Stable Cocrystals and Salts of the Antineoplastic Drug Apatinib with Improved Solubility in Aqueous Solution

Abstract

Apatinib (APA) belongs to the targeted antineoplastic family of drugs by inhibiting the vascular endothelial cell growth factor receptor (VEGFR-2) of tyrosine kinase. APA encounters poor aqueous solubility problems, and its therapeutic dosage form, apatinib mesylate (ATM), is unstable and dissociates completely to APA in aqueous solution. Here, we synthesized and evaluated three new cocrystals of APA with adipic acid (APA + ADA), sebacic acid (APA + SEA), and D/L-mandelic acid (APA + D/L-MA), and four new salts with succinic acid (APA + SUA-H 2 O), salicylic acid (APA + SA), 1-hydroxy-2-naphthoic acid (APA + HNA), and saccharin (APA + SAC). All the solid forms were characterized by powder X-ray diffraction, infrared spectroscopy, differential scanning calorimetry, and dynamic vapor sorption. The molecular components and structures were confirmed by single crystal Xray diffraction. APA + SEA is able to overcome the instability problem and has improved solubility compared with ATM. Hence, APA + SEA has the potential to be a superior candidate for this important drug.

SMINBR: An Integrated Network and Chemoinformatics Tool Specialized for Prediction of Two-Component Crystal Formation

“…Top 10 interaction partners for APA were recommended (Table 4), in which fumaric acid, succinic acid, adipic acid, oxalic acid, benzoic acid, malonic acid, glutaric acid, 4-aminobenzoic acid, and 4-hydroxybenzoic acid have been found to form cocrystals with APA in previous studies. 28,42 In this study, paradioxybenzene (PDB) was subject to experimental screening and found to form a new cocrystal with APA. This new APA-PDB cocrystal was analyzed by powder X-ray diffraction (PXRD) to distinguish it from the parent phases (see Figure 6).…”

“…The cocrystal screening of apatinib (APA), which is a clinical drug for advanced gastric cancer, was conducted by the guidance of SMINBR. Although APA has been reported to form pharmaceutical cocrystals in recent publications, , these cocrystals do not exist in the constructed molecular-interaction network, because the cocrystal data used for network construction were retrieved before 2016. Therefore, APA can be viewed as an NCE and used to evaluate the capability of SMINBR to guide experimental cocrystal screening for new synthetic compounds.…”

Structural and Reactivity Analyses of Nitrofurantoin–4-dimethylaminopyridine Salt Using Spectroscopic and Density Functional Theory Calculations

“…The market value of a drug can be drastically reduced due to its poor physicochemical properties, which in turn can cause the demand to replace it. This is the major reason why there is an increased interest in the physicochemical properties upgradation methods such as salt formation [3]. Pharmaceutical salts are ionizable drugs that have been combined with a counter-ion to form a neutral compound.…”

Improving the solubility and bioavailability of anti-hepatitis B drug PEC via PEC–fumaric acid cocrystal

“…In recent years, the research on cocrystals has become increasingly erce, especially in the pharmaceutical industry. [1][2][3][4][5][6][7][8][9][10] In the pharmaceutical eld, a drug cocrystal is a crystalline solid containing at least one active pharmaceutical ingredient (API) and one or more cocrystal coformers (CCFs). These substances exist in one crystal lattice, and the molecules connected through non-ionic way interacting.…”