Article pubs.acs.org/IECR
Polymorphic Crystallization and Transformation of Candesartan Cilexetil Penglei Cui, Qiuxiang Yin, Yuhong Guo, and Junbo Gong* School of Chemical Engineering and Technology, State Key Laboratory of Chemical Engineering, Tianjin University, Tianjin 300072, People’s Republic of China ABSTRACT: In this paper, the acetone solvate of candesartan cilexetil was preferentially crystallized from the acetone solution by cooling crystallization and was characterized by combination methods of X-ray powder diffraction (XRPD), 13C nuclear magnetic resonance (NMR), thermogravimetric analysis/differential scanning calorimetry (TGA/DSC), Forier transform infrared (FTIR), Raman spectroscopy, and dynamic vapor sorption (DVS). The polymorphic transformation among two polymorphs (form I and form II) and acetone solvates of candesartan cilexetil was investigated, respectively. By regulating the initial solution concentration and composition of solvent mixture (water/acetone), form I or acetone solvate could be obtained. With the aid of in situ Raman spectroscopy, the kinetics of solvent-mediated transformation (form II → acetone solvate) and solid-state transition (acetone solvate → form II) were systematically studied at different temperatures. The results show that the mechanism of solid-state transformation of acetone solvate to form II depends on one-dimensional diffusion.
1. INTRODUCTION
acetone and water with a volume ratio of 3:1, while form II was only obtained from acetone solvent. However, our team has discovered that acetone solvate8 of candesartan cilexetil could be preferentially crystallized from acetone solvent and, subsequently, transformed into form II during the desolvation process by thermal treatment. It is wellknown that the knowledge of polymorphic transformation is essential for design the crystallization process and isolation of desired polymorphic form. Therefore, the study on polymorphic transformation and mechanism of desolvation between different forms and acetone solvate of candesartan cilexetil is of great importance and necessity in obtaining pure forms and acetone solvate.
Polymorphism is the phenomenon that a compound forms more than one crystalline structure. In addition, numerous compounds can form other nonequivalent crystalline structures through solvent molecules incorporating into the lattice, namely, solvates.1,2 Different solid-state forms exhibit different physical and chemical properties, such as solubility, dissolution rate, melting point, crystal habit, and so on, which have a great influence on the bioavailability, stability, and tableting processes of a drug. Therefore, identifying and evaluating the solid-state forms available to an active pharmaceutical ingredient and the transformation behaviors between them are essential for determining the optimum conditions for crystallization and storage of the desired polymorphic form.3,4 Candesartan cilexetil is a useful antihypertensive drug belonging to the class of biphenyltertrazole-containing compounds. During absorption from the gastrointestinal tract, candesartan cilexetil is rapidly and completely hydrolyzed to candesartan, which blocks the receptors AT1 for angiotensin II decreasing the blood pressure levels.5 The molecular structure of candesartan cilexetil is shown in Figure 1. It has been found that candesartan cilexetil is capable of exhibiting several solidstate forms.6 Matsunaga et al. isolated and characterized form I, form II, and amorphous form of candesartan cilexetil.7 It was found that the form I could be prepared in several solvents, e.g., methanol, ethanol, isopropanol, acetonitrile, or a mixture of
2. MATERIALS AND EXPERIMENTS 2.1. Materials. Form I of candesartan cilexetil with fraction purity higher than 99.5% was supplied by Zhejiang Huahai Pharmaceutical Co. Ltd. of China. Acetone was analytical purity and used without further treatment. The deinoized pure water was used in all experiments. 2.2. Solid-State Analysis of Candesartan Cilexetil. Acetone solvates was prepared by dissolving 9.20 g form I in 50.0 g acetone at 50 °C, then the solution was cooled at 10 °C/ h in a temperature range from 50 to 5 °C. After filtration, the solid acetone solvate was dried at room temperature for around 1 h. Further dried at 50 °C in the air mist constant-temperature drybox, the acetone solvate would transform to form II. The solid samples of candesartan cilexetil were characterized by the following solid-state analysis techniques: • X-ray Powder Diffraction (XRPD): XRPD tests (Rigaku, D/max-2500) were used to determine structural differReceived: Revised: Accepted: Published:
Figure 1. Molecular structure of candesartan cilexetil. © 2012 American Chemical Society
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residual solids in the suspension were taken out by filtration and dried at room temperature for around 1 h. Raman spectroscopy was used to validate their final forms. 2.5. Influence of Acetone Diffusion on Solid-State Transition. The experiments were performed under the open and closed system, respectively, with a hot and cold microscope stage (OLYMPUS TMS 94). Approximately 100 mg of power acetone solvate was placed in the slide on the hot stage which had been preheated to 30 °C. Raman spectra were collected in situ from the sample via PhAT probe attached to the 785 nm Raman microscope. The Raman spectra were collected at an interval of 2 min. Each spectrum was the accumulation of 2 scans, and the exposure time for each scan was 15 s. In the closed system, there is no purge gas flowing the surface of the acetone solvate. In the open system, the samples were heated under air, nitrogen, nitrogen + water steam (50/50 v/v), and nitrogen + acetone steam (50/50 v/v), respectively. The above purge gases were at the constant gas flow rate. 2.6. In situ Monitoring of Solid-State Transition. The solid-state polymorphic transition of acetone solvate was also performed using a Raman microscope and a hot and cold microscope stage. The experiment was performed at different temperatures under air purge. The other operations are as same as the experiment above.
ences between the various solid-state forms of candesartan cilexetil. XRPD was conducted at 40 kV and 100 mA with a Cu Ka radiation source (λ = 1.54 Å). The samples were scanned from 4° to 30° (2θ) at a step size of 0.02° and at a scanning rate of 8 °/min. • Thermal Analysis: Differential scanning calorimetry (DSC, NETZSCH 204 Phoenix differential scanning calorimeter) and thermogravimetric analysis (TGA, Mettler Toledo thermogravimetric analyzer) were both performed at a heating rate of 5 °C/min, which provided information about the melting points of polymorphs and the solvent content in the solvates. Samples were heated from 30 to 200 °C in the aluminum crucibles with a cap which has been punched. The nitrogen gas was used as an inert atmosphere. • Raman Spectroscopy: A RAMANRXN2 (Kaiser Optical Systems, Inc.) was applied to record the Raman spectra of the above solid samples. • NMR Spectroscopy: Solid-state NMR spectra were obtained using a Varian Infinity Plus 300 MHz NMR spectrometer. • Fourier Transform Infrared Spectroscopy: FTIR spectra were recorded from KBr disk using a Nexus instrument (Thermo, America). Ground KBr powder was used as the background in the measurements. The measured wavenumber range was from 4000 to 400 cm−1. • Dynamic Vapor Sorption (DVS): The isotherm gravimetric vapor sorption experiments have been carried out using the DVS-Advantage instrument (Surface Measurement Systems, London, UK). The samples (20−30 mg) were placed into the DVS-Advantage instrument at 30 °C. For form I and II, the acetone concentration profile was as follows: 0−90% in 10% steps and back down to 0% P/P0 in a similar program. For the desolvation kinetic studies of the acetone solvate, the concentration was directly increased to 90% P/P 0 , and then, the concentration was decreased to 0% P/P0 following the acetone concentration profile and the mass loss (i.e., desolvation) was measured until complete. 2.3. Formation of Polymorphs from Antisolvent/ Cooling Crystallization. The formation of candesartan cilexetil polymorphs was investigated in the antisolvent/cooling crystallization with acetone as solvent and water as antisolvent. First, the corresponding amount of candesartan cilexetil form I was dissolved in 45.0 g acetone at 50 °C. Once the solutions were clear, the corresponding amount of water was added into the above solution with a constant rate 2 mL/min under a constant stirring speed (400 rpm). Then, the solution was cooled from 50 to 5 °C at a rate of 10 °C/h. After filtration, the solid was dried at room temperature for around 1 h and then analyzed with a Raman microscope. 2.4. In-situ Solvent-Mediated Transformation Measurement. The transformation experiments of the form II into the acetone solvate were carried out in a 100-mL jacketed glass crystallizer under a constant stirring speed of 400 rpm. The initial suspend solution with temperatures at 20, 30, and 40 °C were prepared by adding 3.12, 6.10. and 9.22 g candesartan cilexetil in 40.0 g acetone, respectively. The Raman probe was inserted into the crystallizer to monitor the solid forms composition and the solid form transformation behavior in situ. The calibration of Raman spectra for quantitative analysis was done using the method published in the literature.9−11 The
3. RESULTS AND DISCUSSION 3.1. Solid-State Analysis of Candesartan Cilexetil. The solid state techniques used for analyzing the solvate samples include X-ray power diffraction (XRPD), thermal gravimetric analysis (TGA), Raman spectra, differential scanning calorimetry (DSC), infrared (IR) spectroscopy, and solid-state nuclear magnetic resonance (NMR). The acetone solvate of candesartan cilexetil was obtained form acetone solution in the cooling crystallization, and the TGA/DSC result was shown in Figure 2. On the basis of the
Figure 2. TGA and DSC traces of acetone solvate.
TGA/DSC curves, a single weight loss step exists at about 110 °C. From Figure 3, it can be seen that 110 °C is the melting of the sample, which is different from that of form I (169.2 °C) and form II (123.4 °C). The TGA and DSC patterns showed that the melting process is accompanied with desolvation of solvate. This result preliminarily served as the evidence that acetone could enter the crystal lattice and contact closely with the molecular structure of candesartan cilexetil. TGA analysis also confirms that the stoichiometry is candesartan cilexetil:acetone = 1.5:1−1:1.1 12911
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for form II, and 6.06° for acetone solvate. Acetone solvate has different characteristic peaks, indicating it has a new crystal structure. In Figure 5, 13C spectra for forms I and II are similar, but acetone solvate has a new peak at 204 ppm, which is attributed to the carbonyl group (CO).12 And, the peak at 31 ppm is much higher than that of other two forms, because this higher peak is attributed to saturated alkide of the acetone. In the mid-infrared spectrum (see Figure 6) of candesartan cilexetil, the great difference among the three spectra was the
Figure 3. DSC pattern of candesartan cilexetil.
In order to further confirm whether the acetone solvate is another crystal form, XRPD patterns (Figure 4) and 13C NMR
Figure 6. FTIR spectra of candesartan cilexetil.
strong absorption band at 1735−1716 cm−1 assigned to the carbonyl stretching vibration.13 For form II, the CO stretching vibration occurs at 1735 cm−1, whereas for form I it is observed at 1716 cm−1; for acetone solvate, it is observed at 1727 cm−1. In the Raman spectrum (Figure 7), these bands occur at 1737, 1711, and 1722 cm−1, respectively. During the desolvation process of the acetone solvate by thermal treatment, structural rearrangement with concomitant loss of acetone molecules occured, then form II was obtained. For form II, the CO stretching vibration occurs at 1735 cm−1, and for acetone solvate, this is at 1727 cm−1. The acetone
Figure 4. XRPD pattern of candesartan cilexetil.
(Figure 5) were presented. Figure 4 showed that the characteristic peaks were observed at 9.82° for form I, 7.28°
Figure 5. 13C NMR spectra of candesartan cilexetil.
Figure 7. Raman spectra of candesartan cilexetil. 12912
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solvate has a different crystal structure due to acetone molecules included in the crystal lattice, which brought about the shift of the CO stretching vibration. In the acetone solvate mid-infrared spectrum, there is a very little peak at 1715 cm−1, which is the characteristic peak of acetone. Acetone vapor sorption and desorption isotherm on candesartan cilexetil are displayed in Figure 8. The acetone
Figure 9. Polymorphs identified after filtration using Raman microscopy as a function of the initial concentration and water mass fraction.
neglected. The higher the acetone concentration in solution, the more chance for acetone molecules incorporates into the crystal lattice. When the initial concentration of candesartan cilexetil in solution is very high, the contact between solute molecules become stronger than solute−solvent molecules and the solute molecules have more driving force to form form I. 3.3. In situ Solvent-Mediated Transformation Measurement (Form II → Acetone Solvate). The solventmediated polymorphic transformation behavior of candesartan cilexetil (form II) in acetone was monitored by in situ Raman spectroscopy. On comparison of the Raman spectra of the form II and solvate powders and that of the dissolved form II and solvate in the acetone, it can be observed that the characteristic peak of solvate at 1722 cm−1 is not changed. But for form II, the characteristic peak in acetone is 1711 cm−1, not 1737 cm−1. The displacement of the characteristic peak of form II could be explained by solvent effects. The calibration model was set up by correlating the relative peak height HA/(HII + HA) with the fraction of the acetone solvate in the slurry, where HA and HII are the heights of the selected characteristic peaks of solvate and form II. The calibration model is shown in Figure 10. Figure 11, which was obtained from in situ measurement by Raman spectroscopy, indicates the decrease in form II crystals and an increase in acetone solvate crystals. The peak intensity of form II decreases quickly illustrating the dissolution of the
Figure 8. Acetone vapor sorption and desorption isotherm on candesartan cilexetil at 30 °C.
solvate remained stable over a considerable acetone relative partial pressure range (10−90% P/P0). When the relative partial pressure was dropped below 10% P/P0, the sharp transition points of mass loss are often indicative of desolvation process and acetone molecules were removed from the acetone solvate lattice. Form II gradually adsorbed acetone, with acetone returning to reform the acetone solvate crystal lattice upon exposure to acetone vapor. Form I showed a slight sorption of acetone, and the mass is almost not changed, which means that form I could not transform to acetone solvate even at high acetone relative partial pressure.14,15 3.2. Formation of Polymorphs from Antisolvent/ Cooling Crystallization. The antisolvent/cooling crystallizations have been carried out at different initial concentration C0 (0.128−0.152) and water mass fraction of binary solvent xm,w (0.19−0.28). According to the Raman spectrum, the characteristic peaks of different polymorphs occurred at 1737 (form II), 1711 (form I), and 1722 cm−1 (acetone solvate), respectively. The polymorph of these products was identified by Raman microscopy, and the result can be seen in Figure 9. Form I and acetone solvate were readily obtained in the antisolvent/cooling crystallizations, while form II was never observed. In the area I, only acetone solvate was obtained and form I can only be obtained in area III. However, in the intermediate area II, form I and acetone solvate exist simultaneously. The results indicated that acetone solvate can be obtained at low water mass fraction xm,w, while form I can be obtained at high water mass fraction xm,w. Meanwhile, when 0.22 ≤ xm,w ≤ 0.28, at the same xm,w, the obtained products change from acetone solvate to form I with an increase of the initial concentration. It is believed that solvent plays an important role in polymorphic crystallization. At the water-rich content (area III), form I is the most stable form. When the water content was decreased (area I), acetone solvate crystals is preferable. Meanwhile, the solute−solvent interaction should not be
Figure 10. Calibration line constructed from the value for the relative peak heights HA/(HA + HII). 12913
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desolvation of acetone solvate becomes difficult. On the contrary, in the open system, purge gas without acetone can speed up the diffusion of acetone molecular, which has been also confirmed by DVS experiments (see Figure 8). The diffusion process of the acetone molecule consisted of two steps: one is the interior diffusion which means the movement of acetone molecules from interior to surface of crystal and another is the external diffusion that the acetone molecules were taken away easily by the purge gas. Comparing with the external diffusion, the interior diffusion has to overcome the resistance of crystal lattice, for the above experiments had proved that acetone entered the crystal lattice and contacted closely with candesartan cilexetil. Therefore, the interior diffusion can be considered as the rate-determining step for the process of desolvation. 3.5. In situ Monitoring of Solid-State Transition (Acetone Solvate → Form II). In order to get more information about the solid-state transition, kinetic studies were performed under isothermal conditions using the experimental setup as described above. The Raman spectra between 1700 and 1750 cm−1 were collected in situ during solid-state transition experiments, illustrating only acetone solvate and Form II exist in the course of the transition. The initial materials are pure acetone solvate, and the final materials are pure form II. A semiquantitative analysis could now be employed to convey the original Raman response to mass fraction transformed.
Figure 11. Profiles of acetone solvate and form II during solventmediated transformation experiment.
form II. At the same time, the peak intensity of solvate increased gradually which means the polymorphic transformation has already begun. The transformation from form II to solvate indicates the solvate is more stable than form II in solution. During the solvent-mediated polymorphic transformation experiments at 20, 30, and 40 °C, the suspension of the excess amount of form II in acetone has a great trend of transformation to acetone solvates. Figure 12 shows that the
XII = HII/(HII + HA(HII°/HA°))
where HII and HA note the relative heights of the peaks at 1737 cm−1 for form II and at 1722 cm−1 for acetone solvate, respectively. HA° and HII° are the heights of these peaks for pure acetone solvate and pure form II. The equation means that XII was obtained after replacing the mass of acetone solvate by its form II equivalent.11 Figure 13 presents the transition profiles from isothermal experiments at five different temperatures: 30, 35, 40, 45, and
Figure 12. Transformation profiles of form II to acetone solvate in acetone.
process of polymorphic transformation can be accelerated by raising temperature. Although the transformation times are different, the shapes of transformation profiles at experiment temperatures are quite similar. 3.4. Influence of Acetone Diffusion on Solid-State Transition. The influence of acetone diffusion conditions on the desolvation of the solvate was studied by the hot and cold microscope stage and Raman microscope. The results showed that desolvation and transformation did not happened when these experiments were conducted in the closed systems (no gas flowing the sample solid surfaces in the experiment) and under nitrogen + acetone purge gas. However, in the open system with air, nitrogen and nitrogen + water steam as purge gas, the acetone solvate gradually transformed to form II. In the closed systems, no purge gas flows through the sample solid surfaces which attributed to slow down the escape of acetone molecule from solvate crystal. Similarly, the nitrogen + acetone purge gas increased acetone vapor pressure which can inhibit the diffusion of the acetone molecule. So, the
Figure 13. Content of form II against at different temperatures.
50 °C. The isothermal curves for the form II fractions show similar features, and transform rates increase with increasing temperature. In order to determine the mechanism and kinetics of solidstate transition from acetone solvate to form II, various solid state reaction kinetic models have been employed to derive the transition rate (Table 1).16−19 By fitting the experiment data in the range of 5−95 wt % fraction transformed to the equations f(α), a linear relation is predicted between f(α) and transition time t, and the corresponding slope gives the transition rate constant (k) at different temperatures. A correlation coefficient 12914
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the rate constants based on the M5 model was evaluated by the Arrhenius equation,
Table 1. Kinetic Equations and Mechanisms of Solid-State Reaction model
f(a)
⎛ E ⎞ k = A exp⎜ − a ⎟ ⎝ RT ⎠
mechanism
nuclei-grown M1 [−ln(1 − a)]1/2 Avrami−Erofeev, n = 2 M2 [−ln(1 − a)]1/3 Avrami−Erofeev, n = 3 M3 [−ln(1 − a)]1/4 Avrami−Erofeev, n = 320,21 M4 ln[a/(1 − a)] random nucleation (Prout−Tompikins)22,23 diffusional M5 a2 one-dimensional diffusion M6 (1 − a)ln(1 − a) two-dimensional diffusion +a M7 1 − 2a/3 − (1 − three-dimensional diffusion (Ginstling− a)2/3 Brounshtein)24 M8 [1 −(1 − a)1/3]2 three-dimensional diffusion (Jander)25 reaction order (n) M9 −ln(1 − a) first-order reaction26 M10 1/(1 − a) − 1 second-order reaction phase boundary reaction27−29 M11 a one-dimensional phase boundary reaction M12 1 − (1 − a)1/2 two-dimensional phase boundary reaction (cylindrical symmetry) M13 1 − (1 − a)1/3 three-dimensional phase boundary reaction (spherical symmetry)
where Ea is activation energy, R is gas constant, and T is absolute temperature. The k values determined from the kinetic models were fit to Arrhenius plots of the natural logarithm of rate constants (ln k) against corresponding temperatures. The activation energies thus derived ranged from 30 to 50 °C, the value being 52.4 kJ/mol.
4. CONCLUSIONS This paper identified that the acetone solvate of candesartan cilexetil was first obtained from acetone in cooling crystallization. The structure information of acetone solvate was provided by solid-state analysis including XRPD, NMR, DVS, spectroscopy techniques (FTIR, Raman), and thermal analysis (TGA, DSC) Using an in situ Raman measurement, the polymorphic transformations between acetone solvate and forms I or II were explored. Upon antisolvent/cooling crystallization of candesartan cilexetil from acetone/water mixture, acetone solvate was exclusively obtained at low initial concentration and low water mass fraction, while form I was prepared at high initial concentration and high water mass fraction. The solutionmediated phase transformation of form II to acetone solvate was found that raising temperature shortened the polymorphic transformation time and the shapes of transformation profiles at experiment temperatures are quite similar. With the aid of Raman spectroscopy and a hot and cold microscope stage, the solid-state transformation of acetone solvate to form II was performed at different temperatures under open system and closed system. The results show if acetone molecule can escape from the solvate crystal easily, the solid-state transition can take place, and the kinetic transformation process depends on onedimensional diffusion. The phase transformations between crystalline forms of candesartan cilexetil are summarized as follows:
(R2) analysis was performed for all the kinetic models (Table 2). The results demonstrate that several models fairly fitted the Table 2. Correlation Coefficients (R2) for Different Kinetic Model R2 model
50 °C
45 °C
40 °C
35 °C
30 °C
M1 M2 M3 M4 M5 M6 M7 M8 M9 M10 M11 M12 M13
0.994 0.989 0.983 0.985 0.995 0.980 0.968 0.938 0.974 0.832 0.986 0.997 0.994
0.995 0.989 0.982 0.984 0.996 0.988 0.979 0.954 0.981 0.838 0.982 0.998 0.996
0.996 0.992 0.987 0.987 0.990 0.971 0.959 0.928 0.973 0.827 0.993 0.997 0.993
0.996 0.992 0.987 0.990 0.995 0.988 0.981 0.960 0.985 0.883 0.983 0.997 0.996
0.993 0.995 0.985 0.985 0.992 0.977 0.965 0.934 0.970 0.804 0.988 0.995 0.991
cooling crystallization lower C0 ,lower xm,w
form I XooooooooooooooooooooY acetone solvate cooling crystallization higher C0 ,higher x m,w thermal treatment in the open system
XooooooooooooooooooooY form II
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data well, particularly for Avrami−Erofeev models (M1, M2), diffusional models (M5), and phase boundary reaction model (M12, M13). The development of the Avrami−Erofeev relationship is based on the assumption that the solid phase transformation proceeds by a nucleation-and-growth mechanism. For diffusion model, the rate-limiting step is the diffusion of reactants into reaction sites or products away from reaction sites. For phase boundary reaction, nucleation is assumed to be instantaneous throughout the surface and the rate-limiting step is the progress of the product layer from the surface of the crystal inward and is different for various crystal morphologies. However, associating with the above results that the ratedetermining step of solid state transition is the diffusion of the acetone molecules, the favored model is therefore onedimensional diffusion (M5). The temperature dependence of
suspension in acetone
AUTHOR INFORMATION
Corresponding Author
*Phone: 86-22-27405754. Fax: 86-22-27314971. E-mail:
[email protected]. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work is supported by National Natural Science Foundation of China (Nos. 20836005 and 21176173) and Tianjin Municipal Natural Science Foundation (Nos. 10JCYBJC14200 and 11JCZDJC20700). The analysis tools used in this study were supported by State Key Laboratory of Chemical Engineering (No. SKL-ChE-11B02). 12915
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