Improved in vitro and in vivo performance of carbamazepine enabled by using a succinic acid cocrystal in a stable suspension formulation

• Published in: Pakistan journal of pharmaceutical sciences Vol. 30; no. 6; pp. 2139 - 2145
• Main Authors: Ullah, Majeed, Shah, Mohammad Raza, Bin Asad, Muhammad Hassham Hassan, Hasan, S M Farid, Hussain, Izhar
• Format: Journal Article
• Language: English
• Published: Pakistan Pakistan Journal of Pharmaceutical Sciences 01-11-2017
• Subjects: Bioavailability; Carbamazepine; Drug delivery systems; Patient outcomes; Testing
• ISSN: 1011-601X

Currently cocrystals are considered as an established approach for making crystalline solids with overall improved physico-chemical properties. However, some otherwise well behaving cocrystals undergo rapid dissociation during dissolution, with ultimate conversion to parent drug and thus apparent loss of improved solubility. The polymeric carriers are long known to manipulate this conversion during dissolution to parent crystalline drug, which may hinder or accelerate the dissolution process if used in a dosage form. The goal of this study was to deliver in vivo a more soluble carbamazepine-succinic acid (CBZ-SUC) cocrystal in suspension formulation utilizing Hydroxypropyl methyl cellulose (HPMC-AS) as a crystallization inhibitor and Polyvinyl carpolactam-polyvinyl acetate-polyethylene glycol graft copolymer ® as solubilizer. The concentration of these polymers were systemically varied during in vitro dissolution studies, while selected formulations from dissolution studies were tested in vivo. Pharmacokinetic studies (PK) in rabbits demonstrated that formulation F7-X (1% cocrystal, 1% HPMC-AS and 2% Polyvinyl carpolactam-polyvinyl acetatepolyethylene glycol graft co-polymer®) caused almost 6fold improvement in AUC0-72 (***P k 0.05) as well as much higher C
of 4.73μ.mL-1 to that of 1.07μ.mL-1 of unformulated 'neat' cocrystal given orally. When reference formulation of CBZ (F5-X) with similar composition to F7-X were given to rabbits, cocrystal formulation gave 1.37fold (***P k 0.05) bioavailability than CBZ reference formulation. C
of reference formulation observed was 3.9μmL-1.