(427c) Crystallisation of Pharmaceutical Compounds Via Organic Solvent Nanofiltration

Crystallisation is an important separation methodology for the pharmaceutical and chemical industries.  Crystallisation can achieve high product purities, and is extensively used as most active pharmaceutical ingredients (APIs) are required in solid form[1].  Organic solvent nanofiltration (OSN) has been suggested as a method for enhancing crystallisation in the pharmaceutical industry[2].  OSN crystallisation has the potential to reduce energy and/or chemical inputs and allow tighter control of process conditions, improving crystal parameters.  In the past decade nanofiltration membranes stable in a wide range of organic solvent and conditions have been developed[3]. These membranes are capable of discriminating between molecules present in an organic solvent solution, allowing smaller molecules to permeate, while retaining larger molecules.

OSN membranes can be used to crystallise APIs in a number of ways.  Membranes could be used to remove the solvent from a solution, thus increasing the concentration of the solute past the saturation point, inducing crystal growth.  This is the methodology used thus far in our work.  Crystals can be grown via seeding or allowed to nucleate naturally.  As the OSN membranes have nano-porous structures there is the potential for crystal nucleation at the membrane surface.  This could be used to control crystal morphology.  Alternatively, solutions could be concentrated to a point below saturation and then slightly cooled to induce crystal growth.  This methodology would allow integration with existing cooling crystallisation technology used in the pharmaceutical industry, with the potential for recovery of lost product and thus yield enhancement.  OSN membrane technology could also be used for anti-solvent crystallisation.  Diafiltration has already been suggested for solvent exchange in the pharmaceutical industry[4].  By using diafiltration to introduce an anti-solvent at a steady rate while also removing the original solvent, precise control of the solvent mixture can be achieved.

OSN crystallisation has several potential advantages when it comes to controlling process conditions.  Solution saturation levels can be accurately controlled by adjusting the membrane pressure differential, which controls the membrane flux.  Management of saturation conditions reduces the risk of unwanted nucleation, eliminating unwanted polymorphic structures.  Control of saturation levels also affects the growth rate, leading to precise control over crystal size and size distributions.  Solution conditions such as temperature, pressure and mixing can affect crystallisation processes.  In OSN crystallisation the saturation level in the solution is controlled by solvent removal only, therefore the solution temperature, pressure and level of mixing can be set independently.  This is a clear advantage over both evaporative and cooling crystallisation.

In our work pharmaceutical compounds, including indomethacin and griseofulvin, have been crystallised using OSN membranes in a range of different solvents.  By using membranes with different pore sizes and hydrophobicities the solvent was removed from the solution until the flux was reduced to negligible levels.  Nucleation was allowed to occur spontaneously in order to test whether the membranes had any effect on the crystal parameters.  The results of this work will be reported in the presentation.  Further experimentation focussing on the regeneration of the membranes after crystallisation, the use of diafiltration for anti-solvent crystallisation and the development of a continuous OSN crystallisation method integrated with cooling crystallisation technology is also being undertaken.

1.            Tung, H.-H., et al., Crystallization of organic compounds: an industrial perspective. 2009: John Wiley and Sons.

2.            Charcosset, C., et al., Coupling between Membrane Processes and Crystallization Operations. Industrial and Engineering Chemistry Research 2010(49): p. 5489–5495.

3.            Vandezande, P., L.E.M. Gevers, and I.F.J. Vankelecom, Solvent resistant nanofiltration: separating on a molecular level. Chemical Society Reviews, 2008. 37: p. 365–405.

4.            Sheth, J.P., et al., Nanofiltration-based diafiltration process for solvent exchange in pharmaceutical manufacturing. Journal of Membrane Science, 2003. 211(2): p. 251-261.