ARTICLE pubs.acs.org/IECR
Recrystallization and Micronization of 10-Hydroxycamptothecin by Supercritical Antisolvent Process Yanbin Jiang,* Wenli Sun, and Wei Wang School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou, 510640, People’s Republic of China ABSTRACT: Recrystallzation and micronization of 10-hydroxycamptothecin (HCPT) was investigated in a supercritical antisolvent (SAS) process using the mixture of dichloromethane and ethanol as the solvent, with supercritical carbon dioxide (sc-CO2) as the antisolvent. Five factors—i.e., the volume ratio of the mixed solvent, the concentration of HCPT in the solution, the flow rate of HCPT solution, the precipitation pressure, and the temperature—were optimized using a selected OA16 (45) orthogonal array design. The unprocessed and processed HCPT particles were characterized using laser diffraction particle size analysis, Fourier transform infrared (FT-IR) spectroscopy, headspace gas chromatography, scanning electron microscopy (SEM), powder X-ray diffraction (XRD), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA). The results indicated that the micronized HCPT exhibited a much smaller particle size under the optimal conditions, and the mass median diameter of the micronized HCPT was found to be 223 ( 19 nm. SEM indicated a change in crystal habit for SAS-processed particles, and the results of powder XRD showed that different polymorphs were found after the SAS processing. Polymorph conversation was further demonstrated by DSC and TGA, and the results indicated that the SAS process modified the form of HCPT from monohydrate to anhydrous.
1. INTRODUCTION 10-Hydroxycamptothecin (HCPT), a camptothecin analogue, is a promising anticancer agent that acts on topoisomerase I, inhibiting DNA replication and RNA transcription by formed the cleavable complexes between topoisomerase and DNA.1,2 Therefore, HCPT and other campothecin analogues have been extensively studied worldwide.3 5 However, the practical use of HCPT has been limited, mainly because of its poor solubility in water and other physiologically acceptable organic solvents. In current clinical administration, HCPT are formulated as a sodium salt of the carboxylate, which exhibited minimal anticancer activity and several side effects in clinical trials.6,7 To overcome these limitations of HCPT, various methods have been investigated, including microspheres,8 niosomes,9 emulsions,10 nanosuspensions,11 and prodrugs.12 One of the most simple but effective methods to improve the therapeutic efficacy and bioavailability of drugs is to produce microparticles or nanoparticles. The supercritical antisolvent (SAS) technique is a new micronization technology that has been developed recently, which has been investigated to manufacture fine particles in various fields, such as explosive,13 pharmaceutical,14 agricultural,15 and electronic industries.16 The SAS process is possible to control the particle size, the particle size distribution, and greatly reduce solvent residual. These advantages are significant for the production of pharmaceutical compounds.17 Until now, many drugs were recrystallized using the SAS process.18 22 Besides particle size, its distribution, and morphology, different polymorphic forms of pharmaceuticals also present different physical properties, which affect many characteristics, such as bioavailability.23 The SAS process may also modify the polymorphism24 or crystal habit25 of a pharmaceutical compound; recently, much effort has been devoted into r 2011 American Chemical Society
the polymorphic forms of pharmaceuticals while using the SAS process. The aim of this work is to recrystallize and micronize HCPT by a SAS process using supercritical CO2 as the antisolvent. An orthogonal array (OA) design method is adopted to optimize SAS process conditions, which influence the mass median diameter (Dp50) of micronized HCPT, and the effect of process parameters on polymorphism is particularly emphasized in this study.
2. EXPERIMENTAL SECTION 2.1. Materials. CO2 with a minimum mass purity of 99.9% was purchased from Guangzhou Shengying Gas Co., Ltd., China. HCPT (mass purity >99%) was obtained from Chengdu Lanbei Plant & Chemical Co., Ltd., China. The molecular weight of HCPT is 364.35, and its molecular structure is described in Figure 1. Chemically pure Tween80, as well as analytical-grade dichloromethane (DCM, mass purity >99.5%) and ethanol (mass purity >99.7%), were purchased from Guangdong Guanghua Sci. Tech. Co., Ltd., China. Chromatographic-grade DCM, ethanol, and dimethylformamide were purchased from Tianjin Kermel Chemical Reagent Co., Ltd., China. All materials were used directly without further purification. 2.2. Apparatus and Procedure. The equipment of automatic semicontinuous SAS process (SAS50-2-ASSY, Thar Technologies, Inc., USA) was employed to carry out the micronization Received: May 23, 2011 Accepted: December 20, 2011 Revised: December 14, 2011 Published: December 20, 2011 2596
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experiments. The flow diagram is illustrated in Figure 2. CO2 was liquefied with cooler and continuously introduced into the precipitation vessel via a high-pressure pump. Before entering the injector, the stream of carbon dioxide was preheated by a heat exchanger. The pressure was controlled by a backpressureregulating valve. Temperature in the precipitation vessel was regulated to a prespecified level. While a steady state was achieved, HCPT solution was charged at a given flow rate by another high-pressure pump and sprayed into the precipitation vessel through a nozzle (0.5 mm). CO2 flow rate measured by a flow meter was fed simultaneously at a constant flow rate of 20 g/min. An ultrafiltration membrane (0.22 μm) and a metal filter (5 μm) were located at the bottom of the precipitation vessel for particle collection. After finishing injection of HCPT solution, CO2 was kept flowing for ∼40 min to remove the residual solvent in the precipitation vessel. The precipitation vessel was then depressurized gradually to atmospheric pressure. Finally, the obtained particles were collected from the bottom of the precipitation vessel for further characterization analysis. 2.3. Design of the Experiment. Factors that are considered to have an effect on the performance of the SAS process were considered, including the volume ratio of DCM and ethanol (VR), the concentration of HCPT in the solution (C), the flow
Figure 1. Chemical structure of 10-hydroxycamptothecin (HCPT).
Figure 2. Flow diagram of the supercritical antisolvent (SAS) process.
rate of HCPT solution (F), the precipitation pressure (P), and the precipitation temperature (T). A selected orthogonal array design (i.e., OA16 (45)) was adopted to optimize the operating conditions of the SAS process. The SAS experiments were carried out with five factors and four levels, as shown in Table 1. The range of each level was based on the results of preliminary experiments. 2.4. Analytical Methods. The particle size distribution and Dp50 value of the HCPT samples were measured using a laser diffraction particle size analyzer (Model Mastersizer 2000, Malvern, U.K.). Before each measurement, the micronized HCPT was suspended in pure water. To avoid the aggregation of particles, two drops of Tween80 were added into the sample, then stirred it by ultrasonic for 15 min in order to disperse effectively. Every measurement was repeated at least three times. Fourier transform infrared (FT-IR) spectrometry (Model Nicolet Nexus 670, Thermo Electron Corporation, USA) was used to examine the chemical structure of the processed and unprocessed HCPT. And the residual solvents in the optimal processed HCPT sample were measured by a static headspace gas chromatography (Model GC-MS 4000, Varian, USA). The morphologies of the unprocessed and processed HCPT were observed through a scanning electron microscopy (SEM) (Model LEO 1530VP, LEO, Germany) at an accelerating voltage of 5 kV. When preparing the samples for SEM measurement, particles were spread on a metal stubs using double-side adhesive carbon tap, then coated with a thin layer of gold palladium alloy in an argon atmosphere using a sputter coater at room temperature. The conversion of polymorphs was detected by a powder X-ray diffraction (XRD) (Model D8 ADVANCE, Bruker AXS, Germany). The thermal analysis then was carried out using differential scanning calorimetry (DSC) Model DSC Q200, TA Instruments, USA) and thermogravimetric apparatus (TGA) (Model TGA Q500, TA Instruments, USA) for processed and unprocessed HCPT particles.
3. RESULTS AND DISCUSSION In the SAS process, the solvent system must satisfy the requirements outlined below. First, the solvent system must dissolve HCPT; second, the solvent system must have a greater volume expansion. Stievano26 investigated the density of ethanol, acetone, and DCM in the compressed carbon dioxide, and the results showed that volume expansion of DCM is the largest. For the SAS process, DCM is a good solvent but is difficult to dissolve HCPT. To increase the solubility of HCPT, ethanol was added as a modifier. The phenomenon that the mixture of DCM and ethanol can increase the solubility of HCPT is thought to be due to the cosolvent effect of ethanol. In this study, the mixtures of DCM and ethanol with different volume ratios were used as mixed solvent, while compressed CO2 was used as an antisolvent.
Table 1. Factors and Levels of the Orthogonal Array Design Factors volume ratio of DCM
concentration of HCPT
flow rate of HCPT solution,
precipitation pressure,
precipitation temperature,
level
and ethanol, VR
in the solution, C (mg/mL)
F (mL/min)
P (bar)
T (°C)
1
1:1
0.50
0.2
80
30
2 3
2:1 3:1
0.75 1.00
0.5 0.8
100 120
35 40
4
4:1
1.25
1.1
140
45
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3.1. Optimization Study. The first step in the SAS micronization process is to optimize the operating conditions in order to obtain a minimum Dp50 of micronized HCPT. In this study, all identified factors were examined according to the selected OA16 (45) orthogonal array design, as shown in Table 1. All the experimental results are listed in Table 2 and discussed as follows. It was found that the processed HCPT particles have different Dp50. The data of Dp50 from orthogonal experiments were treated with range (R) analysis to evaluate the effect of each parameter on the optimization criteria. Figure 3 compares several typical mass particle size distributions (PSDs) of the HCPT samples, which indicates that the Dp50 of processed HCPT particles is much smaller than the unprocessed particles, and the PSD becomes narrower. According to the R values, it can be concluded from Table 2 that the order for the influence of the five parameters on Dp50 of micronized HCPT is as follows: F > VR > T > C > P. According to the values of ki listed in Table 2, the optimal conditions are determined as follows: VR = 4:1, C = 0.75 mg/mL, F = 0.8 mL/min, P = 140 bar and T = 40 °C, respectively. Under the optimal conditions, the processed HCPT sample is much smaller, with Dp50 = 223 ( 19 nm. 3.2. Results of FT-IR. FT-IR spectroscopy was applied to determine the chemical structure before and after SAS processing. Figure 4 shows the FT-IR patterns of the unprocessed HCPT and the optimal processed HCPT. The characteristic band at 1652.79 cm 1 is attributed to the acylamino group. The peaks at 1588.48 cm 1 and 1503.83 cm 1 are assigned to the absorption band of the aromatic ring of HCPT. As shown in Figure 4, no significant differences are observed between the two patterns. Therefore, it is clear that the chemical structure of the processed HCPT is the same as that of the raw material. 3.3. Results of Residual Solvents. DCM is an International Conference on Harmonization (ICH) class II solvent, and ethanol is an ICH class IV solvent. When organic solvents are
used, it is essential to determine the residual solvents in the product. In this study, the standard curves for DCM and ethanol were determined, using Varian Model GC-MS 4000. For DCM, the relationship between the concentration (Y) and the peak area (A) is Y = 4 106A (r = 0.9804), whereas, for ethanol, it is Y = 3 105A (r = 0.9465). According to the standard curves, the residual DCM and ethanol in the processed HCPT are 275 ppm and 216 ppm, respectively, which are both lower than the ICH limits for class II and class IV solvents. Thus, the SAS process is suitable for micronizing pharmaceuticals. 3.4. Results of SEM and Powder XRD. All HCPT samples were characterized by SEM and powder XRD for investigating the crystal habits and diffraction peak respectively. The results of crystal habits are summarized in Table 2. The results of SEM indicate that there are three different HCPT crystal habits. Moreover, the results of powder XRD also show that there are three,
Figure 3. Particle size distribution of typical HCPT samples.
Table 2. OA16 (45) Matrix for Optimization of Operating Conditions and the Experimental Results run
VR
C
F
P
Dp50 ( SD* (nm)
T
polymorph
morphology
1
1
1
1
1
1
666 ( 50
Form III
needlelike
2
1
2
2
2
2
464 ( 20
Form III
needlelike
3 4
1 1
3 4
3 4
3 4
3 4
382 ( 27 539 ( 29
Form II Form III
prismatic needlelike
5
2
1
2
3
4
618 ( 40
Form III
needlelike
6
2
2
1
4
3
589 ( 57
Form II
prismatic
7
2
3
4
1
2
568 ( 35
Form III
needlelike
8
2
4
3
2
1
595 ( 45
Form III
needlelike
9
3
1
3
4
2
504 ( 22
Form II
prismatic
10
3
2
4
3
1
578 ( 32
Form III
needlelike
11 12
3 3
3 4
1 2
2 1
4 3
672 ( 31 510 ( 19
Form II Form II
prismatic prismatic needlelike
13
4
1
4
2
3
396 ( 47
Form III
14
4
2
3
1
4
391 ( 24
Form III
needlelike
15
4
3
2
4
1
438 ( 18
Form III
needlelike
608 ( 63
Form III
needlelike
223 ( 19
Form III
needlelike
16
4
4
1
3
2
k1
513 ( 32
546 ( 40
634 ( 50
534 ( 32
569 ( 36
k2
593 ( 44
506 ( 33
508 ( 24
532 ( 36
536 ( 35
k3 k4
566 ( 26 458 ( 38
515 ( 28 563 ( 39
468 ( 30 520 ( 36
547 ( 41 518 ( 32
469 ( 38 555 ( 31
R optimal
135 VR4
57 C2
166 F3
29
100
P4
T3 2598
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Figure 4. FT-IR spectra of raw material and the optimal processed level.
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Figure 6. Powder X-ray diffraction (XRD) result of Form I (raw material).
Figure 5. SEM morphologies of typical HCPT samples: (a) raw material, (b) run 4, (c) run 9, (d) run 11, and (e) the optimal sample.
correspondingly, different types of powder XRD patterns. These results indicate that new polymorphs are produced after SAS processing. Therefore, the polymorph conversation of HCPT before and after the SAS process is emphasized in this study. Figure 5 shows the SEM photomicrographs of typical samples (i.e., (a) unprocessed particles, (b) run 4, (c) run 9, (d) run 11, and (e) the optimal sample). The unprocessed HCPT particles exhibit an irregular biscuit habit with a rough surface, and the SAS-processed HCPT particles have different crystal habits, i.e., prismatic (c, d) and needlelike (b, e). Selected typical patterns of different samples are shown in Figures 6 8, including the unprocessed HCPT, run 9, run 11, run 4, and the optimal sample. Observation of the powder XRD pattern of Figure 6 indicates that the diffraction peaks are located at the diffraction angles (2θ scale) of 8.2°, 10.0°, 12.4°, 16.3°, 25.4°. However, the diffraction pattern of Figure 7 shows
Figure 7. Powder X-ray diffraction (XRD) patterns for typical samples of Form II: (a) run 9 and (b) run 11.
characteristic high-intensity diffraction peaks at 9.4°, 12.0°, and 14.2° of the 2θ scale, and the peaks of Figure 8 distribute in the angles of 6.9°, 9.0°, 11.7°, 13.8°, and 26.2°. According to the above powder XRD results, it can be found that the diffraction peaks of the processed HCPT samples are significantly different from the raw material. Actually, a distinctive diffraction pattern is indicative of a particular crystalline phase, according to Figures 6 8, it 2599
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Figure 8. Powder X-ray diffraction (XRD) patterns for typical samples of Form III: (a) run 4 and (b) optimal sample.
is reasonable to deduce that there are three different HCPT polymorphs, which are defined as Form I, Form II, and Form III, respectively. Thus, Figures 6 8 indicate that the unprocessed HCPT sample (Form I) transforms to other polymorphic forms (Form II and Form III) after processing to some extent. The results of SEM and powder XRD indicate that the SAS process provides a proper environment for the suitable growth of different polymorphs. Moreover, to the best our knowledge, these are two new polymorphs of HCPT. Compared the results listed in Table 2, it can be found that Form III is obtained in most cases. Analyzing the results of runs 3, 6, 9, 11, and 12 listed in Table 2, it can be found that Form II is obtained when VR e 3:1, T > 30, and F e 0.8 at all ranges of C and P. This suggests that the volume ratio of DCM and ethanol, temperature, and the solution flow rate have a more significant effect than other process parameters on the polymorph. Tien also believed that the operation temperature and the solution flow rate have a more significant effect on polymorphs.27 Within the experimental ranges, the higher temperature and lower solution flow rate show synergistic impact on the formation of different polymorphs. Comparing runs 9, 10, 11, and 12, which were processed at a given VR ratio of 3:1, it can be found that the results give evidence that a lower solution flow rate and higher temperature are inclined to obtain Form II. This may due to the effect of volume expansion of the solvent. The driving force of a crystal formation in an antisolvent process is the supersaturation of a solution induced by the mixing of a solution and
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an antisolvent.28 Generally, higher temperature and lower solution flow rate might increase the mass transfer between the solvents and antisolvent, and change the supersaturation of solute more obviously, this might result in different polymorphs. The use of mixed solvents in this study is an important feature that is different from most other research. The parameter VR is also one of the main factors that effect the formation of polymorphs. Summarizing the results of runs 13, 14, 15, and 16 and the optimal level, which produced Form III, it can be found that when VR = 4:1, no matter how other parameters changed, we always obtain Form III. We suggest that it is due to the different physical and chemical property of solvents. Generally, the solvents have an effect on polymorphism via solute solvent interactions during SAS processing. During SAS processing, nucleation occurs within microseconds, and the effect of process parameters on polymorphs is singularly comprehensive. Thus, much effort must be devoted into SAS process for further understanding of polymorphism and polymorphic transformation. 3.5. Results of DSC and TGA. In order to confirm the polymorphs, typical samples were further characterized by DSC and TGA. In general, DSC is used to analyze the phase transition behavior of a solid sample, which includes the solid liquid phase transition (fusion) and solid solid transition (polymorphic transformation). TGA is commonly employed to determine the changes of weight in relation to the changes of temperature. The information about the decomposition of a solid sample can also be provided by DSC and TGA. Figure 9 shows the DSC and TGA curves for the unprocessed HCPT and the typical processed HCPT. It can be observed that all of the DSC curves exhibit the same continuous endothermic exothermic transition in the temperature range of 272 278 °C, and ∼12% weight loss can be found from TGA curves of each sample. The thermal decarboxylation of lactone have been widely studied29 and the thermal-induced decarboxylation of HCPT from the lactone ring have been reported by Wang and Kunadharaju;30,31 ∼12% weight loss is possibly due to the thermal decarboxylation of HCPT. The decarboxylation of HCPT involves the breakage and recombination of chemical bonds, which can give a good explanation to the continuous endothermic exothermic peaks in the DSC curves. Thus, the change of DSC curves is consistent with the change of TGA curves. An endothermal center at 93 °C and 4.65% weight loss when the temperature was within 88 110 °C can be found in Figure 9a. It is reasonable to deduce that the 4.65% weight loss is caused by the separation of water from the sample. The weight loss percentage is equal to ∼1 mol of water per mole of HCPT, which indicates that the untreated HCPT exists in the form of monohydrate. The DSC and TGA scans of processed HCPT (Form II, Form III) are shown in Figures 9b and 9c. The endothermic peak at 138 °C in the DSC curve of Figure 9b is considered as a polymorphic transformation; however, no solid solid transition was observed in the DSC curve of Figure 9c. These imply that the Form III crystals are thermally stable until the decarboxylation temperature is reached, and Form II crystals are not thermally stable. The TGA curves in Figures 9b and 9c indicate almost no relative weight loss within the temperature range of 30 240 °C, which suggests that there is no structural water in the SASprocessed HCPT particles. The result indicates that the SAS process modifies the form of HCPT from monohydrate to anhydrous. Adami32 noted that the absence of structural water 2600
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effects of operating conditions on the HCPT particle size and polymorphs are investigated according to the selected OA16 (45) orthogonal array design. Under the optimal conditions, the minimum Dp50 of HCPT particles is obtained, i.e., Dp50 = 223 ( 19 nm. No significant change in the chemical structure of HCPT is found, and the residual Dichloromethane (DCM) and ethanol in the processed HCPT particles are both lower than their International Conference on Harmonization (ICH) limits. Scanning electron microscopy (SEM) and powder X-ray diffraction (XRD) measurements indicate that two new polymorphs of HCPT are obtained after SAS processing, and the result are corroborated by the measurement results of differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). The volume ratio of DCM and ethanol, temperature and the solution flow rate have more significant effects than other two process parameters on polymorphs. Further analysis of DSC and TGA results indicates that the untreated HCPT (Form I) is monohydrate and the processed HCPT compounds (Form II and Form III) are anhydrous; moreover, Form III is thermally stable, but Form II is not.
’ AUTHOR INFORMATION Corresponding Author
*Tel.: +86-20-8711-2051. E-mail:
[email protected].
’ ACKNOWLEDGMENT Financial supports from National Natural Science Fundation of China (21076084), Guangdong Provincial Science & Technology Project (No. 2011B050400013), and the Fundamental Research Funds for the Central Universities (No. 2011ZZ0006) are greatly appreciated. ’ REFERENCES
Figure 9. DSC and TGA thermograms of typical HCPT samples.
in the processed particles might be related to the fact that ethanol can solubilize water. Ethanol absorbs the water from the solubilized solute, and the ethanol water mixture is then dissolved in sc-CO2. Therefore, the observation about the changes in crystal habits of HCPT samples has been corroborated by the measurement results of DSC and TGA.
4. CONCLUSIONS 10-Hydroxycamptothecin (HCPT) is recrystallized and micronized using the supercritical antisolvent (SAS) process. The
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