Development of a seeding technique for the crystallization of the metastable A modification of Abecarnil

Abecarnil, a partial agonist of the benzodiazepine receptor, crystallizes in three modifications, A, B, and C, Depending on the solvent, the form crystallized in an unseeded process is one of the two metastable forms A or B, Isopropyl acetate was chosen as solvent for the crystallization of the drug substance Abecarnil, yielding the B form for an unseeded crystallization. However, the crystals undergo a slow solution-mediated phase transformation into the stable C form. More readily observed is a partial phase transformation into the A modification, The rate of transformation depends sensitively on the purity of the material. To access this second metastable form quantitatively, reproducibly and irrespective of the purity of the material, a seeding strategy for a batch cooling crystallization from isopropyl acetate is developed, The technique is optimized under laboratory conditions and transferred to pilot plant scale. The physicochemical data necessary for the effective development are given and their relevance is discussed.