Polymorphism in Carbamazepine Cocrystals

Abstract

Cocrystals of carbamazepine with nicotinamide and saccharin are shown to be polymorphic. Two polymorphs of carbamazepine-nicotinamide (CBZ-NCT) cocrystals and two polymorphs of carbamazepine-saccharin (CBZ-SAC) cocrystals were grown from solution in the presence of polymer heteronuclei. The two CBZ-NCT polymorphs, CBZ-NCT I and a polymer nucleated (PN) form of CBZ-NCT, were characterized by Raman spectroscopy and powder X-ray diffraction. CBZ-SAC II, a new polymorph, was found to be in the monoclinic space group C2/c with a = 35.72 Å, b = 6.84 Å, c = 16.11 Å, and β = 98.03°. The unique feature of CBZ-SAC II is the formation of a heterosynthon between the carbamazepine and saccharin. These results are notable because CBZ-NCT and CBZ-SAC are among the most widely studied pharmaceutical cocrystals.Cocystallization has recently been rediscovered as a powerful technique to modify key solidstate properties of pharmaceuticals such as solubility, stability, and dissolution rate. 1,2 From a supramolecular standpoint it is pleasing to see that predictable structural motifs can be introduced by design, offering at least a partial solution to the problem of controlling crystal structure. This element of predictability may be misinterpreted as leading to the formation of a single structure and therefore a lack of crystal polymorphism. Here we investigate this issue for two cocrystals of the highly polymorphic pharmaceutical carbamazepine. 3The crystallization properties of carbamazepine-nicotinamide (CBZ-NCT) have been thoroughly investigated 4-7 and the generation of CBZ-NCT cocrystals has been achieved through solution crystal growth, 4,5 slurry conversion, 6 and melt crystallization. 7 From these studies one form of CBZ-NCT cocrystal has been thoroughly characterized and its structure elucidated by single crystal X-ray diffraction. 4 Crystal growth from the melt results in a second form of CBZ-NCT that is metastable. 7Our study of CBZ-NCT cocrystals utilized functionalized cross-linked polymers as heteronuclei for crystal growth, 8 a strategy that has previously demonstrated effectiveness in polymorph discovery of pharmaceuticals, 8,9 extended solids, 10 and inorganic complexes. 11 Cocrystals were grown by evaporation of ethanol solutions containing a stoichiometric ratio of carbamazepine and nicotinamide contacting 96 individual polymers in a polymer library. Three separate polymer libraries were utilized derived from monomers with non-polar and aromatic functional groups, polar nitrogen rich functional groups, and polar acidic functional groups (see Supporting Information). Optical microscopy of the resulting crystals revealed needle-like morphologies with no readily distinguishable features. Raman spectroscopy of the crystals identified several crystalline forms including carbamazepine, nicotinamide, CBZ-NCT I, and a cocrystal with a Raman spectrum indistinguishable from that reported for CBZ-NCT II. 7 Powder X-ray diffraction (PXRD, Figure 1) of CBZ-NCT I is in accord with the previously reported powder patter...

Physico-mechanical and Stability Evaluation of Carbamazepine Cocrystal with Nicotinamide

“…Nicotinamide has been utilized as a coformer for the cocrystallization of celecoxib (15), theophylline (16), ibuprofen (17), CBZ (18,19), and lamotrigine (20). Reported methods of cocrystal preparation are solution cooling crystallization (21), ambient co-milling (18), cryogenic co-grinding (22), melting (23), and solvent evaporation (24).…”

“…Although CBZ and nicotinamide (NCT) cocrystals have been reported in the literature (18,19), there is a dearth of published information regarding their physicochemical, mechanical, and stability properties. Thus, it is important to evaluate these properties prior to product development in order to select an appropriate dosage form.…”

Análise térmica aplicada a fármacos e formulações farmacêuticas na indústria farmacêutica

“…Na Farmacopeia Brasileira, os di-zeres recomendados pelo ICH (Guidance, 1987) quanto à presença de polimorfismo estão presentes para dois fármacos, cloridrato de ranitidina e zidovudina, e a técnica analítica utilizada na distinção dos polimorfos é a espectrometria de infravermelho. 51,52 Além disso, durante o processo de fabricação do medicamento, algumas etapas de procedimento podem levar a alterações polimór-ficas, tais como, processo de micronização ou moagem; granulação via úmida, secagem, compressão e descontaminação microbiológica com irradiação gama. Desta forma, além da caracterização inicial do fármaco ao chegar à fábrica, é importante avaliar se o processo produtivo também pode alterar a forma polimorfa.…”

Investigation of an Amide-Pseudo Amide Hydrogen Bonding Motif within a Series of Theophylline:Amide Cocrystals

“…22,26 In fact, the number of reports of cocrystal polymorphism is similar to that for single component phases, 27,28 and any historical differences are more likely to be due to difficulties associated with screening for different polymorphic forms of cocrystals than to an inherent tendency for cocrystals to be monomorphic. 13, 29 Cocrystal stability is not yet well understood, but studies have shown that cocrystals can dissociate spontaneously on heating or through partial dissolution of one of the coformers. 2,24,25,[30][31][32] Theophylline is a pharmaceutically active compound used as a treatment for asthma and COPD for which seven polymorphic forms have been reported.…”