Alam Qadir, Ganeshpurkar Ankit, Singh Sushil Kumar, Krishnamurthy Sairam
Neurotherapeutics Laboratory, Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi221005, U.P., India.
Pharmaceutical Chemistry Laboratory, Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi 221005, U.P., India.
ACS Omega. 2023 Jul 11;8(29):26218-26230. doi: 10.1021/acsomega.3c02463. eCollection 2023 Jul 25.
Crystallization has revolutionized the field of solid-state formulations by modulating the physiochemical and release profile of active pharmaceutical ingredients (APIs). Dimethyl fumarate (DF), an FDA-approved first-line drug for relapsing-remitting multiple sclerosis, has a sublimation problem, leading to loss of the drug during its processing. To tackle this problem, DF cocrystal has been prepared by using solvent evaporation technique using nicotinamide as a coformer, which has been chosen based on predictions and their ability to participate in hydrogen bonding. Fourier transform infrared (FT-IR), powder X-ray diffraction (PXRD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and sublimation analysis have characterized the cocrystal and its thermostability. Comparative analysis of the release profile has been done by the dissolution and pharmacokinetic study of DF and its cocrystal. Formulated cocrystal is noncytotoxic, antioxidant and inhibits interleukin-6 and tissue necrosis factor-α in peripheral blood mononuclear cells induced by lipopolysaccharide. We have obtained a thermostable cocrystal of DF with a similar physicochemical and release profile to that of DF. The formulated cocrystal also provides a gastroprotective effect which helps counterbalance the adverse effects of DF by reducing lipid peroxidation and total nitrite levels.
结晶通过调节活性药物成分（API）的物理化学性质和释放曲线，彻底改变了固态制剂领域。富马酸二甲酯（DF）是一种经美国食品药品监督管理局（FDA）批准用于复发缓解型多发性硬化症的一线药物，存在升华问题，导致药物在加工过程中损失。为了解决这个问题，采用溶剂蒸发技术，以烟酰胺作为共形成物制备了DF共晶，烟酰胺是根据预测及其参与氢键形成的能力而选择的。通过傅里叶变换红外光谱（FT-IR）、粉末X射线衍射（PXRD）、热重分析（TGA）、差示扫描量热法（DSC）和升华分析对共晶及其热稳定性进行了表征。通过DF及其共晶的溶出度和药代动力学研究，对释放曲线进行了比较分析。制备的共晶无细胞毒性、具有抗氧化作用，并能抑制脂多糖诱导的外周血单核细胞中的白细胞介素-6和组织坏死因子-α。我们获得了一种DF的热稳定共晶，其物理化学性质和释放曲线与DF相似。制备的共晶还具有胃保护作用，通过降低脂质过氧化和总亚硝酸盐水平，有助于抵消DF的不良反应。
