Agglomeration Mechanism of Azithromycin Dihydrate in Acetone

Apr 13, 2016 - The solubilities and crystallization processes of azithromycin monohydrate and dihydrate in mixed water + acetone systems were measured...
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Agglomeration Mechanism of Azithromycin Dihydrate in Acetone− Water Mixtures and Optimization of the Powder Properties Songgu Wu,†,‡ Huan Shen,†,‡ Kangli Li,†,‡ Bo Yu,†,‡ Shijie Xu,†,‡ Mingyang Chen,†,‡ Junbo Gong,*,†,‡ and Bao hong Hou†,‡ †

School of Chemical Engineering and Technology, State Key Laboratory of Chemical Engineering, Tianjin University, Tianjin 300072, China ‡ The Co-Innovation Center of Chemistry and Chemical Engineering of Tianjin, Tianjin 300072, China ABSTRACT: The main purpose of this investigation was to investigate the agglomeration mechanism of azithromycin dihydrate in mixed water and acetone systems and improve the powder properties of azithromycin dihydrate. The solubilities and crystallization processes of azithromycin monohydrate and dihydrate in mixed water + acetone systems were measured and investigated. The solubilities of the two hydrates were very close, and the products obtained from water + acetone mixtures were strongly agglomerated. It was found that surface nucleation and growth of dihydrate on monohydrate crystals during the hydrate transformation process were the reasons which caused agglomeration. There was no hydrate transformation during the crystallization process of azithromycin in ethyl acetate, and the products were single crystals. By comparison of the powder properties of agglomerated and nonagglomerated solids, the agglomeration has a serious impact on the crystal size distribution, bulk density, and flowability.

1. INTRODUCTION Azithromycin (C38H72N2O12, CAS Registry No. 83905-01-5) is a macrolide antibiotic derived from erythromycin, with a methyl-substituted nitrogen atom incorporated into the lactone ring, thus making the lactone ring 15-membered.1 It is the first azalide antibiotic.2 It is administered orally, absorbed rapidly, and distributed widely throughout the body, except to the brain. It is used in some countries for the prophylaxis of endocarditis in at-risk patients unable to take penicillin. It is also used in the management of trachoma and typhoid.3 Azithromycin is one of the best-selling antibiotics in the world.4 Its chemical structure is shown in Figure 1. The solid form of azithromycin depends on the solvent used in the crystallization process.5 When the antibiotic is crystallized in a water−acetone mixture, the product obtained is the dihydrate. If the antibiotic is crystallized in a water−alcohol mixture the azithromycin form obtained is the monohydrate. The commercial product is formed of dihydrated crystals.4 Due to its ability to provide high-purity products, crystallization is a widely applied separation technique for solid−liquid mixtures in chemical, petrochemical, food, pharmaceutical, and microelectronics industries.6 Considerable effort has been invested to develop crystallization processes for the production of crystalline compounds with consistent crystal properties, i.e., purity, size, morphology, and size distribution.7 However, the crystal size distribution (CSD) and the crystal shape of the product not only play an important role in determining the product solid-state properties such as © XXXX American Chemical Society

Figure 1. Chemical structure of azithromycin.

separation, flowability, compaction, dissolution, and packing but also have considerable impact on the bioavailability of the active pharmaceutical ingredient.8 The particle size, crystal Received: November 22, 2015 Revised: April 10, 2016 Accepted: April 13, 2016

A

DOI: 10.1021/acs.iecr.5b04437 Ind. Eng. Chem. Res. XXXX, XXX, XXX−XXX

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Å; 40 kV × 100 mA) in a wide-angle X-ray powder diffractometer (model D/max-2500, Rigaku). The scans were collected over an angular range of 2−40°, in 0.05° 2θ increments, and counts were accumulated for 1 s at every step. Crystal Morphology Analysis. The surface morphology of samples was determined using an analytical scanning electron microscope (TM3000, HITACHI, Japan). Crystals were fixed on double sided carbon tape, sputter coated with gold, and imaged using a field emission scanning electron microscope. The samples were monitored, and then an image was generated using a 15 kV electron beam. The crystals in suspension can be analyzed by optical microscopy (Olympus U-CMAD3, Japan) at a suitable magnification. Particle Size Distribution (PSD) Analysis. PSD analysis was carried out to measure the distribution pattern of azithromycin dihydrate crystals. The analysis was carried out using Malvern Instruments Mastersizer 3000 particle size analyzer. The equipment was set to process particle size of 0.020−2000.000 μm. Mie-Scattering analysis model was used for diffraction pattern measurement. Azithromycin dihydrate crystals suspension with water was introduced to a designated vessel. Five measurements were done for each sample, and the average value was taken as the final result. Bulk Density and Flowability Measurement. The free flowability was determined by measure of the angle of repose, which was defined as the angle between the base and slope of a heap of powder formed upon dropping of a certain amount of powder from a given elevation.13 The bulk density was calculated by the volume and weight of the powder. The powder tap density and angle of repose were measured by the powder comprehensive characteristic testing instrument (BT1000, Bettersize instruments Ltd., China). Crystallization Experiments. Crystallization experiments were conducted in a 100 mL glass jacketed crystallizer connected to a thermostat bath. A propeller-type agitator was used to stir the crystallization mixture within the crystallization apparatus at an agitation speed of 200 rpm. For the dilution crystallization experiments, solution concentrations were 33.90 g dihydrate/30 g acetone (molar fraction is x = 0.077, 323.15 K saturated solution) at 323.15 K and 25.18 g dihydrate/40 g acetone (x = 0.044, 298.15 K saturated solution) at 298.15 K for A1 and A2 experiments, respectively. Deionized water was the antisolvent. A total of 15 mL of water was introduced to the two concentrations of the solution in 60 min. The solid has been generated in the solution mixture. Samples were taken and analyzed at 15 min intervals when nuclei appeared. The particles were filtered for analysis of the crystal morphology and phase behavior. Then 20 mL of water was added slowly to the remaining suspension in 200 min. The products were obtained after filtering the suspension. For the cooling crystallization experiment, solution was prepared at 338.15 K by dissolving 20 g of azithromycin dihydrate in 30 g of ethyl acetate (x = 0.069), and the supersaturation was obtained by cooling down the solution to 293.15 K. To reach the final temperature, the system took about 5 h. Samples were taken and analyzed by optical microscopy at 15 min intervals when nucleated.

morphology, and size distribution sometimes can be changed by agglomeration in the crystallization process. Furthermore, agglomeration may lead to a profound effect in final product quality, as well as entrapment of an unacceptable level of occluded solvent, causing difficulties in washing and drying.9 Azithromycin dihydrate crystals have the agglomeration tendency in the water and acetone mixtures during the actual crystallization process. The agglomerated crystals present bad powder properties like flowability and bulk density, which are highly sensitive to sieving, pouring, blending, die-filling, and compaction processes and affect the quality of the final product.10 The coalesced powder cannot satisfy the market need. The main goal of this work is to investigate the agglomeration mechanism of azithromycin dihydrate in water and acetone mixtures and to develop a new crystallization process to obtain the product without aggregation, thereby enabling a better understanding of the crystallization process and improving the powder properties of azithromycin dihydrate. By experiments, we screened out a good solvent ethyl acetate, in which we can obtain the product which meets the requirements.

2. MATERIALS AND METHODS 2.1. Materials. Azithromycin dihydrate and monohydrate, with a mass purity of 99.5%, were supplied by Zhejiang Huaihai Pharmaceutical Co. Ltd., China. Acetone, ethanol, and ethyl acetate were purchased from Tianjin Kewei Chemical Co. Ltd., China (all 99% pure). The solvent was used without further purification. Deionized water was produced using a Millipore system. 2.2. Methods. Solubility of Azithromycin. The solubility of azithromycin monohydrate and dihydrate in the temperature range 283.15−323.15 K was determined by the synthetic method in pure acetone and ethyl acetate and in 10%, 20%, 30%, and 40% by weight water (on a solute-free basis) in water−acetone mixtures. The experiments were carried out in a jacketed crystallizer of about 30 mL. The temperature was controlled by thermostat baths (CF41, Julabo) with uncertainty of ±0.01 K. The apparatus for solubility measurement was the same as that described in the literature.11 A laser beam was used to determine the solubility of the solute in the solvent at a known temperature, and the penetrating intensity of the light was recorded during the measurements. An analytical balance (Mettler Toledo AB204-N, Switzerland) with an accuracy of 0.0001 g was used during the measurement. For each solubility point, known mass of about 15 g of solvent was prepared in the crystallizer and kept at equilibrium temperature. Continuous stirring was achieved with a magnetic stir bar. A predetermined mass of solid solute was added to the crystallizer step by step as far as dissolution was observed. Once the solution under determination was close to its equilibrium state, the mass of single time added of the solute was no more than 0.001 g. The last step was identified when few particles remained in the suspension. The suspension was then maintained under agitation for more than 0.5 h in order to be sure that the particles would no longer dissolve. The light intensity of the laser beam penetrating the vessel was kept lower than the maximum and remained constant when the solution equilibrium was reached, and then the mass value of the total amount of solute added was recorded.12 X-ray Powder Diffractometry (XRD). The sample was filled into a glass holder and exposed to Cu Kα radiation (λ = 1.5406

3. RESULTS AND DISCUSSION 3.1. Solubility. Thermodynamic data, including melting enthalpy, melting entropy, solubility, dissolution enthalpy, and dissolution entropy, are crucial for the design and optimization of the crystallization process for active pharmaceutical B

DOI: 10.1021/acs.iecr.5b04437 Ind. Eng. Chem. Res. XXXX, XXX, XXX−XXX

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Industrial & Engineering Chemistry Research Table 1. Molar Fraction Solubility of Azithromycin Monohydrate in Acetone−Water Solvent Mixture mass fraction of water in the mixed solvent (%) temperature (K)

0.000

10.04

20.08

30.12

39.98

283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15

0.03289 0.03534 0.03859 0.04244 0.04644 0.05123 0.05690 0.06304 0.07206

0.00842 0.00972 0.01121 0.01331 0.01608 0.01950 0.02389 0.02918 0.03582

0.00429 0.00483 0.00542 0.00622 0.00740 0.00907 0.01097 0.01357 0.01707

0.00179 0.00207 0.00236 0.00267 0.00310 0.00365 0.00434 0.00523 0.0065

7.97 × 10−04 9.18 × 10−04 0.00112 0.00123 0.00137 0.00161 0.00195 0.00233 0.00290

Table 2. Molar Fraction Solubility of Azithromycin Dihydrate in Acetone−Water Solvent Mixture mass fraction of water in the mixed solvent (%) temperature (K)

0.000

10.04

20.08

30.12

39.98

283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15

0.03539 0.03750 0.04041 0.04445 0.04900 0.05472 0.06153 0.06732 0.07707

0.00749 0.0089 0.01032 0.01184 0.01398 0.01689 0.02043 0.02467 0.03052

0.00337 0.00416 0.0049 0.00558 0.00622 0.00709 0.00876 0.01071 0.01332

0.00171 0.00192 0.00216 0.00242 0.00285 0.00339 0.00407 0.00503 0.00635

8.41 × 10−4 9.32 × 10−4 0.00102 0.00113 0.00130 0.00152 0.00187 0.00222 0.00276

ingredients, especially the solubility, which is the key to the yield and purity.14 The solubility data can be used to effectively describe the mechanism and phenomenon of the crystallization process.15 The solubility of azithromycin monohydrate and dihydrate were expressed using the initial solvent mixture. In reality the dissolution of the hydrate liberates water molecules, and the acetone/water volume ratio in the solvent mixture is thus modified. However, owing to the large difference between the molar mass of azithromycin and water, this modification of the solvent mixture composition can be neglected. Each point of data was measured three times. The solubility of azithromycin monohydrate and dihydrate in acetone + water solvent mixtures is presented in Tables 1 and 2, and the data are plotted versus temperature for several water mass fractions in Figure 2. The solubility increased with increasing temperature and acetone fraction and decreased with increasing the content of water in the system. In pure acetone, the solubility of dihydrate was larger than the solubility of the monohydrate, and azithromycin monohydrate is thus more stable than the dihydrate in pure acetone. In the mixed solvent of acetone + water, azithromycin dihydrate had a lower solubility than the monohydrate; therefore, azithromycin dihydrate is more stable than the monohydrate in acetone + water mixtures. It means that the activity of water can affect the stability of the solid. As the content of water increases and the temperature decreases, the difference in solubility for the two hydrates became small. When the mass content of water exceeded 30%, the solubility of azithromycin was very small, so dilution crystallization was an effective recrystallization method. The content of water had great influence on the solubility. The solution reached supersaturation quickly, and the crystallization phenomenon started subsequently to adding water.

Figure 2. Molar fraction solubility of azithromycin as a function of temperature at different water/acetone mixture compositions: ■, monohydrate in 100% acetone; □, dihydrate in 100% acetone; ▲, monohydrate in 90% acetone +,10% water; △, dihydrate in 90% acetone + 10% water; ◆, monohydrate in 80% acetone + 20% water; ◇, dihydrate in 80% acetone + 20% water; ★, monohydrate in 70% acetone + 30% water; ☆, dihydrate in 70% acetone + 30% water.

The solubility of azithromycin monohydrate and dihydrate in ethyl acetate is presented in Table 3, and the data are plotted versus temperature in Figure 3. The solubility of the monohydrate was much higher than that of the dihydrate. Azithromycin monohydrate is thus the metastable form and dihydrate is the stable form in pure ethyl acetate. The difference of the two hydrates’ solubilities in ethyl acetate was much larger than that in the acetone + water system. The solubility increased with increasing temperature and varied greatly. Cooling crystallization was used to recrystallize azithromycin dihydrate in ethyl acetate. For the cooling experiment, the initial molar concentration was 0.069. During the cooling process, the primary nucleation temperature was about 315 K. C

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but the relative supersaturation was 2.138 for the dihydrate. So it was no doubt that there was no nucleation and growth of the monohydrate. The solution concentration could be controlled in the shaded area (Figure 3), which was undersaturated for the monohydrate and supersaturated for the dihydrate. Only the latter can be recrystallized in this process. 3.2. Agglomeration Mechanism of Azithromycin Dihydrate. In actual production, azithromycin is usually crystallized in a water acetone mixture to obtain the dihydrate. However, the products were aggregated. The SEM of samples taken from the dilution crystallization experiments (A1 experiment, 323.15 K) are shown in Figure 4. When crystallization occurred, the particles had a sheet-like crystal habit, but the final product had a columnar habit with a sharp point and the particles were of irregular shape. The changing of the habit maybe indicated a hydrate transformation. The XRD results of the A1 experiment (Figure 5) confirmed that the

Table 3. Molar Fraction Solubility of Azithromycin in Ethyl Acetate molar fraction solubility temperature (K)

monohydrate

dihydrate

278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15

0.03072 0.03354 0.03663 0.03965 0.04361 0.05217 0.05933 0.06714 0.07415 0.08103 0.09921

0.01263 0.01412 0.01615 0.01823 0.02041 0.02317 0.02648 0.02993 0.0358 0.04031 0.05105

Figure 3. Molar fraction solubility of azithromycin as a function of temperature in ethyl acetate: ■, monohydrate; □, dihydrate.

Figure 5. XRD patterns of azithromycin and interval samples obtained from the dilution crystallization experiments (A1 experiment, at 323.15 K).

The solution did not reach saturation for monohydrate (at T = 315 K, the saturation molar concentration was about 0.0699),

Figure 4. SEM images of interval samples obtained from the dilution crystallization experiments (A1 experiment, at 323.15 K). A: 0.5 h, B: 1 h, C: 1.5 h, D: the final product. D

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Figure 6. SEM images of the product obtained from the dilution crystallization experiment (A, A1 experiment at 323.15 K; B, A2 experiment at 298.15 K) and the cooling crystallization experiments in ethyl acetate (C). The scale applies to all the images.

the cooling process, the supersaturation can meet the requirement of spontaneous nucleation for the dihydrate while the solution is unsaturated for the monohydrate, thus preventing its crystallization. The obtained product from the cooling crystallization in ethyl acetate was dispersed and not agglomerated. By comparing the powder properties obtained from the three experiments (Figure 7, Table 4), we found that there was a

sample obtained 15 min after crystallization occurred was the monohydrate. The X-ray diffraction pattern of the sample obtained 0.5 h after crystallization started to show weak characteristic peaks of the dihydrate, indicating a mixture of monohydrate and dihydrate, and the final product of the dilution crystallization was the dihydrate. (The reference X-ray diffraction patterns should be those calculated from single crystal X-ray diffraction measurements. But it is difficult to get suitable single crystals for single crystal X-ray diffraction to get the data. So we selected the X-ray diffraction patterns of the best quality single crystals as the reference. But before the measurement, we crushed these crystals to eliminate the effects of preferential orientation and enhance the clarity of the small diffraction peaks.) It was a typical solution-mediated solvate transformation.16,17 In the mixed water and acetone system, the monohydrate was the metastable hydrate and the dihydrate was the stable hydrate. During the water adding process, nucleation of monohydrate crystal occurred at first, and the monohydrate transformed into the dihydrate with further adding of water so that, at last, the final product was dihydrate. It is a solventmediated hydrate transformation process.18−20 Crystal surface nanostructures such as trenches and steps in microelectronic layer structures had been considered as stress concentrators that may facilitate nucleation.21 Nucleation of dihydrate crystals on the surface was easier than in the bulk of the solution. So there were many dihydrate particles generated on the monohydrate crystal surface as shown in Figure 4A. During the hydrate transformation process, azithromycin monohydrate particles dissolved gradually, and azithromycin dihydrate crystals grew rapidly. The surface nucleation and cross-growing of dihydrate crystals resulted in the agglomeration phenomenon (Figure 4C,D). Experimental phenomena and results of the dilution crystallization A2 experiment at 298.15 K were similar to the A1 experiment at 323.15 K. Nucleation and growth of monohydrate crystals occurred at first, and then dihydrate nuclei emerged on the surface of monohydrate crystals in a second step. Azithromycin monohydrate transformed into dihydrate, and the aggregated product was obtained as shown in Figure 6A,B. Experimental results of cooling crystallization experiments showed some disparity with those of dilution crystallization experiments. The dihydrate nucleated and grew directly in the solution. There was no monohydrate and hydrate transformation process. The obtained particles had no agglomeration phenomenon (Figure 6C). Owing to the tremendous difference between the solubility of the monohydrate and the dihydrate in ethyl acetate, we suspected that the crystallization process occurred in the shaded area shown in Figure 3. During

Figure 7. Particle size distribution of final products. *, the dilution crystallization experiments at 323.15 K (A1 experiment); ×, the dilution crystallization experiments at 298.15 K (A2 experiment); +, the cooling crystallization experiments in ethyl acetate.

Table 4. Comparison of Powder Properties Obtained from the Three Experiments sample A1 dilution crystallization A2 dilution crystallization cooling crystallization

average particle size (μm)

bulk density (g/cm3)

angle of repose (deg)

389.3 ± 15

0.49 ± 0.02

43.0 ± 0.7

271.5 ± 10

0.53 ± 0.01

41.5 ± 0.4

157.8 ± 10

0.60 ± 0.01

37.2 ± 0.5

great difference in the average particle size of the samples. The dispersed particle of the cooling crystallization in ethyl acetate was the smallest with an average particle size of 157.8 μm. The crystals produced by dilution crystallization were larger than those obtained by cooling crystallization on account of the agglomeration in the mixed water and acetone system. The solubility difference between the monohydrate and the dihydrate at 323.15 K was higher than at 298.15 K. At high temperature, the dissolution rate of monohydrate crystals and the hydrate transformation rate were faster than those at low temperature. Hence, the particles of dihydrate aggregated more E

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preparation of Azithromycin solid dispersions for dissolution rate enhancement. J. Supercrit. Fluids 2014, 87, 9−21. (4) Adeli, E.; Mortazavi, S. A. Design, Formulation and Evaluation of Azithromycin Binary Solid Dispersions Using Kolliphor Series for the Solubility and in Vitro Dissolution Rate Enhancement. J. Pharm. Invest. 2014, 44, 119−131. (5) Montejo-Bernardo, J.; Garcia-Granda, S.; Bayod-Jasanada, M.; Llorente, I.; Llavona, L. On the Interaction of Azithromycin Monohydrate with Metallic Containers. J. Appl. Crystallogr. 2006, 39, 826−830. (6) Quon, J. L.; Chadwick, K.; Wood, G. P.; Sheu, I.; Brettmann, B. K.; Myerson, A. S.; Trout, B. L. Templated Nucleation of Acetaminophen on Spherical Excipient Agglomerates. Langmuir 2013, 29, 3292−3300. (7) Yoshiura, H.; Nagano, H.; Hirasawa, I. New Insights into Additive Structure Effect on Crystal Agglomeration of L-Valine. Chem. Eng. Technol. 2013, 36, 2023−2028. (8) Prlic Kardum, J.; Hrkovac, M.; Leskovac, M. Adjustment of Process Conditions in Seeded Batch Cooling Crystallization. Chem. Eng. Technol. 2013, 36, 1347−1354. (9) Ferreira, A.; Faria, N.; Rocha, F.; Teixeira, J. A. Using an Online Image Analysis Technique to Characterize Sucrose Crystal Morphology during a Crystallization Run. Ind. Eng. Chem. Res. 2011, 50, 6990− 7002. (10) Jallo, L. J.; Ghoroi, C.; Gurumurthy, L.; Patel, U.; Davé, R. N. Improvement of Flow and Bulk Density of Pharmaceutical Powders Using Surface Modification. Int. J. Pharm. 2012, 423, 213−225. (11) Li, D. Q.; Liu, D.; Wang, F. A. Solubilities of Terephthalaldehydic, p-Toluic, Benzoic, Terephthalic, and Isophthalic Acids in NMethyl-2-pyrrolidone from 295.65 to 371.35 K. J. Chem. Eng. Data 2001, 46, 172−173. (12) Wang, L.; Su, M.; Wang, J. Solubility of Sesquihydrous Irbesartan Hydrobromide in Ethanol + Water Binary Solvent Mixtures at pH 1.20 between (283 and 313) K. J. Chem. Eng. Data 2009, 54, 701−704. (13) Mukhopadhyay, I.; Mohandas, V. P.; Desale, G. R.; Chaudhary, A.; Ghosh, P. K. Crystallization of Spherical Common Salt in the Submillimeter Size Range without Habit Modifier. Ind. Eng. Chem. Res. 2010, 49, 12197−12203. (14) Wu, S.; Feng, F.; Gong, J. Determination of the Solubility, Dissolution Enthalpy and Entropy of Donepezil Hydrochloride Polymorphic Form III in Different Solvents. J. Solution Chem. 2013, 42, 841−848. (15) Tang, W.; Xie, C.; Wang, Z.; Wu, S.; Feng, Y.; Wang, X.; Wang, J.; Gong, J. Solubility of Androstenedione in Lower Alcohols. Fluid Phase Equilib. 2014, 363, 86−96. (16) Shaikh, A. A.; Salman, A. D.; McNamara, S.; Littlewood, G.; Ramsay, F.; Hounslow, M. J. In Situ Observation of the Conversion of Sodium Carbonate to Sodium Carbonate Monohydrate in Aqueous Suspension. Ind. Eng. Chem. Res. 2005, 44, 9921−9930. (17) Fu, H.; Jiang, G.; Wang, H.; Wu, Z.; Guan, B. Solution-Mediated Transformation Kinetics of Calcium Sulfate Dihydrate to α-Calcium Sulfate Hemihydrate in CaCl2 Solutions at Elevated Temperature. Ind. Eng. Chem. Res. 2013, 52, 17134−17139. (18) Du, W.; Yin, Q.; Gong, J.; Bao, Y.; Zhang, X.; Sun, X.; Ding, S.; Xie, C.; Zhang, M.; Hao, H. Effects of Solvent on Polymorph Formation and Nucleation of Prasugrel Hydrochloride. Cryst. Growth Des. 2014, 14, 4519−4525. (19) Du, W.; Yin, Q.; Hao, H.; Bao, Y.; Zhang, X.; Huang, J.; Li, X.; Xie, C.; Gong, J. Solution-Mediated Polymorphic Transformation of Prasugrel Hydrochloride from Form II to Form I. Ind. Eng. Chem. Res. 2014, 53, 5652−5659. (20) Zhang, X.; Yin, Q.; Du, W.; Gong, J.; Bao, Y.; Zhang, M.; Hou, B.; Hao, H. Phase Transformation Between Anhydrate and Monohydrate of Sodium Dehydroacetate. Ind. Eng. Chem. Res. 2015, 54, 3438−3444. (21) Li, C.; Xu, G. Geometrical Effect on Eislocation Nucleation at Crystal Surface Nanostructures. Eng. Anal. Bound. Elem. 2007, 31, 443−450.

seriously in A1 dilution crystallization experiments at 323.15 K than that in A2 dilution crystallization experiments at 298.15 K as contrasted in Figure 6A and Figure 6B. The average particle size found after the A2 experiment was less than that determined after the A1 experiment. The single crystals of dihydrate were too large and irregular to aggregate compactly. When packing the particles, there were a lot of voids which decreased the bulk density due to the agglomeration. The agglomeration would result in a decrease of the bulk density and an increase of the angle of repose. The bulk density was increased from 0.49 g/cm3 (A1 dilution experiment) to 0.60 g/ cm3 (cooling crystallization experiment), and the angle of repose was decreased from 43.0° to 37.2°. Inhibiting the agglomeration was an effective method to improve the bulk density and flowability of dihydrate.

4. CONCLUSION The agglomeration mechanism of azithromycin dihydrate in the mixed water and acetone system was due to surface nucleation and hydrate transformation. The difference in solubility of the two hydrates was small in these solvent mixtures. In the pure acetone, dihydrate had a higher solubility so it was the metastable hydrate, while in the mixed water and acetone system, the monohydrate had a higher solubility and was thus the metastable hydrate. The surface nucleation of dihydrate crystals on the monohydrate crystals and the hydrate transformation were the reasons causing the aggregation of the dihydrate. There was a tremendous difference in solubility of monohydrate and dihydrate in ethyl acetate. Using this difference we could obtain the dispersed crystals by cooling crystallization in ethyl acetate. Aggregation had a great influence on the powder properties, particle size distribution, bulk density, flowability, and so on. Inhibiting the agglomeration was an effective method to improve the powder performance. The bulk density could be increased from 0.49 g/cm3 to 0.60 g/cm3, and the angle of repose could be decreased from 43.0° to 37.2°.

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AUTHOR INFORMATION

Corresponding Author

*(J.G.) E-mail: [email protected]. Tel.: 86-22-27405754. Fax: +86-022-27374971. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors are grateful to the financial support of National Natural Science Foundation of China (NNSFC 21176173 and NNSFC 21376164) and Major National Scientific Instrument Development Project 21527812.

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REFERENCES

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DOI: 10.1021/acs.iecr.5b04437 Ind. Eng. Chem. Res. XXXX, XXX, XXX−XXX