Article pubs.acs.org/OPRD
Recrystallizing Primidone through Supercritical Antisolvent Precipitation Hung-Hsin Chen and Chie-Shaan Su* Department of Chemical Engineering and Biotechnology, National Taipei University of Technology, Taipei, Taiwan S Supporting Information *
ABSTRACT: In this study, an active pharmaceutical ingredient, primidone, was recrystallized through supercritical antisolvent precipitation (SAS) by using CO2 as the antisolvent. The operating parameters of SAS, such as the solvent system, operating temperature and pressure, solution concentration and flow rate, CO2 flow rate, and nozzle diameter, were studied systematically. The solid-state properties of the original and processed primidone, including crystal habit, mean particle size, polymorphic form, and residual solvent content, were analyzed and are discussed. Two novel polymorphic forms of primidone, forms C and D, were obtained, and their crystal habits and mean particle sizes before and after SAS differed significantly. In addition, the dissolution profiles of the original and processed primidone were studied and compared. The experimental results showed that the recrystallized primidone had an enhanced dissolution rate compared with the original primidone. These results demonstrate that through SAS the solid-state properties of primidone can be controlled and modified and that microparticles with a novel polymorphic form and enhanced dissolution behavior can be produced.
1. INTRODUCTION In the pharmaceutical industry, controlling and modifying the solid-state properties, such as particle size, crystal habit, and polymorphic form, of active pharmaceutical ingredients (APIs) are critical in improving drug bioavailability, designing drug development strategies, and developing formulation processes.1−3 For example, Lust et al.4 studied the effects of different solid-state forms of a poorly water-soluble API on drug dissolution and bioavailability in rats. Shekunov and York5 discussed the design and development of crystallization processes for controlling solid-state properties in the pharmaceutical industry. Steed6 reviewed the role of cocrystals in pharmaceutical design. The solid-state properties of APIs are generally controlled through solution crystallization and mechanical milling in conventional manufacturing processes. However, this route has several disadvantages, such as batch-tobatch variation, residual solvent contamination, and surface property destruction. Alternative crystallization processes must therefore be designed and developed to manipulate the solidstate properties of APIs. In recent years, supercritical fluid technology has been widely used in various applications. Many studies have used supercritical fluids for recrystallization of pharmaceutical compounds because of their numerous advantages.7−9 Several supercritical fluid crystallization processes have been developed on the basis of the solubility of APIs in supercritical fluids. These techniques include rapid expansion of supercritical solution, supercritical antisolvent precipitation (SAS), supercritical-assisted atomization, and particle from gas-saturated solution.10,11 SAS is most commonly used for processing of pharmaceutical compounds. For example, Bakhbakhi et al.12 used SAS to produce fine ibuprofen sodium particles with control over their particle size and size distribution. The mechanisms underlying this control have been explained using nucleation and growth kinetics. Kim et al.13 recrystallized the anticancer drug silibinin © XXXX American Chemical Society
through SAS and investigated the effect of additives on the crystal habit of the produced silibinin crystals. Brun et al.14 studied the recrystallization of caffeine extracted from coffee beans through SAS using dichloromethane. The effect of process parameters and the modification of polymorphism were compared and discussed. Park et al.15 recrystallized fluconazole through SAS with control over its solid-state characteristics, including polymorphic form and orientation, by changing the operating temperature and pressure. Bettini et al.16 obtained a new polymorph of didanosine, which is highly soluble in water, through SAS. In addition to API recrystallization, SAS has been used to produce composite particles, such as polyvinylpyrrolodone (PVP)/ibuprofen sodium solid dispersions,17 PVP/ insomethacin coprecipitates,18 and itraconazole/L-malic acid cocrystals.19 In addition to laboratory-scale SAS studies, scaleup issues related to SAS, including phase behavior, fluid dynamics, nucleation rate, and growth kinetics, were discussed by Thiering et al.20 Perrut and Clavier21 discussed process choice and scale-up considerations for supercritical fluid processes, including SAS. Guidelines to make the optimal choice and general scale-up rules with specific constraints related to pharmaceutical plants were illustrated. Furthermore, several pilot-scale SAS studies have also been presented in the literature. For example, Reverchon et al.22 micronized an antibiotic, amoxicillin, in an SAS pilot plant. The effect of the scale enlargement and the kind of injection device on the powder size and morphology were investigated. Adami et al.23 compared the micronization results for nalmefene HCl in laboratory- and pilot-scale SAS. The SAS results obtained from the laboratory-scale apparatus were successfully reproduced in the pilot-scale plant. Received: September 7, 2015
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DOI: 10.1021/acs.oprd.5b00279 Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Organic Process Research & Development
Article
0.5 μm was installed at the bottom of the precipitator to collect the produced crystals. First, the supercritical CO2 and pure solvent were delivered into the precipitator until the temperature, pressure, and flow rate reached a steady state. Next, the liquid feed flow was switched from pure solvent to drug solution. After the drug solution came in contact with the supercritical CO2, rapid recrystallization occurred because of the high supersaturation of the solute. After a sufficient quantity of the drug solution was injected, the injection procedure was stopped, and the residual solvent inside the precipitator was removed through supercritical drying in which supercritical CO2 was delivered continuously for more than 30 min. The drying time was determined using a continuous stirred tank reactor model.24 Subsequently, the precipitator was depressurized, and the particles precipitated on the stainless steel frit were collected for further analyses. 2.3. Analytical Method. To compare the solid-state properties before and after SAS, the produced crystals were analyzed through scanning electron microscopy (SEM), laser light scattering particle size analysis, powder X-ray diffractometry (PXRD), differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), and thermogravimetric analysis (TGA). During SEM measurements to compare the crystal habit before and after SAS, the samples were fixed on a conductive adhesive tape and sputtered using a thin gold film. Images of the samples were captured using an SEM instrument (Hitachi S-3000H). To estimate the particle size of the primidone crystals, approximately 30−50 mg of the crystals was suspended in deionized water containing the surfactant Tween 80. The volumetric mean particle size was determined using a laser light scattering particle size analyzer (Malvern Mastersizer 2000). The crystal structures of the primidone particles were detected by PXRD on a PANalytical X’pert diffractometer with a scanning range of 5−50° at a scanning rate of 3 deg/min. The thermal behavior of the crystals was investigated by DSC (PerkinElmer, Jade DSC) and TGA (TA, Dupont 951). For the DSC measurements, the samples were heated from 50 to 240 °C, and for the TGA analyses, the samples were heated from 50 to 680 °C at 20 °C/ min. In addition, the spectroscopic properties of the samples were confirmed through FTIR (PerkinElmer, Spectrum 100) analysis. In addition, the dissolution profiles of the primidone crystals before and after SAS were investigated. The dissolution rate of primidone was elucidated using a dissolution tester (Shin Kwang, DT-3) and a paddle method. The dissolution medium was 900 mL of water. This medium was maintained at 37 °C; the speed of the paddle agitator was 50 rpm. Next, primidone crystals were added to the dissolution medium, and at specific time intervals 3 mL of the liquid was withdrawn and filtered using a 0.45 μm filter. The dissolved amount of primidone was analyzed by UV−vis spectroscopy (Thermo, Evolution 60S) by measuring the absorbance at 257 nm.
In this study, SAS was employed to recrystallize primidone, an anticonvulsant, with control over its solid-state properties, such as mean particle size, crystal habit, and polymorphic form. The effects of the operating parameters of SAS, namely, the solvent system, operating temperature and pressure, solution concentration, CO2 and solution flow rate, and nozzle diameter, on the mean particle size of SAS-processed primidone were studied and compared. The solid-state properties of the recrystallized primidone were investigated and are discussed. In addition, the dissolution profiles of primidone before and after SAS were compared to verify practicability.
2. MATERIALS AND METHODS 2.1. Materials. In this study, CO2 with a minimum purity of 99.9% was purchased from Cheng-Feng Gas Co. (Taiwan) and used as the supercritical antisolvent. The anticonvulsant primidone (C12H14N2O2), with a minimum purity of 99% was purchased from Sigma-Aldrich. Thirteen organic solvents, namely, acetonitrile, acetone, dichloromethane, N,N-dimethylacetamide (DMAC), N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), ethanol, ethyl acetate, n-heptane, methanol, methyl ethyl ketone (MEK), N-methyl-2-pyrrolidinone (NMP), and tetrahydrofuran (THF), were considered in this SAS study for screening of the solvent system. These organic solvents with a minimum purity of 99.5% were purchased from Sigma-Aldrich, Merck, J. T. Baker, and Macron Fine Chemical. All of the chemicals were used as obtained. 2.2. Apparatus and Procedure. Figure 1 illustrates the SAS system, which comprised two high-performance liquid
Figure 1. SAS apparatus.
3. RESULTS AND DISCUSSION 3.1. Solvent Selection. In this study, SAS was used to recrystallize primidone with control over its solid-state properties. According to the ICH Q3C guidelines, 13 organic solvents that are less toxic and are commonly used in pharmaceutical processes were considered: acetonitrile, acetone, dichloromethane, DMAC, DMF, DMSO, ethanol, ethyl acetate, n-heptane, methanol, MEK, NMP, and THF. To obtain
chromatography pumps (SSI, series II), one for CO2 delivery and the other to pump the primidone solution. The CO2 flow rate could be adjusted using a micrometering valve at the exit of the precipitator and was measured using a rotameter under ambient conditions. Pressure in the precipitator was regulated using a back-pressure regulator (Tescom). The precipitator (total volume 70 mL) was immersed in a temperaturecontrolled water bath. A stainless-steel frit with a pore size of B
DOI: 10.1021/acs.oprd.5b00279 Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Organic Process Research & Development
Article
Table 1. Recrystallization of Primidone by SAS operating parameters
a
exp. no.
solvent
T (°C)
P (bar)
conc. (%)
FCO2 (L/min)
original 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
− DMACa DMFb DMSOc NMPd methanol DMAC DMAC DMAC DMAC DMAC DMAC DMAC DMAC DMAC DMAC DMAC DMAC
− 35 35 35 35 35 45 55 35 35 35 35 35 35 35 35 35 35
− 100 100 100 100 100 100 100 80 120 100 100 100 100 100 100 100 100
− 90 90 90 90 90 90 90 90 90 30 60 90 90 90 90 90 90
− 4 4 4 4 4 4 4 4 4 4 4 1 2 4 4 4 4
results Fsoln (mL/min)
nozzle diam. (μm)
recovery (%)
polymorphic form
mean size (μm)
span
− 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.50 1.00 0.25 0.25
− 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 50 200
− 90.8 92.6 72.0 91.7 68.0 91.9 67.2 91.6 85.0 89.1 93.8 65.9 89.4 87.8 84.7 95.7 93.4
A C C C+D A+C D A+C A C C C C A+C C C A+C C C
66.7 14.6 30.4 24.5 24.8 38.3 21.2 24.8 11.4 18.8 18.0 12.6 24.5 20.6 18.0 24.8 22.9 13.8
1.95 1.20 1.98 1.53 1.48 1.86 1.40 1.52 1.28 2.12 1.88 1.61 1.39 1.51 1.56 1.32 1.43 1.66
DMAC: N,N-dimethylacetamide. bDMF: N,N-dimethylformamide. cDMSO: dimethyl sulfoxide. dNMP: 1-methyl-2-pyrrolidinone.
beneficial for SAS processing. The SAS results obtained using DMAC, DMF, DMSO, methanol, and NMP as solvents are listed in Table 1. High recovery yields (>90%) were obtained using DMAC, DMF, and NMP. To investigate the micronization of primidone, DMAC was used as the ideal solvent system because the smallest primidone crystals were obtained using DMAC. 3.2. Effects of Operating Parameters. The effects of six operating parameters, namely, the operating temperature, operating pressure, solution concentration, CO2 flow rate, solution flow rate, and spraying nozzle, on the mean particle size of SAS-processed primidone were investigated using DMAC as the solvent (Figure 2). The particle diameter decreased with decreasing operating temperature. This phenomenon can be explained using crystallization kinetics. Both the nucleation and growth rates decrease with decreasing operating temperature. In this study, the decrease in the growth rate with decreasing temperature might have dominated the process. Small crystals were obtained because the growth rate decreased with decreasing operating temperature (Figure 2a). Similar results have been reported by Rueda et al.,29 Kim et al.,30 and Reverchon et al.31 In addition, the effect of the operating temperature can also be illustrated by thermodynamic principles. Figure 3a shows the predicted VLEs of CO2 + DMAC at 35, 45, and 55 °C obtained using the PSRK equation of state. The operating pressure at 100 bar was also plotted (the CO2 mole fraction in the precipitator was calculated as 0.98). As can be seen, while the operating temperature increased from 35 to 45 °C, the operating regions were shifted from above the MCP to near the gas-phase region. When the operating temperature was further increased to 55 °C, the operating region was below the MCP. According to the literature,32,33 operating above the MCP at 35 °C is beneficial for SAS recrystallization, and these conditions produced the smallest primidone crystals in this study. For the effect of operating pressure, Figure 2b shows that a low operating pressure was favorable for producing small primidone crystals. Thermodynamic principles can also be used
the ideal solvent system, the solubilities of primidone in these 13 organic solvents at 35 °C were measured using the method developed by Lee et al.25 The measured solubility data are listed in Table S1 in the Supporting Information. As can be seen, primidone was poorly soluble in acetonitrile, acetone, dichloromethane, ethanol, ethyl acetate, n-heptane, MEK, and THF (95% of the primidone crystals dissolved within 1 min).
4. CONCLUSION Primidone was recrystallized by SAS with control over its solidstate properties and dissolution behavior. The effect of the operating parameters, namely, the solvent system, operating
Figure 10. Dissolution profiles of the original and SAS-processed primidone.
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DOI: 10.1021/acs.oprd.5b00279 Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Organic Process Research & Development
Article
temperature, operating pressure, solution flow rate, CO2 flow rate, solution concentration, and nozzle diameter, on the mean particle diameter were systematically compared. After SAS, modifications in particle size, crystal habit, and polymorphic form were confirmed through SEM, PXRD, DSC, TGA, FTIR, and particle size analyses. Primidone was successfully micronized from its original size of 66.7 μm to 11.4 μm. In addition, two novel polymorphs of primidone were obtained and characterized by PXRD, DSC, and FTIR analyses. Furthermore, the recrystallized primidone had a considerably higher dissolution rate compared with the original crystal. These results showed that SAS can control the solid-state properties and increase the dissolution profile of APIs.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.oprd.5b00279. Solubilities of primidone in organic solvents, vapor− liquid equilibria of binary mixtures containing CO2, and gas chromatograms from residual solvent analysis (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Tel: (886-2) 2771-2171. Address: 1, Sec. 3, Zhongxiao E. Rd., Taipei 10608, Taiwan. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS The authors are grateful for the support from Ministry of Science and Technology, Taiwan (Project 104-2221-E-027104). The authors are also grateful for the support from Pharmaceutical Engineering Technologies Department, Industrial Technology Research Institute, Taiwan, for residual solvent analysis.
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DOI: 10.1021/acs.oprd.5b00279 Org. Process Res. Dev. XXXX, XXX, XXX−XXX
