(214f) Membrane Assisted Antisolvent Crystallization for the Continuous and Accurate Control of Pharmaceuticals Manufacture

Membrane Assisted Antisolvent Crystallization
for the Continuous and Accurate
Control of Pharmaceuticals Manufacture

Xiaobin
Jiang, Linghan Tuo, Gaohong He*

State Key Laboratory of Fine
Chemicals, School of Chemical Engineering, Research and Development Center of
Membrane Science and Technology, Petrochemical Energy-efficient Separation
Technology Engineering Lab of Liaoning Province, Dalian University of Technology,
Dalian, P. R. China

*Corresponding author: Email: xbjiang@dlut.edu.cn, hgaohong@dlut.edu.cn

Abstract

Different
from batch process, membrane assisted antisolvent crystallization (MAAC) is proposed
as a novel process to optimize pharmaceuticals manufacture significantly in
recent year [1,
2].
MAAC could achieve continuous production and obtain the high quality of crystal
product[3,
4].

In
this work, without introducing vacuum and temperature gradient, the proposed MAAC
process is operated under atmospheric pressure and isothermal conditions in the
hollow fiber membrane module to achieve the continuous and accurate pharmaceuticals
manufacture. Due to the high specific surface area of hollow fiber membrane
module, the accuracy of the interfacial mass transfer rate is greatly higher
than conventional antisolvent crystallization. The accurate mass transfer provides
homogenous supersaturation through the membrane module, intensified micro
mixing and more stable supersaturation gradient for nucleation and growth.

The
driving force of MAAC is determined by the concentration difference, pressure
difference and turbulence of membrane outside (shell side). Thus, the antisolvent
permeation rate can be adjusted flexibly. As reported in the literature[5], an
antisolvent liquid layer could be established on the membrane outer surface by regulating
the process operation parameters. According to Bernoulli equation and liquid membrane
renewal theory [6], high
flow rate accelerates liquid membrane renewal and decreases pressure simultaneity.
Thus, the interaction relationship of membrane inner and outer flow rates have
obvious impact on solution mixing effect. Suitable flow rates keep nucleation occurring
on the boundary layer of the liquid membrane, which would avoid membrane pore
blockage and membrane fouling efficiently. Based on the advantages above, the continuous
MAAC process could be adapted to the various requirements of pharmaceuticals during
a production cycle, timely discharge and deal with the crystal produce could prevent
tube blockage, which is one of the important problems of high viscosity
pharmaceuticals in the convention batch manufacture process [7]. The
proposed MAAC system is utilized in erythritol production to acquire crystals
with desire morphology and size distribution (showed in Fig. 1). Crystals
obtained by MAAC are obvious subuliform polyhedron shape, as a comparison,
crystals obtained by conventional antisolvent crystallization are commonly
spheroid or irregular shape. Moreover, the length-width ratio of MAAC crystals
are closer to the simulated ideal morphology (MAAC: 1.49, conventional: 1.30,
ideal: 1.52)[8]. The coefficient of variation (CV) of crystals decreases from
25.2 % (conventional) to 19.3 % (MAAC), which indicates narrower crystal size
distribution.  

With
the stable and accurate mass transfer process controlled by the introduced
membrane system, MAAC can be expected to expand the application and improve the
performance of antisolvent crystallization in not only pharmaceuticals, but
also food, biomacromolecule, fine chemicals fields.

Fig. 1 Erythritol
crystal size distribution, morphology, interfacial mass transfer rate and CV comparison
between MAAC and conventional antisolvent crystallization.

Refrences

[1]
Di Profio, G., Stabile, C., Caridi, A., Curcio, E., and Drioli, E., Antisolvent
membrane crystallization of pharmaceutical compounds. J Pharm Sci, 98(12).
4902-13(2009).

[2]
Lu, D., Li, P., Xiao, W., He, G., and Jiang, X., Simultaneous recovery and crystallization
control of saline organic wastewater by membrane distillation crystallization.
AIChE Journal, (2016).

[3]
Drioli, E., Di Profio, G., and Curcio, E., Progress in membrane
crystallization. Current Opinion in Chemical Engineering, 1(2).
178-182(2012).

[4]
Zarkadas, D.M. and Sirkar, K.K., Antisolvent crystallization in porous hollow
fiber devices. Chemical Engineering Science, 61(15). 5030-5048(2006).

[5]
Ren, Z., Yang, Y., Zhang, W., Liu, J., and Wang, H., Modeling study on the mass
transfer of hollow fiber renewal liquid membrane: Effect of the hollow fiber
module scale. Journal of Membrane Science, 439. 28-35(2013).

[6]
Chaturabul, S., Srirachat, W., Wannachod, T., Ramakul, P., Pancharoen, U., and
Kheawhom, S., Separation of mercury(II) from petroleum produced water via
hollow fiber supported liquid membrane and mass transfer modeling. Chemical
Engineering Journal, 265. 34-46(2015).

[7]
Blagden, N., de Matas, M., Gavan, P.T., and York, P., Crystal engineering of
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[8]
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