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首页> 外文期刊>Molecular pharmaceutics >Effect of precipitation inhibitors on indomethacin supersaturation maintenance: Mechanisms and modeling
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Effect of precipitation inhibitors on indomethacin supersaturation maintenance: Mechanisms and modeling

机译：沉淀抑制剂对消炎痛维持过饱和的影响：机理与模型

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摘要

This study quantitatively explores the mechanisms underpinning the effects of model pharmaceutical polymeric precipitation inhibitors (PPIs) on the crystal growth and, in turn, maintenance of supersaturation of indomethacin, a model poorly water-soluble drug. A recently developed second-derivative UV spectroscopy method and a first-order empirical crystal growth model were used to determine indomethacin crystal growth rates in the presence of model PPIs. All three model PPIs including HP-β-CD, PVP, and HPMC inhibited indomethacin crystal growth at both high and low degrees of supersaturation (S). The bulk viscosity changes in the presence of model PPIs could not explain their crystal growth inhibitory effects. At 0.05% w/w, PVP (133-fold) and HPMC (28-fold) were better crystal growth inhibitors than HP-β-CD at high S. The inhibitory effect of HP-β-CD on the bulk diffusion-controlled indomethacin crystal growth at high S was successfully modeled using reactive diffusion layer theory, which assumes reversible complexation in the diffusion layer. Although HP-β-CD only modestly inhibited indomethacin crystal growth at either high S (～15%) or low S (～2-fold), the crystal growth inhibitory effects of PVP and HPMC were more dramatic, particularly at high S (0.05% w/w). The superior crystal growth inhibitory effects of PVP and HPMC as compared with HP-β-CD at high S were attributed to a change in the indomethacin crystal growth rate-limiting step from bulk diffusion to surface integration. Indomethacin crystal growth inhibitory effects of all three model PPIs at low S were attributed to retardation of the rate of surface integration of indomethacin, a phenomenon that may reflect the adsorption of PPIs onto the growing crystal surface. The quantitative approaches outlined in this study should be useful in future studies to develop tools to predict supersaturation maintenance effects of PPIs.
机译：这项研究定量研究了模型药物聚合物沉淀抑制剂（PPI）对晶体生长的影响的机制，进而维持了吲哚美辛（一种难溶于水的模型药物）的过饱和。在模型PPI存在的情况下，使用最近开发的二阶导数紫外光谱法和一阶经验晶体生长模型确定吲哚美辛晶体的生长速率。包括HP-β-CD，PVP和HPMC在内的所有三种模型PPI在高和低过饱和度（S）均抑制吲哚美辛晶体的生长。在存在模型PPI的情况下，体积粘度的变化不能解释其晶体生长抑制作用。 w / w为0.05％时，PVP（133倍）和HPMC（28倍）在高S下比HP-β-CD更好的晶体生长抑制剂.HP-β-CD对本体扩散控制的抑制作用使用反应扩散层理论成功地模拟了在高S下消炎痛晶体的生长，该理论假设扩散层中存在可逆络合。尽管HP-β-CD在高S（〜15％）或低S（〜2倍）时仅适度抑制吲哚美辛晶体的生长，但PVP和HPMC的晶体生长抑制作用更为显着，特别是在高S（0.05 ％w / w）。在高S下，与HP-β-CD相比，PVP和HPMC具有更好的晶体生长抑制作用，这归因于消炎痛晶体生长速率限制步骤从本体扩散到表面整合的变化。在低S下，所有三种模型PPI的吲哚美辛晶体生长抑制作用均归因于吲哚美辛表面整合速率的降低，该现象可能反映了PPI在生长的晶体表面上的吸附。本研究中概述的定量方法应在将来的研究中有用，以开发预测PPI过饱和维持作用的工具。

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