Falk R F, Randolph T W
Department of Chemical Engineering, University of Colorado, Boulder 80309, USA.
Pharm Res. 1998 Aug;15(8):1233-7. doi: 10.1023/a:1011991808423.
The purpose was to determine the influence of process parameters in the precipitation with a compressed antisolvent (PCA) process on the morphology and residual dichloromethane (DCM) levels in gentamycin-loaded PLA microparticles.
The three variables studied were the rate of CO2 co-flowed during the polymer and drug post-precipitation, the post-precipitation pure CO2 flush rate, and the post-precipitation CO2 flush volume. Residual DCM levels were determined from headspace gas chromatography-mass spectroscopy (GC-MS) with single ion monitoring. X-ray diffraction (XRD) and differential scanning calorimetry (DSC) were used to estimate the crystallinity within microparticles. DCM was extracted from drug-loaded microparticles by both supercritical CO2 extraction and vacuum drying for up to two days to determine a lower limit for solvent removal.
Increasing either the post-precipitations CO2 flow rate or flush volume resulted in lower residual DCM levels in the microparticle. The CO2 co-flow rate showed an opposite trend. Increasing in value resulted in a higher DCM value after precipitation. XRD and DSC analysis on these samples suggest that those produced at lower CO2 co-flow rates have a higher degree of crystallinity, which increases the diffusivity of DCM through the polymer matrix. Finally, samples subjected to extended (48 hr) CO2 extraction resulted in DCM levels on the order of one to three ppm.
Specific PCA process conditions during microparticle formation have a strong influence on the residual solvent levels within the microparticles. Polymer morphology affects the diffusivity of solvent through the polymer matrix, which in turn determines the solvent removal rates.
本研究旨在确定压缩抗溶剂（PCA）沉淀过程中的工艺参数对载有庆大霉素的聚乳酸（PLA）微粒形态和残余二氯甲烷（DCM）水平的影响。
研究的三个变量分别为聚合物和药物沉淀后二氧化碳的共流速率、沉淀后纯二氧化碳的吹扫速率以及沉淀后二氧化碳的吹扫体积。残余DCM水平通过顶空气相色谱 - 质谱联用仪（GC - MS）的单离子监测来测定。采用X射线衍射（XRD）和差示扫描量热法（DSC）估算微粒内部的结晶度。通过超临界二氧化碳萃取和真空干燥长达两天，从载药微粒中提取DCM，以确定溶剂去除的下限。
增加沉淀后二氧化碳的流速或吹扫体积会使微粒中的残余DCM水平降低。二氧化碳共流速率呈现相反趋势，其值增加会导致沉淀后DCM值升高。对这些样品进行XRD和DSC分析表明，在较低二氧化碳共流速率下制备的样品具有更高的结晶度，这增加了DCM在聚合物基质中的扩散率。最后，经过延长（48小时）二氧化碳萃取的样品，其DCM水平在1至3 ppm量级。
微粒形成过程中的特定PCA工艺条件对微粒内的残余溶剂水平有很大影响。聚合物形态会影响溶剂在聚合物基质中的扩散率，进而决定溶剂去除速率。
