A molecular approach to understanding the directed nucleation and phase transformation of carbamazepine and nitrofurantoin in aqueous and organic solutions

Intermolecular interactions between additives and drug molecules that lead to changes in nucleation and crystal morphology are essential to understanding the selective crystallization of pharmaceutical polymorphs. This research had two purposes: (1) to study the effects of additives on carbamazepine (CBZ) and nitrofurantoin (NTF) hydrate nucleation in aqueous solutions and (2) to investigate the effects of organic solvents on anhydrous CBZ crystallization in the absence and presence of additives. Carbamazepine exists as four anhydrous polymorphs (two monoclinic (CBZ(M) and CBZIV), trigonal (CBZ(Trg)), and triclinic) and two solvates (dihydrate (CBZ(D)) and monoacetonate), while NTF has two anhydrous and two monohydrate crystal forms. Studies were conducted to (1) measure the induction time under constant supersaturation, (2) determine the rate-limiting step for the solvent-mediated phase transformations, and (3) identify intermolecular interactions that direct nucleation and growth by calculating binding energies between additives and morphologically important crystal faces. Additives and solvents were chosen based on their potential to interact with the molecular moieties present on CBZ and NTF crystal surfaces. In aqueous solutions, additives that primarily accept multiple hydrogen bonds at least 13 Å apart inhibited CBZ(D) nucleation, delayed the CBZ(M) to CBZ(D) phase transformation, prevented the nucleation of NTFI monohydrate, and altered CBZ(D) morphology. Molecular simulations revealed that face specific interactions between additives and CBZ(D) {lcub}111{rcub} and NTFI {lcub}011{rcub} and {lcub}110{rcub} crystal faces are responsible for the changes in crystallization behavior. In organic solutions, solvents with donor to acceptor ratios (d/a) < 1 preferentially crystallized CBZ(Trg), while solvents with d/a = 1 or with no hydrogen bonding capability concomitantly crystallized CBZ(Trg) and CBZ(M). Molecular simulations show that solvents selectively interact with CBZ(M) {lcub}011{rcub} faces to prevent the molecular assembly necessary for its nucleation. The presence of nonionic surfactants inhibited CBZ(Trg) nucleation and changed its morphology. Molecular visualizations of CBZ(Trg) crystal structure suggest that the surfactants selectively interact with the hydrogen bonding sites exposed on CBZ(Trg) {lcub}101{rcub} faces, and thereby prevent further incorporation of molecules into the crystal lattice. Face-specific interactions between additives and crystal surfaces are responsible for directing CBZ and NTF nucleation. These results have important implications for controlling nucleation events and crystal morphology.