Dissolution Profiles of Carbamazepine Cocrystals with Cis-Trans Isomeric Coformers.

Purpose: The purpose of the present study was to investigate the dissolution profiles of cocrystals with cis-trans isomeric coformers. Previously, the carbamazepine (CBZ) cocrystals with even-carbon dicarboxylic acids showed higher supersaturation than those with odd-carbon ones, attributed to particle surface solution-mediated phase transformation (PS-SMPT) to CBZ dihydrate (CBZ DH). However, it has been unknown whether this odd-even pattern holds for cis-trans isomeric coformers.

Method: CBZ cocrystals with maleic acid (MLE) and fumaric acid (FUM) (CBZ-FUM anhydrate (CBZ-FUM AH) and monohydrate (CBZ-FUM HO)) were employed as model cocrystals. Hydroxypropyl　methylcellulose (HPMC), polyvinylpyrrolidone, and polyethylene glycol 6000 (PEG) were used as precipitation inhibitors. Dissolution tests were performed under a non-sink condition. Residual particles were analyzed by powder X-ray diffraction, differential scanning calorimetry, polarized light microscope, and scanning electron microscope.

Results: All cocrystals showed little supersaturation in the absence of a polymer. In 0.1% HPMC, CBZ-FUM AH showed significant supersaturation, whereas CBZ-MLE and CBZ-FUM HO did not for the first two hours. HPMC reduced the initial dissolution rate of CBZ-MLE and CBZ-FUM HO while inducing the highest supersaturation among the polymers after 96 h. The particle surface changed from a smooth plane to a striped pattern, but little or no CBZ DH was detected.

Conclusion: The cocrystals with cis-trans isomeric coformers showed different dissolution profiles. HPMC increased the dissolution rate of CBZ-FUM AH by inhibiting PS-SMPT but reduced the dissolution rate of CBZ-MLE and CBZ-FUM HO without inducing PS-SMPT. The striped pattern was suggested to be due to surface etching rather than PS-SMPT.