Gas-Antisolvent (GAS) Crystallization of Aspirin Using Supercritical

Article pubs.acs.org/IECR

Gas-Antisolvent (GAS) Crystallization of Aspirin Using Supercritical Carbon Dioxide: Experimental Study and Characterization Dariush Jafari, Iman Yarnezhad, Seyed Mostafa Nowee,* and Seyed Hossein Noie Baghban Chemical Engineering Department, Faculty of Engineering, Ferdowsi University of Mashhad, Mashhad, P.O. Box 91775-1111, Iran ABSTRACT: Aspirin, which is used as a pain killer and is recommended to cure diseases such as arthritis, was precipitated using the gas-antisolvent (GAS) process. The objective of this study was to investigate the effects of four operating parameters namely, antisolvent addition, process temperature, solute concentration, and solvent type (methanol and acetone)on the final product particle size distribution, morphology, and crystallinity. In accordance to particle size analysis and scanning electron microscopy (SEM), it was observed that the increment of antisolvent addition rate reduced the mean size of precipitated particles and the size distributions became narrower. Furthermore, the process temperature and the solute concentration had a reverse effect on the precipitated aspirin particle size. The crystallized particles had a mean size between 48 μm and 124 μm. In contrast, particles precipitated from methanol solution had smaller mean size than from acetone. X-ray diffraction (XRD) and differential scanning calorimetry (DSC) showed that particles produced from acetone had more crystalline structure in comparison with the samples produced from methanol and also the unprocessed purchased aspirin. This can be explained through reduced involvement of methanol into the crystalline structure. The results proved the capability of GAS process for the production of aspirin for the therapeutic applications. can be produced under moderate conditions.12 In addition, SCF is easily separated from the organic solid product, thereby providing a potentially “green”, recyclable, and environmentally friendly technology.15 Carbon dioxide (CO2) is the most used supercritical fluid and possesses immense properties. In addition to its low critical pressure and temperature (Pc = 74 bar and Tc = 31.3 °C), CO2 is inflammable, nontoxic, and easily available with high purity. Compressed gases such as CO2 exhibit tunable dissolving power, and the expansion caused by induction into an organic solvent decreases the mixture dissolving power; hence, solute precipitation occurs.16 Fine particles can be produced based on several methods, each of which has its benefits and drawbacks.17,18 Drugs that are soluble in a SCF are produced in the best quality using the rapid expansion of supercritical fluid solutions (RESS) process. Since most drugs have a low solubility in SCFs, antisolvent techniques are used.15 High-pressure gases or SCFs are dissolved in organic solvents, which cause the solvent expansion and solubility reduction and, consequently, the solute precipitates. Such processes are called gas-antisolvent (GAS), where the compressed gas or the SCF is the precipitant.19 In a GAS system, which is normally a fed-batch process, initially the vessel is filled with a predetermined solution volume of the primary solvent and the solute. Afterward, CO2 is added at a constant rate to expand the solution and the subsequent solute precipitation.20 Following the precipitation step, the compressed gas or SCF flows continuously to remove the primary solvent and to achieve a dry product. In such a process, it is possible to tune the PSD, mean size, shape, and the remaining

1. INTRODUCTION The investigation of production of fine particles in the range of nanometers to hundreds of micrometers with the controlled particle size distribution (PSD) has been increasingly considered in scientific and industrial communities in various fields such as pharmaceuticals, food, nutraceuticals, chemicals, painting, coating, and polymer industries. The application of supercritical fluid (SCF) techniques has attracted a multitude of interest as an emerging “green” technology for the production of particles in the above-mentioned size ranges.1−3 Approximately two-thirds of pharmaceutical products that are applied in the drug industry are in the solid form.4 The product features, such as size, shape, surface, crystalline structure, and also their morphology, are considered as significant factors for physical and chemical stability, uniformity, flowability, tablettability, crystallographic quality, dissolution rate, and drug bioavailability.5−9 Generally, the size and PSD of produced solid particles are not appropriate for subsequent uses. Thus, post-synthesis (namely, comminution) processes are used on a great scale in the pharmaceuticals industry to achieve the acceptable features for further applications.10,11 The conventional post-synthesis processes include grinding, crushing, milling, sublimation, lyphilization, and recrystallization, which are accompanied by problems such as thermal degradation, coarse particle production, electrostatically charged particles, toxicity, and chemical degradation caused by incomplete solvent elimination.11,12 The aforementioned drawbacks rationalize the application of SCF technology for the micronization of solvent free drugs with narrow PSD.13 The term “supercritical” is used for the reduced pressure and temperature ranges of 1.01 < (P/Pc) < 1.1 and 1.01 < (T/Tc) < 1.1, respectively. The supercritical region is defined by high compressibility, low viscosity, high diffusivity, and liquid-like density.14 This is the key factor in drug production, since microparticles with controlled and reproducible PSD and appropriate quality © 2015 American Chemical Society

Received: Revised: Accepted: Published: 3685

November 26, 2014 February 18, 2015 March 12, 2015 March 12, 2015 DOI: 10.1021/ie5046445 Ind. Eng. Chem. Res. 2015, 54, 3685−3696

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Industrial & Engineering Chemistry Research

temperature were accompanied by reducing the particle size, while no significant change in the mean particle size was found with concentration variation.43 Aspirin or acetyl salicylic acid (IUPAC name: 2-acetoxy benzoic acid), which has chemical properties close to salicylic acid, is used as a pain killer, anticoagulant, antiheumatic, analgestic, antiflammatory, and antipyretic drug. The chemical structure is illustrated in Figure 1. In recent years, there has

solvent concentration by controlling the temperature, pressure, and composition. The solvent selection affects morphology, yield, and particle size.21 GAS removal and recovery is more unchallenging than the liquid primary solvent; thus, GAS is more environmentally acceptable. The significant advantage of this process over RESS is the versatility in solvent selection.22 The main drawback of batch antisolvent precipitation processes is the difficulty in complete removal of the remained solvent. Consequently, a wash-out operation by GAS may be needed to produce drug products at industrial scale.23 Several applications of GAS precipitation process have been reported, such as peptides and protein powder production,24 polymers, organic and drug materials, superconductors, catalyst precursors, dyes, biomolecules, explosives,13,17,25−28 inorganic material and organic acids,29,30 foods, nutraceuticals, chemicals, colors and coatings, and many more. It is also applied for the purpose of polymers fractionation.13,31−35 This process is extensively deployed for the promotion of pure API chemicals such as phenanthrene,36 sulfathiazole,37 hydrocortisone,38 and grisofulvin.39 There are also reported applications in chemical reactions.40 The GAS process was introduced by Gallagher et al. in 1989 for the first time where ordered and shaped, single nitroguanidine crystals and naphthalene particles were produced in low expansion rates and small range of pressure and temperature, respectively.10 Following this report, much research has been performed to study the different aspects of GAS process. Many researchers have studied the effects of operating parameters on the effective particles features of various types of materials such as mean size, PSD, shape, and morphology by varying operating conditions. A study by Müller et al.20 showed that increasing the CO2 feed rate induced a change in pharmaceutical particle size, from 10 μm to 300 nm. Based on their observations, it was possible to optimize the size and PSD by tuning the CO2 addition rate. Bimodal PSDs were achieved at rates that were too high and too low, while unimodal PSDs were produced at intermediate rates. As they varied the organic solvent, it was observed that particles produced from ethanol were amorphous and agglomerated, while pure crystalline particles were achieved from acetone and acetonitrile. Crystallization of an organic drug was examined in another study,41 where an increase in temperature of 5−50 °C changed the particles to amorphous particles that were three times larger, with a higher degree of agglomeration, while the augmentation of CO2 addition rate had a reverse effect. They also showed that, by changing the solvent to acetone and acetonitrile, pure crystals can be achieved. Moreover, unimodal PSDs were achieved for fast and slow antisolvent rates, whereas, for intermediate rates, the PSD was bimodal. A further investigation into the GAS process showed that the CO2 feed rate can be optimized to control the mean particle size of a nondisclosed pharmaceutical intermediate.42 In a detailed examination of the GAS precipitation of beclomethasone17,21-dipropionate (BECD) by Bakhbakhi et al.,15 it was shown that increasing the CO2 feed rate and stirring rate, as well as reducing the temperature and solute concentration, resulted in a decreased particle size. Furthermore, the possible tuning of the PSD was reasoned for further optimization objectives. The XRD patterns indicated that using acetone as the primary solvent produced more crystalline products, compared to ethanol and methanol. Paracetamol monoclinic particles were successfully precipitated by GAS process from acetone in another study in which the final product size was controlled in the range of 50−250 μm by manipulating the CO2 rate. It was observed that increasing the CO2 addition rate and decreasing the

Figure 1. Structure of aspirin molecule.

been an increasing amount of literature on the precipitation of aspirin, to study the impact of the operating parameters. A study was presented by Domingo et al.,44 for the precipitation of aspirin via the RESS method, using a new expansion device called a frit nozzle. It was reported that all products from this technique were smaller than the virgin material. It was also observed that, by increasing the pre-expansion temperature, the particle size varied strongly. By varying the extraction pressure (16−20 MPa) and the nozzle temperature (373−403 K), aspirin crystals 2−5 μm in diameter were precipitated. In another work, Lee et al. produced needlelike and fine powder aspirin, using both an aerosol solvent extraction system (ASES) and RESS. The former product had a mean diameter of 100 μm, while the latter had crystals 20 μm in diameter. The aspirin particles of ASES were longer than the unprocessed material. It was determined that increasing the solution feed rate resulted in the precipitation of bigger particles.45 Huang et al. were also able to precipitate spherical or needlelike aspirin particles via the RESS process, with a diameter of 0.1−0.3 μm; however, they had lower crystallinity, compared to commercial aspirin. In addition, based on their results, it was concluded that extraction pressure and extraction temperature could significantly affect the morphology and size of the precipitated particles. However, the nozzle diameter and pre-expansion temperature apparently did not influence the RESS-produced particles.46 In other research, nanoparticles were obtained by using a water/oil microemulsion technique. The outcome of dynamic light scattering (DLS) and transmission electron microscopy (TEM) revealed that the particle size was found to be within 6−9 nm.47 Although, as mentioned above, extensive research has been carried out on GAS process, to the best of author’s knowledge, no single study exists that covers the precipitation of aspirin via this technique. In contrast, the main purpose of this study was to develop an understanding of the GAS process for the purpose of aspirin crystallization. Thus, this investigation pursued a conceptual theoretical framework to investigate the effect of GAS process parameters including CO2 addition, temperature, initial aspirin concentration, and the solvent type on the 3686

DOI: 10.1021/ie5046445 Ind. Eng. Chem. Res. 2015, 54, 3685−3696

Article

Industrial & Engineering Chemistry Research Table 1. Aspirin Solubility in Different Solventsa T (°C)

a

P (bar)

Table 2. Operating Conditions Used for the GAS Experiments

solubility (mole fraction)

methanol

25

1

0.0719

acetone acetone

25 42.15

1 1

0.0828 0.127

CO2

45

200

0.212 × 10−3

CO2 + 3% methanol

45

200

1.54 × 10−3

CO2 + 3% acetone

45

200

0.615 × 10−3

Data taken from refs 48−50.

properties of aspirin precipitated particles such as particle size distribution, morphology, and degree of crystallinity.

2. EXPERIMENTAL SECTION 2.1. Materials. The solutions studied in the current study were made by dissolving aspirin in acetone or methanol. The organic solvents were purchased from Merck Company of analytical grade. The pharmaceutical solute was a white crystalline powder (99% purity) with a melting point of ∼136 °C. The aspirin used in this work was donated by TEMAD Pharmaceutical Company (Iran) and used without further purification. The GAS experiments were carried out

run label

antisolvent addition, AAR (bar/min)

process temperature, PT (°C)

solute concentration, SC (g aspirin/g solution)

solvent type, ST

A B C D E F G H B1 C1 D1 E1 F1 G1 H1 I1

8 40 40 8 40 8 8 40 8 40 40 8 40 40 8 8

42 37 37 37 42 37 42 42 42 42 37 37 42 37 37 42

0.2 0.27 0.2 0.2 0.2 0.27 0.27 0.27 0.2 0.2 0.2 0.2 0.27 0.27 0.27 0.27

acetone acetone acetone acetone acetone acetone acetone acetone methanol methanol methanol methanol methanol methanol methanol methanol

using analytical-grade CO2 (99% purity, TOOS Co., Iran). The solubility of aspirin in the organic solvents, pure carbon dioxide, and their mixture48−50 is presented in Table 1. As is evident supercritical CO2 has low dissolving power to aspirin and was chosen as the antisolvent in the studied system.

Figure 2. Experimental setup for GAS precipitation. 3687


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stainless steel jacketed vessel with a volume of 700 mL. The vessel temperature was controlled by the circulated water flow rate and temperature. A circulator (Wise Circu, Korea) was used for this purpose. The bottom of the precipitation vessel was equipped with a frit filter, which only allowed the CO2 stream to penetrate while the precipitated particles were trapped behind. The following experimental methodology was exercised for each run: (1) At the beginning of the GAS experiment, a solution of aspirin in acetone or methanol at a predetermined concentration was prepared. (2) The solution was then loaded into the vessel using a pump (Echtop, China) prior to delivering CO2. (3) After the temperature and the antisolvent flow rate were stable at their set points in the dampener vessel, CO2 addition from the bottom of the precipitation vessel started through the frit filter, while the vessel outlet valve on the top was kept closed during the precipitation step. (4) When the experimental pressure value was met, the input vessel valve in the bottom was closed. The time required to reach the desired pressure was dependent on the CO2 addition rate. (5) Following the precipitation step and full expansion, there was a rinsing step by flushing the expanded liquid phase with CO2 at a constant flow rate for a minimum of 5 h. (6) Finally, the precipitation vessel was depressurized, and the dry solid powder was collected for offline characterization. (7) The final product characteristics were identified as particle size distribution (PSD), SEM micrographs, and powder X-ray diffraction.

Table 3. Experimental Results of Aspirin Produced Using the GAS Process run label

mean particle size (μm)

A B C D E F G H B1 C1 D1 E1 F1 G1 H1 I1

114 94 48 101 71 122 124 98 71 59 53 67 63 59 72 78

a

spreada coefficient of variation (× 103) 1.41 3.32 1.58 1.37 0.20 2.39 1.14 1.01 1.41 1.52 1.83 3.52 1.35 4.07 1.83 1.50

2.35 3.30 5.53 1.97 4.81 3.61 1.85 2.52 4.24 4.26 5.11 6.87 3.77 8.67 4.74 2.99

Here, spread = (d90 − d10)/d50.

2.2. Apparatus and Procedure. Figure 2 shows the experimental setup for the GAS batch-fed precipitation process. Liquid carbon dioxide was pumped from a dip tube cylinder with a high-pressure pump (MAXIMATOR, Germany) after being cooled by a heat exchanger to prevent any possible cavitations. The pressure in the system was controlled by a back pressure regulator (TESCOM, USA). The pressure, the temperature, and the antisolvent feed rate were measured and recorded in the system in intervals. The CO2 stream was heated to the desired temperature, using band electrical heaters along the tubes prior to delivery into the pulse dampener vessel and then the precipitation vessel. The precipitation vessel was a

Figure 3. Normalized number density distribution of aspirin particles precipitated from methanol: (a) samples G1−H1, (b) samples C1−B1, (c) samples D1−E1, and (d) samples I1−F1. 3688


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Figure 4. Mean particle size of aspirin particles produced via the GAS process from methanol at different antisolvent addition: (a) samples F1, G1, H1, and I1; and (b) samples B1, C1, D1, and E1.

Figure 5. SEM photomicrographs of aspirin particles precipitated by GAS from methanol (the effect of increasing antisolvent addition): (a) sample F1 (42 °C, 0.27 g aspirin/g solution, 40 bar/min), (b) sample I1 (42 °C, 0.27 g aspirin/g solution, 8 bar/min), and (c) sample H1 (37 °C, 0.27 g aspirin/g solution, 8 bar/min).

2.2. Analytical Procedures. The size distribution of final products was measured via the laser diffraction method, using a Shimadzu Model SALD-2101 particle counter. The photomicrographs of the crystals have been taken using a LEO (1450VP) scanning electron microscopy (SEM) system. The

samples were coated by gold−palladium, using a Model SC7620 sputter coater within 180 s. These micrographs were used to study the size and the degree of agglomeration of precipitated particles visually. The powder X-ray diffraction (XRD) patterns of precipitated particles were recorded by a 3689


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Figure 6. Normalized number density distribution of aspirin particles precipitated from acetone: (a) samples B−F, (b) samples E−A, (c) samples C−D, and (d) samples G−H.

Figure 7. Mean particle size of particles produced by GAS from acetone at different antisolvent addition: (a) samples B, F, G, and H; and (b) samples A, C, D, and E.

variation of the size distribution for each final product were determined. In order to compare the precipitation results directly, the normalized number density distribution of some selected runs are illustrated in Figure 3. 3.1. The Effect of Antisolvent Addition. The AAR rate was varied by pressure increment. The significance of this state variable at two levels, namely, 8 and 40 bar/min of CO2 feed rate, was studied during precipitation of aspirin particles from two organic solvents. During the first set of performed experiments methanol was used as the primary solvent. The comparison between the size distribution of samples B1−C1, D1−E1, G1−H1, and F1−I1 in Figure 3 showed that, when the AAR value was increased, the mean particle size decreased. From Figures 3 and 4, it is apparent that the augmentation of the CO2 addition rate induced the production of narrower particles. In addition, for the aforementioned samples, it can be

Philips X’pert powder diffractometer (Model PW3710) with Cu anode by a graphite crystal to determine their degree of crystallinity. The scanning angle range was from 2°−60° 2θ. The differential scanning calorimetry (DSC) analysis was performed using a Mettler Toledo (England) DSC system to study the thermal behavior of samples. The samples were heated at the scanning rates of 10 and 40 °C per min from 30 °C to 210 °C in the presence of atmospheric air.

3. RESULTS AND DISCUSSION The operating conditions are provided in Table 2, where each run is represented by a specific label, corresponding to AAR (antisolvent addition), PT (process temperature), SC (solute concentration), and ST (solvent type). Table 3 provides the results of particle size measurement of precipitated samples using PSD analysis. In addition, the spread and coefficient of 3690


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Figure 8. SEM photomicrographs of aspirin particles precipitated by GAS from acetone (the effect of increasing antisolvent addition): (a) sample G (42 °C, 0.27 g aspirin/g solution, 8 bar/min) and (b) sample H (42 °C, 0.27 g aspirin/g solution, 40 bar/min).

seen that a smaller particle size distribution was found using higher antisolvent feed rates. Considering samples B1 (42 °C, 8 bar/min, and 0.2 g solute/g solution) and C1 (42 °C, 42 bar/min, and 0.2 g solute/g solution), the antisolvent feed rate was studied in detail. In sample C1, a sudden burst of supersaturation was generated in the system due to the increased CO2 addition rate, which produced a relatively bimodal

curve. That was the outcome of the initial present nuclei growth in the system and secondary nuclei generation. It is worth noting that the number of former growing particles was low. A similar comparison between samples D1 and E1 reveals that both had bimodal PSDs. Apparently, during the run of sample D1, a higher supersaturation occurred, followed by a more intensive nucleation, due to higher CO2 addition rate, 3691


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Figure 9. Mean particle size of aspirin produced via the GAS process from methanol at different solute concentrations: (a) samples B1, C1, F1, and I1; and (b) samples D1, E1, G1, and H1.

Figure 10. Mean particle size of aspirin produced via GAS from acetone at different concentrations: (a) samples A, E, G, and H; and (b) samples B, C, D, and F.

higher nucleation rates and, consequently, a higher number of small particles with narrow PSDs. It is worth mentioning that the findings of the current study are consistent with these interpretations, since, in all of the samples, the particle mean size produced at higher CO2 feed rate values were smaller. The unbalanced competition between the nucleation and the growth phenomenon in the GAS process contribute to the bimodal particle size distributions observed for the precipitated aspirin particles. 3.2. Effect of Temperature. From Figure 4 and the data provided in Table 3, it can be concluded that the augmentation of the operating temperature in the GAS process was accompanied by a relative increase in the mean size of the final product and also changed the PSD characteristics. The SEM micrographs of aspirin particles from methanol solution showed that the temperature increment changed the morphology of the particles from a mixed cubic structure and needlelike to the pure cubic, with an extended degree of agglomeration. Samples D1, E1, G1, and H1 were processed at 37 °C while samples B1, C1, F1, and I1 were precipitated at 42 °C from methanol solvent. Remarkably, the PSDs of all the samples precipitated at 37 °C were somewhat bimodal, whereas those at 42 °C were unimodal. Based on this framework, it can be explained that, at the lower temperature, the induction of CO2 into the solution was higher, which resulted in a greater supersaturation rate during the process. Consequently, in the competition between the growth of existing particles and secondary nucleation, the latter prevailed, resulting in bimodal PSDs. A similar trend was also observed for the samples produced from acetone solution (Figure 7). For the A−D and E−C

while for sample E1, the growth of particles was more evident. Considering the experimentations of samples G1 and H1, particle growth in the former was lower, compared to the latter; the initial fracture in the curve for sample H1 indicated the occurrence of higher nucleation. Figure 5 shows the SEM photomicrographs of samples F1 and I1. Needlelike particles were formed in both samples. By increasing the CO2 addition rate, smaller particles were achieved with a lower degree of agglomeration and a narrower size distribution. The smallest and largest particle sizes formed were 53 and 78 μm, respectively. The reduction of mean particle size with AAR increment is evident in Figure 6 for all the precipitated samples using acetone as the solvent. In addition, PSD curves became narrower with higher CO2 feed rates. From Figure 7, it can be seen that increased AAR provided smaller particles. In these samples, the antisolvent addition impact on the PSD pattern was dominant, in comparison with that of temperature and the solute concentration. Bimodal curves were achieved in higher rates while the distribution curves were unimodal at lower CO2 feed rate values. This was due to the simultaneous occurrence of particle growth and secondary nucleation due to the high supersaturation generation. Considering the SEM photomicrographs of samples G and H in Figure 8, it can be observed that increasing the CO2 addition rate led to smaller particle sizes and lower degree of agglomeration. According to Müller et al.,20 the magnitude of supersaturation is the direct function of volumetric expansion induced in the system, as the result of antisolvent addition. Higher AAR values generate higher supersaturation values, which result in 3692


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Figure 11. XRD patterns for (a) the unprocessed aspirin, (b) aspirin precipitated from methanol, and (c) aspirin precipitated from acetone.

sample pairs, it was noticed that PSDs were broader at 42 °C. Moreover, a bimodal distribution for the latter pair was produced, which showed that the CO2 feed rate had a more dominant impact on defining the size distribution than temperature. The dominancy of the CO2 feed rate was also seen in the B−H and F-G sample pairs, where the size distributions became unimodal when the process temperature was higher. The effect of temperature on the precipitated particles also can be explained through the competition between the nucleation and growth dynamics. Increasing the temperature induces a solubility increment in organic solvents; this is followed by the movement of supersaturation toward the critical line.20 In addition, the temperature augmentation changes the shape of precipitated particles in the GAS process. In other words, the decline of supersaturation induced by the increase in temperature corresponded with the decrease in volumetric expansion rate, which provided the opportunity for the particles to grow and, thus, produced broad size distributions.15 3.3. Effect of Concentration. The current study sought the influence of initial solute concentration (mass fraction) on the mean particle size and size distribution at two levels

(0.2 and 0.27 g solute/g solution). Based on the results provided in Table 3 and Figure 9, initial concentration of aspirin in the solution had a direct impact on the mean particle size and resulted in broader PSDs. For samples D1 and G1 produced from methanol, higher concentrations led to an uncontrolled supersaturation generation in the system, which caused a third burst of nucleation. In addition, increasing the concentration in samples B1 and I1 resulted in larger mean size with broader size distributions. The significance of the aspirin concentration on acetoneprecipitated samples is observed in Figure 10. The concentration rise contributed to particle growth from 48 μm to 124 μm; and made the size distributions bimodal and broader. These outcomes can be studied in the light of nucleation and growth kinetics. At higher concentrations, due to rapid precipitation of particles, the growth during the process was higher. In contrast, at lower concentration values, the precipitation happens later and the dominant nucleation resulted in the production of fine particles. It can be acclaimed that primary nucleation was less sensitive to the solute concentration, compared to secondary nucleation.15 At higher solute concentrations, 3693


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Figure 12. DSC thermograms of aspirin precipitated from methanol and acetone.

compared to the unprocessed sample, which indicate a more crystalline structure of the solids. The patterns show that the aspirin particles crystallized from methanol retained their crystallinity and they were pure crystals, while the crystallinity of the particles precipitated from acetone was more as the peaks were sharper. The difference between the morphology and the crystallinity of crystals produced from different solvents was studied by Gallagher et al.51 and Müller et al.20 The diverse morphologies observed in various research have been related either to the interaction between the solvent and the growing crystal surface or to the presence of solvent in the solute lattice. Relative intensity in the pattern explains the molecular arrangement at each orientation. The difference observed in the peak intensities of the produced crystals may be due to the impact of the primary solvent on the molecular arrangement during precipitation. The DSC analysis is carried out with the objective of assessing the crystallinity and the thermal stability of the crystallized pharmaceutical particles by the measurement of the temperature and energy variations occurred during the solid phase transitions.52 The size and the shape of the DSC peak were considered for the investigation of the solid-state crystallinity. In addition, changes made to the reprocessed drug compound could affect their efficacy. The DSC thermograms in Figure 12 show that the melting point of the aspirin particles precipitated via the GAS process was almost the same as that of unprocessed material. As it can be observed, aspirin showed sharp endothermic peaks at 134.7, 138.24, and 136.51 °C for the unprocessed sample and the samples produced from methanol and acetone, respectively. The heats of fusion were −179.23 J/g and −181.21 J/g for samples crystallized from methanol and acetone, respectively. A similar DSC result has been reported for aspirin in the literature.52 The absence of a secondary peak in DSC thermograms indicated that the solvent content in the crystals was negligible, which was in agreement with the FDA guidelines for the solvent residual minimization in pharmaceutical products. As it can be seen in the thermograms,

the supersaturation profile had a tendency to be closer to the saturation line and induced the primary nucleation; therefore, the particles produced during the burst of primary nucleation had the time to grow. Therefore, the growth mechanism was predominant over the secondary nucleation, which resulted in the precipitation of larger particles with broad size distributions. 3.4. The Solvent Impact. The purpose of studying the solvent role was to determine its impact on the growth mechanism and crystal characteristics, which has been the subject of much research. The degree of crystallinity of precipitated fine particles is important, because it has a significant impact on the growth mechanism during the process and defines the characteristics of the final pharmaceutical product. As previously mentioned, two organic solvents (namely, methanol and acetone) were used for the comparison of the degree of crystallinity of aspirin particles. The particles that precipitated from the solvents mainly had a needlelike form. XRD patterns of samples from both solvents and the unprocessed aspirin are shown in Figure 11. Peaks observed from the analysis were identical to those observed at diffraction angles of the reference pattern for aspirin and in agreement with the results obtained by Huang et al.46 Furthermore, sharp peaks, especially at 2θ ≈ 15°, indicate the crystalline structure of the produced aspirin. The comparison between XRD patterns for all three samples showed different peak intensities at diffraction angles (2θ). The unprocessed raw aspirin presented minor diffractions at 2θ = 20.86°, 20.98°, 32.9°, and 42.24°; and major peaks at 2θ = 8.1°, 15.82°, 22.86°, and 31.3°. The GAS final product from methanol had minor diffractions at 2θ = 23.06°, 26.82°, and 31.3°, whereas for the sample from acetone, they were at 2θ = 20.42°, 28.78°, 31.32°, and 32.44°. The major peaks for the former were observed at 2θ = 7.64° and 15.46°; the major peaks for the latter are observed at 2θ = 7.7°, 15.48°, 22.48°, 23.02°, and 26.9°. What is significant in these results is that all the samples had one major peak at

Gas-Antisolvent (GAS) Crystallization of Aspirin Using Supercritical

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