(361f) Continuous Purification of Active Pharmaceutical Ingredients Using Multistage Organic Solvent Nanofiltration Membrane Cascade

Generally in the production of pharmaceutical drugs, a large part of the production costs stem from the downstream processing. One important, time consuming and expensive downstream process in pharmaceutical manufacture is Active Pharmaceutical Ingredient (API) purification.  To date the processes preferably used for API purification include distillation, adsorption–desorption, solvent extraction, fractional crystallisation and chromatography. For difficult separations where tiny amounts of impurities need to be removed, purification primarily relies on crystallisation or chromatography in their various forms. Crystallisation unit operations are complex processes while process chromatography is expensive and consumes large quantities of solvents, which require further downstream processing. In addition chromatography is poorly suited for large scale and continuous process operations. Thus developing new continuous downstream processing operations is an attractive area for research and development.

Organic solvent nanofiltration (OSN) is an emerging technology for performing membrane separation/purification processes in organic solvents and has been successfully applied for API purification, albeit mainly at laboratory scale. The widely used configuration of constant volume diafiltration usually requires high solvent usage, and, due to imperfect separation (solute rejection <100%) results in significant API losses. These problems could be overcome when using a membrane cascade. Organic solvent nanofiltration performed in a membrane cascade offers an interesting possibility for a continuous downstream processing unit operation.

This work demonstrates continuous purification of Active Pharmaceutical Ingredient (API) Roxithromycin from potential Genotoxic Impurity (GTI) 4-dimethylaminopyridine (DMAP) in a simple and efficient two stage membrane cascade. The presented membrane cascade operates using a single high pressure pump as the primary pressure source, and has no need for a buffer tank between membrane stages which simplifies its control.  The cascade configuration is highly flexible in terms of membrane areas and flow rates and can be operated using multiple membrane cells or small membrane modules [1].   

Cascade performance is initially evaluated via mathematical simulations, and then validated experimentally. We demonstrated that by careful selection of operating parameters, high purity of the API >99% could be achieved from feed stream purity of 78%. The continuous cascade could be easily coupled with an adsorption column, utilising an inexpensive non-selective adsorbent such as charcoal, as a solvent recovery stage. The batch and the continuous purifications in membrane cascade were evaluated in terms of the environmental impact – E factor and Mass Intensity (MI). With an E factor of  ~20 and MI index of 21 the continuous membrane cascade process with a solvent recovery stage falls into the lowest range of the pharmaceutical industry segment [1]. The continuous process combined with a solvent recovery stage generates orders of magnitude less waste than a batch diafiltration which makes it an attractive alternative purification process for pharmaceutical industry.

References

1. L. Peeva, J. da Silva Burgal, I. Valtcheva, A. G. Livingston. Chem. Eng. Sci. (2014) in Press.