Solid‐State Forms of Sodium Valproate, Active Component of the Anticonvulsant Drug Epilim

Abstract The results of the first detailed and systematic investigation of the solid‐state forms of sodium valproate, one of the most potent and widely used anticonvulsant medicines, are presented. By using wet and dry methods, eight solid forms of varying stability in air were obtained and characterized. Three extremely hygroscopic polycrystalline hydrates, Na(C 8 H 15 O 2 )⋅H 2 O (form A), Na(C 8 H 15 O 2 )⋅ x H 2 O (form B), and Na(C 8 H 15 O 2 )⋅ y H 2 O (form D), three acid‐stabilized stoichiometric solvates, Na 3 (C 8 H 15 O 2 ) 3 (C 8 H 16 O 2 )⋅H 2 O (form C), Na(C 8 H 15 O 2 )(C 8 H 16 O 2 ) (form E), and Na 3 (C 8 H 15 O 2 ) 3 (C 8 H 16 O 2 )⋅2 H 2 O (form F), the pure anhydrous salt Na(C 8 H 15 O 2 ) (form H), and an additional unstable thermal intermediate Na 3 (C 8 H 15 O 2 ) 3 (C 8 H 16 O 2 ) 0.5 (form G) were prepared. Under ambient conditions, forms A and B as well as the commercially available compound appear as very hygroscopic white powders. Form C is less hygroscopic, while forms E and F are stable and are not hygroscopic. Partial stabilization of forms A and B can be achieved by evacuation and pressing, which results in a lower hydrate D, or after a heating–cooling cycle, resulting in crystallization of the anhydrous salt H. Addition of one molecule of valproic acid and saturation with one molecule of water of forms A and B results in the less hygroscopic form C. Addition to form C of a second water molecule affords form F, which is not hygroscopic and is indefinitely stable. The symmetric structure and medium alkyl chain length of the valproate ion are some of the probable reasons for the presence of a number of solid solvates: in its most stable conformation, the valproate ion cannot simultaneously pack efficiently and interact strongly through the negatively charged carboxylate group without leaving voids in the crystalline lattice. The conformational flexibility of the aliphatic chains probably aids the penetration of water molecules, which results in a strong affinity for the absorption of water.