Development of a Seeding Technique for the Crystallization of the Metastable A Modification of Abecarnil

Abstract

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.

Computer simulation of metastable zone width for unseeded potassium sulfate aqueous solution

“…This sudden appearance of ''first crystals'' is described in the literature as an avalanche [5] or showers of crystals [6]. However, it is questionable whether such crystals are really the first ones or not.…”

Raman and ATR FTIR spectroscopy in reactive crystallization: Simultaneous monitoring of solute concentration and polymorphic state of the crystals

“…The well known Ostwald's rule of stages [5] predicts that the least stable form is produced first by spontaneous crystallization and then transforms into the more stable form. Ostwald's rule of stages rule has, however, no general proof in industrial practice, and the form of the crystals depends on the crystallizing system and the operation parameters, such as solvent, temperature range, supersaturation level, mixing condition, presence of impurities or additives, and seeding parameters [6][7][8][9]. The well known historical case about Ritonavir has shown that insufficient understanding of the crystallization mechanisms of the polymorphs could cause serious problems in drug manufacturing [10].…”

Simulation of metastable zone width and induction time for a seeded aqueous solution of potassium sulfate

“…2a and b. This kind of particle increasing trend has been reported in actual crystallization experiments as an avalanche [25] or showers of crystals [26]. The avalanche or showers of crystals have been treated incorrectly as the appearance of ''first crystals'', as pointed out in the previous paper [21].…”