(141d) Use of a Crystallization Modifier to Enhance Impurity Rejection in the Crystallization of a Pharmaceutical Intermediate

During the pilot plant campaign to make an API intermediate, an impurity not previously seen was detected during the work-up at a level of greater than 3%. The kinetics of the impurity crystallization in the given solvent system demonstrated that within several hours, the impurity concentration decreased significantly, thus facilitating very limited rejection. The extensive screening of alternative solvent systems to improve rejection of the impurity was unsuccessful. Moreover, the impurity was not significantly rejected in subsequent processing steps. We used an additive to modify the crystallization kinetics of both the impurity and API intermediate to effect the desupersaturation of both compounds in such a way to favor rejection of the impurity over a specific time period. The process was optimized with respect to the amount of crystallization modifier and temperature profile. A quantitative NMR method was developed to determine the crystallization modifier content in the isolated intermediate. The process was implemented in the pilot plant, and the isolated intermediate contained less than 0.1% of the impurity.