Control of Product Quality in Batch Crystallization of Pharmaceuticals and Fine Chemicals.Part 1: Design of the Crystallization Process and the Effect of Solvent

摘要

The product quality in a crystallization process refers to the crystal size distribution (CSD),crystal morphology,polymorphic outcome and the degree of crystallinity,and purity.In addition,the product yield is also important.Properties such as the filterability and solid bulk density are directly related to the CSD.To obtain the desired product quality,attention should be paid to the various operating conditions such as the local and average levels of supersaturation,the type of the solvent,the operating temperature and pressure,the type and concentration of impurities and tailor-made additives,degree of mixedness,geometry and the mode of operation of the crys-tallizer,and seeding and feeding policies.In addition to these variables,the implementation of external control either in the form of a feedback controller or an optimal control policy can further improve the product quality.In Part 1 of the present communication,an attempt is made to present a systematic approach to investigate the effect of various operating conditions,i.e.,the design of the crystallization processes,on the product quality.In particular the effect of the solvent in terms of the solubility and its ability to participate in forming hydrogen bonds with the solute molecules will be studied.The effect of mixing,the seeding policy,and the design of the feed system on the product quality will also be discussed.Experimental results are presented to demonstrate the effect of the operating conditions in improving the filterability and solid bulk density of ranitidine hydrochloride and another pharmaceutical compound.In Part 2,the effect of the "external control" on the product quality will be discussed.