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Antisolvent membrane crystallization of pharmaceutical compounds
Antisolvent Membrane Crystallization of Pharmaceutical Compounds GIANLUCA DI PROFIO,1,2 CARMEN STABILE,1 ANTONELLA CARIDI,1 EFREM CURCIO,2 ENRICO DRIOLI1,2 1
Institute on Membrane Technology (ITM-CNR), Via P. Bucci Cubo 17/C, c/o University of Calabria, I-87030 Rende (CS), Italy 2
Department of Chemical and Materials Engineering, University of Calabria, Rende, Italy
Received 1 December 2008; revised 24 February 2009; accepted 5 March 2009 Published online 4 August 2009 in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.21785
ABSTRACT: This article describes a modification of the conventional membrane crystallization technique in which a membrane is used to dose the solvent/antisolvent composition to generate supersaturation and induce crystallization in a drug solution. Two operative configurations are proposed: (a) solvent/antisolvent demixing crystallization, where the solvent is removed in at higher flow rate than the antisolvent so that phase inversion promotes supersaturation and (b) antisolvent addition, in which the antisolvent is dosed into the crystallizing drug solution. In both cases, solvent/antisolvent migration occurs in vapor phase and it is controlled by the porous membrane structure, acting on the operative process parameters. This mechanism is different than that observed when forcing the liquid phases through the pores and the more finely controllable supersaturated environment would generate crystals with the desired characteristics. Two organic molecules of relevant industrial implication, like paracetamol and glycine, were used to test the new systems. Experiments demonstrated that, by using antisolvent membrane crystallization in both configurations, accurate control of solution composition at the crystallization point has been achieved with effects on crystals morphology. ß 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:4902–4913, 2009
Keywords: antisolvent; crystallization; crystal shape; formulation; glycine; membrane; paracetamol; pharmaceutical crystallization; polymorphism; unit operations
INTRODUCTION Crystallization from solution is a widely used unit operation in the production of crystalline commodity products such as pharmaceuticals, bulk chemicals, fertilizers, and many others.1–3 Its extensive use is based on the fact that crystallization is both a separation and purification process whereby a solid crystalline product can be
Correspondence to: Gianluca Di Profio (Telephone: þ390984-492010/496698; Fax: þ39-0984-402103; E-mail: [email protected]; [email protected]) Journal of Pharmaceutical Sciences, Vol. 98, 4902–4913 (2009) ß 2009 Wiley-Liss, Inc. and the American Pharmacists Association
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isolated with enough degree of purity and with relatively low capital and operating costs. As a common example, over 90% of all active pharmaceutical ingredients (APIs) are supplied as particulate.4 In recent years, the increased impact of fine chemicals and other special added value products in human daily uses have shifted the interest of research and industrial community towards the crystallization of organic materials5 with specific target crystal characteristics.6 Especially in the pharmaceutical industry, these necessities are even more imposed by regulatory processing and product quality requirements. The most important properties for a crystalline product are crystal size and size distribution
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(CSD)—which should be as narrow as possible— shape, habit, polymorphism, and purity. Crystal morphology and structure can impact, for example, dissolution rate and bioavailability7,8 as well as manufacture operations such as filtration,9,10 drying, and final product formulation.11 Crystal properties are determined from a variety of factors such as crystallization technique employed, type and size of equipment used, and operating conditions. Therefore, crude fixed-recipe methods, forcing nonoptimal processes, are still being used in industry to address product characteristics. However, particular problems associated with batch-to-batch variability and irregularly product properties are often encountered especially when considering scale-up from laboratory to industrial plants. Among the different techniques employed, antisolvent (or drowning-out) crystallization is increasingly being used as an alternative to cooling and evaporative crystallization processes for the isolation and separation of organic fine chemicals, especially for APIs whose biological activity might be degraded when using hightemperature conditions.2,12,13 Moreover, antisolvent is used for the control of solubility considering yield from the viewpoint of manufacturing. In this method, a secondary solvent known as antisolvent (or drowning-out agent or precipitant) is added to the solution resulting in the reduction of the solubility of the solute in the original solvent with the consequent generation of supersaturation. The precise setting of supersaturation, when the adequate amount of antisolvent is added to the drug solution, would effects crystal morphology and, finally, solubility.14–17 In this respect, the control of solubility would have an important impact considering yield and target concentration of the solid dosage forms from a manufacture point of view. The drowning-out agents can be solids, liquids, or gases. They must be soluble in the original solvent (gas or solid drowning-out agents) or miscible with it (liquid drowning-out agents) and should not react with the solute to be precipitated. Generally, water has been the mostly used antisolvent for hydrophobic compounds, and alcohols (methanol, ethanol), or other organic solvents (acetone and some hydrocarbons) were used for hydrophilic molecules.9,18,19 The effects of various process parameters on crystal morphology and structure (polymorphism), including type of antisolvent,13,20 feed concentration,21,22 solution concentration,23,24 antisolvent addition rate,21,25 and agitation intensity20,26 DOI 10.1002/jps
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have been studied in numerous works. From those studies arises that supersaturation and solvent composition are the principal parameters affecting crystal properties.20 Therefore, the development of crystallization techniques where supersaturation and solvent composition can be controlled on a microscale, resulting in a narrow CSD and controlled crystal morphology, would be extremely attractive. According to this, in the present article, a development of the membrane crystallization technique, where gradual and well-controlled antisolvent dosing is carried out by means of a porous membrane, is presented. Experiments on two organic molecules relevant in pharmaceutical industry, like glycine and paracetamol, addressed to explore the potentiality of this new technique, are presented.
ANTISOLVENT MEMBRANE CRYSTALLIZATION In a conventional membrane crystallizer27 a solution containing the specie to be crystallized is contacted on the retentate (or feed) side with the distillate side by means of a hydrophobic microporous membrane. For a pressure below the entry limit, the hydrophobic nature prevents the wetting of the membrane by the aqueous solutions. Therefore, at the mouth of each pore, liquid/vapor equilibrium is established. In these conditions, when a gradient of chemical potential between the two-liquid/vapor interfaces is generated by a temperature or an osmotic pressure difference, a net flux of solvent, in vapor phase, is observed from the retentate to the distillate side so that supersaturation is generated in the crystallizing solution. Accordingly, the role of the membrane is not simply as a sieving barrier but as a physical support which, by removal of the vaporized solvent, generates and sustains a controlled supersaturated environment in which crystals can nucleate and grow. A crystallization apparatus in which an antisolvent (or the crystallizing solution) is added to the crystallizing solution (or to the antisolvent) by using a porous membrane to produce particles with narrow CSD has been proposed some years ago.28 Subsequently, Zarkadas and Sirkar29 used the same concept for the crystallization of L-asparagine monohydrate. In this system, however, solutions (whatever the crystallizing solution or the antisolvent) are pressed directly in the
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liquid phase trough the porous structure of the membrane by overcoming the entry pressure. Accordingly, the hydrophobic/hydrophilic nature of the membrane was not an issue for the process, except for the fact that hydrophilic membranes would achieve high fluxes for aqueous solutions. Here, the antisolvent membrane crystallization process described in this article operates on the base of the same principle of a conventional membrane crystallizer. In other words, contrary to the above-mentioned configuration, the selective dosing of the antisolvent is not performed by forcing it, in liquid phase, through the membrane. Instead, the transfer of solvent/antisolvent is carried out in vapor phase, thus allowing a more fine control of the crystallizing solution composition during the process and at the nucleation point.
The system operates according to the two schemes shown in Figure 1. Figure 1a depicts the case in which a certain solute is dissolved in an appropriate mix of a solvent and an antisolvent whose composition is chosen in such a way that the solute remains indefinitely in solution, in the original conditions. When a gradient of partial pressure is generated between the two sides of the membranes, for example, by a temperature difference, the solvent, which is supposed to have a higher vapor pressure than the antisolvent at the same temperature, evaporates at higher flow rate thus achieving solvent/antisolvent demixing. As the amount of solvent in the mixture decrease, a phase inversion, in which the antisolvent becomes predominant, occurs and the lower solubility of the solute generates supersaturation. The requirements for this configuration are that:
Figure 1. Principle of the antisolvent membrane crystallizer. (a) Solvent/antisolvent demixing and supersaturation are generated by removing the solvent at higher velocity from a mix in which the solute is dissolved. (b) An antisolvent is gradually evaporated from the other side of the membrane in a solution in which the solute is dissolved (Tf: feed temperature; Td: distillate temperature). JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 12, DECEMBER 2009
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(i) the antisolvent and the solvent are miscible; (ii) the initial solvent/antisolvent balance in the mixture guarantees that the solute is under its solubility limit; (iii) the solvent evaporates at higher velocity than the antisolvent. A typical case of such a system is a solute which is highly soluble in ethanol and poorly soluble in water. Figure 1b shows the operating scheme in which a solute is dissolved in a solvent and then an antisolvent is gradually evaporated from the other side of the membrane by applying a gradient of temperature. As the antisolvent mixes with the solvent, the solute dilutes but the composition of the mixture changes. At a certain point, phase inversion creates supersaturation and solute crystallization. This configuration requires that the antisolvent and the solvent are miscible. In this case, the specie to be crystallized can be soluble, for example, in water and poorly soluble in ethanol.
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Figure 2. Scheme of the plant used for the experiment. For solvent/antisolvent demixing tests (Tf > Td) the feed tank contains the solute dissolved in a solvent/ antisolvent mixture while pure water is circulated on the distillate side. In the case of antisolvent addition experiments (Tf < Td) the solute dissolved in a solvent is located in the feed tank whilst the antisolvent is on the distillate side.
EXPERIMENTAL Materials Ethanol and bi-distilled water were used to prepare solvent/antisolvent mixtures with the required initial composition. Paracetamol (acetaminophen, 4-hydroxyacetanilide, C8H9NO2, MW 151.16 g mol1) was dissolved in a water/ethanol mixture with the desired initial concentration. Glycine (C2H5NO2, MW 75.07 g mol1) was dissolved in bi-distilled water at the appropriate initial concentration. All chemicals, in reagent grade, were from Sigma–Aldrich (Sigma–Aldrich S.r.l., Milan, Italy). Solutions were filtered by syringe filters with nominal pore size of 0.22 mm. Hydrophobic polypropylene hollow fibers membranes (Accurel1 PPS6/2, from Membrana GmbH, Wuppertal, Germany), were used in all the experiments to assemble the modules. A newly prepared module was used for each test.
Solvent/Antisolvent Demixing Experiments Paracetamol, at an initial concentration c0, was dissolved in a water/ethanol mixture with a composition spanning in the range 10–40% (v/v) of alcohol. Due to the different solubility of paracetamol in ethanol and water,30 ethanol is the solvent whilst water the antisolvent. The crystallizing solution was circulated on the retentate side DOI 10.1002/jps
(or feed) of the membrane module and heated at a specific temperature Tf, as showed in Figure 2. Pure water, at a temperature Td ¼ 58C, was circulated on the distillate side. The temperature of the feed was maintained higher than the distillate (Tf > Td) in order to let the component of the mixture with higher vapor pressure (ethanol) to evaporate at a higher flow rate than water.
Antisolvent Addition Experiments Glycine solutions, at a proper initial concentration c0, were recirculated in the retentate side of the plant showed in Figure 2 at the temperature Tf ¼ 108C. Mixture of water/ethanol, with different starting composition, was circulated on the distillate side. The amount of ethanol in the distillate never exceeded 40% (v/v), as for higher content of ethanol wetting of the polypropylene membrane, and consequently loss of hydrophobicity, was observed. Temperature on the distillate side was always higher than that of the retentate (Tf < Td) in order to generate and sustain the driving force for ethanol evaporation from the distillate to the retentate side. Due to the consistent difference of solubility of glycine in
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water and ethanol31 water is the solvent and ethanol is the antisolvent.
Solubility Measurements The solubility of paracetamol and glycine in water/ethanol mixtures was measured, at different temperatures, as a function of ethanol volume fraction. Excess amounts of each substance were dissolved into the water/ethanol mixture, while stirring with a magnetic bar, to saturate the solutions. After 24 h of stirring the suspensions were filtered over a 0.22 mm filter and the saturated solutions were evaporated at 608C until no variation in the weight were registered. The weight of the dry residue sample was used to calculate the solubility at the specific ethanol volume fraction.
Mass Transfer Measurements In both ‘‘solvent/antisolvent demixing’’ and ‘‘antisolvent addition’’ experiments, the extent of solvent/antisolvent evaporation through the membrane was evaluated by measuring the variation of the volume of the crystallizing solutions as a function of the time. Accordingly, the concentration c(t) of the solute, at the time t, in the crystallizing solution of volume V(t) was calculated as: c(t) ¼ c0/V(t). Although ethanol evaporates at higher rate than water, a certain amount of water evaporates through the membrane as well, thus contributing to the variation of volume. Therefore, the effective content of ethanol on the distillate side was evaluated by a refractometer (model Abbe 60/DR from Bellingham and Stanley Ltd, Kent, UK) after calibration. The amount of ethanol left in the retentate was then calculated by mass balance.
Crystal’s Characterization Crystal morphology was assessed by an optical microscope (model DM 2500M from Leica Microsystems GmbH, Wetzlar, Germany) equipped with a video camera. Average particle size and crystal size distribution were obtained through image analysis. At least 250 particles per sample were considered to properly catch the statistics. This time-consuming procedure allows distinguishing clearly between primary particles, agglomerates, and fragments, thus yielding a
rather precise characterization of the particle population. After each experiment, the paracetamol and glycine crystalline product obtained was harvested from its mother liqueur, dried in a desiccators for 24 h, and analyzed by Fourier Transformed Infrared (FTIR) spectroscopy (by using a spectrophotomer model Spectrum One, from Perkin–Elmer, Waltham, MA).
RESULTS AND DISCUSSION Solvent/Antisolvent Demixing Membrane Crystallization In a membrane crystallizer solvent evaporation rate can be selected by choosing the opportune operating process parameters and/or the appropriate membrane characteristics affecting the driving force for evaporation: the gradient of partial pressure between the two sides of the membrane.32,33 In the present work, control of the driving force to modulate the supersaturation of the crystallizing solution was achieved by modifying the circulation rate Q (mL min1) of the feed and the distillate solutions, the feed temperature Tf (8C), and the initial ethanol volume fraction Et.% (%, v/v) in the retentate. For all the experiments, the volume V (mL) of the crystallizing solution were observed to changed with the time t (h) following a law of the type: t VðtÞ ¼ y0 þ A exp (1) t where t (h) is the evaporation rate constant, related to the rate at which the volume of solution reduces with the time, y0 and A are constant so that y0 þ A ¼ V0, with V0 the initial volume of the solution at the time t ¼ 0. In order to compare the rate of solvent evaporation for the different experiments by comparing the different values of t, best fitting of the experimental points were carried out by setting y0 ¼ 0 and A ¼ V0. According to Eq. (1) t has an inverse proportionality with the solvent evaporation rate: as t decreases the evaporation rate increases and volume reduces faster. Therefore, t is used in this section to designate the rate at which solvent was removed, and hence supersaturation was generated, in the feed. Figure 3 shows the dependence of t from the combination of the different operative para-
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Figure 3. Dependence of the evaporation rate constant t from the initial ethanol concentration Et.% for different values of circulating solution velocity Q and feed temperature Tf. Td was fixed at 58C for all experiments.
meters. As the initial amount of ethanol increases t decreases and the evaporation rate rises. For the same initial ethanol content, increasing the recirculation rate Q the transport of fluid to the membrane surface, whereby evaporation occurs, increases so that t decreases. Finally, increasing feed temperature Tf evaporation increases thus reducing t. Results in Figure 3 demonstrated that solvent evaporation rate can be easily controlled by acting on either one of the process parameters Et.%, Q, and Tf. By doing so, both the extent and the rate of solvent demixing, and consequently supersaturation, can be tuned through the crystallization process. During a crystallization experiment, ethanol evaporates at higher rate than water so that demixing is obtained. However, a certain amount of vaporized water goes through the membrane as well. Therefore, reduction of volume of the feed is not indicative to estimate the exact amount of ethanol that has left the crystallizing solution. The amount of ethanol in the feed was then estimated by mass balance, after detecting the effective amount of ethanol in the permeate by refractive index analysis. Figure 4a shows the volume fraction F of ethanol and water, with respect to their initial feed concentration, extracted from the retentate side with the time t, for different evaporation rates. From the figure is clear the differential evaporation rate between DOI 10.1002/jps
Figure 4. Variation of the volume fraction of ethanol (FEt.) and water (FWa.) transferred with the time t: (a) from the retentate to the distillate side for different solvent evaporation rate (t) in solvent/antisolvent demixing crystallization experiments and (b) from the distillate to the retentate side for different transmembrane flow rate J in antisolvent addition tests (lines are only guides for the eyes).
ethanol and water that also increases when t decreases. Accordingly, the extent of demixing (supersaturation generation rate) can be adjusted by acting on the driving force of evaporation. Figure 5 shows the dependence from t of crystals aspect ratio r, defined as crystal length to width ratio. As the evaporation rate decreases (t increases) the aspect ratio r decreases too. Plots of r as function of the different parameters Q, Tf, and Et.% (data not shown) did not indicate any systematic dependence. This means that the aspect ratio is only dependent, in this system, on the solvent evaporation rate.
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Figure 5. Variation of the crystals aspect ratio r (defined as crystals length to width ratio) as a function of the solvent evaporation rate constant t (line is only a guide for the eyes).
The variation coefficient CV (%) was calculated from the crystals size distribution of the different crystalline samples obtained from the experiments. As shown in Figure 6a, decreasing solvent evaporation rate (increasing t) results in a reduction of CV. This behavior can be explained by considering the different effects of solution circulation rate on the process. On the one side, increasing Q would produce better mixing and higher supersaturation homogeneity in the bulk of the solution. On the other hand, higher circulation rate will increase the convective transport of solvent molecules to the membrane surface, so that evaporation rate increases. As ethanol evaporates with higher velocity than water, the extent of solvent/antisolvent demixing at the mouth of a very large number of pores increases with Q. Here, the molecules of the antisolvent that were originally combined with the solvent evaporate. Consequently, the lack of free solvent molecules that can couple with solute molecules initiates locally high levels of supersaturation and subsequent nucleation and crystal growth. Inhomogeneous supersaturation leads to broader CSDs and, consequently, to higher values for CV. This explanation seems to be confirmed by Figure 6b, where the increase of CV with Q is shown for the experiments with Et.% ¼ 40% and Tf ¼ 308C. Nevertheless, opportune values of evaporation rate favored the formation of crystalline products with CV as low as 20%. These values
Figure 6. Dependence of the variation coefficient CV from: (a) the evaporation rate constant t and (b) the recirculation rate Q (lines are only guides for the eyes).
seems to be rather interesting if compared with CV generally obtained not only with conventional antisolvent processes26 but also when using supercritical gas antisolvent34 and drowning-out crystallization with feedback control processes.35,36 At the end of each test, the obtained crystalline paracetamol was analyzed by optical microscopy and FTIR37 to check its polymorphic nature. For all samples, according to infrared analysis, monoclinic form I was obtained from all the tests. However, for experiments carried out with high solvent/antisolvent demixing rates, some crystals whose morphology looks like that of the orthorhombic polymorph38–40 were observed at the early stages of crystallization (see circled in Fig. 7).
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These crystals were not persistent for enough time to be isolated from the mother liqueur at the end of the experiments. Moreover, no crystals with needle shape were observed during experiments carried out with lower solvent evaporation rate. According to these observations, it is expected that for high demixing rate, high local degrees of supersaturation lead to the formation of the metastable form II of paracetamol that converted rapidly in the stable form I by the end of the experiment. The presence of ethanol would also enhance the conversion rate, as reported in the literature.38 Figure 8 displays the behavior with t of the supersaturation at the crystallization point, Scry. A decrease of Scry with t is indicative of the increase of the supersaturation at the nucleation point with the increase of the demixing rate (or antisolvent addition rate). This behavior is in accordance with the well-known effect of supersaturation generation rate on the location of the metastable zone. As supersaturation is generated at higher rate, the width of the metastable zone increases thus effecting the final crystals properties.41
Antisolvent Addition Membrane Crystallization In antisolvent addition membrane crystallization, the antisolvent (ethanol) is added to the crystallizing solution consisting in an aqueous solution of glycine, by evaporating it trough the pores of the membrane under the action of the driving force. Also in this case, the magnitude of the driving force affects the degree of supersaturation at the crystallization point, Scry, and its generation rate. Contrary to the demixing operation, as antisolvent is added to the feed, the volume V of the retentate increases with the time t following a law of the type: VðtÞ ¼ y0 þ A1 ð1 et=t1 Þ þ A2 ð1 et=t2 Þ
(2)
Figure 7. Paracetamol crystals obtained by solvent/ antisolvent demixing experiments. (a and c) Crystals with the typical needle shape of the metastable polymorph II (circled) appeared during the initial minutes since the appearance of the first crystals. (b and d) Samples from the same experiments after few minutes of residence in the mother liqueur. Images (a and b) refer to the experiment with t ¼ 10.1 while images (c and d) to the experiment with t ¼ 10.7. DOI 10.1002/jps
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Figure 8. Dependence of the supersaturation at the crystallization point, Scry, with the evaporation rate constant t.
with the constants: y0, A1 and A2, t1, and t2. To indicate the rate of solvent evaporation the transmembrane flux J (mL h1), calculated as the increase in volume of the crystallizing solution with the time, is used in this section. With respect of the demixing approach, a different pathway is followed by the undersaturated solution towards crystallization, as showed in Figure 9. The figure shows the variation with the time t of the feed volume factor, V(t)/V0, and the supersaturation S(t) for a typical solvent/antisolvent demixing and antisolvent addition experiment. In demixing configuration, the feed volume decreases continuously so that solution concentrates with the time. Moreover, as the solvent volume fraction
decreases, because of ethanol evaporation, paracetamol solubility lowers. As a result, a steep increase in supersaturation is observed. In the case of solvent addition, the volume of the feed solution increases as antisolvent is added, therefore the volume fraction decrease with t. However, although the solute dilutes with the time, as the volume fraction of the solvent (water) decreases with the added ethanol, glycine solubility decreases so that supersaturation induces crystallization. As consequence of the two opposite effects of solute dilution and phase inversion, supersaturation changes with the time smoother in addition experiments than the demixing case. As for demixing tests, the opportune combination of the operative parameters, namely the distillate temperature Td (for the same values of Tf ¼ 108C), the solutions recirculation rate Q and the initial ethanol content in the distillate, generates a different driving force and, consequently, a specific trans-membrane evaporation rate J, that reflects on crystallization kinetics. Figure 10a shows, for example, the variation of the crystallization time, tcry, with the ethanol addition rate. Increasing J an exponential decrease of the crystallization time was observed. As for the demixing configuration, also in this case increasing antisolvent addition rate, the value of supersaturation in correspondence of which the nucleation occurs increases as well, as shown in Figure 10b. This behavior can be explained with the enlargement of the metastable zone width by increasing the supersaturation generation rate with the antisolvent addition rate.
CONCLUSIONS
Figure 9. Variation, with the time t, of the feed volume factor, V(t)/V0, and the supersaturation S(t) for a typical solvent/antisolvent demixing and antisolvent addition experiment.
A modified version of the conventional membrane crystallization technique, in which a membrane is used to dose the solvent/antisolvent composition inside a crystallizing solution to generate supersaturation, has been presented. For both the solvent/antisolvent demixing and antisolvent addition configurations, antisolvent migration between the two sides of the membrane was easily modulated by acting on the operative process parameters. Experiments demonstrated that accurate control of solution composition at the crystallization point allowed a fine control of the supersaturated environment where glycine and paracetamol crystals with adjustable properties were grown.
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As drowning-out crystallization is getting increasing involvement in pharmaceutical industry, the proposed systems represents a further improvement of the technique if considering that a membrane acts as an adjustable gate for antisolvent dosing, and hence supersaturation control, inside the crystallizing solutions. Moreover, this technology, although tested for hydrophilic solutions, is theoretically exploitable also for the crystallization of substances soluble in organic hydrophobic media, by employing hydrophilic membranes, thus extending the range of applicability in pharmaceutical and other hightech fields like, for example, single crystal organic semiconductors.
NOMENCLATURE c0 c(t) CV Et.% Q r Scry
Figure 10. (a) Glycine crystallization time, tcry, and (b) supersaturation at the crystallization point, Scry, as function of antisolvent addition rate J (lines are only guides for the eyes).
The two operative conditions allow a wide range of applications for the crystallization of organic molecules showing different affinities for hydrophilic solvents. Demixing configuration would be especially useful for solutes poorly soluble in water and more soluble in hydrophilic solvents with higher vapor pressure, as alcohols or other organic solvents. As small temperature gradients are sufficient to create a steady driving force, feed temperature as low as 25–308C generates transmembrane fluxes in the order of 1 L m2 h1 or more. Antisolvent addition technique is an easy and feasible process where the only requirement is that solvent and antisolvent must be miscible. Moreover, because the crystallizing solution is kept at lower temperature than the distillate, thermo-labile species can be successfully crystallized without detrimental effects. DOI 10.1002/jps
S(t) t tcry Tf Td V0 V(t) F t
initial concentration (mg/mL) concentration at the time t (mg/mL) variation coefficient (%) initial ethanol volume fraction in the feed (%, v/v) flow rate (mL/min) crystals aspect ratio supersaturation at the crystallization point supersaturation at the time t time (h) crystallization time (h) feed temperature (8C) distillate temperature (8C) initial volume of the feed (mL) volume of the feed at the time t (mL) fraction of the initial volume migrated from the feed to the distillate side evaporation rate constant (h)
ACKNOWLEDGMENTS Authors would like to acknowledge INSTM (Consorzio Interuniversitario Nazionale per la Scienza e la Tecnologia dei Materiali) for financial support.
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18. Pina CM, Fernandez-Diaz L, Prieto M, Veintemillas-Verdaguer S. 2001. Metastability in drowningout crystallisation: Precipitation of highly soluble sulphates. J Cryst Growth 222:317–327. 19. Alfassi ZB, Mosseri S. 1984. Solventing out of electrolytes from their aqueous solution. AIChE J 30: 874–876. 20. Takiyama H, Otsuhata T, Matsuoka M. 1998. Morphology of NaCl crystals in drowning-out precipitation operation. Chem Eng Res Des 76:809– 814. 21. Holmba¨ ck X, Rasmuson AC. 1999. Size and morphology of benzoic acid crystals produced by drowning-out crystallization. J Cryst Growth 199: 780–788. 22. Barata A, Serrano ML. 1998. Salting-out precipitation of potassium dihydrogen phosphate (KDP): IV. Characterisation of the final product. J Cryst Growth 194:109–118. 23. Kaneko S, Yamagami Y, Tochihara H, Hirasawa I. 2002. Effect of supersaturation on crystal size and number of crystals produced in antisolvent crystallization. J Chem Eng Japan 35:1219–1223. 24. Kitamura M, Sugimoto M. 2003. Anti-solvent crystallization and transformation of thiazole-derivative polymorphs-I: Effect of addition rate and initial concentrations. J Cryst Growth 257:177–184. 25. Beckmann W. 1999. Nucleation phenomena during the crystallisation and precipitation of Abecarnil. J Cryst Growth 199:1307–1314. 26. Yu ZQ, Tan RBH, Chow PS. 2005. Effects of operating conditions on agglomeration and habit of paracetamol crystals in anti-solvent crystallization. J Cryst Growth 279:477–488. 27. Curcio E, Criscuoli A, Drioli E. 2001. Membrane crystallizers. Ind Eng Chem Res 40:2679–2684. 28. Bakker WJW, Geertman RM, Reedijk MF, Baltussen JJM, Bargeman G, van Lare CEJ. Antisolvent solidification process. WO2004/096405A1. 29. Zarkadas DM, Sirkar KK. 2006. Antisolvent crystallization in porous hollow fiber devices. Chem Eng Sci 61:5030–5048. 30. Granberg RA, Rasmuson AC. 1999. Solubility of paracetamol in pure solvents. J Chem Eng Data 44:1391–1395. 31. Bouchard A, Hofland GW, Witkam GJ. 2007. Solubility of glycine polymorphs and recrystallization of b-glycine. J Chem Eng Data 52:1626–1629. 32. Di Profio G, Tucci S, Curcio E, Drioli E. 2007. Selective glycine polymorph crystallization by using microporous membranes. Cryst Growth Des 7:526– 530. 33. Di Profio G, Tucci S, Curcio E, Drioli E. 2007. Controlling polymorphism with membrane-based crystallizers: Application to form I and II of paracetamol. Chem Mat 19:2386–2388. 34. Fusaro F, Mazzotti M, Muhrer G. 2004. Gas antisolvent recrystallization of paracetamol from
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acetone using compressed carbon dioxide as antisolvent. Cryst Growth Des 4:881–889. 35. Rohani S, Horne S, Murthy K. 2005. Control of product quality in batch crystallization of pharmaceuticals and fine chemicals. Part 2: External control. Org Proc Res Devel 9:873–883. 36. Yu ZQ, Chow PS, Tan RBH. 2006. Application of attenuated total reflectance-fourier transform infrared (ATR-FTIR) technique in the monitoring and control of anti-solvent crystallization. Ind Eng Chem Res 45:438–444. 37. Al-Zoubi N, Koundourellis I, Malamataris S. 2002. FT-IR and Raman spectroscopic methods for identification and quantitation of orthorhombic and monoclinic paracetamol in powder mixes. J Pharm Biomed Anal 29:459–467.
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38. Nichols G, Frampton CS. 1998. Physicochemical characterization of the orthorhombic polymorph of paracetamol crystallized from solution. J Pharm Sci 87:684–693. 39. Barthe SC, Grover MA, Rousseau RW. 2008. Observation of polymorphic change through analysis of FBRM data: Transformation of paracetamol from form II to form I. Cryst Growth Des 8:3316–3322. 40. Me´ ndez del Rı`o JR, Rousseau RW. 2006. Batch and tubular-batch crystallization of paracetamol: Crystal size distribution and polymorph formation. Cryst Growth Des 6:1407–1414. 41. Ulrich J, Strege CJ. 2002. Some aspects of the importance of metastable zone width and nucleation in industrial crystallizers. J Cryst Growth 237– 239:2130–2135.
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Institute on Membrane Technology (ITM-CNR), Via P. Bucci Cubo 17/C, c/o University of Calabria, I-87030 Rende (CS), Italy 2
Department of Chemical and Materials Engineering, University of Calabria, Rende, Italy
Received 1 December 2008; revised 24 February 2009; accepted 5 March 2009 Published online 4 August 2009 in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.21785
ABSTRACT: This article describes a modification of the conventional membrane crystallization technique in which a membrane is used to dose the solvent/antisolvent composition to generate supersaturation and induce crystallization in a drug solution. Two operative configurations are proposed: (a) solvent/antisolvent demixing crystallization, where the solvent is removed in at higher flow rate than the antisolvent so that phase inversion promotes supersaturation and (b) antisolvent addition, in which the antisolvent is dosed into the crystallizing drug solution. In both cases, solvent/antisolvent migration occurs in vapor phase and it is controlled by the porous membrane structure, acting on the operative process parameters. This mechanism is different than that observed when forcing the liquid phases through the pores and the more finely controllable supersaturated environment would generate crystals with the desired characteristics. Two organic molecules of relevant industrial implication, like paracetamol and glycine, were used to test the new systems. Experiments demonstrated that, by using antisolvent membrane crystallization in both configurations, accurate control of solution composition at the crystallization point has been achieved with effects on crystals morphology. ß 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:4902–4913, 2009
Keywords: antisolvent; crystallization; crystal shape; formulation; glycine; membrane; paracetamol; pharmaceutical crystallization; polymorphism; unit operations
INTRODUCTION Crystallization from solution is a widely used unit operation in the production of crystalline commodity products such as pharmaceuticals, bulk chemicals, fertilizers, and many others.1–3 Its extensive use is based on the fact that crystallization is both a separation and purification process whereby a solid crystalline product can be
Correspondence to: Gianluca Di Profio (Telephone: þ390984-492010/496698; Fax: þ39-0984-402103; E-mail: [email protected]; [email protected]) Journal of Pharmaceutical Sciences, Vol. 98, 4902–4913 (2009) ß 2009 Wiley-Liss, Inc. and the American Pharmacists Association
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isolated with enough degree of purity and with relatively low capital and operating costs. As a common example, over 90% of all active pharmaceutical ingredients (APIs) are supplied as particulate.4 In recent years, the increased impact of fine chemicals and other special added value products in human daily uses have shifted the interest of research and industrial community towards the crystallization of organic materials5 with specific target crystal characteristics.6 Especially in the pharmaceutical industry, these necessities are even more imposed by regulatory processing and product quality requirements. The most important properties for a crystalline product are crystal size and size distribution
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(CSD)—which should be as narrow as possible— shape, habit, polymorphism, and purity. Crystal morphology and structure can impact, for example, dissolution rate and bioavailability7,8 as well as manufacture operations such as filtration,9,10 drying, and final product formulation.11 Crystal properties are determined from a variety of factors such as crystallization technique employed, type and size of equipment used, and operating conditions. Therefore, crude fixed-recipe methods, forcing nonoptimal processes, are still being used in industry to address product characteristics. However, particular problems associated with batch-to-batch variability and irregularly product properties are often encountered especially when considering scale-up from laboratory to industrial plants. Among the different techniques employed, antisolvent (or drowning-out) crystallization is increasingly being used as an alternative to cooling and evaporative crystallization processes for the isolation and separation of organic fine chemicals, especially for APIs whose biological activity might be degraded when using hightemperature conditions.2,12,13 Moreover, antisolvent is used for the control of solubility considering yield from the viewpoint of manufacturing. In this method, a secondary solvent known as antisolvent (or drowning-out agent or precipitant) is added to the solution resulting in the reduction of the solubility of the solute in the original solvent with the consequent generation of supersaturation. The precise setting of supersaturation, when the adequate amount of antisolvent is added to the drug solution, would effects crystal morphology and, finally, solubility.14–17 In this respect, the control of solubility would have an important impact considering yield and target concentration of the solid dosage forms from a manufacture point of view. The drowning-out agents can be solids, liquids, or gases. They must be soluble in the original solvent (gas or solid drowning-out agents) or miscible with it (liquid drowning-out agents) and should not react with the solute to be precipitated. Generally, water has been the mostly used antisolvent for hydrophobic compounds, and alcohols (methanol, ethanol), or other organic solvents (acetone and some hydrocarbons) were used for hydrophilic molecules.9,18,19 The effects of various process parameters on crystal morphology and structure (polymorphism), including type of antisolvent,13,20 feed concentration,21,22 solution concentration,23,24 antisolvent addition rate,21,25 and agitation intensity20,26 DOI 10.1002/jps
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have been studied in numerous works. From those studies arises that supersaturation and solvent composition are the principal parameters affecting crystal properties.20 Therefore, the development of crystallization techniques where supersaturation and solvent composition can be controlled on a microscale, resulting in a narrow CSD and controlled crystal morphology, would be extremely attractive. According to this, in the present article, a development of the membrane crystallization technique, where gradual and well-controlled antisolvent dosing is carried out by means of a porous membrane, is presented. Experiments on two organic molecules relevant in pharmaceutical industry, like glycine and paracetamol, addressed to explore the potentiality of this new technique, are presented.
ANTISOLVENT MEMBRANE CRYSTALLIZATION In a conventional membrane crystallizer27 a solution containing the specie to be crystallized is contacted on the retentate (or feed) side with the distillate side by means of a hydrophobic microporous membrane. For a pressure below the entry limit, the hydrophobic nature prevents the wetting of the membrane by the aqueous solutions. Therefore, at the mouth of each pore, liquid/vapor equilibrium is established. In these conditions, when a gradient of chemical potential between the two-liquid/vapor interfaces is generated by a temperature or an osmotic pressure difference, a net flux of solvent, in vapor phase, is observed from the retentate to the distillate side so that supersaturation is generated in the crystallizing solution. Accordingly, the role of the membrane is not simply as a sieving barrier but as a physical support which, by removal of the vaporized solvent, generates and sustains a controlled supersaturated environment in which crystals can nucleate and grow. A crystallization apparatus in which an antisolvent (or the crystallizing solution) is added to the crystallizing solution (or to the antisolvent) by using a porous membrane to produce particles with narrow CSD has been proposed some years ago.28 Subsequently, Zarkadas and Sirkar29 used the same concept for the crystallization of L-asparagine monohydrate. In this system, however, solutions (whatever the crystallizing solution or the antisolvent) are pressed directly in the
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liquid phase trough the porous structure of the membrane by overcoming the entry pressure. Accordingly, the hydrophobic/hydrophilic nature of the membrane was not an issue for the process, except for the fact that hydrophilic membranes would achieve high fluxes for aqueous solutions. Here, the antisolvent membrane crystallization process described in this article operates on the base of the same principle of a conventional membrane crystallizer. In other words, contrary to the above-mentioned configuration, the selective dosing of the antisolvent is not performed by forcing it, in liquid phase, through the membrane. Instead, the transfer of solvent/antisolvent is carried out in vapor phase, thus allowing a more fine control of the crystallizing solution composition during the process and at the nucleation point.
The system operates according to the two schemes shown in Figure 1. Figure 1a depicts the case in which a certain solute is dissolved in an appropriate mix of a solvent and an antisolvent whose composition is chosen in such a way that the solute remains indefinitely in solution, in the original conditions. When a gradient of partial pressure is generated between the two sides of the membranes, for example, by a temperature difference, the solvent, which is supposed to have a higher vapor pressure than the antisolvent at the same temperature, evaporates at higher flow rate thus achieving solvent/antisolvent demixing. As the amount of solvent in the mixture decrease, a phase inversion, in which the antisolvent becomes predominant, occurs and the lower solubility of the solute generates supersaturation. The requirements for this configuration are that:
Figure 1. Principle of the antisolvent membrane crystallizer. (a) Solvent/antisolvent demixing and supersaturation are generated by removing the solvent at higher velocity from a mix in which the solute is dissolved. (b) An antisolvent is gradually evaporated from the other side of the membrane in a solution in which the solute is dissolved (Tf: feed temperature; Td: distillate temperature). JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 12, DECEMBER 2009
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(i) the antisolvent and the solvent are miscible; (ii) the initial solvent/antisolvent balance in the mixture guarantees that the solute is under its solubility limit; (iii) the solvent evaporates at higher velocity than the antisolvent. A typical case of such a system is a solute which is highly soluble in ethanol and poorly soluble in water. Figure 1b shows the operating scheme in which a solute is dissolved in a solvent and then an antisolvent is gradually evaporated from the other side of the membrane by applying a gradient of temperature. As the antisolvent mixes with the solvent, the solute dilutes but the composition of the mixture changes. At a certain point, phase inversion creates supersaturation and solute crystallization. This configuration requires that the antisolvent and the solvent are miscible. In this case, the specie to be crystallized can be soluble, for example, in water and poorly soluble in ethanol.
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Figure 2. Scheme of the plant used for the experiment. For solvent/antisolvent demixing tests (Tf > Td) the feed tank contains the solute dissolved in a solvent/ antisolvent mixture while pure water is circulated on the distillate side. In the case of antisolvent addition experiments (Tf < Td) the solute dissolved in a solvent is located in the feed tank whilst the antisolvent is on the distillate side.
EXPERIMENTAL Materials Ethanol and bi-distilled water were used to prepare solvent/antisolvent mixtures with the required initial composition. Paracetamol (acetaminophen, 4-hydroxyacetanilide, C8H9NO2, MW 151.16 g mol1) was dissolved in a water/ethanol mixture with the desired initial concentration. Glycine (C2H5NO2, MW 75.07 g mol1) was dissolved in bi-distilled water at the appropriate initial concentration. All chemicals, in reagent grade, were from Sigma–Aldrich (Sigma–Aldrich S.r.l., Milan, Italy). Solutions were filtered by syringe filters with nominal pore size of 0.22 mm. Hydrophobic polypropylene hollow fibers membranes (Accurel1 PPS6/2, from Membrana GmbH, Wuppertal, Germany), were used in all the experiments to assemble the modules. A newly prepared module was used for each test.
Solvent/Antisolvent Demixing Experiments Paracetamol, at an initial concentration c0, was dissolved in a water/ethanol mixture with a composition spanning in the range 10–40% (v/v) of alcohol. Due to the different solubility of paracetamol in ethanol and water,30 ethanol is the solvent whilst water the antisolvent. The crystallizing solution was circulated on the retentate side DOI 10.1002/jps
(or feed) of the membrane module and heated at a specific temperature Tf, as showed in Figure 2. Pure water, at a temperature Td ¼ 58C, was circulated on the distillate side. The temperature of the feed was maintained higher than the distillate (Tf > Td) in order to let the component of the mixture with higher vapor pressure (ethanol) to evaporate at a higher flow rate than water.
Antisolvent Addition Experiments Glycine solutions, at a proper initial concentration c0, were recirculated in the retentate side of the plant showed in Figure 2 at the temperature Tf ¼ 108C. Mixture of water/ethanol, with different starting composition, was circulated on the distillate side. The amount of ethanol in the distillate never exceeded 40% (v/v), as for higher content of ethanol wetting of the polypropylene membrane, and consequently loss of hydrophobicity, was observed. Temperature on the distillate side was always higher than that of the retentate (Tf < Td) in order to generate and sustain the driving force for ethanol evaporation from the distillate to the retentate side. Due to the consistent difference of solubility of glycine in
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water and ethanol31 water is the solvent and ethanol is the antisolvent.
Solubility Measurements The solubility of paracetamol and glycine in water/ethanol mixtures was measured, at different temperatures, as a function of ethanol volume fraction. Excess amounts of each substance were dissolved into the water/ethanol mixture, while stirring with a magnetic bar, to saturate the solutions. After 24 h of stirring the suspensions were filtered over a 0.22 mm filter and the saturated solutions were evaporated at 608C until no variation in the weight were registered. The weight of the dry residue sample was used to calculate the solubility at the specific ethanol volume fraction.
Mass Transfer Measurements In both ‘‘solvent/antisolvent demixing’’ and ‘‘antisolvent addition’’ experiments, the extent of solvent/antisolvent evaporation through the membrane was evaluated by measuring the variation of the volume of the crystallizing solutions as a function of the time. Accordingly, the concentration c(t) of the solute, at the time t, in the crystallizing solution of volume V(t) was calculated as: c(t) ¼ c0/V(t). Although ethanol evaporates at higher rate than water, a certain amount of water evaporates through the membrane as well, thus contributing to the variation of volume. Therefore, the effective content of ethanol on the distillate side was evaluated by a refractometer (model Abbe 60/DR from Bellingham and Stanley Ltd, Kent, UK) after calibration. The amount of ethanol left in the retentate was then calculated by mass balance.
Crystal’s Characterization Crystal morphology was assessed by an optical microscope (model DM 2500M from Leica Microsystems GmbH, Wetzlar, Germany) equipped with a video camera. Average particle size and crystal size distribution were obtained through image analysis. At least 250 particles per sample were considered to properly catch the statistics. This time-consuming procedure allows distinguishing clearly between primary particles, agglomerates, and fragments, thus yielding a
rather precise characterization of the particle population. After each experiment, the paracetamol and glycine crystalline product obtained was harvested from its mother liqueur, dried in a desiccators for 24 h, and analyzed by Fourier Transformed Infrared (FTIR) spectroscopy (by using a spectrophotomer model Spectrum One, from Perkin–Elmer, Waltham, MA).
RESULTS AND DISCUSSION Solvent/Antisolvent Demixing Membrane Crystallization In a membrane crystallizer solvent evaporation rate can be selected by choosing the opportune operating process parameters and/or the appropriate membrane characteristics affecting the driving force for evaporation: the gradient of partial pressure between the two sides of the membrane.32,33 In the present work, control of the driving force to modulate the supersaturation of the crystallizing solution was achieved by modifying the circulation rate Q (mL min1) of the feed and the distillate solutions, the feed temperature Tf (8C), and the initial ethanol volume fraction Et.% (%, v/v) in the retentate. For all the experiments, the volume V (mL) of the crystallizing solution were observed to changed with the time t (h) following a law of the type: t VðtÞ ¼ y0 þ A exp (1) t where t (h) is the evaporation rate constant, related to the rate at which the volume of solution reduces with the time, y0 and A are constant so that y0 þ A ¼ V0, with V0 the initial volume of the solution at the time t ¼ 0. In order to compare the rate of solvent evaporation for the different experiments by comparing the different values of t, best fitting of the experimental points were carried out by setting y0 ¼ 0 and A ¼ V0. According to Eq. (1) t has an inverse proportionality with the solvent evaporation rate: as t decreases the evaporation rate increases and volume reduces faster. Therefore, t is used in this section to designate the rate at which solvent was removed, and hence supersaturation was generated, in the feed. Figure 3 shows the dependence of t from the combination of the different operative para-
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Figure 3. Dependence of the evaporation rate constant t from the initial ethanol concentration Et.% for different values of circulating solution velocity Q and feed temperature Tf. Td was fixed at 58C for all experiments.
meters. As the initial amount of ethanol increases t decreases and the evaporation rate rises. For the same initial ethanol content, increasing the recirculation rate Q the transport of fluid to the membrane surface, whereby evaporation occurs, increases so that t decreases. Finally, increasing feed temperature Tf evaporation increases thus reducing t. Results in Figure 3 demonstrated that solvent evaporation rate can be easily controlled by acting on either one of the process parameters Et.%, Q, and Tf. By doing so, both the extent and the rate of solvent demixing, and consequently supersaturation, can be tuned through the crystallization process. During a crystallization experiment, ethanol evaporates at higher rate than water so that demixing is obtained. However, a certain amount of vaporized water goes through the membrane as well. Therefore, reduction of volume of the feed is not indicative to estimate the exact amount of ethanol that has left the crystallizing solution. The amount of ethanol in the feed was then estimated by mass balance, after detecting the effective amount of ethanol in the permeate by refractive index analysis. Figure 4a shows the volume fraction F of ethanol and water, with respect to their initial feed concentration, extracted from the retentate side with the time t, for different evaporation rates. From the figure is clear the differential evaporation rate between DOI 10.1002/jps
Figure 4. Variation of the volume fraction of ethanol (FEt.) and water (FWa.) transferred with the time t: (a) from the retentate to the distillate side for different solvent evaporation rate (t) in solvent/antisolvent demixing crystallization experiments and (b) from the distillate to the retentate side for different transmembrane flow rate J in antisolvent addition tests (lines are only guides for the eyes).
ethanol and water that also increases when t decreases. Accordingly, the extent of demixing (supersaturation generation rate) can be adjusted by acting on the driving force of evaporation. Figure 5 shows the dependence from t of crystals aspect ratio r, defined as crystal length to width ratio. As the evaporation rate decreases (t increases) the aspect ratio r decreases too. Plots of r as function of the different parameters Q, Tf, and Et.% (data not shown) did not indicate any systematic dependence. This means that the aspect ratio is only dependent, in this system, on the solvent evaporation rate.
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Figure 5. Variation of the crystals aspect ratio r (defined as crystals length to width ratio) as a function of the solvent evaporation rate constant t (line is only a guide for the eyes).
The variation coefficient CV (%) was calculated from the crystals size distribution of the different crystalline samples obtained from the experiments. As shown in Figure 6a, decreasing solvent evaporation rate (increasing t) results in a reduction of CV. This behavior can be explained by considering the different effects of solution circulation rate on the process. On the one side, increasing Q would produce better mixing and higher supersaturation homogeneity in the bulk of the solution. On the other hand, higher circulation rate will increase the convective transport of solvent molecules to the membrane surface, so that evaporation rate increases. As ethanol evaporates with higher velocity than water, the extent of solvent/antisolvent demixing at the mouth of a very large number of pores increases with Q. Here, the molecules of the antisolvent that were originally combined with the solvent evaporate. Consequently, the lack of free solvent molecules that can couple with solute molecules initiates locally high levels of supersaturation and subsequent nucleation and crystal growth. Inhomogeneous supersaturation leads to broader CSDs and, consequently, to higher values for CV. This explanation seems to be confirmed by Figure 6b, where the increase of CV with Q is shown for the experiments with Et.% ¼ 40% and Tf ¼ 308C. Nevertheless, opportune values of evaporation rate favored the formation of crystalline products with CV as low as 20%. These values
Figure 6. Dependence of the variation coefficient CV from: (a) the evaporation rate constant t and (b) the recirculation rate Q (lines are only guides for the eyes).
seems to be rather interesting if compared with CV generally obtained not only with conventional antisolvent processes26 but also when using supercritical gas antisolvent34 and drowning-out crystallization with feedback control processes.35,36 At the end of each test, the obtained crystalline paracetamol was analyzed by optical microscopy and FTIR37 to check its polymorphic nature. For all samples, according to infrared analysis, monoclinic form I was obtained from all the tests. However, for experiments carried out with high solvent/antisolvent demixing rates, some crystals whose morphology looks like that of the orthorhombic polymorph38–40 were observed at the early stages of crystallization (see circled in Fig. 7).
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These crystals were not persistent for enough time to be isolated from the mother liqueur at the end of the experiments. Moreover, no crystals with needle shape were observed during experiments carried out with lower solvent evaporation rate. According to these observations, it is expected that for high demixing rate, high local degrees of supersaturation lead to the formation of the metastable form II of paracetamol that converted rapidly in the stable form I by the end of the experiment. The presence of ethanol would also enhance the conversion rate, as reported in the literature.38 Figure 8 displays the behavior with t of the supersaturation at the crystallization point, Scry. A decrease of Scry with t is indicative of the increase of the supersaturation at the nucleation point with the increase of the demixing rate (or antisolvent addition rate). This behavior is in accordance with the well-known effect of supersaturation generation rate on the location of the metastable zone. As supersaturation is generated at higher rate, the width of the metastable zone increases thus effecting the final crystals properties.41
Antisolvent Addition Membrane Crystallization In antisolvent addition membrane crystallization, the antisolvent (ethanol) is added to the crystallizing solution consisting in an aqueous solution of glycine, by evaporating it trough the pores of the membrane under the action of the driving force. Also in this case, the magnitude of the driving force affects the degree of supersaturation at the crystallization point, Scry, and its generation rate. Contrary to the demixing operation, as antisolvent is added to the feed, the volume V of the retentate increases with the time t following a law of the type: VðtÞ ¼ y0 þ A1 ð1 et=t1 Þ þ A2 ð1 et=t2 Þ
(2)
Figure 7. Paracetamol crystals obtained by solvent/ antisolvent demixing experiments. (a and c) Crystals with the typical needle shape of the metastable polymorph II (circled) appeared during the initial minutes since the appearance of the first crystals. (b and d) Samples from the same experiments after few minutes of residence in the mother liqueur. Images (a and b) refer to the experiment with t ¼ 10.1 while images (c and d) to the experiment with t ¼ 10.7. DOI 10.1002/jps
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Figure 8. Dependence of the supersaturation at the crystallization point, Scry, with the evaporation rate constant t.
with the constants: y0, A1 and A2, t1, and t2. To indicate the rate of solvent evaporation the transmembrane flux J (mL h1), calculated as the increase in volume of the crystallizing solution with the time, is used in this section. With respect of the demixing approach, a different pathway is followed by the undersaturated solution towards crystallization, as showed in Figure 9. The figure shows the variation with the time t of the feed volume factor, V(t)/V0, and the supersaturation S(t) for a typical solvent/antisolvent demixing and antisolvent addition experiment. In demixing configuration, the feed volume decreases continuously so that solution concentrates with the time. Moreover, as the solvent volume fraction
decreases, because of ethanol evaporation, paracetamol solubility lowers. As a result, a steep increase in supersaturation is observed. In the case of solvent addition, the volume of the feed solution increases as antisolvent is added, therefore the volume fraction decrease with t. However, although the solute dilutes with the time, as the volume fraction of the solvent (water) decreases with the added ethanol, glycine solubility decreases so that supersaturation induces crystallization. As consequence of the two opposite effects of solute dilution and phase inversion, supersaturation changes with the time smoother in addition experiments than the demixing case. As for demixing tests, the opportune combination of the operative parameters, namely the distillate temperature Td (for the same values of Tf ¼ 108C), the solutions recirculation rate Q and the initial ethanol content in the distillate, generates a different driving force and, consequently, a specific trans-membrane evaporation rate J, that reflects on crystallization kinetics. Figure 10a shows, for example, the variation of the crystallization time, tcry, with the ethanol addition rate. Increasing J an exponential decrease of the crystallization time was observed. As for the demixing configuration, also in this case increasing antisolvent addition rate, the value of supersaturation in correspondence of which the nucleation occurs increases as well, as shown in Figure 10b. This behavior can be explained with the enlargement of the metastable zone width by increasing the supersaturation generation rate with the antisolvent addition rate.
CONCLUSIONS
Figure 9. Variation, with the time t, of the feed volume factor, V(t)/V0, and the supersaturation S(t) for a typical solvent/antisolvent demixing and antisolvent addition experiment.
A modified version of the conventional membrane crystallization technique, in which a membrane is used to dose the solvent/antisolvent composition inside a crystallizing solution to generate supersaturation, has been presented. For both the solvent/antisolvent demixing and antisolvent addition configurations, antisolvent migration between the two sides of the membrane was easily modulated by acting on the operative process parameters. Experiments demonstrated that accurate control of solution composition at the crystallization point allowed a fine control of the supersaturated environment where glycine and paracetamol crystals with adjustable properties were grown.
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As drowning-out crystallization is getting increasing involvement in pharmaceutical industry, the proposed systems represents a further improvement of the technique if considering that a membrane acts as an adjustable gate for antisolvent dosing, and hence supersaturation control, inside the crystallizing solutions. Moreover, this technology, although tested for hydrophilic solutions, is theoretically exploitable also for the crystallization of substances soluble in organic hydrophobic media, by employing hydrophilic membranes, thus extending the range of applicability in pharmaceutical and other hightech fields like, for example, single crystal organic semiconductors.
NOMENCLATURE c0 c(t) CV Et.% Q r Scry
Figure 10. (a) Glycine crystallization time, tcry, and (b) supersaturation at the crystallization point, Scry, as function of antisolvent addition rate J (lines are only guides for the eyes).
The two operative conditions allow a wide range of applications for the crystallization of organic molecules showing different affinities for hydrophilic solvents. Demixing configuration would be especially useful for solutes poorly soluble in water and more soluble in hydrophilic solvents with higher vapor pressure, as alcohols or other organic solvents. As small temperature gradients are sufficient to create a steady driving force, feed temperature as low as 25–308C generates transmembrane fluxes in the order of 1 L m2 h1 or more. Antisolvent addition technique is an easy and feasible process where the only requirement is that solvent and antisolvent must be miscible. Moreover, because the crystallizing solution is kept at lower temperature than the distillate, thermo-labile species can be successfully crystallized without detrimental effects. DOI 10.1002/jps
S(t) t tcry Tf Td V0 V(t) F t
initial concentration (mg/mL) concentration at the time t (mg/mL) variation coefficient (%) initial ethanol volume fraction in the feed (%, v/v) flow rate (mL/min) crystals aspect ratio supersaturation at the crystallization point supersaturation at the time t time (h) crystallization time (h) feed temperature (8C) distillate temperature (8C) initial volume of the feed (mL) volume of the feed at the time t (mL) fraction of the initial volume migrated from the feed to the distillate side evaporation rate constant (h)
ACKNOWLEDGMENTS Authors would like to acknowledge INSTM (Consorzio Interuniversitario Nazionale per la Scienza e la Tecnologia dei Materiali) for financial support.
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