Pharmaceutical Salts and Co-crystal Development; from Conformer Selection to Continuous Manufacture: A Quality by Design Approach

3/9/2020 09:30 - 10:05

Cocrystals provide exciting opportunities in the pharmaceutical industry for the development and manufacturing of new medicines. A wide range of potential compounds that can form cocrystals necessitate the development of sophisticated screening systems to predict the likelihood of cocrystallization. Here, computational modelling and High-throughput screening (HTS) were combined to identify and rank the ideal coformers and stoichiometric ratios for cocrystals of poorly water-soluble drugs, before being scaled-up via Hot-melt extrusion (HME) for continuous manufacture. The purpose of this work was to highlight how a combination of two computational screening systems coupled with Jet dispensing technology allows for a Quality-by-design (QbD) approch for rapid cocrystal screening to large-scale, continuous manufacture.

After completing complementarity screening, based on shape and polarity of cocrystal formers, high ranking coformers were selected and ranked in order of likelihood to form H-bonds with PF4, forming Heterosynthons. The 6 most promising coformers, were experimentally screened via jet dispensing in a variety of different ratios, with successful cocrystal formation found using 1:1 ratios, with the exception of Biotin (1:1.1). The 6 coformers chosen from the computational modelling, Hesperitin, Genistine, Thiabendazole and Biotin were able to form new cocrystals of PF4. These cocrystals were then scaled up via HME. 

This work highlights the effectiveness of Jet dispensing combined with two methods of computational screening to quickly and efficiently identify potential cocrystal systems. Through modelling, it was possible to identify likely coformer candidates, while high throughput screening verified cocrystallization and allowed rapid identification of their preferred stoichiometric ratios, with minimal waste due to the low amounts of material required. This was then scaled up for continuous HME production, with 4 new cocrystal forms of PF4 discovered. ​

Steven Ross, Research Associate in pharmaceutical processes Pharmaceutical, University of Greenwich