Hygroscopicity Reduction and Interconversion of Ligustrazine in <i>Ligusticum chuanxiong</i> Hort. via Cocrystallization and Mechanochemical Technology

The green and sustainable production of pharmaceuticals has always been a concern, and mechanochemistry as an effective means of green chemistry can reduce the use of solvents and the environmental hazards of intermediates in drug production. Ligustrazine, also known as 2,3,5,6-tetramethylpyrazine (TMP), is an effective drug for the treatment of cardiovascular and cerebrovascular diseases, but it tends to sublimate under ambient conditions, is unstable under light conditions, and is highly hygroscopic. The cocrystallization technique is an effective method to improve its stability. In this paper, four cocrystals, namely, TMP–MG (1.5:2), TMP–MG–H2O (2.5:1:1), TMP–EG (1:1), and TMP–PG (1:1), were obtained by mechanochemical and cocrystallization techniques, and the stability and hygroscopicity were studied. Characterization and structural analysis were carried out using different techniques. It showed that four new cocrystals showed significantly higher hygroscopicity and improved stability under strong light. In addition, interconversion between TMP–MG and TMP–MG–H2O was found by mechanochemical methods. Cocrystallization combined with mechanochemical technique as a simple and effective green method provides strong support for the improvement of pharmaceutical properties and sustainable production.