| dc.description.abstract | The aim of this thesis is to integrate the different research aspects of acetaminophen from the point of view of chemical and materials engineering to optimize the process. In reaction section, the recipe for acetaminophen is acetylating p-aminophenol with acetic anhydride. However, there are three distinct cases of crystallization routes including different agitational method and the time point of neutralization as the main experiments. The average conversion of three different cases is around 86.3%. Weight percent of solid particles retained on 297 μm sieve are in the order of Case II > Case III > Case I. The concentration profile of acetaminophen, pH values, and temperature throughout the reaction, crystallization, and neutralization are monitored by the in-process controls. When local concentration in the reaction solution was compared with the particular saturated concentration obtained from the solubility curve, the driving force for nucleation could be realized. The driving force in Case I was large causing the generation of many small nuclei but insufficient growth in early crystallization among the three cases. As for the other unit operations of filtration and drying, we used the formula of specific cake resistance and Krischer curve to measure the effect of agglomeration. The specific cake resistance was in the order of Case I > Case III > Case II, respectively, and the short drying curve for the wet cake of Case II indicated that it had more large pores within the agglomerates among the three cases. The mixed suspension, mixed product removal (MSMPR) formalism and particle size distribution were employed to calculate the rates of nucleation, crystal growth and agglomeration during crystallization. The results conformed to our expectation that the nucleation and crystal growth rates were in the order of Case I > Case III > Case II, and Case II > Case III > Case I, respectively. The size-dependent aggregation rate for Cases II was the largest meaning the highest frequency of aggregation. In addition, the Carr’s index and dissolution test were used to qualify the flowability of dry powder and the acetaminophen released rate in the simulated environment of human body, respectively. Among these three cases, Case II gave the best rheological property and relatively the slowest drug release rate. Finally, the overall materials balance revealed that the yields and purities of different cases were almost the same. However, the different crystallization paths could affect the crystal habits causing the total different results in physicochemical properties. Furthermore, in Case III paths, we accidentally discovered acetaminophen Form II which was the visionary form for pharmaceutical workers in the world. The DSC scan of the sample showed a melting peak at around 151oC. Meanwhile, the PXRD pattern and IR spectrum of the sample verified that it was acetaminophen Form II. The detail experimental procedures were discussed in the Appendix. We hope that this thesis can provide a significant influence to the pharmaceutical industry in the related research of acetaminophen and other active pharmaceutical ingredient. | en_US |