Basic design of a dexketoprofen trometamol production plant

Abstract

Dexketoprofen trometamol is an active pharmaceutical ingredient belonging to the NSAID (Nonsteroidal Anti-Inflammatory Drugs) class, commonly used to treat mild to acute pain, such as postoperative pain. Its consumption has been increasing over the years, since, unlike the most widely used NSAID in Spain, ibuprofen, it has considerably fewer side effects at the gastric level, while maintaining its efficacy in pain inhibition. The main objective of this work is to carry out a basic design for the production of this active ingredient. To this end, a market study has been performed, in which the annual European demand for dexketoprofen trometamol was estimated at approximately 100 tons. On the basis of this figure, it has been decided to cover 10 % of this demand, which equals about 10 t/year. This production is designed to be carried out in 20 batches, each containing 500 kg of DKT with 98 % purity, and packed in drums of 25 kg. A patent search was then carried out to obtain information on how to produce the desired product, including operating conditions, reaction times and other relevant parameters, since this study does not delve into the kinetics of the synthesis. Among the different patents analyzed, patent CN101928214A was selected as the main reference for the process design. However, since the process described in this patent is too extensive for the purposes of this study, the battery limit was limited from the synthesis of dexketoprofen trometamol from dexketoprofen and tromethamine to the final packaging of dexketoprofen trometamol. Based on the selected patent and the defined battery limit, a recipe adapted to industrial production has been developed, describing in detail each stage of the process and its respective operating conditions. Subsequently, a block diagram has been developed to visualize the process, together with a mass balance to determine the quantities of material required to produce 500 kg of product per batch. Once the process and its unit operations have been defined, the required equipment has been specified. The reaction (V-1) and crystallization (V-2) tanks have been designed, both of 5.3 m³.A bag filter (F-1) has been selected for the separation of solid impurities, a Nutsche filter (F-2) for the purification and drying of the crystals, and a pin mill (M-1) for the size reduction of the final product. The corresponding technical specification sheets have been prepared for each of these units. From all this information and the adapted recipe, the P&ID (Piping and Instrumentation Diagram) of the designed process was drawn. Next, a study of the occupancy time of each equipment has been carried out, obtaining a batch time of 32 h and a cycle time of 18.5 h, being the Nutsche filter (F-2) the limiting equipment for requiring the longest operation time. With this information, two types of batch production scheduling have been compared: overlapping and non-overlapping batches. The scheduling with overlapping batches has been chosen for being more efficient in terms of time. Within this context, a constraint related to thermal services has been considered, since both the reaction tank (V-1) and the Nutsche filter (F-2) require steam water during a certain time in the overlapping schedule. Based on this constraint, two configurations have been evaluated: with and without heating services overlap. For both configurations, a KPI analysis has been performed, determining the maximum production capacity and minimum production time: 17.48 t/year and 16.75 days/year for the configuration without services constraint, and 14.87 t/year and 19.46 days/year for the configuration with such constraint. Finally, a campaign scheduling study has been carried out, in which it has been decided to distribute the production in 4 campaigns, one every 2.5 months of 5 batches each. This distribution avoids the accumulation of stock and leaves enough time between campaigns for the manufacture of other products in the plant.