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Thermodynamic stability analysis of m-nisoldipine polymorphs
J. Chem. Thermodynamics 58 (2013) 300–306
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Thermodynamic stability analysis of m-nisoldipine polymorphs Caiqin Yang, Tiankun Ren, Jing Wang ⇑, Yongli Wang ⇑, Xinglong Tao School of Pharmaceutical Sciences, Hebei Medical University, Shijiazhuang 050017, China
a r t i c l e
i n f o
Article history: Received 14 July 2012 Received in revised form 12 November 2012 Accepted 15 November 2012 Available online 7 December 2012 Keywords: Polymorphs Solubility Thermodynamics Phase transition FTIR X-ray powder diffractometry
a b s t r a c t Two polymorphic crystal forms of m-nisoldipine (1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5pyridinedicarboxylic acid methyl 2-methylpropyl ester) were characterized by X-ray powder diffraction and IR-spectroscopy. The solubility of the two polymorphs in water at 25, 31, 37, 42, and 49 °C was investigated; the values obtained were used to calculate the thermodynamic parameters of the phase transition. The results show that the two forms A and B are enantiotropic. The temperature of polymorphic phase transition was 47 °C, and the values of DGhA;B , DHhA;B , and DShA;B at 25 °C were 2.47, 36.01, and 112.48 J mol1 K1, respectively. Form A is thermodynamically stable below the transition temperature; it accorded with interaction energies of the two forms obtained from Density Function Theory (DFT) calculations on the hydrogen-bonding and p-stacking interactions. The character of the solid-state decomposition, studied using DSC analysis, showed that the activation energies of decomposition of the polymorphs A and B after melting at high temperatures were 109.80 and 59.14 kJ mol1, respectively. It is conclusion that melted states of polymorphs A and B reserved ‘‘the memories’’ of their respective crystalline state. Furthermore, phase transition of the polymorphs was not found under solid-state grinding conditions. Moisture sorption/desorption experiments showed that the two forms of m-nisoldipine are nonhygroscopic. Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction Polymorphs are different solid crystalline phases of a given compound, which result from at least two distinct crystal structures. Polymorphism is important about pharmaceutical drugs as a result of their different physiochemical properties and bioactivity in many cases, for example, crystal habit, intermolecular force, particle density, thermodynamic activity, the chemical and physical stability, solubility, dissolution rate, and bioavailability [1–6]. Owing to different lattice energies of polymorph, the more energetic ones seek to revert to the most stable form during the kneading and tabletting processes [7,8]. Moreover, storage conditions (such as temperature and humidity), grinding conditions, or pharmaceutical excipients affect the stability of the metastable crystal forms [9–11]. Therefore, characterization of polymorphs and elucidation of the physicochemical properties of bulk drugs during both the manufacturing process and the storage period are extremely important. M-nisoldipine (figure 1), as a dihydropyridine calcium ion antagonist, was first synthesized in the School of Pharmacy, Hebei Medical University [12]. Compared with its analogs, m-nisoldipine significantly increases cardiac output and cardiac index, dramati⇑ Corresponding authors. Tel.: +86 311 86265622; fax: +86 311 86266419. E-mail addresses: [email protected] (J. Wang), [email protected] (Y. Wang). 0021-9614/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jct.2012.11.023
cally reduces the negative inotropic effect on the myocardium, and has relatively higher selectivity for the thoracic aorta [13,14]. Furthermore, m-nisoldipine has two polymorphs, A (yellow color) and B (white color). The studies of pharmacokinetics and the relative bioavailability of m-nisoldipine polymorphs indicated that the polymorphs A and B of m-nisoldipine were not bioequivalent [15]; it supposes that there are differences between A and B in their thermodynamic activity, solubility, dissolution rate, and chemical and physical stability. The relative thermodynamic stability of polymorphs and the driving force for a transition are determined by the change of Gibbs free energy (DG). The DG versus temperature diagram can provide information about the stability relationship of polymorphs [16,17]. The DG and its temperature dependence can be obtained from solubility dependence on temperature data, and melting data (melting temperature, enthalpy of fusion), enthalpy of transformation if available. The melting data method requires less sample compared to the solubility method, however, it exposes the material to potential degradation chemically. Furthermore, when polymorphs have no distinct differences on the enthalpies of fusion or/and no phase transition peak is found in DSC scan [18], the enthalpies and melting point determined from DSC are not accurate enough for detailed evaluation of transition rule and thermodynamic stability. Solubility data are of special importance in the study of crystal nucleation/growth kinetics and transition thermodynamic of polymorphs [19]. In this study, we present our results
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current, 20 mA; voltage, 20 kV; receiving slit, 0.3 mm; scan range, 5°–40° (2h); and step size, 0.05°. Approximately 50 mg of the mnisoldipine powder was carefully loaded into a glass holder, and the sample surface was flattened softly to avoid particle orientation. The simulated XRD patterns were extracted using Mercury 1.4.2 software (Cambrige Crystallographic Data Centre). 2.3. FT-IR
FIGURE 1. Molecule sturcture of m-nisoldipine.
on the measurement of solubility of both polymorphs of m-nisoldipine; the data were used to investigate more precisely the thermodynamic stability of the polymorphs A and B, in addition to studying their respective phases. 2. Experimental 2.1. Sample preparation and crystallization M-nisoldipine was kindly supplied as batches by organic synthesis research laboratory of Hebei Medical University in China. Its synthesis procedure can be found in its Chinese patent [12], in which 1H NMR, elemental analysis, and mass spectrometry were all presented. The Polymorphs A and B used in present work were obtained by recrystallization in ethanol. Polymorphs A and B appeared at the upper and lower parts of the solvent, respectively, during cooling of the hot ethanol solvent in the refrigerator. Single crystals of polymorph A were grown from a solution of acetone/ethanol (1:1) by slow evaporation, whereas crystals of polymorph B were obtained from a solution of ethyl acetate/hexane (1:1), as described in our previous study [18]. The melting temperatures, enthalpies of fusion, and densities of these crystal forms are presented in table 1. Polymorph A crystallizes in space group P21/c (Monoclinic) with Z = 4, and cell parameters a = 0.93045(2) nm, b = 1.65991(5) nm, c = 1.30018(3) nm, b = 91.539(2)°, V = 2.00736(9) nm3, R1 [I > 2sigma(I)] = 0.0688. While Polymorph B crystallizes in space group P-1 (Triclinic) with Z = 2, and cell parameters a = 0.74965(2) nm, b = 1.14692(4) nm, c = 1.23648(5) nm, a = 68.093(2)°, b = 88.655(2)°, c = 81.853(2)°, V = 0.97589(6) nm3, R1 [I>2sigma(I)] = 0.0676. In both polymorphs, the m-nisoldipine molecules are linked through the N–HO hydrogen bonds [NO = 0.2927(2) nm and 0.3089 nm, N–HO = 139.1° and 171.0° for A and B, respectively]. Moreover, in B, the nitrobenzene moieties from the neighboring ribbon are held together by p–p stacking with the centroid distance being 0.4044 nm. Those information of crystal lattices are adapted from the data presented by Wang et al. [18]. 2.2. X-ray diffraction analysis Powder X-ray diffraction (PXRD) profiles were characterized with an X-ray diffractometer (RINT 2100 Ultima, Rigaku Co., Japan). The measurement conditions were as follows: target, Cu; filter, Ni; TABLE 1 Physical characteristics of the polymorphs A and B of m-nisoldipine. Polymorph
Melting temperature/°C
Enthalpies of fusion/ (J g1)
Density/ (kg m3)a
A B
137.79±1.56 130.16±2.08
88.88±1.55 90.28±1.09
1.285 1.322
a
The densities are obtained from single crystal X-ray diffraction.
All infrared spectra were recorded from (4000 to 400) cm-1, using the EQUINOX 55 (Bruker) FT-IR spectrometer. Each spectrum was the average of 40 scans. The IR spectra were recorded and stored using spectroscopic software (OPUS, Version 2.0). FT-IR spectra of the samples were obtained by mixing 4 mg pure substances in an agate mortar with 160 mg of desiccated IR grade potassium bromide (Merck) in a dry box. 2.4. Thermal analysis Polymorphs A and B were characterized by differential scanning calorimetry/thermo-gravimetry (DSC/TG) studies on a Perkin-Elmer Pyris 1 apparatus. Accurately weighed (about 15 mg) specimens were hermetically sealed using a sealing machine. The DSC/TG scans were operated in the temperature range of (25 to 500) °C at heating rates of 10, 20, 30, and 40 °C min1 to explore the decomposition process. Nitrogen was used as the purging gas, and its flow rate was 20 °C min1. 2.5. Analyses of solubility, transition temperature, and thermodynamics 2.5.1. Solubility The solubility levels in water (double distilled H2O, ddH2O) were determined at 25, 31, 37, 42, and 49 °C. An excess amount of the solid sample was weighed and placed in a 50 mL screwcapped vial. Afterward, 50 mL of each solvent was added to the respective vials, and they were capped. The vials were shaken at 100 spm in a water bath for 72 h. The concentration of solubilized m-nisoldipine was measured at 238 nm using an ultraviolet spectrophotometer (UV-160A, Shimadzu Co., Japan) after filtering through a 0.45 lm membrane filter. Each solubility measurement was repeated at least three times. 2.5.2. Analyses of transition temperature and thermodynamics At standard conditions, the relationship of c and Hh of the two polymorphs A and B are given by Van’t Hoff’s equation:
ð@ ln cA =ch Þ=@T ¼ DHhA =RT 2 ;
ð1aÞ
ð@ ln cB =ch Þ=@T ¼ DHhB =RT 2 ;
ð1bÞ
where Hh is standard enthalpy; c is solubility; ch is standard concentration and its value is 1 mol L1. Then, we get the following expressions:
ð@ ln cA =ch Þ=@ð1=TÞ ¼ DHhA =R;
ð2aÞ
ð@ ln cB =ch Þ=@ð1=TÞ ¼ DHhB =R:
ð2bÞ
Combining equations (2a) and (2b), we get
ð@ ln cA =cB Þ=@T ¼ DHhA;B =RT 2 :
ð3Þ
The temperature Tt indicates the transition temperature when cA = cB. Then,
DHhA;B ¼ T t DShA;B
where T ¼ T t ;
ð4Þ
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where DHhA;B and DShA;B are standard enthalpy change and standard entropy change of phase transition of the two polymorphs A and B. Subsequently, DGh at different temperatures was calculated from the equation:
DGhA;B ¼ DHhA;B T DShA;B ;
ð5Þ
where DGhA;B is the Gibbs free energy change of phase transition of the two polymorphs A and B. According to Eqs. (1a) and (1b), curves were drawn with ln c as the Y-coordinate versus 1/T as the abscissa for the two polymorphs A and B. The temperature corresponding to the point of intersection of the two curves is the transition temperature. Subsequently, according to equation (3), a curve was drawn with ln (cA/cB) as the Y-coordinate versus 1/T as the abscissa. The values of DHhA;B was obtained from the slopes of the curves, and DGhA;B and DShA;B were calculated from equations (4) and (5).
2.6. Storage conditions The stability of the polymorphs under high temperatures was evaluated as follows: the unsealed samples (0.5 g each) were placed in ovens at the following temperatures: (40 and 80) °C for 10 days; and 105 °C for 12 h. Afterward, the samples were subjected to XRD characterization to determine the crystal phase and UV to verify the purity.
3. Results and discussion 3.1. Physicochemical characterization of the polymorphs A and B 3.1.1. PXRD analysis The single crystal structures of the two polymorphs were solved in our previous work [18], in which intermolecular force and packing motifs were presented for polymorphs A and B. The simulated XRD patterns from single crystal x-ray diffraction are shown in figures 2(I) and 3(I). At present study, the experimental powder XRD spectra (shown in figure 2(II) and 3(II)) of m-nisoldipine are obtained in order to identify the purity of the batch powder qualitatively, as well as provide another solid characterization. The diffraction patterns of batch powder have good consistency with the simulated diffraction patterns and no other excess peaks appear, indicating higher purity for batch powder. The discrepancies between the relative peak intensity arise due to the preferred orientation effects of microcrystalline particles in the sample. There are significant differences in the patterns of form A and B, which can be used to identify their form. For example, m-nisoldipine polymorph A shows major reflections at 2h = 9.50° and 23.40°, whereas the polymorph B shows reflections at 2h = 14.40° and
2.7. Studies on grinding conditions The samples (2 g) were ground at a constant grinding speed. The specimens were sampled at 4-, 30-, and 60-minute intervals. Afterward, the samples were subjected to XRD characterization to determine the crystal phase and UV to verify the purity.
2.8. Analysis of the kinetics of solid-state decomposition Kinetics of the solid-state decomposition was studied using DSC analysis. Accurately weighed specimens (5 mg) were subjected to DSC determination in the temperature range of (25 to 500) °C at heating rates of 10, 20, 30, and 40 °C min1. The relationship between the heating rate b and the temperature of solid-state decomposition of a polymorph is given by the Kissinger equation [20]:
½d lnðb=T m Þ=½d lnð1=T m Þ ¼ ðE=RÞ;
FIGURE 2. XRD spectra of the polymorph A. Match of the experimental powder trace (I) with simulated XRD pattern converted from the single-crystal data (II) is good. Single crystal x-ray diffraction was from the data presented by Wang et al. [18].
ð6Þ
where b is the heating rate; Tm is the temperature corresponding to the first decomposition endothermic peak in DSC curves; and E is the activation energy of solid-state decomposition. A curve was drawn with lnðb=T 2m Þ as the Y-coordinate and 1/Tm as the abscissa. The active energy of solid decomposition, E, was obtained from the slope of this curve.
2.9. Moisture sorption/desorption experiments Moisture sorption/desorption data were collected on a VTI SGA100 vapor sorption analyzer (VTI Corporation, Hialeah, FL) over a range of relative humidity (RH) from 5% to 95%, at 5% intervals, under nitrogen purge. Samples were not dried before analysis. The equilibrium criterion used for analysis was a weight change of less than 0.01% (wt%) in five minutes. Sodium chloride and polyvinylpyrrolidone were used as the calibration standards.
FIGURE 3. XRD spectra of the polymorph B. Match of the experimental powder trace (I) with simulated XRD pattern converted from the single-crystal diffraction data (II) is good. Single crystal x-ray diffraction was from the data presented by Wang et al. [18].
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3.1.2. IR spectra The IR spectra (figure 4) of the two polymorphs display distinct features, which can be employed to distinguish the two polymorphs. IR spectra of the two crystal forms relate well to the structural composition of m-nisoldipine. The characteristic band for m-nisoldipine are in the range of (3300 to 3400) cm1 where N–H valence vibration occurs, in the range of (1680 to 1700) cm1 where –C=O–R vibration is pronounced, then in the range of (1000 to 1300) cm1 where C–O is observed. These are also the main regions for distinguishing between the two polymorphs by IR spectrum (figure 4a). Here, we particularly report the differences of N–H stretching vibration and mC=O bands between form A and B to detect the information of stability and phase transition. As can be seen from figure 4b, sharp peak at 3337 cm1 in form B is shifted to band at 3353 cm1 in form A. The N–H stretching vibration of the form A, confirmed as a stable form (confirmed by solubility experiments, vide infra), lies at higher wavenumbers than that of unstable form B, which evidences a larger entropy for form A than for form B. This is contradictory to the IR rule [21] and suggests that intermolecular hydrogen-bonding to the N amino-function is not the driving force in the molecular arrangements of the two crystal forms A and B. Moreover, the mC=O bands at (1650 and 1676) cm1 of form A are shifted to the bands at (1655 and 1699) cm1 in the case of form B. These findings agree with the suggestion of a layer structure, which causes the phase transition by modifying the molecular packing [22]. 3.2. Solubility, transition temperature, and thermodynamics
FIGURE 4. FT-IR spectra of three forms of m-nisoldipine. 3001800 cm1 (a) and 25004000 cm1 (b) (T: transmittance, v: wavenumber).
TABLE 2 The transformation temperature and thermodynamic parameters in aqueous solution.(c: solubility, DHhA;B , DShA;B ; and DGhA;B : change of enthalpy, entropy, and Gibbs free energy of phase transition of the two polymorphs A and B, Tt: transition temperature). T/°C cA/ (lg mL1)
c B/ (lg mL1)
Tt/°C DHhA;B / DGhA;B / DShA;B / (kJ mol-1) (kJ mol–1) (J mol–1 K–1)
25 31 37 42 49
0.912±0.025 1.028±0.019 1.215±0.023 1.405±0.036 1.562±0.056
2.47 1.79 1.12 0.56 0.23
0.323±0.008 0.513±0.012 0.829±0.011 1.129±0.020 1.642±0.029
36.01
112.48
47
21.48°. Furthermore, the peaks at 10.78°, 12.70°, 13.62°, 15.96°, 22.54°, and 24.57° can serve to differentiate the polymorph A from B. Thus, this technique appears to be a suitable tool not only for identifying both the polymorphs during the crystallization process, but also for formulating, developing, and synthesizing the necessary compounds when needed.
Following the characterization of the two polymorphs, an attempt was made to understand the thermodynamic relationships between forms A and B of m-nisoldipine. Polymorph rule of enthalpy of fusion states that if the higher melting polymorph has the lower enthalpy of fusion, then the two polymorphs are enantiotropic. DSC data in table 1 indicate that polymorphs A and B have no distinct difference on the enthalpy of fusion [18]. So, the enthalpies and melting point determined from DSC are not accurate enough for detailed evaluation of transform rule and thermodynamic stability. In order to determine the relative stability of the polymorphs, temperature-dependent solubility data were collected in aqueous solution at the temperatures 25, 31, 37, 42, and 49 °C. As can be seen from the solubility data listed in table 2, the solubility of form A below 42 °C is lower than that of form B, while, form B shows higher solubility at the 49 °C, suggesting that phase transition of forms A and B happens between (42 and 49) °C. Based on the solubility in aqueous solution, the curves of ln c versus 1/T as the Y-coordinate and abscissa, respectively, of the polymorphs A and B are shown in figure 5. The values of DHhA and DHhB obtained from the slopes of the two curves were (54.35 and 18.34) kJ mol–1 respectively. The temperature corresponding to the point of intersection of the two curves, namely, 47 °C, is the transition temperature (figure 5). The corresponding thermodynamic parameters are listed in table 2. The form A is thermodynamically stable below the transition temperature. When form A crystal partially dissolves in the water, it subsequently crystallizes as the form A below the phase transition temperature, while, crystallizes as the form B above the phase transition temperature. So, the phase transition process involves the dissolve-recrystallization process [19]. In our previous study [18], crystal structures were solved for the two polymorphs. Both A and B, the m-nisoldipine molecules are linked through the N–HO hydrogen bonds, moreover, in B, the nitrobenzene moieties from the neighboring ribbon are held together by p-p stacking, which are illustrated in figure 6. In our another paper [23], in which theoretical calculations on the hydrogen-bonding and p-stacking interactions in the m-nisoldipine
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polymorphism dimers were studied; the interaction energies of dimers A and B were obtained under the B3LYP/6-31G(d,p) levels. The interaction energies of the dimer A and dimer B are (17.15 and 3.96) kJ mol–1. It can be seen that the interaction energy of dimer A is distinctly larger than that of dimer B, that is to say, dimer A with OH–N hydrogen-bonding interaction is more stable than dimer B with p-stacking interaction. It is known that both of polymorphs A and B include four monomers. In crystal A, only OH–N type hydrogen-bonding interactions exist between monomers A; while in crystal B, not only OH–N type hydrogen-bonding interactions but also p-stacking interactions are existed between monomers. As discussed above, the OH–N type hydrogen-bonding interaction is stronger than the p-stacking interaction. Therefore, it can be concluded that polymorph A is more stable than polymorph B, since OH–N type hydrogen-bonding interactions play the crucial role in crystal A whereas p-stacking interactions play the crucial role in crystal B. This conclusion accords with the fact that melting point of form A is higher than that of form B. 3.3. Kinetics of solid-state decomposition FIGURE 5. Curves of ln c versus 1/T of polymorphs A and B (c: solubility). A: polymorph A, the linear equation: lncA = 6537.4/T + 7.9849 r = 0.9981. B: polymorph B, The linear equation: lncB = 22605.8/T 5.5528 r = 0.9961.
The melting points of the two forms are followed by several broad overlapping thermal events (both exo- and endothermic)
FIGURE 6. Molecular packing in the crystals of polymorphs A and B showing the intermolecular hydrogen bonds, and p-stacking interactions. (a) Only hydrogen bonds in polymorph A; (b) Both hydrogen bonds and p-stacking interactions in polymorph B. Adapted from the data presented by Wang et al. [18].
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TABLE 3 The decomposition temperature at different heating rates and active energies of solid-state decomposition for polymorphs A and B. (b: heating rate, Tm: the temperature of solidstate decomposition of the polymorph, E: active energy of solid-state decomposition). Polymorph
b/°C min1
Tm/K
1000/Tm
ln (b/Tm2)
A
10 20 30 40
508.12±0.97 520.15±1.03 527.11±1.14 534.96±1.05
1.968 1.923 1.897 1.869
–10.16 –9.513 –9.134 –8.876
10 20 30 40
508.01±2.00 528.06±1.10 544.45±1.56 555.73±1.78
1.968 1.893 1.837 1.799
–10.16 –9.543 –9.198 –8.952
B
r
E/kJ mol–1
0.9959
109.80
0.9973
59.14
TABLE 4 The contents (%) of the polymorphs A and B determined after depositing at high temperatures and experiencing different time grinding. (S0: initial specimen; S1: sampled after depositing at 40 °C for 10 days; S2: 80 °C for 10 days; S3: 105 °C for 12 h; S4: grinding for 4 min; S5: 30 min; S6: 60 min). Polymorph
S0
S1
S2
S3
S4
S5
S6
A B
99.34±1.27 99.56±1.15
98.86±1.50 101.12±0.89
99.48±0.75 100.25±0.97
99.23±1.26 99.81±2.11
99.10±0.98 98.96±1.63
98.56±2.17 99.18±1.07
99.57±0.69 100.56±1.63
between (230 and 450) °C. However, the occurrence of both endoand exothermic events, observed in the DSC/TG curve, suggest that decomposition is also involved. The region above the m-nisoldipine melting point was further investigated to ascertain the temperature regions corresponding to m-nisoldipine loss due to decomposition (verified by TG curves). The kinetic parameters for the first decomposition stage are calculated. The decomposition temperature at different heating rates and the activation energies of the solid-state decomposition were listed in table 3. The results show that the decompounding activation energy of melted state is higher for polymorph A than for polymorph B. It is well known that amorphous state is formed after melting crystalline state; the activation energies of decompounding of the two polymorphs are actually involved with the decompounding of their respective melted state. As described above, the interaction energy of crystalline form A is higher than that of form B; it can be concluded that melted states of polymorphs A and B reserved ‘‘the memories’’ of their respective crystalline state.
intervals; however, the intensity of the diffraction peaks decreases with time due to the decreasing of particle size.
3.5. Moisture sorption/desorption Moisture sorption/desorption isotherms describe the interactions between moisture and solid substances. They relate the total
3.4. Effect of temperature and grinding on solid-state transition Usually, a grinding operation is carried out to obtain a homogeneous mixture of a drug and an excipient [24]; or to decrease the particle size of a drug to enhance its bioavailability. Recently, crystal-phase transition was found during the grinding operation in some drugs having two or more polymorphs, which may affect the bioavailability and, as a consequence, curative effect of the initial active pharmaceutical ingredient [10]. One possible reason for this crystal-phase transition is the increase in temperature during the mechanical grinding operation. To investigate the effect of temperature on solid-state transition, unsealed samples of polymorphs A and B (0.5 g each) were placed in ovens at (40 and 80) °C for 10 days, and at 105 °C for 12 h. The samples were subjected to XRD characterization to determine the crystal phase, and the results show that no crystal-form transitions occur in both the polymorphs A and B during aging at different temperatures. Furthermore, the purity of the samples after depositing at higher temperature is verified using content determination by UV and the data were listed in Table 4. It shows that the contents have no obvious change during the temperature accelerating experiment. Moreover, the XRD patterns of the specimens sampled at 4-, 30-, and 60-minute grinding intervals indicate that no crystal-form transitions and no content change (shown in table 4) take place during the grinding process at different time
FIGURE 7. Isotherms of moisture adsorption/desorption of forms A (a) and B (b) (Dw: weight change, RH: relative humidity).
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water content of a material to the RH of the environment in which the material is treated. Moisture sorption/desorption isotherms (figure 7) show that forms A and B of m-nisoldipine are nonhygroscopic, undergoing a weight gain of less than 0.1% even at 95% RH. Moreover, Form B is nonhygroscopic to a lesser extent compared to form A, which is due to its higher density and closer packing in the crystal structure [18].
4. Conclusions Solubility information can be used to distinguish the differences between two polymorphs of m-nisoldipine, especially in the case of that the rule of enthalpy of fusion of polymorph cannot give the affirmatory results. The Gibbs free energy differences were obtained from the solubility data of two polymorphs and it confirms that the two forms are enantiotropically related with a transition temperature of 47 °C. Form A is thermodynamically stable below the transition temperature, which has low solubility at room temperature. Form B crystals have higher solubility than that of form A at room temperature and it is therefore preferable for pharmaceutical preparation. Moreover, no phase transition of solid polymorphs takes place during the grinding process or during aging at different temperatures. This study highlights the importance of polymorph screening and form selection during drug formulation.
Acknowledgments The financial support for this work by National Natural Science Foundation of China (NSFC, 81202504), the Hebei Science and Technology Supporting Program Fund of China (12276402D), Science Fund of Education Department (2009148) and Science Fund of Health Department of Hebei Province of China (20090059) are greatly acknowledged.
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.jct.2012.11.023. References [1] N. Chieng, T. Rades, J. Aaltonen, J. Pharm. Biomed. Anal. 55 (2010) 618–644. [2] S. Sehic, G. Betz, S. Hadzidedic, Int. J. Pharm. 386 (2010) 77–90. [3] L.M. Katrincic, Y.T. Sun, R.A. Carlton, A.M. Diederich, R.L. Mueller, F.G. Vogt, Int. J. Pharm. 366 (2009) 1–13. [4] K. Fujii, H. Uekusa, N. Itoda, G. Hasegawa, E. Yonemochi, K. Terada, Z. Pan, K.D.M. Harris, J. Phys. Chem. C 114 (2010) 580–586. [5] A. Lemmerer, N.B. BaÌthori, C. Esterhuysen, S.A. Bourne, M.R. Caira, Cryst. Growth Des. 9 (2009) 2646–2655. [6] I. Karabas, M.G. Orkoula, C.G. Kontoyannis, Talanta 71 (2007) 1382–1386. [7] S. Airaksinen, P. Luukkonen, A. Jorgensen, M. Karjalainen, J. Rantanen, J. Yliruusi, J. Pharm. Sci. 92 (2003) 516–528. [8] C.B. Romanuk, L.Y. Garro, A.K. Chattah, G.A. Monti, S.L. Cuffini, M.T. Garland, R. Baggio, R.H. Manzo, M.E. Olivera, Int. J. Pharm. 391 (2010) 197–202. [9] F. Kato, M. Otsuk, Y. Matsud, Int. J. Pharm. 321 (2006) 18–26. [10] S.Y. Lin, Ch.H. Hsu, W.T. Ke, Int. J. Pharm. 396 (2010) 83–90. [11] B. Zimmermann, G. Baranovic, J. Pharm. Biomed. Anal. 54 (2011) 295–302. [12] F.Y. Yuan, Y.W. Wu, H. Nie, T.R. Yan, C.H. Bao, Z.M. Chen, Y.M. Du, J.Q. Zhao, D.Q. Man, H.L. Geng, 1994, CN93103759.X. [13] Y.J. Gao, Y.S. Li, S.X. Fu, Chin. Pharmacol. Bull. 6 (1990) 114–117. [14] Y.J. Gao, Y.S. Li, S.X. Fu, Chin. J. Pharmacol. Toxicol. 4 (1990) 21–24. [15] H.R. Wang, L.T. Zhang, Q. Wang, Z.F. Yuan, M. Li, J. Chromatogr. B 835 (2006) 71–76. [16] L. Yu, S.M. Reutzel, G.A. Stephenson, Pharm. Sci. Technol. Today 1 (1998) 118– 127. [17] L. Yu, J. Pharm. Sci. 84 (1995) 966–974. [18] C.Q. Yang, Z.W. Zhang, Y.L. Zeng, J. Wang, CrystEngComm. 14 (2012) 2589– 2594. [19] F. Kato, M. Otsuka, Y. Matsuda, Int. J. Pharm. 321 (2006) 18–26. [20] P. Budrugeac, E. Segal, J. Therm. Anal. Calorim. 88 (2007) 703–707. [21] A. Burger, R. Ramberger, Mikrochemica Acta 2 (1979) 259–271. [22] A.C. Schmida, Int. J. Pharm. 298 (2005) 186–197. [23] M. Zhu, L.P. Meng, S.J. Zheng, J. Wang, Y.L. Zeng, Chin. J. Chem. 30 (2012) 233– 240. [24] Y. Corvis, P. Négrier, P. Espeau, J. Pharm. Sci. 100 (2011) 5235–5243.
JCT 12-399
Contents lists available at SciVerse ScienceDirect
J. Chem. Thermodynamics journal homepage: www.elsevier.com/locate/jct
Thermodynamic stability analysis of m-nisoldipine polymorphs Caiqin Yang, Tiankun Ren, Jing Wang ⇑, Yongli Wang ⇑, Xinglong Tao School of Pharmaceutical Sciences, Hebei Medical University, Shijiazhuang 050017, China
a r t i c l e
i n f o
Article history: Received 14 July 2012 Received in revised form 12 November 2012 Accepted 15 November 2012 Available online 7 December 2012 Keywords: Polymorphs Solubility Thermodynamics Phase transition FTIR X-ray powder diffractometry
a b s t r a c t Two polymorphic crystal forms of m-nisoldipine (1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5pyridinedicarboxylic acid methyl 2-methylpropyl ester) were characterized by X-ray powder diffraction and IR-spectroscopy. The solubility of the two polymorphs in water at 25, 31, 37, 42, and 49 °C was investigated; the values obtained were used to calculate the thermodynamic parameters of the phase transition. The results show that the two forms A and B are enantiotropic. The temperature of polymorphic phase transition was 47 °C, and the values of DGhA;B , DHhA;B , and DShA;B at 25 °C were 2.47, 36.01, and 112.48 J mol1 K1, respectively. Form A is thermodynamically stable below the transition temperature; it accorded with interaction energies of the two forms obtained from Density Function Theory (DFT) calculations on the hydrogen-bonding and p-stacking interactions. The character of the solid-state decomposition, studied using DSC analysis, showed that the activation energies of decomposition of the polymorphs A and B after melting at high temperatures were 109.80 and 59.14 kJ mol1, respectively. It is conclusion that melted states of polymorphs A and B reserved ‘‘the memories’’ of their respective crystalline state. Furthermore, phase transition of the polymorphs was not found under solid-state grinding conditions. Moisture sorption/desorption experiments showed that the two forms of m-nisoldipine are nonhygroscopic. Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction Polymorphs are different solid crystalline phases of a given compound, which result from at least two distinct crystal structures. Polymorphism is important about pharmaceutical drugs as a result of their different physiochemical properties and bioactivity in many cases, for example, crystal habit, intermolecular force, particle density, thermodynamic activity, the chemical and physical stability, solubility, dissolution rate, and bioavailability [1–6]. Owing to different lattice energies of polymorph, the more energetic ones seek to revert to the most stable form during the kneading and tabletting processes [7,8]. Moreover, storage conditions (such as temperature and humidity), grinding conditions, or pharmaceutical excipients affect the stability of the metastable crystal forms [9–11]. Therefore, characterization of polymorphs and elucidation of the physicochemical properties of bulk drugs during both the manufacturing process and the storage period are extremely important. M-nisoldipine (figure 1), as a dihydropyridine calcium ion antagonist, was first synthesized in the School of Pharmacy, Hebei Medical University [12]. Compared with its analogs, m-nisoldipine significantly increases cardiac output and cardiac index, dramati⇑ Corresponding authors. Tel.: +86 311 86265622; fax: +86 311 86266419. E-mail addresses: [email protected] (J. Wang), [email protected] (Y. Wang). 0021-9614/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jct.2012.11.023
cally reduces the negative inotropic effect on the myocardium, and has relatively higher selectivity for the thoracic aorta [13,14]. Furthermore, m-nisoldipine has two polymorphs, A (yellow color) and B (white color). The studies of pharmacokinetics and the relative bioavailability of m-nisoldipine polymorphs indicated that the polymorphs A and B of m-nisoldipine were not bioequivalent [15]; it supposes that there are differences between A and B in their thermodynamic activity, solubility, dissolution rate, and chemical and physical stability. The relative thermodynamic stability of polymorphs and the driving force for a transition are determined by the change of Gibbs free energy (DG). The DG versus temperature diagram can provide information about the stability relationship of polymorphs [16,17]. The DG and its temperature dependence can be obtained from solubility dependence on temperature data, and melting data (melting temperature, enthalpy of fusion), enthalpy of transformation if available. The melting data method requires less sample compared to the solubility method, however, it exposes the material to potential degradation chemically. Furthermore, when polymorphs have no distinct differences on the enthalpies of fusion or/and no phase transition peak is found in DSC scan [18], the enthalpies and melting point determined from DSC are not accurate enough for detailed evaluation of transition rule and thermodynamic stability. Solubility data are of special importance in the study of crystal nucleation/growth kinetics and transition thermodynamic of polymorphs [19]. In this study, we present our results
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current, 20 mA; voltage, 20 kV; receiving slit, 0.3 mm; scan range, 5°–40° (2h); and step size, 0.05°. Approximately 50 mg of the mnisoldipine powder was carefully loaded into a glass holder, and the sample surface was flattened softly to avoid particle orientation. The simulated XRD patterns were extracted using Mercury 1.4.2 software (Cambrige Crystallographic Data Centre). 2.3. FT-IR
FIGURE 1. Molecule sturcture of m-nisoldipine.
on the measurement of solubility of both polymorphs of m-nisoldipine; the data were used to investigate more precisely the thermodynamic stability of the polymorphs A and B, in addition to studying their respective phases. 2. Experimental 2.1. Sample preparation and crystallization M-nisoldipine was kindly supplied as batches by organic synthesis research laboratory of Hebei Medical University in China. Its synthesis procedure can be found in its Chinese patent [12], in which 1H NMR, elemental analysis, and mass spectrometry were all presented. The Polymorphs A and B used in present work were obtained by recrystallization in ethanol. Polymorphs A and B appeared at the upper and lower parts of the solvent, respectively, during cooling of the hot ethanol solvent in the refrigerator. Single crystals of polymorph A were grown from a solution of acetone/ethanol (1:1) by slow evaporation, whereas crystals of polymorph B were obtained from a solution of ethyl acetate/hexane (1:1), as described in our previous study [18]. The melting temperatures, enthalpies of fusion, and densities of these crystal forms are presented in table 1. Polymorph A crystallizes in space group P21/c (Monoclinic) with Z = 4, and cell parameters a = 0.93045(2) nm, b = 1.65991(5) nm, c = 1.30018(3) nm, b = 91.539(2)°, V = 2.00736(9) nm3, R1 [I > 2sigma(I)] = 0.0688. While Polymorph B crystallizes in space group P-1 (Triclinic) with Z = 2, and cell parameters a = 0.74965(2) nm, b = 1.14692(4) nm, c = 1.23648(5) nm, a = 68.093(2)°, b = 88.655(2)°, c = 81.853(2)°, V = 0.97589(6) nm3, R1 [I>2sigma(I)] = 0.0676. In both polymorphs, the m-nisoldipine molecules are linked through the N–HO hydrogen bonds [NO = 0.2927(2) nm and 0.3089 nm, N–HO = 139.1° and 171.0° for A and B, respectively]. Moreover, in B, the nitrobenzene moieties from the neighboring ribbon are held together by p–p stacking with the centroid distance being 0.4044 nm. Those information of crystal lattices are adapted from the data presented by Wang et al. [18]. 2.2. X-ray diffraction analysis Powder X-ray diffraction (PXRD) profiles were characterized with an X-ray diffractometer (RINT 2100 Ultima, Rigaku Co., Japan). The measurement conditions were as follows: target, Cu; filter, Ni; TABLE 1 Physical characteristics of the polymorphs A and B of m-nisoldipine. Polymorph
Melting temperature/°C
Enthalpies of fusion/ (J g1)
Density/ (kg m3)a
A B
137.79±1.56 130.16±2.08
88.88±1.55 90.28±1.09
1.285 1.322
a
The densities are obtained from single crystal X-ray diffraction.
All infrared spectra were recorded from (4000 to 400) cm-1, using the EQUINOX 55 (Bruker) FT-IR spectrometer. Each spectrum was the average of 40 scans. The IR spectra were recorded and stored using spectroscopic software (OPUS, Version 2.0). FT-IR spectra of the samples were obtained by mixing 4 mg pure substances in an agate mortar with 160 mg of desiccated IR grade potassium bromide (Merck) in a dry box. 2.4. Thermal analysis Polymorphs A and B were characterized by differential scanning calorimetry/thermo-gravimetry (DSC/TG) studies on a Perkin-Elmer Pyris 1 apparatus. Accurately weighed (about 15 mg) specimens were hermetically sealed using a sealing machine. The DSC/TG scans were operated in the temperature range of (25 to 500) °C at heating rates of 10, 20, 30, and 40 °C min1 to explore the decomposition process. Nitrogen was used as the purging gas, and its flow rate was 20 °C min1. 2.5. Analyses of solubility, transition temperature, and thermodynamics 2.5.1. Solubility The solubility levels in water (double distilled H2O, ddH2O) were determined at 25, 31, 37, 42, and 49 °C. An excess amount of the solid sample was weighed and placed in a 50 mL screwcapped vial. Afterward, 50 mL of each solvent was added to the respective vials, and they were capped. The vials were shaken at 100 spm in a water bath for 72 h. The concentration of solubilized m-nisoldipine was measured at 238 nm using an ultraviolet spectrophotometer (UV-160A, Shimadzu Co., Japan) after filtering through a 0.45 lm membrane filter. Each solubility measurement was repeated at least three times. 2.5.2. Analyses of transition temperature and thermodynamics At standard conditions, the relationship of c and Hh of the two polymorphs A and B are given by Van’t Hoff’s equation:
ð@ ln cA =ch Þ=@T ¼ DHhA =RT 2 ;
ð1aÞ
ð@ ln cB =ch Þ=@T ¼ DHhB =RT 2 ;
ð1bÞ
where Hh is standard enthalpy; c is solubility; ch is standard concentration and its value is 1 mol L1. Then, we get the following expressions:
ð@ ln cA =ch Þ=@ð1=TÞ ¼ DHhA =R;
ð2aÞ
ð@ ln cB =ch Þ=@ð1=TÞ ¼ DHhB =R:
ð2bÞ
Combining equations (2a) and (2b), we get
ð@ ln cA =cB Þ=@T ¼ DHhA;B =RT 2 :
ð3Þ
The temperature Tt indicates the transition temperature when cA = cB. Then,
DHhA;B ¼ T t DShA;B
where T ¼ T t ;
ð4Þ
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where DHhA;B and DShA;B are standard enthalpy change and standard entropy change of phase transition of the two polymorphs A and B. Subsequently, DGh at different temperatures was calculated from the equation:
DGhA;B ¼ DHhA;B T DShA;B ;
ð5Þ
where DGhA;B is the Gibbs free energy change of phase transition of the two polymorphs A and B. According to Eqs. (1a) and (1b), curves were drawn with ln c as the Y-coordinate versus 1/T as the abscissa for the two polymorphs A and B. The temperature corresponding to the point of intersection of the two curves is the transition temperature. Subsequently, according to equation (3), a curve was drawn with ln (cA/cB) as the Y-coordinate versus 1/T as the abscissa. The values of DHhA;B was obtained from the slopes of the curves, and DGhA;B and DShA;B were calculated from equations (4) and (5).
2.6. Storage conditions The stability of the polymorphs under high temperatures was evaluated as follows: the unsealed samples (0.5 g each) were placed in ovens at the following temperatures: (40 and 80) °C for 10 days; and 105 °C for 12 h. Afterward, the samples were subjected to XRD characterization to determine the crystal phase and UV to verify the purity.
3. Results and discussion 3.1. Physicochemical characterization of the polymorphs A and B 3.1.1. PXRD analysis The single crystal structures of the two polymorphs were solved in our previous work [18], in which intermolecular force and packing motifs were presented for polymorphs A and B. The simulated XRD patterns from single crystal x-ray diffraction are shown in figures 2(I) and 3(I). At present study, the experimental powder XRD spectra (shown in figure 2(II) and 3(II)) of m-nisoldipine are obtained in order to identify the purity of the batch powder qualitatively, as well as provide another solid characterization. The diffraction patterns of batch powder have good consistency with the simulated diffraction patterns and no other excess peaks appear, indicating higher purity for batch powder. The discrepancies between the relative peak intensity arise due to the preferred orientation effects of microcrystalline particles in the sample. There are significant differences in the patterns of form A and B, which can be used to identify their form. For example, m-nisoldipine polymorph A shows major reflections at 2h = 9.50° and 23.40°, whereas the polymorph B shows reflections at 2h = 14.40° and
2.7. Studies on grinding conditions The samples (2 g) were ground at a constant grinding speed. The specimens were sampled at 4-, 30-, and 60-minute intervals. Afterward, the samples were subjected to XRD characterization to determine the crystal phase and UV to verify the purity.
2.8. Analysis of the kinetics of solid-state decomposition Kinetics of the solid-state decomposition was studied using DSC analysis. Accurately weighed specimens (5 mg) were subjected to DSC determination in the temperature range of (25 to 500) °C at heating rates of 10, 20, 30, and 40 °C min1. The relationship between the heating rate b and the temperature of solid-state decomposition of a polymorph is given by the Kissinger equation [20]:
½d lnðb=T m Þ=½d lnð1=T m Þ ¼ ðE=RÞ;
FIGURE 2. XRD spectra of the polymorph A. Match of the experimental powder trace (I) with simulated XRD pattern converted from the single-crystal data (II) is good. Single crystal x-ray diffraction was from the data presented by Wang et al. [18].
ð6Þ
where b is the heating rate; Tm is the temperature corresponding to the first decomposition endothermic peak in DSC curves; and E is the activation energy of solid-state decomposition. A curve was drawn with lnðb=T 2m Þ as the Y-coordinate and 1/Tm as the abscissa. The active energy of solid decomposition, E, was obtained from the slope of this curve.
2.9. Moisture sorption/desorption experiments Moisture sorption/desorption data were collected on a VTI SGA100 vapor sorption analyzer (VTI Corporation, Hialeah, FL) over a range of relative humidity (RH) from 5% to 95%, at 5% intervals, under nitrogen purge. Samples were not dried before analysis. The equilibrium criterion used for analysis was a weight change of less than 0.01% (wt%) in five minutes. Sodium chloride and polyvinylpyrrolidone were used as the calibration standards.
FIGURE 3. XRD spectra of the polymorph B. Match of the experimental powder trace (I) with simulated XRD pattern converted from the single-crystal diffraction data (II) is good. Single crystal x-ray diffraction was from the data presented by Wang et al. [18].
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3.1.2. IR spectra The IR spectra (figure 4) of the two polymorphs display distinct features, which can be employed to distinguish the two polymorphs. IR spectra of the two crystal forms relate well to the structural composition of m-nisoldipine. The characteristic band for m-nisoldipine are in the range of (3300 to 3400) cm1 where N–H valence vibration occurs, in the range of (1680 to 1700) cm1 where –C=O–R vibration is pronounced, then in the range of (1000 to 1300) cm1 where C–O is observed. These are also the main regions for distinguishing between the two polymorphs by IR spectrum (figure 4a). Here, we particularly report the differences of N–H stretching vibration and mC=O bands between form A and B to detect the information of stability and phase transition. As can be seen from figure 4b, sharp peak at 3337 cm1 in form B is shifted to band at 3353 cm1 in form A. The N–H stretching vibration of the form A, confirmed as a stable form (confirmed by solubility experiments, vide infra), lies at higher wavenumbers than that of unstable form B, which evidences a larger entropy for form A than for form B. This is contradictory to the IR rule [21] and suggests that intermolecular hydrogen-bonding to the N amino-function is not the driving force in the molecular arrangements of the two crystal forms A and B. Moreover, the mC=O bands at (1650 and 1676) cm1 of form A are shifted to the bands at (1655 and 1699) cm1 in the case of form B. These findings agree with the suggestion of a layer structure, which causes the phase transition by modifying the molecular packing [22]. 3.2. Solubility, transition temperature, and thermodynamics
FIGURE 4. FT-IR spectra of three forms of m-nisoldipine. 3001800 cm1 (a) and 25004000 cm1 (b) (T: transmittance, v: wavenumber).
TABLE 2 The transformation temperature and thermodynamic parameters in aqueous solution.(c: solubility, DHhA;B , DShA;B ; and DGhA;B : change of enthalpy, entropy, and Gibbs free energy of phase transition of the two polymorphs A and B, Tt: transition temperature). T/°C cA/ (lg mL1)
c B/ (lg mL1)
Tt/°C DHhA;B / DGhA;B / DShA;B / (kJ mol-1) (kJ mol–1) (J mol–1 K–1)
25 31 37 42 49
0.912±0.025 1.028±0.019 1.215±0.023 1.405±0.036 1.562±0.056
2.47 1.79 1.12 0.56 0.23
0.323±0.008 0.513±0.012 0.829±0.011 1.129±0.020 1.642±0.029
36.01
112.48
47
21.48°. Furthermore, the peaks at 10.78°, 12.70°, 13.62°, 15.96°, 22.54°, and 24.57° can serve to differentiate the polymorph A from B. Thus, this technique appears to be a suitable tool not only for identifying both the polymorphs during the crystallization process, but also for formulating, developing, and synthesizing the necessary compounds when needed.
Following the characterization of the two polymorphs, an attempt was made to understand the thermodynamic relationships between forms A and B of m-nisoldipine. Polymorph rule of enthalpy of fusion states that if the higher melting polymorph has the lower enthalpy of fusion, then the two polymorphs are enantiotropic. DSC data in table 1 indicate that polymorphs A and B have no distinct difference on the enthalpy of fusion [18]. So, the enthalpies and melting point determined from DSC are not accurate enough for detailed evaluation of transform rule and thermodynamic stability. In order to determine the relative stability of the polymorphs, temperature-dependent solubility data were collected in aqueous solution at the temperatures 25, 31, 37, 42, and 49 °C. As can be seen from the solubility data listed in table 2, the solubility of form A below 42 °C is lower than that of form B, while, form B shows higher solubility at the 49 °C, suggesting that phase transition of forms A and B happens between (42 and 49) °C. Based on the solubility in aqueous solution, the curves of ln c versus 1/T as the Y-coordinate and abscissa, respectively, of the polymorphs A and B are shown in figure 5. The values of DHhA and DHhB obtained from the slopes of the two curves were (54.35 and 18.34) kJ mol–1 respectively. The temperature corresponding to the point of intersection of the two curves, namely, 47 °C, is the transition temperature (figure 5). The corresponding thermodynamic parameters are listed in table 2. The form A is thermodynamically stable below the transition temperature. When form A crystal partially dissolves in the water, it subsequently crystallizes as the form A below the phase transition temperature, while, crystallizes as the form B above the phase transition temperature. So, the phase transition process involves the dissolve-recrystallization process [19]. In our previous study [18], crystal structures were solved for the two polymorphs. Both A and B, the m-nisoldipine molecules are linked through the N–HO hydrogen bonds, moreover, in B, the nitrobenzene moieties from the neighboring ribbon are held together by p-p stacking, which are illustrated in figure 6. In our another paper [23], in which theoretical calculations on the hydrogen-bonding and p-stacking interactions in the m-nisoldipine
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polymorphism dimers were studied; the interaction energies of dimers A and B were obtained under the B3LYP/6-31G(d,p) levels. The interaction energies of the dimer A and dimer B are (17.15 and 3.96) kJ mol–1. It can be seen that the interaction energy of dimer A is distinctly larger than that of dimer B, that is to say, dimer A with OH–N hydrogen-bonding interaction is more stable than dimer B with p-stacking interaction. It is known that both of polymorphs A and B include four monomers. In crystal A, only OH–N type hydrogen-bonding interactions exist between monomers A; while in crystal B, not only OH–N type hydrogen-bonding interactions but also p-stacking interactions are existed between monomers. As discussed above, the OH–N type hydrogen-bonding interaction is stronger than the p-stacking interaction. Therefore, it can be concluded that polymorph A is more stable than polymorph B, since OH–N type hydrogen-bonding interactions play the crucial role in crystal A whereas p-stacking interactions play the crucial role in crystal B. This conclusion accords with the fact that melting point of form A is higher than that of form B. 3.3. Kinetics of solid-state decomposition FIGURE 5. Curves of ln c versus 1/T of polymorphs A and B (c: solubility). A: polymorph A, the linear equation: lncA = 6537.4/T + 7.9849 r = 0.9981. B: polymorph B, The linear equation: lncB = 22605.8/T 5.5528 r = 0.9961.
The melting points of the two forms are followed by several broad overlapping thermal events (both exo- and endothermic)
FIGURE 6. Molecular packing in the crystals of polymorphs A and B showing the intermolecular hydrogen bonds, and p-stacking interactions. (a) Only hydrogen bonds in polymorph A; (b) Both hydrogen bonds and p-stacking interactions in polymorph B. Adapted from the data presented by Wang et al. [18].
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TABLE 3 The decomposition temperature at different heating rates and active energies of solid-state decomposition for polymorphs A and B. (b: heating rate, Tm: the temperature of solidstate decomposition of the polymorph, E: active energy of solid-state decomposition). Polymorph
b/°C min1
Tm/K
1000/Tm
ln (b/Tm2)
A
10 20 30 40
508.12±0.97 520.15±1.03 527.11±1.14 534.96±1.05
1.968 1.923 1.897 1.869
–10.16 –9.513 –9.134 –8.876
10 20 30 40
508.01±2.00 528.06±1.10 544.45±1.56 555.73±1.78
1.968 1.893 1.837 1.799
–10.16 –9.543 –9.198 –8.952
B
r
E/kJ mol–1
0.9959
109.80
0.9973
59.14
TABLE 4 The contents (%) of the polymorphs A and B determined after depositing at high temperatures and experiencing different time grinding. (S0: initial specimen; S1: sampled after depositing at 40 °C for 10 days; S2: 80 °C for 10 days; S3: 105 °C for 12 h; S4: grinding for 4 min; S5: 30 min; S6: 60 min). Polymorph
S0
S1
S2
S3
S4
S5
S6
A B
99.34±1.27 99.56±1.15
98.86±1.50 101.12±0.89
99.48±0.75 100.25±0.97
99.23±1.26 99.81±2.11
99.10±0.98 98.96±1.63
98.56±2.17 99.18±1.07
99.57±0.69 100.56±1.63
between (230 and 450) °C. However, the occurrence of both endoand exothermic events, observed in the DSC/TG curve, suggest that decomposition is also involved. The region above the m-nisoldipine melting point was further investigated to ascertain the temperature regions corresponding to m-nisoldipine loss due to decomposition (verified by TG curves). The kinetic parameters for the first decomposition stage are calculated. The decomposition temperature at different heating rates and the activation energies of the solid-state decomposition were listed in table 3. The results show that the decompounding activation energy of melted state is higher for polymorph A than for polymorph B. It is well known that amorphous state is formed after melting crystalline state; the activation energies of decompounding of the two polymorphs are actually involved with the decompounding of their respective melted state. As described above, the interaction energy of crystalline form A is higher than that of form B; it can be concluded that melted states of polymorphs A and B reserved ‘‘the memories’’ of their respective crystalline state.
intervals; however, the intensity of the diffraction peaks decreases with time due to the decreasing of particle size.
3.5. Moisture sorption/desorption Moisture sorption/desorption isotherms describe the interactions between moisture and solid substances. They relate the total
3.4. Effect of temperature and grinding on solid-state transition Usually, a grinding operation is carried out to obtain a homogeneous mixture of a drug and an excipient [24]; or to decrease the particle size of a drug to enhance its bioavailability. Recently, crystal-phase transition was found during the grinding operation in some drugs having two or more polymorphs, which may affect the bioavailability and, as a consequence, curative effect of the initial active pharmaceutical ingredient [10]. One possible reason for this crystal-phase transition is the increase in temperature during the mechanical grinding operation. To investigate the effect of temperature on solid-state transition, unsealed samples of polymorphs A and B (0.5 g each) were placed in ovens at (40 and 80) °C for 10 days, and at 105 °C for 12 h. The samples were subjected to XRD characterization to determine the crystal phase, and the results show that no crystal-form transitions occur in both the polymorphs A and B during aging at different temperatures. Furthermore, the purity of the samples after depositing at higher temperature is verified using content determination by UV and the data were listed in Table 4. It shows that the contents have no obvious change during the temperature accelerating experiment. Moreover, the XRD patterns of the specimens sampled at 4-, 30-, and 60-minute grinding intervals indicate that no crystal-form transitions and no content change (shown in table 4) take place during the grinding process at different time
FIGURE 7. Isotherms of moisture adsorption/desorption of forms A (a) and B (b) (Dw: weight change, RH: relative humidity).
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water content of a material to the RH of the environment in which the material is treated. Moisture sorption/desorption isotherms (figure 7) show that forms A and B of m-nisoldipine are nonhygroscopic, undergoing a weight gain of less than 0.1% even at 95% RH. Moreover, Form B is nonhygroscopic to a lesser extent compared to form A, which is due to its higher density and closer packing in the crystal structure [18].
4. Conclusions Solubility information can be used to distinguish the differences between two polymorphs of m-nisoldipine, especially in the case of that the rule of enthalpy of fusion of polymorph cannot give the affirmatory results. The Gibbs free energy differences were obtained from the solubility data of two polymorphs and it confirms that the two forms are enantiotropically related with a transition temperature of 47 °C. Form A is thermodynamically stable below the transition temperature, which has low solubility at room temperature. Form B crystals have higher solubility than that of form A at room temperature and it is therefore preferable for pharmaceutical preparation. Moreover, no phase transition of solid polymorphs takes place during the grinding process or during aging at different temperatures. This study highlights the importance of polymorph screening and form selection during drug formulation.
Acknowledgments The financial support for this work by National Natural Science Foundation of China (NSFC, 81202504), the Hebei Science and Technology Supporting Program Fund of China (12276402D), Science Fund of Education Department (2009148) and Science Fund of Health Department of Hebei Province of China (20090059) are greatly acknowledged.
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.jct.2012.11.023. References [1] N. Chieng, T. Rades, J. Aaltonen, J. Pharm. Biomed. Anal. 55 (2010) 618–644. [2] S. Sehic, G. Betz, S. Hadzidedic, Int. J. Pharm. 386 (2010) 77–90. [3] L.M. Katrincic, Y.T. Sun, R.A. Carlton, A.M. Diederich, R.L. Mueller, F.G. Vogt, Int. J. Pharm. 366 (2009) 1–13. [4] K. Fujii, H. Uekusa, N. Itoda, G. Hasegawa, E. Yonemochi, K. Terada, Z. Pan, K.D.M. Harris, J. Phys. Chem. C 114 (2010) 580–586. [5] A. Lemmerer, N.B. BaÌthori, C. Esterhuysen, S.A. Bourne, M.R. Caira, Cryst. Growth Des. 9 (2009) 2646–2655. [6] I. Karabas, M.G. Orkoula, C.G. Kontoyannis, Talanta 71 (2007) 1382–1386. [7] S. Airaksinen, P. Luukkonen, A. Jorgensen, M. Karjalainen, J. Rantanen, J. Yliruusi, J. Pharm. Sci. 92 (2003) 516–528. [8] C.B. Romanuk, L.Y. Garro, A.K. Chattah, G.A. Monti, S.L. Cuffini, M.T. Garland, R. Baggio, R.H. Manzo, M.E. Olivera, Int. J. Pharm. 391 (2010) 197–202. [9] F. Kato, M. Otsuk, Y. Matsud, Int. J. Pharm. 321 (2006) 18–26. [10] S.Y. Lin, Ch.H. Hsu, W.T. Ke, Int. J. Pharm. 396 (2010) 83–90. [11] B. Zimmermann, G. Baranovic, J. Pharm. Biomed. Anal. 54 (2011) 295–302. [12] F.Y. Yuan, Y.W. Wu, H. Nie, T.R. Yan, C.H. Bao, Z.M. Chen, Y.M. Du, J.Q. Zhao, D.Q. Man, H.L. Geng, 1994, CN93103759.X. [13] Y.J. Gao, Y.S. Li, S.X. Fu, Chin. Pharmacol. Bull. 6 (1990) 114–117. [14] Y.J. Gao, Y.S. Li, S.X. Fu, Chin. J. Pharmacol. Toxicol. 4 (1990) 21–24. [15] H.R. Wang, L.T. Zhang, Q. Wang, Z.F. Yuan, M. Li, J. Chromatogr. B 835 (2006) 71–76. [16] L. Yu, S.M. Reutzel, G.A. Stephenson, Pharm. Sci. Technol. Today 1 (1998) 118– 127. [17] L. Yu, J. Pharm. Sci. 84 (1995) 966–974. [18] C.Q. Yang, Z.W. Zhang, Y.L. Zeng, J. Wang, CrystEngComm. 14 (2012) 2589– 2594. [19] F. Kato, M. Otsuka, Y. Matsuda, Int. J. Pharm. 321 (2006) 18–26. [20] P. Budrugeac, E. Segal, J. Therm. Anal. Calorim. 88 (2007) 703–707. [21] A. Burger, R. Ramberger, Mikrochemica Acta 2 (1979) 259–271. [22] A.C. Schmida, Int. J. Pharm. 298 (2005) 186–197. [23] M. Zhu, L.P. Meng, S.J. Zheng, J. Wang, Y.L. Zeng, Chin. J. Chem. 30 (2012) 233– 240. [24] Y. Corvis, P. Négrier, P. Espeau, J. Pharm. Sci. 100 (2011) 5235–5243.
JCT 12-399