Cocrystal and Salt Forms of an Imidazopyridazine Antimalarial Drug Lead

Cocrystallization and salt formation were used to produce new multicomponent forms of a novel antimalarial imidazopyridazine drug lead (MMV652103) that displayed improved physicochemical properties. The drug lead had earlier shown good in vitro potency against multidrug resistant (K1) and sensitive (NF54) strains of the human malaria parasite Plasmodium falciparum, and high in vivo efficacy in both Plasmodium berghei and Plasmodium falciparum mouse models. A major drawback of MMV652103 is its limited aqueous solubility. Various new supramolecular products, including several multicomponent solid forms, are reported here, namely 3 cocrystal forms with the dicarboxylic acid coformers adipic acid, glutaric acid, and fumaric acid, and a salt form with malonic acid. These were characterized by thermal methods and their structures elucidated by single-crystal X-ray diffraction. A customized solubility experiment was performed in fasted-state simulated intestinal fluid for comparison of the solubility behavior of each new form of the drug lead with that of the untreated starting material. All of the multicomponent forms showed an improvement in the maximum concentrations (C_max) attained by the drug lead and the rate at which it dissolved. The recorded C_max values exceeded the concentration of the untreated compound by factors in the range 4.6-5.6.     

HPLC determination of olanzapine and carbamazepine in their nicotinamide cocrystals and investigation of the dissolution profiles of cocrystal tablet formulations

Abstract

Cocrystals have recently gained importance in the pharmaceutical industry. In this study, olanzapine and carbamazepine cocrystals were synthesized by using nicotinamide as cocrystal forming agent to achieve improvements in the physicochemical characteristics of the active ingredients. An HPLC method was developed to determine the amount, thus, the stoichiometric ratios of olanzapine and carbamazepine in the synthesized cocrystals. Olanzapine:nicotinamide and olanzapine tablet formulations were prepared and the developed HPLC method was applied successfully in order to compare the dissolution profiles of these formulations. An ACE 5 CN, 25?cm?×?4.6?mm, 5?µm column was used and a gradient elution program was performed for simultaneous determination of olanzapine, carbamazepine and nicotinamide. Phosphate buffer (pH 5.0, 25?mM) and methanol was used in a ratio from 80:20 to 70:30 while the flow rate was 1?mL?min^?1 for the elution of the compounds within 12?min. In conclusion, two different aims were achieved, the first one was to indicate the stoichiometric ratios of the active ingredients olanzapine and carbamazepine with nicotinamide in their cocrystals, and the second one was the comparison of the dissolution profiles of the olanzapine and olanzapine:nicotinamide cocrystal formulations. It was found that the cocrystal formulation with nicotinamide improved the dissolution profile of olanzapine.     

黄芩素-茶碱共晶的溶剂体系筛选及体外溶出度评价

[目的] 优选制备黄芩素-茶碱共晶的溶剂体系,通过体外溶出实验考察共晶对黄芩素和茶碱各自溶出度的影响。[方法] 通过测定黄芩素-茶碱共晶在茶碱-乙酸乙酯、茶碱-甲醇和茶碱-丙酮溶液中的溶解度,得出三相平衡点,绘制黄芩素-茶碱-溶剂体系的三元相图,筛选最优溶剂体系制备共晶,并以人工肠液和人工胃液为溶出介质,对共晶进行体外溶出度评价。[结果] 丙酮溶液体系中的共晶形成区面积大于乙酸乙酯、甲醇。通过丙酮溶剂挥发法制备的共晶中,黄芩素在人工肠液和人工胃液中的累积溶出度分别是原料药的1.38和2.02倍,分别是物理混合物的1.27和1.80倍。两种介质中共晶对茶碱均起到了一定的缓释作用。[结论] 共晶的形成能够促进难溶性成分黄芩素的体外溶出度,并且对茶碱的溶出度有一定延缓作用,为黄芩素-茶碱共晶的进一步研究和临床应用提供了借鉴。     

Discovery and Structure-Based Optimization of Adenain Inhibitors

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药物的共晶与盐

药物的固体形态直接影响其安全性与有效性,共晶和盐作为两种不同的固体形态,可有效改善药物的理化性质,是目前制药工业领域的研究热点。本文归纳并总结了共晶和盐的研究现状,结合FDA最新发布的《药物共晶监管分类指南》,根据各自的物理结构差异,阐明了共晶和盐的不同定义,讨论了两者在提高药物溶解度、稳定性和生物利用度等方面的作用和可能存在的问题,介绍了一些重要的鉴别共晶与盐的现代分析方法。     

Mechanistic Insight into the Peptide Binding Modes to Two M. tb MazF Toxins

Tuberculosis (TB) is a contagious disease caused by Mycobacterium tuberculosis (M. tb). It is regarded as a major health threat all over the world, mainly because of its high mortality and drug-resistant nature. Toxin-antitoxin (TA) systems are modules ubiquitously found in prokaryotic organisms, and the well-studied MazEF systems (MazE means “what is it?” in Hebrew) are implicated in the formation of “persister cells” in the M. tb pathogen. Here, we report cocrystal structures of M. tb MazF-mt1 and -mt9, two important MazF members responsible for specific mRNA and tRNA cleavages, respectively, in complexes with truncated forms of their cognate antitoxin peptides. These peptides bind to the toxins with comparable affinities to their full-length antitoxins, which would reduce the RNA-cleavage capacities of the toxins in vitro. After structural analysis of the binding modes, we systemically tested the influence of the substitutions of individual residues in the truncated MazE-mt9 peptide on its affinity. This study provides structural insight into the binding modes and the inhibition mechanisms between the MazE/F-mt TA pairs. More importantly, it contributes to the future design of peptide-based antimicrobial agents against TB and potentially relieves the drug-resistance problems by targeting novel M. tb proteins.     

姜黄素-赖氨酸共晶在无水乙醇中的热力学研究

目的：考察在三元体系中各条件下的平衡状态,计算姜黄素共晶的相关热力学常数,探讨无水乙醇作为特异性溶剂的合理性。方法：采用溶液法分别测定姜黄素在不同温度下、不同浓度赖氨酸的无水乙醇中的溶解度,通过数学推导,得出姜黄素共晶的热力学常数。结果：绘制了姜黄素-赖氨酸-无水乙醇的三元相图,并求得了Ksp、Kll、△G°、△H及△S等热力学参数。结论：无水乙醇可以作为特异性溶剂用于提取姜黄素共晶中混杂的姜黄素单体。     

Cocrystal Formation during Cogrinding and Storage is Mediated by Amorphous Phase

Purpose The purpose of this work was to investigate the mechanisms of cocrystal formation during cogrinding and storage of solid reactants, and to establish the effects of water by cogrinding with hydrated form of reactants and varying RH conditions during storage.Methods The hydrogen bonded 1:1 carbamazepine–saccharin cocrystal (CBZ–SAC) was used as a model compound. Cogrinding of solid reactants was studied under ambient and cryogenic conditions. The anhydrous, CBZ (III), and dihydrate forms of CBZ were studied. Coground samples were stored at room temperature at 0% and 75% RH. Samples were analyzed by XRPD, FTIR and DSC.Results Cocrystals prepared by cogrinding and during storage were similar to those prepared by solvent methods. The rate of cocrystallization was increased by cogrinding the hydrated form of CBZ and by increasing RH during storage. Cryogenic cogrinding led to higher levels of amorphization than room temperature cogrinding. The amorphous phase exhibited a T _g around 41°C and transformed to cocrystal during storage.Conclusions Amorphous phases generated by pharmaceutical processes lead to cocrystal formation under conditions where there is increased molecular mobility and complementarity. Water, a potent plasticizer, enhances the rate of cocrystallization. This has powerful implications to control process induced transformations.     

共晶技术提高黄芩素溶出度及生物利用度的研究

采用混悬液结晶法制备1∶1物质的量比的黄芩素-咖啡因(BE-CA)共晶,以提高BE的溶出度及口服生物利用度。差示扫描热分析、X射线粉末衍射法、傅里叶红外光谱法等分析表明所制备的共晶为区别于BE及CA的一种长针状晶体新物质。溶出试验表明BE-CA共晶的溶出度均显著高于BE晶体及其与CA的晶体混合物。大鼠体内药代动力学研究表明,与BE相比,BE-CA共晶缩短BE及其活性代谢物黄芩苷(BI)的达峰时间(t_max),并显著提高了BE及BI的峰浓度(c_max)及血药浓度-时间曲线下面积(AUC),极大地提高了黄芩素口服生物利用度。     

熔融法制备卡马西平-烟酰胺共结晶固体分散体

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