Forster A, Hempenstall J, Rades T
School of Pharmacy, University of Otago, New Zealand.
Drug Dev Ind Pharm. 2001 Jul;27(6):549-60. doi: 10.1081/ddc-100105180.
The aim of this study was to investigate the use of small-scale fusion experiments and the Gordon-Taylor (GT) equation to predict whether melt extrusion of a drug with an amorphous polymer produces a stable amorphous dispersion with increased drug dissolution. Indomethacin, lacidipine, nifedipine, piroxicam, and tolbutamide were used as poorly soluble drugs. Drug/polyvinylpyrrolidone (PVP) blends were prepared at a 1:1 mass ratio. Small-scale fusion experiments were performed in a differential scanning calorimeter (DSC) and in stainless steel beakers. Extrusion was performed in a Brabender Plasti-corder. The glass transition temperatures Tg were determined by DSC. Taking an average Tg from the DSC melt, beaker melt, and GT equation accurately predicted the extrudate Tg. Physical stability of beaker melt and extrudate samples was tested by X-ray powder diffraction (XRPD) and DSC after storage at 30 degrees C (beaker melt) or 25 degrees C (extrudate) and less than 10%, 60%, and 75% relative humidity, (RH). Beaker melts were amorphous, apart from some residual crystallinity. Extrudates were amorphous after preparation. Except for indomethacin/PVP, which remained amorphous, the crystallinity of beaker melts and extrudates increased only at 75% RH. Recrystallization occurred even when the Tg of the sample was well above the storage temperature. Chemical stability of the beaker melts and extrudates was tested by capillary electrophoresis and high-performance liquid chromatography (HPLC). Stability was slightly improved in the extrudate compared to the beaker melt. In general, the order for rate of dissolution was crystalline drug was less than the physical mixture, which was less than the drug/PVP beaker melt, which was approximately equal to the extrudate. The use of beaker melts allows a conservative estimate of the potential to melt extrude a drug. To predict physical stability, analysis of the Tg must be combined with physical stability experiments.
本研究的目的是研究小规模熔融实验和戈登-泰勒（GT）方程的应用，以预测药物与无定形聚合物的熔融挤出是否会产生具有增加药物溶出度的稳定无定形分散体。吲哚美辛、拉西地平、硝苯地平、吡罗昔康和甲苯磺丁脲用作难溶性药物。以1:1的质量比制备药物/聚乙烯吡咯烷酮（PVP）共混物。在差示扫描量热仪（DSC）和不锈钢烧杯中进行小规模熔融实验。在布拉本德塑度仪中进行挤出。通过DSC测定玻璃化转变温度Tg。取DSC熔体、烧杯熔体和GT方程的平均Tg能准确预测挤出物的Tg。在30℃（烧杯熔体）或25℃（挤出物）以及低于10%、60%和75%相对湿度（RH）下储存后，通过X射线粉末衍射（XRPD）和DSC测试烧杯熔体和挤出物样品的物理稳定性。除了一些残余结晶度外，烧杯熔体是无定形的。挤出物在制备后是无定形的。除了仍为无定形的吲哚美辛/PVP外，烧杯熔体和挤出物的结晶度仅在75%RH时增加。即使样品的Tg远高于储存温度，也会发生重结晶。通过毛细管电泳和高效液相色谱（HPLC）测试烧杯熔体和挤出物的化学稳定性。与烧杯熔体相比，挤出物的稳定性略有提高。一般来说，溶出速率的顺序为结晶药物＜物理混合物＜药物/PVP烧杯熔体≈挤出物。使用烧杯熔体可以对药物熔融挤出的潜力进行保守估计。为了预测物理稳定性，必须将Tg分析与物理稳定性实验相结合。
