Didanosine polymorphism in a supercritical antisolvent process.
Didanosine polymorphism in a supercritical antisolvent process.
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超临界反溶剂过程中的去羟肌苷多晶型。
DOI：
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发表时间：
2010
期刊：
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通讯作者：
L. Pellegrino
中科院分区：
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作者：
R. Bettini;R. Menabeni;R. Tozzi;M. B. Pranzo;I. Pasquali;M. R. Chierotti;R. Gobetto;L. Pellegrino
活性成分的固态性质在药物开发中至关重要，因为它们具有重要的临床和经济意义。在目前的工作中，我们研究了固态性质和在水中的溶解度的去羟肌苷，DDI，从二甲亚砜溶液中使用超临界CO（2）作为抗溶剂（SAS过程）的比较，与市售的药物产品重结晶。我们还应用了现代固体核磁共振（SS NMR）技术，即2D（1）H DQ CRAMPS（组合旋转和多脉冲光谱）和（1）H-（13）C共振和非共振CP（交叉极化）FSLG-HETCOR实验，以提供关于（1）H-（1）H和（1）H-（13）C分子内和分子间邻近性的可靠信息而闻名，以解决在超临界方法中由新形式的结晶引起的多晶型问题。采用超临界抗溶剂法合成了去羟肌苷的一种新晶型，并用1D和2D多核（1H，13 C，15 N）SS NMR对其结构进行了表征。通过增加压力来改变反溶剂密度，从而减小新晶相的粒径。商业产品和SAS重结晶DDI之间的结构差异通过X射线衍射法突出显示，并通过固态NMR充分描述。碳C6（13）C化学位移表明，商业和重结晶的去羟肌苷样品都是烯醇形式。通过2D NMR实验获得的同质和异质邻近性的分析表明，商业和SAS重结晶DDI具有非常相似的分子构象和氢键网络，但不同的包装。新的多晶型物被证明在环境条件下是亚稳态形式，显示出在水中的较高溶解度和对机械应力的较低稳定性。
Solid-state properties of active ingredients are crucial in pharmaceutical development owing to their significant clinical and economical implications. In the present work we investigated the solid-state properties and the solubility in water of didanosine, DDI, re-crystallized from a dimethylsulfoxide solution using supercritical CO(2) as an antisolvent (SAS process) for comparison with the commercially available drug product. We also applied modern solid-state NMR (SS NMR) techniques, namely 2D (1)H DQ CRAMPS (Combined Rotation And Multiple Pulse Spectroscopy) and (1)H-(13)C on- and off-resonance CP (cross polarization) FSLG-HETCOR experiments, known for providing reliable information about (1)H-(1)H and (1)H-(13)C intra- and intermolecular proximities, in order to address polymorphism issues arising from the crystallization of a new form in the supercritical process. A new polymorph of didanosine was obtained from the supercritical antisolvent process and characterized by means of 1D and 2D multinuclear ((1)H, (13)C, (15)N) SS NMR. The particle size of the new crystal phase was reduced by varying the antisolvent density through a pressure increase. The structural differences between the commercial product and the SAS re-crystallized DDI are highlighted by X-ray diffractometry and well described by solid-state NMR. The carbon C6 (13)C chemical shift suggests that both commercial and re-crystallized didanosine samples are in the enol form. The analysis of homo- and heteronuclear proximities obtained by means of 2D NMR experiments shows that commercial and SAS re-crystallized DDI possess very similar molecular conformation and hydrogen bond network, but different packing. The new polymorph proved to be a metastable form at ambient conditions, showing higher solubility in water and lower stability to mechanical stress.