Tailoring Chlorthalidone Aqueous Solubility by Cocrystallization: Stability and Dissolution Behavior of a Novel Chlorthalidone-Caffeine Cocrystal
A cocrystal of the antihypertensive drug chlorthalidone (CTD) with caffeine (CAF) was obtained (CTD-CAF) by the slurry method, for which a 2:1 stoichiometric ratio was found by powder and single-crystal X-ray diffraction analysis. Cocrystal CTD-CAF showed a supramolecular organization in which CAF molecules are embedded in channels of a 3D network of CTD molecules.
The advantage of the cocrystal in comparison to CTD is reflected in a threefold solubility increase and in the dose/solubility ratios, which diminished from near-unit values for D0D to 0.29 for D0CC. Furthermore, dissolution experiments under non-sink conditions showed improved performance of CTD-CAF compared with pure CTD. Subsequent studies showed that CTD-CAF cocrystals transform to CTD form I where CTD precipitation inhibition could be achieved in the presence of pre-dissolved polymer HPMC 80–120 cPs, maintaining supersaturation drug concentrations for at least 180 min.
Finally, dissolution experiments under sink conditions unveiled that the CTD-CAF cocrystal induced, in pH-independent manner, faster and more complete CTD dissolution when compared to commercial tablets of CTD. Due to the stability and dissolution behavior of the novel CTD-CAF cocrystal, it could be used to develop solid dosage forms using a lower CTD dose to obtain the same therapeutic response and fewer adverse effects.
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Materials: Chlorthalidone (99% purity) was obtained from Shaanxi Dideu Medichem Co. Ltd. (Shaanxi, China). Anhydrous Caffeine (98.5–100% purity) was obtained from Productos Químicos Monterrey (Monterrey, México). Copovidone (Kollidon VA® 64 Fine) and polyvinylpyrrolidone (Kollidon® 90) were obtained from BASF Chemical Co. (Ludwigshafen, Germany). Methylcellulose (Methocel® A15), hydroxypropyl methylcellulose (Methocel® E5LV, Methocel® E15LV, and Methocel® E50LV) were kindly donated by Colorcon Inc. (West Point, PA, USA). Hydroxypropyl methylcellulose (HPMC 80–120 cPs), methylcellulose (Methocel® 60 HG), hydroxypropyl cellulose (HPC 80,000, and HPC 370,000), polyvinylpyrrolidone (Kollidon® 25), poloxamer (Kolliphor® P 188 and Kolliphor® P 407), monobasic potassium phosphate (99% purity), sodium hydroxide (97% purity), and HPLCgrade methanol were obtained from Sigma-Aldrich Co. (St. Louis, MO, USA). Hydrochloric acid, absolute ethanol, and dibasic sodium phosphate (99% purity) were obtained from J.T. Baker (Philipsburg, NJ, USA). All other chemicals and the solvents were analytical or reagent grade and used as received without further purification. Ultra-pure water obtained from a Classic UVF water purification system (ELGA LabWater Ltd., High Wycombe, Bucks, UK) was used in this study.
Article information: Rodríguez-Ruiz, C.; Montes-Tolentino, P.; Domínguez-Chávez, J.G.; Morales-Rojas, H.; Höpfl, H.; Herrera-Ruiz, D. Tailoring Chlorthalidone Aqueous Solubility by Cocrystallization: Stability and Dissolution Behavior of a Novel Chlorthalidone-Caffeine Cocrystal. Pharmaceutics 2022, 14, 334. https://doi.org/10.3390/pharmaceutics14020334