Factors that influence the spontaneous formation of pharmaceutical cocrystals by simply mixing solid reactants
Factors that influence the spontaneous formation of pharmaceutical cocrystals by simply mixing solid reactants
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通过简单混合固体反应物影响药物共晶体自发形成的因素
DOI：
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发表时间：
2009
期刊：
影响因子：
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通讯作者：
N. Rodríguez
中科院分区：
文献类型：
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作者：
C. Maheshwari;A. Jayasankar;N. A. Khan;G. Amidon;N. Rodríguez
这项研究的目的是调查是否通过简单地混合纯固体成分而不需要磨砂来形成共晶体。在纯组分受到不同水平的机械应力的二元混合物中，研究了储存期间水分和温度的影响：(A)两组分未球磨，(B)一组分球磨，或(3)两组分单独球磨。无水单斜III型卡马西平(CBZ)与I型烟酰胺(NCT)或糖精(SAC)等摩尔混合物分别储存在25°C~75%RH、45°C~0%RH和45°C~75%RH。用FTIR和XRPD分析了其向共晶转变的情况。结果表明，除未球磨的CBZ/SAC在25°C-75%RH条件下外，其他组分在3个月内都没有机械应力，也会发生向共晶的转变。根据溶解度和平衡常数计算的自由能证实，从反应物到共晶的转变在热力学上是有利的。提高温度和相对湿度以及通过单独球磨反应物进行机械活化可以增强共晶体的形成。在所有储存条件下，CBZ-NCT共晶的形成速度均快于CBZ-SAC。在单独研磨的CBZ和SAC的混合物中检测到亚稳的CBZ-SAC多晶型。
The purpose of this study was to investigate whether cocrystals form by simply mixing pure solid components without the need to comill. The effects of moisture and temperature during storage were studied in binary mixtures where pure components were exposed to different levels of mechanical stress: (a) two components unmilled, (b) one component milled, or (3) two components individually milled. Equimolar mixtures of anhydrous monoclinic form III carbamazepine (CBZ) with form I nicotinamide (NCT) or saccharin (SAC) were stored at 25 °C-75%RH, 45 °C-0%RH and 45 °C-75%RH. Transformation to cocrystal was monitored by FTIR and XRPD. Results show that conversion to cocrystal occurs even when components are not mechanically stressed at all storage conditions within 3 months except for unmilled CBZ/SAC at 25 °C-75%RH. Free energy calculations from solubilities and equilibrium constants confirm that transformation from reactants to cocrystal is thermodynamically favorable. Increasing temperature and relative humidity as well as mechanical activation by individually milling reactants enhances cocrystal formation. CBZ-NCT cocrystal forms faster than CBZ-SAC at all storage conditions. A metastable CBZ-SAC polymorph was detected in mixtures of individually milled CBZ and SAC.
影响因子：
3.8
作者：
Berry, David J.;Seaton, Colin C.;Blagden, Nicholas
通讯作者：
Blagden, Nicholas
影响因子：
3.8
作者：
Porter, William W., III;Elie, Sophia C.;Matzger, Adam J.
通讯作者：
Matzger, Adam J.