Shuang Du‡
,
Wen Sheng Li‡,
Ya Rong Wu,
Yan Fu,
Caiqin Yang and
Jing Wang*
College of Pharmaceutical Sciences, Hebei Medical University, Shijiazhuang, 050017, People’s Republic of China. E-mail: jingwang@home.ipe.ac.cn; Fax: +86-311-86265622; Tel: +86-311-86265622
First published on 21st September 2018
A major challenge in drug development is that the majority of drugs are water insoluble, and a powerful method to conquer this obstacle is to transfer a crystalline drug into its amorphous phase (AP) or coamorphous phase (CAP) with a coformer. In the present study, the physical and chemical stabilities of an AP and a CAP based on the dihydropyridine calcium ion antagonist azelnidipine (AZE) were investigated using thermal analysis and a solution chemistry method. The identification of two APs (named α-AP and β-AP, from crystalline α-AZE and β-AZE, respectively) and one AZE-piperazine CAP was attempted using powder X-ray diffraction, temperature modulated differential scanning calorimetry and Fourier-transform infrared spectroscopy. The transition thermodynamics from the two APs and the CAP to stable crystalline β-AZE (β-Cry) were investigated using a solubility method. The solubility of the two APs, the CAP and β-Cry in 0.01 M HCl medium at 298, 304, 310, 316 and 322 K was investigated; the values obtained were used to calculate the thermodynamic parameters of the transition reaction. The transition temperatures of α-AP, β-AP and the CAP to form β-Cry in 0.01 M HCl were 237.7, 400.3, and 231.4 K, respectively. The glass transition temperature (Tg) values of α-AP, β-AP and the CAP were 365.5, 358.9 and 347.6 K, respectively, indicating a high physical stability for α-AP. However, β-AP proved to be the most thermodynamically stable form at room temperature compared with α-AP and CAP in the 0.01 M HCl medium. As evidenced by those observations, no general relationship occurred between the solid physical stability and the solution chemical stability for AP and CAP. The kinetics of the solid-state decomposition, studied using DSC analysis, showed that the activation energies for decomposition of α-AP, β-AP and CAP at high temperatures were 133.0, 114.2 and 131.6 kJ mol−1, respectively.
The physicochemical properties of the AP can be affected by the preparation method,8 thermal history,9 or starting crystalline form when a cryo-milling preparation method is used.3,10 Differences in the stability and physicochemical properties, regarding APs produced using various preparation techniques, have been reported for indomethacin, dipyridamole, and carbamazepine.8 Amorphous indomethacin prepared using spray drying had some remaining residual crystallinity, and AP samples produced using a grinding procedure had small degrees of undetected crystallinity remaining or differences in the hydrogen bonding in the different APs.8 The results of an investigation by Rades et al. indicate the existence of an AP for cryo-milled simvastatin that is spectrally distinguishable from the quench-cooled AP. The thermodynamic parameters suggest that this form is less disordered compared to the quench-cooled form.11 Furthermore, differences regarding the physical stability and recrystallization behavior for amorphous forms produced from different crystalline starting counterparts by ball-milling have been reported for anhydrate piroxicam form I and form II.3 The results indicate that amorphous piroxicam prepared from crystalline form I had a lower physical stability than that of amorphous piroxicam prepared from form II, which was linked to the higher residual order in the amorphous samples prepared from crystalline form I; the recrystallization behavior of the amorphous samples prepared from anhydrate piroxicam form I was closely related to the starting material, whereas the recrystallization behavior of the amorphous samples prepared from form II resembled that of form III. Because these APs are formed via different intermediate states (melt, solution, solid) or different polymorphic forms, the question arises whether there are indeed differences in the amorphous solids formed. Hancock et al. used the term “pseudopolyamorphism” for those different amorphous forms.12 For true polyamorphs, a first-order transition between them would have to be observed, which has never been seen in any organic substance.11 Although, using melting techniques, the amorphous state is obtained through destruction of the existing molecular order, it is not clear if the differences exist in APs produced from different crystalline starting counterparts by melting or if local molecular order may still be present in the APs.
However, an AP with a high internal energy and specific volume relative to the crystalline state has a possibility that it may undergo partial crystallization during processing (mechanical stress) and storage (temperature and humidity stress) or in a solvent medium. Hence, exploitation of the full potential of amorphous solids requires their stabilization in the solid state and in solvent media as well as during application. A coamorphous phase (CAP), an amorphous combination consisting of the active pharmaceutical ingredient (API) and a small molecule coformer, possesses special advantages in improving the solubility and dissolution rate of the API and enhancing the stability of single amorphous drugs.13–15 For this reason, the CAP is considered as an efficient replacement for drug-polymer molecular association (solid dispersions) and cocrystals. This approach creates solubility advantages and stabilizes the amorphous system through intermolecular interactions, such as hydrogen bonds, and might conquer shortcomings associated with solid dispersions. However, there are very few reports on the thermodynamic mechanism for improving the stability of the CAP compared to the single AP.
Azelnidipine (AZE) is a new long-acting dihydropyridine calcium channel blocker for the treatment of patients with hypertension. It belongs to the group of polymorph drugs that have two, α and β, polymorphs, and the α form is a metastable phase that easily transforms to the β form under suitable conditions. In our previous studies, the thermodynamic stability of crystalline AZE polymorphs was investigated.16 The present paper addresses the question of whether the different polymorphs result in differing forms of the AP using a melting technique. Furthermore, AZE is a good model API to screen API-coformer amorphous combinations and many CAPs were obtained in our previous study.14,15
Based on the above considerations, the purpose of this study is to investigate the physical and thermodynamic stabilities of the AP and CAP and to find out if there is a general rule for the relationship between the physical stability in the solid state and the thermodynamic stability in solution. In this study, we present our results on the measurement of solubility in a 0.01 M HCl solution for different APs prepared from two polymorphs and a new CAP produced from AZE and piperazine (PEZ); the solubility data at different temperatures were used to investigate and evaluate the thermodynamic stability of the CAP compared to the single AP. Furthermore, the physical stability in the solid state and the thermal decomposition of the two APs and the CAP were also investigated.
As mentioned above, the solubility of the different forms of AZE was investigated; the values obtained were used to calculate the transition temperature and thermodynamic parameters of the transition reaction using the thermodynamics formulas in ref. 16.
Briefly, at standard conditions, when different forms of AZE coexist in solvent, the relationship between ΔGθ, ΔHθ, and ΔSθ of the transition reaction of two forms A and B is given by eqn (1) and (2):
(1) |
(2) |
According to Henry’s law, we get:
(3) |
(4) |
T indicates the transition temperature when cA = cB. Then:
ΔHθA,B = TΔSA,Bθ T = Tt |
Using eqn (3), a line was drawn with lnc as the Y-axis versus as the X-axis. The Tt can be obtained from the point of intersection of the two curves of the two different forms. Afterwards, using eqn (4), a curve was drawn with lncA/cB as the Y-coordinate versus as the abscissa. The values of ΔHθA,B and ΔSA,Bθ can be calculated according to the slope and intercept of the curves, and the value of ΔGA,Bθ was obtained from:
ΔGA,Bθ = ΔHθA,B − TΔSA,Bθ. |
Fig. 2 TMDSC total heat flow signal (dash) and reversing heat flow signal (solid) for AZE amorphous systems: (a) α-AP; (b) β-AP; (c) α-AZE-PEZ CAP. TMDSC curves of the two APs were obtained from the data presented by Pan et al.15 |
Here, we focus on the differences between crystalline and amorphous forms. IR spectroscopy is used extensively to investigate hydrogen bonding because the peak position of the X–H stretch is very sensitive to the extent of association. Peak positions and assignments for selected interesting peaks which are related to hydrogen bonding for the crystalline and amorphous phases (AP and CAP) are shown in Fig. 3. The spectra of polymorphs α and β were compared with their amorphous counterparts to clarify the nature of the hydrogen bond interactions in the amorphous phase. Apparently, in addition to a broadening of the peaks in the amorphous sample, changes in peak shape, intensity, and position between the crystalline phases and their amorphous counterparts have occurred in the IR spectra. As can be seen in the spectrum of α-AP (Fig. 3d), the N–H peak has shifted slightly by 2 cm−1 to a higher wavenumber; simultaneously, the peaks for the CO groups merged into one peak. Generally, an unbonded X–H stretch gives rise to a relatively sharp peak, whereas on formation of a hydrogen bond X–H⋯Y (where Y is the acceptor atom), the peak shifts to a lower wavenumber and becomes much broader.20 The downward shift is caused by the lengthening of the X–H bond, which occurs on hydrogen bond formation. Based on this consideration, a stronger hydrogen bond will lengthen X–H more and produce a shift to a lower wavenumber. In contrast to the crystalline state, a small upward shift of the N–H vibration occurred for the amorphous α, indicating that the hydrogen bond strength slightly increased or remained almost unchanged with loss of order in the crystalline structure.
Fig. 3 FT-IR spectra of crystalline and amorphous phases of AZE. (a) PEZ; (b) α-Cry; (c) β-Cry; (d) α-AP; (e) β-AP; (f) CAP of AZE-PEZ. |
A similar type of analysis of the IR spectral data was carried out for β-Cry and β-AP. On comparing with β-Cry, the N–H peak is broader and has shifted dramatically by 30 cm−1 to a higher wavenumber for β-AP. Moreover, the peaks for the CO groups also merged into one peak. A large upward shift of the N–H vibration in β-AP indicates that the hydrogen bond strength dramatically decreases with loss of the crystalline structure. It seems amazing that hydrogen bond strength slightly increases for form α but decreases for form β when the crystalline structure is destroyed. This difference may be derived from the differences in the crystalline structure between α-Cry and β-Cry. Single crystal XRD analysis revealed that β-Cry crystallized in an acentric space group of Pca21, in which hydrogen bonds played a crucial role in the 1D, 2D network in the crystal structure.14 When the crystal structure is destroyed, hydrogen bond interactions in β-Cry, which are responsible for stabilization the crystal structure, disappear. The reformed hydrogen bonds in the amorphous form are weaker than those in the crystalline form. Unfortunately, a single crystal of α-Cry has not been obtained and no crystal structure is referenced. Due to an almost unchanging hydrogen bond strength before and after transferring from the crystalline to amorphous phase, we can deduce reasonably that π⋯π intermolecular interactions but not hydrogen bonds play an important role in the crystal structure of α-Cry.
Using IR spectral data, the hydrogen bonding strength and pattern can be elucidated for the polymorphs and APs by monitoring the N–H (hydrogen bonding donor) and CO (hydrogen bonding acceptor) stretching frequency. In α-Cry and β-Cry, the extent of variation in the N–H and CO peak positions suggests a difference in the hydrogen bonding patterns and thus in the strengths, which is consistent with the crystallographic data. However, the widths of the N–H and CO peaks of the AP were greater than for the crystalline counterparts, which is consistent with a broader distribution of hydrogen bond lengths in the disordered phase. From Fig. 3, it was apparent, perhaps somewhat surprisingly, that form α appeared to have stronger hydrogen bonding on average in the amorphous state than in the crystalline state, while for form β, the opposite situation was observed, and the hydrogen bonding weakens on changing from the ordered to the disordered state. Obviously, there is no difference in the hydrogen bonding pattern and strength between α-AP and β-AP, but the opposite situation was observed for α-Cry and β-Cry. Different energetic barriers exist for rearrangement within the amorphous phase prior to crystallization depending on the differences in molecular association between α-Cry and β-Cry. There are few studies comparing the two polymorphs and amorphous forms. Based on the above observations, we can speculate that a weakening of the hydrogen bonding on progressing from an ordered to a disordered phase is probably more typical for form β than for form α because crystalline β is a stable form, in which hydrogen bonding interactions play a crucial role in the molecular packing.
When the small molecule PEZ was introduced to destroy the order of the crystal structure of AZE, the same peak broadening in the IR spectrum occurred for AZE-PEZ CAP. Furthermore, compared with the crystalline AZE, a downward shift of the CO vibration and disappearance of the N–H vibration from PEZ for the AZE-PEZ CAP indicated that hydrogen bonding occurred in the AZE-PEZ heterodimer and that the hydrogen bond strength increased in the heterodimer compared to the homogenous dimer. Furthermore, as can be seen in the spectra of the AP and CAP, the vibrations derived from the hydrogen bonding donors and acceptors in the AP and CAP appear at almost the same wavenumbers, suggesting the random weak interactions in the disordered phases are somewhat identical regardless hetero (AP) or homogenous (CAP) combination.
Sample | Temperature (K) | ||||
---|---|---|---|---|---|
298 | 304 | 310 | 316 | 322 | |
α-Cry | 77.45 ± 2.85 | 132.38 ± 8.47 | 170.59 ± 13.30 | 240.18 ± 11.32 | 333.21 ± 5.47 |
α-AP | 122.32 ± 4.01 | 188.34 ± 9.65 | 255.86 ± 13.72 | 310.59 ± 16.11 | 469.47 ± 9.33 |
CAP | 117.97 ± 6.54 | 153.31 ± 3.82 | 217.76 ± 2.07 | 263.93 ± 14.35 | 420.81 ± 30.00 |
β-Cry | 57.09 ± 0.75 | 82.49 ± 3.79 | 100.87 ± 8.62 | 117.69 ± 5.98 | 166.47 ± 6.42 |
β-AP | 16.10 ± 1.22 | 24.37 ± 2.24 | 31.06 ± 0.70 | 38.19 ± 1.51 | 79.00 ± 5.59 |
Based on the solubility data, curves were drawn with lnc as the Y-coordinate versus 1/T × 103 as the abscissa (Fig. 4). Tt can be obtained from the point of intersection of the two curves. The values of ΔHθα-AP, ΔHθβ-AP and ΔHθCAP obtained from the slopes of the curves were 36.31, 40.85, and 34.44 kJ mol−1, respectively. Since β-Cry was thermodynamically stable at room temperature,12 we especially discuss the transition reactions of three different transition pairs α-AP/β-Cry, β-AP/β-Cry, and CAP/β-Cry. Based on the solubility data of α-AP, β-AP, CAP and β-Cry, curves were drawn with lncA/cB as the Y-coordinate versus 1/T × 103 as the abscissa (Fig. S1†); the corresponding thermodynamic parameters and Tt for the transition reactions are listed in Table 2. The Tt values of the transition pairs α-AP/β-Cry and CAP/β-Cry were 237.5 K and 231.4 K, respectively, suggesting that α-AP and CAP are stable below those Tt values and β-Cry is stable above those Tt values, for example, at room temperature. While, the pair of β-AP/β-Cry showed a Tt of 400.3 K, indicating that the stable temperature range of β-AP is below this Tt value. β-AP manifested a broader stable temperature range compared to α-AP and CAP, including room temperature (ΔGθ > 0 meaning a nonspontaneous reaction of transition from β-AP to β-Cry at room temperature). However, α-AP and CAP were not stable at room temperature, they transformed to β-Cry spontaneously with a value of ΔGθ < 0 (Table 2).
Fig. 4 Curves of lnc vs. 1000/T for the AZE systems in 0.01 M HCl medium: (a) α-Cry; (b) β-Cry; (c) α-AP; (d) β-AP; (e) α-AZE-PEZ CAP. |
T (K) | ΔGθ (kJ mol−1) | ΔHθ (kJ mol−1) | ΔSθ (J mol−1 K−1) | Tt (K) | |
---|---|---|---|---|---|
α-AP, β-Cry | 298 | −1.89 | 9.24 | 37.36 | 237.5 |
304 | −2.11 | ||||
310 | −2.34 | ||||
316 | −2.56 | ||||
322 | −2.79 | ||||
β-AP, β-Cry | 298 | 3.31 | 14.91 | 38.93 | 400.3 |
304 | 3.07 | ||||
310 | 2.84 | ||||
316 | 2.61 | ||||
322 | 2.37 | ||||
CAP, β-Cry | 298 | −1.61 | 7.77 | 31.47 | 231.4 |
304 | −1.80 | ||||
310 | −1.99 | ||||
316 | −2.18 | ||||
322 | −2.37 |
To verify the stability of the two APs and CAP in 0.01 M HCl solution, the remaining solids were collected and subjected to PXRD analysis after determination of the solubility of the crystalline and amorphous samples at room temperature; the patterns are shown in Fig. 5. For α- and β-Cry, the PXRD patterns showed subtle changes, such as the appearance of small new peaks, before and after the dissolving-recrystallization process in HCl medium (Fig. 5c and d). This indicated that AZE is ionized partially in a strong acid medium owing to the existence of -N-H in the molecular structure. In the PXRD patterns of the solids from the suspensions after solubility determination of the α-AP and CAP, peaks assigned to β-Cry emerged, indicating that α-AP and CAP are unstable in the 0.01 M HCl medium and transformed to β-Cry at room temperature (Fig. 5e and g). β-AP had maintained its amorphous nature after the solution procedure (Fig. 5f), which is consistent with the results deduced from the Tt values that β-AP is stable at room temperature in the 0.01 M HCl medium.
Fig. 7 DSC curves for the α-AP (A) and β-AP (B) systems at different heating rates: (a) 10 °C min−1; (b) 20 °C min−1; (c) 30 °C min−1; (d) 40 °C min−1. |
Fig. 8 (A) DTG and TG curves for the AZE-PEZ CAP (20 °C min−1) and (B) DSC curves for the AZE-PEZ CAP at different heating rates: (a) 10 °C min−1; (b) 20 °C min−1; (c) 30 °C min−1; (d) 40 °C min−1. |
Sample | β (°C min−1) | Tm/K | 1/Tm × 1000 | ln (β/Tm2) | r | E (kJ mol−1) |
---|---|---|---|---|---|---|
α-AP | 10 | 590 | 1.695 | −10.458 | 0.9874 | 133.0 |
20 | 605 | 1.652 | −9.816 | |||
30 | 615 | 1.625 | −9.443 | |||
40 | 617 | 1.618 | −9.164 | |||
β-AP | 10 | 587 | 1.704 | −10.447 | 0.9944 | 114.2 |
20 | 601 | 1.663 | −9.802 | |||
30 | 614 | 1.629 | −9.439 | |||
40 | 620 | 1.614 | −9.170 | |||
CAP | 10 | 583 | 1.716 | −10.43 | 0.9866 | 131.6 |
20 | 595 | 1.682 | −9.780 | |||
30 | 605 | 1.653 | −9.409 | |||
40 | 611 | 1.636 | −9.143 |
Footnotes |
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c8ra05535a |
‡ Both authors have contributed equally. |
This journal is © The Royal Society of Chemistry 2018 |