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.
Highlights
Drug combination has attracted the expanding interests in pharmaceutical research in recent years
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, and the fracture of the hydrogen bonds of Apx, which was the joint of the adjacent Que chains, facilitated the break-up of the structures
Apx–Que–2ACN was crystallized in the monoclinic space group P21 /n with one Apx, one Que, and two acetonitrile molecules in its asymmetric unit (Figure 1a)
Summary
Drug combination has attracted the expanding interests in pharmaceutical research in recent years. Drug combinations exhibit advantages in the increased patient compliance and adherence, the simplification of disease management, the reduced cost of drug products and the reduced probability of mono-therapy-induced resistant bacilli strains [1–9]. The promising applications of drug combinations are impeded by the limitations encountered in the formulation stages, such as poor solubility and stability, chemical interactions of ingredients, and decreased bioavailability. Many approaches were conducted to improve the solubility and bioavailability of poorly soluble compounds of drug combination, for example, inclusion complex with hydroxypropylβ-cyclodextrin (HP-β-CD), solid dispersion with highly water-soluble polymers, and microemulsion formulation [10–15]. There are still more limitations including potential chemical interactions caused by introducing new materials into the formulation, and the high standard storage conditions required for the stability of the products
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