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“DEVELOPMENT AND EVALUATION OF SOME
NOVEL NANOSUSPENSION”
A
Thesis
Submitted
In the fulfillment of the requirements for the award of
DOCTor OF PHILOSOPY
IN
PHARMACY
(PHARMACEUTICS)
SUPERVISOR SUBMITTED BY
DR.SWATI C JAGDALE SUNIL JAGANNATH AHER
( M.Pharm,PhD) E. No: SGVU112806006
SURESH GYAN VIHAR UNIVERSITY
MAHAL JAGATPURA, JAIPUR
MAY-2015
Supervisor’s Certificate
This is to certify that the thesis entitled: “DEVELOPMENT AND EVALUATION
OF SOME NOVEL NANOSUSPENSION” submitted by Mr. Sunil Jagannath Aher
to the Suresh Gyan Vihar University towards fulfillment of the requirements for the
award of the Degree of Doctor of Philosophy in Pharmacy is a bonafide record of
the work carried out by him under my supervision and guidance.
It is certified that the comments given by experts in DRC have been suitably
incorporated under my supervision in the thesis.
It is also certified that the candidate Mr. Sunil Jagannath Aher have attended the
course work of one semester at Suresh Gyan Vihar University,Jaipur.
Signed by supervisor:
Place: Jaipur
Signature of Dean Research
Suresh Gyan Vihar University
Candidate’s Declaration
"I hereby declare that the work ,which is being presented in the Thesis, entitled
“DEVELOPMENT AND EVALUATION OF SOME NOVEL NANOSUSPENSION” is my own
work and that, to the best of my knowledge and belief, it contains no material previously
published or written by another person nor material which has been accepted for the award of
any other degree or diploma of the university or other institute of higher learning, except where
due acknowledgment has been made in the text.
It is certified that the comments given by experts in DRC have been suitably incorporated under
the advice of my supervisor in the thesis.
It is also certified that I have taken course work of one semester at Suresh Gyan Vihar
University, Jaipur.
Place: Jaipur Signature :
Date: Name: Sunil Jagannath Aher
Reg.No : RS/SGVU/DeRes/Pharma/43
Enrolment No.: SGVU112806006
Signature of Supervisor:
Name: Dr. Swati C . Jagdale
ACKNOWLEDGEMENT
I have great pleasure & dedicated gratitude to those personalities who gave me their valuable
blessings, guidance & esteemed co-operation in motivating me to complete my dissertation
work.
I take this opportunity with pride & immense pleasure expressing my deep sense of gratitude to
my respectable guide Dr.Swati Jagdale Madam whose active guidance, innovative ideas,
constant inspiration, untiring efforts help encouragement & continuous supervision has made the
presentation of dissertation a grand and glaring success.
I express my deep sense of gratitude to our, Principal Dr. S B Kasture & Dr.S R Arote sir,
Chairman Hon’ Amit dada Kolhe saheb for providing all facilities and encouragement to
complete this research work successfully.
I am also thankful to all faculty members, laboratory assistants and non-teaching staffs as
well as SICART Lab Gujarat, STIC Lab cochin ,ZCL Laboratory for their kind cooperation and
support for the evaluation of the sample without that it was not possible.
I am also thankful to my family my brother and sister as well as friends Dr.G S Asane, Shankar
Pol, Deepak musmade for their generous cooperation, help & sharing all the moments of joy and
sadness.
At last but not the least my words fail in expressing my gratitude to my mother & And specially
happy to thanks my wife Poonam she always encourage and motivate me for the research
moreover thanks to my father in law for the constant support and constant inspiration etc etc
And, at last my head bows down in front of almighty that made all things possible, true and
success by his blessing & mentally support.
Date: 27/05/2015
Place: Jaipur Sunil Jagannath Aher
Thesis Approval
This is to certify that research work embodied in this entitled “DEVELOPMENT AND
EVALUATION OF SOME NOVEL NANOSUSPENSION” was carried out by Mr.Sunil
Jagannath Aher, Reg.No: RS/SGVU/DeRes/Pharma/43 , is approved for the award of the degree
of Doctor of Philosophy in the faculty of Pharmacy by Suresh Gyan Vihar University.
Date:
Place:
Signature of External Examiner : Signature of Dean-Research
Signature of Internal Examiner:
Dr. Swati C Jagdale, Professor& HOD
Dept of Pharmaceutics MAEER’s MIP ,Pune.
Abstract
In the present study the formulation of nanosuspension was prepared by Quassi emulsification
solvent diffusion method .With a aim to improve water solubility of the poorly water soluble
drug such as Zaltoprofen, Lornoxicam,Ketoprofen,,Meloxicam belong to the BCS Class-II, the
total eight formulation of each drug was prepared with varying proportion of polymer such as
Eudragit RS100/Eudragit RL100 along with the stabilizer poloxamber 407.The formulated all
nanosuspension were evaluate for the Particle size analysis, Saturation Solubility , drug
entrapment , invitro dissolution studies, Zeta potential, short term stability studies and the
result show the stable nanosuspension with nanosize drug reduction with polymer Eudragit
RS100 with proper coat on drug with maximum drug entrap compare to Eudragit RL00.
Saturation solubility of such nanosuspension reveals that the aqueous solubility of drug is
significantly increased due to decrease in particle size(80-300 nm). The short term stability
studies was performed at two set of temperature 4 oC & 37
oC prove that the drug in
nanosuspension can be remain stable at temperature 4 oC .Zeta potential was found to be
optimum which show the formulation are stable. Invitro drug release from the nanosuspension
show sustained /diffusion release of drug from the polymeric nanosuspension.
From the above studies it is concluded that the poloxamber 407 stabilizer (Pluronic 127) can be
used for formulating stable nanosuspension with varying concentration in range of 0.5-1.0 %. It
gives effective size as well as stability to nanosuspension. The ratio of Drug, polymer and
stabilizer (Drug, Eudragit RS100 and Poloxamber 407) is important to obtain the stable
nanosuspension. The ratios which were selected for preparation of nanosuspension i.e. 1:2:0.5
and 1:2:1.Eudragit RS100 is more effective polymer in the formulation of nanosuspensions than
Eudragit RL100.
Sr.No List of figures Page
no.
4.1 U.V. absorption spectrum of Zaltoprofen in 7.4 pH Phosphate buffer 66
4.2 shows the calibration curve of Zaltoprofen in 7.4 pH Phosphate Buffer 67
4.3 Structure of Zaltoprofen 67
4.4 IR spectrum of Zaltoprofen 68
4.5 shows the DSC of Pure Zaltoprofen. 69
4.6 IR spectra for compatibility study: Zaltoprofen (a); Eudragit RS100 (b); Eudragit
RS100 (c); Poloxomber 407 (d).
70
4.7 DSC thermographs for compatibility study: Zaltoprofen (a); Eudragit RS100 (b);
Eudragit RS100 (c); Poloxomber 407 (d).
71
4.8 U.V. absorption spectrum of Ketoprofen 72
4.9 shows the Calibration curve of Ketoprofen in 7.4 pH Phosphate buffer 73
4.10 Structure of ketoprofen (a); 4.10: IR spectrum of ketoprofen(b). 74
4.11 shows the DSC of Ketoprofen 75
4.12 IR spectra for compatibility study:ketoprofen (a); Eudragit RS100 (b); Eudragit
RS100 (c); Poloxamer 407 (d).
76
4.13 DSC thermographs for compatibility study: Ketoprofen (a); Eudragit RS100 (b);
Eudragit RS100 (c); Poloxamer 407 (d).
77
4.14 U.V. absorption spectrum of lornoxicam in 7.4 pH Phosphate buffer 78
4.15 Shows Calibration curve of Lornoxicam in 7.4pH phosphate buffer 79
4.16 Structure of Lornoxicam (a); 4.16: IR spectrum of Lornoxicam(b) 80
4.17 DSC of Lornoxicam 81
4.18 IR spectra for compatibility study: Lornoxicam (a); Eudragit RS100 (b);
Eudragit RS100 (c); Poloxamer 407 (d).
82
4.19 DSC thermographs for compatibility study: Lornoxicam (a); Eudragit RS100
(b); Eudragit RS100 (c); Poloxamer 407 (d).
83
4.20 U.V. absorption spectrum of Meloxicam in 7.4 pH Phosphate buffer 85
4.21 Calibration curve of Meloxicam in 7.4 pH phosphate buffer 86
4.22 Structure of Meloxicam (a); 4.22: IR spectrum of Meloxicam(b) 86
4.23 DSC of Meloxicam 88
4.24 IR spectra for compatibility study: Meloxicam (a); Eudragit RS100 (b); Eudragit
RS100 (c); Poloxamer 407 (d).
89
4.25 DSC thermographs for compatibility study: Meloxicam (a); Eudragit RS100 (b);
Eudragit RS100 (c); Poloxamer 407 (d).
90
4.26 IR spectra of Eudragit RS100 and Eudragit RL100 and poloxomber 91
4.27 Structure of Eudragit RS100/ Eudragit RL100. 93
4.28 DSC thermograms of Eudragit RS100 and Eudragit RL100 & poloxamber407 994
4.29 SEM of ZRS- F1 Formulation 97
4.30 SEM of ZRS-F2 Formulation. 97
4.31 SEM of ZRS100-F3 Formulation 98
4.32 SEM of ZRS100-F4 Formulation 98
4.33 SEM of ZRS100-F5 ZRL Formulation 99
4.34 SEM of ZRS100-F6 ZRL Formulation 99
4.35 SEM of F7 ZRL Formulation 100
4.36 SEM of F8 ZRL Formulation 100
4.37 Drug release of zaltoprofen nanosuspension with Eudragit RS100 105
4.38 Drug release of zaltoprofen nanosuspension with Eudragit RL100 106
4.39 First order plot for ZRS-F4 107
4.40 Plot of Higuchi for the ZRS-F4 Formulation 108
4.41 Korseymer plot for the ZRS-F4 Formulation 109
4.42 SEM of MRS100- F1 Formulation 111
4.43 SEM ofMRS100- F2 Formulation 111
4.44 SEM ofMRS100- F3 Formulation 112
4.45 SEM of MRS100-F4 Formulation 112
4.46 SEM of MRL100-F5 Formulation 113
4.47 SEM of MRL100-F6 Formulation 113
4.48 SEM of MRL100-F7 Formulation 114
4.49 SEM of MRL100-F8 Formulation 114
4.50 Graph for the Percentage cumulative drug release of Meloxicam nanosuspension
with Eudragit RS100.
119
4.51 Graph for Percentage cumulative drug release of Meloxicam nanosuspension 120
with Eudragit RL100.
4.52 Higuchi plot for the MRS-F2 Formulation 121
4.53 Korseymer peppas plot for the MRS-F2 Formulation 122
4.54 first order plot of MRS-F2 Nanosuspension 123
4.55 SEM of KRS-F1 Formulation 125
4.56 SEM of KRS- F2 Formulation 125
4.57 SEM of KRS- F3 Formulation 126
4.58 SEM of KRS- F4 Formulation 126
4.59 SEM of KRS- F5 Formulation 127
4.60 SEM of KRS- F6 Formulation 127
4.61 SEM of KRS- F7 Formulation 128
4.62 SEM of KRS- F8 Formulation 128
4.63 Graph of Percentage cumulative drug release of Ketoprofen nanosuspension
with Eudragit RS100
133
4.64 Graph of Percentage cumulative drug release of Ketoprofen nanosuspension
with Eudragit RL100
134
4.65 Data of Higuchi plot for the KRS-F4 Formulation 135
4.66 Korseymer Peppas plot for the KRS-F4 Formulation 136
4.67 Plot for first order of formulationKRS-F4 137
4.68 SEM of LRS100- F1 Formulation 139
4.69 SEM of LRS100- F2 Formulation 139
4.70 SEM of LRS100- F3 Formulation 140
4.71 SEM of LRS100- F4 Formulation 140
4.72 i. SEM of LRL100- F5 Formulation 141
4.73 SEM of LRL100- F6 Formulation 141
4.74 SEM of LRL100- F7 Formulation 142
4.75 1. SEM of LRL100- F8 Formulation 142
4.76 Graph of Percentage cumulative drug release of Lornoxicam nanosuspension
with Eudragit RS100 (LRS-F1 to LRS-F4)
147
4.77 Plot of percentage cumulative drug release of Lornoxicam nanosuspension with
Eudragit RL100(LRL-F5 to LRL-F8).
148
4.78 Higuchi Plot for formulation LRS-F4 150
4.79 Korseymer Peppas plot for the LRS-F4 Formulation 151
4.80 Plot of first order of formulation LRS-F4 152
4.81 Invitro drug release of formulation KRS-F4 (Stability studies at 4 oC) 154
4.82 Invitro drug release of formulation KRS-F4 (Stability studies at 37 o
C) 155
4.83 Invitro drug release of formulation ZRS-F4 (Stability studies at 4 oC) 156
4.84 Invitro drug release of formulation ZRS-F4 (Stability studies at 37 oC) 157
4.85 Invitro drug release of formulation MRS-F2 (Stability studies at 4 oC) 158
4.86 Invitro drug release of formulation MRS-F2 (Stability studies at 37 o
C) 159
4.87 Invitro drug release formulation LRS-F4 (Stability studies at 4 oC) 160
4.88 Invitro drug release of formulation LRS-F4 (Stability studies at 37 o
C) 161
Sr.No List of Tables Page
no.
3.1 Detail drug profile of Zaltoprofen 39
3.2 Drug Profile of Ketoprofen 41
3.3 Drug profile of Lornoxicam 42
3.4 Drug profile of Meloxicam 44
3.5 Shows the list of drug, excipients and chemicals used during the study. 45
3.6 Details of Equipments/Instrument used. 45
3.7 Details about formulation contents of Zaltoprofen polymeric nanosuspension
batches.
56
3.8 Details about formulation contents of Meloxicam polymeric nanosuspension
batches.
57
3.9 Details about formulation contents of Ketoprofen polymeric nanosuspension
batches.
58
3.10 Details about formulation contents of polymeric nanosuspension batches.(
Lornoxicam )
59
4.1 show λ max values of Zaltoprofen in7.4 pH Phosphate buffer. 66
4.2 UV absorption data of Zaltoprofen 66
4.3 Shows characteristic frequencies in IR spectrum of Zaltoprofen. 68
4.4 λ max values of in various solvents. 72
4.5 Ketoprofen concentrations and absorbance data 73
4.6 Characteristic frequencies in IR spectrum of ketoprofen. 74
4.7 λ max values of in 7.4 pH Phosphate buffer 78
4.8 Lornoxicam concentrations & absorbance data in7.4 pH phosphate buffer. 79
4.9 Characteristic frequencies in IR spectrum of Lornoxicam. 80
4.10 λ max values of in 7.4 pH Phosphate buffer. 84
4.11 Meloxicam concentrations and absorbance data in 7.4 pH Phosphate buffer 85
4.12 Shows characteristic frequencies in IR spectrum of Meloxicam. 87
4.13 Appearance and melting point of Eudragit RS100 and Eudragit RL100. 91
4.14 Characteristic frequencies in IR spectrum of Eudragit RS100/ Eudragit RL100 93
4.15 Showing the ZLT nanosuspension particle size in nanometer (nm):
96
4.16 Percentage drug unincorporated and entrapped for nanosuspension 101
4.17 Zeta potential of nanosuspension of ZLT nanosuspension 102
4.18 Shows the saturation solubility of pure ZLT drug & ZLT nanosuspension in
Distilled Water.
103
4.19 Percentage cumulative drug release of ZLT nanosuspension formulated with
Eudragit RS100.
104
4.20 Percentage cumulative drug release of ZLT nanosuspension formulated with
Eudragit RL100
105
4.21 Data for the first order plot of ZRS-F4 107
4.22 Data of Higuchi plot for the ZRS-F4 Formulation 108
4.23 Data of Korseymer plot for the ZRS-F4 Formulation 109
4.24 Showing the MLX nanosuspension and the particle size in nanometer (nm) 110
4.25 Percentage drug unincorporated and entrapped for nanosuspension 115
4.26 Zeta potential of nanosuspension of MLX nanosuspension 116
4.27 shows the saturation solubility of pure MLX drug & MLX Nanosuspension in
Distilled Water
117
4.28 Percentage cumulative drug release of Meloxicam nanosuspension with
Eudragit RS100.
118
4.29 Percentage cumulative drug release of Meloxicam nanosuspension with
Eudragit RL100.
119
4.30 Data of Higuchi plot for the MRS-F2 Formulation 121
4.31 Data of Korseymer plot for the MRS-F2 Formulation 122
4.32 Data for the first order plot of MRS-F2 Nanosuspension 123
4.33 Showing the Ketoprofen nanosuspension particle size in nm 124
4.34 Percentage drug unincorporated and entrapped for nanosuspension 129
4.35 Zeta potential of ketoprofen nanosuspension 130
4.36 shows the saturation solubility of pure ketoprofen drug & ketoprofen
Nanosuspension in Distilled Water
131
4.37 Percentage cumulative drug release of Ketoprofen nanosuspension with
Eudragit RS100
132
4.38 Percentage cumulative drug release of Ketoprofen nanosuspension with
Eudragit RL100
133
4.39 Data of Higuchi plot for the KRS-F4 Formulation 135
4.40 Data of Korseymer Peppas plot for the KRS-F4 Formulation 136
4.41 Data for first order plot for formulation : KRS-F4 137
4.42 Showing the Lornoxicam nanosuspension particle size in nm 138
4.43 Percentage drug unincorporated and entrapped for nanosuspension 143
4.44 Zeta potential of Lornoxicam nanosuspension 144
4.45 shows the saturation solubility of pure LRM drug & LRM Nanosuspension in
Distilled Water
145
4.46 Percentage cumulative drug release of Lornoxicam nanosuspension with
Eudragit RS100 (LRS-F1 to LRS-F4).
146
4.47 Percentage cumulative drug release of Lornoxicam nanosuspension with
EudragitRL100 (LRL-F5 to LRL-F8).
147
4.48 Data for the Higuchi Plot for formulation LRS-F4 149
4.49 Data of Korseymer Peppas plot for the LRS-F4 Formulation 151
4.50 Data for first order plot of formulation LRS-F4 152
4.51 Data of In-vitro drug release of KRS-F4 (Stability studies at 4 oC) 154
4.52 Data of In-vitro drug release of KRS-F4 (Stability studies at 37 oC) 155
4.53 Data of In-vitro drug release of ZRS-F4 (Stability studies at 4 oC) 156
4.54 Data of In-vitro drug release of ZRS-F4 (Stability studies at 37 oC) 157
4.55 Data of In-vitro drug release of MRS-F2 (Stability studies at 4 oC) 158
4.56 Data of In-vitro drug release of MRS-F2 (Stability studies at 37 oC) 159
4.57 Data of In-vitro drug release LRS-F4 (Stability studies at 4 oC) 160
4.58 Data of In-vitro drug release of LRS-F4 (Stability studies at 37 oC) 161
4.59 Mathematical model for all the formulation 165
5.1 Drug and their particle size (nm) 168
List of Abbreviations
ZLT Zaltoprofen
MLX Meloxicam
KTN Ketoprofen
LRN Lornoxicam
SEM Scanning Electron Microscopy
DSC Differential Scannig colorimetry
IR Infra red Spectroscopy
BCS Biopharmaceutical Classification System
UK United Kingdom
NSAID Non steroidal Anti-inflammatory drug
COX Cyclo-oxygenase
COX-2 Cyclo-oxygenase-2
PGE2 Prostaglandin –E2
USA United state of America
HPC Hydroxyl Propyl Cellulose
SDC Sodium Dodecyl sulfate
SD Sodium Docusate
HPMC Hydroxyl Propyl Methyl Cellulose
PEG Polyethylene glycol
PCA Precipitation along with compressed antisolvent process
DDS Drug Delivery System
SLN Solid Lipid Nano-particulate
AUC Area under curve
nm Nanometer
ZRS-F1 Zaltoprofen formulation code F1 with Eudragit RS100 polymer
ZRS-F2 Zaltoprofen formulation code F2 with Eudragit RS100 polymer
ZRS-F3 Zaltoprofen formulation code F3 with Eudragit RS100 polyme3
ZRS-F4 Zaltoprofen formulation code F4 with Eudragit RS100 polymer
ZRL-F5 Zaltoprofen formulation code F5 with Eudragit RL100 polymer
ZRL-F6 Zaltoprofen formulation code F6 with Eudragit RL100 polymer
ZRL-F7 Zaltoprofen formulation code F7 with Eudragit RL100 polymer
ZRL-F8 Zaltoprofen formulation code F8with Eudragit RL100 polymer
MRS-F1 Meloxicam formulation code F1 with Eudragit RS100 polymer
MRS-F2 Meloxicam formulation code F2 with Eudragit RS100 polymer
MRS-F3 Meloxicam formulation code F3 with Eudragit RS100 polymer
MRS-F4 Meloxicam formulation code F4 with Eudragit RS100 polymer
MRL-F5 Meloxicam formulation code F5 with Eudragit RL100 polymer
MRL-F6 Meloxicam formulation code F6 with Eudragit RL100 polymer
MRL-F7 Meloxicam formulation code F7 with Eudragit RL100 polymer
MRL-F8 Meloxicam formulation code F8 with Eudragit RL100 polymer
KRS-F1 Ketoprofen formulation code F1 with Eudragit RS100 polymer
KRS-F2 Ketoprofen formulation code F2 with Eudragit RS100 polymer
KRS-F3 Ketoprofen formulation code F3 with Eudragit RS100 polymer
KRS-F4 Ketoprofen formulation code F4 with Eudragit RS100 polymer
KRL-F5 Ketoprofen formulation code F5 with Eudragit RL100 polymer
KRL-F6 Ketoprofen formulation code F6 with Eudragit RL100 polymer
KRL-F7 Ketoprofen formulation code F7 with Eudragit RL100 polymer
KRL-F8 Ketoprofen formulation code F8 with Eudragit RL100 polymer
LRS-F1 Lornoxicam formulation code F1with Eudragit RS100 polymer
LRS-F2 Lornoxicam formulation code F2with Eudragit RS100 polymer
LRS-F3 Lornoxicam formulation code F3with Eudragit RS100 polymer
LRS-F4 Lornoxicam formulation code F4with Eudragit RS100 polymer
LRL-F5 Lornoxicam formulation code F5with Eudragit RL100 polymer
LRL-F6 Lornoxicam formulation code F6with Eudragit RL100 polymer
LRL-F7 Lornoxicam formulation code F7with Eudragit RL100 polymer
LRL-F8 Lornoxicam formulation code F8with Eudragit RL100 polymer
KRS-F4-1 Ketoprofen formulation code F4 with Eudragit RS100 ,Stability one month
KRS-F4-2 Ketoprofen formulation code F4 with Eudragit RS100 ,Stability two month
KRS-F4-3 Ketoprofen formulation code F4 with Eudragit RS100 ,Stability three month
LRS-F4-1 Lornoxicam formulation code F4with Eudragit RS100 ,Stability one month
LRS-F4-2 Lornoxicam formulation code F4with Eudragit RS100 ,Stability two month
LRS-F4-3 Lornoxicam formulation code F4with Eudragit RS100 ,Stability three month
MRS-F2-1 Meloxicam formulation code F2 with Eudragit RS100 ,Stability one month
MRS-F2-2 Meloxicam formulation code F2 with Eudragit RS100 ,Stability two month
MRS-F2-3 Meloxicam formulation code F2 with Eudragit RS100 ,Stability three month
ZRS-F4-1 Lornoxicam formulation code F4 with Eudragit RS100 ,Stability one month
ZRS-F4-2 Lornoxicam formulation code F4 with Eudragit RS100 ,Stability two month
ZRS-F4-3 Lornoxicam formulation code F4 with Eudragit RS100 ,Stability three month
