Development of Continuous Crystallisation Processes of ... · Development of Continuous Crystallisation Processes of Pharmaceutical Compounds to Achieve Better Control Over Final

Development of Continuous Crystallisation

Processes of Pharmaceutical Compounds to Achieve

Better Control Over Final Product Attributes

Anna Jawor-Baczynska

Department of Chemical & Process Engineering

University of Strathclyde, Glasgow

Overview

1. Pharmaceutical crystallisation- continuous processing

2. Modular test bench for continuous crystallisation: mixing, nucleation and growth

3. Continuous generation of seed suspensions

4. Continuous growth of seed crystals

5. Conclusions

23 September 2014 Glasgow

Pharmaceutical crystallisation

Crystallisation is crucial in the pharmaceutical industry, widely used for separation and purification in the

manufacture of active pharmaceutical ingredients (API). Over 90% of all pharmaceutical products, such

as tablets, aerosols, capsules and suspensions contain drug in crystalline form.

Crystallisation is used for:

• synthesis of compounds through reactive

crystallisation/precipitation

• purification of intermediate/final

products

• formulation and product engineering through control of particles attributes (e.g.

shape, size, form etc.)

• assembly of advanced functional materials

• screening for possible polymorphs

• separation of pure compounds

from mixtures


Chen, J., Sarma, B., Evans, J. M. B. & Myerson, A. S. Crystal Growth & Design (2011)

Shekunov, B. Y. & York, P. Journal of Crystal Growth (2000).

Pharmaceutical industry requires strict control over product attributes which are governed by crystallisation process.

FINAL

PRODUCT

SECONDARY

PROCESSES

Tablets, capsules, suspensions …


Design aspects of crystallisation process

CRYSTALLISATION

PROCESS

• purity: chemical and phase (minimize exposure to anything other than therapeutic agent) • particle size distribution (affect bioavailability) • morphology (affect also breakage and flow characteristic of the powder)


Pharmaceutical industry requires strict control over product attributes which are governed by crystallisation process.


Bene

• Reduced plant scale (manufacture using laboratory equipment, no scale-up risk)

• Increased flexibility (moving processes between sites)

• Improved process robustness (greater control, producing the same product every time)

• Potential to exploit faster/ more selective/ hazardous routes

• Lower costs, more sustainable

• Steady state operation (consistent product quality)

• Continuous on-line quality measurements to build understanding

• Better control of product (particle size, polymorphism…)

Benefits of continuous processing



Continuous processing

Flexible modular test bench including

mixing, nucleation and growth units

which enable better control over key

product particle attributes (form, size,

yield, purity) through continuous

crystallisation

AREA OF INTEREST

Mixing unit: • T, X, Y mixers • Vortex mixer • Kenics mixer • Confined Impinging Jet • Jet mixer

Nucleation unit: • Stirred crystalliser • Oscillatory Baffled Crystalliser • Ultrasonic crystalliser • Coflore crystalliser

Growth unit: • Tubular crystalliser • Oscillatory Baffled Crystalliser • Stirred tank

`````````` Nucleation Mixing Growth

CRYSTALLISATION

Continuous nucleation and growth- review

Wong, Cui, et al. Crystal Growth &

Design (2013)

Continuous secondary nucleator and tubular crystalliser

Continuous tubular crystalliser

Eder, Schrank, et al. Crystal Growth & Design

(2012)


Jongen, et al. Chemical Engineering &

Technology (2003).

Continuous tubular crystalliser with seed generation


Example arrangement of continuous nucleation and growth units


Continuous seed generation setup I

Mixing nozzle

Nozzle size: d=0.25mm

Reynolds Number: Re=6901400

Velocity: v=1.76.8m/s

Residence time=30sec

Glycine


Continuous generation of seed crystals by antisolvent precipitation

DL-valine L-glutamic Acid

Paracetamol Benzoic Acid

Compound Mean size [µm]

Solid Recovery [%]

DL-valine (S=4.3) 33.9 ±1.7 90.5 ±6.6

Benzoic Acid (S=3.7) 35.2 ±4.6 76.4 ± 10.5

Paracetamol (S=1.6) 89.9 ±11.1 62.2 ± 2.4

L-glutamic Acid (S=13) 10.1 ± 0.9 (LD) 98.0± 1.2

Glycine (S=15) 90.9 ± 11.5 (LD) 86.4± 1.5

DL-valine Paracetamol

Benzoic Acid L-glutamic Acid

Glycine

200µm


Average

D10 (µm) LD 34.8± 10.3

D50 (µm) LD 90.9± 11.5

D90 (µm) LD 162.9± 23.0

Solid recovery (%) 86.4± 1.5

Continuous generation of seed crystals- process consistency (glycine)

Laser diffraction FBRM- total counts

Microscopic images

Continuous generation of seed crystals- effect of solvent/ antisolvent

Compound Solvent/ Antisolvent

Mean size [µm]

Solid Recovery [%]

Paracetamol

Water-Isopropanol (S=1.6)

89.9 ±11.1 62.2 ±2.4

Isopropyl myristate- Isopropanol

(S=2.6)

40.4 ±3.3

84.9 ± 14.2

H2O-Isopropanol

Isopropyl Myristate-

Isopropanol

Solubility of paracetamol in IPA-H2O* and IPA-IPM**

*Hojjati, H. & Rohani, S. Organic Process

Research & Development (2006).


**Measured using Crystal16

Continuous seed generation setup II- tubular nucleator

Mixing nozzle

Nozzle size: d=0.25mm

Reynolds Number: Re=1400

Velocity: v= 6.8m/s


Solution

Antisolvent


Setup I Setup II

D10 (µm) 34.8± 10.3 69.0± 10.2

D50 (µm) 90.9± 11.5 143.3± 14.6

D90 (µm) 162.9± 23.0 231.0± 32.9

Solid recovery (%) 86.4± 1.45 85.6± 2.2

Continuous generation of seed crystals- Glycine setup I and II


Laser diffraction

Microscopic images

FBRM- Total counts (#) FBRM- chord length distribution

Continuous seed generation setup II- tubular nucleator


Total flow: 100g/min (20g/min

solution-80g/min antisolvent)

d=0.5mm, Re=652, v=1.70m/s


The Inno-spec RedEye hyperspectral camera Laser diffraction

Low flow rate High flow rate Cooling: 1C/min, 400rpm, 100ml

Total flow: 200g/min

(40g/minsolution- 160g/min antisolvent)

d=0.5mm, Re=1304, v=3.4m/s

Residence time=5sec

Growth of seed crystals: paracetamol


Growth of seed crystals: paracetamol

Seed crystals

Growth - addition sol

Growth - cooling

Mean size [µm]

Solid Recovery [%]

Growth by mass [%]

Seeds 190 6.4 91.0 15.4 -

Growth – addition sol. 257 6.4 44.8 5.7 67.8

Growth – cooling 287 6.9 51.1 1.3 151.4


Summary

1. Separation of nucleation process (formation of seed crystals) from subsequent growth

helps to better control the final product attributes in continuous crystallisation

2. Modular test bench provides range of units tailored for specific mixing, nucleation and

growth requirements of particular systems

3. Examples of continuous generation of seeding suspensions have been demonstrated

through rapid antisolvent crystallisation for a wide range of systems

4. Continuous feeding of seeding suspensions into continuous crystal growth units

(MSPMPR, COBC, etc.) allows for fully continuous crystallisation process

5. Using in situ PAT improve understanding of continuous nucleation/crystallisation process


Acknowledgements

Colleagues from CMAC

Prof. Jan Sefcik

Prof. Alastair Florence

Centre for Continuous Manufacturing and Crystallisation

GSK

AstraZeneca

Novartis

EPSRC


Thank you for your attention


Documents

Development of Continuous Crystallisation Processes of ... · Development of Continuous Crystallisation Processes of Pharmaceutical Compounds to Achieve Better Control Over Final