Solvent Effects on the Crystallization and Preferential Nucleation of Carbamazepine Anhydrous Polymorphs: A Molecular Recognition Perspective

Abstract

This contribution reports the effects of molecular recognition events and solubility on the crystallization of carbamazepine (CBZ) polymorphs from organic solvents. Solvents were chosen on the basis of their hydrogen-bonding potential. Experiments were conducted to (1) measure solubilities and induction times, (2) monitor solution concentrations and solid phase compositions, and (3) identify intermolecular interactions between solvents and CBZ molecules. Primitive monoclinic, CBZ(M), and trigonal, CBZ(Trg), carbamazepine anhydrous polymorphs readily crystallized from the organic solvents. CBZ(Trg) is the metastable form at 25 °C with a solubility approximately 1.2 times that of CBZ(M). Results show that relative nucleation rates of CBZ polymorphs are dependent on the hydrogen-bonding nature of the solvent and are not dependent on solubility. Solvents that primarily accept hydrogen bonds (donor-to-acceptor ratio (d/a) = 0) preferentially crystallized CBZ(Trg), whereas solvents that accept and donate hydrogen bonds (d/a > 0.5) concomitantly crystallized CBZ(M) and CBZ(Trg). Evaluation of the crystal structures shows that specific interactions between acceptor solvents and the CBZ dimer led to the prevention of the molecular motif necessary for CBZ(M) nucleation. It is concluded that intermolecular interactions and specifically the hydrogen-bonding propensity of solvents with CBZ molecules have profound effects on the molecular self-assembly and selective crystallization of CBZ polymorphs.