Cocrystal of metaxalone and succinic acid: Research on spectroscopic characterization, Molecular Vibration Mode and Dissolution Performance Optimization

Abstract

Metaxalone is a muscle relaxant. However, its low solubility limits its bioavailability. Drug cocrystal technology can improve the physicochemical properties of the active pharmaceutical ingredient, achieving a synergistic effect without altering the mechanism of action of the drug. In this paper, a drug cocrystal composed of metaxalone and succinic acid in a stochemical ratio of 2:1 was prepared. Its formation was confirmed by characterization methods such as PXRD, DSC, THz-TDS and SEM. The vibration modes corresponding to each absorption peak in the terahertz spectrum of the cocrystal were studied in combination with the DFT method. In the simulated gastric juice and simulated intestinal fluid, the equilibrium solubility of the prepared cocrystal was significantly improved compared with the parent drug metaxalone. The addition of surfactants and polymers also had certain effects on the solubility of metaxalone and the cocrystal. This study provides a useful idea for understanding the solubility of cocrystal and researching cocrystal solubilization.

Introduction

In recent years, as an important technology in drug development, pharmaceutical cocrystals have shown extraordinary potential in the field of pharmacy. Active pharmaceutical ingredient (API) and co-crystal former (CCF) combine in a specific stoichiometric ratio to form novel drug molecules by means of non-covalent bonds or hydrogen bonds, namely drug cocrystal [1]. Cocrystal can effectively boost the important properties of APIs including solubility, stability and bioavailability without changing the molecular structure, providing an innovative solution for breaking through the bottleneck in the development of poorly soluble drugs [[2], [3], [4]].

As shown in Fig. 1(a), the molecular formula of metaxalone (MTX) is C12H15NO3, which is a white powder central muscle relaxant with anticholinergic, antipyretic, analgesic and mild sedative effects, and is suitable for relieving skeletal muscle spasmodic pain [5].

However, the low solubility and short half-life of MTX limit its clinical application. Common side effects include dizziness, nausea, drowsiness, abnormal liver function, and long-term use may increase the risk of liver poisoning, etc. Therefore, in order to boost the pharmaceutical properties of MTX, particularly by enhancing its solubility to increase bioavailability, there is an urgent need to explore a new drug development method. Co-crystallization technique in retention under the premise of pharmacological activities, can significantly optimize the specific API physical and chemical properties and clinical performance [6]. In recent years, a series of cases of MTX forming drug cocrystals with different CCFs have been reported. Rajendrakumar et al. successfully prepared pharmaceutical cocrystals of MTX with a variety of dicarboxylic acids using solvent assisted milling [7] and characterized them using characterization methods such as powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC) [8]. Gohel et al. used MTX to cocrystal with nicotinamide, salicylamide and 4-hydroxybenzoic acid, respectively, and the solubility of the prepared cocrystals was 3-9 times higher than that of the parent drug MTX, which effectively enhanced the solubility and dissolution rate of MTX and further improved the bioavailability of MTX [9]. Succinic acid (SUC), as shown in Fig. 1(b), has the molecular formula C4H6O4. It is a white or colorless crystal with excellent solubility and thermal stability. Its low toxicity makes it permitted to be used as a food additive and a drug excipient [10]. In addition, succinic acid contains two carboxyl groups (-COOH), which makes it easy to form stable hydrogen bonds with API molecules, thereby improving the solubility and stability of API [11,12]. For the above reasons, SUC is an ideal cocrystal forming agent and was used to form drug cocrystal with MTX in this study.

In this study, cocrystal of MTX-SUC was produced by slow solvent evaporation method with the mole ratio of MTX to SUC of 2:1. MTX, SUC, MTX-SUC physical mixture and MTX-SUC cocrystal were characterized by several means such as PXRD, DSC, terahertz time-domain spectroscopy (THz-TDS) and scanning electron microscopy (SEM) to obtain their respective unique fingerprint information. Density functional theory (DFT) is a computational approach based on quantum mechanics, used to study the molecular structure and physicochemical properties of multi-electron systems [13]. THz spectroscopy can detect the vibration characteristics of cocrystal molecules at low frequencies [[14], [15], [16]], but the absorption peak positions of THz experimental spectra are sometimes rather complex, making it difficult to study the vibration modes of molecules. Therefore, we combine the DFT method with THz spectroscopy characterization. By calculating the vibration frequency and dipole moment changes of molecules, DFT can simulate the position and intensity of absorption peaks in THz spectroscopy, further helping to identify the vibration modes corresponding to weak interactions within or between molecules (hydrogen bonds, van der Waals forces) [17]. In addition, the solubility of MTX and MTX-SUC cocrystal in two different pH environments (hydrochloric acid solution with pH 1.2 and phosphate buffer solution with pH 6.8) was studied, and the effects of different concentrations of surfactants and polymers on their solubility were explored. This study provides new ideas for the rapid identification and recognition of drugs and the understanding of the dissolution performance of cocrystal under different concentrations of surfactants and polymers.

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Materials

MTX (98% purity), SUC (99.5% purity), sodium dodecyl sulfate (SDS) (97% purity) and polyethylene glycol (PEG 6000) were all purchased from Macklin Biochemical Co., Ltd. (China). All solvents are provided by commercial suppliers, and the purchased materials are used directly without any purification.

Haofei Sun, Xinyi Bai, Mingyu Wang, Bo Su, Cunlin Zhang, Hailin Cui, Shengbo Zhang, Kai Li, Zhaoxin Geng, Cocrystal of metaxalone and succinic acid: Research on spectroscopic characterization, Molecular Vibration Mode and Dissolution Performance Optimization, Journal of Molecular Structure, 2026, 145868, ISSN 0022-2860, https://doi.org/10.1016/j.molstruc.2026.145868.

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