Cocrystal of Apixaban–Quercetin: Improving Solubility and Bioavailability of Drug Combination of Two Poorly Soluble Drugs

Abstract

Drug combinations have been the hotspot of the pharmaceutical industry, but the promising applications are limited by the unmet solubility and low bioavailability. In this work, novel cocrystals, consisting of two antithrombotic drugs with poor solubility and low bioavailability in vivo, namely, apixaban (Apx) and quercetin (Que), were developed to discover a potential method to improve the poor solubility and internal absorption of the drug combination. Compared with Apx, the dissolution behavior of Apx–Que (1:1) and Apx–Que–2ACN (1:1:2) was enhanced significantly, while the physical mixture of the chemicals failed to exhibit the advantages. The dissolution improvements of Apx–Que–2ACN could be explained by the fact that the solid dispersion-like structure and column-shaped cage of Que accelerated the access of the solvent to the inner layer of Apx. The fracture of the hydrogen bonds of Apx, which was the joint of the adjacent Que chains, facilitated the break-up of the structures. Besides, the bioavailability of Apx–Que was increased compared with the physical mixture and Apx, and Apx–Que remained stable in high temperature and illumination conditions. Therefore, a drug–drug cocrystal of two antithrombotic agents with poor solubility was developed, which exhibited greatly improved solubility, bioavailability and superior stability, indicating a novel method to overcome the shortages of drug combination.

Therapeutic application of quercetin in aging-related diseases: SIRT1 as a potential mechanism

“…Several studies have shown that quercetin protects against neurodegenerative diseases by enhancing the mechanism of SIRT1 deacetylase (203,204). However, low bioavailability and solubility of quercetin limits its clinical application (205). In addition, most of the current studies only focused on quercetin glycosides, however, the functions of the gut micobiota helps to breakdown quercetin into serious biological metabolites such as phloroglucinol, 3,4-dihydroxyphenylacetic acid, 4hydroxyphenylacetic acid, and 3,4-dihydroxybenzaldehyde (206).…”

Crystal Engineering of Pharmaceutical Cocrystals in the Discovery and Development of Improved Drugs

“…Cocrystals of quercetin with caffeine (QUE–CAF) and its methanol solvate (QUE–CAF·MeOH) exhibited 14 and 8 times higher solubility, whereas quercetin–theobromine dihydrate (QUETBR·2H 2 O) is slightly better than the stable quercetin dihydrate. Their dissolution profile is shown in Figure . , …”

“…Their dissolution profile is shown in Figure 44. 250,251 Four cocrystals of the model drug propylthiouracil (PTU) 252 for the treatment of hyperthyroidism, which has a short half-life, were demonstrated as sustained-release forms to overcome hepatotoxicity associated with rapid high drug concentration. Nutritional coformers cinnamic acid (CA), gentisic acid (GA), ellagic acid (EA), and kaempferol (KA) with PTU afforded cocrystals of excellent stability (at accelerated ICH conditions of 40 °C, 75% RH over 12 weeks), and PTU−CA, PTU−EA, PTU−KA cocrystals decelerated the intrinsic dissolution rate (IDR) due to their lower solubility.…”

Cocrystals of Praziquantel with Phenolic Acids: Discovery, Characterization, and Evaluation

“…To investigate whether the plasma concentration of cocrystal in rats increased compared with API, we performed a pharmacokinetics experiment of cocrystal PRA-FA in vivo [ 26 , 27 ]. SD rats were randomly divided into three groups with two rats in each group.…”