利用噴射結晶技術探討添加物對水難溶性藥物的影響

The Effect of Additives on Poorly Water-Soluble Drugs by Using the Impinging-Jets Crystallization Technique

周世偉(Shih-Wei Chou)

指導教授 ： 魏正琪

國立臺北科技大學/工程學院/化學工程所/碩士(2005年)

摘要

本文以噴射結晶技術針對難溶性藥物進行結晶研究，並藉由添加物的加入，以改善難溶性藥物的溶離速率，進而提高藥物的療效。文中採用tolbutamide（TBM）及phenylbutazone（PBZ）為模式藥物，四種添加物分別為hydroxypropylcellulose（HPC）、polyvinylpyrrolidone（PVP）、sodium lauryl sulfate（SDS）以及D-mannitol（D-M）進行實驗。以丙酮為藥物的溶劑，水為反溶劑，針對不同的過飽和度以及添加物濃度等操作變數進行探討。由觀察得知，不同的添加物會使藥物晶體獲得不同的晶貌如片狀、針狀或是棒狀等。由TBM藥物的研究結果顯示，當溶液的過飽和度愈高，所析出的晶體粒徑愈小且分佈愈集中，其中以流量比T1：3.57W獲得的最為細小及均勻。由噴射後的藥物晶體發現，經噴射後所獲得的PBZ藥物晶體將會發生多晶型相轉變，同時由DSC以及XRD鑑別加入添加物後，將會引起另一種多晶型的出現。再進一步將藥物粉體進行體外溶離試驗發現，噴射結晶中加入添加物將會改善TBM藥物溶離速率。至於加入添加物的改善效果依序為添加HPC＞SDS＞PVP＞D-M＞未添加。另一方面，PBZ藥物溶離速率快慢依序則是添加SDS＞HPC＞PVP＞D-M＞未添加。因此證實添加物的加入確實可以提升藥物粉體的潤濕效果，進而使溶離速率大幅上升，有助於提升藥物的療效。

關鍵字

噴射結晶技術 ； 添加物 ； 溶離速率 ； 粒徑分佈

並列摘要

The research conducts the study of impinging-jets crystallization for poorly water-soluble drugs by adding additives to improve dissolution rate, thus enhancing the therapeutic effect of drugs. Tolbutamide and phenylbutazone were used as model drugs while hydroxyproplcellulose（HPC）, polyvinylpyrrolidone（PVP）, sodium lauryl sulfate（SDS） and D-mannitol（D-M） were additives used in this work. Also, acetone was the solvent for the drugs, while water was the anti-solvent. In the experiments, different operating variables such as supersaturation as well as the ratios of additive to drug were studied.
According to the observations of crystal shapes, different additives would lead to different crystal morphologies, such as tabular, needle or rod. The results of tolbutamide showed that as the supersaturation of solution increases, the crystal size becomes smaller and the particle distribution becomes narrower. Furthermore, for a mixed solution of acetone and water with a volume ratio of 1:3.57, the most uniform and smallest size of crystals was found. A polymorphism phase shift for phenylbutazone from the rod-like crystals to the needle-like crystals was observed through impinging-jet crystallization. In addition, adding additives were shown to cause another phase transformation, which was characterized by DSC and XRD. Furthermore, a dissolution test in vitro was performed for the drug products. The test illustrated that the impinging-jets crystallization with the additives will improve the dissolution rate of tolbutamide. The effect of improvement for the additives is in the order of adding HPC> SDS> PVP> D-M> non-added. On the other hand, the improvement in the dissolution rate for phenylbutazone takes the order of adding SDS> HPC> PVP> D-M > non-added. The results show that the additives may enhance the wetting effect of particles, which will result in greatly improving the dissolution rate of poorly water-soluble drugs, thus raising the therapeutic effect of drugs.

並列關鍵字

Impinging-jets crystallization ； Additive ； Dissolution rate

參考文獻

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