Fabrication of Carbamazepine Cocrystals: Characterization, In Vitro and Comparative In Vivo Evaluation.

Muhammad Wasim,Izhar Hussain,Muhammad Hassham Hassan Bin Asad,Muhammad Shafique,Abdul Mannan,Muhammad Imran Amirzada,Dr Abdul Ahad

doi:10.1155/2021/6685806

Abstract

Carbamazepine (CBZ) is an antiepileptic drug having low bioavailability due to its hydrophobic nature. In the current study, efforts are made to investigate the effect of dicarboxylic acid coformer spacer groups (aliphatic chain length) on physicochemical properties, relative humidity (RH) stability, and oral bioavailability of CBZ cocrystals. Slurry crystallization technique was employed for the preparation of CBZ cocrystals with the following coformers: adipic (AA), glutaric (GA), succinic (SA), and malonic acid (MA). Powder X-ray diffractometry and Fourier-transform infrared spectroscopy confirmed cocrystal preparation. Physicochemical properties, RH stability, and oral bioavailability of cocrystals were investigated. Among the prepared cocrystals, CBZ-GA showed maximum solubility as well as improved dissolution profile (CBZ-GA > CBZ-MA > CBZ-AA > pure CBZ > CBZ-SA) in ethanol. Maximum RH stability was shown by CBZ-AA, CBZ-SA, and CBZ-MA. In vivo studies confirmed boosted oral bioavailability of cocrystals compared to pure CBZ. Furthermore, in vivo studies depicted the oral bioavailability order of cocrystals as CBZ-GA > CBZ-MA > Tegral® > CBZ-AA > CBZ-SA > pure CBZ. Thus, pharmaceutical scientists can effectively employ cocrystallization technique for tuning physicochemical properties of hydrophobic drugs to achieve the desired oral bioavailability. Overall, results reflect no consistent effect of spacer group on physicochemical properties, RH stability, and oral bioavailability of cocrystals.

Highlights

IntroductionPharmaceutical cocrystal (multicomponent system) consists of an active pharmaceutical ingredient (API) and coformer/cocrystal former [1]
Pharmaceutical cocrystal consists of an active pharmaceutical ingredient (API) and coformer/cocrystal former [1]
The XRPD patterns of CBZ-adipic acid (AA), CBZ-GA, CBZ-succinic acid (SA), and CBZ-malonic acid (MA) are perfectly matched with their XRPD powder patterns provided in the Cambridge Structural Database (CSD) as MOXVEB, MOXVOL, XOBCIB, and XOBCEX, respectively (Figure 2)

Summary

Introduction

Pharmaceutical cocrystal (multicomponent system) consists of an active pharmaceutical ingredient (API) and coformer/cocrystal former [1]. Pharmaceutical cocrystallization is a good technique for enhancing the physicochemical properties of active pharmaceutical ingredients [5]. Many cocrystals have been synthesized for modification of physicochemical properties like posaconazole–4-aminobenzoic acid which exhibited high solubility and improved dissolution [8]. Two factors determined the solubility: cocrystal components solvation and crystal lattice energy Both factors can be influenced to various extents by cocrystallization [12, 13]. As stated by biopharmaceutical classification system (BCS), drugs having low solubility despite of high permeability are considered BCS class II drugs. These drugs have dissolution-restricted absorption and low oral bioavailability [15]. To get the desired therapeutic effect, CBZ is used generally in a high dose [14]

Methods

Results

Discussion

Conclusion