Suppressed hydration in metoclopramide hydrochloride by salt cocrystallisation†,CrystEngComm

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Suppressed hydration in metoclopramide hydrochloride by salt cocrystallisation†
CrystEngComm ( IF 2.6 ) Pub Date : 2018-02-28 00:00:00 , DOI: 10.1039/c8ce00129d
Yuda Prasetya Nugraha _{1,

2,

3,

4,

5} , Hidehiro Uekusa _{3,

4,

5,

6,

7}

Affiliation

Metoclopramide (MCP), a widely used antiemetic drug, is marketed as hydrochloride salt existing in the monohydrate and anhydrate forms. In this study, the hydration/dehydration behaviour of MCP hydrochloride salt was investigated by thermal and crystal structure analysis. Major structural rearrangement occurred upon dehydration, indicating the important role of water in stabilising the structure of the monohydrate form. Crystal structure analysis revealed that the lack of strong hydrogen bonds and less efficient packing in the anhydrate form contributed to the conversion to the monohydrate form in high humidity by increasing the solid state stability. To overcome hydrate/anhydrate conversion, a cocrystal of MCP hydrochloride with oxalic acid was synthesised, in which all hydrogen bond donor and acceptor sites of MCP were utilised with comparable packing efficiency to the monohydrate form. These features are responsible for the stability of the salt cocrystal against hydration. In addition, the salt cocrystal showed stability against dissociation in aqueous slurry experiments. This pharmaceutically acceptable salt cocrystal exhibits superior thermal and humidity stability and its slower dissolution rate is promising for extended release formulations. This study highlights the role of salt cocrystallisation in improving the physicochemical properties of active pharmaceutical ingredients in salt form.

中文翻译：

盐共结晶抑制了甲氧氯普胺盐酸盐的水合作用†

甲氧氯普胺（MCP）是一种广泛使用的止吐药，以一水合物和无水物形式存在的盐酸盐形式销售。在这项研究中，通过热和晶体结构分析研究了MCP盐酸盐的水合/脱水行为。脱水时发生主要的结构重排，表明水在稳定一水合物形式的结构中起重要作用。晶体结构分析表明，无水形式缺乏强氢键和低效堆积，通过增加固态稳定性，有助于在高湿度下转化为一水合物形式。为了克服水合物/无水物的转化，合成了MCP盐酸盐与草酸的共晶体，其中使用了MCP的所有氢键供体和受体位点，其堆积效率与一水合物形式相当。这些特征决定了盐共结晶抗水合作用的稳定性。另外，盐共晶体在含水浆液实验中显示出对解离的稳定性。这种可药用的盐共晶体表现出优异的热稳定性和湿度稳定性，其较慢的溶解速度有望用于缓释制剂。这项研究强调了盐共结晶在改善盐形式活性药物成分的理化特性中的作用。盐共结晶在水性浆液实验中显示出对解离的稳定性。这种可药用的盐共晶体表现出优异的热稳定性和湿度稳定性，其较慢的溶解速度有望用于缓释制剂。这项研究强调了盐共结晶在改善盐形式活性药物成分的理化特性中的作用。盐共结晶在水性浆液实验中显示出对解离的稳定性。这种可药用的盐共晶体表现出优异的热稳定性和湿度稳定性，其较慢的溶解速度有望用于缓释制剂。这项研究强调了盐共结晶在改善盐形式活性药物成分的理化特性中的作用。

更新日期：2018-02-28

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