Pharmorphix^® Crystallization Development

Crystallization is still the most important method of purification for the process chemist. The ability to isolate critical intermediates and final products in high yield and purity without the need for expensive and time-consuming chromatography is fundamental to the successful development of nearly all synthetic chemistry processes.

For all of our crystallization services we have the capability of scaling up procedures from initial screens and micro litre volumes to ~20 litres in order to validate crystallization parameters and test process robustness. On completion, all procedures can be efficiently transferred to the client’s facility, contract manufacturer or another SAFC® site.

The isolation of critical intermediates and final products as amorphous powders can present significant challenges for the process chemist and indeed for the future progression of a development compound. Variations in purity, stability, bulk density and hygroscopity can significantly impact on the performance and behavior of materials which in turn can result in production delays and in extreme circumstances even lead to the redesign of both synthesis and isolation.

SAFC’s Pharmorphix team have many years of experience handling “difficult to crystallize” amorphous materials and developing methods for reliably isolating the products in a crystalline phase. By designing rigorous tailored screening studies we are able to determine the importance of parameters such as seeding strategies and the influence of structure and impurities in the form a crystalline phase.

Classical resolution of acidic or basic racemic drug substances using chiral resolving agents is often the simplest and cheapest way to prepare initial quantities of enantiomerically pure drug substance for testing and characterization. SAFC offers a classical resolution screening service to identify diastereoemeric salts that are suitable for separation of the individual enantiomers. Initial screening experiments are performed in parallel, typically on a milligram scale to increase project efficiencies and reduce material consumption. Experience of the SAFC - Pharmorphix team has shown that the solid state characterization of the diastereomeric salts is critical for an understanding of the resolution process as different polymorphic forms and / or solvates can provide varying resolution results.

For small molecule compounds that lack an ionisable centre, separation of racemic mixtures can sometimes be achieved by a process of kinetic entrainment. This methodology takes advantage of a phenomenon known as conglomeration in which racemic materials are composed of a 50:50 mixture of enantiomerically pure crystals. As conglomeration is only observed in the crystallization of ~10% of small molecules, it is very important to build up a full understanding of each particular system. Our experts utilise complex phase diagrams, constructed from thermal and solubility data, to design experiments that maximise the likelihood of identifying a suitable resolution methodology.