Tailoring Physicochemical Properties of Chlorthalidone through Cocrystal Engineering and Delayed Precipitation by Polymers

The limited solubility and bioavailability of the Biopharmaceutics Classification System (BCS) Class IV drug chlorthalidone (CTD) hinders its therapeutic efficacy. This study utilizes a crystal engineering approach to enhance CTD’s physicochemical properties through the synthesis of cocrystals and a coamorphous formulation. Cocrystals of CTD with caprolactam (CTD-CAP, 1:2) and theophylline (CTD-TP, 1:1) were prepared via solvent-assisted grinding and slurry techniques, while a coamorphous CTD-vanillic acid (CTD-VA, 1:1) formulation was obtained by ball-milling. The novel solid phases were characterized using Powder X-ray Diffraction (PXRD), Differential Scanning Calorimetry (DSC), Fourier Transform Infrared (FTIR) spectroscopy, Proton Nuclear Magnetic Resonance (¹H NMR), and Single Crystal X-ray Diffraction (SCXRD). Solubility, dissolution, and membrane diffusion studies of these phases in phosphate-buffer saline (pH 7.0) showed a reasonable improvement, with a maximum enhancement in the case of the coamorphous phase CTD-VA. The addition of an induced precipitation delay (IPD) polymer hydroxypropyl methylcellulose (HPMC) further enhanced drug release (defined as the product of dissolution and diffusion at 8 h), particularly at 1% w/v HPMC. CTD-VA showed maximum dissolution, while CTD-CAP appeared to be the most stable formulation for sustained release of the drug. These findings underline the ability of cocrystals and coamorphous compounds with polymer-based formulation strategies to enhance the physicochemical properties of poorly soluble drugs and open the avenue for further research on pharmaceutical formulations.