The Crystallization of Active Pharmaceutical Ingredients with Low Melting Points in the Presence of Liquid–Liquid Phase Separation

Wei Han Lin,Pui Shan Chow,Zai-Qun Yu,Reginald Beng Hee Tan

doi:10.3390/cryst11111326

Abstract

Liquid–liquid phase separation (LLPS) during the crystallization of active pharmaceutical ingredients (APIs) often causes agglomeration and other quality issues in crystal products; thus, it should be avoided if possible. However, LLPS in the crystallization of APIs with low melting points cannot be circumvented in some cases due to yield considerations. The crystallization of ibuprofen in an ethanol/water mixture was studied to explore methods to reduce agglomeration in the presence of LLPS. It was found that unseeded crystallization produced agglomerates when LLPS took place. The two liquid phases resulting from LLPS underwent LLPS again when they were cooled separately, indicating the dynamic nature of LLPS. Seeding and seed ageing at a low supersaturation were very effective in mitigating agglomeration. The effects of two widely used surfactants, i.e., Tween 80 and hydroxypropyl methylcellulose (HPMC), on LLPS and crystallization were confirmed preliminarily. More work needs to be conducted to explore their usefulness in LLPS handling. The findings and techniques presented in this study may be applicable to the crystallization of other APIs with low melting points.

Highlights

Crystallization defines the quality attributes of small-molecule active pharmaceutical ingredients (APIs), including purity, polymorphism, particle size distribution, crystal shape and morphology, etc
LLPS is often associated with impeded spontaneous nucleation, excessively long batch times, ‘desert rose’ morphology and ineffective impurity rejection
This paper aims to test the hypo2thofe1-1 sis that agglomeration that happens in the presence of LLPS can be mitigated by adjusting seed loadings and cooling profiles

Summary

Introduction

Crystallization defines the quality attributes of small-molecule active pharmaceutical ingredients (APIs), including purity, polymorphism, particle size distribution, crystal shape and morphology, etc. These quality attributes must be tightly controlled as they have impacts either on the therapeutic effects of pharmaceutical products or on the process performance in downstream units such as filtration, drying, blending with excipients and tableting. Due to its detrimental effects on the quality attributes of crystals, various strategies have been adopted to avoid LLPS [1], including lowering the starting concentration and impurity levels, solvent switching, seeding and supersaturation control [2,3], and ultrasound application [4,5]. LLPS cannot be circumvented in their crystallization due to yield considerations

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