Study of liquid–liquid demixing from drug solution

Abstract

In pharmaceutical industry, a deep understanding of the phase diagram is required in design of crystallization processes. We have investigated the phase diagram of a pharmaceutical compound (C 35H 41Cl 2N 3O 2) in a mixture of ethanol/water. This phase diagram exhibits a solid–solid (polymorphism) and a liquid–liquid-phase separation (LLPS) as a function of temperature and drug substance concentration. This study focuses on the LLPS which is metastable with respect to the crystallization of the two polymorphs F I and F II of C 35H 41Cl 2N 3O 2 in an ethanol/water mixture. The LLPS is metastable towards the solubility curve on the whole solvent-solute concentrations and temperature range studied. The LLPS occurred within the metastable zone for crystallization. In our experiments the liquid–liquid-phase transition prevented the drug from crystallizing, while it changed the medium and the conditions of crystallization, which consequently affected the process. The coexistence curves for the liquid phases, also named T L–L boundary, and the spinodal line were measured for a ternary mixture of water-drug-ethanol at atmospheric pressure over a temperature range of 10–50°C. This temperature range corresponds to that used in the crystallization process. Static Light Scattering, HPLC measurements and Karl–Fischer titration were applied to investigate the drug-phase diagram. The isoplethe section of the phase diagram exhibits four regions: one homogeneous (one liquid) and three two-phases (two regions with one liquid+one solid and one region with two liquids), the two solids phases being two polymorphs.