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Methods to prepare amorphous material for rapid dissolution solid dosage forms.

机译：制备用于快速溶解固体剂型的无定形物质的方法。

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摘要

Poorly water-soluble drugs with dissolution as the rate-limiting step in gastrointestinal absorption commonly show increased bioavailability when dissolution is improved by conversion to the amorphous form. In this study, different techniques were employed to convert a model drug, indomethacin, into the amorphous state. The techniques involved the use of spray-drying and supercritical carbon dioxide (SC-CO2) as an antisolvent and as a solvent. The products were characterised using differential scanning calorimetry (DSC) and Powder X-ray diffraction (PXRD). In the spray drying method, indomethacin was co-spray dried with microcrystalline cellulose (MCC) and polyvinylpyrrolidone (PVP) at various proportions. At 20% PVP and above, amorphous indomethacin could be produced but MCC had no effect on crystallinity. When SC-CO2 was used as an antisolvent, it was not possible to form amorphous indomethacin or coprecipitates of indomethacin-PVP. After modification of the rig, SC-CO2 was employed as a solvent. Coprecipitated indomethacin at various PVP weight fractions were successfully prepared, and amorphous products were obtained at PVP weight fraction of 0.80 and above. The dissolution rates of indomethacin-PVP mixtures prepared using SC-CO2, physical mixing and solvent evaporation methods were compared. PVP enhanced the dissolution of indomethacin at low concentration but increase in PVP content above 30% retarded the dissolution rate. The dissolution was dependent on the PVP content and the preparation method. The stability of indomethacin-PVP mixtures at different temperatures and relative humidities was monitored over a 3-month period. Coprecipitation of indomethacin- PVP retarded the crystallization process. The coprecipitates where indomethacin existed in completely amorphous form did not crystallize after storage at 30, 50 and 70°C for 3 months. Similarly, coprecipitation of indomethacin with PVP also retarded the crystallization process at 35% RH for 3 months. At 76% and 98% RH, products absorbed large quantities of water but did not crystallize. In summary, a solvent free, porous and rapid dissolution amorphous indomethacin can be prepared by SC-CO2 based process. This method could provide a viable and practical alternative to spray drying for the production of amorphous material.
机译：当通过转化为无定形形式改善溶解度时，以溶解为胃肠吸收速率限制步骤的水溶性差的药物通常显示出更高的生物利用度。在这项研究中，采用了不同的技术将模型药物吲哚美辛转化为非晶态。这些技术涉及使用喷雾干燥和超临界二氧化碳（SC-CO2）作为抗溶剂和溶剂。使用差示扫描量热法（DSC）和粉末X射线衍射（PXRD）对产品进行表征。在喷雾干燥法中，将吲哚美辛与微晶纤维素（MCC）和聚乙烯吡咯烷酮（PVP）以不同比例共同喷雾干燥。 PVP在20％或更高时，可以生成非晶吲哚美辛，但MCC对结晶度没有影响。当使用SC-CO2作为抗溶剂时，不可能形成无定形的吲哚美辛或吲哚美辛-PVP的共沉淀物。修改钻机后，将SC-CO2用作溶剂。成功制备了各种PVP重量分数的共沉淀消炎痛，并获得了PVP重量分数为0.80及更高的无定形产物。比较了使用SC-CO2，物理混合和溶剂蒸发方法制备的消炎痛-PVP混合物的溶解速率。 PVP在低浓度时增强了吲哚美辛的溶出度，但PVP含量超过30％时，则增加了溶出度。溶出度取决于PVP含量和制备方法。在三个月的时间内监测了吲哚美辛-PVP混合物在不同温度和相对湿度下的稳定性。消炎痛-PVP的共沉淀会延迟结晶过程。吲哚美辛以完全无定形形式存在的共沉淀在30、50和70°C下保存3个月后未结晶。同样，消炎痛与PVP的共沉淀也使35％RH下的结晶过程延迟了3个月。在相对湿度为76％和98％时，产品吸收了大量的水，但没有结晶。总之，可以通过基于SC-CO 2的方法制备无溶剂的，多孔的且快速溶解的无定形消炎痛。该方法可为喷雾干燥生产非晶态材料提供可行且实用的替代方法。

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  • 作者

    Viboonkiat, Runglawan.;

  • 作者单位

    University of London, University College London (United Kingdom).;

  • 授予单位 University of London, University College London (United Kingdom).;
  • 学科 Pharmacology.
  • 学位 Ph.D.
  • 年度 2003
  • 页码 211 p.
  • 总页数 211
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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