The development of carbamazepine-succinic acid cocrystal tablet formulations with improved in vitro and in vivo performance

Abstract

The use of soluble cocrystal for delivering drugs with low solubility, although a potentially effective approach, often suffers the problem of rapid disproportionation during dissolution, which negates the solubility advantages offered by the cocrystal. This necessitates their robust stabilization in order for successful use in a tablet dosage form. The cocrystal between carbamezepine and succinic acid (CBZ-SUC) exhibits a higher aqueous solubility than its dihydrate, which is the stable form of CBZ in water. Using this model system, we demonstrate an efficient and material-sparing tablet formulation screening approach enabled by intrinsic dissolution rate measurements. Three tablet formulations capable of stabilizing the cocrystal both under accelerated condition of 40 °C and 75% RH and during dissolution were developed using three different polymers, Soluplus® (F₁), Kollidon VA/64 (F₂) and Hydroxypropyl methyl cellulose acetate succinate (F₃). When compared to a marketed product, Epitol® 200 mg tablets (F₀), drug release after 60 min from formulations F₁ (∼82%), F₂ (∼95%) and F₃ (∼95%) was all higher than that from Epitol® (79%) in a modified simulated intestinal fluid. Studies in albino rabbits show correspondingly better bioavailability of F₁–F₃ than Epitol.

• Cocrystal
• intrinsic dissolution rate
• stability
• tablet formulation

Acknowledgements

We thank Dr Raza Shah (Centre for bioequivalence studies and bioavailability research, University of Karachi, Pakistan) for assistance in collecting in vivo data and Dr Amjad Alhalaweh for suggesting this research topic and initial discussions.

Declaration of interest

The authors report no declarations of interest.

M.U. thanks Higher Education Commission, Pakistan, for Indigenous PhD scholarship as well as for supporting the visit to University of Minnesota under International Research Support Initiative Program for six months.

Supplementary material available online Supplementary Figures S1-S9.