A framework for systematic crystal shape tuning – case of Lovastatin's needle-shaped crystals
One of the most important challenges in the pharmaceutical industry is to produce crystals with desired size and shape distributions, to enhance the critical quality attributes of the drug product, such as efficacy, and to improve manufacturability during downstream processing, such as filtration, drying and granulation. The paper provides a framework for effective crystal shape and size tuning, based on a systematic exploration of standard techniques, such as the linear cooling and supersaturation control (SSC), and novel methods based on the systematic combination of several techniques, namely direct nucleation control (DNC), wet milling, SSC and shape modification additives. The crystallization of lovastatin, which is notorious for its challenging needle-shaped crystals, with an extremely high aspect ratio, was used as a case study, and polypropylene glycol (PPG-4000), at different concentrations, was used as an effective shape modifier from small-scale tests studied previously. The proposed techniques were implemented in the case of seeded and unseeded systems. It was demonstrated that the combination of temperature cycling and polymer additive enhances greatly the control over the aspect ratio and crystal size distribution, compared to conventional linear cooling and SSC strategies. The implementation of wet milling at the beginning of the process, or the introduction of seeds, enhances even further the control of the critical quality attributes of the crystalline product.
Funding
Future Continuous Manufacturing and Advanced Crystallisation Research Hub
Engineering and Physical Sciences Research Council
Find out more...Intelligent Decision Support and Control Technologies for Continuous Manufacturing of Pharmaceuticals and Fine Chemicals
Engineering and Physical Sciences Research Council
Find out more...History
School
- Aeronautical, Automotive, Chemical and Materials Engineering
Department
- Chemical Engineering
Published in
Chemical Engineering Research and DesignVolume
202Pages
126 - 146Publisher
ElsevierVersion
- VoR (Version of Record)
Rights holder
© The AuthorsPublisher statement
This is an Open Access Article. It is published by Elsevier under the Creative Commons Attribution 4.0 International Licence (CC BY). Full details of this licence are available at: https://creativecommons.org/licenses/by/4.0/Acceptance date
2023-12-11Publication date
2023-12-15Copyright date
2023ISSN
0263-8762eISSN
1744-3563Publisher version
Language
- en