Determination of composition distributions of multi-particle crystalline samples by sequential dissolution with concomitant particle sizing and solution analysis

Abstract

Impurities arise in the production of molecular pharmaceutical and fine chemical products and are often addressed by crystallisation. However, impurities are not always adequately removed by crystallisations and in some cases impurities are to a certain extent incorporated within crystal particles. The present work aims to develop approaches to mapping the distribution of impurities within crystal particles for samples of multiple particles by controlled stepwise dissolution in conjunction with analysis by HPLC and sizing of the crystals. 2-Nitro-4-trifluoromethylacetanilide (1) was selected as the compound for study while 4-methyl-2-nitroacetanilide (2), 4-chloro-2-nitroacetanilide (3) and N-(2-nitro-4-trifluoromethylphenyl)pivalamide (4) were selected as the added impurities. The degree of incorporation of additives 2, 3 and 4 into crystals of compound 1 grown from solutions containing up to 10% of the additive was determined, using 50% aqueous ethanol and toluene as solvents. The stepwise dissolution of samples of crystals of compound 1 in hexane, in which compound 1 has low solubility, containing 2-(2-ethylhexyloxy)ethanol to inhibit flocculation, showed reasonably even dissolution of all crystal particles. Analysis of the resulting solutions by HPLC gave composition data which could be assigned to averaged dissolution regions of the crystals, generating distributions of the level of each additive throughout the crystal particle, these being found to be relatively even for additive 2 and 3, and uneven for additive 4.