Study of the RESS Process for the Micronization of Ethenzamide, Carbimazole and Menadione

• Main Authors: Chun-Lin Wu, 吳俊霖
• Other Authors: Yan-Ping Chen
• Format: Others
• Language: zh-TW
• Published: 2017
• Online Access: http://ndltd.ncl.edu.tw/handle/ucd5g9

碩士 === 國立臺灣大學 === 化學工程學研究所 === 105 === In this study, the rapid expansion of supercritical solution (RESS) process was applied to produce micronized particles of two active pharmaceutical ingredients (APIs) and one kind of food additives. They were ethenzamide, carbimazole and menadione, respectively. The solubility of APIs and food additives is usually insoluble and poorly bioavailable. Therefore, by the reduction of targeted drug particles into submicron scale, it leads to a significant increase in dissolution rate and bioavailability. For ethenzamide, the micronized result was not found obviously under the operating condition (Text at 338 K, Pext at 200 bar, Tpost at 298 K and nozzle diameter at 1000 μm). The mean particle size was only reduced from 17.69 μm to 9.37 μm after the RESS process. However, in the dissolution rate test, the dissolution rate constant (kw) was increased from 0.0254 min-1 to 0.2471 min-1. The rate of dissolution was significantly enhanced by 9.73 times. Besides, the thermal and spectrometric properties of the ethenzamide were nearly consistent between the original and RESS processed particles. For carbimazole, the mean particle size was reduced from 84.58 μm to 3.63 μm under the operating condition (Text at 348 K, Pext at 220 bar, Tpost at 298 K and nozzle diameter at 1000 μm). The micronized degree was up to 23.3 times. The chemical properties of carbimazole were same. However, the melting point and the enthalpy of fusion were decreased because of the lower crystallinity after the RESS process. In addition, the dissolution rate constant (kw) of original and RESS processed particles was 0.1263 min-1 and 1.8957 min-1. Although the original dissolution rate of carbimazole was decent enough, the dissolution rate still improved 15.01 times after the RESS process. For menadione, the factorial design was applied as the design of experiment. It was for the purpose of discussing the effect of the different parameters on the value of micronized mean particle size. Three parameters, extraction temperature (Text), extraction pressure (Pext) and post-expansion temperature (Tpost), were chosen in this 23 factorial design. After finishing the 23 factorial design, nozzle diameter (DN) was selected as another parameter to discuss. Results from the analysis of variance (ANOVA) showed that post-expansion temperature was the most significantly parameter whose contribution was high to 91.086%. Then, the product in the most moderate condition (Run 4) was subsequently selected to be analyzed. The mean particle size was dramatically micronized from 129.14 μm to 1.17 μm. In qualitative analysis, there was no change of the physical and chemical properties after the RESS process. Moreover, the RESS processed menadione was closed to amorphous form because of its quite small intensity of crystallinity. In the dissolution rate test, the dissolution rate constant (kw) was changed from 0.0144 min-1 to 0.0631 min-1. As a result, the dissolution rate enhanced 4.38 times.