Abstract
Vonoprazan (VPZ) is the first-in-class potassium-competitive acid blocker (P-CAB), and has many advantages over proton pump inhibitors (PPIs). It is administered as a fumarate salt for the treatment of acid-related diseases, including reflux esophagitis, gastric ulcer, and duodenal ulcer, and for eradication of Helicobacter pylori. To discover novel cocrystals of VPZ, we adopted an artificial neural network (ANN)-based machine learning model as a virtual screening tool that can guide selection of the most promising coformers for VPZ cocrystals. Experimental screening by liquid-assisted grinding (LAG) confirmed that 8 of 19 coformers selected by the ANN model were likely to create new solid forms with VPZ. Structurally similar benzenediols and benzenetriols, i.e., catechol (CAT), resorcinol (RES), hydroquinone (HYQ), and pyrogallol (GAL), were used as coformers to obtain phase pure cocrystals with VPZ by reaction crystallization. We successfully prepared and characterized three novel cocrystals: VPZ–RES, VPZ–CAT, and VPZ–GAL. VPZ–RES had the highest solubility among the novel cocrystals studied here, and was even more soluble than the commercially available fumarate salt of VPZ in solution at pH 6.8. In addition, novel VPZ cocrystals had superior stability in aqueous media than VPZ fumarates, demonstrating their potential for improved pharmaceutical performance.
Highlights
Publisher’s Note: MDPI stays neutralVonoprazan (VPZ; Takecab® ) is an orally bioavailable potassium-competitive acid blocker (P-CAB) developed by Takeda Pharmaceutical Company (Osaka, Japan) for the treatment and prevention of acid-related diseases, as the first in a new class of drugs that inhibit gastric H+ /K+ -ATPase at the final stage of the acid secretory pathway in gastric parietal cells [1,2]
Vonoprazan–catechol (VPZ–CAT): Approximately 0.77 g (7 mmol) of CAT were completely dissolved in 10 mL of acetonitrile and 2.42 g (7 mmol) of VPZ free base were added to the solution in increments of 345 mg (1 mmol)
Vonoprazan–pyrogallol (VPZ–GAL): Approximately 1.26 g (10 mmol) of GAL were completely dissolved in 15 mL of acetonitrile and 3.45 g (10 mmol) of VPZ free base were added to the solution in increments of 690 mg (2 mmol)
Summary
Vonoprazan (VPZ; Takecab® ) is an orally bioavailable potassium-competitive acid blocker (P-CAB) developed by Takeda Pharmaceutical Company (Osaka, Japan) for the treatment and prevention of acid-related diseases, as the first in a new class of drugs that inhibit gastric H+ /K+ -ATPase at the final stage of the acid secretory pathway in gastric parietal cells [1,2]. As solid-state formulations, polymorphs, amorphous forms, cocrystals, salts, and their hydrates can be used to alter the physicochemical properties of drugs [10]. The physicochemical properties of an active pharmaceutical ingredient (API), such as stability, dissolution, hygroscopicity, and solubility, have a direct impact on the processing, delivery, and therapeutic performance of drugs [11]. Various virtual screening tools have been proposed to identify appropriate coformers for APIs based on hydrogen bond propensity [23], molecular electrostatic potential surface [24,25], Hansen solubility parameter [26], conductor-like screening model for real solvents [27], and crystal structure prediction [28]. The solubility and intrinsic dissolution rate (IDR) of the novel cocrystals were determined and compared to Discussion the commercial fumarate salt of VPZ
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