Article Cite This: Ind. Eng. Chem. Res. 2019, 58, 12431−12437
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An Extended Duration Operation for Porous Hollow Fiber-Based Antisolvent Crystallization Xinyi Zhou,†,1 Bing Wang,‡,1 Qiuhong Liu,† Chen Liu,† Xuemin Gao,† Kamalesh K. Sirkar,*,§ and Dengyue Chen*,† †
School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian 361102, China Key Laboratory of Urban Pollutant Conversion, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021, China § New Jersey Institute of Technology, Otto York Department of Chemical and Materials Engineering, Newark, New Jersey 07102, United States
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‡
ABSTRACT: Poor aqueous solubility of numerous active pharmaceutical ingredients has raised considerable concern about the bioavailability of drugs. A porous hollow fiber antisolvent crystallization (PHFAC) device was designed to continuously produce drug nanocrystals under ambient conditions. The drug solution pumped into the shell side of the module encountered jets of antisolvent deionized water from tiny pores on the hollow fiber walls inducing a high degree of supersaturation as well as crystallization of the obtained nanoparticles. To study the effect of duration of operation for the PHFAC module and the stability of the nanocrystal production, a larger-scale and a smaller-scale module were designed to compare the nanocrystals in a 60 min long experiment. The characterized results showed that the nanocrystals were stable in size and morphology, and the nanocrystals produced by the larger-scale module presented no difference from those of the small-scale module. Meanwhile, the drug nanoparticles remained unchanged for the 28 days during repeated production, indicating excellent stability. It appears possible that the experiment could be scaled up to bring the application to industrial practice.
1. INTRODUCTION Nanoparticles are defined as particles sized between 10 and 1000 nm in general.1 Compared with particles in themicrometer size range, nanoparticles stand out with distinct chemical and physical properties of aspects such as loading efficiency, degree of congeries, permeability through biomembranes, and cell entrance.2,3 In drug delivery systems, nanoparticles can be employed in the development of a controlled and targeted delivery system so as to solve the problems such as low bioavailability of drugs and absorption in the process of getting through the cell membrane.4 In drug development activity, poor water solubility of numerous active pharmaceutical ingredients (APIs) has great influence on the bioavailability of the drugs. As the Noyes− Whitney equation points out, decreasing drug particle size with an increase in surface area resulted in higher dissolution rate and improved bioavailability.5 With controllable composition, shape, size, and morphology, nanoparticles can improve solubility of API and achieve immunocompatibility and cellular uptake due to their surface properties.6 Meanwhile, the smaller dimension, custom-built surface, enhanced solubility, and multifunctionality of nanoparticles make them promising and versatile in biomedical applications.7 To obtain nanoparticles of drugs, top-down as well as bottom-up methods are used. Top-down approaches are high© 2019 American Chemical Society
energy procedures that focus on decreasing the size of the larger particles into nanoparticles, such as high-pressure homogenization and media milling.8 Meanwhile, the bottomup approaches pay attention to assembling and controlling precipitations so as to attain particles in the nanoscale, such as confined impinging liquid jet precipitation and supercritical fluid-based techniques.9 Compared with top-down means, bottom-up methods consume lower energy, are less expensive, and may synthesize particles in a narrower size distribution.10 This becomes clear by considering details of various top-down methods for producing microparticles such as fluid energy milling and ball milling.11,12 High-pressure homogenization is another high-energy procedure.10 In bottom-up methods, drug is deposited from supersaturated drug solution by either solvent transpiration or adding nonsolvents.9 Antisolvent precipitation has been considered as a robust and scalable approach; ultrasound is utilized to offer uniform environment in the container in the antisolvent procedure.13,14 Simultaneously, supercritical fluidbased methods such as rapid expansion of supercritical solution Received: Revised: Accepted: Published: 12431
April 14, 2019 June 17, 2019 June 20, 2019 June 20, 2019 DOI: 10.1021/acs.iecr.9b02028 Ind. Eng. Chem. Res. 2019, 58, 12431−12437
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Industrial & Engineering Chemistry Research
Figure 1. (a) Perspective of single porous hollow fiber in the tube side. (b) Diagram of experimental system of the porous hollow fiber antisolvent crystallizer (PHFAC). (c) Small-scale module. (d) Larger-scale module.
antisolvent crystallization. Moreover, the PHFAC module and the HFM technique were applied for developing polymercoated silica particles in submicron- and nanoscale as well,23 using a suspension of silica particles of appropriate dimensions. This indicated the possibility of achieving the goal of drug nanocrystals through control of the nucleation, crystal-growing conditions, as well as device hydrodynamic majorization.24 However, this PHFAC process for nanocrystal production was carried out for a short time period of less than 1 min.25 One cannot claim this process as continuous unless such a process can be demonstrated to operate over an extended period of time without any change. A similar situation arose in another crystallization technique based on cooling crystallization, namely, solid hollow fiber cooling crystallization (SHFCC) technique26,27 which used solid hollow fiber membranes of polypropylene. Since the experiments there were carried out for only 5−10 min, a separate study was recently completed,28 where the continuous operation was demonstrated for 60−120 min. In the same vein, in order to produce GF drug crystals of nanosize instead of micrometer size, the PHFAC module is improved to produce drug nanocrystals in a continuous process at ambient pressure and temperature. A small-scale module and a larger-scale module are designed to study the performance of the PHFAC device in the 60 min long experiment. The obtained continuously produced drug nanocrystals are studied for their characterization and stability.
(RESS), rapid expansion from supercritical to aqueous solution (RESAS), solution-enhanced dispersion by the supercritical fluids (SEDS), and spray freezing into liquid (SFL) are also employed to synthesize nanocrystals.15 In the RESS process, hydrophobic drugs are dissolved in a solution of supercritical fluid, which subsequently went through a narrow spray head to precipitate under the rapid change of pressure.16 In the technique of spray freezing into liquid (SFL), the excipient is dissolved in the drug solution, and the mixture is atomized into the cryogenic liquid for rapidly freezing amorphous nanoparticles.17 In the meantime, membrane crystallization by antisolvent has been explored to produce nanoparticles. Ma et al. pressed saturated ammonium perchlorate solution into the crystallizer under the pressure of 0.3 MPa through the pores of the ceramic membrane where Fe2O3 nanoparticles were dispersed in ethyl acetate to obtain Fe2O3/femonium perchlorate nanocomposites.18 Profio et al. proposed a membrane-based crystallization technique to remove solvent faster than the antisolvent-inducing phase inversion or to add antisolvent to introduce supersaturation process, which took place in the vapor phase.19 Fern et al. utilized a commercial microfiltration (MF) pencil scale module to produce the nanosuspension of a model drug, Indomethacin, by way of antisolvent crystallization.20 At a somewhat earlier time, porous hollow fiber membrane-based devices have been utilized to achieve successive phase-change procedures to illustrate the broad reach of membrane-contacting processes.21 Chen et al.22 investigated an antisolvent crystallization approach for producing polymer-coated drug particles by a porous hollow fiber membrane module. In this study, porous hollow fiberbased antisolvent crystallization (PHFAC)-based module was utilized to synthesize micrometer-sized Griseofulvin (GF) crystals ranging from 1.61 to 11.83 μm in size. The deionized water as the antisolvent was designed to penetrate from the pores in the hollow fiber wall into the shell side to contact the drug solution, hence achieving shell-side crystallization (Figure 1a). The encounter of drug solution with deionized water as the antisolvent from tiny pores in the porous hollow fiber contributed to sufficient contact in the microenvironment in the HFM module, offering convenient conditions for
2. EXPERIMENTAL METHODS 2.1. Materials. Griseofulvin (purity 99.2%) was obtained from Yuanchenggongchuang Technology Co. Ltd. (Wuhan, Hubei, China). Acetone (analytical purity) was purchased from Xilong Chemical Co. Ltd. (Guangzhou, Guangdong, China). Deionized water was generated by multifunction ultrapure water system (Unique-R20, Ruisijie Water-Purification Technology Co. Ltd., Xiamen, Fujian, China). All chemicals were purchased from commercial suppliers and utilized without further purification. 2.2. Apparatus and Procedures. In this experiment, two hollow fiber membrane modules were designed for producing drug crystals in nanoscale: the small-scale module and the 12432
DOI: 10.1021/acs.iecr.9b02028 Ind. Eng. Chem. Res. 2019, 58, 12431−12437
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Industrial & Engineering Chemistry Research larger-scale nodule. The hollow fiber membrane modules were fabricated using the basis used in the earlier study;25 the experimental apparatuses are shown in Figure 1. Fluorinated ethylene propylene (FEP) formed the shell side of the modules with poly(vinylidene fluoride) (PVDF) being the polymer used for making porous hollow fiber membranes with 0.1−0.15 μm pore size and porosity of 0.75. As depicted in Figure 1b, the left sides of the modules were plugged by epoxy resin, stopping deionized water from fleeing the ends to make the mixing streams flow directionally to the exits of the module. The small-scale module had a shell of 19 mm in outer diameter (OD) and 17 mm in inner diameter (ID), while that of the larger-scale module was 29 mm in outer diameter (OD) and 24 mm in inner diameter (ID). Along with the same effective length of 26 cm, the small-scale and larger-scale modules contained 14 and 28 PVDF porous hollow fiber membranes respectively with 0.1−0.15 μm pore size and porosity of 0.75 (shown in Figure 1c, 1d); each porous hollow fiber membrane was 2.5 mm in OD and 1.8 mm in ID. It is depicted in Figure 1b that the modules were laid at an angle of 15° to the horizontal, so as to provide sufficient contact area of the drug solution and antisolvent. The experimental systems were made up of three sectors, including inlet system, crystallization system, and vacuum filtration system. The inlet system consisted of two portions, those dealing with the drug solution and deionized water. After GF had been fully dissolved by magnetic stirring in a conical flask, the drug solution having a GF concentration of 0.030 g/ mL was prepared for the process. When the deionized water was pumped into the tube side of the crystallization system as the antisolvent by a peristaltic pump (YZ1515x, Shenchen Pump Industry Co. Ltd., Baoding, Hebei, China), drug solution was introduced to the shell side of the device through another peristaltic pump subsequently. In the crystallization system, as shown in Figure 1a, the drug solution sent to the shell side of the device was fully exposed to the small jets ejected from the pores of 0.1−0.15 μm in size in the porous hollow fiber membranes due to the pressure of the tube side. Then the obtained drug crystals suspended in the solution were moved to the vacuum filtration system (1000 mL, Tianjin Jinteng Experimental Equipment Co. Ltd., Tianjin, China). Vacuum filtration was utilized to gather nanocrystals from the solution in the experiments. The samples were gathered every 10 min from the first minute in the 60 min long experiment. As long as the drug nanocrystals precipitated in the module due to the encounter of the deionized water pumped from the tiny pores on the hollow fiber wall and the drug solution pumped into the shell side of the device, the attained nanocrystals were retained on the 0.1 μm pore-sized membrane filters (VVLP04700, Merck Millipore Ltd., County Cork, Ireland). Meanwhile, the redundant acetone solution was removed, after which the drug crystals were freeze-dried before characterization. 2.3. Experimental Operating Conditions. In the previous study,25 the experimental time for the obtained drug particles under different experimental conditions was less than 1 min. With the aim of exploring the duration of the PHFAC module along with the stability of the continuously generated drug crystals, the larger-scale module and small-scale module were designed to make comparison of the nanocrystals during 60 min long experiment. Fifteen grams of GF was dissolved in a conical flask in 550 mL of liquid mixture with 500 mL of solvent of acetone and
antisolvent of deionized water at the ratio of 10:1 for the smallscale module. Thirty grams of GF was also prepared in a conical flask in 1100 mL of liquid mixture with 1000 mL of acetone as solvent and deionized water as anti-solvent in the proportion of 10:1 for the larger-scale module. Under successive stirring on a magnetic stirrer, the liquid mixture turned into a solution of GF. The flow rates of drug solution and antisolvent were both 6.8 mL/min for the small-scale module, and the flow rates of drug solution and antisolvent were both 13.6 mL/min for the large-scale module. To study the quality of the obtained drug crystals in the experiments, the samples were collected at the set time points and characterized using a variety of characterization techniques. 2.4. Particle Characterization. 2.4.1. Scanning Electron Microscopy (SEM). After being suspended in deionized water, a droplet containing drug crystals was put on a silicon pellet. Samples were then dried and sputter-coated by platinum for 30 s under a current of 20 mA. Subsequently, the surface morphology of the obtained drug nanocrystals was studied with a scanning electron microscope (SEM, S-4800, Hitachi, Japan). 2.4.2. Dynamic Light Scattering (DLS). A dynamic light scattering (DLS) instrument (Nano-ZS, Malvern Instruments Ltd., Worcestershire, U.K.) was utilized to measure the particle size distribution. The freshly prepared specimens were diluted in deionized water and studied at 1.33 medium refractive index at 25 °C. Each size measurement contained more than 10 runs. 2.4.3. Raman Spectroscopy. A confocal Raman system (Xplora, Horiba, Japan) was employed for observing the molecular structure of the obtained nanocrystals with the laser power of 10 mW and the incident laser wavelength of 780 nm. The range of Raman spectroscopy was from 0 to 3500 cm−1. 2.4.4. Energy Dispersive X-ray Spectroscopy (EDX). The components of the elementary substance of as-received and obtained drug particles were characterized by an EDX spectroscopy analysis (7593-H, Horiba UK Ltd., England). 2.4.5. X-ray Diffractometer (XRD). An Ultima IV X-ray diffractometer (Rigaku, Matsubara-cho, Tokyo, Japan) was applied to carry out X-ray diffraction (XRD) measurement on the drug crystals with a Cu−Kα radiation source (λ = 0.154 18 nm) at ambient temperature. The voltage was set at 40 kV, and the current was at 30 mA. The samples were flattened into thin layers on glass sample holders and then scanned between 5° and 40° 2θ with a scanning velocity of 10°/min at a step width of 0.02° 2θ. 2.4.6. Differential Scanning Calorimetry (DSC). Differential scanning calorimetry (DSC) analysis was implemented under a nitrogen atmosphere with a Synchronous TG-DSC Thermal Analyzer (STA 449 F5 Jupiter, Netzsch, Bavaria, Germany). Taking an empty alumina crucible as a blank control, an amount of 10 mg of drug nanocrystals was weighed, covering a scope of 75−250 °C. The heating and cooling velocities were both 10 °C/min, and the successive airflow velocity was 20 mL/min. 2.4.7. Fourier Transformer Infrared Spectroscopy (FT-IR). A FT-IR spectrometer (Bruker, Germany) was employed for recording the Fourier transform infrared (FT-IR) spectra, which verified the chemical structure of the samples. After being ground and dried, the samples were blended with potassium bromide and subsequently condensed to thin slices. The scanning range was from 400 to 4000 cm−1. 2.4.8. Stability Analysis. Nanocrystals produced from the small-scale module and the larger-scale module were 12433
DOI: 10.1021/acs.iecr.9b02028 Ind. Eng. Chem. Res. 2019, 58, 12431−12437
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Industrial & Engineering Chemistry Research maintained at room temperature of 25 °C. On the 1st, 7th, 14th, 21st, and 28th days, the sizes of the particles generated from the modules at the 40th min were tested with a dynamic light scattering (DLS) instrument (Nano-ZS, Malvern Instruments Ltd., Worcestershire, U.K.).
3. RESULTS AND DISCUSSION 3.1. Production of Drug Nanoparticles. The received drug Griseofulvin was regenerated in the modules by means of Figure 5. FT-IR results of the GF nanoparticles synthesized by PHFAC in small-scale module and the larger-scale module and the asreceived pure GF powder.
Figure 2. SEM images of (a) as-received pure GF powder, (b) synthesized drug nanocrystals in PHFAC small-scale module at the 1st min, and (c) synthesized drug nanocrystals in PHFAC larger-scale module at the 1st min.
Figure 6. XRD results of the GF nanoparticles synthesized by PHFAC small-scale module and the larger-scale module and asreceived GF powder.
Figure 3. EDX spectroscopy analysis results of (a) as-received pure GF powder, (b) synthesized drug nanocrystals by PHFAC in smallscale module, and (c) synthesized drug nanocrystals by PHFAC in larger-scale module.
Figure 4. Raman spectroscopy results for the obtained drug nanoparticles synthesized by PHFAC small-scale module and the larger-scale module and the as-received pure drug powder.
Figure 7. DSC results of the GF nanoparticles synthesized by PHFAC in small-scale module and the larger-scale module and the as-received GF powder.
antisolvent-introduced crystallization. During the crystallization process, deionized water pumped out from the 0.1−0.15 μm pores of the hollow fiber wall was fully contacted with the drug solution running into the shell side of the device. This gave rise to a swift decrease of the drug solubility and thus a high level of supersaturation, bringing about the drug nanocrystals to be precipitated. Drug solution (3.28% by wt) was prepared for the experiments. 3.1.1. Morphology and Component Analysis. The morphology of the obtained nanocrystals was determined by SEM. As revealed in Figure 2a, the dimension of as-received drug powder was around 4−5 μm, which was considerably decreased to about 100 nm after the PHFAC procedure, as
Figure 8. SEM images of the drug nanocrystals produced by PHFAC small-scale module at (a) the 1st min, (b) the 30th min, and (c) the 60th min.
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DOI: 10.1021/acs.iecr.9b02028 Ind. Eng. Chem. Res. 2019, 58, 12431−12437
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the carbonyl groups (vCO). The aromatic CC stretching vibration (vCC) contributed to the peaks at 1467, 1508, 1578, 1619 cm−1, while C−H stretching vibration (vC−H) resulted in the peaks at 2990 cm−1. The results proved that the nanocrystals produced from small-scale module and the larger-scale module were stable in chemical structures, for the reason that the characteristic peaks remained unchanged compared with the peaks of the as-received drug powder. 3.1.4. Crystallinity Analysis. XRD patterns are displayed in Figure 6. The crystalline shapes of the as-received drug powder as well as nanocrystals precipitated from the two types of modules are certified by their steep peaks. Apparently, the peaks of drug nanocrystals produced in two sizes of modules were in accordance with those of the as-received pure GF powder. In the meantime, as shown in Figure 6, the intensity of crystalline peaks of the attained drug nanocrystals was lower than that of the as-received pure GF powder, which can be ascribed to the decrease in the particle dimension. 3.1.5. Thermal Analysis. DSC thermal curves are shown in Figure 7. The nanocrystals produced by the small-scale module decomposed at 220.063 °C, which was equal to the decomposition temperature of the as-received pure GF powder. Meanwhile, the melting point of the nanocrystals produced by the larger-scale module was at 221.063 °C, and it was clear that the endothermic peaks of the attained nanocrystals did not present significant change compared with those of the as-received drug powder. 3.2. Duration of Experiments in the PHFAC Module. The duration of experiments in the device could be critical for industrial production processes; it will have great influence on the operational convenience as well as production efficiency. With the aim of investigating the duration of operation in the PHFAC module, a series of time points were set to collect nanocrystals for study. At the 1st, 10th, 20th, 30th, 40th, 50th, and 60th min, the nanocrystals produced from the modules were held up and gathered by the vacuum filtration system. The results of SEM in Figure 8 a revealed that the size of the nanocrystals obtained from the small-scale module was less than 100 nm at the first min. In the meantime, Figure 8b and 8c showed that the nanocrystals obtained were of similar size at the 30th and the 60th min. Moreover, the morphology of the nanocrystals at various time points continued to be angular crystalline, indicating stability in the products in the continuous process. DLS analysis presented in Figure 9 shows that the mean particle size of nanocrystals synthesized by PHFAC small-scale module at the first min was 75.8 nm, and those at the 30th min was similar at 78.8 nm, whereas the mean particle size slightly increased to 91.3 nm at the 60th min. With continuous flowing mixture of the drug crystals and the excess solution going through the module to the outlet, some nanocrystals might fail to be taken away by the solvent mixture, thus lingering in the module to grow into larger sizes. 3.3. Variation of Module Size. In the previous study,25 the PHFAC module successfully fabricated nanocrystals under
Figure 9. Particle size distribution (PSD) of drug nanocrystals produced by PHFAC small-scale module at the 1st, 30th, and 60th min.
Figure 10. SEM images of the drug nanocrystals produced by PHFAC larger-scale module at (a) the 1st min, (b) the 30th min, and (c) the 60th min.
Table 1. Mean Particle Size of the Nanocrystals Produced by PHFAC in Small-Scale Module and Larger-Scale Module at the 1st, 30th, and 60th min module size
1st min (nm)
30th min (nm)
60th min (nm)
small large
71.1 ± 10.8 72.4 ± 6.7
76.3 ± 16.4 78.1 ± 9.8
93.9 ± 27.3 95.0 ± 9.8
presented in Figure 2b and 2c. Moreover, the crystalline structures of the synthesized nanocrystals are obvious in Figure 2b and 2c. The constituent elements of the received drug and the obtained drug nanocrystals generated from the small-scale device as well as the larger-scale device were determined by SEM-EDX spectroscopy. Figures 3a, 3b, and 3c revealed that the characteristic component elements of the generated drug nanocrystals from the small-scale and the larger-scale device were detected as carbon, oxygen, and chlorine, which were consistent with those of the received drug particles. 3.1.2. Molecular Structure Analysis. Raman spectroscopy results illustrated in Figure 4 reveal that the main peaks of the nanocrystals generated from the small-scale device and the larger-scale device were at 2950.07, 1616.93, 1344.49, 651.673, and 377.56 cm−1, consistent with the characteristic peaks of the as-received drug powder. The consequences showed that within the scope between 0 and 3500 cm−1, the obtained nanocrystals in the continuous process preserved their initial molecular structures. 3.1.3. Chemical Structure Analysis. FT-IR patterns in Figure 5 show that the two characteristic peaks at 1663 and 1710 cm−1 could be attributed to the stretching vibration of
Table 2. Particle Size of the Nanocrystals Produced by PHFAC Small-Scale Module and Larger-Scale Module at the 40th min over 28 Days experiment
1st (day)
7th (day)
14th (day)
21st (day)
28th (day)
nanocrystals produced at the 40th min by the small-scale module nanocrystals produced at the 40th min by the larger-scale module
80.5 ± 26.1 84.4 ± 12.2
85.6 ± 7.9 85.1 ± 8.8
79.7 ± 16.4 84.6 ± 29.9
83.8 ± 5.3 88.4 ± 24.4
84.8 ± 9.2 85.1 ± 8.81
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a moderate condition. In order to investigate their possible application in industrial production, a scaled-up module was designed to study the continuous production of PHFAC in a larger scale. The larger-scale module was twice the size of the small-scale module, and the nanocrystals produced by the two modules were compared as follows. The yields of the nanocrystals in the small-scale module and the large-scale module were 68.8% and 65.5% respectively. The results of SEM in Figure 10a, 10b, and 10c showed that the nanocrystals produced by the larger-scale module were crystals in a size of less than 100 nm. Compared with the nanocrystals produced from the small-scale module in Figure 8a, 8b, and 8c above, the nanoparticles in Figure 10 a, 10b, and 10c generated from the larger-scale module presented no obvious change in size and morphology during the procedure. In the meantime, Table 1 presented that the trends of the particle sizes of the obtained nanocrystals in the larger-scale module were similar to those of the small-scale module. It is indicated that the performance of the scaled-up module was steady and applicable, which paved the way for any future study with great promise. 3.4. Stability of the Nanocrystals. With the purpose of studying the stability of the nanocrystals produced by the modules, a stability analysis was conducted to verify the nanocrystals grain size. On the 1st, 7th, 14th, 21st, and 28th day after the process, the particle sizes of the nanocrystals were measured and recorded. As displayed in Table 2, the particle sizes of the nanocrystals produced on the 40th min by the small-scale module remained around 80−85 nm, which were relatively stable in the 28 days after production. Moreover, that was the same case as the nanocrystals produced on the 40th min by the larger-scale module, whose size was maintained at about 85−90 nm during the 28 days.
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AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Kamalesh K. Sirkar: 0000-0001-7157-5010 Dengyue Chen: 0000-0002-3573-5520 Author Contributions 1
X.Z. and B.W. contributed equally to this work and should be considered as cofirst authors. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China (grant numbers 81772278, 21706221, and 21878284) and the Natural Science Foundation of Fujian Province (grant number 2018J05143).
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REFERENCES
(1) Hamidi, M.; Azadi, A.; Rafiei, P. Hydrogel nanoparticles in drug delivery. Adv. Drug. Deliver. Rev. 2008, 60, 1638−1649. (2) Youssef, A. M.; El-Sayed, S. M. Bionanocomposites Materials for Food Packaging Applications: Concepts and Future Outlook. Carbohydr. Polym. 2018, 193, 19−27. (3) Wong, C. Y.; Al-Salami, H.; Dass, C. Microparticles, microcapsules and microspheres: a review of recent developments and prospects for oral delivery of insulin. Int. J. Pharm. 2018, 537, 223− 244. (4) Aftab, S.; Shah, A.; Nadhman, A.; Kurbanoglu, S.; Ozkan, S. A.; Dionysiou, D. D.; Shukla, S. S.; Aminabhavi, T. M. Nanomedicine: an effective tool in cancer therapy. Int. J. Pharm. 2018, 540, 132−149. (5) Siepmann, J.; Siepmann, F. Mathematical modeling of drug dissolution. Int. J. Pharm. 2013, 453, 12−24. (6) Goldberg, M.; Langer, R.; Jia, X. J. Nanostructured materials for applications in drug delivery and tissue engineering. J. Biomater. Sci., Polym. Ed. 2007, 18, 241−268. (7) Singh, R.; Lillard, J. W. Nanoparticle-based targeted drug delivery. Exp. Mol. Phathol. 2009, 86, 215−223. (8) Van Eerdenbrugh, B.; Van den Mooter, G.; Augustijns, P. Topdown production of drug nanocrystals: nanosuspension stabilization, miniaturization and transformation into solid products. Int. J. Pharm. 2008, 364, 64−75. (9) Chan, H.-K.; Kwok, P. C. L. Production methods for nanodrug particles using the bottom-up approach. Adv. Drug. Deliver. Rev. 2011, 63, 406−416. (10) Al-Kassas, R.; Bansal, M.; Shaw, J. Nanosizing techniques for improving bioavailability of drugs. J. Controlled Release 2017, 260, 202−212. (11) Loh, Z.H.; Samanta, A. K.; Heng, P. W. S. Overview of milling techniques for improving the solubility of poorly water-soluble drugs. Asian. J. Pharm. Sci. 2015, 10, 255−274. (12) Saleem, I. Y.; Smyth, H. D. C. Micronization of a Soft Material: Air-Jet and Micro-Ball Milling. AAPS PharmSciTech 2010, 11, 1642− 1649. (13) D’Addio, S. M.; Prud’Homme, R. K. Controlling drug nanoparticle formation by rapid precipitation. Adv. Drug Delivery Rev. 2011, 63, 417−426. (14) Dhumal, R. S.; Biradar, S. V.; Yamamura, S.; Paradkar, A. R.; York, P. Preparation of amorphous cefuroxime axetil nanoparticles by sonoprecipitation for enhancement of bioavailability. Eur. J. Pharm. Biopharm. 2008, 70, 109−115. (15) Salazar, J.; Ghanem, A.; Müller, R. H.; Möschwitzer, J. P. Nanocrystals: Comparison of the size reduction effectiveness of a novel combinative method with conventional top-down approaches. Eur. J. Pharm. Biopharm. 2012, 81, 82−90.
4. CONCLUDING REMARKS A porous hollow fiber crystallization (PHFAC) module was projected for continuously producing drug nanocrystals in a moderate manner. The drug solution pumped into the shell side of the device met with deionized water jets from the tiny pores in the hollow fiber walls, inducing a high supersaturation extent in a number of tiny zones along the length of module. In this situation, nucleation process took place giving rise to crystallization of the obtained nanoparticles. For the purpose of investigating the duration of the operation in a PHFAC module as well as the stability of the continuously synthesized drug crystals, a larger-scale module and a small-scale membrane module were designed to make comparison of the nanocrystals in 60 min long experiments. Results showed that the nanocrystals were stable in size and morphology in the continuous process of 60 min; the nanocrystals produced by the larger-scale module presented no difference from those of the small-scale module. Meanwhile, the drug nanoparticles remained unchanged for 28 days during repeated production, indicating good stability. The results in the investigation revealed that the PHFAC technique achieving successive production of drug nanocrystals was viable as well as practical under general conditions. By adjusting the interior parameters of the module, it was possible that the experiment could be scaled up to a certain range, which suggests a possibility of its application to industrial practice. 12436
DOI: 10.1021/acs.iecr.9b02028 Ind. Eng. Chem. Res. 2019, 58, 12431−12437
Article
Industrial & Engineering Chemistry Research (16) Sinha, B.; Müller, R. H.; Möschwitzer, J. P. Bottom-up approaches for preparing drug nanocrystals: Formulations and factors affecting particle size. Int. J. Pharm. 2013, 453, 126−141. (17) Hu, J.; Johnston, K. P.; Williams, R. O. Rapid dissolving high potency danazol powders produced by spray freezing into liquid process. Int. J. Pharm. 2004, 271, 145−154. (18) Ma, Z.; Wu, R.; Song, J.; Li, C.; Chen, R.; Zhang, L. Preparation and characterization of Fe2O3/ammonium perchlorate (AP) nanocomposites through ceramic membrane anti-solvent crystallization. Propellants, Explos., Pyrotech. 2012, 37, 183−190. (19) Di Profio, G.; Stabile, C.; Caridi, A.; Curcio, E.; Drioli, E.; et al. Antisolvent membrane crystallization of pharmaceutical compounds. J. Pharm. Sci-us. 2009, 98, 4902−4913. (20) Fern, J. C. W.; Ohsaki, S.; Watano, S.; et al. Continuous synthesis of nano-drug particles by antisolvent crystallization using a porous hollow-fiber membrane module. Int. J. Pharm. 2018, 543, 139−150. (21) Zarkadas, D. M.; Sirkar, K. K. Antisolvent crystallization in porous hollow fiber devices. Chem. Eng. Sci. 2006, 61, 5030−5048. (22) Chen, D.; Singh, D.; Sirkar, K. K.; Pfeffer, R. Continuous synthesis of polymer-coated drug particles by porous hollow fiber membrane-based antisolvent crystallization. Langmuir 2015, 31, 432− 441. (23) Chen, D.; Singh, D.; Sirkar, K. K.; Pfeffer, R. Porous Hollow Fiber Membrane-Based Continuous Technique of Polymer Coating on Submicron and Nanoparticles via Antisolvent Crystallization. Ind. Eng. Chem. Res. 2015, 54, 5237−5245. (24) Chen, D.; Wang, B.; Sirkar, K. K. Hydrodynamic modeling of porous hollow fiber anti-solvent crystallizer for continuous production of drug crystals. J. Membr. Sci. 2018, 556, 185−195. (25) Zhou, X.; Zhu, X.; Wang, B.; Li, J.; Liu, Q.; Gao, X.; Sirkar, K. K.; Chen, D. Continuous production of drug nanocrystals by porous hollow fiber-based anti-solvent crystallization. J. Membr. Sci. 2018, 564, 682−690. (26) Chen, D.; Singh, D.; Sirkar, K. K.; Pfeffer, R. Continuous Polymer Coating/Encapsulation of Submicrometer Particles Using a Solid Hollow Fiber Cooling Crystallization Method. Ind. Eng. Chem. Res. 2014, 53, 6388−6400. (27) Chen, D.; Singh, D.; Sirkar, K. K.; Zhu, J.; Pfeffer, R. Continuous polymer nanocoating on silica nanoparticles. Langmuir 2014, 30, 7804−7810. (28) Jin, C.; Chen, D.; Sirkar, K. K.; Pfeffer, R. Anextended duration operation for solid hollow fiber membrane-based cooling crystallization. Powder Technol. 2019, DOI: 10.1016/j.powtec.2019.04.010.
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DOI: 10.1021/acs.iecr.9b02028 Ind. Eng. Chem. Res. 2019, 58, 12431−12437
