(171c) Distillation in the Pharmaceutical Industry

Authors: 
Galan, R., Astrazeneca
Distillation in the pharmaceutical industry

Distillation is the process of separating the components or substances from a liquid mixture by selective boiling and condensation to increase the concentration of selected components of the mixture. The process exploits differences in the volatility of the mixture's components and this physical separation makes distillation a unit operation of practically universal importance.

Distillation plays an important role in the pharmaceutical industry where single stage batch distillations are frequently used and not the multistage distillation in columns studied at university. Distillation can be operated in batch or continuous modes, in single or multiple steps (put and take), and can be run for a variety of objectives: separation, solvent swap, drying from water, purification from volatile or non-volatile impurities and crystallization.

Distillation within the pharma industry is often used to solvent swap because the reaction solvent is usually different to the crystallization solvent or to concentrate a solution before crystallization. They offer many challenges, the environment of the Active Pharmaceutical Ingredient (API) and intermediates need to be controlled and the solubility limits known, impurity formation needs to be restricted by controlling the temperature and distillation time. Also, it is important to consider that dissolved species can affect phase equilibria.

Distillation can achieve different results depending on the conditions and equipment selected. There are a range of equipment and operating choices used at production and laboratory scale but often these are limited by the constraints from the chemistry involved. Phase equilibria is independent of scale, but other factors such as heat losses, vacuum or minimum and maximum stir volume are not. Distillation times can be increased considerably on plant, therefore it is difficult to scale up using experimental information. Phase diagram understanding is fundamental for distillation and simulations help in the decision-making process for optimal conditions and process specific requirements.

As an API moves through development, the scale and site of manufacture is subject to change. Understanding distillation and de-risking this operation by analysing the impact of different parameters such as pressure and equipment capability is fundamental in the technical transfer process. An overview on this fundamental unit operation focussing on different case studies showing continuous distillation, crystallization distillation and process optimisation through simulations will be given showing distillation lessons learn from the past and learnings for the future.

One case study will show a solvent swap simulated with Aspen Properties & Batch Modeller and demonstrate how modelling led to an improved process reducing both cost and environmental burden

Another case study will show how a put and take distillation which led to product oiling / gumming, was changed to a constant volume operation significantly improving robustness and product quality.

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