Gupta Manish K, Tseng Yin-Chao, Goldman David, Bogner Robin H
School of Pharmacy, University of Connecticut, Storrs 06269, USA.
Pharm Res. 2002 Nov;19(11):1663-72. doi: 10.1023/a:1020905412654.
To investigate changes in drug dissolution on storage of ternary solid-dispersion granules containing poorly water-soluble drugs.
Hot-melt granulation was used to prepare ternary solid-dispersion granules in which the drug was dispersed in a carrier and coated onto an adsorbent. Seven drugs including four carboxylic acid-containing drugs (BAY 12-9566, naproxen, ketoprofen, and indomethacin). a hydroxyl-containing drug (testosterone), an amide-containing drug (phenacetin), and a drug with no proton-donating group (progesterone) were studied. Gelucire 50/13 and polyethylene glycol (PEG) 8000 were used as dispersion carriers whereas Neusilin US2 (magnesium aluminosilicate) was used as the surface adsorbent.
Two competing mechanisms have been proposed to explain the complex changes observed in drug dissolution upon storage of solid dispersion granules. Conversion of the crystalline drug to the amorphous hydrogen bonded (to Neusilin) state seems to increase dissolution, whereas, the phenomenon of Ostwald ripening can be used to explain the decrease in drug dissolution upon storage. The solubility of the drug in Gelucire is a crucial factor in determining the predominant mechanism by governing the flux toward the surface of Neusilin. The mobility for this phenomenon was provided by the existence of the eutectic mixture in the molten liquid state during storage.
A competitive balance between hydrogen bonding of the drugs with Neusilin and Ostwald ripening determines drug dissolution from solid-dispersion granules upon storage.
研究含难溶性药物的三元固体分散体颗粒在储存过程中药物溶出度的变化。
采用热熔制粒法制备三元固体分散体颗粒，其中药物分散于载体中并包被于吸附剂上。研究了七种药物，包括四种含羧酸药物（BAY 12 - 9566、萘普生、酮洛芬和吲哚美辛）、一种含羟基药物（睾酮）、一种含酰胺药物（非那西丁）以及一种无质子供体基团的药物（孕酮）。采用Gelucire 50/13和聚乙二醇（PEG）8000作为分散载体，而Neusilin US2（硅酸铝镁）用作表面吸附剂。
提出了两种相互竞争的机制来解释固体分散体颗粒储存后药物溶出度观察到的复杂变化。结晶药物向无定形氢键结合（与Neusilin）状态的转变似乎会增加溶出度，而奥斯特瓦尔德熟化现象可用于解释储存后药物溶出度的降低。药物在Gelucire中的溶解度是通过控制向Neusilin表面的通量来决定主要机制的关键因素。储存期间熔融液态中共晶混合物的存在为这种现象提供了流动性。
药物与Neusilin的氢键作用和奥斯特瓦尔德熟化之间的竞争平衡决定了储存后固体分散体颗粒中药物的溶出度。
