A novel bottom-up process to produce drug nanocrystals: Controlled crystallization during freeze-drying
A novel bottom-up process to produce drug nanocrystals: Controlled crystallization during freeze-drying
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DOI：
10.1016/j.jconrel.2008.03.002
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发表时间：
2008-06-04
影响因子：
10.8
通讯作者：
Frijlink, H. W.
中科院分区：
文献类型：
--
作者：
de Waard, H.;Hinrichs, W. L. J.;Frijlink, H. W.
为了改善亲脂性药物的溶出行为，开发了一种基于冷冻干燥的新型自下而上工艺，可以生产纳米晶体颗粒：“冷冻干燥期间的受控结晶”。这种新工艺可以极大地提高非诺贝特的溶出行为。例如，在药物负载量为 30% w/w 时，由受控结晶分散体制备的片剂在 10 分钟内溶解了 80% 的药物，而由物理混合物制备的片剂在 120 分钟后仅溶解了 50%。此外，还发现更快的冷冻或使用具有较低水/叔丁醇(TBA)比例的溶液导致更快的溶解，表明结晶分散体含有更小的晶体。药物的结晶可能在冷冻或干燥过程中发生。当冷冻过程中发生结晶时，更快的冷冻或使用水/TBA 比例较低的溶液会导致形成更多的核，从而形成更小的晶体。当干燥过程中发生结晶时，更快的冷冻或使用水/TBA 比例较高的溶液会导致形成较小的溶剂晶体，从而形成包含冷冻浓缩部分的较小的间隙空间。由于结晶发生在冷冻浓缩级分中并且晶体的尺寸受限于间隙空间的尺寸，因此在这些情况下形成较小的晶体。 (C) 2008 Elsevier B.V. 保留所有权利。
To improve the dissolution behavior of lipophilic drugs, a novel bottom-up process based upon freeze drying which allows for the production of nanocrystalline particles was developed: "controlled crystallization during freeze drying". This novel process could strongly increase the dissolution behavior of fenofibrate. For example at a drug load of 30% w/w, 80% of the drug dissolved within 10 min from tablets prepared from the controlled crystallized dispersions, while from tablets prepared from the physical mixture only 50% was dissolved after 120 min. Furthermore it was found that faster freezing or using a solution with a lower water/tertiary butyl alcohol (TBA) ratio resulted in faster dissolution, indicating that the crystalline dispersions contained smaller crystals. Crystallization of the drug could occur during freezing or during drying. When crystallization occurs during freezing, faster freezing or using solutions with a lower water/TBA ratio results in the formation of more nuclei and consequently smaller crystals. When crystallization occurs during drying, faster freezing or using solutions with a higher water/TBA ratio results in the formation of smaller solvent crystals and therefore smaller interstitial spaces which contain the freeze-concentrated fraction. Since crystallization occurs in the freeze-concentrated fraction and the size of the crystals are limited to the size of the interstitial spaces, smaller crystals are formed in these situations. (C) 2008 Elsevier B.V. All rights reserved.