One-solvent polymorph screen of carbamazepine.

Area of Science:

• Crystallization Science
• Materials Science
• Pharmaceutical Chemistry

Background:

• Polymorphism, the ability of a solid material to exist in multiple crystal forms, significantly impacts drug properties.
• Identifying diverse polymorphs is crucial for drug development, but traditional screening methods often require numerous solvents.
• Carbamazepine (CBZ) is a well-known drug exhibiting complex polymorphism.

Purpose of the Study:

• To demonstrate a method for obtaining multiple carbamazepine (CBZ) polymorphs using a single solvent.
• To investigate the influence of crystallization temperature and supersaturation on CBZ polymorph formation.
• To assess the efficiency of polymorph screening by minimizing solvent usage.

Main Methods:

• Crystallization of carbamazepine (CBZ) from cumene (isopropyl benzene) under varied temperature and supersaturation conditions.
• Utilizing competition slurries to determine transition temperatures between polymorphs.
• Analysis of resulting crystal forms to identify specific polymorphs (Form I, II, and III).

Main Results:

• Three of the four known carbamazepine (CBZ) polymorphs (Forms I, II, and III) were successfully crystallized from cumene.
• Form III was obtained below 60°C with low supersaturation; Form II at <60°C with higher supersaturation.
• Form I was produced above 80°C, irrespective of supersaturation, while intermediate temperatures yielded mixtures.
• The transition temperature between enantiotropically related Forms III and I was determined to be between 79°C and 82°C.

Conclusions:

• Solvent choice can be critical or immaterial in crystallizing specific polymorphs, challenging the need for extensive solvent screening.
• Rational experimental design, focusing on temperature and supersaturation, can efficiently yield multiple polymorphs from a single solvent.
• This approach significantly reduces the number of solvents and crystallization conditions required for polymorph discovery.