between particles in the tablet.46 Therefore, crystal
plasticity was assessed using a combined energy framework and topological analysis to
gain structural insights.47 In the γ-IMC crystal, the visually identified slip layers parallel to
the (011) plane are energetically unfavored to slip due to strong interlayer interactions. On
the other hand, the energetically more favorable molecular planes parallel to the (001)
plane, recognized by an energy framework analysis, can undergo only very restricted slip
because of the rough layer surface topology (Figure 5.11a).29 In the IMC-SAC cocrystals,
SAC-SAC and IMC-IMC dimers are held together through N-H…O (2.859 Å) and O-H…O
(2.659 Å) hydrogen bonds, respectively. Those dimers assemble in 2D layers extending
along the (001) plane through O-H…O=C (3.005 Å) and O-H…O=S (2.964 Å) hydrogen
bonds. Only weak interactions between the neighboring layers, mediated by the edge to
141
face π-π interactions (3.490 Å) and C-H…Cl (3.539 Å) hydrogen bonds were observed.
This is consistent with the energy framework, which suggests (001) as the most likely
primary slip plane in IMC-ACS (Figure 5.11b). However, such molecular layers are
interlocked, due to the rough topology of the layer surface, as shown by the negative
interlayer distance (-0.2 Å). The structural analyses above suggest that the poor plasticity
of both IMC and IMC-SAC can be attributed to the absence of active slip systems.
However, the QESD-CC powder exhibited profoundly improved tableting
performance relative to IMC-SAC (p < 0.05), even though they are the same crystal
polymorph. The highest tensile strength of ~ 3.6 MPa was approximately 6 times that of
AS (~ 0.6 MPa) (Figure 5.10b). At 150 MPa compaction pressure, the tablet tensile strength
was already higher than 2 MPa, suggesting adequate tablet mechanical strength for
handling and processing under a relatively mild compaction pressure.48 At least two factors
can contribute to the improved tabletability: 1) coating of the crystals by HPMC and 2)
much smaller primary crystal size. Surface coating is an effective particle engineering
strategy to improve tabletability by increasing bonding area. Therefore, with as little as
0.67% HPMC, tabletability significantly improves.19, 49, 50 Smaller primary crystal size
corresponds to larger surface area available for bonding and hence favors stronger tablets.51
We excluded the fracture of large QESD-CC particles as a major factor, because the
tabletability of the QESD-CC powder after milling for 5 min remained nearly identical
below 250 MPa (Figure 5.10b).
5.4.4 Formulation development
142
The excellent flow and tableting properties of QESD-CC are expected to enable the
formulation development of DC tablet with a high IMC loading. The blend of components
in a successful DC tablet formulation must be sufficiently free flowing to make tablets with
consistent weight and uniform drug content during high-speed tablet manufacturing. In this
regard, the QESD-CC formulation meets the minimum flowability criterion, since it
exhibits better flowability than Avicel PH102, while IMC and AS formulations do not
(Figure 5.12a). This result highlights the important role of the API on the flowability of
high drug loading formulations.
The tableting performance of formulations followed the same order as that of API
powders, i.e., QESD-CC > as received IMC > AS. When the compaction pressure was
higher than 200 MPa, the tablet tensile strength for all formulations exceeded 2 MPa
(Figure 5.12b), despite both as-received IMC and AS powders exhibiting poor tabletability
with maximum tensile strengths of approximately 0.6 and 0.5 MPa, respectively (Figure
5.10b). The improved tabletability indicates that the presence of plastic Avicel PH102
(24.5 wt% in cocrystal formulations and 48.2 wt% in IMC formulation) could overcome
the poor tabletability of API in both formulations. This is attributed to the excellent
tabletability of Avicel PH102.52 Considering the otherwise identical composition between
QESD-CC and AS formulations (Table 1), the better tabletability of QESD-CC formulation
than AS formulation suggests that the tableting performance of API also influences
tabletability of high dose DC tablet formulations (Figure 5.10b).
Friability characterizes the propensity of a tablet to lose mass when exposed to
external impact during downstream processing, shipping, and handling.53 The friability of
IMC and QESD-CC formulations met the friability requirement that tablets compressed at
143
compaction pressures higher than 150 MPa and 100 MPa, respectively, exhibited weight
loss of ≤ 0.8%. The tablet friability of AS formulation remained higher than 0.8% in the
entire range of compaction pressure (Figure 5.12c). Therefore, it is unlikely to be a
successful DC tablet formulation.
5.4.5 Dissolution
The final remaining consideration for assessing the suitability of the DC process is
dissolution. Tablets containing 50 mg of as-received IMC or an equivalent amount of
QESD-CC (75.6 mg) were prepared at a compaction pressure of 200 MPa, and their
dissolution performance was determined in simulated gastric fluid (250 mL of pH 2.0 HCl
aqueous solution). The 200 MPa compaction pressure was used because tablets from both
formulations exhibited sufficient mechanical strength, as shown by > 2 MPa tensile
strength (Figure 5.12b) and < 0.8% friability (Figure 5.12c). As expected, the formulated
QESD-CC showed much improved drug release compared to IMC, with the area under
curve of QESD-CC being ~9-fold higher than IMC (Figure 5.12d). Thus, the dissolution
data confirms that the QESD-CC approach can indeed be used to enable the development
of high dose DC tablets of IMC.
5.4.6 Drug-polymer molecular interaction
To better understand the mechanism in formation of the spherical cocrystal
agglomerates, we further probed the underlying intermolecular interactions between
HPMC and IMC/SAC molecules by solution 1H NMR. To mimic the aqueous environment
in the QESD process, deuterium oxide would be the ideal solvent to use. However, the poor
144
water solubility of IMC led us to characterize these interactions in DMSO-d6 in order to
co-dissolve all three components involved in this process.
When the concentration of IMC-SAC in DMSO-d6 increased from 2 to 8 mg/mL,
the peaks positions correlated with IMC at 7.60–7.70 ppm did not change (Figure 5.13a).
However, downfield shifts of 1H NMR spectral peaks were observed in the range 7.80–
8.20 ppm (Figure 5.13a), which correspond to the H atom resonances on the aromatic ring
of SAC (Figures 1b). The downfield shift indicates decreased electron density in the
aromatic ring, which is induced by a stronger hydrogen bonding between adjacent SAC
molecules through amide moieties, which is analogous to the amide dimer (N-H...O;
2.859(3) Å) synthon (R22 (8) motif) formed between two SAC molecules in the IMC-SAC
crystal structure as depicted in Figure 5.13c. With the addition of 0.5 mg/mL HPMC to a
2 mg/mL IMC-SAC solution, an upfield shift of these peaks is observed that suggests
weakening of the N-H...O H-bond between SAC dimers induced by HPMC (Figure 5.13a).
Additionally, the peaks corresponding to the hydroxyl substituents on HPMC broaden in
the presence of IMC-SAC (Figure 5.13b), indicating conformational restriction of the –OH
side chains of the HPMC, likely due to their interactions with the SAC molecules. Similar
peak shifts and peak smearing in 1H NMR spectra of SAC and HPMC were observed in
the absence of IMC (Figure 5.14). These observations suggest that the hydroxyl groups on
HPMC form hydrogen bonds with SAC, which weaken the original strong intermolecular
N-H...O hydrogen bonds between SAC molecules while IMC is not directly involved. Since
the 1H NMR spectra of IMC remained the same in the presence and absence of HPMC
(Figure 5.13a), IMC does not significantly interact with HPMC.
145
The preferential interaction of HPMC with SAC instead of IMC was further
investigated using DFT computational simulations, which revealed hydrogen bonds
formed between SAC and HPMC monomer units through S=O…H-O (2.889 Å), N-H…O
(2.704 Å, 2.832 Å), and C=O…H-O (2.775 Å) interactions (Figure 5.15). In comparison,
no hydrogen bonds between HPMC and IMC were suggested by the simulations. These
results corroborate the intermolecular interactions inferred from the 1H NMR data (Figures
7 and S6), i.e., the dominant intermolecular interactions between HPMC and IMC-SAC
are hydrogen bonds between SAC and HPMC.
5.4.7 Formation mechanism of spherical cocrystal agglomerates
The observed hollow structure of the QESD-CC particles (Figures 3e,f) provide
some insights into a possible formation mechanism. Emulsion droplets first form on
mixing the concentrated drug solution and aqueous medium. HPMC in the aqueous
medium interacts with SAC at the organic-aqueous interface through the hydrogen bonds
described above to stabilize the emulsion (Figure 5.16c). The counter diffusion of water
and DMF drives a high degree of supersaturation near the drop surface and results in the
precipitation of very fine IMC-SAC crystals to form a crust. As DMF diffuses into the
aqueous phase, interfacially-adsorbed HPMC precipitates and coats the surface of the
particles because of the poorer solubility of HPMC in the DMF-rich solvent mixture
adjacent to the particle surface. The crust grows inward as the solvent counter diffusion
continue until cocrystallization is complete. This process naturally leads to particles with a
core-shell structure with a HPMC coating. Upon drying, the entrapped solvent escapes
through pores in the shell by evaporation. This particle formation mechanism is consistent
146
with the greatly enhanced tabletability, which is possible if HPMC coats the QESD-CC
particles instead of distributing throughout the bulk. Additionally, such hollow particles
are more deformable during compression, which maximizes the interparticle contact area
and favors higher tablet strength.
5.5 Conclusion
We have designed and successfully applied a novel quasi-emulsion solvent
diffusion cocrystallization (QESD-CC) method to simultaneously overcome poor
flowability, poor tabletability, and slow dissolution of IMC. HPMC stabilizes the emulsion
through hydrogen bond interactions with saccharin molecules at the emulsion surface.
Subsequent solvent counter-diffusion leads to the initiation of the IMC-SAC crystallization
at the emulsion drop surface. The cocrystal grows inward to form a core-shell structure,
resulting in round shape and large size of QESD-CC particles, which exhibits excellent
powder flowability. The HPMC coating of particle surface and much smaller size of
primary IMC-SAC crystals account for significantly improved tabletability. The improved
flowability and tabletability enable the successful manufacturing of a high IMC loading
(46.3 wt%) tablet formulation using the direct compression process. Tablets also exhibited
excellent dissolution due to the much higher solubility of the IMC-SAC cocrystal than IMC.
Thus, for poorly soluble drugs that also exhibit poor flowability the QESD-CC approach
is a potentially highly effective and efficient engineering strategy to enable the successful
manufacturing of high drug loading tablets using the most economical direct compression
process.
147
Table 5.1. N2 physisorption isotherms of QESD-CC and AS.
Isotherm Linear Plot Isotherm Linear Plot Isotherm Linear Plot
QESD-CC - Adsorption QESD-CC - Adsorption QESD-CC - Adsorption
Relative
Pressure
(P/Po)
Quantity
Adsorbed
(cm³/g STP)
Relative
Pressure
(P/Po)
Quantity
Adsorbed
(cm³/g STP)
Relative
Pressure
(P/Po)
Quantity
Adsorbed
(cm³/g STP)
0.002296 0.069851 0.002296 0.069646 0.002281 0.069826
0.022375 0.147844 0.022316 0.14575 0.022187 0.145737
0.046561 0.183815 0.046806 0.18157 0.046495 0.181907
0.070131 0.207943 0.070155 0.204569 0.070135 0.204573
0.081668 0.218059 0.081686 0.21384 0.081621 0.214242
0.102193 0.233145 0.102187 0.227887 0.10212 0.228296
0.122601 0.246278 0.122938 0.241759 0.122505 0.241146
0.142968 0.258061 0.142931 0.252569 0.142904 0.253097
0.163739 0.26979 0.163227 0.263408 0.163085 0.263622
0.184183 0.280032 0.183657 0.273268 0.183584 0.273683
0.203991 0.290134 0.20411 0.283246 0.204478 0.28405
0.224358 0.300368 0.224472 0.293123 0.224292 0.293487
0.245248 0.310374 0.244644 0.301945 0.245266 0.302919
0.265213 0.319642 0.265231 0.311345 0.2652 0.312214
0.286282 0.328656 0.285598 0.320121 0.285397 0.320344
0.306039 0.338387 0.306036 0.328738 0.306508 0.32901
0.326516 0.347864 0.326506 0.337448 0.32691 0.337886
0.336741 0.352942 0.336692 0.342958 0.336288 0.341999
0.347647 0.357827 0.347909 0.348286 0.34704 0.347842
0.357199 0.362346 0.357178 0.351921 0.356894 0.35175
0.368029 0.367752 0.3685 0.356771 0.367714 0.356661
0.378798 0.372597 0.377592 0.360134 0.377224 0.361035
0.387892 0.37639 0.388289 0.365577 0.388018 0.36518
0.40873 0.385813 0.408918 0.374844 0.408534 0.373417
0.414393 0.389464 0.413323 0.377178 0.412915 0.37598
0.418519 0.391566 0.419062 0.380089 0.419161 0.379727
0.429687 0.396734 0.428786 0.384686 0.428217 0.384009
0.450394 0.407119 0.450171 0.39381 0.449371 0.392946
0.470993 0.417112 0.470718 0.40274 0.469748 0.402941
0.491271 0.426844 0.490848 0.412567 0.490219 0.412714
0.511432 0.43714 0.511013 0.422675 0.510421 0.422718
0.53203 0.448404 0.53208 0.433204 0.531203 0.43305
0.552499 0.460812 0.552211 0.444525 0.551266 0.443542
0.57297 0.472303 0.573233 0.456581 0.572096 0.45527
0.593603 0.485822 0.593186 0.468368 0.592108 0.466559
148
0.613509 0.498563 0.613559 0.480781 0.61272 0.47981
0.634472 0.513603 0.63402 0.494322 0.633004 0.493226
0.654273 0.527648 0.654546 0.50839 0.653725 0.508163
0.67516 0.544407 0.674924 0.522751 0.673576 0.522959
0.695657 0.562899 0.695384 0.539559 0.694159 0.540075
0.716591 0.583136 0.715858 0.55729 0.714751 0.557629
0.736194 0.601777 0.736317 0.576457 0.735105 0.575719
0.756995 0.625864 0.756818 0.598681 0.755336 0.59691
0.777643 0.652227 0.777319 0.622691 0.775761 0.620937
0.79828 0.681685 0.797711 0.648934 0.796186 0.646323
0.818472 0.715554 0.818197 0.679693 0.816603 0.6772
0.839022 0.756604 0.838621 0.717066 0.837045 0.711893
0.859762 0.806147 0.859068 0.76072 0.85736 0.753309
0.880087 0.86835 0.879387 0.814854 0.877765 0.806106
0.898693 0.939791 0.899984 0.887515 0.898112 0.875111
0.918913 1.04532 0.919252 0.979711 0.919113 0.972597
0.929333 1.12184 0.929266 1.04729 0.929174 1.03899
0.939494 1.21368 0.939464 1.13227 0.939148 1.12185
0.949578 1.33149 0.949502 1.24139 0.949271 1.23216
0.959799 1.49198 0.95964 1.39317 0.959342 1.38419
0.969851 1.74645 0.969489 1.61935 0.969118 1.61627
0.975408 1.95214 0.975097 1.82493 0.97463 1.82567
0.980154 2.19513 0.979947 2.07792 0.979486 2.08368
0.985208 2.56209 0.984938 2.45054 0.984377 2.45561
0.987212 2.75546 0.986894 2.64781 0.986185 2.65953
0.988115 2.88251 0.987768 2.77777 0.98738 2.81067
0.989908 3.10941 0.98967 3.00986 0.988255 2.95666
0.99048 3.21658 0.989861 3.09908 0.989791 3.18788
AS - Adsorption AS - Adsorption AS - Adsorption
Relative
Pressure
(P/Po)
Quantity
Adsorbed
(cm³/g STP)
Relative
Pressure
(P/Po)
Quantity
Adsorbed
(cm³/g STP)
Relative
Pressure
(P/Po)
Quantity
Adsorbed
(cm³/g STP)
0.002679 0.055584 0.002452 0.054007 0.002418 0.05529
0.023056 0.104172 0.02297 0.109396 0.022999 0.109689
0.046877 0.122074 0.046795 0.129999 0.047113 0.13236
0.07039 0.131833 0.070327 0.143343 0.070344 0.145297
0.081743 0.135894 0.081695 0.147475 0.081706 0.151092
0.102224 0.139538 0.10205 0.155689 0.102456 0.15929
0.122552 0.144073 0.122506 0.162061 0.122525 0.165033
0.1427 0.147478 0.143025 0.168968 0.142892 0.172262
0.16332 0.149634 0.162957 0.173974 0.16349 0.177031
0.183975 0.15207 0.183566 0.179952 0.183545 0.183036
149
0.204047 0.153155 0.203962 0.182327 0.203888 0.187285
0.224334 0.154635 0.224392 0.186953 0.22425 0.192312
0.24468 0.155088 0.244553 0.191999 0.24507 0.197801
0.265542 0.156772 0.26491 0.197141 0.264991 0.201585
0.286158 0.158076 0.285379 0.199859 0.285345 0.205597
0.306566 0.159003 0.305857 0.203564 0.305787 0.208924
0.32665 0.160649 0.326134 0.207414 0.326227 0.212992
0.337173 0.162431 0.336094 0.209914 0.336332 0.215656
0.347556 0.161867 0.346295 0.213355 0.346551 0.217778
0.358166 0.162598 0.357809 0.215121 0.356852 0.220446
0.367329 0.162145 0.366843 0.217135 0.367734 0.222817
0.37746 0.162912 0.376951 0.219714 0.377204 0.225516
0.38769 0.163321 0.387211 0.220861 0.387934 0.226642
0.408196 0.164739 0.408422 0.225035 0.408785 0.231052
0.413187 0.166265 0.412518 0.225514 0.413585 0.23249
0.419097 0.166357 0.417555 0.228224 0.417904 0.232998
0.42919 0.165325 0.427824 0.2284 0.429121 0.234702
0.449677 0.165296 0.448978 0.232209 0.449731 0.239752
0.469591 0.164869 0.469744 0.236762 0.470189 0.244506
0.491019 0.167629 0.48978 0.242854 0.490292 0.250302
0.511465 0.170625 0.510699 0.246697 0.510767 0.256266
0.531661 0.176543 0.530608 0.251463 0.531177 0.261243
0.552331 0.179419 0.551186 0.257633 0.551702 0.266657
0.572461 0.180196 0.571215 0.265656 0.572067 0.272858
0.593085 0.183683 0.592147 0.274354 0.592525 0.28151
0.613235 0.191017 0.612276 0.282425 0.612612 0.291236
0.633655 0.199402 0.632175 0.292908 0.632882 0.303399
0.65445 0.211224 0.652599 0.307963 0.653408 0.317425
0.674476 0.22465 0.672971 0.323195 0.673658 0.33376
0.694828 0.23669 0.693627 0.336891 0.693889 0.350482
0.715339 0.246493 0.713833 0.350001 0.714526 0.364091
0.735824 0.253985 0.734059 0.362725 0.735175 0.37287
0.756085 0.260854 0.754376 0.374666 0.755518 0.38148
0.776886 0.267156 0.774785 0.386196 0.775812 0.391792
0.79708 0.277895 0.795053 0.394377 0.795785 0.404317
0.817876 0.287299 0.814938 0.40609 0.816494 0.418888
0.837968 0.297879 0.83574 0.424878 0.836236 0.435911
0.858539 0.307645 0.858336 0.439 0.857317 0.450653
0.878889 0.330234 0.878322 0.458573 0.878352 0.472247
0.898619 0.353675 0.898834 0.486355 0.898904 0.499065
0.919382 0.38337 0.9192 0.520258 0.919286 0.535408
0.929355 0.400002 0.928999 0.542827 0.929121 0.559275
0.939411 0.422752 0.939266 0.573748 0.939492 0.587954
150
0.949562 0.456087 0.949234 0.612801 0.949777 0.62432
0.9597 0.501805 0.959724 0.661852 0.959494 0.678726
0.969364 0.572115 0.969594 0.756994 0.969203 0.77624
0.975016 0.632246 0.974794 0.832113 0.974663 0.849678
0.980069 0.705292 0.979852 0.923025 0.979797 0.943283
0.985482 0.809309 0.98496 1.03842 0.985078 1.06793
0.986783 0.840634 0.986424 1.08499 0.986087 1.10232
0.987817 0.86837 0.987736 1.13276 0.987159 1.13736
0.989104 0.903081 0.988809 1.168 0.98872 1.1909
0.990405 0.944236 0.989884 1.20401 0.989824 1.23648
151
Figure 5.1. Correlation between the actual measured HPMC concentration by the SEC
method.
152
Table 5.2. Intermolecular interaction energies estimated using B3LYP+D2/6+31G(d,p)
dispersion corrected DFT model. Both the total energy (E(tot)) and electrostatic (E(ele)),
polarization (E(pol)), dispersion (E(dis)), and exchange repulsion (E(rep)) components of the
energy are listed. R indicated the distance between centers of mass of the pair of molecules.
Symop R Eele Epol Edis Erep Etot
IMC γ Form
-x, -y, -z 6.25 -20.1 -1.6 -79.2 54.6 -57.7
x, y, z 9.24 -7.6 -0.2 -23.3 16.9 -18.0
-x, -y, -z 6.22 -19.6 -6.3 -49.3 34.2 -47.2
x, y, z 13.10 0.0 -2.9 -11.8 6.7 -8.3
-x, -y, -z 12.54 -123.6 -0.6 -13.8 144.1 -54.1
-x, -y, -z 8.57 -7.0 -5.2 -49.3 29.2 -36.1
-x, -y, -z 9.44 -6.9 -0.8 -41.2 27.5 -26.7
-x, -y, -z 7.98 -5.9 -0.4 -18.4 9.9 -16.5
-x, -y, -z 8.52 0.5 -0.5 -20.6 10.5 -11.4
x, y, z 11.79 -6.3 -0.6 -9.2 7.2 -10.6
-x, -y, -z 15.21 -0.6 -0.2 -3.0 2.4 -1.9
IMCSAC
x, y, z 7.11 -9.8 -3.1 -45.2 33.3 -31.4
-x, -y, -z 12.58 -117.4 -27.2 -14.0 141.9 -68.8
-x, -y, -z 8.34 -8.9 -1.8 -31.4 24.6 -22.9
-x, -y, -z 10.27 0.3 -8.2 -11.1 0.9 -14.9
- 4.97 -27.7 -0.7 -57.5 44.8 -52.1
- 7.69 -3.0 -1.2 -5.8 1.5 -8.3
-x, -y, -z 6.05 -17.9 0.0 -56.4 38.9 -44.0
x, y, z 11.45 -0.3 -4.4 -8.4 4.7 -7.9
- 8.59 -20.9 -0.9 -24.5 24.0 -29.3
- 7.99 -5.6 -2.8 -14.5 11.9 -13.3
153
-x, -y, -z 11.82 -2.4 -1.2 -12.9 6.9 -10.3
- 10.95 3.6 -0.7 -4.0 2.2 1.2
- 12.32 3.1 -0.9 -2.0 0.1 1.0
-x, -y, -z 12.11 -3.3 -1.5 -19.5 14.7 -12.5
- 11.71 1.2 -0.4 -2.4 1.1 -0.4
- 9.42 -9.7 -2.9 -10.3 9.5 -15.5
- 10.46 -3.3 -0.0 -7.0 8.6 -4.3
- 10.06 0.1 -0.2 -1.6 0.0 -1.3
- 10.06 0.1 -0.2 -1.6 0.0 -1.3
- 8.59 -20.9 -5.2 -24.5 24.0 -32.5
- 10.95 3.6 -0.7 -4.0 2.2 1.2
- 7.69 -3.0 -1.2 -5.8 1.5 -8.3
-x, -y, -z 6.99 -69.7 -13.5 -12.5 65.5 -54.1
-x, -y, -z 4.47 -9.4 -2.1 -41.7 28.6 -30.2
- 4.97 -27.7 -6.3 -57.5 44.8 -56.3
- 11.71 1.2 -0.4 -2.4 1.1 -0.4
x, y, z 7.11 -4.4 -0.9 -8.9 1.9 -11.9
- 7.99 -5.6 -2.8 -14.5 11.9 -13.3
- 12.32 3.1 -0.4 -2.0 0.1 1.3
- 9.42 -9.7 -2.9 -10.3 9.5 -15.5
- 10.46 -3.3 -0.6 -7.0 8.6 -4.7
154
Figure 5.2. Chemical structures of (a) IMC, (b) SAC and (c) HPMC. Hydrogen atoms that
participate in intermolecular interactions responsible for QESD-CC are marked with
different colors in accordance to their chemical shifts in solution 1H NMR spectra.
(a) (b) (c)
155
Table 5.3. Formulation composition of IMC-containing tablets using different IMC forms
Material Function IMC AS QESD-CC
IMC/IMC-SAC API 46.3 % 70 % 70 %
Avicel PH102 Binder 48.2 % 24.5 % 24.5 %
CCM-Na Super-
disintegrant 5.0 % 5.0 % 5.0 %
MgSt Lubricant 0.5 % 0.5 % 0.5 %
Total 100 % 100 % 100 %
156
Figure 5.3. Optical microscopy images of particles prepared with aqueous solutions of
HPMC in different concentrations from 0% to 0.5% (scale bar = 500 µm).
0.01 % HPMC
0.1 % HPMC 0.5 % HPMC
0 % HPMC
157
Figure 5.4. Particle size distribution of as-received IMC, IMC-SAC prepared by AS and
QESD-CC processes, indicating that the QESD-CC yields highly spherical particles with
a relatively narrower size distribution.
158
Figure 5.5. Optical microscopy images of particles (a) with and (b) without 0.5% HPMC
in the crystallization medium (scale bar = 500 µm).
a) b)
159
Figure 5.6. PXRD patterns of calculated IMC-SAC, AS, QESD-CC), as-received IMC,
and as-received SAC.
160
Figure 5.7. DSC profiles of as received IMC, IMC-SAC prepared by AS, and QESD-CC
processes.
161
Figure 5.8. TGA profiles of as received IMC, IMC-SAC prepared by AS and QESD-CC
processes.
Cocrystal melting point
162
Figure 5.9. SEM images of AS (a and b) and QESD-CC (c and d) powders at low (x 50)
and high (x 20,000) magnifications. Images e) and f) show the hollow structure of QESD-
CC particles
(a) (b)
(e) (f)
(d) (c)
163
Figure 5.10. Powder properties of as-received IMC, AS, and QESD-CC powders, a)
flowability and b) tabletability.
a)
Avicel PH102
b)
164
Figure 5.11. Energy frameworks for (a) IMC and (b) IMC-SAC with a likely slip layer
shaded in pink. The thickness of each cylinder (blue) represents the relative strength of
intermolecular interaction. The energy threshold for the energy framework is set at −10
kJ/mol.
a) b)
165
Figure 5.12. Performance of tablet formulations based on as-received IMC, AS, and
QESD-CC, (a) flowability, (b) tabletability, c) tablet friability, and d) tablet dissolution.
QESD-CC
IMC
AS
a) b)
Avicel PH102
QESD-CC
IMC
c) d)
166
Figure 5.13. Partial 1H NMR spectra of (a) 2 mg/mL IMC-SAC, 2 mg/mL IMC-SAC with
0.5 mg/mL HPMC and 8 mg/mL IMC-SAC, and (b) 0.5 mg/mL HPMC with and without
2 mg/mL of IMC-SAC, (c) Intermolecular hydrogen bonding interactions in IMC-SAC
cocrystal. Each group of peaks corresponds to H atoms in Figure 5.2 labelled by the dots
of the same color.
a) b)
c)
167
Figure 5.14. Partial 1H NMR spectra of (a) 2 mg/mL SAC, 8 mg/mL SAC and 2 mg/mL
SAC with 0.5 mg/mL HPMC, and (b) 0.5 mg/mL HPMC and 2 mg/mL SAC with 0.5
mg/mL HPMC.
a) b)
168
Figure 5.15. Optimized geometric complexes between IMC-SAC and three HPMC
monomer units with different substituents: a) -H, b) -CH3, c) -CH2CH(OH)CH3.
a) b)
c)
169
Figure 5.16. Formation process of QESD-CC particles.
HPMC Emulsion droplet Cocrystal
Water phase
Oil phase
170
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174
Chapter 6
Reduction of punch-sticking propensity of celecoxib by spherical
crystallization via polymer assisted quasi-emulsion solvent diffusion
175
6.1 Synopsis
Punch-sticking during tablet compression is a common problem for many active
pharmaceutical ingredients (APIs), which renders tablet formulation development
challenging. Herein, we demonstrate that the punch-sticking propensity of a highly sticky
API, celecoxib (CEL), can be effectively reduced by spherical crystallization enabled by a
polymer-assisted quasi-emulsion solvent diffusion (QESD) process. Among three
commonly used pharmaceutical polymers, poly(vinylpyrrolidone) (PVP), hydroxypropyl
cellulose (HPC), and hydroxypropyl methylcellulose (HPMC), HPMC was the most
effective in stabilizing the transient emulsion during QESD and retarding the coalescence
of emulsion droplets and the initiation of CEL crystallization. These observations may arise
from stronger intermolecular interactions between HPMC and CEL, consistent with
solution 1H NMR analyses. SEM and X-ray photoelectron spectroscopy confirmed the
presence of a thin layer of HPMC on the surface of spherical particles. Thus, the sticking
propensity was significantly reduced because the HPMC coating prevented direct contact
between CEL and the punch tip during tablet compression.
6.2 Introduction
Several powder properties of active pharmaceutical ingredients (APIs), such as
tabletability, flowability, bulk density, and punch-sticking propensity are critical for
efficient and successful tablet formulation design, especially at high drug loadings (> 30%,
w/w).1-3 The punch-sticking propensity refers to the tendency of the API powder to adhere
to the punch tip during tablet compression. Relative to other powder properties, the punch-
sticking propensity of an API is rarely evaluated during early stage therapeutic
176
development, even though it is a well-recognized common problem in tablet manufacturing
that adversely affects the aesthetic qualities of a finished tablet product.4-6 Punch-sticking
is influenced by process variables such as tableting speed, compaction pressure7, tooling
material8, and tooling design9, as well as API material properties, including mechanical
properties10, surface chemistry10, particle sizes7, and choice of excipients11. As compared
to modifying tablet compaction tools, elimination of punch-sticking through formulation
approaches is more desirable to ensure tablet quality because of its economy, effectiveness,
and broad applicability.
Among the formulation techniques that have been pursued to reduce the punch-
sticking propensity, crystal engineering presents an attractive approach as it addresses the
root cause, instead of the symptoms, of API deficiency by altering the API crystal structure
and its consequent material properties. For example, salt formation can reduce the punch-
sticking propensity by altering the mechanical properties and surface chemistries of
crystalline APIs.10, 12 When crystal structure engineering is not possible, another effective
approach to address API punch-sticking is particle engineering through processes such as
mixing with suitable excipients11 and dry granulation13. Quasi-emulsion solvent diffusion
(QESD) is a particle engineering process for preparing spherical agglomerates (SA)
consisting of fine API crystals.14 QESD has been employed to improve flowability, bulk
density, tabletability, and dissolution characteristics of APIs.15-19 However, it remains
unclear whether API engineering by QESD can be used to overcome the punch-sticking
problem.
Celecoxib (CEL) is a COX-2 selective nonsteroidal anti-inflammatory drug for
treating chronic pain and inflammation associated with osteoarthritis, rheumatoid arthritis,
177
and other acute pain symptoms in adults.20 The commercial CEL crystal (Form III), which
exhibits high one dimensional elasticity,21 is a challenging API for tablet formulation
development because of its significant punch-sticking propensity.4 In this work, we
explored the specific use of QESD as a means to reduce the punch-sticking propensity of
CEL. Our studies reveal that QESD processing with (hydroxypropyl)methyl cellulose
(HPMC) can reduce CEL punch-sticking propensity while simultaneously improving its
tabletability and flowability, by forming spherical HPMC-coated CEL crystals.
6.3 Materials and methods
6.3.1 Materials
Celecoxib (CEL, Form III, Aarti Pvt Ltd., Mumbai, India), Microcrystalline
cellulose (Avicel PH102, FMC, Philadelphia, PA), HPMC (K15M, MW 575,000 g/mol,
Ashland Specialty Ingredients, Wilmington, DE), HPC (EF Pharm, MW 80,000 g/mol,
Ashland Specialty Ingredients, Wilmington, DE), PVP (90F, MW 1,000,000–1,500,000
g/mol, BASF, Ludwigshafen, Germany), magnesium stearate (MgSt, Mallinckrodt Inc., St.
Louis, MO), ethyl acetate (EA, Sigma-Aldrich, St. Louis, MO), ultra-pure deionized water
(0.066 μS/cm, Thermo Scientific, USA) were used as received. The chemical structures of
CEL, HPMC, HPC, and PVP are given in Figure 6.1. All crystallization experiments were
performed in glass beakers at the specified temperatures.
6.3.2 Polymer Screening for Quasi-Emulsion Solvent Diffusion (QESD)
Ethyl acetate (EA) and water were selected as good and poor solvent for the QESD
process based on solubility of CEL in the solvents and solvents miscibility. A solution
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containing 3 g CEL in 9 mL of EA at 70 °C was added dropwise to 70 mL of an aqueous
solution of 0.5% (w/w) polymer (HPMC, HPC, or PVP) at 22 °C to form spherical
agglomerates over 3 minutes. The mixture was agitated at 600 rpm using an overhead mixer.
Spherical agglomerates were captured on filter paper (Fisher Scientific, Pittsburgh, PA)
supported with a Brinell funnel after 15 min when the suspension no longer appeared to
change, and they were dried at 60 °C overnight in an oven. The morphology of produced
agglomerates was assessed to guide the selection of more appropriate polymer additives.
6.3.3 QESD Spherical Agglomerate Growth Kinetics
An 0.9 mL aliquot of a 0.33 mg/mL CEL solution in EA at 70 °C was added at once
to a 7 mL of a 0.5% (w/w) polymer (HPMC, HPC or PVP) aqueous solution under 600 rpm
agitation using a magnetic stir bar at room temperature. The time-dependence of the QESD
process was monitored in increments appropriate to the rates of drop solidification
associated with the different polymer additives. At each time point, a small volume of
suspension (less than 1 mL) was withdrawn using a disposable plastic pipette and
immediately transferred onto a glass slide for imaging under a polarized light microscope
(Eclipse E200; Nikon, Tokyo, Japan).
6.3.4 Particle Size Distribution
Particle size distribution measurement of CEL and CEL-QESD was carried out
using a particle size analyzer (Microtrac SIA, Montgomeryville, PA). Each powder (~50
mg) was suspended in Isopar G Fluid (∼10 mL), in which the solubility of CEL is
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negligible. The suspension was added dropwise into a sample delivery controller (SDC,
Montgomeryville, PA) until the particle density reached the acceptable range for each
measurement. A high-speed camera captured image of particles in focus, from which the
area equivalent diameter of each particle was determined using image analysis software
(Microtrac Flex) provided with the instrument. All experiments were performed in
triplicate.
6.3.5 Powder X-ray Diffractometry (PXRD)
Crystallographic properties of samples were characterized using a X’Pert PRO
powder X-ray diffractometer (PANalytical Inc., West Borough, MA) equipped with a
copper X-ray source (45 kV and 40 mA) to provide Kα radiation (1.5406 Å) over the
angular range 5° ≤ 2θ ≤ 35° using a 0.017° step size and a dwell time of 1.15 s. The
divergence and antiscattering slits on the incident beam path were 1/16 and 1/8 degree,
respectively, and the antiscattering slit on the diffracted beam path was 5.5 mm
(X’Celerator). The expected PXRD pattern of CEL Form III was calculated from its crystal
structure.21
6.3.6 Thermal Analyses
Powder samples (3−5 mg) were loaded into hermetically sealed, aluminum pans
and heated from 20 to 180 °C at a rate of 10 °C/min on a Q1000 differential scanning
calorimeter (DSC, TA Instruments, New Castle, DE) under a continuous nitrogen purge
at a flow rate of 50 mL/min. The DSC cell temperature was calibrated with both indium
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and cyclohexane, and the heat flow cell parameter was calibrated using the indium standard.
To measure the residual volatile content in the solids obtained by QESD,
thermogravimetric analyses were performed using a Q500 Thermogravimetric Analyzer
(TA Instruments, New Castle, DE). Solid samples (~3−10 mg) were placed in an open
aluminum pan and heated from 22 to 300 °C at a rate of 10 °C/min under 25 mL/min
nitrogen gas purge.
6.3.7 True density measurement
The true density of CEL was measured using a helium pycnometer (Quantachrome
Instruments, Ultrapycnometer 1000e, Byonton Beach, FL). Accurately weighed powders
(1−2 g) was filled into the sample cell. Sample volume was measured repeatedly until the
coefficient of variation of the last five consecutive measurements was below 0.005%. The
mean and standard deviation of the last five measurements were calculated and reported.
The true density of CEL-QESD was assumed to be the same as CEL since the amount of
HPMC in CEL-QESD was small and the density difference between HPMC and CEL is
also small.
6.3.8 Powder Flowability, Tabletability, and Punch Sticking Assessment
A ring shear cell tester (RST-XS; Dietmar Schulze, Wolfenbüttel, Germany) with
a 10 mL cell was used to assess powder flowability at a 1 kPa pre-shear normal stress. A
yield locus was obtained by conducting shear test under different normal stresses (0.25,
0.40, 0.55, 0.70, and 0.85 kPa), from which the unconfined yield strength (fc) and major
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principal stress (σn) were obtained by drawing Mohr’s circles. The flowability index (ffc)
was calculated using Eq. (1).
𝑓𝑓c =𝜎𝑛
𝑓c (1)
Tabletability was analyzed for both pure components and formulations consisting
of 79.5 wt% Avicel PH102, 20 wt% CEL powder, and 0.5 wt% MgSt. Tablets were
prepared by single-sided compression at compaction pressures ranging 50–300 MPa using
a Universal Material Testing Machine (Model 1485, Zwick/Roell, Germany) at a speed of
4 mm/min. A 5% (w/v) suspension of magnesium stearate in ethanol was used to coat the
punch tip and die wall, which was air dried with a fan for ~ 1 min to complete dryness.
Tablets were allowed to relax under ambient conditions for at least 24 h prior to being
broken diametrically using a Texture Analyzer (TA-XT2i, Texture Technologies
Corporation, Scarsdale, NY). Tablet flashing was carefully removed to improve the
accuracy of measured tablet thickness.22 Tablet tensile strength was calculated from the
breaking force (F), tablet thickness (h), and tablet diameter (d) according to Eq. (2):23
𝜎 =2𝐹
𝜋𝑑ℎ (2)
Punch sticking propensity was assessed for formulations consisting of 79.5 wt%
Avicel PH102, 20 wt% CEL powder, and 0.5 wt% MgSt using a Presster Compaction
Simulator (Measurement Control Corp., East Hanover, NJ) with a 12.7 mm diameter flat-
faced upper punch with a removable tip (tare weight 3 g). A total of 50 tablets were
compressed at 250 MPa with a dwell time of 25 ms, simulating a Korsch XL100 press (10
stations) operating at a production rate of 49,300 tablets/h. The punch tip was removed and
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weighed with precision of 0.01 mg after punching batches of 10 tablets to determine the
punch sticking kinetics, and the mean weight gain over three independent trials was plotted
against the number of compressions.
6.3.9 Compressibility and Compactibility Analyses
Compressibility, which is derived from a plot of tablet porosity as a function of
compaction pressure, indicates the extent of powder volume reduction under a given
compaction pressure. Porosity of the compacts (𝜀) was calculated from tablet density (𝜌𝑐)
and true density (𝜌𝑡 = 1.4833 ± 0.0004 g/cm3 for CEL) of the material using Eq. (3):
𝜀 = 1 − 𝜌𝑐/𝜌𝑡 (3)
Compactibility, which is derived from a plot of σ as a function of ε, was analyzed by
nonlinear regression according to Eq. (4):24
𝜎 = 𝜎0𝑒−𝑏·𝜀 (4)
where 𝜎0 is the tablet tensile strength at zero porosity and b is a constant, which represents
the sensitivity of σ to a change in 𝜀.
6.3.10 Scanning Electron Microscopy (SEM)
Samples were mounted onto carbon tapes and sputter-coated with a thin layer of
platinum (thickness ~ 75 Å) using an ion-beam sputter (IBS TM200S, VCR Group Inc.,
San Clemente, CA). Particle morphology and surface features were evaluated using a JEOL
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6500F scanning electron microscope (JEOL Ltd., Tokyo, Japan), operated at SEI mode
with an acceleration voltage of 5 kV under high vacuum (10-4–10-5 Pa) during imaging.
6.3.11 X-ray Photoelectron Spectroscopy (XPS)
The XPS measurements were performed using a PHI Versa Probe III XPS system
(ULVAC-PHI; Physical Electronics, Inc., Chanhassen, MN, USA) with monochromated
Al K X-ray source (1486.6 eV, power of 50 W under 15 kV) with a base pressure of 5.0
x 10-8 Pa and a 0.2 mm diameter X-ray spot size. During data collection, the pressure in
the sample chamber was maintained near 1.0 x 10-6 Pa. Samples were mounted on a
stainless steel holder using carbon tape. Tablet samples were mounted in such a way that
the surface of interest faced upward for elemental analysis. Charge neutralization was used
since the materials are electrically non-conductive. The incidence angle of X-ray was 90°
and take-off angle of electrons was 45°. The pass energy used was 280 eV with 1.0 eV/step.
Atomic percentages were calculated from the average survey spectrum (n = 3) using the
Multipak software provided with the XPS system.
6.3.12 HPMC Content Determination
HPMC content in CEL samples prepared by QESD was determined by size-
exclusion chromatography (SEC) using an Agilent 1260 liquid chromatography (LC)
operating with an aqueous mobile phase containing 0.1 M Na2SO4 and 1 wt% acetic acid
at a flow rate of 0.4 mL/min. The LC was equipped with one guard column and three
CATSEC separation columns with pore sizes of 1000, 300 and 100 Å, respectively.
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Analyte detection by an inline Wyatt Optilab T-rEX refractive-index detector (Wyatt
Technologies, Santa Barbara, CA) enabled HPMC concentration determination from the
peak area corresponding to polymer fraction in the ASTRA software. 25, 26 The refractive
index increment was dn/dc = 0.1165 mL/g for HPMC under the analysis conditions, which
was determined by SEC analyses of HPMC (K15M) solutions of known concentrations
assuming 100% mass recovery. For each measurement, CEL-QESD powder (0.65 g) was
dissolved in 5 mL HPLC grade tetrahydrofuran (THF) to separate the insoluble HPMC.
The insoluble HPMC polymer was then isolated by centrifugation force at 11,644 x g for
10 min and the CEL solution in THF was carefully decanted. In order to remove any
residual CEL, the HPMC polymer was re-dispersed in 5 mL THF by sonication for 10 min
and isolated again by centrifugation. Upon removal of residual THF under vacuum, the
isolated HPMC was dissolved in 5 mL of the aqueous SEC mobile phase, and the
concentration was determined by SEC. The reported HPMC content in each CEL-QESD
sample represents an average of three independent measurements.
6.3.13 1H NMR Spectroscopy
1D solution 1H NMR spectra in DMSO-d6 were acquired at 298 K on a Bruker AV-
400 NMR spectrometer (Bruker BioSpin GmbH, Rheinstetten, Germany) operating at a
proton resonance frequency of 400 MHz. Chemical shifts were referenced with respect to
the residual proton resonance of DMSO-d6 (2.50 ppm).
6.4 Results and discussion
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6.4.1 Polymer Screening and Granule Growth Process
During the QESD process, the polymer used in aqueous solution significantly
influenced the morphology of the resulting agglomerates. The sphericity of the CEL
agglomerates qualitatively decreased in the order of HPMC >> HPC > PVP ≈ no polymer
(Figure 6.2). The addition of HPMC notably led to spherical agglomerates with smooth
surfaces, while only irregular agglomerates with rough surfaces were produced in the
presence of HPC. The agglomerates produced from PVP solutions were large and even
more irregular than those from the HPC solution, in a manner similar to those obtained
from QESD without any polymer (Figure 6.2).
To better understand the origin of the distinct granule morphologies, the time-
dependent process of granule growth was monitored for each polymer additive (Figure 6.3).
In all aqueous polymer solutions examined here, emulsions were formed upon addition of
CEL solution. The emulsion formed by the HPMC solution was stable for 6 min, after
which the phase separated CEL droplets gradually solidified to form spherical
agglomerates (Figure 6.3a). In contrast, emulsions formed in the HPC and PVP solutions
were less stable, since crystallization of CEL droplets began after about 1 min and 30 sec,
respectively (Figures 6.3b & 6.3c). In the PVP solution, coalescence of emulsion droplets
also rapidly took place, which led to the formation of large granules (Figure 6.3c).
Thus, sufficient emulsion stability against coalescence is required for
crystallization of the droplets to occur at the surfaces and propagate into the droplet core.
This confined crystallization mode results in a spherical particle morphology that mimics
that of the parent emulsion droplets. Unstable emulsions, wherein coalescence of small
droplets of CEL takes place more quickly than crystallization, leads to the formation of
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large and irregular agglomerates. Therefore, the crystallization onset time represents a good
criterion for selecting appropriate polymers to enable the successful development of a
QESD process. This was achieved with 0.5% (w/w) HPMC, which was then used in
subsequent studies as the crystallization medium to produce high quality, spherical
agglomerates of CEL, designated as CEL-QESD.
6.4.2 Sticking propensity reduction by CEL-QESD
During tablet compression, a significant amount of the as-received CEL powder
visibly adhered to the punch surface after a single compression (Figure 6.4a), consistent
with the known severe punch-sticking propensity of CEL.11 In contrast, the CEL-QESD
powders exhibited significantly less punch-sticking propensity than as-received CEL.
Moreover, the degree of reduction was visually evident as the HPMC concentration in the
QESD process increased from 0.1 to 0.5 wt% (Figures 6.4b–6.4d). The CEL powder
prepared from the 0.5% HPMC aqueous solution exhibited a completely sticking free
performance upon compression (Figure 6.4d).
Quantitative evaluation of punch-sticking propensity was carried out following an
established method using formulated CEL,4 comprising of Avicel PH102 (79.5 wt%), CEL
(20 wt%), and MgSt (0.5 wt%). Results showed severe sticking propensity of the as-
received CEL formulation, where >1.80 mg weight gain was recorded after 50
compressions (Figure 6.4e). In comparison, the CEL-QESD formulation only had ~ 0.10
mg weight gain recorded after 50 compressions. Having established the successful
reduction of punch sticking by spherical crystallization of CEL (CEL-QESD), we further
examined the possible mechanisms in the following sections.
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6.4.3 Solid form and residual solvent
Both DSC (Figure 6.5a) and powder XRD (Figure 6.5b) analysis revealed that the
CEL-QESD, derived from the 0.5% HMPC emulsion, and the as-received CEL exhibited
the same thermal properties and crystal structure consistent with those of Form III.
Thermogravimetric analyses further demonstrated the absence of detectable residual
solvent in the CEL-QESD, since no sample weight loss was observed with increasing the
temperature to 180 °C (Figure 6.5c). Therefore, the drastically reduced punch sticking
propensity cannot be ascribed to the presence of residual solvent nor change in CEL crystal
form.
6.4.4 Manufacturability of CEL Powders
To evaluate the manufacturability of CEL-QESD, we characterized the flowability
and tabletability. The flowability index ffc of CEL-QESD was much higher than that of the
as-received CEL (Figure 6.6a). By the measure of ffc, CEL-QESD exhibited flowability
suitable for high-speed tableting given that it flows better than Avicel PH102, but the as-
received CEL did not (Figure 6.6a).27 The improvement in powder flowability is an
expected outcome for SA powders, due to the combination of the spherical morphology,
smooth surface, and larger particle size of the CEL-QESD. Compared to the elongated fine
crystals of the as-received CEL, CEL-QESD agglomerates were larger and more spherical.
The spherical shape of the fine CEL-QESD particles in the range of 10–40 µm (Figures 6.2
and 6.7a) suggests that they were likely resulted from the solidification of small droplets
during the QESD process.
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CEL-QESD also exhibited profoundly improved tabletability, with tablet tensile
strength more than two-fold higher than that of as-received CEL (Figure 6.6b). Analysis
of the results shows that the concentration of HMPC content in the prepared CEL-QESD
samples positively correlates with the HPMC concentration in the aqueous medium for
QESD (Figure 6.7b). From the 0.5% HPMC solution, the CEL-QESD sample contained
1.04 ± 0.07% (w/w) HPMC (Figure 6.7b). Thus, the much improved tabletability may arise
from a HMPC surface coating layer on the spherical agglomerate that facilitates the
formation of a 3D bonding network upon powder compression, which was shown to
extremely effective in improving powder tabletability.28
Consistent with the higher tabletability of the pure CEL-QESD powders (Figure
6.6b), CEL-QESD also exhibited much better tabletability than the CEL formulation
(Figure 6.8a). According to the bonding area (BA) – bonding strength (BS) interplay
model,29 a higher tabletability is a consequence of large BA, higher BS, or both among the
adjacent particles. BA and BS may be assessed using compressibility and compactibility
plots, respectively. The nearly identical compressibility profiles of the two formulations
(Figure 6.9) imply similar BA in tablets formed under the same compaction pressures. On
the other hand, the compactibility profile of the CEL-QESD formulation was much higher
than that of as-received CEL formulation, as shown by the higher σ at the same tablet
porosity (Figure 6.8b), indicative of its higher apparent BS. Therefore, the higher
tabletability of CEL-QESD formulation was driven by the higher BS. A higher BS among
particles tends to lower sticking propensity, because the inter-particle adhesion is preferred
to punch-particle adhesion, when the tablet is separated from the punch during tablet
manufacturing.
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6.4.5 Polymer Coating on CEL-QESD
To confirm the suspected surface HPMC coating, based on the improved
tabletability, we first compared the surface properties of the different CEL and CEL-QESD
particles. When viewed at a high magnification, the irregular and rough surfaces of CEL-
QESD sharply contrasted the smooth surfaces of as-received CEL crystals (Figure 6.10).
The presence of irregular surfaces can suggest the presence of non-crystalline (amorphous)
material. However, given the high degree of CEL crystallinity observed by DSC and PXRD
(Figures 6.5 and 6.9), this possibility could be eliminated. Another possible origin of the
irregular surface features of the CEL-QESD is the presence of a thin HPMC coating. Such
HPMC coating would be consistent with the reduced punch-sticking propensity (Figure
6.4e), because it prevents the direct contact between CEL and punch.
The presence of a surface HPMC layer is further supported by the XPS data, which
provides the surface elemental composition. The oxygen-rich nature of the cellulosic
backbone of HMPC coupled with the unique occurrence of F and N in CEL (Figure 6.1)
makes it possible to probe particle surface compositions by assessing the relative
abundances of O, F, and N. Compared to the neat CEL powder, the CEL-QESD powder
exhibited a significantly higher O 1s signal with concomitant suppression of the N 1s and
F 1s signals (Figure 6.11a, Table 6.1). This result is consistent with the aforementioned
notion that HMPC decorated the outer surface of the CEL-QESD. Upon compression into
tablets, the CEL-QESD tablet also exhibited significantly lower F 1s and N 1s signals as
compared to the tablets of the as-received CEL (Figure 6.11b, Table 6.1). This confirms
the presence of a surface HPMC layer on the CEL-QESD particles and at the surface of
190
tablet. Given the shallow take-off angle (45 o) employed in the XPS measurements, the
observation of a F 1s signal in the CEL-QESD samples suggests that the minimum
thickness of the HPMC layer coating the particle surfaces was thinner than the typical
sampling depth of organic compounds by XPS, ~5 nm.10, 30 Otherwise, N and F in CEL
would have not been detected if the HPMC layer was always thicker than the maximum
sampling thickness by XPS.
6.4.6 Interactions between CEL and polymers
To gain molecular-level insight into the very different performances of PVP, HPC,
and HPMC in facilitating the QESD process of CEL (Figures 6.2 and 6.3), we sought to
identify preferential intermolecular interactions between CEL and the various polymers
using solution 1H NMR (Figure 6.12). We directed our attention to changes in the
appearance of the peaks associated with protons ortho to the aryl sulfonamide (H15 and
17), meta to the arylsulfonamide (H14 and H18), the sulfonamide –NH2 (H23), tolyl
protons (H7, H8, H10, H11, H12), and the pyrazole proton (H4) (see the numbering scheme
in Figure 6.1). Although deuterium oxide is the most relevant solvent to investigate the
drug-polymer interactions in the QESD process carried out in water, deuterium oxide could
not be used because CEL is insoluble in it. Therefore, we employed DMSO-d6 as the
alternative solvent because of its high polarity and ability to dissolve both the polymers
and CEL. Addition of HPMC (3 mg/mL) into a DMSO-d6 solution of CEL (3 mg/mL) led
to clear upfield shifts in the 1H NMR resonances associated with H14 and H18 ( 7.84–
7.90 ppm), H15 and H17 ( 7.52–7.60 ppm), H4, H7, H8, and H10 ( 7.16–7.24 ppm), and
H12 ( 2.28–2.36 ppm). The observed upfield shifts of the 1H NMR resonances suggest
191
intermolecular hydrophobic interactions between CEL molecules and/or CEL and HMPC
that resulted in increased electron densities at these positions.31, 32 We note that upfield
shifts of the 1H NMR resonances of aromatic compounds are often observed in their guest-
host inclusion complexes with cyclodextrins,33 the latter of which are cyclic saccharides
that are structurally related to HPMC. The more hydrophilic variant of HPC, apparently
resulted in much smaller shifts in the 1H NMR resonances of CEL, indicating weaker
intermolecular polymer/CEL interactions. Finally, very minimal peak shifts were observed
with the most hydrophilic polymer PVP. These 1H NMR observations lead us to conclude
that hydrophobic interactions between the aryl and aliphatic moieties of the CEL and the
permethylated HMPC additive drive their association in DMSO-d6 solutions. We note that
HMPC addition drove a downfield shift of the peak associated with H23 ( 7.50–7.52 ppm).
This last downfield shift of peaks indicated a decrease in electron density at these protons,
suggestive of sulfonamide hydrogen bond donation to either the HPMC or to other CEL
molecules that are hydrophobically associated with the polymer. No such peak shifts were
observed with the more hydrophilic HPC and PVP additives, even though PVP is solely a
hydrogen bond acceptor that could form complementary interactions with free CEL. This
last observation suggests that intermolecular interactions between hydrophobically
associated CEL molecules along a HPMC chain drive substantial changed in the chemical
environment around the amino group that lead to the observed chemical shift.
The NMR data shown in Figure 6.12 suggests that CEL-polymer association
strength follows the descending order of HPMC >> HPC > PVP. This order is consistent
with their CEL emulsion stabilization abilities discerned from the time-dependent optical
micrographs (Figure 6.3). Thus, hydrophobic association between the CEL and HPMC
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appears to play a critical role in stabilizing the quasi-emulsion and enabling the formation
of spherical agglomerates. Compared to that observed by 1H NMR in DMSO-d6, the
hydrophobic association is likely stronger in the higher polarity H2O during the QESD
process. HPMC chains may thus be driven from the aqueous medium to adsorb onto the
emulsion droplet interfaces, leading to their temporal stabilization that allows for spherical
agglomerate formation with a thin HPMC coating. These findings concur with previous
studies that demonstrated the ability of HPMC to form specific intermolecular interactions
with CEL to significantly reduce the crystal growth in a supersaturated solution,34 whereas
the more hydrophilic PVP did not.35
6.5 Conclusions
We have shown that the strength of the intermolecular interactions between CEL
and HPMC, HPC, and PVP is positively correlated with their ability in facilitating spherical
agglomeration of CEL by the QESD process. CEL-QESD agglomerates exhibit
significantly reduced the punch sticking propensity of CEL with substantially improved
tabletability and flowability. These significant enhancements in CEL powder properties are
attributed to QESD emulsion droplet stabilization by HPMC adsorption to the droplet
surfaces. This results in a thin HPMC coating on the surfaces of the resulting CEL particles,
which reduces punch sticking propensity by forming a physical barrier to separate CEL
from punch surface during compression. This first successful example of reducing punch-
sticking propensity of a highly sticky API by QESD, coupled with molecular-level insight
into the underlying mechanism, adds another powerful particle engineering strategy to the
arsenal of tools that can be used to solve common tablet manufacturing problems.
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Figure 6.1. Chemical structures of (a) the model API CEL, and commonly used polymeric
stabilizers (b) HPMC, (c) HPC, and (d) PVP.
(a) (b) (c) (d)
194
Figure 6.2. Micrographs of agglomerates prepared by QESD method in the absence and
presence of various polymers.
Without polymer 0.5% HPMC
0.5% HPC 0.5% PVP
100μm
m
500μm
m 500μm
m
500μm
m
195
Figure 6.3. Time-dependent growth of CEL spherical agglomerates in various aqueous
polymer solutions assessed by a polarized light microscopy: a) HPMC, b) HPC, and c)
PVP. All scale bars are 500 µm.
30 sec 3 min 6 min 15 min
a)
30 sec 1 min 1.5 min 2 min
b)
5 sec 15 sec 30 sec 2 min
c)
196
Figure 6.4. Punch sticking propensity of CEL after compaction at 50 MPa: a) as-received
CEL, and CEL-QESD prepared from different concentrations of HPMC solutions b) 0.1%,
c) 0.3%, d) 0.5%. (e) Quantitative sticking propensity assessment using formulated CEL
powders (79.5% (w/w) Avicel PH102, 20% CEL, and 0.5% MgSt).
a) b)
c) d)
e)
197
Figure 6.5. Thermal behavior of CEL as-received and CEL QESD (from a 0.5% HPMC
solution) a) differential scanning calorimetry, b) thermogravimetric analysis of as-received
and CEL-QESD samples, and c) PXRD patterns for calculated, as-received, and CEL-
QESD samples.
a) b)
c)
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Figure 6.6. a) Flowability (at 1 kPa pre-shear normal stress) and b) Tabletability of CEL-
QESD as compared to as-received CEL.
a) b)
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Figure 6.7. a) particle size distributions of as-received CEL and CEL-QESD powders, b)
HPMC content in solid CEL-QESD plotted as a function of the HPMC solution
concentration (n = 3).
a) b)
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Figure 6.8. Compaction properties of as-received CEL and CEL-QESD formulations
consisting of 79.5 wt% Avicel PH102, 20 wt% CEL powder, and 0.5 wt% MgSt: a)
tabletability and b) compactibility.
a) b)
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Figure 6.9. Compressibility plot of 20% (w/w) as-received CEL and CEL-QESD
formulations in 79.5% Avicel PH102 and 0.5% Magnesium stearate.
202
Figure 6.10. SEM images of CEL-QESD (top row) and as-received CEL (bottom row) at
low (left column) and high (right column) magnifications.
100 µm
100 µm 10 µm
10 µm
203
Figure 6.11. X-ray photoelectron spectral analysis of the particle surface elemental
compositions of as-received CEL and CEL-QESD, (a) powder, and (b) tablets.
a) b)
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Table 6.1. Elemental composition of sample surfaces
CEL (%) CEL-QESD (%) CEL/Tablet (%) CEL-QESD/Tablet (%)
C1s 69.13 (±1.5) 60.27 (±1.55) 69.1 (±1.5) 86.30 (±0.30)
N1s 8.93 (±0.32) 3.37 (±0.42) 3.4 (±0.4) 0
O1s 9.83 (±0.29) 32.00 (±2.65) 9.8 (±0.3) 11.20 (±1.51)
F1s 9.57 (±0.95) 3.17 (±0.70) 9.1 (±1.3) 2.07 (±1.44)
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Figure 6.12. 1D 1H NMR spectra of CEL (3 mg/mL) with different polymer additives (3
mg/mL) in DMSO-d6 over the chemical shift ranges a) 7.80-7.90 ppm, b) 7.40-7.60
ppm, c) 7.12-7.28 ppm, and d) 2.20-2.40 ppm. The numbering of the resonances
corresponds to that given in Figure 6.1.
b) a)
c) d)
H14, 18 H15, 17 H23
H7, 8, 10, and 11 H4 H12
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6.6 References
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Chaper 7
Research summary and future work
210
Research summary
The thesis work aims to develop robust high drug loading direct compression tablet
formulations using the spherical crystallization technique. The key points of each chapter
are summarized.
In Chapter 2, an extremely high drug loading (99%) direct compression tablet
formulation was successfully developed via the spherical crystallization on the model API
ferulic acid. A tablet formulation requires to meet different crucial properties such as
adequate tablet tensile strength, powder free-flowing, fast dissolution, short disintegration
time, small tablet ejection force, low tablet friability, etc. Among these essential
requirements, tabletability, flowability and dissolution are the most challenging criteria to
deliver in a tablet formulation. Spherical crystallization, a technique that can
simultaneously improve the tabletability and flowability of API, provides a unique
advantage to enable the formulation development. Herein, spherical agglomerates of
ferulic acid was successfully prepared using the QESD method, generating QESD powder
with excellent flow and tableting performance. Owing to these exceptional properties, a
99% API loading direct compression tablet formulation was successfully developed.
In Chapter 3, an in-situ solvation and desolvation process during spherical
crystallization was observed, which generated spherical agglomerates with excellent
plasticity and consequently strong tablet. The solvent DCM not only functioned as the
bridging liquid but also reacted with the API GSF to form a solvate GSF-DCM during the
SA process. Since GSF-DCM is not stable even at room temperature, the spherical
agglomerates of solvate desolvated into the parent drug GSF completely during the drying
211
process. This solvation-desolvation process led to the porous structure of the primary
crystals owing to the escaping of the solvent DCM. During tablet compaction, the
nanopores collapse and the particles are more deformable, which explains the origin of
superior plasticity of spherical agglomerates.
In Chapter 4 and 5, spherical cocrystallization techniques were developed to
simultaneously improve the manufacturability and dissolution performance of BCS Class
II drugs and thus enable high drug loading tablet formulation development. In Chapter 4,
the spherical cocrystallization, based on the combination of SA and cocrystallization, was
applied on the model drug GSF with coformer Acs. In addition, a highly water-soluble
polymer HPC was incorporated to enhance tabletability as well as the wettability of
spherical cocrystal agglomerates. The excellent properties of spherical cocrystal
agglomerates enabled the successful high drug loading (55.7%) tablet formulation
development. In Chapter 5, the spherical cocrystallization technique, a combination of
QESD method and cocrystallization, was applied on the model drug IMC and coformer
SAC, and the polymer HPMC in the water phase functioned as a stabilizer of the emulsions.
1H NMR and DFT computational simulation studies suggest that HPMC interacted with
the SAC molecule through the hydrogen bonds, through which the emulsions were
stabilized. The resulting agglomerates presented spherical shape and large size, leading to
excellent powder flowability. Polymer coating on the particle surface as well as much
smaller primary crystals consisted of agglomerates resulted in excellent tabletability.
Additionally, the much higher solubility of cocrystal over the parent drug IMC implies the
better dissolution. Owing to the exceptional flowability, tabletability and enhanced
212
solubility, a high IMC loading (46.3%) tablet formulation using the direct compression
process was developed.
Based on the mechanism of QESD process, in Chapter 6, the QESD method on the
model drug CEL was applied to reduce the punch sticking propensity. The polymer coating
on the particle surface confirmed by the SEM and XPS analysis, form a physical barrier
between the CEL and punch, which is the key for the reduced the punch sticking propensity.
In addition, the polymer coating substantially improved tabletability of CEL owing to the
formation of a strong 3D bonding structure during tablet compaction. To understand the
origin of the polymer coating, 1H NMR study was carried out to investigate the molecular
interactions between CEL and different polymers. The result suggests that the
intermolecular interactions between CEL and HPMC is the strongest, which is essential to
stabilize the emulsions and form the spherical agglomerates.
213
Future work
Spherical cocrystallization
In Chapter 4 and 5, we successfully developed spherical cocrystallization
techniques based on the SA and QESD methods, and the generated spherical cocrystal
agglomerates presented promising properties (e.g., manufacturability, solubility) that are
attractive in the pharmaceutical product development. However, these properties
improvement are API dependent, and therefore intensive preliminary investigations are
required to ensure the spherical cocrystallization process development.
Selection of a suitable cocrystal with favored mechanical property and solubility is
the first step but crucial to the following development. To improve the solubility of the
drug, a highly water-soluble coformer is preferred since the cocrystal solubility may be
directly proportional to the solubility of constituent reactants.1 Caution should be taken
here since a highly soluble cocrystal has a higher free energy than the parent drug. The
high free energy difference is prone to lead to the phase transformation from cocrystal form
to parent drug during the dissolution, which can be detrimental to the dissolution
performance.
Secondly, screening of a bridging liquid that can wet the cocrystal well to generate
spherical cocrystal agglomerates. Solubility measurement in various solvents, a routine
way to screen the bridging liquid in the spherical crystallization technique, may not be
easily applicable here since the solubility measurement of cocrystal is more tedious. From
parent drug to cocrystal, transferring from one component to multiple components,
selection of bridging liquids using calculation tools may require more calculation resources
214
and longer time to finish. Therefore, the development of a quicker and easier screening
method is necessary.
Thirdly, although the cocrystal has higher solubility than the parent drug, the
dissolution of spherical cocrystal agglomerates may be even worse due to the reduced
surface area exposed to the medium2. In this scenario, incorporation of superdisintegrant
or highly water-soluble polymer in the spherical cocrystal agglomerates will be helpful,
which can break down the large agglomerates into small primary crystals or wet the
agglomerates to increase the exposure of cocrystal to the medium.
Spherical amorphization
Amorphous drugs are becoming more and more attractive owing to its solubility
advantage over its crystalline form. Spherical amorphization, a technique that combines
the spherical agglomeration and amorphization, may be developed to simultaneously
improve the manufacturability and dissolution. Spherical amorphization may have
advantages comparing to the commonly used amorphization techniques such as spray
drying and hot melt extrusion. The particles produced by the spray drying method are
relatively small and require further unit operations such as dry granulation to improve the
flow property. The hot melt extrusion has high energy consumption and requires the drug
to be stable at high temperature.
Continuous manufacturing of spherical crystallization
As discussed in the Chapter 1, many parameters are involved in the spherical
crystallization process and have the potential to influence the properties of spherical
agglomerates. Batch manufacturing process in large scale can cause noticeable batch to
215
batch variation and therefore is not preferred. Instead, a continuous manufacturing process
of spherical crystallization is recommended where the spherical agglomerate is generated
continuously, and the properties can be monitored on-time. Recent advances on the
continuous spherical crystallization process development imply the potential to
manufacture the spherical agglomerates continuously. Still, more investigations are needed
to explore the influence of processing parameters during the continuous manufacturing on
the generated spherical agglomerates comparing to batch manufacturing in small scale. In
addition, no work has been reported on the development of continuous spherical
cocrystallization, which is preferred especially for the water insoluble BCS Class II and IV
drugs.
7.1 Reference
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Microstructures and pharmaceutical properties of ferulic acid agglomerates prepared by
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