Control of Reaction Crystallization of Organic Compounds Using the Supersaturation Profile

Abstract

Neutralization reaction crystallization is useful for manufacturing drugs that require high bioavailability (i.e., high solubility). Because drug crystals must be of high quality, with the optimal form and particle size, the development of procedures that can produce high quality crystals by reaction crystallization is important. In cooling crystallization, analysis of the supersaturation profile (SSP) is an effective way to improve the crystal quality. SSP analysis is also important in reaction crystallization. However, the changes in the operation parameters (e.g., pH) necessary for crystallization strongly depend on the deposition of the crystals. Thus, solution pH also changes with deposition of the crystals. The purpose of this study is to propose an optimal crystallization point for the improvement of crystal quality through SSP analysis in reaction crystallization. The experimental system involved the reaction of hydrochloric acid and L-arginine to crystallize L-arginine hydrochloride monohydrate. The SSP was computed using HPLC and a pH meter. The relationship among the amount of feed added, crystal size distribution (CSD), and the crystal morphology was investigated through SSP analysis. Control of minute crystals was found to be crucial for CSD improvement. Moreover, operation at a neutral pH and the use of seed crystals were found to effectively inhibit the formation of minute crystals. Furthermore, operation at basic pH effectively produced good crystal morphology. Finally, using these results to modulate the addition technique in the reaction crystallization process, quality crystals with the desired CSD and morphology have been produced.