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Controlled Liquid Antisolvent Precipitation of Hydrophobic Pharmaceutical Nanoparticles in a Microchannel Reactor Hong Zhao,†,‡ Jie-Xin Wang,†,‡ Qi-An Wang,‡ Jian-Feng Chen,*,†,‡ and Jimmy Yun§ Sin-China Nano Technology Center, Key Lab for Nanomaterials, Ministry of Education, Beijing UniVersity of Chemical Technology, Beijing 100029, People’s Republic of China, Research Center of the Ministry of Education for High GraVity Engineering and Technology, Beijing UniVersity of Chemical Technology, Beijing 10029, People’s Republic of China, and Nanomaterial Technology Pte., Ltd., Singapore
Microchannel reactors are a rapidly emerging and promising technology field for their enhanced mass transfer and excellent heat exchange induced by dimensional effects. A method, the liquid antisolvent precipitation (LASP) process in a microchannel reactor (MCR), is proposed here to directly synthesize danazol nanoparticles without additives. The mean particle size decreased from 55 µm to 364 nm, and the specific surface area increased from 0.66 to 14.37 m2/g after the LASP process in MCR. The mean particle size can be facilely controlled by regulating the parameter of the MCR setup. The chemical composition and physical characteristics of the as-prepared danazol nanoparticles were demonstrated to be unchanged after processing according to FT-IR and XRD analyses. Correspondingly, the dissolution rate of the nanoparticles within 5 min was enhanced from 35% to 100% compared to the raw danazol particles. Combined with the controlled LASP method, MCR exhibits great potential for preparation of hydrophobic drugs with uniform particle size distribution in the nanometer range. 1. Introduction Presently, it has been estimated that 40% or more of newly developed pharmaceutically active substances will be poorly water soluble. In the case of hydrophobic drugs with high permeabilities through biomembranes, the dissolution rate limits the bioavailability.1 Therefore, the poor aqueous solubilities of these drug candidates leads to significant problems in drug development and related requirements such as bioavailability and a normal absorption pattern.2 Among various strategies to address the solubility issue, reducing the drug particle sizes has emerged as an effective and versatile option.3-5 Many top-down and bottom-up methods such as ultrafine mechanical milling, spray drying, and high-pressure homogenization3,6 were developed to generate micro- or nanodrug particles. Nevertheless, they still have some limitations, such as high-energy input, low yield, pharmaceutical contaminants, and hard to control particle size and surface properties,7 which restrict their wider applications and further commercialization. Spray freezing into liquid (SFL)4 and supercritical antisolvent precipitation (SASP)8-10 were recently developed to prepare drug nanoparticles. However, they need complex operating conditions and have enormous production costs, such as high pressure and extreme low temperature. Compared with SASP using CO2 as the antisolvent, there are few reports on liquid antisolvent precipitation (LASP) with water as the antisolvent for preparing drug nanoparticles.11-13 LASP provides a more convenient procedure at normal temperature and pressure with no requirement of expensive equipment. Thus, LASP offers an attractive alternative for drug nanoparticle formation. In the LASP method, a solvent and an antisolvent need to be properly * To whom correspondence should be addressed. Tel.: +86-1064446466. Fax: +86-10-64434784. E-mail:
[email protected]. † Sin-China Nano Technology Center, Key Lab for Nanomaterials, Beijing University of Chemical Technology. ‡ Research Center of the Ministry of Education for High Gravity Engineering and Technology, Beijing University of Chemical Technology. § Nanomaterial Technology Pte., Ltd.
selected. The driving force of a precipitation formation is the supersaturation of a solution created by mixing the drug solution and an antisolvent. During mixing, the nucleation rate depends on the degree of supersaturation (S).14 To obtain nanoparticles with narrow size distribution, therefore, one should do as much as possible to meet the requirements of (a) a high degree of supersaturation, (b) uniform spatial concentration distributions, and (c) the same growth time for all crystals.15 It has been widely demonstrated that higher degree of supersaturation usually results in lower Gibbs free energy, which will lead to the smaller critical nuclei size.16-18 Experimental results reported by Chen et al.19 and Tosun20 showed that micromixing (mixing on the molecular scale) has a significant effect on the particle size distribution (PSD), especially for rapid chemical processes.21 Uniform spatial concentration distribution on the molecular scale can only be reached by intense micromixing. Micromixing is a key factor determining the degree of the supersaturation concentration of the solute and its local spatial distribution. Herein, we defined τm as the characteristic time of micromixing for species reaching a maximum mixed state at the molecular level. τi is the induction time, which is from the first creation of the conditions for homogeneous nucleation to that of the establishment of a steadystate nucleation rate. Because of the very strong nonlinearity of homogeneous nucleation, intensification of micromixing to reach the region of τm < τi should be taken so that the rates of nucleation at different locations in a precipitator will be nearly the same, and the PSD can be controlled at a uniform level. The characteristic micromixing time can be estimated according to Li et al.:22
τm ) km(υ/)1/2
(1)
where km is a constant. Its value has been given variously by different researchers;15,22-24 km ) 16 is taken here. As an example, in a common stirred tank, the value of the energy dissipation rate, , is on the order of 0.1-10 W/kg and that of kinematic viscosity, υ, is 1 × 10-6 m2/s in aqueous solutions.
10.1021/ie070498e CCC: $37.00 © 2007 American Chemical Society Published on Web 10/06/2007
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Figure 2. Molecular structure of danazol.
Figure 1. Schematic diagram explaining effect of mixing for precipitation process in MCR and in conventional stirred tank,14,17,26 where Cmin is the critical concentration for nucleation and Ceq is the equilibrium solubility of the drug in the mixture.
In this case, the characteristic micromixing time, τm, is estimated to be on the order of 5-50 ms. In aqueous solutions, the value of the nucleation induction time is often on the order of 1 ms or less.22 Therefore, τm . τi. This implies that the PSD in a stirred tank cannot be easily controlled, and the scale-up effect will play a more important role, owing to the poor micromixing. This is in agreement with practice. On the other hand, within the Y-type microchannel reactor we used here is in the range of 2000-4000 estimated by the method of Chen et al.25 Therefore, the corresponding τm is 0.25-0.35 ms calculated by eq 1. We find that it fulfills the condition of τm < τi which is essential to form nanoparticles with uniform size distribution. Figure 1 illustrates the schematic diagram of the mixing behavior for the precipitation process in MCR and in a conventional stirred tank. Based on the analysis of kinetics hereinbefore, a reactor with excellent mixing performance will be crucial to forming uniform drug nanoparticles. The microchannel reactor (MCR) is a rapidly emerging technology field. This technology has gained great attention from various aspects worldwide. The enhanced mass transfer, which lies on the microsized channel diameter that leads to a reduction of mixing times even at a laminar flow regime due to short diffusion path length,27 and the excellent heat exchange, which is based on the large surface-to-volume ratio,28 are the two most promising merits of MCR. The reactor miniaturization with the above advantages enables us to proceed with reactions under more precisely controlled conditions than conventional macroscale reactors, leading to a possibility of improved yield and selectivity of desired products.29 MCR has recently exhibited great versatile potential in the synthesis of organic,30 inorganic,31 and biological materials,32 semiconductor nanoparticles of CdSe33 and TiO2,34 noble metal nanoparticles of Au and Ag,35,36 and even catalytic reactions.37 MCR provides a reaction volume or a microchannel that is more homogeneous with respect to concentration, temperature, and mass transfer, leading to a better control of reaction or the precipitation step that governs the particle size and its distribution, i.e., nucleation and growth.38 Therefore, MCR would be a promising platform for drug micronization. Herein, we propose a technique that can be used to prepare drug particles in the nanometer range having a narrow size distribution. This new technique, LASP with intensified micromixing in MCR, is a modification of the conventional LASP process and overcomes the limitations of the LASP process in conventional reactors. To the best of our knowledge, there is no report on the controlled LASP for drug nanoparticles without surfactants in MCR. Danazol, which is a synthetic steroid (the molecular structure is shown in Figure 2) for the treatment of endometriosis, hereditary angioedema, etc., was selected as the model drug. It is a hydrophobic drug belonging to the category that is highly
permeable through biomembranes but slightly water soluble,39 which indicates the advantages of nanonization to enhance the dissolving rate for better bioavailability. No surfactant was added to inhibit the crystal growth during the whole process in order to gain concrete information on the effect of the MCR combined with LASP on the control of pharmaceutical particle size and morphology. A Y-type MCR, which is a simple mixing structure but widely studied for liquid mixing,40-42 was used here as the example of a micromixer to investigate the MCRbased LASP method. Optimal experimental parameters were obtained. The particle size and morphology of the as-prepared danazol were observed by scanning electron microscopy (SEM), while the chemical structure and physical characteristics were detected by Fourier transform infrared (FT-IR) spectroscopy and X-ray diffraction (XRD). The BET surface area and the corresponding drug dissolution rate were also measured in this study. 2. Experimental Section 2.1. Materials and Setup. The raw danazol material was purchased from Beijing Zizhu Tiangong Science and Technology Co., Ltd. Ethanol was bought from Beijing Chemical Reagents Company (AR grade). A continuous nonpulsatile pump was supplied by Beijing Satellite Manufacturing Factory. The structure of a typical experimental setup for the liquid antisolvent precipitation is illustrated in Figure 3a. The key part consists of a microchannel reactor (MCR) as shown in Figure 3b. The values of x and y are 300 µm and 300 µm for microchannel 8 and are 300 µm and 600 µm for microchannel 9 (Figure 3c). 2.2. Preparation of the Danazol Nanoparticles. A slight excess of bulk danazol was first dissolved in ethanol. The solution was then filtrated through a 0.22 µm nylon filter membrane to remove solid impurities and obtain clear danazol solution. Afterward, the danazol solution and deionized water as the antisolvent were pumped from their storage containers into the two feed-in channels. The concentration of the danazol solution and the flow rate of water were fixed. The flow rate of the solution was tuned to achieve different antisolvent/solution (AS/S) ratios. The two liquid streams came into contact at the crossing of the two channels and precipitation immediately occurred. Finally, the precipitate was collected by vacuum filtration through a 0.45 µm filter. 2.3. Particle Size and Morphology. The morphology of danazol samples was observed by scanning electron microscopy (SEM), Cambridge S250MK3 (Cambridge Instruments Inc., U.K.) and JSM-6360LV (JEOL Inc., Japan). The dry powder or a glass slide with sample was fixed on an SEM stub using double-sided adhesive tape and with Au sputter coated. The column chart of the particle size distribution (PSD) was generated by using the Image-Pro 5.1 (Media Cybernetics, Inc.) software according to the obtained SEM images. The width of the particle was prescribed as the specific particle size. A Gauss fitting curve was also fabricated to give an apparent illustration for PSD comparison. 2.4. Specific Surface Area. An ASAP 2010 surface area analyzer (Micromeritics Instrument Corp.) was used to deter-
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Figure 3. (a) Schematic diagram of the MCR setup: (1 and 2) continuous nonpulsatile pump; (3 and 4) solvent and antisolvent storage container; (5) slurry storage container; (6) inlet; (7) outlet; (8 and 9) microchannels. (b) Photograph of the MCR. (c) Dimension illustration of the microchannels of (8) and (9).
mine the specific surface area of raw danazol and the as-prepared nanosized danazol powder via the gas absorption method. Calculation was based on the BET equation. 2.5. Chemical Composition and Physical Characteristics. FT-IR analysis was carried out in the range 400-4000 cm-1 using a resolution of 2 cm-1 and 32 scans to evaluate the molecular states of raw danazol and the nanosized danazol. Samples were diluted with KBr mixing powder at 1% and pressed into self-supporting disks. X-ray diffraction (XRD) was employed to detect the crystallinity of danazol, which was conducted using a XRD-6000 diffractometer (Shimadzu, Japan). The sample powder was placed in a glass sample holder. Cu KR1 radiation was generated at 30 mA and 40 kV. Samples were scanned from 10° to 60° (2θ) at a rate of 5°/min. 2.6. Dissolution Rate Test. Dissolution rate tests were carried out following the USP Apparatus 2 (paddle) method (D-800LS, Tianjin, CN). The paddle speed and bath temperature were set at 75 rpm and 37.0 ( 0.5 °C, respectively. A 0.75% SLS aqueous solution was employed as the dissolution medium. The dissolution rate tests were performed at sink conditions. A 20 mg sample of raw danazol or nanosized danazol powder was respectively added into different vessels containing 900 mL of the dissolution medium. A 5 mL aliquot was taken each time at specific time intervals and filtered though a 0.45 µm syringe filter. The concentration of the samples was assayed by a UV spectrophotometer (UV-2501, Shimadzu, Japan) at 286 nm. 3. Results and Discussion 3.1. Effects of Flow Rate Ratios of the Antisolvent to Danazol Solution on the Particle Size and Morphology. Since the driving force of precipitation formation is the supersaturation of a solution induced by the mixing of drug solution and an antisolvent, a high degree of the supersaturation, which resulted
Table 1. Relationship of Solubility to Specific AS/S Ratios and Mean Particle Sizes AS/S ratio (v/v)
solubility (µg/mL)
flow rate of S (mL/min)
flow rate of AS (mL/min)
0 1 2 5 10 20 40 ∞ 20 (at 4 °C)
35000 1336.03 79.30 4.40 2.83 2.18 2.16 1.84 1.63
80 80 40 16 8 4 2 0 4
0 80 80 80 80 80 80 80 80
mean particle size (nm)
1250 900 510 505 364
from the solute concentration fall in the mixture, will generate a homogeneous nucleation process. The nucleation time will be shortened according to the C - Ceq increase of the concentration fall.16 Table 1 shows the danazol equilibrium solubility at different AS/S ratios. The mixing performance in a Y-type MCR always improves with increasing Reynolds number.41 Using this tendency, we set the flow rate of the antisolvent at 80 mL/min (maximum value) and regulate the flow rate of the solution to achieve various AS/S ratios, expecting possible small particle sizes. The flow rate of the antisolvent inlet was fixed at 80 mL/ min, while the flow rate of the solution at the inlet was regulated via the continuous nonpulsatile pump to adjust the AS/S ratio from 1 to 40. As shown in Figure 4a-d, the particles appear to have a platelet shape. With the increase of the AS/S ratio from 5 to 40, the decrease of the danazol particle size can be clearly observed. The SEM images and the corresponding PSD results (Figure 4e) indicate that there is an inverse proportional relationship between the AS/S ratio and the particle size. There are two probable reasons for this phenomenon. First, the instantaneous supersaturation level of the solution was greatly increased due to the reduction of the solvent concentration from the enhancement of the AS/S ratio when the danazol solution
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Figure 4. SEM images of danazol particles prepared at different AS/S ratios: (a) AS/S ) 5; (b) AS/S ) 10; (c) AS/S ) 20; (d) AS/S ) 40. (e) Particle size distributions of danazol particles prepared at different ratios.
and the deionized water were mixed. Second, the crystal growth can be expressed by16
dl ) Kg(Ci - C*)b dt
(2)
where Kg is the crystal growth rate constant; Ci and C* are the solute concentration on the crystal surface and the saturation concentration, respectively. The value of the parameter b is usually between 1 and 3. The increased antisolvent volume virtually decreases the solute concentration on the formed danazol crystal surface. Therefore, the decreased value of Ci C* results in a lower crystal growth rate of the danazol crystal embryo, thereby resulting in smaller ultimate particle size. However, when the AS/S ratio was larger than 20, the danazol particle size would not obviously decrease with the increase of the ratio. The reason for this is that the value of Ci - C* had already achieved a relatively constant level. 3.2. Effect of Preparation Temperatures on the Particle Size. Figure 5shows SEM images and the corresponding particle size distributions of danazol particles precipitated under the conditions of different antisolvent temperatures. The particle size of danazol prepared at 4 °C was apparently smaller than that obtained at 30 °C. The probable reasons are (1) lower
temperature results in higher supersaturation level, which leads to smaller critical nuclei size (r*), and (2) the precipitation in the liquid phase is a diffusion-limited process.43 Low temperature would decrease the diffusion rate and accordingly the crystal growth rate. Therefore, lower temperatures tended to lead to smaller particles. The particle morphologies and the corresponding particle size distributions of the raw danazol and nanosized danazol are displayed in Figure 6. The particle sizes of the as-prepared danazol were centered at 364 nm. In comparison, the particle sizes of the raw danazol with irregular morphologies widely ranged from 20 to 120 µm. The mean particle size was sharply decreased from 55 µm of the raw danazol to 364 nm of the as-prepared (optimal parameter AS/S ) 20; AS ) 4 °C) danazol nanoparticles. 3.3. FT-IR and XRD Analyses. FT-IR analysis was performed to evaluate the molecular states of raw danazol and the as-prepared danazol nanoparticles. The corresponding FT-IR spectra are presented in Figure 7. The identical FT-IR spectra curves suggest that there was no chemical structure change, as was to be expected in the danazol molecules. The XRD patterns of the raw danazol and danazol nanoparticles are given in Figure 8. The same peak position of the raw
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Figure 5. SEM images of (a) danazol particles prepared at 30 °C and antisolvent (b) at 4 °C and (c) corresponding particle size distributions.
Figure 6. (a, b) SEM images of raw danazol and nanosized danazol, and (c, d) corresponding particle size distributions of raw and nanosized danazol.
Figure 8. XRD patterns of raw danazol and nanoparticles.
Figure 7. FT-IR spectra of raw danazol and nanoparticles.
danazol and the nanosized danazol proved that the physical characteristics were not affected by the antisolvent based nanonization process.
3.4. Dissolution Rate Test. After nanonization, the sharply decreased particle size resulted in a 21-fold increase of the specific surface area from 0.66 to 14.37 m2/g. The dissolution profiles of the raw danazol and the nanoparticles are compared in Figure 9. The nanoparticles reached 100% drug dissolution within 5 min. However, only 35% of raw danazol was dissolved during the same period. The raw danazol
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Figure 9. Dissolution rate tests for raw danazol and nanoparticles.
achieved complete dissolution after 40 min. The results indicate that the dissolution rate of danazol after nanonization was significantly enhanced. Since no surfactants were included in raw danazol or the nanoparticles, the decreased particle size and the accordingly increased specific surface area resulted in the increased dissolution rate of the danazol nanoparticles. Moreover, the decrease in the particle size would lead to a thinner hydrodynamic layer around the particles, which also confirmed the fact that the danazol nanoparticles possessed a much better dissolving property than the raw danazol particles.44 4. Conclusion Because of the created great concentration fall of LASP, which was the driving force for triggering homogeneous nucleation, and the excellent micromixing property in the MCR, danazol nanoparticles with narrow size distribution and large specific surface area were successfully synthesized without any additives. The effects of various AS/S ratios and preparation temperatures on mean particle size and size distribution of danazol were investigated in this study. The particle size exhibited a decreasing tendency with the AS/S ratio increase and antisolvent temperature decrease. Under the conditions of AS/S ratio of 20 and antisolvent temperature of 4 °C, danazol nanoparticles with a mean size of 364 nm were successfully prepared. Correspondingly, the specific surface area markedly increased from 0.66 to 14.37 m2/g after nanonization. Thus, the reduced particle size and enlarged specific surface area led to significant improvement of the danazol dissolution rate. There was no change in the molecular state and physical characteristics after processing according to FT-IR and XRD analyses. Therefore, LASP in MCR would offer a great opportunity for poorly water-soluble drugs to achieve uniform nanosized particles and concomitant dissolution rate enhancement. Acknowledgment This work was financially supported by NSF of China (No. 20325621). Literature Cited (1) Rasenack, N.; Mu¨ller, B. W. Dissolution rate enhancement by in situ micronization of poorly water-soluble drugs. Pharm. Res. 2002, 19, 1894-1900. (2) Mu¨ller, R. H.; Jacobs, C.; Kayser, O. Nanosuspensions as particulate drug formulation in therapy rationale for development and what we can expect for the future. AdV. Drug DeliVery ReV. 2001, 47, 3-19. (3) Merisko-Liversidge, E.; Liversidge, G. G.; Cooper, E. R. Nanosizing: a formulation approach for poorly-water-soluble compounds. Eur. J. Pharm. Sci. 2003, 18 (2), 113-120. (4) Hu, J. H.; Johnston, K. P.; Williams, R. O., III. Rapid dissolving high potency danazol powders produced by spray freezing into liquid process. Int. J. Pharm. 2004, 271 (1-2), 145-154.
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ReceiVed for reView April 9, 2007 ReVised manuscript receiVed July 6, 2007 Accepted August 10, 2007 IE070498E
