Cooling Crystallization of Indomethacin: Effect of Supersaturation, Temperature, and Seeding on Polymorphism and Crystal Size Distribution

Abstract

In this work, the effect of crystallization parameters, i.e., supersaturation, seeding, and temperature, on the polymorphism and crystal size of a nonsteroidal anti-inflammatory drug, indomethacin (IMC), was investigated. First, several crystallization solvents (ethanol, methanol, ethyl acetate, acetone, acetonitrile, and dichloromethane) were screened through the measurement of IMC solubility at different temperatures. This was followed by the investigation of IMC nucleation through measurement of induction times in selected solvents at two supersaturations. Finally, seeded cooling crystallization of IMC in ethanol was performed with different process parameters to investigate the influence on the polymorphism and crystal size distribution. Remarkably long induction times were observed for IMC in ethanol and ethyl acetate solutions, while a shorter induction time was observed in acetone. Cooling crystallization of IMC from ethanol confirmed that supersaturation, operating temperature, and seeding do affect the polymorphism as well as crystal size distribution of IMC. Fine needle-shaped crystals of metastable α-IMC were obtained at 5 °C with high supersaturation even in the presence of γ-IMC seeds, while rhombic platelike crystals of thermodynamically stable γ-IMC were obtained in the remaining experiments. The seed loading only marginally influenced the crystal growth rate and median particle diameter. Particle size analysis of the crystals obtained showed a bimodal distribution in all experiments, and a larger median particle diameter was observed at 15 °C with high supersaturation.

Antisolvent Crystallization of Indomethacin from a Ternary Solvent System with High Productivity, Better Polymorphism, and Particle Size Control

“…Therefore, the solubility measurement of APIs in different solvents or solvent mixtures is indispensable in the development of crystallization processes. Previously measured solubilities of γ-IMC in pure organic solvents at different temperatures and in the binary solvent mixtures at 25 °C are shown in Figure a,b, respectively. , It is obvious from Figure b that the solubility of γ-IMC reaches a maximum at a certain binary solvent mixture composition, which is significantly higher than the solubility in pure solvents. This kind of solubility behavior, where a maximum solubility is observed at a certain binary mixture composition, is very often observed for many APIs. − Therefore, the use of binary solvent mixtures with a high solubility of APIs can allow a higher initial concentration of APIs, thereby increasing the batch yield as well as lowering the crystallizer volume.…”

“…Solubility of γ-IMC in (a) pure organic solvents, modified from Malwade et al, and (b) binary solvent mixtures at 25 °C, modified from Hellstén et al Solid and dashed lines are drawn for visual guidance.…”

“…As shown in the previous section, the crystallization of the undesired acetone solvate of IMC occurs during the unseeded antisolvent crystallization from acetone–methanol solution. Seeding with the desired polymorph is a widely used strategy for controlling the polymorphism, even though it is not always guaranteed to obtain the seeded polymorph as a product . In this case, the degree of supersaturation and the amount of seed load can affect the outcome.…”

“…So far, very few studies have reported the crystallization processes for the production of a stable γ-IMC polymorph, and most of the studies do not discuss the crystal yield or productivity of the process and report very long batch times. ,, In our previous work, we have reported the seeded cooling crystallization of IMC from ethanol at different temperatures, initial IMC concentrations, and seed loads. Although it was shown to produce γ-IMC consistently with a high initial IMC concentration (5.5 g/100 g of solvent) at 15 °C, the yield was very low as a result of the low solubility of IMC in ethanol and very long batch times of up to 20 h were observed, leading to the poor productivity . A comparison of the results from the present work to the cooling crystallization of IMC from ethanol is summarized in Table.…”

“…In our previous work, we have performed seeded cooling crystallization of IMC from ethanol. The desired γ-IMC was obtained in the seeded experiments; however, the yield of IMC was very low because of the lower solubility of IMC in ethanol and longer observed batch times of up to 20 h . Therefore, antisolvent crystallization of IMC with an acetone–methanol (66.5–33.5 wt %) binary mixture as a solvent was investigated in this work on the basis of the high solubility of IMC in the solvent reported earlier .…”