The growing attention regarding a more sustainable future, and thus into energy recovery and waste reduction technologies, has intensified the interest towards processes which allow to exploit waste and biomasses to generate energy, such as the anaerobic digestion. Improving the efficiency of this industrial application is crucial to increase methane production, and is essential from the economic, environmental and safety point of view. This study focuses on the thermodynamic modelling of a steady-state reactor as a flash unit, in order to determine the best operating conditions to produce the maximum amount of pure bio-methane. To this purpose, a new hybrid approach based on the Peng–Robinson cubic equation of state and on the Multi-Parameter Helmholtz-Energy EoS has been proposed. The simulations, performed using the developed algorithm at temperatures between 20 and 55 °C and at pressure values between 0.3 atm and 1.5 atm, point out that the fugacity of the mixture evaluated with the proposed technique is much more accurate and reliable than the one calculated with the PR EoS. In addition, this research has shown not only that the purity and the production of the biogas can be optimised by working at mesophilic conditions and at pressure between 1 atm and 1.5 atm, but also that it is not convenient to operate in a temperature range of 42 °C–45 °C, since about 20 % more ${\mathrm{H}}_2\mathrm{S}$ goes into the exiting biogas, reducing the $\mathrm{C}{\mathrm{H}}_4$ amount and raising the post-treatment costs. Lastly, it has been seen that there is a significant water content in the vapour phase (∼5 %wt.), and this is a factor to be taken into account in order to improve the process.