Markeev Vladimir B, Tishkov Sergey V, Vorobei Anton M, Parenago Olga O, Blynskaya Evgenia V, Alekseev Konstantin V, Marakhova Anna I, Vetcher Alexandre A
V.V. Zakusov Research Institute of Pharmacology, 8 Baltiyskaya St., 125315 Moscow, Russia.
Kurnakov Institute of General and Inorganic Chemistry, Russian Academy of Sciences, 31Leninsky Pr., 119071 Moscow, Russia.
Polymers (Basel). 2023 Oct 18;15(20):4136. doi: 10.3390/polym15204136.
N-butyl-N-methyl-1-phenylpyrrole[1,2-a] pyrazine-3-carboxamide (GML-3) is a potential candidate for combination drug therapy due to its anxiolytic and antidepressant activity. The anxiolytic activity of GML-3 is comparable to diazepam. The antidepressant activity of GML-3 is comparable to amitriptyline. GML-3 is an 18 kDa mitochondrial translocator protein (TSPO) ligand and is devoid of most of the side effects of diazepam, which makes the research on the creation of drugs based on it promising. However, its low water solubility and tendency to agglomerate prevented its release. This research aimed to study the effect of dry grinding, the rapid expansion of a supercritical solution (RESS), and the eutectic mixture (composite) of GML-3 with polyvinylpyrrolidone (PVP) on the particle size, dissolution rate, and lattice retention of GML-3. The use of supercritical CO in the RESS method was promising in terms of particle size reduction, resulting in a reduction in the particle size of GML-3 to 20-40 nm with a 430-fold increase in dissolution rate. However, in addition to particle size reduction after RESS, GML-3 began to show signs of a polymorphism phenomenon, which was also studied in this article. It was found that coarse grinding reduced particle size by a factor of 2 but did not significantly affect solubility or crystal structure. Co-milling with the polymer made it possible to level the effect of the appearance of a residual electrostatic charge on the particles, as in the case of grinding, and the increased solubility in the resulting mechanical mixtures of GML-3 with the polymer may also indicate the dissolving properties of polymers (an increase in 400-800 times). The best result in terms of GML-3 solubility was demonstrated by the resulting GML-3:PVP composite at a ratio of 1:4, which made it possible to achieve a solubility of about 80% active pharmaceutical ingredient (API) within an hour with an increase in the dissolution rate by 1600 times. Thus, the creation of composites is the most effective method for improving the solubility of GML-3, superior to micronization.
N-丁基-N-甲基-1-苯基吡咯并[1,2-a]吡嗪-3-甲酰胺（GML-3）因其抗焦虑和抗抑郁活性，是联合药物治疗的潜在候选药物。GML-3的抗焦虑活性与地西泮相当。GML-3的抗抑郁活性与阿米替林相当。GML-3是一种18 kDa的线粒体转位蛋白（TSPO）配体，且没有地西泮的大多数副作用，这使得基于它开发药物的研究很有前景。然而，其低水溶性和团聚倾向阻碍了它的释放。本研究旨在探讨干磨、超临界溶液快速膨胀法（RESS）以及GML-3与聚乙烯吡咯烷酮（PVP）的低共熔混合物（复合物）对GML-3粒径、溶解速率和晶格保留的影响。RESS法中使用超临界CO₂在减小粒径方面很有前景，可使GML-3的粒径减小到20 - 40 nm，溶解速率提高430倍。然而，RESS处理后除了粒径减小外，GML-3开始出现多晶型现象，本文也对此进行了研究。发现粗磨使粒径减小了2倍，但对溶解度或晶体结构没有显著影响。与聚合物共研磨能够消除颗粒上残留静电荷出现的影响，如同研磨的情况一样，并且GML-3与聚合物形成的机械混合物中溶解度增加也可能表明了聚合物的溶解特性（增加了400 - 800倍）。GML-3与PVP以质量比1:4形成的复合物在GML-3溶解度方面表现出最佳结果，可在一小时内实现约80%活性药物成分（API）的溶解度，溶解速率提高了1600倍。因此，可以得出结论，复合物的形成是提高GML-3溶解度的最有效方法，优于微粉化。
