Dimensionless Entropy of Fusion as a Simple Criterion To Predict

Article pubs.acs.org/crystal

Dimensionless Entropy of Fusion as a Simple Criterion To Predict Agglomeration in the Supercritical Antisolvent Process Tae Jun Yoon,‡ Yong-Suk Youn,‡ Won-Su Son, Bumjoon Seo, Ki Ho Ahn, and Youn-Woo Lee* School of Chemical and Biological Engineering and Institute of Chemical Processes, Seoul National University, 1 Gwananak-ro, Gwanak-gu, Seoul 151-744, Republic of Korea ABSTRACT: The aim of this work was to understand the agglomeration phenomenon and to predict the agglomeration behavior of materials in the supercritical antisolvent (SAS) process. Carbon dioxide-induced melting point depression is believed to be one of the major causes of the formation of agglomerates during the SAS process. Here, we attempted to observe the CO2-induced melting behaviors of nine target materials and to recrystallize them in the SAS process. On the basis of the multicomponent Clapeyron equation, which describes the interaction between solute and carbon dioxide, the thermodynamic properties of 32 materials were investigated to correlate melting point depression with the agglomeration phenomenon. In this analysis, the dimensionless entropy of fusion was utilized as a simple criterion to predict agglomeration behavior. The extent of melting point depression was assumed to be inversely proportional to the entropy of fusion of the solute. This assumption enables us to predict the agglomeration behavior of recrystallized pharmaceuticals with dimensionless entropy of fusion during the SAS process. Furthermore, a correlation between the tendency of agglomeration and whether the recrystallized particles have either faceted or nonfaceted form was observed.

1. INTRODUCTION Scientists and engineers have extensively examined the recrystallization processes using supercritical fluids for the processing of pharmaceutical compounds.1,2 In these processes, supercritical carbon dioxide has mainly been used as a solvent or an antisolvent due to its nonflammability, mild operating condition, and nontoxicity. In this work, supercritical carbon dioxide was used as an antisolvent. The supercritical antisolvent (SAS) process exploits the ability of carbon dioxide to dissolve in organic liquids and to lower the solvent power of the liquid for compounds in solution, which results in the precipitation or crystallization of solid drugs.3 Many pharmaceuticals have been successfully recrystallized using the SAS process.4−6 However, some of the materials such as valsartan and tetracycline hydrochloride form agglomerates during this process.7,8 The agglomeration phenomenon can be defined as a secondary structure in which primary particles are connected to each other by a solid bridge.9 When agglomeration occurs, the surface to volume ratio randomly decreases and the particle size distribution is broadened. As a result, unwanted agglomeration makes it difficult to control the dissolution rate of pharmaceuticals and its physicochemical properties.7 Several attempts have been devoted to explain the agglomeration mechanism and to prevent the unwanted agglomeration phenomenon under different operating conditions during the SAS process. York reported that operating parameters such as pressure, temperature, solute/solvent interaction, nozzle geometry, and solute concentration were closely related to agglomeration. He argued that rapid initial supersaturation could prevent agglomeration in the SAS process.10 © 2013 American Chemical Society

On the other hand, Bleich et al. recrystallized poly (L-lactide) (PLLA) in a mixture of dichloromethane/methanol (85:15) and carbon dioxide. They found that the tendency for agglomeration increased when the operating temperature was higher than the glass transition temperature of the materials. The agglomerates obtained at an operating temperature higher than the glass transition temperature had different properties from those produced at a lower operating temperature. They concluded that there was a correlation between operating parameters, particle size, and distribution and agglomeration phenomenon; however, they did not determine the mechanism of agglomeration.11 Apart from the aforementioned studies, this study suggests CO2-induced melting point depression at a high-pressure region is one of the major factors causing agglomeration of solutes in the SAS process. So far, there have been many studies on CO2-induced melting point depression of both polymeric and nonpolymeric compounds. Weidner et al. measured the melting point depression of polyethyleneglycols at different pressure conditions,12 and Takahashi et al. used an optical view cell to observe the carbon dioxide-induced melting behavior of biodegradable polyesters, such as poly(ε-caprolactone), poly(3hydroxybutyrate), and poly(3-hydroxybutyrate-co-3-hydroxyvalerate).13 Likewise, Grandelli et al. measured CO2-induced melting depression of piroxicam, a nonpolymeric compound, in a mixture of supercritical carbon dioxide and organic solvent.14 Knez et al. measured melting point depression of vitamin D2, D3, and K3 in a high-pressure carbon dioxide atmosphere.15 By Received: March 13, 2013 Revised: July 1, 2013 Published: July 3, 2013 3481

dx.doi.org/10.1021/cg400374a | Cryst. Growth Des. 2013, 13, 3481−3489

Crystal Growth & Design

Article

discussed in the following section. Dimensionless entropy of fusion, also called Jackson’s α factor, has been used to predict whether the particles obtained from equilibrium crystallization process were either in a faceted or in a nonfaceted form. Jackson suggested that ΔSm/R = 2 is a criterion value of whether a crystal has faceted or nonfaceted forms in the equilibrium crystallization process.18

using multicomponent Clapeyron equation, Lian et al. developed a mathematical formulation of CO2-induced melting point depression of polymeric and nonpolymeric materials in both low- and high-pressure regions. 16 This equation represented a simplified multicomponent Clapeyron equation at a low-pressure region in the form of eq 1.

dTm = dP

1 SC ∑ xiSCHiSC xuSC xCO2 T 1 L ∑ xiLHiL xuL xCO2 T 1 S ∑ xiSHiS xuS xCO2 T SC V SC x uSC xCO2

VL

L x uL xCO2

VS

S x uS xCO2

2. EXPERIMENTAL SECTION

≈−

2.1. Materials. Ampicillin anhydrous (96−100.5%, Product No A9393), xylitol (≥99% Product No X3375), polyethylene glycol 6000 (PEG 6000, Product No 81260), and tetracycline hydrochloride (min 95%, Product No T3383) were purchased from Sigma Aldrich, Korea. Valsartan was supplied by Yuyu Pharm. Inc., Korea. Clarithromycin, cetirizine dihydrochloride, and cefpodoxime proxetil were supplied by Hanmi Fine Chemical Product Co., Korea. Ethyl alcohol (99.5%), methyl alcohol (99.5%), dichloromethane (99.5%), acetone (99.7%), and ethyl acetate (99.5%) were purchased from Samchun Pure Chemical Co. Ltd., Korea. Carbon dioxide (99.0%) was purchased from Hyup-Shin Gas Industry Co., Korea. Additional purification was not conducted for all of the materials. 2.2. Optical View Cell. A schematic of the optical view cell used to observe the melting point depression is shown in Figure 1.

ZRkHTm 2 ΔHm

(1)

Although there have been many studies on CO2-induced melting point depression, the correlation between agglomeration phenomenon and melting point depression has been rarely mentioned in previous studies. Youn et al. reported that less agglomerated valsartan particles were obtained at a low operating temperature.7 They used liquid carbon dioxide as an antisolvent and successfully increased the dissolution rate of nonagglomerated valsartan particles. Liparoti et al. observed a partial softening of polyethylene glycol (PEG) 10000 and 6000 in the supercritical assisted atomization process. They found that the amount of PEG 6000 agglomerates gradually increased as the operating pressure increased. They successfully obtained nonagglomerated and spherical PEG 10000 particles from a supercritical assisted atomization (SAA) process under reduced pressure and temperature.17 Therefore, the goals of this study were to determine the relationship between the agglomeration phenomena and CO2induced melting point depression and to predict the agglomeration behavior of a solute in the SAS process. To better understand the relationship between the agglomeration behavior and melting point depression, an optical view cell was used to observe the melting behavior of nine unprocessed materials in a high-pressure carbon dioxide atmosphere. To develop a method to predict the agglomeration behavior of SAS-processed pharmaceuticals, the multicomponent Clapeyron equation that had been simplified by Lian et al. was used. As shown in eq 1, there are several operating parameters and thermodynamic properties of a solute in the simplified Clapeyron equation. To elicit what innate property was germane to the agglomeration behavior of solutes in the SAS process, it was assumed that the contribution of Henry’s constants and compressibility factors to the extent of melting point depression was minor. Thus, the extent of melting point depression was assumed to be inversely proportional to dimensionless entropy of fusion. If the agglomeration phenomenon has a causal relationship with the extent of carbon dioxide-induced melting point depression, pharmaceuticals with a small value of dimensionless entropy of fusion will have a greater chance to become agglomerated than materials that have large values of dimensionless entropy of fusion. The physical meaning of dimensionless entropy of fusion will be

Figure 1. Optical cell used to observe the melting behavior of solutes in a glass capillary tube: (a) high-pressure vessel, (b) sight glass, (c) capillary glass tube with substance, (d) piston, (e) heating bath, (f) pressure generator, (g) heat transfer jackets, (h) CO2 carrier, (i) CCD camera, and (j) computer. Approximately 0.3 mg of sample was placed on the center of a narrow capillary (inner diameter 0.2 mm, sodium-heparinized, Marienfeld). The sample-loaded capillary was placed around the entrance of the cell; a metal cylindrical container was used for PEG 6000. The cell was designed to withstand pressures up to 500 bar. After the capillary was located at the entrance, the cell was filled with liquid carbon dioxide up to 72 bar at room temperature. By considering the operation condition of SAS process, the experimental temperature range was selected to range from 293 to 343 K. The cell was heated from room temperature, and the melting behaviors of the sample were recorded at 10 K intervals. When the cell was heated, the volume of the optical cell was unchanged, and the inner pressure of the cell increased. The inner pressure of the cell was measured using a microprocessor-based pressure-transducer (SM 21-R, Instech), and a thermocouple was used to measure temperature. The melting behavior of the samples was recorded using a HAD CCD camera (ICS-305B, Sometech). 2.3. Supercritical Antisolvent (SAS) Apparatus. A basic scheme of the SAS apparatus used in the previous work is shown in Figure 2. The apparatus consisted of two high-pressure plunger pumps to supply organic solvents and carbon dioxide, a precipitator, a filter, and 3482



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Figure 3. Observation of melting point depression induced by carbon dioxide: (a) polyethylene glycol 6000, (b) cefpodoxime proxetil, and (c) valsartan.

Figure 2. Schematic diagram of the ASES apparatus: (a) CO2 cylinder, (b) cooling bath, (c) CO2 pump, (d) heating bath, (e) preheater, (f) precipitator with sight glasses, (g) heat transfer jackets, (h) T-type filters, (i) back pressure regulator with heater, (j) solution pump, (k) solution reservoir, (l) vent, and (m) thermostat air bath.

temperature of 318 K. During liquefaction, the faceted shapes disappeared and became rounded and amalgamation between particles occurred. As the melting process continued, a totally molten form of PEG 6000 was observed at 169 bar and 323 K. The molten polymer was observed to have a meniscus with negative curvature. The melting point and pressure measured were consistent with the result of Kukova et al.19 The melting behavior of unprocessed cefpodoxime proxetil is presented in Figure 3b. At the initial condition of 88 bar and 298 K, the center of the capillary was filled with solid cefpodoxime proxetil. Those particles were observed as a form of white powders. A change in the sample was first observed at a pressure of 136 bar and temperature of 313 K. A liquid layer of cefpodoxime proxetil was not observed, but the size of the packed particles decreased as the melting process was continued. When the operation temperature was increased, the extent of shrinkage increased. At a pressure of 194 bar and temperature of 328 K, most of the particles were stuck to one side of the capillary wall, and the surface of the particles adopted a glittery appearance. Figure 3c shows the melting behavior of unprocessed valsartan. Until the temperature reached 333 K, there was no evidence that phase transformation had occurred. After 1 h, at 231 bar and 333 K, a translucent liquid layer appeared around the solid valsartan particles. As the temperature was increased further, the solid particles disappeared, and the translucent liquid layer and an opaque molten layer of valsartan were observed. The portion of liquid or molten-state layer increased as the temperature was increased up to 343 K. Although the melting phenomenon induced by supercritical carbon dioxide was observed at high pressure, the processed materials were expected to have a larger extent of melting point depression due to a reduction in the crystallinity of the solutes in the SAS process. Figure 4 shows a thermogram of unprocessed valsartan and SAS-processed valsartan recrystallized at 100 bar and 313 K. The thermodynamic properties of valsartan were largely changed: the melting point was changed from 370 to 335 K. The molar enthalpy of fusion was changed from 11.15 to 3.25 kJ/mol. The sharp peak of unprocessed valsartan became broader and smaller after the SAS process. This means that the crystal structure of valsartan was largely changed after the SAS process. A reduction in the crystallinity was likely due to the large supersaturation induced by supercritical carbon dioxide. Generally, a large supersaturation leads to the formation of an

a separator. The volume of the vessel was 60 mL, and it was made of SUS 316. A recrystallization or precipitation process can be observed via the high-pressure glass. The operating temperature was controlled using heat transfer jackets. The operating temperature was measured using two K-type thermocouples and recorded with a strip chart recorder (μR 100, Yokogawa, Japan). A pressure regulator (26-172124, Tescom, U.S.) was used to control the operating pressure. Hydrophobic fluoropore membrane, PTFE, with pore size of 0.45 μm from Millipore was used as a filter paper. After the operating pressure and temperature were stabilized, organic solution was sprayed into the precipitator at the desired flow rate. The injection nozzle with an inner diameter of 0.01 in. was used, and no premixing was applied before the organic solutions are sprayed into the precipitator. After all of the solution was supplied, the product in the filter was washed with only carbon dioxide to remove residual solvent entrapped in the precipitated particles. After the washing step, the filter and the precipitator were depressurized, and the filter was separated from the apparatus. From the separated filter, the particles were taken out. 2.4. Analytical Methods. Field emission scanning electron microscopy (FE-SEM, model SUPRA 55VP, Carl Zeiss, Germany) was used to observe the agglomeration behavior of particles. Some of samples were properly dispersed on a carbon tape glued to an aluminum pan. It was then coated with gold and palladium using a sputtering coating machine. Thermodynamic properties of samples were measured with a differential scanning calorimeter (model DSCQ100, TA Instruments, UK). Samples were weighed accurately and placed on the bottom of the aluminum pan so that the entire bottom was covered with sample to ensure good thermal contact. The type of pans used was an aluminum and nonhermetic pan. The temperature heating rate was 5 K/min for every material. Linear peak integration method was used to characterize the melting temperature and enthalpy of fusion. The peak temperature was set to be the normal melting point, and the enthalpy of fusion (kJ/mol) was calculated by peak integration.

3. RESULTS AND DISCUSSION 3.1. CO2-Induced Melting Point Depression. The melting behaviors of nine target materials induced by supercritical carbon dioxide were observed. In these experiments, only PEG 6000, valsartan, and cefpodoxime proxetil were liquefied in the temperature range from 298 to 343 K. Figure 3a shows the melting behavior of PEG 6000. At the initial condition of 66 bar and 294 K, solid PEG 6000 particles show faceted shapes and appeared opaque. As the temperature was increased, the melting phenomenon of solid surface of PEG 6000 particles was first observed at a pressure of 153 bar and 3483



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experimental conditions are provided in Table 1. When determining the experimental conditions, the washing time, solvent/antisolvent ratio, and operating pressure were first set to minimize the effect of the residual solvent because it has been reported that residual solvent has a great effect on the agglomeration behavior.22 Taking into consideration that most of the residual solvent is removed from the processed materials due to great extractability of supercritical carbon dioxide in a few minutes, 20 min of washing time was chosen; Chu measured that amount of dichloromethane in the recrystallized cefpodoxime proxetil. He reported that less than 10 min of washing time was required to remove residual solvent.23 The antisolvent/solvent ratio was set to be 40−100. This ratio was set to be higher than 50 for the materials with large amount of residual solvent such as ampicillin anhydrous, valsartan, and cetirizine dihydrochloride. The operating temperature and pressure were set to 313 K and 100 bar, respectively; however, cetirizine dihydrochloride was recrystallized at a pressure of 150 bar to prevent agglomeration induced by residual solvent. As shown in Figure 6, valsartan (a), cefpodoxime proxetil (b), PEG 6000 (c), and tetracycline hydrochloride (d) were obtained as severe agglomerates. The shapes of the valsartan and PEG 6000 agglomerates were irregular. The primary and secondary structures of those materials were not observed. This result means that severe agglomeration induced by partial melting occurred. To distinguish whether the agglomerates were formed by partial melting or solute−solvent interaction, time of washing was varied to verify that partial melting of the processed materials mainly causes the agglomeration.

Figure 4. DSC thermogram of unprocessed and processed valsartan.

imperfect and irregular crystal structure.20 However, the valsartan obtained did not take purely amorphous form; Rukhman et al. reported that purely amorphous valsartan shows no endothermic peak or polymorphic transformation under 373 K.21 It can be determined that a broad endothermic peak around 333 K indicates the processed valsartan takes essentially amorphous form, which contains a small amount of crystalline valsartan as impurity. Youn et al. examined the melting behavior of SAS-processed valsartan, which was recrystallized at 100 bar and 313 K. The recrystallized valsartan started melting at 70 bar and 328 K in the supercritical carbon dioxide atmosphere in the work.7 3.2. Agglomeration, Faceted/Nonfaceted Crystals, and Dimensionless Entropy of Fusion. Figure 5 shows SEM images of the unprocessed materials. A series of SAS experiments were conducted to evaluate the agglomeration behavior of processed particles. The SAS

Figure 5. SEM images of unprocessed materials: (a) valsartan, (b) cefpodoxime proxetil, (c) PEG 6000, (d) tetracycline hydrochloride, (e) ampicillin anhydrous, (f) clarithromycin, (g) xylitol, (h) cetirizine, and (i) itraconazole. 3484



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Table 1. A Summary of the Experiments Performed solute

solvent

C (wt %)

P (bar)

T (K)

FCO2 (g/min)

Fsolution (g/min)

valsartan PEG 6000 tetracycline hydrochloride ampicillin anhydrous cefpodoxime proxetil xylitol clarithromycin itraconazole cetirizine dihydrochloride

ethyl acetate acetone ethanol methanol dichloromethane DMSO ethyl acetate dichloromethane DMSO

1 1 1 1 1 2 2 2 2

100 100 100 100 100 100 100 100 150

313 313 313 313 313 313 313 313 313

40 50 50 100 50 50 40 40 100

0.5 1.0 1.0 1.0 0.5 1.0 1.0 1.0 1.0

figures Figure Figure Figure Figure Figure Figure Figure Figure Figure

6a 6b 6c 6d 6e 6f 6g 6h 6i

Figure 6. SEM images of processed compounds: (a) valsartan, (b) cefpodoxime proxetil, (c) PEG 6000, (d) tetracycline hydrochloride, (e) ampicillin anhydrous, (f) clarithromycin, (g) xylitol, (h) cetirizine, and (i) itraconazole.

ginger-like forms, interconnected spherical particles, and bridges were observed. Ampicillin anhydrous (e) and cetirizine dihydrochloride (h) were slightly agglomerated and tended to be in nonfaceted forms. In addition, faceted forms of clarithromycin (f), xylitol (g), and itraconazole (i) were obtained. The particles that adopted a faceted form tended to be larger than nonfaceted precipitates. Clarithromycin particles (f) were obtained as a cubic form, and xylitol particles (g) were in stubby or tabular forms. Itraconazole (i) was obtained as platy particles whose edges were roughened. These results indicate that all three materials including valsartan, cefpodoxime proxetil, and PEG 6000, which showed CO2-induced melting point depression, were obtained as severe agglomerates. In addition, tetracycline hydrochloride was also shown to form agglomerates. As deduced from the simplified multicomponent Clapeyron equation, the correlation of the agglomeration behavior with melting point depression could be analyzed on the basis of the dimensionless entropy of fusion per mole. Thus, the thermodynamic properties of 32 kinds of materials and SEM images of those materials were compared.

Figure 7 shows that longer time of washing makes the distinction between primary and secondary structure of valsartan vanish. In addition, it indicates that severe agglomeration of those materials is mainly caused by partial melting, not by solute−solvent interaction or Ostwald ripening. As mentioned earlier, due to great extractability of supercritical carbon dioxide, most of the residual solvent in the processed materials is removed during washing step. However, as shown in Figure 7, severe agglomeration occurred between primary particles even when most of the residual solvent is removed. This agglomeration behavior cannot be attributed to Ostwald ripening because Ostwald ripening or partial dissolution− precipitation of the processed materials can happen only when the processed material is dissolved in the supercritical carbon dioxide; however, all of the materials show poor solubility in the pure supercritical carbon dioxide. Spherical primary particles of processed tetracycline hydrochloride and cefpodoxime proxetil were observed, and they showed a distinct secondary structure, interconnecting solid bridges among particles. As a result of agglomeration, several 3485



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Figure 7. SEM images of valsartan particles obtained by ASES show degree of agglomeration by time with condition of supercritical antisolvent (T, 313 K; P, 100 bar; C, 2 wt %; Dnozzle, 0.01 in.; flow rate of CO2, 40 g/min; flow rate of solution, 0.5 g/min).24

Table 2. Correlation between Thermodynamic Data and the Agglomeration Behavior no.

material

Tm (K)

ΔHm (kJ/mol)

ΔSm/R

1 2 3 4 5 6

nalmefene hydrochloride rifampicin (amorphous) rifampicin II cefpdoxoime proxetil PEG 6000a valsartan poly(L-lactic acid)a

456.4225 462.526 467.026 373.00 332.6016 369.56 448.0016

0.3425 0.5426 29.7226 4.06 8.2916 11.15 14.616

0.0892 0.1413 7.6538 1.3092 2.9979 3.6301 3.9198

amoxicillin trihydrate tetracycline hydrochloride carbamazepine I paracetamol II p-hyroxybenzoic acid sulfabenzamide A budesonide ampicillin anhydrous sulfamethizole piroxicam simvastatin diuron griseofulvin hydrocortisone I (S)-sodium ibuprofen clarithromycin xylitol cilostazol A cetirizine dihydrochloride chlorphenirarmine maleate itraconazole loperamide hydrochloride ipratropium bromide fluconazole anhydrous I albuterol sulfate

463.1030 490.0032 463.0033 430.0035 487.0037 454.0039 534.0041 478.0043 482.0044 472.8045 412.5047 429.7048 492.6050 497.7051 506.8053 492.96 367.47 432.0054 490.89 406.00 441.97 501.00 505.8357 412.2158 477.0057

7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 24 25 26 27 28 29 30 31 32 a

16.4430 27.6932 26.4033 26.5035 31.4037 29.5039 34.7041 33.8943 34.8644 34.5445 32.3947 33.8948 39.5150 44.6551 43.8953 48.91 38.16 47.1854 55.93 47.70 55.34 64.96 85.1157 84.7558 115.3457

4.2694 6.7970 6.8582 7.4125 7.7552 7.8155 7.8159 8.5278 8.6989 8.7869 9.4454 9.4864 9.6473 10.7096 10.4165 11.8373 12.4901 13.1360 13.7029 14.1306 15.0592 15.5949 20.2374 24.7284 29.0838

agglomeration behavior severely agglomerated25 severely/nonagglomerated27 severely agglomerated severely agglomerated severely agglomerated severely28/moderately29 agglomerated severely/nonagglomerated31 moderately agglomerated nonagglomerated34 nonagglomerated36 nonagglomerated38 nonagglomerated40 moderately agglomerated42 moderately agglomerated nonagglomerated44 nonagglomerated46 nonagglomerated47 nonagglomerated49 nonagglomerated50 nonagglomerated52 nonagglomerated20 nonagglomerated nonagglomerated moderately agglomerated55 moderately agglomerated nonagglomerated56 nonagglomerated nonagglomerated7 nonagglomerated57 nonagglomerated59 nonagglomerated57

crystal form nonfaceted25 nonfaceted27 nonfaceted nonfaceted nonfaceted nonfaceted28,29 nonfaceted31 nonfaceted faceted34 faceted36 faceted38 faceted40 nonfaceted42 nonfaceted faceted44 faceted46 faceted47 faceted49 faceted50 faceted52 faceted20 faceted faceted faceted55 nonfaceted faceted56 faceted faceted7 faceted57 faceted59 faceted57

Enthalpy of fusion of Kuhn monomer unit was used.

used to predict agglomeration behavior because measuring the molar enthalpy of fusion and melting temperature in an atmosphere of supercritical carbon dioxide was problematic. Therefore, data from unprocessed materials were used for the prediction. The materials whose melting temperature and heat

Many of the thermodynamic properties of unprocessed materials were estimated from differential scanning calorimeter or previous studies. Although the thermodynamic properties of materials, such as valsartan and ibuprofen sodium,20 change after the SAS process, those of the unprocessed materials were 3486



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of fusion (J/g) were measured by DSC were cefpodoxime proxetil, valsartan, PEG 6000, clarithromycin, xylitol, cetirizine dihydrochloride, chlorpheniramine maleate, itraconazole, and loperamide hydrochloride. It was difficult to obtain the enthalpy of fusion and normal melting point of tetracycline hydrochloride and ampicillin anhydrous from differential scanning calorimeter. It is highly probable that tetracycline hydrochloride decomposes before melting.60 Therefore, the enthalpy of fusion and melting point were estimated using Yalkowsky’s method. Yalkowsky showed that most of the pharmaceuticals and rigid molecules with intermediate size have ΔSm = 56.51 J/mol·K.32 The thermodynamic data used for the analysis of ampicillin anhydrous were obtained from the study by Liu et al.43 The enthalpy of fusion of polymeric materials such as PEG 6000 and poly (L-lactic acid) was calculated by multiplying the measured enthalpy of fusion (J/g) with the Kuhn segment weight as proposed by Lian et al. They proposed that Kuhn monomer unit can be adopted to explain crystallization behavior of polymeric materials.16 The thermodynamic properties and SEM images of other materials not recrystallized in this work were also investigated. The SEM images of the processed materials or the description by the authors were used to determine whether the processed particles formed agglomerates or not. A processed material was classified as nonagglomerated if solid bridges or interconnected particles were not observed. Table 2 contains the normal melting point, molar enthalpy of fusion, dimensionless entropy of fusion, and structural characters of recrystallized materials. As shown in Table 2, the agglomeration phenomenon rarely occurred when the dimensionless entropy of fusion increased. Specifically, unprocessed materials with ΔSm/R ≤ 5 were frequently obtained as agglomerates. Other materials with 5 ≤ ΔSm/R ≤ 7 were either agglomerated slightly or nonagglomerated. When the dimensionless entropy of fusion was larger than 7, no agglomeration occurred and most of the materials displayed faceted growth. This criterion value, ΔSm/R = 7, is higher than Jackson suggested; he suggested that compounds with ΔSm/R > 2 normally show faceted growth. Granted, some of the materials showed deviation from the tendency of agglomeration as well as a formation of the faceted/nonfaceted particles. To illustrate, cilostazol form A had a high entropy of fusion value but was obtained as agglomerates in the previous study.55 Ampicillin anhydrous and cetirizine dihydrochloride, which have high entropy of fusion, were also obtained as spherical particles, which are slightly agglomerated. It is possible that one of the major reasons for this discrepancy was that the thermodynamic properties of unprocessed materials were used. As mentioned earlier, large supersaturation induced by supercritical carbon dioxide leads to a reduction in the crystallinity of particles. In the case of the processed materials in this study, DSC measurement indicated that valsartan, PEG 6000, cefpodoxime proxetil, xylitol, clarithromycin, itraconazole, and cetirizine dihydrochloride showed lower crystallinity than unprocessed ones; all of the materials showed a decrease in the molar enthalpy of fusion value and melting temperature. Table 3 shows the melting temperature and molar enthalpy of fusion value of the processed materials. As for PEG 6000, split peaks were shown, which means that processed PEG 6000 contains different polymorphic forms. Processed cetirizine dihyodrochloride showed a largely broadened peak under normal

Table 3. Thermal Characteristics of Processed Materials processed materials

Tm (K)

ΔHm (kJ/mol)

valsartan PEG 6000a cefpodoxime proxetil xylitol clarithromycin itraconazole cetirizine dihydrochlorideb

335.10 332.71/335.27 371.17 362.62 498.76 440.2 483.13

3.25 8.43 2.94 21.48 46.27 47.01 49.03

a Splitting of melting peak was detected. bA largely broadened peak under normal melting point was detected.

melting point. The thermograms of processed tetracycline hydrochloride and ampicillin anhydrous were not able to be obtained due to degradation before melting. It seems that the extent of reduction of solute crystallinity after SAS process is different for each material: some pharmaceuticals, such as valsartan7 and cefpodoxime proxetil,61 showed significant reduction of crystallinity. On the other hand, the processed materials such as PEG 1000017 and atenolol62 only showed a slight change of crystallinity. As for cetirizine dihydrochloride, both a largely broadened peak under normal melting point and the melting peak were detected. Quantitative analysis on the amorphization of the processed materials should be studied further. Although the use of entropy of fusion value of the unprocessed materials can make it uncertain to classify materials with entropy of fusion, transition of the criterion value from ΔSm/R = 2 to ΔSm/R = 7 indicates that an amorphization effect is taken into consideration to some extent. The other potential reason for this discrepancy was the fact that the solute/solvent interaction was ignored in this work. As a rule, inclusion of solvent molecules in the solid lattice and solvent/solute interaction has a significant impact on crystal morphology.63 Obviously, it is expected that partial melting or softening of the processed materials in the supercritical carbon dioxide atmosphere will not affect the agglomeration behavior when ΔSm/R of the materials is enough high to prevent the melting temperature from placing around the operation temperature. Instead, solvent/solute interaction would play a significant role in occurring agglomeration between substances with large entropy of fusion value. Despite those decencies, the findings of this study indicate that the dimensionless fusion enthalpy of solute, an innate property of unprocessed materials, should be considered when predicting agglomeration behavior. In addition, as mentioned earlier, Table 2 shows that there was a correlation between dimensionless entropy of fusion and whether or not faceted or nonfaceted crystal appeared. When the melting entropy of a solute was small, nonfaceted crystals were usually obtained. When the melting entropy value was greater than 7, faceted particles were usually obtained from the SAS process. It seems that there is a significant relationship between agglomeration behavior and the shape of the processed materials. Scheme 1 shows the growth of particles and agglomeration phenomenon of nonfaceted and faceted particles in the SAS process. Scheme 1a shows a schematic of the formation of primary and secondary structure of particles with low entropy of fusion. Particles with low entropy of fusion have a rough surface; thus, there are a lot of favorable binding sites for the attachment of molecules.64 This leads to crystal growth without orientation, and round-shaped primary particles are obtained. As the 3487



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Scheme 1. Correlation between Faceted/Nonfaceted Crystal Formation and the Agglomeration Behavior: (a) Growth of Nonfaceted Particles, and (b) Growth of Faceted Particles

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AUTHOR INFORMATION

Corresponding Author

*Phone: +82-2-880-1883. Fax: +82-2-883-9124. E-mail: [email protected]. Author Contributions ‡

These authors contributed equally.

Notes

The authors declare no competing financial interest.

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ABBREVIATIONS

■

REFERENCES

ΔHm, enthalpy of fusion (kJ/mol); ΔSm, entropy of fusion (J/ mol K); kH, Henry’s constant; R, universal gas constant (J/mol K); Tm, melting point (K); Z, compressibility factor; T, operation temperature (K); P, operation pressure (bar); C, weight concentration (wt %); Dnozzle, diameter of the nozzle used (in.)

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particles grow, antisolvent/solute interactions induce melting point depression of the solute, which results in the formation of agglomerates, a secondary structure. Scheme 1b shows the growth of faceted particles with high entropy of fusion. A disparity in growth rates between the low index planes and high-index planes results from a high melting entropy of solute.64 This restricts the number of favorable binding sites; thus, crystal growth with specific orientation occurs. As a result, faceted primary particles are obtained, and the probability for the formation of a secondary structure is lower than the nonfaceted particles due to the high entropy of fusion.

4. CONCLUSION In this study, a correlation between the agglomeration phenomenon and dimensionless entropy of fusion was shown on the basis of the hypothesis that CO2-induced melting point depression is one of major factors resulting in the formation of a secondary structure, called agglomerates, in the SAS process. The melting behavior of nine target materials in the supercritical carbon dioxide was observed, and the melting behaviors of three highly agglomerable materials were observed over the experimental temperature range. SEM images and the thermodynamic properties of 32 materials were investigated. On the basis of the analysis, the agglomeration phenomenon and the formation of faceted/nonfaceted particles in the SAS process were found to be highly dependent on the dimensionless melting entropy of the solute. It was estimated that the transition from agglomerated/nonfaceted particles to nonagglomerated/faceted particles occurs when ΔSm/R has a value ranging from five to seven. 3488



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Dimensionless Entropy of Fusion as a Simple Criterion To Predict

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