Journal of Pharmaceutical and Biomedical Analysis 107 (2015) 265–272
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Solid-state characterization of sertraline base–-cyclodextrin inclusion complex Noriko Ogawa a,∗ , Takuro Hashimoto b,1 , Takayuki Furuishi b,1 , Hiromasa Nagase b,1 , Tomohiro Endo b,1 , Hiromitsu Yamamoto a , Yoshiaki Kawashima a , Haruhisa Ueda c,2 a Department of Pharmaceutical Engineering, School of Pharmacy, Aichi Gakuin University, 1-100 Kusumoto-cho, Chikusa-ku, Nagoya, Aichi 464-8650, Japan b Department of Physical Chemistry, Faculty of Pharmaceutical Sciences, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan c Department of Physical Chemistry, Nihon Pharmaceutical University, 10281 Komuro Ina-machi, Kitaadachi-gun, Saitama 362-0806, Japan
a r t i c l e
i n f o
Article history: Received 23 September 2014 Received in revised form 8 December 2014 Accepted 20 December 2014 Available online 15 January 2015 Keywords: Sertraline base -Cyclodextrin Complexation Solid-state analysis Computational interpretation
a b s t r a c t Sertraline is one of the serotonin-specific reuptake inhibitors that is effective in treating several disorders such as major depression, obsessive–compulsive disorder, panic disorder, and social phobia. It is marketed in the form of its hydrochloride salt, which exhibits better solubility in water than its free base form. However, the absorption of sertraline through biological membranes could be improved by enhancing the solubility of its base because it is more hydrophobic than sertraline hydrochloride. To clarify the mechanism for the interaction of sertraline base with -CD, it is important to study the basic interaction between the -CD ring and sertraline base. Therefore, in this study, the currently used hydrochloride salt form was converted into the free base and -CD was used as a model for -CD derivatives to evaluate the interaction between -CD and the sertraline base. The solid-state physicochemical characteristics of the sertraline–-CD complex were investigated by the phase solubility method, differential scanning calorimetry, Fourier transform IR spectroscopy, FT-Raman spectroscopy, powder X-ray diffraction, and 13 C cross-polarization magic-angle spinning NMR measurements. The results showed that sertraline base and -CD form an inclusion complex, and the stoichiometric ratio of the solid-state sertraline base–-CD complex is 1:1, which was estimated by the 1 H NMR measurements of the complex dissolved in DMSO-d6 . © 2014 Elsevier B.V. All rights reserved.
1. Introduction Sertraline, (1S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroN-methyl-1-naphthaleneamine (Fig. 1a), is a serotonin-specific reuptake inhibitor that is effective in treating several disorders such as major depression, obsessive–compulsive disorder, panic disorder, and social phobia [1,2]. It is marketed in the form of its hydrochloride salt. Salt forms are frequently used in formulations because they improve aqueous solubility and chemical stability relative to the free base or acid of the active compound.
∗ Corresponding author. Tel.: +81 52 757 6771; fax: +81 52 757 6799. E-mail addresses: [email protected] (N. Ogawa), [email protected] (T. Hashimoto), [email protected] (T. Furuishi), [email protected] (H. Nagase), [email protected] (T. Endo), [email protected] (H. Yamamoto), [email protected] (Y. Kawashima), [email protected] (H. Ueda). 1 Tel.: +81 3 5498 5159; fax: +81 3 5498 5159. 2 Tel.: +81 48 721 1155; fax: +81 48 721 6718. http://dx.doi.org/10.1016/j.jpba.2014.12.036 0731-7085/© 2014 Elsevier B.V. All rights reserved.
However, it is better to utilize the free base or acid when an active pharmaceutical ingredient has a low pKa value and the resulting salts are less stable, more hygroscopic, or when complex polymorphism/pseudopolymorphism is exhibited [3–5]. Sertraline hydrochloride is a highly polymorphic salt, and several crystalline salt forms have been reported [5,6]. He et al. [5] reported that the sertraline free base enantiomer is relatively less polymorphic than the sertraline hydrochloride salt. In addition, enhancing the solubility of the free base can improve the absorption of sertraline through biological membranes because the base is more hydrophobic than sertraline hydrochloride. Poor treatment compliance is a major problem for patients that use antipsychotic drugs to treat psychiatric disease, which results in the deterioration of patient’s symptoms over time [7]. Sertraline is an antipsychotic drug that is orally administered during the acute exacerbation phase and for maintenance treatment. Developing transdermal or transmucosal parenteral sustained-release dosage forms of antipsychotic drugs will serve patients’ needs and improve compliance. Thus, using sertraline base will be beneficial for
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Figure 1. Chemical structures of sertraline base (a) and -CD (b).
developing parenteral dosage forms if its solubility or absorption through biological membranes is enhanced by the use of pharmaceutical additives or processes. Cyclodextrins (CDs) are cyclic oligosaccharides consisting of 6, 7, or 8 d-glucose units, called ␣, -, and ␥-CD, respectively, and are linked by ␣-1,4 glycosidic bonds. CDs have a conical shape with external hydrophilic properties caused by its hydroxyl groups and an internal hydrophobic cavity, which allows different guest molecules to form inclusion complexes [8,9]. They have attracted attention in pharmaceutical formulation, in food, and in biological fields because the inclusion complexes formed with guest molecules can occur in solutions or in solid state. In addition, CDs may improve the solubility of poor water-soluble drugs and may enhance their physical and chemical stability. Passos et al. [10–12] reported inclusion complexes formed between sertraline hydrochloride and -CD (Fig. 1b) at molar ratios of 1:1 and 1:2 by freeze drying. When water was used as a solvent, for inclusion complexes of sertraline hydrochloride and -CD at molar ratios of 1:1 and 1:2, the solubility of sertraline hydrochloride increased to 6 and 8 times higher than that of sertraline hydrochloride alone, respectively. Thus, using -CD with sertraline base will be beneficial because hydrophilic -CD derivatives such as hydroxypropyl -CD and sulfobutylether -CD can exhibit a strong solubility enhancement effect; however, analyzing the interaction is difficult since the structures of these derivatives are complicated compared with those of natural -CD. The basic interaction between the -CD ring and sertraline base is important and needs to be studied for clarifying the sertraline base–-CD interaction mechanism. In this study, the sertraline hydrochloride salt was converted into the free base form and used with -CD to evaluate the interaction between -CD or -CD derivatives and sertraline base. -CD has a simpler structure than -CD derivatives, which are also used as pharmaceutical additives. -CD was used to investigate the sertraline base–-CD interaction mechanism, which was examined by the phase solubility method. We evaluated the solid-state physicochemical characteristics of the sertraline base–-CD complex using differential scanning calorimetry (DSC), Fourier transform IR (FTIR) spectroscopy, FT-Raman spectroscopy, powder X-ray diffraction (PXRD), and 13 C cross-polarization magic-angle spinning (13 C-CP/MAS) NMR. We estimated the stoichiometric ratio of the solid-state sertraline base–-CD complex using the 1 H NMR measurements of the complex dissolved in DMSO-d6 . 2. Materials and methods 2.1. Materials Sertraline hydrochloride was purchased from Tokyo Chemical Industry Co., Ltd. (Tokyo, Japan). -CD was purchased from Nihon Shokuhin Kako Co., Ltd (Tokyo, Japan) in its hydrate form (-CD·10.5H2 O); the -CD water content was confirmed as 10.5H2 O by thermogravimetry. Deuterated dimethyl sulfoxide-d6
(DMSO-d6 ; NMR measurement grade), ethyl acetate, sodium hydroxide, sodium sulfate, sodium dihydrogen phosphate dihydrate, acetonitrile, phosphoric acid, and triethylamine were purchased from Wako Pure Chemical Industries, Ltd. (Osaka, Japan). All other chemicals were of reagent grade. 2.2. Sample preparation 2.2.1. Preparation of sertraline base Liquid–liquid extraction was used to prepare sertraline base from the sertraline hydrochloride salt (100 mg) using an ethyl acetate (100 mL)/carbonate buffer solution (pH 10, 30 mL). The organic phase was separated, and water was removed by sodium sulfate. Ethyl acetate was evaporated under reduced pressure, and an oily distillation residue was obtained. Water was added to the oily residue, and the mixture was dispersed by ultrasonic waves and freeze-dried; then, sertraline base was obtained as a microcrystalline powder. Sertraline base was dissolved in DMSO-d6 and its presence was confirmed by 1 H NMR measurements. NMR spectra were recorded at 30 ◦ C on a JNM Lambda 500 spectrometer (JEOL Ltd., Tokyo, Japan). Tetramethylsilane was used as an external standard. 2.2.2. Preparation of the physical mixture sample (PM) Sertraline base and -CD were physically mixed at a 1:1 molar ratio to prepare the physical mixture sample (PM) without applying pressure. 2.2.3. Preparation of precipitated sample (PPT) The physical characteristics and stoichiometry of the sertraline base–-CD inclusion complex were evaluated by preparing a precipitated sample (PPT). There are many kinds of methods for obtaining the drug–CD complex, e.g. kneading, co-evaporation, spray-drying, freeze-drying, and precipitation. We selected the precipitation method because it is basic and reliable for obtaining the drug–CD complex that precipitation due to complexation. This material, which precipitated as a microcrystalline powder, was prepared by mixing sertraline base (2 mg) with a 5 mL of -CD solution (12 mM). The mixed solution was shaken (120 strokes/min) for 7 days at 25 ◦ C, and the precipitate was filtered. We chose 7 days to make sure that the sertraline base and -CD were in an equilibrium. The precipitate was washed with cold water to remove free -CD, and the solid material which was presumed to be free sertraline base was removed when the precipitate was dissolved until the hot water solution at above 70 ◦ C was supersaturated and filtered. The dissolved solution was cooled, and the precipitate was filtered and dried under vacuum at room temperature for 24 h. The precipitate obtained was PPT, which was used for thermal analysis, PXRD measurements, 13 C-CP/MAS NMR experiment, FTIR spectroscopy, FT-Raman spectroscopy, and the estimation of the stoichiometric ratio of the sertraline base–-CD complex.
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2.3. Phase solubility studies Phase solubility studies were conducted according to the method reported by Higuchi and Connors [13]. Five milliliters of -CD solutions (2–15 mM) were added to an excess of sertraline base (2 mg), and the mixture was mechanically shaken (120 strokes/min) for 7 days at 25 ◦ C. The equilibrium-attained system was filtered using a membrane filter (0.45 m), and the sertraline concentration was determined by HPLC, the conditions for which are as follows [14]. Briefly, the HPLC system comprised a PU-2080 plus intelligent HPLC pump, a UV-2075 intelligent UV/VIS detector, a CO-2065 plus intelligent column oven, an AS-2055 plus intelligent sampler and a ChromNAV chromatography data system (all from JASCO Co., Tokyo, Japan). An AlltimaTM C18 column (250 mm × 4.6 mm I.D., Alltech Associates, Inc.) was used for separation. The mobile phase consisted of acetonitrile and phosphate buffer (pH 5.5; adjusted with phosphoric acid and triethylamine) (50/50, v/v). The analysis was carried out at 40 ◦ C using a flow rate of 1 mL/min. Chromatograms were run with an injection volume of 20 L and recorded with a UV detector at 230 nm. Stability constants for the formation of sertraline–-CD inclusion complexes were determined from phase solubility data using Eq. (1) below: KA =
slope S0 (1 − slope)
(1)
where KA (M−1 ) is the apparent stability constant of the sertraline base–-CD complex, slope denotes the initial upward linear portion of the solubility phase diagram, and S0 (mM) is the intrinsic solubility of the sertraline base. 2.4. Solid-state characterization of the sertraline base–ˇ-CD complex 2.4.1. Thermal analysis DSC was performed on samples (2 mg) sealed in aluminum pans using a thermal analyzer system (DSC 8240D, Rigaku Co., Ltd., Japan). Al2 O3 was used as reference. Samples were heated from 40 to 220 ◦ C at 10 ◦ C/min under nitrogen flow. 2.4.2. Fourier transform IR (FTIR) spectroscopy FTIR spectra were obtained using an FTIR spectrometer (FT/IR 5300; Jasco Co., Ltd., Japan) and the KBr disc method. For each sample, 32 scans in the 4000 and 400 cm−1 spectral ranges were recorded with a resolution of 4 cm−1 . 2.4.3. FT-Raman spectroscopy Raman spectra were acquired using an FT-Raman system (RFT6000; Jasco Co., Ltd., Japan) equipped with an indium gallium arsenide detector. Nd3+ /YAG laser with an excitation wavelength of 1064 nm was used to irradiate the sample. For each spectrum, up to 4500 scans were collected with a spectral resolution of 1 cm−1 . 2.4.4. Powder X-ray diffraction (PXRD) experiment PXRD measurements were recorded on a RINT-1400 X-ray diffractometer (Rigaku Corporation, Tokyo, Japan). Graphite˚ 60 kV and 150 mA) monochromated Cu K␣ radiation ( = 1.54178 A, was used to perform X-ray diffraction. Measurements were obtained using a scanning interval of 2 between 3◦ and 35◦ with a scanning speed of 2◦ /min. 2.4.5. 13 C Cross-polarization magic-angle spinning (13 C-CP/MAS) NMR measurements 13 C-CP/MAS NMR measurements were recorded on an ECA400 spectrometer (JEOL Ltd., Tokyo, Japan) with a frequency of 100.5 MHz for 13 C. The spectrometer was equipped with a 3.2 mm MAS probehead. The repetition delay time was 4 s, and the spectral
Figure 2. Phase solubility diagram of sertraline base and -CD. Each point is the mean ± S.D. (n = 3).
width was 25 kHz. Adamantane was used as an external standard (29.5 ppm). 2.4.6. Estimation of the stoichiometric ratio of the sertraline base–ˇ-CD complex Sertraline base, -CD, and PPT were separately dissolved in 10 mg/mL DMSO-d6 , and 1 H NMR measurements were performed. 2.5. Computational studies The structural optimization of sertraline was studied using the density functional theory (DFT) and the Gaussian-09 program package [15]. Geometries were optimized at the B3LYP/6-311 theory level. Theoretical Raman and IR spectra of sertraline were calculated at the B3LYP/6-311 + G(d, p) theory level. Theoretical NMR chemical shifts were based on the GIAO B3LYP approach, which used the 6-311G + (2d, p) basis set that was implemented in the Gaussian software package [15]. 3. Results and discussion 3.1. Phase solubility studies The phase solubility curve of the sertraline base–-CD complex is shown in Fig. 2. The sertraline base–-CD system is considered to display a Bs-type solubility curve according to the classification system of Higuchi and Connors [13]. In Bs-type curves, the initial increase in solubility is followed by a plateau region and a decrease in the total drug concentration, which is caused by the precipitation of a microcrystalline complex. In this study, the sertraline base–-CD system displayed a Bs-type solubility curve because the initial increase in solubility was followed by a decrease in the total drug concentration, which was caused by the precipitation of the microcrystalline powder; however, the plateau region was too short to define it accurately. The solubility of sertraline base was 4.38 × 10−2 mM (13.4 g/mL, water), which increased to 0.75 mM (229.8 g/mL) when the -CD concentration was 5 mM on the solubility curve. In the presence of -CD, the solubility of sertraline base was approximately 17-fold higher than that of sertraline base alone. Johnson et al. [16] reported the solubility of sertraline hydrochloride as 11.09 mM (3.8 mg/mL). The solubility of sertraline hydrochloride is higher than that of sertraline base. However, if the solubility of sertraline base is improved by pharmaceutical techniques, it can have useful applications in parenteral dosage forms.
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Figure 3. DSC thermograms of sertraline base (a), -CD (b), PM (c), and PPT (d). PM, physical mixture sample; PPT, precipitated sample.
The apparent stability constant (KA ) of the sertraline base–CD complex was calculated according to Eq. (1). The data that was inputted into the equation was the initial ascending portion of the solubility diagram where the complex could be formed. The KA value of the sertraline base–-CD complex was calculated using four values obtained from the -CD concentration range (0.0–4.0 mM). Using 0.1585 as the slope and 4.38 × 10−2 mM as S0 , Eq. (1) was calculated, and the stability constant was 4300 M−1 . The observed value of K1:1 (KA in this study) is reported to be between 50 and 2000 M−1 with mean values of 129, 490, and 355 M−1 for the parent ␣-, - and ␥-CDs, respectively [17,18]. In this study, the high stability constant suggests a strong affinity between the guest and host in the aqueous phase and a high stability of the complexes. Passos et al. [10,11] used isothermal titration calorimetry and reported a high value of 4999.3 ± 495.4 M−1 for the binding of sertraline hydrochloride into the -CD cavity, suggesting a high affinity between sertraline and -CD. The KA value of the sertraline base–-CD complex obtained in this study concurred with the reported value. In this study, a poor water-soluble precipitate was obtained at high concentration of -CD in the phase solubility curve of the sertraline base–-CD complex, as stated above. To investigate the stoichiometry of sertraline and -CD inclusion complexes, a precipitated sample (PPT) was prepared and was used for thermal analysis, PXRD measurements, 13 C-CP/MAS NMR experiment, FTRaman spectroscopy, and the estimation of the stoichiometric ratio of the sertraline–-CD complex. 3.2. Solid-state characterization of the sertraline base–ˇ-CD complex 3.2.1. Thermal analysis DSC analysis was conducted to understand the thermal behavior of PPT. The DSC thermograms of sertraline base, -CD, PM, and PPT are shown in Fig. 3. In this study, the DSC thermogram of sertraline base exhibited an endothermic peak at 68.3 ◦ C, which is attributable to its melting point; this value is also in agreement with the melting point [66.5 ± 0.5 ◦ C (onset)] of the sertraline enantiomer reported by He et al. [5]. In the DSC thermogram of -CD, broad endothermic peaks were observed from 145 to 200 ◦ C, which were attributable to dehydration during the heating process (Fig. 3b). In PM, the endothermic peak of the drug was shifted to 66.7 ◦ C (Fig. 3c), and the result was probably due to the interaction between the pure components in the physical mixture. Endothermic peaks from 140
Figure 4. FTIR spectrum of sertraline base theoretically calculated from the geometric models of the drug (I) and of that prepared in this study (II).
to 190 ◦ C were observed in the DSC thermogram of PM, which were attributable to the dehydration process and interaction between sertraline base and -CD caused by the heating process. However, the endothermic peak observed at 68.3 ◦ C was due to sertraline base, and it completely disappeared in PPT (Fig. 3d). Free sertraline base was not in PPT because the endothermic peak of sertraline base was not detected. The endothermic peaks at 185 and 198 ◦ C may be attributed to the dehydration process. These results indicate that PPT may be a new material, which differs from the original sertraline base and -CD. 3.2.2. Fourier transform IR (FTIR) spectroscopy FTIR spectra were recorded to detect spectral signals that may reveal the existence of intermolecular interactions between sertraline base and -CD in PPT. The theoretical and experimental FTIR spectra of sertraline base are shown in Fig. 4. Experimental absorption peaks (Fig. 4(II)) due to sertraline base were compared to the corresponding DFT values, which were calculated using a 6-311 + G(d, p) basis set for the B3LYP density functional theory (6311G basis set) with optimized geometric models of sertraline base (Fig. 4(I)) [15]. The 2783 cm−1 absorption band corresponds to the C H stretching vibration modes (C1, C17), while the 1128 cm−1 absorption band could be assigned to vibrations of the aromatic groups (C11–16). The 828 cm−1 absorption band can be assigned to vibrations of aromatic groups (C15 and C16). Ab initio harmonic vibrational frequencies (wavenumbers) are typically larger than the fundamentals observed experimentally [19,20]. A major source of this discrepancy is the neglect of anharmonicity effects in the theoretical treatment [20]. The ab initio wavenumbers calculated by the Hartree–Fock (HF) method were consistently higher than the experimental wavenumbers of the fundamentals by approximately 10% because the electron correlation and anharmonicity effects were neglected [21]. The scaled quantum mechanical method proposed by Pulay et al. was used to solve these problems [21–23]. In the method, the force constants of similar chemical fragments shared the same scale factor [21]. Thus, the scale factor values are optimized by minimizing weighted mean-square deviations of the calculated wavenumbers from the observed wavenumbers [21]. However, a more accurate prediction of vibrational spectra needs to be obtained; thus, more sophisticated methods, including an electron correlation spectra, have been suggested as post-HF methods [21]. The evolution of DFT, which includes an alternative electron correlation method, has permitted a cost-effective vibrational analysis of moderately large molecules since the 1990s [21,24,25]. The
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Figure 6. FT-Raman theoretical spectrum of sertraline base calculated from the geometric models of the drug (a) and FT-Raman experimental spectrum in this study (b).
Figure 5. FTIR spectra of sertraline base (a), -CD (b), PM (c), and PPT (d). PM, physical mixture sample; PPT, precipitated sample.
procedures that use Becke’s three parameter hybrid functional (B3) with correlation functions such as the one proposed by Lee, Yang, and Parr (LYP) are the most promising in that correct vibrational wavenumbers are provided [21,26,27]. These studies have shown the superiority of B3’s functional quality; however, the scaling procedures for each of the calculated wavenumbers were different [21]. Yoshida et al. [21] reported that large positive deviations from unscaled calculated wavenumbers and from the observed values at higher wavenumbers were almost exclusively attributed to the neglect of anharmonicity in the calculated wavenumbers. Thus, the wavenumber-linear scaling (WLS) method was adopted, which is based on the linear relationship between the scale factor and vibrational wavenumbers [21,28–30]. The relationship between the unscaled calculated wavenumbers (vcalc ) and observed wavenumbers (vobs ) is reported in Eq. (2) [21]:
vobs = 1.0087(9) − 0.0000163(6) × vcalc vcalc
Figure 7. FT-Raman spectra of PM (a) and PPT (b) in a range of 2600–3400 cm−1 (I) and 100–1700 cm−1 (II). PM, physical mixture sample; PPT, precipitated sample.
(Fig. 5(II), (ii)), and the 880–820 cm−1 region (Fig. 5(II), (iii)) were shifted. These shifts may be due to conformational -CD changes caused by the interaction with sertraline base in PPT.
(2)
where vobs and vcalc are given in cm−1 , and the errors shown in the parentheses apply to the last significant figure. The ratio vobs /vcalc in Eq. (2) is denoted as the wavenumber scale factor that is applied to the B3LYP/6-311 + G(d, p) calculation [21]. In this study, the unscaled calculated wavenumbers are shown in Fig. 4(I), and these wavenumbers were larger than the experimental wavenumbers, especially at higher wavenumbers (Fig. 4(I)). The scaled wavenumbers that employed the WLS method used the vobs /vcalc ratio in Eq. (2) as the wavenumber scale factor, and the results of these wavenumbers concurred with the experimental values. FTIR spectral comparisons of sertraline base, -CD, PM, and PPT are shown in Fig. 5. The FTIR spectrum of PM corresponds to the superposition of sertraline base and -CD spectra, with a little shift in the major peaks corresponding to the components (Fig. 5c). The 2783 cm−1 absorption band was assigned to the C H stretching vibration (C1, C17), and the band was shifted (Fig. 5c(I)). The observation indicates that there is little interaction between sertraline base and -CD in PM. However, in PPT spectrum, the 2783 cm−1 absorption band, assigned to C H stretching vibrations (C1, C17), disappeared, and the 828 cm−1 absorption band, assigned to vibrations of aromatic groups (C15 and C16), was broader (Fig. 5d). This shift is due to the interaction between the functional group of sertraline and the hydroxyl group of -CD. Furthermore, the peaks in the 1270–1180 cm−1 region (Fig. 5(II), (i)), 960–900 cm−1 region
3.2.3. FT-Raman spectroscopy As with FTIR spectra, FT-Raman spectra were also recorded to detect spectral signals that may reveal the existence of intermolecular interactions between sertraline base and -CD. The theoretical and experimental FT-Raman spectra of sertraline base are shown in Fig. 6. Experimental peaks (Fig. 6b) due to sertraline base were compared to the corresponding DFT values calculated using a 6-311 + G(d, p) basis set for the B3LYP density functional theory [6-311G basis set] optimized by geometric models of sertraline base (Fig. 6a) [15]. The 3350 and 3326 cm−1 absorption bands were assigned to the N H stretching vibration mode (N18), and the 3056 cm−1 absorption band was assigned to the C H stretching vibration of the aromatic groups (C5–C8, C15, C16). The 2789 cm−1 absorption band was assigned to the C H stretching vibration modes (C1, C17). And the 1592 cm−1 absorption bands were assigned to C C stretching vibration of the aromatic groups (C5–C10, C11–C16). FT-Raman spectral comparisons of PM and PPT are shown in Fig. 7. The FT-Raman PM spectrum corresponds to the superposition of sertraline base and -CD spectra, with little shifts in the major peaks corresponding to the components. In PPT spectrum, the 2789 cm−1 absorption peak assigned to C H stretching vibrations (C1, C17) and the 3350 cm−1 absorption peaks assigned to N H stretching vibration (N18) were absent; however, both of these peaks were present in the sertraline spectrum. The
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N. Ogawa et al. / Journal of Pharmaceutical and Biomedical Analysis 107 (2015) 265–272 Table 1 13 C NMR chemical shifts of sertraline. C atom Chemical shift (ppm) Sertraline base ıtheoretical
C(1) C(2) C(3) C(4) C(5) C(6) C(7) C(8) C(9) C(10) C(11) C(12) C(13) C(14) C(15) C(16) C(17)
Figure 8. 13 C-CP/MAS NMR spectra of sertraline base (a), -CD (b), PM (c), and PPT (d). PM, physical mixture sample; PPT, precipitated sample.
61.88 35.80 33.22 51.90 135.12 131.97 128.95 134.74 142.08 147.73 155.42 135.89 144.87 143.13 135.56 132.06 35.79
Sertraline hydrochloride ıexperimental
59.20
46.99
150.00
ıliterature (Form I, solid) [33] 58.7 28.5a 28.5a 47.5
ıliterature (Form III, solid) [33] 54.9 22.9 28.8 47.3
140.7 144.7
140.8 148.0
31.9
31.2
a
C H stretching vibration mode of the aromatic groups (C5–C8 and C15, C16) in sertraline base was broader, and the peak was shifted from 3056 to 3062 cm−1 (Fig. 7b(I)); further, the 1592 cm−1 peaks assigned to the C C stretching vibration of the aromatic groups in sertraline base were broadened and shifted in PPT spectrum. These results were consistent with FTIR spectroscopy results. Unfortunately, there is a large amount of overlap in the 1500–100 cm−1 regions with the Raman bands due to -CD and sertraline base, which makes PPT spectra analysis extremely difficult. However, comparing PM and PPT spectra revealed that many peaks in the region were shifted, and these shifts resulted from conformational changes of -CD and sertraline base caused by the interaction as a host and guest, respectively, in PPT. 3.2.4. 13 C Cross-polarization magic-angle spinning (13 C-CP/MAS) NMR measurements The 13 C-CP/MAS NMR experiment was used to investigate the interaction between sertraline base and -CD. The NMR spectra of sertraline base, -CD, PM, and PPT are shown in Fig. 8. The 13 CCP/MAS NMR spectrum of -CD was assigned on the basis of the 13 C NMR spectral information obtained from the literature data of the compound in the solid form [31,32]. The 13 C-CP/MAS NMR spectrum of sertraline base was assigned on the basis of the corresponding DFT values calculated using a 6-311G basis set for the B3LYP density functional theory (6-311G basis set), which was optimized by the geometric models of sertraline base [15]; further, the13 C-CP/MAS NMR spectral information obtained from the literature data of sertraline hydrochloride was also used as a reference [33]. The 13 C-CP/MAS NMR chemical shifts for sertraline base were shown in Table 1. In PM, sertraline base and -CD spectra overlapped, with little changes in the peak shape and chemical shifts (Fig. 8c). However, sertraline base and -CD peaks were markedly broadened in PPT (Fig. 8d). In general, line broadening in the 13 CCP/MAS NMR spectra is due to a large distribution of chemical environments or to a significant change in molecular dynamics [34,35]. An amorphous state of sertraline base and -CD probably contributes to the line broadening of the NMR peaks. Furthermore, changes in the peak shape indicate a new interaction between sertraline base and -CD in PPT. The 13 C-CP/MAS NMR spectrum of PPT was different from those of -CD and PM in the range of -CD resonances (50–110 ppm) (Fig. 8b–d). Specifically, the multiplicity of signals for each carbon atom was reduced in PPT. For each carbon atom, the chemical shift dispersion values monotonically
Novoselsky and Glaser reported that the chemical shifts were not resolved; approximately double intensity [33].
Figure 9. PXRD patterns of sertraline base (a), -CD (b), PM (c), and PPT (d) (2 = 5◦ –30◦ ). PM, physical mixture sample; PPT, precipitated sample.
decreased for PPT (Fig. 8d), and it is well known that the free CD spectrum exhibits multiple resonances for each type of carbon atom. These features have been largely correlated with the different torsion angles around the ␣(1 → 4) linkages and with the torsion angles that described the orientation of the hydroxyl angles [31,32,36]. These findings suggest that an inclusion compound is formed by sertraline base and -CD in PPT, presumably due to the improved symmetry of the -CD macrocycle, which was revealed by the greater equivalence of the various carbon atoms with respect to -CD in the 13 C-CP/MAS NMR spectrum. These findings indicate that an inclusion compound is formed by sertraline and -CD in PPT. 3.2.5. Powder X-ray diffraction (PXRD) experiment The PXRD patterns of sertraline base, -CD, PM, and PPT are shown in Fig. 9. PPT (Fig. 9d) displayed some specific peaks that were significantly different from those observed for -CD, sertraline base, and PM (Fig. 9c). PXRD measurements are occasionally used to identify the type of crystal packing in the CD inclusion compounds by applying the crystal isostructurality concept reported by
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shows the experimental and theoretical 1 H NMR chemical shifts for sertraline base in DMSO-d6 . Fig. 10 shows the 1 H NMR spectra of PPT dissolved in DMSO-d6 at 30 ◦ C. The proton signals arising from the H atoms attached to C1 of -CD (Fig. 10(i)) and those arising from the H atom attached to C4 of sertraline base (Fig. 10(ii)) was observed at approximately 4.8 and 4.1 ppm, respectively. These peak integrations were used to calculate the stoichiometry of the complex. The peak integration of the protons in the H atoms attached to C1 of -CD was 7.20 (Fig. 10(i)) and that of proton attached to C4 of sertraline base was 0.90 (Fig. 10(ii)). Since -CD comprises seven glucopyranose units, seven H atoms are attached to seven C1 atoms in a -CD molecule. For sertraline base, one H atom was attached to C4 in a molecule. Therefore, the number of -CD molecules encapsulating a sertraline molecule in PPT was estimated to be 1.1. Thus, these results suggest that -CD and sertraline base form a 1:1 inclusion complex (host:guest).
Figure 10. sample.
1
4. Conclusions H NMR spectrum of PPT in DMSO-d6 (ı = 0–8.0 ppm). PPT, precipitated
Table 2 H NMR chemical shifts of sertraline base in DMSO-d6 .
1
H atom
Chemical shift (ppm) ıexperimental
ıtheoretical
H (2, 3, 17)
1.68–2.51
H (1) H (4) H (5) H (6–8, 15, 16)
3.65 4.07–4.10 6.68–6.70 7.07–7.40
H (12)
7.52–7.55
1.94 1.95 2.00 2.35 2.41 2.50 2.59 3.70 4.17 7.19 7.23 7.41 7.41 7.41 7.63 7.81
Caira [37]. The main features of the PXRD patterns should be highly similar regardless of the nature of inclusion within an isostructural series of the crystalline inclusion compounds for a particular CD [37]. In this study, the PXRD pattern of PPT (Fig. 9d) was different from those of the parent crystalline sertraline base and -CD (Fig. 9a- and b). PPT displayed novel peaks, suggesting the formation of -CD–sertraline base complex (Fig. 9d). 3.2.6. Estimation of the stoichiometric ratio for the sertraline base–ˇ-CD complex To estimate the stoichiometric ratio of the complex that was prepared in the phase solubility studies, the 1 H NMR spectrum of PPT was measured after the solid complex was dissolved in DMSO-d6 [38]. In this study, under the present experimental conditions, only information regarding the stoichiometry of the complex but not the formation of the complex was obtained because -CD molecules should dissociate from the complex. The NMR spectrum of the -CD was assigned on the basis of 1 H NMR spectral information obtained from the literature data of the compound in solution [38]. The 1 H NMR spectrum of sertraline base was due to the corresponding DFT values that were calculated using a 6-311 + G(2d, p) basis set for the B3LYP density functional theory (6-311G basis set), which was optimized by the geometric models of sertraline base. 1 H NMR spectral information obtained from the literature data of sertraline hydrochloride in DMSO-d6 was also used as a reference [33]. Table 2
According to the results of the phase solubility study, an inclusion complex (sertraline base–-CD) was formed at higher -CD concentrations. To clarify the properties of the complex, physicochemical analysis of PPT was conducted. DSC analysis results indicated that PPT was new material, which was different from sertraline base and -CD. In addition, FTIR and FT-Raman spectroscopy results suggested that C17, N18, and aromatic groups, especially C5–C10, in sertraline base were interacting with -CD. Furthermore, the results from the 13 C-CP/MAS NMR experiment and the PXRD studies indicate that an inclusion compound was formed by sertraline and -CD in PPT. The results of PPT stoichiometric ratio estimation suggested that the -CD and sertraline base could form a 1:1 inclusion complex (host:guest). In conclusion, converting sertraline from a salt form into a free base form and investigating the free base as a candidate for CD inclusion have revealed that the free base form of sertraline is well suited for this type of application, and this approach may lead to novel formulations of the drug. Acknowledgments This study was supported in part by a research grant from the Ministry of Education, Culture, Sports, Science and Technology of Japan. This study was also supported in part by The Hori Sciences and Arts Foundation. The authors are grateful to Prof. Dr. Kimio Higashiyama and Dr. Mayumi Ikegami-Kawai at Hoshi University for their insightful comments and suggestions. The authors also thank Mr. Yuuki Hattori and Mr. Ryota Igarashi for their experimental work. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.jpba.2014.12.036. References [1] C.L. DeVane, H.L. Liston, J.S. Markowitz, Clinical pharmacokinetics of sertraline, Clin. Pharmacokinet. 41 (2002) 1247–1266. [2] D. Murdoch, D. McTavish, Sertraline, A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in depression and obsessive-compulsive disorder, Drugs 44 (1992) 604–624. [3] R.J. Bastin, M.J. Bowker, B.J. Slater, Salt selection and optimization procedures for pharmaceutical new chemical entities, Org. Process Res. Dev. 4 (2000) 427–435. [4] J. Lu, S. Rohani, Polymorphism and crystallization of active pharmaceutical ingredients, Curr. Med. Chem. 16 (2009) 884–905. [5] Q. He, S. Rohani, J. Zhu, H. Gomaa, Sertraline racemate and enantiomer: solidstate characterization, binary phase diagram, and crystal structures, Cryst. Growth Des. 10 (2010) 1633–1645.
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Solid-state characterization of sertraline base–-cyclodextrin inclusion complex Noriko Ogawa a,∗ , Takuro Hashimoto b,1 , Takayuki Furuishi b,1 , Hiromasa Nagase b,1 , Tomohiro Endo b,1 , Hiromitsu Yamamoto a , Yoshiaki Kawashima a , Haruhisa Ueda c,2 a Department of Pharmaceutical Engineering, School of Pharmacy, Aichi Gakuin University, 1-100 Kusumoto-cho, Chikusa-ku, Nagoya, Aichi 464-8650, Japan b Department of Physical Chemistry, Faculty of Pharmaceutical Sciences, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan c Department of Physical Chemistry, Nihon Pharmaceutical University, 10281 Komuro Ina-machi, Kitaadachi-gun, Saitama 362-0806, Japan
a r t i c l e
i n f o
Article history: Received 23 September 2014 Received in revised form 8 December 2014 Accepted 20 December 2014 Available online 15 January 2015 Keywords: Sertraline base -Cyclodextrin Complexation Solid-state analysis Computational interpretation
a b s t r a c t Sertraline is one of the serotonin-specific reuptake inhibitors that is effective in treating several disorders such as major depression, obsessive–compulsive disorder, panic disorder, and social phobia. It is marketed in the form of its hydrochloride salt, which exhibits better solubility in water than its free base form. However, the absorption of sertraline through biological membranes could be improved by enhancing the solubility of its base because it is more hydrophobic than sertraline hydrochloride. To clarify the mechanism for the interaction of sertraline base with -CD, it is important to study the basic interaction between the -CD ring and sertraline base. Therefore, in this study, the currently used hydrochloride salt form was converted into the free base and -CD was used as a model for -CD derivatives to evaluate the interaction between -CD and the sertraline base. The solid-state physicochemical characteristics of the sertraline–-CD complex were investigated by the phase solubility method, differential scanning calorimetry, Fourier transform IR spectroscopy, FT-Raman spectroscopy, powder X-ray diffraction, and 13 C cross-polarization magic-angle spinning NMR measurements. The results showed that sertraline base and -CD form an inclusion complex, and the stoichiometric ratio of the solid-state sertraline base–-CD complex is 1:1, which was estimated by the 1 H NMR measurements of the complex dissolved in DMSO-d6 . © 2014 Elsevier B.V. All rights reserved.
1. Introduction Sertraline, (1S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroN-methyl-1-naphthaleneamine (Fig. 1a), is a serotonin-specific reuptake inhibitor that is effective in treating several disorders such as major depression, obsessive–compulsive disorder, panic disorder, and social phobia [1,2]. It is marketed in the form of its hydrochloride salt. Salt forms are frequently used in formulations because they improve aqueous solubility and chemical stability relative to the free base or acid of the active compound.
∗ Corresponding author. Tel.: +81 52 757 6771; fax: +81 52 757 6799. E-mail addresses: [email protected] (N. Ogawa), [email protected] (T. Hashimoto), [email protected] (T. Furuishi), [email protected] (H. Nagase), [email protected] (T. Endo), [email protected] (H. Yamamoto), [email protected] (Y. Kawashima), [email protected] (H. Ueda). 1 Tel.: +81 3 5498 5159; fax: +81 3 5498 5159. 2 Tel.: +81 48 721 1155; fax: +81 48 721 6718. http://dx.doi.org/10.1016/j.jpba.2014.12.036 0731-7085/© 2014 Elsevier B.V. All rights reserved.
However, it is better to utilize the free base or acid when an active pharmaceutical ingredient has a low pKa value and the resulting salts are less stable, more hygroscopic, or when complex polymorphism/pseudopolymorphism is exhibited [3–5]. Sertraline hydrochloride is a highly polymorphic salt, and several crystalline salt forms have been reported [5,6]. He et al. [5] reported that the sertraline free base enantiomer is relatively less polymorphic than the sertraline hydrochloride salt. In addition, enhancing the solubility of the free base can improve the absorption of sertraline through biological membranes because the base is more hydrophobic than sertraline hydrochloride. Poor treatment compliance is a major problem for patients that use antipsychotic drugs to treat psychiatric disease, which results in the deterioration of patient’s symptoms over time [7]. Sertraline is an antipsychotic drug that is orally administered during the acute exacerbation phase and for maintenance treatment. Developing transdermal or transmucosal parenteral sustained-release dosage forms of antipsychotic drugs will serve patients’ needs and improve compliance. Thus, using sertraline base will be beneficial for
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Figure 1. Chemical structures of sertraline base (a) and -CD (b).
developing parenteral dosage forms if its solubility or absorption through biological membranes is enhanced by the use of pharmaceutical additives or processes. Cyclodextrins (CDs) are cyclic oligosaccharides consisting of 6, 7, or 8 d-glucose units, called ␣, -, and ␥-CD, respectively, and are linked by ␣-1,4 glycosidic bonds. CDs have a conical shape with external hydrophilic properties caused by its hydroxyl groups and an internal hydrophobic cavity, which allows different guest molecules to form inclusion complexes [8,9]. They have attracted attention in pharmaceutical formulation, in food, and in biological fields because the inclusion complexes formed with guest molecules can occur in solutions or in solid state. In addition, CDs may improve the solubility of poor water-soluble drugs and may enhance their physical and chemical stability. Passos et al. [10–12] reported inclusion complexes formed between sertraline hydrochloride and -CD (Fig. 1b) at molar ratios of 1:1 and 1:2 by freeze drying. When water was used as a solvent, for inclusion complexes of sertraline hydrochloride and -CD at molar ratios of 1:1 and 1:2, the solubility of sertraline hydrochloride increased to 6 and 8 times higher than that of sertraline hydrochloride alone, respectively. Thus, using -CD with sertraline base will be beneficial because hydrophilic -CD derivatives such as hydroxypropyl -CD and sulfobutylether -CD can exhibit a strong solubility enhancement effect; however, analyzing the interaction is difficult since the structures of these derivatives are complicated compared with those of natural -CD. The basic interaction between the -CD ring and sertraline base is important and needs to be studied for clarifying the sertraline base–-CD interaction mechanism. In this study, the sertraline hydrochloride salt was converted into the free base form and used with -CD to evaluate the interaction between -CD or -CD derivatives and sertraline base. -CD has a simpler structure than -CD derivatives, which are also used as pharmaceutical additives. -CD was used to investigate the sertraline base–-CD interaction mechanism, which was examined by the phase solubility method. We evaluated the solid-state physicochemical characteristics of the sertraline base–-CD complex using differential scanning calorimetry (DSC), Fourier transform IR (FTIR) spectroscopy, FT-Raman spectroscopy, powder X-ray diffraction (PXRD), and 13 C cross-polarization magic-angle spinning (13 C-CP/MAS) NMR. We estimated the stoichiometric ratio of the solid-state sertraline base–-CD complex using the 1 H NMR measurements of the complex dissolved in DMSO-d6 . 2. Materials and methods 2.1. Materials Sertraline hydrochloride was purchased from Tokyo Chemical Industry Co., Ltd. (Tokyo, Japan). -CD was purchased from Nihon Shokuhin Kako Co., Ltd (Tokyo, Japan) in its hydrate form (-CD·10.5H2 O); the -CD water content was confirmed as 10.5H2 O by thermogravimetry. Deuterated dimethyl sulfoxide-d6
(DMSO-d6 ; NMR measurement grade), ethyl acetate, sodium hydroxide, sodium sulfate, sodium dihydrogen phosphate dihydrate, acetonitrile, phosphoric acid, and triethylamine were purchased from Wako Pure Chemical Industries, Ltd. (Osaka, Japan). All other chemicals were of reagent grade. 2.2. Sample preparation 2.2.1. Preparation of sertraline base Liquid–liquid extraction was used to prepare sertraline base from the sertraline hydrochloride salt (100 mg) using an ethyl acetate (100 mL)/carbonate buffer solution (pH 10, 30 mL). The organic phase was separated, and water was removed by sodium sulfate. Ethyl acetate was evaporated under reduced pressure, and an oily distillation residue was obtained. Water was added to the oily residue, and the mixture was dispersed by ultrasonic waves and freeze-dried; then, sertraline base was obtained as a microcrystalline powder. Sertraline base was dissolved in DMSO-d6 and its presence was confirmed by 1 H NMR measurements. NMR spectra were recorded at 30 ◦ C on a JNM Lambda 500 spectrometer (JEOL Ltd., Tokyo, Japan). Tetramethylsilane was used as an external standard. 2.2.2. Preparation of the physical mixture sample (PM) Sertraline base and -CD were physically mixed at a 1:1 molar ratio to prepare the physical mixture sample (PM) without applying pressure. 2.2.3. Preparation of precipitated sample (PPT) The physical characteristics and stoichiometry of the sertraline base–-CD inclusion complex were evaluated by preparing a precipitated sample (PPT). There are many kinds of methods for obtaining the drug–CD complex, e.g. kneading, co-evaporation, spray-drying, freeze-drying, and precipitation. We selected the precipitation method because it is basic and reliable for obtaining the drug–CD complex that precipitation due to complexation. This material, which precipitated as a microcrystalline powder, was prepared by mixing sertraline base (2 mg) with a 5 mL of -CD solution (12 mM). The mixed solution was shaken (120 strokes/min) for 7 days at 25 ◦ C, and the precipitate was filtered. We chose 7 days to make sure that the sertraline base and -CD were in an equilibrium. The precipitate was washed with cold water to remove free -CD, and the solid material which was presumed to be free sertraline base was removed when the precipitate was dissolved until the hot water solution at above 70 ◦ C was supersaturated and filtered. The dissolved solution was cooled, and the precipitate was filtered and dried under vacuum at room temperature for 24 h. The precipitate obtained was PPT, which was used for thermal analysis, PXRD measurements, 13 C-CP/MAS NMR experiment, FTIR spectroscopy, FT-Raman spectroscopy, and the estimation of the stoichiometric ratio of the sertraline base–-CD complex.
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2.3. Phase solubility studies Phase solubility studies were conducted according to the method reported by Higuchi and Connors [13]. Five milliliters of -CD solutions (2–15 mM) were added to an excess of sertraline base (2 mg), and the mixture was mechanically shaken (120 strokes/min) for 7 days at 25 ◦ C. The equilibrium-attained system was filtered using a membrane filter (0.45 m), and the sertraline concentration was determined by HPLC, the conditions for which are as follows [14]. Briefly, the HPLC system comprised a PU-2080 plus intelligent HPLC pump, a UV-2075 intelligent UV/VIS detector, a CO-2065 plus intelligent column oven, an AS-2055 plus intelligent sampler and a ChromNAV chromatography data system (all from JASCO Co., Tokyo, Japan). An AlltimaTM C18 column (250 mm × 4.6 mm I.D., Alltech Associates, Inc.) was used for separation. The mobile phase consisted of acetonitrile and phosphate buffer (pH 5.5; adjusted with phosphoric acid and triethylamine) (50/50, v/v). The analysis was carried out at 40 ◦ C using a flow rate of 1 mL/min. Chromatograms were run with an injection volume of 20 L and recorded with a UV detector at 230 nm. Stability constants for the formation of sertraline–-CD inclusion complexes were determined from phase solubility data using Eq. (1) below: KA =
slope S0 (1 − slope)
(1)
where KA (M−1 ) is the apparent stability constant of the sertraline base–-CD complex, slope denotes the initial upward linear portion of the solubility phase diagram, and S0 (mM) is the intrinsic solubility of the sertraline base. 2.4. Solid-state characterization of the sertraline base–ˇ-CD complex 2.4.1. Thermal analysis DSC was performed on samples (2 mg) sealed in aluminum pans using a thermal analyzer system (DSC 8240D, Rigaku Co., Ltd., Japan). Al2 O3 was used as reference. Samples were heated from 40 to 220 ◦ C at 10 ◦ C/min under nitrogen flow. 2.4.2. Fourier transform IR (FTIR) spectroscopy FTIR spectra were obtained using an FTIR spectrometer (FT/IR 5300; Jasco Co., Ltd., Japan) and the KBr disc method. For each sample, 32 scans in the 4000 and 400 cm−1 spectral ranges were recorded with a resolution of 4 cm−1 . 2.4.3. FT-Raman spectroscopy Raman spectra were acquired using an FT-Raman system (RFT6000; Jasco Co., Ltd., Japan) equipped with an indium gallium arsenide detector. Nd3+ /YAG laser with an excitation wavelength of 1064 nm was used to irradiate the sample. For each spectrum, up to 4500 scans were collected with a spectral resolution of 1 cm−1 . 2.4.4. Powder X-ray diffraction (PXRD) experiment PXRD measurements were recorded on a RINT-1400 X-ray diffractometer (Rigaku Corporation, Tokyo, Japan). Graphite˚ 60 kV and 150 mA) monochromated Cu K␣ radiation ( = 1.54178 A, was used to perform X-ray diffraction. Measurements were obtained using a scanning interval of 2 between 3◦ and 35◦ with a scanning speed of 2◦ /min. 2.4.5. 13 C Cross-polarization magic-angle spinning (13 C-CP/MAS) NMR measurements 13 C-CP/MAS NMR measurements were recorded on an ECA400 spectrometer (JEOL Ltd., Tokyo, Japan) with a frequency of 100.5 MHz for 13 C. The spectrometer was equipped with a 3.2 mm MAS probehead. The repetition delay time was 4 s, and the spectral
Figure 2. Phase solubility diagram of sertraline base and -CD. Each point is the mean ± S.D. (n = 3).
width was 25 kHz. Adamantane was used as an external standard (29.5 ppm). 2.4.6. Estimation of the stoichiometric ratio of the sertraline base–ˇ-CD complex Sertraline base, -CD, and PPT were separately dissolved in 10 mg/mL DMSO-d6 , and 1 H NMR measurements were performed. 2.5. Computational studies The structural optimization of sertraline was studied using the density functional theory (DFT) and the Gaussian-09 program package [15]. Geometries were optimized at the B3LYP/6-311 theory level. Theoretical Raman and IR spectra of sertraline were calculated at the B3LYP/6-311 + G(d, p) theory level. Theoretical NMR chemical shifts were based on the GIAO B3LYP approach, which used the 6-311G + (2d, p) basis set that was implemented in the Gaussian software package [15]. 3. Results and discussion 3.1. Phase solubility studies The phase solubility curve of the sertraline base–-CD complex is shown in Fig. 2. The sertraline base–-CD system is considered to display a Bs-type solubility curve according to the classification system of Higuchi and Connors [13]. In Bs-type curves, the initial increase in solubility is followed by a plateau region and a decrease in the total drug concentration, which is caused by the precipitation of a microcrystalline complex. In this study, the sertraline base–-CD system displayed a Bs-type solubility curve because the initial increase in solubility was followed by a decrease in the total drug concentration, which was caused by the precipitation of the microcrystalline powder; however, the plateau region was too short to define it accurately. The solubility of sertraline base was 4.38 × 10−2 mM (13.4 g/mL, water), which increased to 0.75 mM (229.8 g/mL) when the -CD concentration was 5 mM on the solubility curve. In the presence of -CD, the solubility of sertraline base was approximately 17-fold higher than that of sertraline base alone. Johnson et al. [16] reported the solubility of sertraline hydrochloride as 11.09 mM (3.8 mg/mL). The solubility of sertraline hydrochloride is higher than that of sertraline base. However, if the solubility of sertraline base is improved by pharmaceutical techniques, it can have useful applications in parenteral dosage forms.
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Figure 3. DSC thermograms of sertraline base (a), -CD (b), PM (c), and PPT (d). PM, physical mixture sample; PPT, precipitated sample.
The apparent stability constant (KA ) of the sertraline base–CD complex was calculated according to Eq. (1). The data that was inputted into the equation was the initial ascending portion of the solubility diagram where the complex could be formed. The KA value of the sertraline base–-CD complex was calculated using four values obtained from the -CD concentration range (0.0–4.0 mM). Using 0.1585 as the slope and 4.38 × 10−2 mM as S0 , Eq. (1) was calculated, and the stability constant was 4300 M−1 . The observed value of K1:1 (KA in this study) is reported to be between 50 and 2000 M−1 with mean values of 129, 490, and 355 M−1 for the parent ␣-, - and ␥-CDs, respectively [17,18]. In this study, the high stability constant suggests a strong affinity between the guest and host in the aqueous phase and a high stability of the complexes. Passos et al. [10,11] used isothermal titration calorimetry and reported a high value of 4999.3 ± 495.4 M−1 for the binding of sertraline hydrochloride into the -CD cavity, suggesting a high affinity between sertraline and -CD. The KA value of the sertraline base–-CD complex obtained in this study concurred with the reported value. In this study, a poor water-soluble precipitate was obtained at high concentration of -CD in the phase solubility curve of the sertraline base–-CD complex, as stated above. To investigate the stoichiometry of sertraline and -CD inclusion complexes, a precipitated sample (PPT) was prepared and was used for thermal analysis, PXRD measurements, 13 C-CP/MAS NMR experiment, FTRaman spectroscopy, and the estimation of the stoichiometric ratio of the sertraline–-CD complex. 3.2. Solid-state characterization of the sertraline base–ˇ-CD complex 3.2.1. Thermal analysis DSC analysis was conducted to understand the thermal behavior of PPT. The DSC thermograms of sertraline base, -CD, PM, and PPT are shown in Fig. 3. In this study, the DSC thermogram of sertraline base exhibited an endothermic peak at 68.3 ◦ C, which is attributable to its melting point; this value is also in agreement with the melting point [66.5 ± 0.5 ◦ C (onset)] of the sertraline enantiomer reported by He et al. [5]. In the DSC thermogram of -CD, broad endothermic peaks were observed from 145 to 200 ◦ C, which were attributable to dehydration during the heating process (Fig. 3b). In PM, the endothermic peak of the drug was shifted to 66.7 ◦ C (Fig. 3c), and the result was probably due to the interaction between the pure components in the physical mixture. Endothermic peaks from 140
Figure 4. FTIR spectrum of sertraline base theoretically calculated from the geometric models of the drug (I) and of that prepared in this study (II).
to 190 ◦ C were observed in the DSC thermogram of PM, which were attributable to the dehydration process and interaction between sertraline base and -CD caused by the heating process. However, the endothermic peak observed at 68.3 ◦ C was due to sertraline base, and it completely disappeared in PPT (Fig. 3d). Free sertraline base was not in PPT because the endothermic peak of sertraline base was not detected. The endothermic peaks at 185 and 198 ◦ C may be attributed to the dehydration process. These results indicate that PPT may be a new material, which differs from the original sertraline base and -CD. 3.2.2. Fourier transform IR (FTIR) spectroscopy FTIR spectra were recorded to detect spectral signals that may reveal the existence of intermolecular interactions between sertraline base and -CD in PPT. The theoretical and experimental FTIR spectra of sertraline base are shown in Fig. 4. Experimental absorption peaks (Fig. 4(II)) due to sertraline base were compared to the corresponding DFT values, which were calculated using a 6-311 + G(d, p) basis set for the B3LYP density functional theory (6311G basis set) with optimized geometric models of sertraline base (Fig. 4(I)) [15]. The 2783 cm−1 absorption band corresponds to the C H stretching vibration modes (C1, C17), while the 1128 cm−1 absorption band could be assigned to vibrations of the aromatic groups (C11–16). The 828 cm−1 absorption band can be assigned to vibrations of aromatic groups (C15 and C16). Ab initio harmonic vibrational frequencies (wavenumbers) are typically larger than the fundamentals observed experimentally [19,20]. A major source of this discrepancy is the neglect of anharmonicity effects in the theoretical treatment [20]. The ab initio wavenumbers calculated by the Hartree–Fock (HF) method were consistently higher than the experimental wavenumbers of the fundamentals by approximately 10% because the electron correlation and anharmonicity effects were neglected [21]. The scaled quantum mechanical method proposed by Pulay et al. was used to solve these problems [21–23]. In the method, the force constants of similar chemical fragments shared the same scale factor [21]. Thus, the scale factor values are optimized by minimizing weighted mean-square deviations of the calculated wavenumbers from the observed wavenumbers [21]. However, a more accurate prediction of vibrational spectra needs to be obtained; thus, more sophisticated methods, including an electron correlation spectra, have been suggested as post-HF methods [21]. The evolution of DFT, which includes an alternative electron correlation method, has permitted a cost-effective vibrational analysis of moderately large molecules since the 1990s [21,24,25]. The
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Figure 6. FT-Raman theoretical spectrum of sertraline base calculated from the geometric models of the drug (a) and FT-Raman experimental spectrum in this study (b).
Figure 5. FTIR spectra of sertraline base (a), -CD (b), PM (c), and PPT (d). PM, physical mixture sample; PPT, precipitated sample.
procedures that use Becke’s three parameter hybrid functional (B3) with correlation functions such as the one proposed by Lee, Yang, and Parr (LYP) are the most promising in that correct vibrational wavenumbers are provided [21,26,27]. These studies have shown the superiority of B3’s functional quality; however, the scaling procedures for each of the calculated wavenumbers were different [21]. Yoshida et al. [21] reported that large positive deviations from unscaled calculated wavenumbers and from the observed values at higher wavenumbers were almost exclusively attributed to the neglect of anharmonicity in the calculated wavenumbers. Thus, the wavenumber-linear scaling (WLS) method was adopted, which is based on the linear relationship between the scale factor and vibrational wavenumbers [21,28–30]. The relationship between the unscaled calculated wavenumbers (vcalc ) and observed wavenumbers (vobs ) is reported in Eq. (2) [21]:
vobs = 1.0087(9) − 0.0000163(6) × vcalc vcalc
Figure 7. FT-Raman spectra of PM (a) and PPT (b) in a range of 2600–3400 cm−1 (I) and 100–1700 cm−1 (II). PM, physical mixture sample; PPT, precipitated sample.
(Fig. 5(II), (ii)), and the 880–820 cm−1 region (Fig. 5(II), (iii)) were shifted. These shifts may be due to conformational -CD changes caused by the interaction with sertraline base in PPT.
(2)
where vobs and vcalc are given in cm−1 , and the errors shown in the parentheses apply to the last significant figure. The ratio vobs /vcalc in Eq. (2) is denoted as the wavenumber scale factor that is applied to the B3LYP/6-311 + G(d, p) calculation [21]. In this study, the unscaled calculated wavenumbers are shown in Fig. 4(I), and these wavenumbers were larger than the experimental wavenumbers, especially at higher wavenumbers (Fig. 4(I)). The scaled wavenumbers that employed the WLS method used the vobs /vcalc ratio in Eq. (2) as the wavenumber scale factor, and the results of these wavenumbers concurred with the experimental values. FTIR spectral comparisons of sertraline base, -CD, PM, and PPT are shown in Fig. 5. The FTIR spectrum of PM corresponds to the superposition of sertraline base and -CD spectra, with a little shift in the major peaks corresponding to the components (Fig. 5c). The 2783 cm−1 absorption band was assigned to the C H stretching vibration (C1, C17), and the band was shifted (Fig. 5c(I)). The observation indicates that there is little interaction between sertraline base and -CD in PM. However, in PPT spectrum, the 2783 cm−1 absorption band, assigned to C H stretching vibrations (C1, C17), disappeared, and the 828 cm−1 absorption band, assigned to vibrations of aromatic groups (C15 and C16), was broader (Fig. 5d). This shift is due to the interaction between the functional group of sertraline and the hydroxyl group of -CD. Furthermore, the peaks in the 1270–1180 cm−1 region (Fig. 5(II), (i)), 960–900 cm−1 region
3.2.3. FT-Raman spectroscopy As with FTIR spectra, FT-Raman spectra were also recorded to detect spectral signals that may reveal the existence of intermolecular interactions between sertraline base and -CD. The theoretical and experimental FT-Raman spectra of sertraline base are shown in Fig. 6. Experimental peaks (Fig. 6b) due to sertraline base were compared to the corresponding DFT values calculated using a 6-311 + G(d, p) basis set for the B3LYP density functional theory [6-311G basis set] optimized by geometric models of sertraline base (Fig. 6a) [15]. The 3350 and 3326 cm−1 absorption bands were assigned to the N H stretching vibration mode (N18), and the 3056 cm−1 absorption band was assigned to the C H stretching vibration of the aromatic groups (C5–C8, C15, C16). The 2789 cm−1 absorption band was assigned to the C H stretching vibration modes (C1, C17). And the 1592 cm−1 absorption bands were assigned to C C stretching vibration of the aromatic groups (C5–C10, C11–C16). FT-Raman spectral comparisons of PM and PPT are shown in Fig. 7. The FT-Raman PM spectrum corresponds to the superposition of sertraline base and -CD spectra, with little shifts in the major peaks corresponding to the components. In PPT spectrum, the 2789 cm−1 absorption peak assigned to C H stretching vibrations (C1, C17) and the 3350 cm−1 absorption peaks assigned to N H stretching vibration (N18) were absent; however, both of these peaks were present in the sertraline spectrum. The
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N. Ogawa et al. / Journal of Pharmaceutical and Biomedical Analysis 107 (2015) 265–272 Table 1 13 C NMR chemical shifts of sertraline. C atom Chemical shift (ppm) Sertraline base ıtheoretical
C(1) C(2) C(3) C(4) C(5) C(6) C(7) C(8) C(9) C(10) C(11) C(12) C(13) C(14) C(15) C(16) C(17)
Figure 8. 13 C-CP/MAS NMR spectra of sertraline base (a), -CD (b), PM (c), and PPT (d). PM, physical mixture sample; PPT, precipitated sample.
61.88 35.80 33.22 51.90 135.12 131.97 128.95 134.74 142.08 147.73 155.42 135.89 144.87 143.13 135.56 132.06 35.79
Sertraline hydrochloride ıexperimental
59.20
46.99
150.00
ıliterature (Form I, solid) [33] 58.7 28.5a 28.5a 47.5
ıliterature (Form III, solid) [33] 54.9 22.9 28.8 47.3
140.7 144.7
140.8 148.0
31.9
31.2
a
C H stretching vibration mode of the aromatic groups (C5–C8 and C15, C16) in sertraline base was broader, and the peak was shifted from 3056 to 3062 cm−1 (Fig. 7b(I)); further, the 1592 cm−1 peaks assigned to the C C stretching vibration of the aromatic groups in sertraline base were broadened and shifted in PPT spectrum. These results were consistent with FTIR spectroscopy results. Unfortunately, there is a large amount of overlap in the 1500–100 cm−1 regions with the Raman bands due to -CD and sertraline base, which makes PPT spectra analysis extremely difficult. However, comparing PM and PPT spectra revealed that many peaks in the region were shifted, and these shifts resulted from conformational changes of -CD and sertraline base caused by the interaction as a host and guest, respectively, in PPT. 3.2.4. 13 C Cross-polarization magic-angle spinning (13 C-CP/MAS) NMR measurements The 13 C-CP/MAS NMR experiment was used to investigate the interaction between sertraline base and -CD. The NMR spectra of sertraline base, -CD, PM, and PPT are shown in Fig. 8. The 13 CCP/MAS NMR spectrum of -CD was assigned on the basis of the 13 C NMR spectral information obtained from the literature data of the compound in the solid form [31,32]. The 13 C-CP/MAS NMR spectrum of sertraline base was assigned on the basis of the corresponding DFT values calculated using a 6-311G basis set for the B3LYP density functional theory (6-311G basis set), which was optimized by the geometric models of sertraline base [15]; further, the13 C-CP/MAS NMR spectral information obtained from the literature data of sertraline hydrochloride was also used as a reference [33]. The 13 C-CP/MAS NMR chemical shifts for sertraline base were shown in Table 1. In PM, sertraline base and -CD spectra overlapped, with little changes in the peak shape and chemical shifts (Fig. 8c). However, sertraline base and -CD peaks were markedly broadened in PPT (Fig. 8d). In general, line broadening in the 13 CCP/MAS NMR spectra is due to a large distribution of chemical environments or to a significant change in molecular dynamics [34,35]. An amorphous state of sertraline base and -CD probably contributes to the line broadening of the NMR peaks. Furthermore, changes in the peak shape indicate a new interaction between sertraline base and -CD in PPT. The 13 C-CP/MAS NMR spectrum of PPT was different from those of -CD and PM in the range of -CD resonances (50–110 ppm) (Fig. 8b–d). Specifically, the multiplicity of signals for each carbon atom was reduced in PPT. For each carbon atom, the chemical shift dispersion values monotonically
Novoselsky and Glaser reported that the chemical shifts were not resolved; approximately double intensity [33].
Figure 9. PXRD patterns of sertraline base (a), -CD (b), PM (c), and PPT (d) (2 = 5◦ –30◦ ). PM, physical mixture sample; PPT, precipitated sample.
decreased for PPT (Fig. 8d), and it is well known that the free CD spectrum exhibits multiple resonances for each type of carbon atom. These features have been largely correlated with the different torsion angles around the ␣(1 → 4) linkages and with the torsion angles that described the orientation of the hydroxyl angles [31,32,36]. These findings suggest that an inclusion compound is formed by sertraline base and -CD in PPT, presumably due to the improved symmetry of the -CD macrocycle, which was revealed by the greater equivalence of the various carbon atoms with respect to -CD in the 13 C-CP/MAS NMR spectrum. These findings indicate that an inclusion compound is formed by sertraline and -CD in PPT. 3.2.5. Powder X-ray diffraction (PXRD) experiment The PXRD patterns of sertraline base, -CD, PM, and PPT are shown in Fig. 9. PPT (Fig. 9d) displayed some specific peaks that were significantly different from those observed for -CD, sertraline base, and PM (Fig. 9c). PXRD measurements are occasionally used to identify the type of crystal packing in the CD inclusion compounds by applying the crystal isostructurality concept reported by
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shows the experimental and theoretical 1 H NMR chemical shifts for sertraline base in DMSO-d6 . Fig. 10 shows the 1 H NMR spectra of PPT dissolved in DMSO-d6 at 30 ◦ C. The proton signals arising from the H atoms attached to C1 of -CD (Fig. 10(i)) and those arising from the H atom attached to C4 of sertraline base (Fig. 10(ii)) was observed at approximately 4.8 and 4.1 ppm, respectively. These peak integrations were used to calculate the stoichiometry of the complex. The peak integration of the protons in the H atoms attached to C1 of -CD was 7.20 (Fig. 10(i)) and that of proton attached to C4 of sertraline base was 0.90 (Fig. 10(ii)). Since -CD comprises seven glucopyranose units, seven H atoms are attached to seven C1 atoms in a -CD molecule. For sertraline base, one H atom was attached to C4 in a molecule. Therefore, the number of -CD molecules encapsulating a sertraline molecule in PPT was estimated to be 1.1. Thus, these results suggest that -CD and sertraline base form a 1:1 inclusion complex (host:guest).
Figure 10. sample.
1
4. Conclusions H NMR spectrum of PPT in DMSO-d6 (ı = 0–8.0 ppm). PPT, precipitated
Table 2 H NMR chemical shifts of sertraline base in DMSO-d6 .
1
H atom
Chemical shift (ppm) ıexperimental
ıtheoretical
H (2, 3, 17)
1.68–2.51
H (1) H (4) H (5) H (6–8, 15, 16)
3.65 4.07–4.10 6.68–6.70 7.07–7.40
H (12)
7.52–7.55
1.94 1.95 2.00 2.35 2.41 2.50 2.59 3.70 4.17 7.19 7.23 7.41 7.41 7.41 7.63 7.81
Caira [37]. The main features of the PXRD patterns should be highly similar regardless of the nature of inclusion within an isostructural series of the crystalline inclusion compounds for a particular CD [37]. In this study, the PXRD pattern of PPT (Fig. 9d) was different from those of the parent crystalline sertraline base and -CD (Fig. 9a- and b). PPT displayed novel peaks, suggesting the formation of -CD–sertraline base complex (Fig. 9d). 3.2.6. Estimation of the stoichiometric ratio for the sertraline base–ˇ-CD complex To estimate the stoichiometric ratio of the complex that was prepared in the phase solubility studies, the 1 H NMR spectrum of PPT was measured after the solid complex was dissolved in DMSO-d6 [38]. In this study, under the present experimental conditions, only information regarding the stoichiometry of the complex but not the formation of the complex was obtained because -CD molecules should dissociate from the complex. The NMR spectrum of the -CD was assigned on the basis of 1 H NMR spectral information obtained from the literature data of the compound in solution [38]. The 1 H NMR spectrum of sertraline base was due to the corresponding DFT values that were calculated using a 6-311 + G(2d, p) basis set for the B3LYP density functional theory (6-311G basis set), which was optimized by the geometric models of sertraline base. 1 H NMR spectral information obtained from the literature data of sertraline hydrochloride in DMSO-d6 was also used as a reference [33]. Table 2
According to the results of the phase solubility study, an inclusion complex (sertraline base–-CD) was formed at higher -CD concentrations. To clarify the properties of the complex, physicochemical analysis of PPT was conducted. DSC analysis results indicated that PPT was new material, which was different from sertraline base and -CD. In addition, FTIR and FT-Raman spectroscopy results suggested that C17, N18, and aromatic groups, especially C5–C10, in sertraline base were interacting with -CD. Furthermore, the results from the 13 C-CP/MAS NMR experiment and the PXRD studies indicate that an inclusion compound was formed by sertraline and -CD in PPT. The results of PPT stoichiometric ratio estimation suggested that the -CD and sertraline base could form a 1:1 inclusion complex (host:guest). In conclusion, converting sertraline from a salt form into a free base form and investigating the free base as a candidate for CD inclusion have revealed that the free base form of sertraline is well suited for this type of application, and this approach may lead to novel formulations of the drug. Acknowledgments This study was supported in part by a research grant from the Ministry of Education, Culture, Sports, Science and Technology of Japan. This study was also supported in part by The Hori Sciences and Arts Foundation. The authors are grateful to Prof. Dr. Kimio Higashiyama and Dr. Mayumi Ikegami-Kawai at Hoshi University for their insightful comments and suggestions. The authors also thank Mr. Yuuki Hattori and Mr. Ryota Igarashi for their experimental work. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.jpba.2014.12.036. References [1] C.L. DeVane, H.L. Liston, J.S. Markowitz, Clinical pharmacokinetics of sertraline, Clin. Pharmacokinet. 41 (2002) 1247–1266. [2] D. Murdoch, D. McTavish, Sertraline, A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in depression and obsessive-compulsive disorder, Drugs 44 (1992) 604–624. [3] R.J. Bastin, M.J. Bowker, B.J. Slater, Salt selection and optimization procedures for pharmaceutical new chemical entities, Org. Process Res. Dev. 4 (2000) 427–435. [4] J. Lu, S. Rohani, Polymorphism and crystallization of active pharmaceutical ingredients, Curr. Med. Chem. 16 (2009) 884–905. [5] Q. He, S. Rohani, J. Zhu, H. Gomaa, Sertraline racemate and enantiomer: solidstate characterization, binary phase diagram, and crystal structures, Cryst. Growth Des. 10 (2010) 1633–1645.
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