Phase Solution and Solution Recrystallization Equilibrium Constants of Hydroxypropyl-β-cyclodextrin Complexes with Nifedipine and Nicardipine Hydrochloride

Abstract

The calcium-channel blockers nifedipine (NIF) and nicardipine (NIC) hydrochloride (Scheme 1) are ester derivatives of 4-aryl-1,4-dihydropyridine-3,5-dicarboxylate, and they are widely used for the treatment of moderate hypertension and cerebral disease1,2). Because NIF and neutral NIC have low solubility in aqueous solutions and high permeability across biomembranes, they are categorized as class-II drugs on the Biopharmaceutics Classi cation System (BCS) catalog 3). The poor solubility of class-II drugs decreases both their absorption and distribution; therefore, an improvement in their solubility is required to enhance the bioavailability and transportability toward their cellular targets. Cyclodextrin (CD) is a cyclic (α-1,4)-linked oligosaccharide of α-D-glucopyranose. It is widely used to increase the aqueous solubility, stability, and bioavailability of drugs; in addition, it is used to convert crystalline drugs into microcrystalline powders, prevent drug-drug or drug-additive interactions, decrease gastrointestinal irritation, and eliminate unpleasant taste4). These applications exploit the ability of CD and its derivatives to capture insoluble drugs, either by inclusion in the hydrophobic central cavity or by adsorption at the hydrophilic outer surface5). Hydroxypropyl-β-cyclodextrin (HP-β-CD) is a CD alternative, and shows improved aqueous solubility of drugs and resistance to chemical and photodegradation6~8). Moreover, HP-β-CD is utilized in medicines approved for clinical use in oral and intravenous products and suppositories in the United States, Belgium, and Switzerland9). In a previous study, we investigated the physicochemical properties of NIF/HP-β-CD and NIC/ HP-β-CD complexes by differential scanning calorimJ. Pharm. Sci. Technol., Jpn., 76 (4), 267-273 (2016)