(700e) Solid Solution-Enabled Approach for Polymorph Screening

Polymorph screening is one of the important steps in drug development. Polymorphs have been screened for almost three decades with various methods, e.g. cooling, evaporation, antisolvent addition, vapor diffusion and slurries, from which solvent choice, solvent mixtures, antisolvent, temperatures, cooling rate, concentration, rate of addition etc. could also be considered^1,2. New polymorphs have been observed with the solid solution formed between the model drug and the impurity³, indicating the solid solution has altered the thermodynamics. Therefore, more polymorphs are being observed with solid solution presents. However, there is no systematic study that has been conducted to evaluate the efficiency of the solid solution-enabled methodology for polymorph screening.

This presentation provides a novel polymorph screening approach with the solid solution formed between the model drug and the additive/impurity. Salicylic acid, benzoic acid, salicylamide, 3-hydroxybenzoic acid, 4-hydroxybenzoic acid, anthranilic acid, 2,3-dihydroxybenzoic acid were used in the polymorph screening. A model drug and a structurally similar additive were selected in pairs from these seven compounds with approximately 1%, 5%, 10% and 30% additive in the mixture of the model drug and the additive. Thermodynamic, and kinetic experiments, as well as the melt quench⁴ methods with the solid solution between the model drug and the impurity/additive were performed. (1) For thermodynamic experiments, each mixture of the model drug and the additive was slurried in 40 w% methanol in water or acetonitrile for at least one week. (2) The kinetic experiments were carried out by dissolving each mixture of the model drug and the additive in methanol, followed by a fast evaporation at room temperature at the ambient condition. (3) The melt quench was conducted by heating the mixture of the model drug and the additive to the offset temperature of the melting of the model drug, followed by a fast cool (30°C/min) to 60°C and a hold it for 20 min for nucleation and crystal growth; then the sample was cooled (10°C/min) to 25°C. All recovered solids were analyzed by an X-ray powder diffractor (XRPD). If a new XRPD pattern was observed, a single crystal X-ray diffraction analysis was used to determine the crystal structure of the hit. The effectiveness among the three methods with the solid solution formed between the model drug and the impurity was compared and discussed based on over 300 experiments, which provides a novel methodology and guidance for polymorph screening in future.

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(2) Lee, E. H. A Practical Guide to Pharmaceutical Polymorph Screening & Selection. Asian J. Pharm. Sci. 2014, 9 (4), 163–175. https://doi.org/10.1016/j.ajps.2014.05.002.

(3) Paolello, M.; Mohajerani, S. S.; Linehan, B.; Ricci, F.; Capellades, G.; Nordstrom, F. L. Polymorphic Stability Shifts, Co-Crystals, and Crystalline Solid Solutions: The T-X Phase Diagram of Salicylic Acid–Salicylamide. Cryst. Growth Des. 2024, 24 (5), 2188–2201. https://doi.org/10.1021/acs.cgd.3c01501.

(4) Parent, S. D.; Smith, P. A.; Purcell, D. K.; Smith, D. T.; Bogdanowich-Knipp, S. J.; Bhavsar, A. S.; Chan, L. R.; Croom, J. M.; Bauser, H. C.; McCalip, A.; Byrn, S. R.; Radocea, A. Ritonavir Form III: A Coincidental Concurrent Discovery. Cryst. Growth Des. 2023, 23 (1), 320–325. https://doi.org/10.1021/acs.cgd.2c01017.