Viboonkiat, Runglawan; (2002) Methods to prepare amorphous material for rapid dissolution solid dosage forms. Doctoral thesis , UCL (University College London).

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Abstract

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.

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