Recrystallization of a Pharmaceutical Compound Using Liquid and

Figure 1 The experimental apparatus used for the supercritical antisolvent experiment. .... These experiments were performed using methanol as a solve...
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Ind. Eng. Chem. Res. 2006, 45, 2287-2293

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SEPARATIONS Recrystallization of a Pharmaceutical Compound Using Liquid and Supercritical Antisolvents Su-Jin Park, Se-Yeoun Jeon, and Sang-Do Yeo* Department of Chemical Engineering, Kyungpook National UniVersity, Daegu 702-701, South Korea

Sulfabenzamide was recrystallized from its solutions by using liquid and supercritical fluid as antisolvents. The drug compound was dissolved in various organic solvents, such as acetone, methanol, ethanol, and ethyl acetate, and the solutions came into contact with two antisolvents, water (liquid) and carbon dioxide (supercritical fluid). Variations of the habit, particle size, and the thermal behavior of the crystals were examined to investigate the effect of the operating temperature, type of solvent and antisolvent, mixing method, and the presence of ultrasound. Crystal habits such as acicular, columnar, prismatic, equant, and tabular were obtained depending on the solvents and antisolvents used. Larger crystals with a broader distribution were produced at higher temperatures, and crystal size was reduced when the solution was sonicated while precipitation occurred. The variations of crystal size were correlated with the use of solubility parameters of solvents and antisolvents. The thermal analysis of crystals revealed that the types of solvent and antisolvent employed in crystallization have influenced the internal structure of the resulting crystals and produced different polymorphs of sulfabenzamide. 1. Introduction The particle formation of pharmaceutical compounds using dense gas or supercritical fluid has become promising technology in industrial applications. Supercritical fluids have been employed not only as solvents but also as antisolvents to produce drug particles depending on whether the drugs are supercritical fluid-soluble or insoluble. Sometimes the supercritical fluids acted as a solute when the drug compounds were processed with polymeric materials for the purpose of impregnating active ingredients in the polymer carriers. Among the three roles of supercritical fluids (solvent, antisolvent, and solute) in the drug particle formation processes, supercritical fluids have mostly been used as antisolvents because of their very limited solubility toward drug compounds and high miscibility with most of the organic solvents. Indeed, a wide variety of pharmaceutical compounds have been processed using supercritical fluids as antisolvents in which the drug-containing organic solutions came into contact with antisolvents, and hence the drug particles became precipitated.1-14 The important feature of the supercritical antisolvent process is the diversity of operating conditions such as large pressureand temperature-dependency of antisolvent properties, variable mixing configurations of the solution and antisolvent, and flexibility in the crystallization induction time. These factors influence the degree of supersaturation and the mechanism of nucleation and crystal growth that may alter the properties of the resulting crystals. The physical properties of crystals such as crystal habit, surface texture, particle size and distribution, particle density, crystal internal structure, and crystallinity may affect the overall quality of a particular crystalline material. This notion is especially important in the case of pharmaceutical * To whom correspondence should be addressed. Tel.: +82-53-9505618. Fax: +82-53-950-6615. E-mail: [email protected].

compounds that show different bioavailability depending on the modified crystalline properties. This is the reason why supercritical antisolvents have been widely used to process drug compounds for the purpose of micronization as well as structure modification. The driving force of a crystal formation in antisolvent process is the supersaturation of a solution induced by the mixing of a solution and an antisolvent. The mixing of two miscible fluids such as water and ethanol is an instantaneous process in which the two different molecules are physically binding. The molecules of antisolvent preferentially mix with solvent molecules that were originally combined with the solute. Consequently, the lack of free solvent molecules that can couple with solute molecules initiates the supersaturation and subsequent nucleation and crystal growth. Therefore, the key factor in antisolvent crystallization is the degree of miscibility or solubility between the solvent and antisolvent, which can be estimated by using the concept of solubility parameters of the solvent and antisolvent. In this respect, the crystallization mechanism mainly depends on the mixing behavior of the solvent and antisolvent, which is governed by not only the flow configuration of the two streams but also by the physicochemical properties of the solvent and antisolvent. Research on the supercritical antisolvent crystallization of pharmaceutical compounds has employed various modified mixing devices and flow configurations for the solution and antisolvent that create different process concepts.15,16 Researchers have focused mainly on the micronization of drug particles by changing adjustable experimental variables such as temperature, pressure, and concentration. In these studies, most of the drug compounds dissolved in a single organic solvent and were crystallized using carbon dioxide as an antisolvent. The effects of different types of solvents and antisolvents, which may show a significant impact on the resulting crystal, have rarely been

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investigated. In addition, the use of carbon dioxide as the primary antisolvent in the previous researches is additional motivation in exploring the use of another antisolvent that is not a supercritical fluid. In this study, we investigated the performance of two types of antisolvents, which are liquid (water) and supercritical fluid (carbon dioxide). The major difference between the two media is isothermal compressibility. The compressibility of liquid and supercritical fluid is different in orders of magnitude, and therefore the volumetric expansion of drug solutions will vary to a large extent upon the addition of two different antisolvents. Moreover, the difference in physicochemical properties such as polarity and solubility parameter may lead to a variation in mixing behavior that can bring about a property change of the resulting crystals. Here, we crystallized sulfabenzamide, an antibacterial drug, as a model compound. Our objective was not micronization of the drug particles, and we rather investigated the physical changes of drug crystals. The changes in crystal habit, particle size, and thermal stability were examined as a function of the experimental conditions. In particular, we focused on the effect of different solvents from which the drug was crystallized. The influence of ultrasonic waves in the reduction of crystal size was also examined in liquid antisolvent experiments. 2. Experimental Section 2.1. Materials. Sulfabenzamide (Cat. No. S9757) was purchased from Sigma. Acetone (99.5%), methanol (99.8%), ethanol (99.5%), and ethyl acetate (99.5%) were selected as solvents to dissolve sulfabenzamide. All of the solvents were purchased from Aldrich. Carbon dioxide (99.5%) and deionized water were used as the supercritical and liquid antisolvents, respectively. All of the chemicals were used as received. 2.2. Experimental Procedure. Liquid and supercritical antisolvent experiments were conducted using two different experimental apparatus. First, sulfabenzamide was dissolved in four different solvents, acetone, methanol, ethanol, and ethyl acetate, with a concentration of 0.035 g/mL. At this concentration, the drug completely dissolved in all solvents. These four solutions were used in both the liquid and the supercritical antisolvent experiments. The liquid antisolvent experiments were conducted using a glass flask that was immersed in a constant-temperature bath. A known amount of the prepared drug solution (20 mL) and 60 mL of deionized water were mixed in a flask at a constant temperature. This mixing process was performed using two different methods. One involved the injection of a drug solution into water, and the other was the injection of water into the drug solution. The injection was made using a pipet at a feed rate of 10 mL/min. During the injection, the mixture was vigorously agitated to encourage crystallization. In this study, most of the liquid antisolvent experiments were conducted by injecting the solution into water unless otherwise mentioned. The experiments were also conducted in the presence of ultrasound. An ultrasonic homogenizer (Microson, XL2000) was used to sonicate the system by immersing a probe in the solution. Ultrasound was supplied at a constant frequency of 22.5 kHz with a power of 10 W. Sonication was applied to the system for 2 min upon the mixing of the drug solutions and water. It was observed that when the drug solution was injected into the water, the instantaneous precipitation of drug particles occurred near the injected stream of the drug solution. In the case of a water injection, the precipitation took place in the whole solution phase after about 20 mL of water was added to the drug solution.

Figure 1. The experimental apparatus used for the supercritical antisolvent experiment. (A) Carbon dioxide cylinder, (B) cooler, (C) high-pressure pump, (D) back pressure regulator, (E) crystallizing chamber, (F) ventilation valve, (G) solvent trap, (H) rotameter.

When the mixing process of the drug solution and water was completed, the precipitated crystals were immediately separated from the suspension by filtering. Supercritical antisolvent experiments were performed using an apparatus, as shown in Figure 1. The equipment consists of three parts: carbon dioxide supplying system, a crystallizing chamber (Jerguson Gauge, model 19-T-40), and a depressurizing section. The chamber has dual-view windows that enable us to observe the crystallization phenomena inside the solution. The crystallizing chamber is located in a constant-temperature air chamber. For the experiment, 10 mL of the prepared drug solution was charged into the crystallizing chamber, and temperature was uniformly maintained. Carbon dioxide was introduced from the bottom of the crystallizing chamber, and the mixing of the solution and antisolvent took place. Two different injection rates were used for the introduction of carbon dioxide, which were rapid and slow injections. The carbon dioxide injection rate was controlled so that the pressure inside the crystallizing chamber could increase at a rate of 21.0 bar/ min for the rapid injection and 0.3 bar/min for the slow injection. The injection of carbon dioxide into the solution caused the mixing of the solution and antisolvent, and hence precipitation occurred. Normally, the solution became cloudy in the pressure range within 20-30 bar, depending on the operating temperature. The system was pressurized until the carbon dioxide-rich and solvent-rich phases merged to become a single phase (typically up to 95 bar), at which stage the crystallization was assumed to be complete. The carbon dioxide and solvent mixture was then vented from the chamber by the use of a ventilation valve. The residual solvent on the crystal surface was removed by flowing pure carbon dioxide continuously through the crystallizing chamber for 30 min at 35 °C and 95 bar. Finally, the crystallizing chamber was depressurized to atmospheric pressure, and the crystals were collected. 2.3. Crystal Characterization. The morphology of the crystals was examined by a scanning electron microscope (SEM, Hitachi S-4200). Crystal size distribution was measured via a particle size analyzer (PSA, Ankersmid CIS-50). The thermal behavior of the crystals was analyzed by differential scanning calorimetry (DSC, Rhometric STA-1500). 3. Results and Discussion 3.1. Crystal Habit. The external shape, imparted to a crystal by the development of its various forms, is referred to as crystal

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Figure 2. SEM photomicrographs of sulfabenzamide crystals obtained from (a) methanol, (b) acetone, and (c) ethyl acetate in the liquid antisolvent experiments. All experiments were conducted at 20 °C.

Figure 3. SEM photomicrographs of sulfabenzamide crystals obtained from (a) methanol, (b) acetone, and (c) ethyl acetate in supercritical antisolvent experiments. All experiments were conducted at 30 °C.

habit. Habit is not exclusively controlled by the internal structure of a crystal, and environmental conditions during nucleation and growth also affect crystal habit.17 In this study, a variety of crystal habits of sulfabenzamide were observed depending upon the type of solvent, antisolvent, and operating conditions utilized. Figures 2 and 3 show the SEM photomicrographs of sulfabenzamide crystals obtained in this study. In liquid antisolvent experiments (Figure 2), when water was used as an antisolvent, the type of solvent strongly influenced the crystal habit of sulfabenzamide. When methanol, acetone, and ethyl acetate were employed as solvents, crystals with acicular (Figure 2a), columnar (Figure 2b), and equant (Figure 2c) habits were produced, respectively. In supercritical antisolvent experiments (Figure 3), when carbon dioxide was used as an antisolvent, the crystal habits also changed with the solvents used. Methanol, acetone, and ethyl acetate solvents generated tabular (Figure 3a), prismatic (Figure 3b), and acicular (Figure 3c) habits, respectively. It is noteworthy that even though sulfabenzamide

was crystallized from the same solvent, the habit changed dramatically depending upon the type of antisolvent. For example, when methanol was used as a solvent, the water antisolvent produced an acicular habit (Figure 2a), and the carbon dioxide antisolvent generated a tabular habit (Figure 3a). Although not shown here, the carbon dioxide injection rate appeared to alter the crystal habit such that a higher injection rate produced more needlelike crystals. The initial concentration of solutions and the operating temperature did not show any appreciable effect on the crystal habit within the concentration and temperature range investigated. Table 1 summarized the habit of crystals produced from the liquid and supercritical antisolvent experiments. Crystals of a single compound that show various habits imply that there are different directions of crystal growth within crystal structures. For example, acicular crystals indicate a fastest direction of growth parallel to the needle axis, and tabular crystals indicate the crystal growth parallel to two or more

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Table 1. Crystal Habit of Sulfabenzamide Obtained from Various Solvents and Antisolvents antisolvent water carbon dioxide

solvent

crystal habit

methanol acetone ethyl acetate methanol acetone ethyl acetate

acicular columnar equant tabular prismatic acicular

directions within the crystal, but none are normal to it.18 These modifications of crystal habits are attributed to the differences in chemical properties of the solvents and antisolvents. The fluid mixing dynamics of the solvent and antisolvent may not influence the crystal habit under the experimental conditions investigated in this study. Indeed nucleation and crystal growth took place within the environment of a mixture of solvent and antisolvent. Therefore, properties such as the dipole moment and dielectric constant of the crystallizing solution may significantly affect the directions of the periodic bond chains under the influence of solvent and antisolvent molecules, on the growing crystal surface. The crystal habit does not reflect the internal structure of a crystal. The crystal habit, however, influences the storage and flow characteristics of drug particles. Moreover, the habit may be closely related to the surface texture of a crystal that can alter the surface free energy of a particle and the release rate of the drug compound. The difference in the mixing behavior of the two experiments also influenced the crystallizing process and hence the external shape of the crystals. In supercritical antisolvent experiments, the mixing of the solvents and antisolvents occurs only by the injected carbon dioxide stream, which appears to be less efficient as compared to the vigorous mixing caused by an internal agitator in the liquid antisolvent experiments. Therefore, a higher mechanical agitation in liquid antisolvent experiments may bring about enhanced nucleation that can generate smaller crystals. 3.2. Particle Size Analysis. Particle size and the distribution of sulfabenzamide crystals were measured to investigate the effect of solvent, operating temperature, the mixing method of the solvent and antisolvent, and the presence of ultrasound. Figure 4 shows the particle size distribution of sulfabenzamide produced from various experimental conditions. Figure 4a displays the variations of the cumulative distribution of particles generated in liquid antisolvent experiments, in which four different solvents were used. The cumulative distribution stands for the percentage of particles that are smaller than a given particle size. For example, in Figure 4a, ca. 70% of the unprocessed particles is smaller than 10 µm. All experiments were conducted at a constant temperature of 30 °C. Observations indicated that particle size and its distribution were significantly affected by the solvent used, noting that the abscissa of the figure is log-scale. The overall size of the crystals ranged approximately between 10 and 100 µm. The results show that the largest crystals were produced when ethyl acetate was used as a solvent, and the smallest crystals were obtained if methanol was used. All of the crystals obtained from the liquid antisolvent experiments were larger than the particles of the purchased sulfabenzamide. Figure 4b shows the effects of the mixing method and ultrasound on the particle size distribution in liquid antisolvent experiments. These experiments were performed using methanol as a solvent at 20 °C. It was found that the crystals obtained by injecting water into the drug solution were larger than the crystals produced by the injection of a solution into water. These results imply that the rate of nucleation and the resulting crystal size were definitely affected by the mixing method of the

Figure 4. Cumulative size distribution of sulfabenzamide crystals obtained from (a) liquid antisolvent experiments using four different solvents at 30 °C, (b) liquid antisolvent experiments using a methanol solvent at 20 °C, with different mixing methods of the solution and antisolvent and with the presence of ultrasound, and (c) supercritical antisolvent experiments using acetone solvent at 30 °C, with a different carbon dioxide injection rate.

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solution and antisolvent. First, when a small amount of the drug solution was dropped into an excess volume antisolvent, the dilution of the solution by the antisolvent occurred immediately and prompt supersaturation took place. In this case, the high rate of nucleation may result in the production of a large number of nuclei and hence caused a reduction in crystal size. Second, when the antisolvent was continuously added into the excess volume solution, the solution became cloudy after a sufficient amount of antisolvent (20 mL of water in this study) was added. In this experiment, the nucleation of the solution was delayed, which in turn produced less nuclei, and hence larger crystals were generated. The reduction in crystal size was confirmed when the solution was sonicated during the mixing step of the solution and antisolvent. The enhanced formation of nuclei in the presence of ultrasound resulted in an increased number of crystals that are smaller. Figure 4c shows the effect of the carbon dioxide injection rate on particle size distribution in supercritical antisolvent experiments. Here, acetone was used as a solvent at 30 °C. It was observed that the crystals produced from the rapid injection experiment were significantly smaller than those from the slow injection experiment. These results suggest that the carbon dioxide injection rate strongly influenced the supersaturation and nucleation rate of the solution, and hence it had a major impact on the size control of the drug crystals. To interpret the dependency of crystal size on the solvents used, we employed the concept of solubility parameter. The solubility parameter is defined as the square root of the cohesive energy density of a component in a pure state.19 Cohesive energy density is the measure of the strength of intermolecular forces that hold molecules together in a liquid state per unit volume of liquid, and this is given by the ratio of the latent energy of vaporization (∆Ev)i to the molar volume Vi of component i. Therefore, the solubility parameter δi is expressed as δi ) [∆Ev)i/Vi]1/2. Solubility parameter has been used to predict the solubility or miscibility of two substances based on the approximation “like dissolves like”. In other words, it is easier to mix substances that have similar solubility parameters than to mix substances that have substantially different solubility parameters. Mixing of two different liquids is analogous to the vaporization process of each liquid, in which the distance between the same type of molecules increases and the interaction energy between the same molecules is overcome by different molecules. Therefore, if the intermolecular forces of the two different pairs of molecules are similar, it is easy for each molecule to interact, that is, to mix with different molecules. This concept can be applied to the mixing of the drug solution and antisolvent. It can be stated that similarities in the solubility parameters of the solvent and antisolvent may govern the mixing rate of the two media and hence determine the rate of supersaturation and nucleation of the containing drug. Therefore, as the difference in solubility parameters of the solvent and antisolvent becomes smaller, the rate of nucleation may increase, and the resulting crystal size will be reduced. In this respect, the variation of crystal size was correlated with the solubility parameters of the solvent used. Figure 5 shows the crystal size of sulfabenzamide as a function of the solubility parameter of the solvents in liquid and supercritical antisolvent experiments. Figure 5a shows the variation of crystal sizes with the solubility parameter of the solvent when water was used as an antisolvent. The solubility parameter of water is 23.5 (cal/cm3)1/2, and those of solvents, ethyl acetate (EA), acetone, ethanol, and methanol, are 9.1, 9.8, 12.9, and 14.3 (cal/cm3)1/2, respectively. It has been shown that crystal size

Figure 5. Correlation of particle size with the solubility parameters of solvents when (a) water was used as an antisolvent at 30 °C, and (b) carbon dioxide was used as an antisolvent at 30 °C.

decreases with the solubility parameter of solvents, indicating that the crystal size reduces as the solubility parameter of the solvent becomes closer to that of water. Figure 5b shows the relation between crystal size and the solubility parameter of solvent when carbon dioxide was used as an antisolvent. It has been known that the solubility parameter of carbon dioxide is close to that of n-hexane. Here, we adopted the solubility parameter of carbon dioxide from the literature,20 which is 6.01 (cal/cm3)1/2. The solubility parameters of all of the solvents used are larger than this value. The results show that the overall crystal size tends to increase as the solubility parameter of the solvent moves away from that of carbon dioxide. These results, which were obtained from the two antisolvent experiments, suggest the possible manipulation of crystal size by the selection of proper solvents and antisolvents based on the solubility parameter approach. The solubility parameter, in fact, is closely related to other intermolecular forces such as dipole-dipole interaction and the hydrogen bonding of molecules. These results encourage the investigation of the correlation of solvent and antisolvent properties and those of the obtained crystals. In this study, the solubility parameter of the solute (sulfabenzamide) was not considered because we judged that the solubility parameter of solute might not influence the crystal-

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Figure 6. Particle size range of sulfabenzamide crystals as a function of operating temperature in liquid antisolvent experiments. Methanol was used as a solvent.

lization behavior of the solute. The solute precipitates upon the addition of the antisolvents (water and CO2), and the solubility of the solute in these two antisolvents is nearly zero. Because the solute does not dissolve in the two antisolvents, the value of solubility parameter of the solute would not influence the behavior of the mixing process of the solutions and antisolvents. Figure 6 shows the variations of crystal size as a function of temperature in liquid antisolvent experiments, in which methanol was used as a solvent. The rectangular bar in this figure represents the size range of crystals excluding the particles whose sizes are in the upper and lower 10% of the particles counted. For example, the crystal size ranged from 7.5 to 49.5 µm at 30 °C, indicating that 10% of the produced particles were larger than 49.5 µm and another 10% was smaller than 7.5 µm. It was found that as the temperature increased, larger-sized crystals and those with a broad distribution were consistently obtained. It is generally known that the rate of nucleation of the crystallizing material is inversely proportional to temperature. Moreover, a higher temperature may lead to an increased solubility of sulfabenzamide in the given solvent, and hence this could cause a delayed supersaturation upon the mixing of the solution and antisolvent. These effects reduced the formation of the number of nuclei or crystals, and, therefore, the size of each crystal would increase. Even though the effect of the temperature in the supercritical antisolvent experiment was not investigated in this study, a similar trend was observed in previous research when carbon dioxide was used as an antisolvent.1 3.3. Thermal Behavior of Crystal. DSC measurement was performed to analyze the thermal behavior of crystals, which reflect their degree of crystallinity and stability. The measurement would also indicate the possible existence of polymorphic states of sulfabenzamide. DSC scans provide information on fusion temperature and enthalpy change involved in the phase transition. The analysis focused on the effect of solvent, the operating temperature, and the existence of ultrasound, as shown in Figure 7. The heating rate for all DSC measurements was 10 °C/min. Figure 7a displays the DSC thermograms of sulfabenzamide crystals produced from the liquid antisolvent experiments at 20 °C. Different DSC thermograms were obtained depending upon the solvents from which the crystals were precipitated. Overall observation indicated that sulfa-

Figure 7. DSC thermograms of sulfabenzamide crystals obtained from (a) liquid antisolvent experiments using three different solvents at 20 °C, (b) supercritical antisolvent experiments using three different solvents at 30 °C, and (c) liquid antisolvent experiments using acetone solvent conducted at various temperatures. ∆Hm and ∆Ht are the heat of fusion and the heat of solid-liquid or solid-solid transition, respectively.

benzamide exhibited endothermic behavior when fusion took place.21 When acetone was used as a solvent, one melting peak was observed at 182 °C with a minor endothermic peak at 174 °C, and the corresponding heat of fusion was 146 J/g. The thermogram of crystals that were obtained from acetone with

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applied sonication, however, shows two endothermic transitions where the first peak may correspond to the solid-liquid transformation of a part of the crystalline mixture or the solidsolid transition between the two different solid states, and the second peak corresponds to melting from the solid to the liquid state. The first peak occurred at 174 °C, and the melting peak was at 182 °C. The heats of transition of the two peaks were 50 and 148 J/g, respectively. These results imply that the presence of ultrasound may affect the packing mechanism of molecules and hence alter the crystalline state of crystals. The thermogram of the crystals obtained from methanol also shows the two transition peaks with a greater heat of transition for the first peak (97 J/g), as compared to the heat of fusion (58 J/g). Crystals obtained from ethyl acetate exhibited one melting peak at 182 °C with the heat of fusion of 147 J/g. The thermal behavior of the crystals indicates that the type of solvent from which the crystals were precipitated may influence the internal structure of crystalline particles and generate different polymorphs of sulfabenzamide. It has been known that sulfabenzamide exhibits two polymorphic forms (form A and form B).21 It was reported that the two polymorphs showed transition temperatures of 171 and 181 °C, respectively, which reasonably agree with our results. Figure 7b shows the DSC scans of sulfabenzamide when carbon dioxide was used as an antisolvent. All experiments were conducted at 30 °C. The thermograms demonstrate that the type of antisolvent as well as solvent influence the thermal behavior of crystals. When acetone was used as a solvent, two peaks were observed at 118 and 181 °C. If this thermogram is compared to the acetone curve in Figure 7a, the two thermograms show different patterns, indicating that even though the solvents are identical, different antisolvents, water and carbon dioxide, produced different thermograms. The first peak observed at 118 °C was presumed to be the enthalpy change due to the loss of solvent entrapped inside the crystals. When methanol was used as a solvent, the first transition peak at 174 °C was depressed as compared to the methanol curve in Figure 7a. Two ethyl acetate curves in Figure 7a and b show basically the same pattern. Figure 7c describes the thermograms of crystals produced from liquid antisolvent experiments conducted at various temperatures. Acetone was used as a solvent in all of these experiments. The results show that the location of the melting peak did not change with the temperature. The crystals that were precipitated at a lower temperature, however, showed a higher level of heat of fusion. The heat of fusion changed from 146 to 126 J/g as the precipitation temperature increased from 20 to 45 °C. The heat of fusion is generally used to estimate the degree of crystallinity.22 Crystals that have a higher crystallinity require greater heat of fusion when melting takes place. Therefore, these results imply that the crystallinity of sulfabenzamide crystals may increase when crystals are precipitated at a lower temperature, which provides a more suitable environment for the regular packing of molecules. 4. Conclusions A variety of sulfabenzamide crystal habits such as acicular, columnar, prismatic, equant, and tabular were obtained depending upon the type of solvent and antisolvent used. The size distribution of the crystals was significantly influenced by operating conditions such as temperature, type of solvent, mixing method of the solution and antisolvent, and the presence of ultrasound. The dependency of the particle size on employed solvents and antisolvents was correlated with the use of the concept of solubility parameter. It was found that as the

difference in solubility parameters of solvent and antisolvent becomes smaller, the size of the resulting crystals was reduced. The thermal analysis of crystals indicated that different polymorphs of sulfabenzamide were produced when the solvent and antisolvent were changed. The crystals that were precipitated at a lower temperature showed higher crystallinity. Acknowledgment This work was supported by a grant from the Korea Research Foundation (KRF-2004-041-D00157). Literature Cited (1) Yeo, S.; Kiran, E. Formation of polymer particles with supercritical fluids: A review. J. Supercrit. Fluids 2005, 34, 287. (2) Foster, N.; Mammucari, R.; Dehghani, F.; Barrett, A.; Bezanehtak, K.; Coen, E.; Combes, G.; Meure, L.; Ng, A.; Regtop, H. L.; Tandya, A. Processing pharmaceutical compounds using dense gas technology. Ind. Eng. Chem. Res. 2003, 42, 6476. (3) Reverchon, E.; De Marco, I.; Della Porta, G. Rifampicin microparticles production by supercritical antisolvent precipitation. Int. J. Pharm. 2002, 243, 83. (4) Fusaro, F.; Hanchen, M.; Mazzotti, M.; Muhrer, G.; Subramaniam, B. Dense gas antisolvent precipitation: A comparative investigation of the GAS and PCA techniques. Ind. Eng. Chem. Res. 2005, 44, 1502. (5) Subramaniam, B.; Rajewski, R. A.; Snavely, K. Pharmaceutical processing with supercritical carbon dioxide. J. Pharm. Sci. 1997, 86, 885. (6) Reverchon, E. Supercritical antisolvent precipitation of micro- and nanoparticles. J. Supercrit. Fluids 1999, 15, 1. (7) Rogers, T. L.; Johnston, K. P.; Williams, R. O., III. Solution-based particle formation of pharmaceutical powders by supercritical or compressed fluid CO2 and cryogenic spray-freezing technologies. Drug DeV. Ind. Pharm. 2001, 27, 1003. (8) Tan, H. S.; Borsadia, S. Particle formation using supercritical fluids: pharmaceutical applications. Expert Opin. Ther. Pat. 2001, 11, 861. (9) Stanton, L. A.; Dehghani, F.; Foster, N. R. Improving drug delivery using polymers and supercritical fluid technology. Aust. J. Chem. 2002, 55, 443. (10) Chou, Y. H.; Tomasko, K. L. GAS crystallization of polymerpharmaceutical composite particles, Proceedings of the 4th International Symposium on Supercritical Fluids, Sendai (Japane), 11-14 May, 1997. (11) Falk, R.; Randolph, T. W.; Meyer, J. D.; Kelly, R. M.; Manning, M. C. Controlled release of ionic compounds from poly(L-lactide) microspheres produced by precipitation with a compressed antisolvent. J. Controlled Release 1997, 44, 77. (12) Ghaderi, R.; Artursson, P.; Carlfors, J. A new method for preparing biodegradable microparticles and entrapment of hydrocortisone in DL-PLG microparticles using supercritical fluids. Eur. J. Pharm. Sci. 2001, 10, 1. (13) Taki, S.; Badens, E.; Charbit, G. Controlled release system formed by supercritical anti-solvent coprecipitation of a herbicide and a biodegradable polymer. J. Supercrit. Fluids 2001, 21, 61. (14) Elvassore, N.; Bertucco, A.; Caliceti, P. Production of protein-loaded polymeric microcapsules by compressed CO2 in a mixed solvent. Ind. Eng. Chem. Res. 2001, 40, 795. (15) Jung, J.; Perrut, M. Particle design using supercritical fluids; Literature and patent survey. J. Supercrit. Fluids 2001, 20, 179. (16) Kompella, U. B.; Koushik, K. Preparation of drug delivery systems using supercritical fluid technology. Crit. ReV. Ther. Drug Carrier Syst. 2001, 18, 173. (17) Mullin, J. W. Crystallization; Butterworth & Co.: London, 1971. (18) Bloss, F. D. Crystallography and Crystal Chemistry: An Introduction; Mineralogical Society of America: New York, 1994. (19) King, C. J. Separation Processes; McGraw-Hill: New York, 1980. (20) Dixon, D. J.; Johnston, K. P. Molecular thermodynamics of solubilities in gas antisolvent crystallization. AIChE J. 1991, 37, 1441. (21) Chan, H. K.; Doelker, E. Polymorphic transformation of some drugs under compression. Drug DeV. Ind. Pharm. 1985, 11, 315. (22) Ford, J. L.; Timmins, P. Pharmaceutical Thermal Analysis; Ellis Horwood: New York, 1989.

ReceiVed for reView September 26, 2005 ReVised manuscript receiVed January 24, 2006 Accepted January 30, 2006 IE0510775