Reaction kinetics and population balance modelling of telmisartan neutralisation by sodium carbonate

Telmisartan is one of the most widely used cardiovascular drugs, with over 2.6 million annual prescriptions in the USA alone and a global sales volume over $4.3 billion in 2025. Telmisartan in the form of free acid is practically insoluble in water and its oral bioavailability is only about 43%, which represents a substantial environmental and economic waste. The conversion of telmisartan free acid to a sodium salt was shown to improve aqueous solubility dramatically. Hence, the kinetics of telmisartan neutralisation is of immense practical significance and industrial interest. Commercially available telmisartan sodium salt produced by a neutralisation reaction of telmisartan with sodium hydroxide can suffer from unfavourable physical properties such as hygroscopicity or sticking. An alternative is to use sodium carbonate as a base in the neutralisation reaction. This is a multi-phase reaction that involves solid particles of telmisartan free acid, aqueous solution of sodium carbonate and telmisartan sodium salt, and the evolution of carbon dioxide gas as a reaction by-product. Relatively little is known about the rate and parametric sensitivity of this reaction where a complex interplay between reaction kinetics, acid-base equilibria, particle size distribution and mass transfer occurs. The present work reports a newly developed mathematical model of telmisartan neutralisation with sodium carbonate, validated using experimental data. It provides insights into the effect of process parameters including temperature and reactant concentration on the progress of the reaction and reveals that CO 2 desorption from the reaction mixture can be a rate-limiting step at higher reactant concentrations. The mathematical model provides a basis for optimising the material throughput in a combined process comprising reaction followed by drying to produce the final telmisartan sodium powder. • Solvent-free method of producing sodium salt of telmisartan, a major cardiovascular drug • Mechanistic model of reactive particle dissolution with complex acid-base equilibria and mass transfer • Experimental study into parametric sensitivity of reaction kinetics and rate-limiting step • Model-based optimisation of process workflow to produce final dry product