Pharmaceutical Cocrystal: A Novel Approach to Tailor the Biopharmaceutical Properties of a Poorly Water Soluble Drug

Abstract

Background: The present study reports the formation of a cocrystal of candesartan with the coformer methyl paraben, its characterization and determination of its bioavailability. Candesartan is a poorly water-soluble drug having an anti-hypertensive activity. The recent patents on the cocrystals of the drugs Progesterone (US9982007B2), Epalrestat (EP2326632B1), Gefitinib (WO2015170345A1), and Valsartan (CN102702118B) for enhancement of solubility, helped in selection of the drug for this work. Methods: Candesartan cocrystal was prepared by solution crystallization method. The formation of a new crystalline phase was characterized by Differential Scanning Calorimetry (DSC), Fourier Transform Infrared (FTIR) and Powder X-ray Diffraction (PXRD) studies. Saturation solubility studies were carried out in ethanol: water (50:50 % v/v) mixture. The dissolution studies were conducted in 900 ml of phosphate buffer at pH 7.4(I.P.) with 0.7% w/w of Tween 20 at 50 rpm, maintained at a temperature of 37±0.5°C in a USP type II dissolution apparatus. The pharmacokinetic behavior of candesartan and its cocrystal was thereof investigated in male Wistar rats. Results: There was 6.94 fold enhancement in the solubility of candesartan after its cocrystallization. The dissolution profile of the cocrystal exhibited significant improvement in solubility at 60 and 120 minutes and it remained stable in ethanol: water (50:50%v/v) mixture for 48 h as confirmed by PXRD studies. The AUC0-24of the cocrystal was found to be increased by 2.9 fold in terms of bioavailability as compared to the pure drug. Conclusion: The prepared cocrystal was found to be relatively more soluble than the pure drug and also showed an enhanced oral bioavailability as compared to the pure drug.

Candesartan Cilexetil In Vitro–In Vivo Correlation: Predictive Dissolution as a Development Tool

“…In fact, several technological innovations developed to increase candesartan solubility have demonstrated to increase drug bioavailability. The formation of co-crystals improved the drug bioavailability in Wistar rats [31] and nanosized suspensions with higher saturation solubility showed improved bioavailability in a murine model [32]. Candesartan loaded proniosomes showed faster dissolution and higher bioavailability after oral administration in rats [5].…”

Formation of a New Cocrystal Methyl‐4‐hydroxybenzoate:Urea and Its Structural and Thermal Properties

“…[8] Similarly, the antihypertensive drug candesartan was cocrystallized with p-MHB through solution crystallization method and characterized using PXRD, FTIR, and DSC analyses which show that it has improved solubility compared with that of the pure drug. [9] Khan et al reported that one of the antimalarial drugs Quinidine was successfully cocrystallized with p-MHB and confirmed through solid-state NMR and DFT studies that in which p-MHB is acting as a molecular hook via hydrogen bonding. [10] Similarly, the second compound selected, urea [CO(NH 2 ) 2 ], is also a well-known and highly potential material in human history assessed from the early century's and it has several applications in various industries such as agriculture, dietary technology, pharmaceutical, medicine, etc.…”

Solid State Characterization and Dissolution Enhancement of Nevirapine Cocrystals

“…Nevirapine (pKa 2.8), at higher doses exhibit solubility limited absorption with low bioavailability. 7,8 It is possible to prepare novel solid forms of nevirapine with greater therapeutic efficacy and commercial value via cocrystallization. The various cocrystals of nevirapine with amides, carboxylic acid, amino acids have been reported possessing enhanced solubility and dissolution.…”