Abstract: Carbamazepine is a widely used psychotropic drug applied for therapy of epilepsy, trigeminal neuralgia and bipolar affective disorder. The polymorphism of CBZ has been well studied and 5 polymorphic modifications of this substance are currently known. Form III is the most thermodynamically stable, whereas other modifications are metastable. Based on the results of the DSC, form II is the most metastable polymorph. Our work demonstrates an ability to obtain metastable polymorphs II and IV in mechanochemical experiments. An influence of contamination, time processing scheme, vibrating ball mill type and ball-to-powder mass ratio on the polymorphic transition of CBZ III to form IV was investigated. Mechanochemical treatment of CBZ III with addition of saturated fatty acids leads to obtaining of least thermodynamically stable CBZ polymorph II. Maximal yield of CBZ II at fixed treatment time was obtained using long-chained fatty acids such as palmitic and stearic acids. The effect of saturated fatty acids on polymorphism of CBZ was also studied in crystallization experiments from melt. For this purpose, palmitic acid was selected. Crystallization from suspension of CBZ III in palmitic melt during 60 min mixing at 100 °C shows total recrystallization of form III to polymorph II. Detailed microscopic observation made on Kofler hot-stage shows formation of thin needle crystals of CBZ II on the surface of CBZ III crystals. The needle crystals could be gently separated after cooling down the melt. XRPD and Raman spectroscopy were used to confirm polymorphic composition of the mixture. In conclusion, two different techniques were applied to obtain metastable polymorphs of CBZ. The role of amorphous state in mechanochemical polymorphic transition CBZ III → IV is considered. Template effect of saturated fatty acids on crystallization of least thermodynamically stable CBZ polymorph II was studied in mechanochemical and meltcrystallization experiments. The work demonstrates an ability of potential influence of excipients on polymorphism of CBZ that could be important for pharmaceutical industry. Acknowledgements: This work was supported by Ministry of Science and Higher Education of the Russian Federation within the governmental assignment for Boreskov lnstitute of Catalysis (project FWUR-2024-0032). Experimental facilities of the Chair of Solid State Chemistry (Novosibirsk State University) were used.

Cite: Losev E.A. , Zheltikova D.Y. , Boldyreva E.V.
Control over Metastable Polymorphs of Carbamazepine: Mechanochemistry and Crystallization from Fatty Acid Melt
9th IAPC Meeting International Conference on Emerging Technologies in Drug Discovery and Development 23-25 Sep 2024