Rogers True L, Nelsen Andrew C, Hu Jiahui, Brown Judith N, Sarkari Marazban, Young Timothy J, Johnston Keith P, Williams Robert O
College of Pharmacy, University of Texas at Austin, Austin, TX, USA.
Eur J Pharm Biopharm. 2002 Nov;54(3):271-80. doi: 10.1016/s0939-6411(02)00063-2.
A novel cryogenic spray-freezing into liquid (SFL) process was developed to produce microparticulate powders consisting of an active pharmaceutical ingredient (API) molecularly embedded within a pharmaceutical excipient matrix. In the SFL process, a feed solution containing the API was atomized beneath the surface of a cryogenic liquid such that the liquid-liquid impingement between the feed and cryogenic liquids resulted in intense atomization into microdroplets, which were frozen instantaneously into microparticles. The SFL micronized powder was obtained following lyophilization of the frozen microparticles. The objective of this study was to develop a particle engineering technology to produce micronized powders of the hydrophobic drug, danazol, complexed with hydroxypropyl-beta-cyclodextrin (HPbetaCD) and to compare these SFL micronized powders to inclusion complex powders produced from other techniques, such as co-grinding of dry powder mixtures and lyophilization of bulk solutions. Danazol and HPbetaCD were dissolved in a water/tetrahydrofuran cosolvent mixture prior to SFL processing or slow freezing. Identical quantities of the API and HPbetaCD used in the solutions were co-ground in a mortar and pestle and blended to produce a co-ground physical mixture for comparison. The powder samples were characterized by differential scanning calorimetry (DSC), powder X-ray diffraction (XRD), Fourier transform infrared spectrometry (FTIR), scanning electron microscopy, surface area analysis, and dissolution testing. The results provided by DSC, XRD, and FTIR suggested the formation of inclusion complexes by both slow-freezing and SFL. However, the specific surface area was significantly higher for the latter. Dissolution results suggested that equilibration of the danazol/HPbetaCD solution prior to SFL processing was required to produce the most soluble conformation of the resulting inclusion complex following SFL. SFL micronized powders exhibited better dissolution profiles than the slowly frozen aggregate powder. Results indicated that micronized SFL inclusion complex powders dissolved faster in aqueous dissolution media than inclusion complexes formed by conventional techniques due to higher surface areas and stabilized inclusion complexes obtained by ultra-rapid freezing.
开发了一种新型的低温喷雾冷冻成液（SFL）工艺，以生产由分子嵌入药物赋形剂基质中的活性药物成分（API）组成的微粒粉末。在SFL工艺中，含有API的进料溶液在低温液体表面下方雾化，使得进料和低温液体之间的液 - 液撞击导致强烈雾化成微滴，这些微滴立即冷冻成微粒。冷冻微粒冻干后得到SFL微粉化粉末。本研究的目的是开发一种颗粒工程技术，以生产与羟丙基 - β - 环糊精（HPβCD）复合的疏水药物达那唑的微粉化粉末，并将这些SFL微粉化粉末与通过其他技术生产的包合物粉末进行比较，例如干粉混合物的共研磨和本体溶液的冻干。在进行SFL处理或缓慢冷冻之前，将达那唑和HPβCD溶解在水/四氢呋喃共溶剂混合物中。将溶液中使用的相同量的API和HPβCD在研钵和研杵中共同研磨并混合，以制备共研磨的物理混合物用于比较。通过差示扫描量热法（DSC）、粉末X射线衍射（XRD）、傅里叶变换红外光谱法（FTIR）、扫描电子显微镜、表面积分析和溶出度测试对粉末样品进行表征。DSC、XRD和FTIR提供的结果表明，缓慢冷冻和SFL均形成了包合物。然而，后者的比表面积明显更高。溶出结果表明，在SFL处理之前需要使达那唑/ HPβCD溶液平衡，以在SFL后产生所得包合物的最易溶构象。SFL微粉化粉末比缓慢冷冻的聚集体粉末表现出更好的溶出曲线。结果表明，微粉化的SFL包合物粉末在水性溶出介质中的溶解速度比通过传统技术形成的包合物更快，这是由于更高的表面积和通过超快速冷冻获得的稳定包合物。
