DEVELOPMENT OF A SEEDING TECHNIQUE FOR THE CRYSTALLIZATION OF THE METASTABLE-A MODIFICATION OF ABECARNIL

Abecarnil, a partial agonist of the benzodiazepine receptor, crystalli zes 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 crystal lization of the drug substance Abecarnil, yielding the B form for an u nseeded crystallization. However, the crystals undergo a slow solution -mediated phase transformation into the stable C form. More readily ob served is a partial phase transformation into the A modification, The rate of transformation depends sensitively on the purity of the materi al. To access this second metastable form quantitatively, reproducibly and irrespective of the purity of the material, a seeding strategy fo r a batch cooling crystallization from isopropyl acetate is developed, The technique is optimized under laboratory conditions and transferre d to pilot plant scale. The physicochemical data necessary for the eff ective development are given and their relevance is discussed.