Sinomenine-phenolic acid coamorphous drug systems: Solubilization, sustained release, and improved physical stability

Abstract

Sinomenine (SIN), isolated from Caulis sinomenii, is a benzyltetrahydroisoquinoline-type alkaloid with potent anti-inflammatory and analgesic effects. SIN-HCl has been used in the forms of tablets or enteric-coated tablets in the treatment of rheumatoid arthritis in China for years, while its short half-life leads to attenuated therapeutic effects and serious side effects. In the current study, three phenolic acids, including salicylic acid (SAA), 2,3-dihydroxybenzoic acid (23DHB), and 2,4-dihydroxybenzoic acid (24DHB), were firstly employed as coamorphous coformers to prepare three binary SIN-phenolic acid coamorphous systems. These new coamorphous systems were characterized by powder X-ray diffraction (PXRD), modulated temperature differential scanning calorimetry (mDSC), and Fourier transform infrared spectroscopy (FTIR). The formation of SIN-phenolic acid coamorphous systems are supported by the absence of diffraction peaks in their PXRD spectra, as well as the single Tgs of three samples (i.e., SIN-SAA, SIN-23DHB, and SIN-24DHB) at 109.5 °C, 124.9 °C, and 135.3 °C. Importantly, the salt formation between SIN and phenolic acids was observed in FTIR. In three coamorphous systems, coamorphous SIN-24DHB shows superior physicochemical stability under both low humidity and accelerated storage conditions. They were also more soluble than crystalline SIN, while were released slower than the commercial SIN-HCl in dissolution experiments. Therefore, our study suggests that phenolic acids may be used as a new type of coformers in the preparation of coamorphous systems for active pharmaceutical ingredients.