Membrane-Based Solvent Exchange Process for Purification of API Crystal Suspensions

Abstract

Bottom-up approaches to producing aqueous crystal suspensions of active pharmaceutical ingredients (APIs), such as anti-solvent crystallisation, are gaining interest as they offer better control over surface properties compared to top-down approaches. However, one of the major challenges that needs to be addressed is the removal of organic solvents after the crystallisation step due to strict limitations regarding human exposure. Within this work, we investigated a process concept for the removal of solvent (i.e., ethanol) from the API crystal suspension using membrane-based diafiltration. A four-stage diafiltration process successfully reduced the ethanol concentration in the API (here, naproxen) crystal suspension below 0.5 wt% (the residual solvent limit as per ICH guidelines) with a water consumption of 1.5 g of added water per g of feed. The solvent exchange process had no negative influence on the stability of the crystals in suspension, as their size and polymorphic form remained unchanged. This work is a step towards the bottom-up production of API crystal suspension by applying solvent/anti-solvent crystallisation. It provides the proof of concept for establishing a process of organic solvent removal and offers an experimental framework to serve as the foundation for the design of experiments implementing a solvent exchange in API production processes.

Organic Solvent Nanofiltration in Pharmaceutical Applications

“…The experiment was carried out through both discontinuous and semicontinuous diafiltration modes and showed that the exchange of Naproxen suspension in 5% ethanol to water can be achieved in a four-stage diafiltration process, using 1.5 g of water per g of feed. 180 The feasibility of using OSN as assistance for traditional separation techniques during pharmaceutical processes was also investigated by Rundquist et al They applied OSN to countercurrent chromatography (CCC) during pharmaceutical separations. 182 Applications of CCC usually start with solvent exchange to transfer the solute from the process solvent to the desired solvent mixture for the mobile phase.…”

“…Hence, it was selected to further investigate the solvent exchange from ethanol to water after antisolvent crystallization. The experiment was carried out through both discontinuous and semicontinuous diafiltration modes and showed that the exchange of Naproxen suspension in 5% ethanol to water can be achieved in a four-stage diafiltration process, using 1.5 g of water per g of feed …”

“…A guideline to assist in successfully implementing OSN for solvent exchange using constant volume diafiltration is as follows: Performing membrane screening. The suitable OSN membranes used for solvent exchange should provide proper stability in interested solvents, a reasonable flux during the operations (≥10 L·m –2 ·h –1 ), and a sufficient rejection for the solutes to be retained …”

“…The experiment was carried out through both discontinuous and semicontinuous diafiltration modes and showed that the exchange of Naproxen suspension in 5% ethanol to water can be achieved in a four-stage diafiltration process, using 1.5 g of water per g of feed. 180 …”

Continuous Microfluidic Antisolvent Crystallization as a Bottom-Up Solution for the Development of Long-Acting Injectable Formulations

“…Hugo Silva et al pointed out that the LASC process can indeed be used as an alternative energy-efficient bottom-up method for the production of aqueous suspension-based LAIs with a reduced risk of contamination from milling equipment and fewer processing steps and that it may prove to be comparable in terms of stability and particle size distribution (PSD) to current industrially accepted top-down approaches [ 21 , 22 , 23 ]. Others, too, have demonstrated that this approach allows finetuning and control of drug product characteristics, such as PSD, crystallinity, and morphology, and that it is a simple, more sustainable, and less expensive process [ 24 , 25 , 26 ].…”