Process modelling issues in the design of a continuous flow route for the production of pharmaceuticals in multiphase processes: the case of Ibuprofen
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Data di Pubblicazione:
2021
Citazione:
Process modelling issues in the design of a continuous flow route for the production of pharmaceuticals in multiphase processes: the case of Ibuprofen / F. Conte, A. Tripodi, G. Ramis, I. Rossetti. ((Intervento presentato al convegno 11th International Symposium on Catalysis in Multiphase Reactors (CAMURE - 11) & 10th International Symposium on Multifunctional Reactors (ISMR - 10) tenutosi a Milano nel 2021.
Abstract:
Process modelling issues in the design of a continuous flow route for the production of pharmaceuticals in multiphase processes: the case of Ibuprofen
Antonio Tripodi1, Francesco Conte1, Gianguido Ramis2, Ilenia Rossetti1*
1 Chemical Plants and Industrial Chemistry Group, Dip. Chimica, Università degli Studi di Milano, CNR-ISTM and INSTM Unit Milano-Università, via C. Golgi 19, 20133 Milano, Italy; 2 DICCA, Università degli Studi di Genova and INSTM Unit-Genova, via all’Opera Pia 15A, 16100 Genoa, Italy
*Corresponding author E-Mail: ilenia.rossetti@unimi.it
1. Introduction
Continuous Pharmaceutical Manufacturing (CPM) of Active Pharmaceutical Ingredient (API) may offer many advantages over batch practice: lower costs, reduced wastes, decreased time-to-market for new drugs. Continuous flow reactors can deliver significantly higher yields and lower solvent and energy waste.
Ibuprofen (2-[4-(2methylpropyl)phenyl)]propanoic acid) is one the most sold Non Steroidal Anti Inflammatory Drug in the world and it is considered suitable for continuous manufacturing on the basis of technical and economic considerations [1]. While the continuous synthesis of the API has lately been established at the lab-scale level [2], the purification and crystallization section are still treated with batch procedures. Also, the reviewed simulation attempts are quite general [1,3,4]. Hence, we investigated the process in detail to evidence the lacking information for process optimization and intensification: detailed reaction kinetics is often missing, preventing reactor modelling, sizing and cost evaluation. Furthermore, the product separation is as important as the continuous flow synthesis, but its conversion from a batch to a continuous protocol is usually missing. Finally, the molecules taken into account are often very complex, undergo very specific transformations, whose thermodynamic description is mostly unavailable. This can lead to unreliable heat consumption/release predictions and to misleading prevision of products separation.
2. Methods
The flowsheet is based, for the reactive part, on the work of Bogdan et al. [5] as already rescaled by Jolliffe et al. [3], while the separation and crystallization part is originally derived from the experimental protocol of the former article and of similar patented procedures [6]. Since the API has to be separated from organic (e.g. unreacted isobutylbenzene), but also polar (e.g. acetic acid) residues, the adopted process design (yielding the soluble potassium salt in presence of methanol) imposes two purification stages in series. The material and heat balances of the process were calculated using Aspen Plus V9®. The molecular structures and properties for all the involved chemicals were retrieved from the APV9-PURE35, APV9-AQUEOUS and NIST-TRC databanks. Due to the strongly polar or even ionic character of liquid phase, the ENRTL model (Elec-Non-Random Two Liquids). The UNIFAC (Unified Activity Coefficients) system was much more reliable when dealing with the crucial methanol-water-solvent phase split and thus it was applied to the extraction section, due to its good prevision of liquid-liquid equilibria. The gas-phase behavior was described via the RK (Redlich-Kwong) equation of state.
3. Results and discussion
The Elec-NRTL thermodynamic model was found adequate to describe the mass balances of the reaction section, while mixing and heat exchangers were modeled based on literature data. Despite its importance in this process, triflic acid is not already fully parametrized in the archives available. The presence of electrolytes, prevents a safe estimation of the properties of the mixture by the predictive UNIFAC method, that was instead used for the separation section, involving acc
Tipologia IRIS:
14 - Intervento a convegno non pubblicato
Elenco autori:
F. Conte, A. Tripodi, G. Ramis, I. Rossetti
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