Novel Pharmaceutical Cocrystal of Telmisartan and Hydrochlorothiazide

Abstract

Objective: Telmisartan (TEL), commonly used antihypertensive, is poorly soluble in water and has limited and variable bioavailability. Commercially, TEL is available as a single drug and in combination with hydrochlorothiazide (HYZ). Researchers have developed cocrystals of TEL with coformers, namely, oxalic acid, glutaric acid, and saccharin. An attempt was made to prepare the cocrystals of TEL with HYZ, an active pharmaceutical ingredient (API) itself so that both the APIs are available in a single tablet. The present study was aimed at enhancement in solubility of TEL by formation of its cocrystals.
 Methods: The cocrystals of TEL with HYZ, in different stoichiometric ratios (1:0.5, 1:1, and 1:2), were prepared by solvent coevaporation and liquid-assisted grinding methods. The cocrystals, consisting of TEL:HYZ (in 1:0.5 ratio and 1:1 ratio), depicted maximum yield, drug content, saturation solubility, and flow properties. These cocrystals were characterized by X-ray analysis, infrared spectroscopy, and thermal analysis.
 Results: The crystal structure of TEL-HYX revealed that it was a cocrystal, since no proton was transferred between the TEL and HYZ molecules. It was predicted that two molecules are associated through a hydrogen bond between an acidic group of TEL and sulfonamido group of HYZ. The cocrystallization improved the solubility of TEL 7 times. In vitro release rate of tablets of cocrystals was higher than that of marketed TEL tablets. HYZ has a potential to form the cocrystals of TEL.
 Conclusion: The objective of improvement in the solubility of TEL was successfully achieved by the formation of cocrystals of TEL: HYZ.

New Perspectives for Antihypertensive Sartans as Components of Co-crystals and Co-amorphous Solids with Improved Properties and Multipurpose Activity

“…The authors of the aforementioned study conclude that if there are reports of a synthesized co-crystal with a specific co-former, obtaining a co-amorphic system with this co-former is possible, but this system will recrystallize in a very short time. However, TEL is an exception to this rule, because two research teams independently obtained a cocrystal of TEL with hydrochlorothiazide (HCT) 162 and a coamorphous TEL/HCT system 194 which was stable up to 180 days (25 °C, 0% RH), 30 days (60 °C, 0% RH) or 90 days (40 °C, 75% RH) depending on the applied conditions. The above example shows the importance of humidity and temperature in determining the stability of co-amorphous systems.…”

“…Taking into account the type of TEL interactions with the coformer, a group of co-crystals which are formed due to the interaction of the TEL carboxyl group with the OH or NH coformer groups can be distinguished. To date, this group includes two co-crystals of the API−API type, in which TEL is combined with atenolol (AT) 161 and hydrochlorothiazide (HCT) 162 as well as one API−carboxylic acid co-crystal with glutaric acid (GLA). 156 The API−API type combination reflects a regimen of combined treatment of hypertension in which beta-blockers (AT) and diuretics (HCT) are used in addition to ARBs (TEL).…”

“…The authors obtained TEL/HCT co-crystals in 1:0.5, 1:1, and 1:2 molar ratios. 162 In addition, they used two synthesis methods: solvent evaporation (SE) and liquid assisted grinding (LAG). The TEL/HCT(SE) 1:0.5 co-crystal and the TEL/HCT(LAG) 1:1 co-crystal exhibited the best flow properties and solubility.…”

“…The combination of TEL with HCT is believed to provide a better control of hypertension than TEL alone and is recommended by the WHO. The authors obtained TEL/HCT co-crystals in 1:0.5, 1:1, and 1:2 molar ratios . In addition, they used two synthesis methods: solvent evaporation (SE) and liquid assisted grinding (LAG).…”

Enhancement of Solubility and Dissolution Rate of Acetylsalicylic Acid via Co-Crystallization Technique: A Novel Asa-Valine Cocrystal

“…The absorbance of the resultant solution was recorded at 268 nm using UV-1700 double beam spectrophotometer (Shimadzu, Japan). The average of three readings was taken [39].…”