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通过与亲水性无定形聚合物熔融挤出制备的难溶性药物玻璃溶液的表征

Characterization of glass solutions of poorly water-soluble drugs produced by melt extrusion with hydrophilic amorphous polymers.

作者信息

Forster A, Hempenstall J, Rades T

机构信息

School of Pharmacy, University of Otago, Dunedin, New Zealand.

出版信息

J Pharm Pharmacol. 2001 Mar;53(3):303-15. doi: 10.1211/0022357011775532.

Abstract

Indomethacin, lacidipine, nifedipine and tolbutamide are poorly soluble in water and may show dissolution-related low oral bioavailability. This study describes the formulation and characterization of these drugs as glass solutions with the amorphous polymers polyvinylpyrrolidone (PVP) and polyvinylpyrrolidone-co-vinyl acetate by melt extrusion. The extrudates were compared with physical mixtures of drug and polymer. X-ray powder diffraction, thermal analysis, infrared spectroscopy, scanning electron microscopy, HPLC, moisture analysis and dissolution were used to examine the physicochemical properties and chemical stability of the glass solutions prepared by melt extrusion at a 1:1 drug/polymer ratio. Depending on the temperature used, melt extrusion produced amorphous glass solutions, with markedly improved dissolution rates compared with crystalline drug. A significant physico-chemical interaction between drug and polymer was found for all extrudates. This interaction was caused by hydrogen bonding (H-bonding) between the carbonyl group of the pyrrole ring of the polymer and a H-donor group of the drug. Indomethacin also showed evidence of H-bonding when physical mixtures of amorphous drug and PVP were prepared. After storage of the extrudates for 4-8 weeks at 25 degrees C/75% relative humidity (RH) only indomethacin/polymer (1:1) extrudate remained totally amorphous. All extrudates remained amorphous when stored at 25 degrees C/< 10% RH. Differences in the physical stability of drug/polymer extrudates may be due to differences in H-bonding between the components.

摘要

吲哚美辛、拉西地平、硝苯地平和甲苯磺丁脲在水中溶解度低,可能表现出与溶出相关的低口服生物利用度。本研究描述了通过熔融挤出将这些药物与无定形聚合物聚乙烯吡咯烷酮(PVP)和聚乙烯吡咯烷酮-醋酸乙烯酯制成玻璃溶液的配方及特性。将挤出物与药物和聚合物的物理混合物进行比较。采用X射线粉末衍射、热分析、红外光谱、扫描电子显微镜、高效液相色谱、水分分析和溶出度测定等方法,考察了在药物/聚合物比例为1:1时通过熔融挤出制备的玻璃溶液的理化性质和化学稳定性。根据所用温度,熔融挤出可产生无定形玻璃溶液,与结晶药物相比,其溶出速率显著提高。所有挤出物中药物与聚合物之间均存在显著的物理化学相互作用。这种相互作用是由聚合物吡咯环的羰基与药物的氢供体基团之间的氢键(H键)引起的。制备无定形药物与PVP的物理混合物时,吲哚美辛也显示出氢键的证据。将挤出物在25℃/75%相对湿度(RH)下储存4-8周后,只有吲哚美辛/聚合物(1:1)挤出物仍完全无定形。在25℃/<10%RH下储存时,所有挤出物均保持无定形。药物/聚合物挤出物物理稳定性的差异可能是由于各组分之间氢键的差异所致。

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