Effects of Polymers on Carbamazepine cocrystals phase transformation and release profiles
The aim of this study is to investigate the effects of coformers and polymers on the phase transformation and release profiles of cocrystals. Pharmaceutical cocrystals of Carbamazepine (CBZ) (namely 1:1 carbamazepine-nicotinamide (CBZ-NIC), 1:1 carbamazepine-saccharin (CBZ-SAC) and 1:1 carbamazepine-cinnamic acid (CBZ-CIN) cocrystals, were synthesized. A Quality by Design (QbD) approach was used to construct the formulation. Dissolution and solubility were studied using UV imaging and High Performance Liquid Chromatography (HPLC). The polymorphic transitions of cocrystals and crystalline properties were examined using Differential Scanning Calorimetry (DSC), X-Ray Powder Diffraction (XRPD), Raman spectroscopy (Raman) and Scanning Electron Microscopy (SEM). JMP 11 software was used to design the formulation. It has been found that Hydroxupropyl methylcellulose (HPMC) cannot inhibit the transformation of CBZ-NIC cocrystals to Carbamazepine Dihydrate (CBZ DH) in solution or in the gel layer of the matrix, as opposed to its ability to inhibit CBZ Form III (CBZ III) phase transition to CBZ DH. The selection of different coformers of SAC and CIN can affect the stability of CBZ in solution, resulting in significant differences in the apparent solubility of CBZ. The dissolution advantage of the CBZ-SAC cocrystal can only be shown for 20 minutes during dissolution because of the conversion to its dihydrate form (CBZ DH). In contrast, the improved CBZ dissolution rate of the CBZ-CIN cocrystal can be realised in both solution and formulation because of its stability. The polymer of Hypromellose Acetate Succinate (HPMCAS) seemed to best augment the extent of CBZ-SAC and CBZ-CIN cocrystal supersaturation in solution. At 2 mg/ml of HPMCAS concentration, the apparent CBZ solubility of CBZ-SAC and CBZ-CIN cocrystals can increase the solubility of CBZ III in pH 6.8 phosphate buffer solutions (PBS) by 3.0 and 2.7 times respectively. All pre-dissolved polymers in pH 6.8 PBS can increase the dissolution rates of CBZ cocrystals. In the presence of a 2 mg/ml HPMCAS in pH 6.8 PBS, the cocrystals of CBZ-NIC and CBZ-CIN can dissolve by about 80% within five minutes in comparison with 10% of CBZ III in the same dissolution period. Finally, CBZ-NIC cocrystal formulation was designed using the QbD principle. The potential risk factors were determined by fish-bone risk assessment in the initial design, after which Box-Behnken design was used to optimize and evaluate the main interaction effects on formulation quality. The results indicate that in the Design Space (DS), CBZ sustained release tablets meeting the required Quality Target Product Profile (QTPP) were produced. The tablets’ dissolution performance could also be predicted using the established mathematical model.
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