Study of yield variation in a pharmaceutical manufacturing process and optimization of purification subsection : By a design of experiments study of the production parameters and a laboratory study of the purification step

Abstract: The product R1-MR2E is an ester formed from an esterification of a carboxylic acid and an alcohol at Cambrex Karlskoga AB. The production of the intermediate R1-MR2E is a large-scale production and there are two main objectives and two sub-objectives that this project aims to study of the manufacturing.The manufacturing of R1-MR2E experience big variations in the product yield which is affecting theproductions stability and economic aspects of it. Thus, one of the main objectives in this project was to use experimental design to find significant factors that causes yield variations. The results from this study showed five significant factors that affect the yield positively or negatively by resulting in higher or lower product weight. The factors found are the amount of charged toluene solution containing the by-product R1-DR2E from the recycling system, the amount of charged carboxylic acid, the reaction time, the amount of added Na2SO3 in the neutralisation step and the regulated pH value after the crystallisation step. The other main objective is to optimize the purification sub-section using activated carbon (AC). There are two sub-objectives for this part of the study where the first sub-objective is to evaluate how much activated carbon that is needed to remove the impurities and colouration in the product. The second sub-objective is to investigate if an activated carbon filter could be used as a substitute for the commonly used loose powder activated carbon. To answer this objective a laboratory method was used, where the large-scale purification- and crystallisation step as well as after treatment were scaled down to lab scaleand then experiments were conducted to determine the effects of different amounts of activated carbon, using no carbon, and utilizing another type of activated carbon known as activated carbon filters. The results were then analysed for colour and purity by a visual observation method and High-Performance Liquid Chromatography (HPLC) method. The conclusion from this study is that only 25% of the amount of activated carbon used today is needed to remove the colouration in the product. The activated carbon did not completely remove the impurities in the product. The other conclusion was that the idea that the activated carbon removed the small impurities was wrong, and the levels of the impurities are already small enough in the large-scale production that the purification step is not needed to reach approved levels of these impurities. The activated carbon filter also works to remove the colouration with only one filtration but does not work well on removing the impurities in the product.