Trimorphism of Betamethasone Valerate: Preparation, Crystal

Dec 11, 2014 - Synopsis. Three polymorphic modifications and one methanol solvate of the glucocorticoid bethamethasone valerate were discovered and in...
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Trimorphism of Betamethasone Valerate: Preparation, Crystal Structures, and Thermodynamic Relations Christian Naẗ her,*,† Inke Jess,† Lena Seyfarth,‡ Kilian Bar̈ winkel,‡ and Jürgen Senker‡ †

Institut für Anorganische Chemie, Christian-Albrechts-Universität zu Kiel, Max-Eyth-Str. 2, 24118 Kiel, Germany Department of Chemistry, Universität Bayreuth, Universitätsstraße 30, D-95447 Bayreuth, Germany

‡

S Supporting Information *

ABSTRACT: The glucocorticoide bethamethasone valerate was investigated for polymorphism. The commercially available modification (Form I) and one methanol solvate were characterized by single crystal structure analysis. DTATG and DSC investigations reveal that on solvent removal the methanol solvate decomposes into a new polymorphic modification (Form III), which, upon further heating, transforms into another modification (Form II) via melting and recrystallization. The crystal structures of forms II and III were determined by a combination of 13C NMR spectroscopy and X-ray powder diffraction. In all modifications as well as in the methanol solvate differences in the conformation and the packing of the molecules are observed. Solvent mediated conversion experiments reveal that form I represents the thermodynamically stable form at room temperature. Thermomicroscopic, XRPD, and heating rate dependent DSC measurements on forms I−III do not show any interconversion of these forms via the solid. Further DSC measurements indicate both a higher melting point and heat of fusion for form I compared to form II and form III. Therefore, form I should also be the thermodynamically stable form over the whole temperature range and all forms seems to be monotropically related.

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INTRODUCTION Investigating the polymorphism of compounds is still an important field in solid state research and of special importance in a number of industries.1−10 In this context, drug polymorphism is of special importance because it has a large impact on different aspects like, e.g., authorization of a drug, patent law, and investigations on the influence of a given modification to the properties of a drug.9−14 Finally, investigations on the properties of cocrystals, sometimes denoted as pseudopolymorphs, like hydrates, or generally solvates, are also of interest because the modification formed by solvent removal must be determined. Therefore, if polymorphic modifications are detected, one must investigate under which conditions a special form is thermodynamically stable, how these forms can selectively be prepared, and if these forms can be transformed into each other.15−24 Some years ago we reported on the polymorphism of some glucocorticoids, still among the most effective and versatile drugs.25−28 In the course of this project we detected several new polymorphic modifications and cocrystals for, e.g., hydrocortisone, triamcinoloneacetonide, and prednisolone.29−33 In continuation of this work we report here on our investigations on betamethasone valerate (Figure 1), a compound which is used in therapy because of its immune suppressive and antiallergic properties. For betamethasone valerate only minor investigations on the polymorphism and pseudopolymorphism are found in the literature and no crystal © 2014 American Chemical Society

Figure 1. Structural formula of betamethasone valerate.

structures are available in the CCDC database.34−36 In 1966 Mesley reported two polymorphic modifications of this compound, which were identified by IR spectroscopic investigations.34 In contrast, Kuhnert-Brandstätter and Gasser have not found any hints that this drug exists in different forms.35,36 However, we have found three polymorphic modifications and one methanol solvate. If the solvent is removed, a consecutive transformation into two of these modifications is observed. Here we report on our investigations. Received: October 1, 2014 Revised: November 21, 2014 Published: December 11, 2014 366

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age.38,39 The (optimized) molecules were treated as rigid bodies, with the translational and rotational degrees of freedom of the rigid body set free. Additionally, the torsion angles of the side chains were left unconstrained. The best solution was found in space group P212121 for form II and in P21 for form III. Finally, a Rietveld refinement using rigid bodies and isotropic displacement parameters were performed for each form. The C−H hydrogen atoms were positioned with idealized geometry and the O−H hydrogen atoms were placed in ideal positions where the shortest O−H···O hydrogen bridges are obtained. This procedure leads to reasonable reliability factors and smooth difference curves (Figure S3−S4 in the Supporting Information). The absolute configuration was assigned based on the known absolute configuration of the pristine compound. Both the Pawley fit and the Rietveld refinement steps have been conducted using the Reflex Plus module within the Materials Studio software.39 X-ray Powder Diffraction Experiments. X-ray powder diffraction experiments were performed using a STOE STADI P transmission powder diffractometer in Bragg−Brentano geometry with an 2° to 130° IP-PSD (image plate position sensitive detector) using CuKα1 radiation (λ = 1.540598 Å). Thermomicroscopy. Thermomicroscopic measurements were performed using a hot stage FP82 from Mettler and a microscope (BX60) from Olympus using the Analysis software package from Mettler. The calibration was checked using benzoic acid.

EXPERIMENTAL SECTION

Chemicals. Betamethasone valerate is commercially available and was obtained from Symbiotec Pharmalab LTD, India. All solvents used for the crystallization experiments were of analytical grade. Differential Thermal Analysis and Thermogravimetry. DTATG measurements were performed in Al2O3 crucibles using a STA409CD thermobalance from Netzsch. Several measurements under nitrogen atmosphere (purity 5.0) with different heating rates were performed. All measurements were performed with a flow rate of 75 mL/min and were corrected for buoyancy and current effects. Differential Scanning Calorimetry. DSC investigations were performed with the DSC 204/1/F from Netzsch and the DSC 1 Star System with STARe Excellence Software from Mettler-Toledo AG. The measurements were performed in Al pans with different heating rates under nitrogen. The instruments were calibrated using standard reference materials. Single Crystal Structure Analysis. All data were measured at 170 K using a STOE IPDS-1 Imaging Plate Diffraction system with Kα1 radiation (λ = 0.71073 Å). Structure solutions were performed with direct methods using SHELXS-97. The structure refinements were performed against F2 using SHELXL-97. All non-hydrogen atoms were refined using anisotropic displacement parameters. The C−H hydrogen atoms were positioned with idealized geometry (some of the methyl H atoms were allowed to rotate but not tip) and refined with isotropic displacement parameters (U iso (C) = 1.2 × Ueq(Cmethin/methylene) = 1.5 × Ueq(Cmethyl) using a riding model with C−Hmethin = 0.95 Å, C−Hmethylene = 0.99 Å, and C−Hmethyl = 0.98 Å. The O−H hydrogen atoms were located in difference map but positioned with idealized geometry, allowed to rotate but not tip, and were refined isotropically using a riding model with O−H = 0.84 Å. Because no heavy elements are present, the absolute structure and the absolute configuration cannot be determined. Therefore, Friedel equivalents were merged and the absolute configuration was assigned based on the known absolute configuration of the starting compound. Crystallographic data have been deposited with the Cambridge Crystallographic Data Centre: CCDC 1033447 (form I) and CCDC 1033448 (methanol solvate). Copies may be obtained free of charge on application to the Director, CCDC, 12 Union Road, Cambridge CB2 1E2, UK (fax: Int. Code +(44)01223/3 36−033, e-mail: [email protected]). Structure Determination from X-ray Powder Data. The structure determinations were performed using the following steps, which in the beginning were successfully tested to determine the crystal structure of form I known from single crystal data. In the beginning, all forms were investigated by 13C NMR spectroscopy to determine the number of signals in the spectra, which allow estimation of the number of molecules in the asymmetric unit. For the commercially available form I 27 signals are observed in the 13C NMR spectra which exactly correspond to the number of carbon atoms in the molecule and which are in agreement with one crystallographically independent molecule in the asymmetric unit (Figure S1 and S2 in the Supporting Information). The same number of signals is observed for form II, indicating that only one distinct betamethasone molecule is present. In contrast, most typical 13C signals are doubled for form III which is most obvious in the low field region. Prominent examples are the signal groups around 95, 155, 188, and 205 ppm. Consequently, this form must contain two crystallographically independent molecules in the asymmetric unit. In the following, all X-ray powder patterns were successfully indexed leading to an orthorhombic unit cell for form II and a monoclinic unit cell for form III (Table 2). Indexing was performed using the Program WinXPOW.37 Afterward, the respective profile parameters were determined using a Pawley fit leading to wRp(Pawley) of 3.17% (II) and 2.39% (III). The structure of each form was solved using a real space approach and a simulated annealing algorithm in all possible space groups. For the structure solution the structure of a single molecule was taken from the single crystal structure analysis and subsequently geometry optimized with DFT methods using the DMol3 module of the Materials Studio pack-

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RESULTS AND DISCUSSION Solvent Mediated Conversion Experiments on Form I. To investigate if the commercially available form of betamethasone valerate might represent the thermodynamically stable form at room temperature and if additional solvates can be prepared, a suspension of form I was stirred in different solvents for 4 weeks, and afterward the solid residues were investigated by X-ray powder diffraction (XRPD). In almost all solvents, the powder patterns correspond to the one of the commercially available form, and thus, it can be assumed that this modification represents the thermodynamically stable form at room temperature (Table S1 in the Supporting Information). In contrast, the X-ray powder pattern of the residue obtained from methanol is completely different from that of form I. Single crystal structure investigations have shown that this form represents a solvate (Table S1 in the Supporting Information and see below). Single crystals of form I were grown from acetonitrile, whereas crystals of the methanol solvate were obtained from methanol. Comparison of the experimental powder pattern with the one calculated from single crystal data prove that form I and the methanol solvate were obtained as single crystalline phases (Figures S5 and S6 in the Supporting Information). Differential Thermoanalysis and Thermogravimetry (DTA-TG) of the Methanol Solvate. DTA-TG investigations show a complex thermal behavior for the methanol solvate. Upon heating one mass step of 6.3% is observed in the TG curve at about 94 °C, which can be attributed to the removal of one methanol molecule (Δmcalc. (− methanol) = 6.3%). Further heating reveals a second endothermic event at Tp = 121 °C, followed by an exothermic peak at Tp = 142 °C. On further heating a strong endothermic peak is detected at Tp = 191 °C, and afterward the sample mass decreases, which indicates vaporization and/or decomposition to volatiles of the material (Figure 2). All phases formed after each thermal event were investigated by XRPD. The residues formed after solvent removal and after the first exothermic event yield powder patterns differing both each other as well as from form I, indicating that two more polymorphic modifications, form II and form III, have been 367

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crystals of the methanol solvate exhibit a needle-like morphology (Figure S7 in the Supporting Information). The crystal structures of forms II and III were determined by a combination of solid state 13C NMR spectroscopy and X-ray powder diffraction (see Experimental Section). From the NMR measurements the number of signals observed in the spectra allow definite conclusions on the number of molecules in the asymmetric unit of each form, which was tested in the beginning for form I (Figure S1 and S2 in the Supporting Information). Afterward, all powder patterns were indexed, and the structures were solved by real space methods and simulated annealing and finally refined by the Rietveld method (Supporting Information Figures S3−S4). Even if the O−H hydrogen atoms were considered in the refinements, details on hydrogen bonding in forms II and III will not be discussed because they were only placed in the direction of the next acceptor atom. The methanol solvate of betamethasone valerate crystallizes in space group P212121 with four molecules in the unit cell. In the crystal structure the molecules are arranged into columns, which elongate in the direction of the crystallographic a-axis (Figure 4: bottom right). The molecules of neighboring columns are connected by intermolecular O−H···O hydrogen bonding into corrugated layers (Figure 4 bottom right, and Table S2 in the Supporting Information). The columns form channels along the a-axis incorporating methanol solvate molecules. These solvate molecules act as both donor and acceptor in hydrogen bonds connecting the columns into a three-dimensional network. Forms I and II of betamethasone valerate crystallize orthorhombic in space group P212121 with Z = 4 molecules in the unit cell (Table 1 and 2). The 13C NMR spectra of these forms reveal 27 signals, proving that each asymmetric unit consists of one crystallographically independent betamethasone molecule in the asymmetric unit (Figure S1 and S2 in the Supporting Information). In contrast, form III crystallizes monoclinically in space group P21 with two crystallographically independent molecules in the asymmetric unit, and thus, 54 different 13C NMR signals are observed (Table 2 and Figure S1 and S2 in the Supporting Information). All modifications I−III as well as the methanol solvate exhibit differences in the conformations of the betamethasone molecules and, therefore, represent conformational polymorphs (Figure S9 in the Supporting Information). Differences are also found in the conformation of both crystallographically independent molecules in form III, proving in accordance to its NMR spectra that they are not equivalent (Figure S10 in the Supporting Information). In the crystal structure of all modifications the betamethasone molecules are stacked in the direction of the crystallographic a-axis, but differences are observed especially in the arrangement of the stacks and the orientation of the betamethasone molecules within these stacks (Figure 4). It is noted that the crystal structures of the methanol solvate and of form III are very similar, which might explain why the methanol solvate transforms into form III on thermal annealing at relatively low temperatures. Therefore, there is some structural relationship between these modifications. In form I, intermolecular O−H···O hydrogen bonding is found between the hydroxyl hydrogen atom H2 and the carbonyl oxygen atom O1, connecting the molecules within the columns into chains elongating along the a-axis (Figure 4 top left and Table S3 in the Supporting Information). There is one

Figure 2. DTA, TG, and DTG curves for the methanol solvate (heating rate: 4 °C/min; N2 atmosphere; peak temperatures Tp in °C and the mass loss in %).

obtained (Figure 3A and B). In contrast, the residue obtained after the second endothermic event is either amorphous to Xrays or partly crystalline with form III as the major phase.

Figure 3. Experimental X-ray powder patterns of the residues isolated after the first (A; Form III) and second (B) endothermic and the first exothermic event (C; Form II) as observed in the DTA-TG measurement of the methanol solvate. (D) depicts the calculated Xray powder pattern for the commercially available form I.

We also investigated if the solvent can be removed at room temperature in vacuum and which modification will form on solvent removal. These experiments clearly show that even after 2 days in vacuum no decomposition takes place. However, if the methanol solvate is annealed at 50 °C in vacuum a transformation into form III is observed within 1 day. Crystal Structures of Forms I, II, and III and the Methanol Solvate. Single crystals of the methanol solvate and of form I were prepared by slow evaporation of a solution of bethamethasone valerate in methanol and acetonitrile, respectively, and were characterized by single crystal X-ray analysis. Form I crystallizes as a small block, whereas the 368

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Figure 4. Crystal structure of form I (top: left), form II (top: right), form III (bottom: left), and the methanol solvate (bottom: right) with view along the a-axis. For form I and the solvate intermolecular hydrogen bonding is indicated as dashed lines. An ORTEP with labeling of the methanol solvate and of I is given in Figures S8 and S11 in the Supporting Information.

the Supporting Information). In contrast, if a similar measurement is performed under air directly after melting, the DSC curve drops down, indicating the decomposition of this material (Figure S18 in the Supporting Information). If the thermal behavior of form I is investigated as a function of the heating rate there is no hint for any further polymorphic transition (Figure 5). Surprisingly, at a heating rate of 1 °C/min the onset temperature is lower, and after the strong endothermic peak a second very low intense and broad maximum is observed indicating that the behavior is more complex (Figure 5). In the following, the melting point (onset temperature) and the enthalpy of fusion for form I were determined using several DSC measurements with 10 °C/min and the average values are Tm(I) = 192.6 °C and ΔHf(I) = 30.3 kJ/mol (Figure S19 and Table S4 in the Supporting Information). Heating rate dependent DSC measurements on the methanol solvate look comparable to the DTA measurements but are much better resolved. Between 80 and 100 °C an endothermic peak is observed, which corresponds to the removal of the solvent molecules and the formation of form III (denoted as 1 in Figure 6). On further heating, an additional endothermic peak is observed at about 118 °C that might correspond either to melting or to a polymorphic transformation of form III (denoted as 2 in Figure 6). In the following a strong exothermic peak is observed at Tp = 142 °C that corresponds to the formation of form II (denoted as 3 Figure 6). If the temperature is raised again an endothermic peak is observed at Tp = 184 °C, which might correspond to the melting of form II (denoted as 4 in Figure 6). It is noted that with decreasing heating rate the intensity of the endothermic event at about 115 °C increases, and an

very weak intramolecular hydrogen bond between a hydroxyl hydrogen atom and a carbonyl oxygen atom with an O···H distance of 2.126 Å and an O−H···O angle of 159.2° (Table S3 in the Supporting Information). Finally, based on the results of the Rietveld refinements, Xray powder patterns were calculated for form II and III and compared with the experimental patterns (Figure S12 and S13 in the Supporting Information). Thermodynamic and Kinetic Aspects of the Trimorphism. To investigate the thermal properties of all modifications in more detail and to find the thermodynamic relations between the different forms, detailed investigations using simultaneous differential thermoanalysis and thermogravimetry, differential scanning calorimetry, and thermomicroscopy were performed. DTA-TG measurements of the commercially available form I shows only an endothermic event at a peak temperature of about 185 °C which is followed by a mass loss in the TG curve (Figure S14 in the Supporting Information). Thus, it can be assumed that the endothermic event corresponds to the melting point of form I and the TG step to the vaporization or decomposition of this form. To determine the melting point and the enthalpy of fusion of form I more precisely several DSC measurements were performed under nitrogen. Upon heating with 10 °C/min, melting is observed at an onset temperature of 192.6 °C, and on cooling, no crystallization takes place (Figure S15 in the Supporting Information). If the solidified melt is investigated by X-ray powder diffraction it is proven to be amorphous to Xrays (Figure S16 in the Supporting Information). IR spectroscopic investigations show that the spectra of form I and of the amorphous residue are identical, which exclude a decomposition of this material after melting (Figure S17 and in 369

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Table 1. Crystal Data and Results of the Structure Refinement for Form I of Betamethasone Valerate and for Its Methanol Solvatea Empirical Formula MW/g·mol−1 Crystal color Crystal system Space group a/Å b/Å c/Å V/Å3 Temperature/K Z Dcalculated mg·cm−3 F(000) 2θ-range/° h/k/l ranges

λ(MoKα/mm−1) Reflections collected Rint. Independent refl. Refl. with F0 > 4σ(F0) Refined parameters R1 [F0 > 4σ(F0)] wR2 [all data] GooF Min./max. res. e/Å−3 a

form I

methanol solvate

C27H37FO6 476.57 colorless orthorhombic P212121 9.0752(6) 12.9092(7) 20.972(1) 2456.9(2) 166 4 1.288 1024.0 4.9 to 56.1 −11 ≤ h ≤11 −13 ≤ k ≤ 17 −22 ≤ l ≤ 27 0.09 11867 0.0425 3285 2879 310 0.0402 0.1040 1.050 0.206/−0.216

C27H37FO6···CH3OH 508.61 colorless orthorhombic P212121 7.7774(3) 15.2985(7) 22.041(2) 2622.5(2) 170 4 1.288 1096.0 4.6 to 56.1 −10 ≤ h ≤ 9 −13 ≤ k ≤ 20 −25 ≤ l ≤29 0.10 9243 0.0457 3521 2974 330 0.0396 0.0985 1.030 0.204/−0.189

Figure 5. Heating rate dependent DSC curves for form I (given are the onset temperature T0 and the peak temperature Tp in °C as well as the enthalpy of fusion ΔHf(I) in kJ/mol).

Please note the densities of both forms are accidentally identical.

Table 2. Crystal Data and Results of the Structure Refinement for Forms II and III Empirical Formula MW/g⊕mol−1 Crystal color Crystal system Space group a/Å b/Å c/Å β/° V/Å3 Temperature/°C Z Dcalc g·cm−3 wRp Rbragg

form II

form III

C27H37FO6 476.57 colorless orthorhombic P212121 8.5321(4) 13.9535(5) 21.3919(7) 2546.8(2) RT 4 1.243 0.06354 0.04044

C27H37FO6 476.57 colorless orthorhombic P21 7.6893(6) 23.033(2) 14.515(2) 98.502(6) 2542.4(4) RT 4 1.169 0.0450 0.0216

Figure 6. DSC curve of the methanol solvate measured at different heating rates. The numbers refer to the different thermal events, and the corresponding peak and onset temperatures as well as the heat of transformation can be found in Table S5 in the Supporting Information.

80 °C lower than that of forms I and II. Therefore, form III prepared as a microcrystalline powder by solvent removal of the methanol solvate was investigated by thermomicroscopy. These investigations clearly show that under these conditions form III starts to melt at about 118 °C. On further heating crystallization of a new form occurs, which is finished at about 148 °C (Figure 7 and Figure S20 in the Supporting Information). It is noted that a similar behavior is also observed for one of the modifications of premafloxacin, which also transforms via melting and crystallization into a new form.9,40 On further heating this new form starts to melt at about 184 °C. According to these investigations the second endothermic peak observed after solvent removal corresponds to the melting of form III and the following exothermic peak to the crystallization of form II (see Figure 6). This experiment also explains that the residue isolated after this thermal event (2) is amorphous and sometimes contains a small amount of form III because of incomplete melting or the formation of the solid residue under kinetic control (compare Figure 6). Additional heating rate dependent measurements on form II look similar to the measurement of the methanol solvate, except for the occurrence of the endothermic peak correspond-

additional peak starts to grow after the last endothermic event until both signals have more or less equal intensity (denoted as 4 and 5 in Figure 6). This strongly indicates that the overall behavior is more complex and that the kinetics of all reactions involved will play an important role. In the following it was investigated whether the second endothermic signal could be traced back to a solid-to-solid phase transition or to the melting of form III, which would be surprising because in this case its melting point would be about 370

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Figure 8. DSC curve of form III measured at different heating rates. The numbers refer to the different thermal events, and the corresponding peak and onset temperatures as well as the heat of transformation can be found in Table S6 in the Supporting Information).

Figure 7. Microscopic images of form III as a function of temperature measured at 3 °C/min. For the full temperature range, see Figure S20 in the Supporting Information.

ing to solvent removal (Figure S21 in the Supporting Information). Moreover, in contrast to the DSC measurement of the methanol solvate, the last endothermic event (denoted as 5 in Figure 6) does not occur. The melting enthalpy ΔHf(III) and the melting temperature (onset temperature To) were determined from three DSC runs at 1 °C/min. The average values are 9.0 kJ/mol and To = 107.6 °C (Table S7 in the Supporting Information). Heating rate dependent DSC measurements on form III obtained by thermal decomposition of the methanol solvate gave no hint for further polymorphic transformations, but the onset temperatures strongly depend on the actual heating rate (Figure 7 and Table S7 in the Supporting Information). As mentioned above, no polymorphic solid-to-solid transformation between the different modifications is observed, which does not allow definitive conclusions on their thermodynamic relation. However, a decision would be possible based on the heat of fusion rule, which states that if the higher melting polymorph has the higher heat of fusion, the polymorphic modifications are monotropically related; otherwise, they are enantiotropic.41 Because the melting points of form I and form II are roughly in the same range, we performed a DSC measurement in which form I was used as the sample whereas form II was used as the reference (Figure 9). In this case where form II melts at lower temperatures, one would expect an exothermic peak in the beginning, whereas in those cases where form I melts at lower temperatures, it would be endothermic. From Figure 9 it is obvious that form I exhibited the higher melting point and, therefore, must also be stable at higher temperatures. To determine which of the two modifications I and II exhibits the higher heat of fusion, additional DSC measurements were performed. In this context, it must be pointed out that in this case where form II starts to melt, some amount of form I could crystallize because it will melt at higher

Figure 9. DSC curve at 5 °C/min of a measurement where form I was used as the sample and form II as the reference.

temperatures. This is not unusual behavior, but in this case the experimental values for the heat of fusion could be wrong.16 To suppress this possible transformation, DSC measurements at relatively high heating rates of 40 and 60 °C/min were performed and the average onset and peak temperatures as well as the average heat of fusion are given in Table 3. It is noted that for the determination of the heat of fusion of form III a low heating rate must be used, because otherwise this event cannot be resolved (see Figure 8). However, the differences between the heat of fusion of forms I and III, respectively, II Table 3. Peak and Onset Temperatures as Well as Heat of Fusion for Forms I and II at 40 and 60 °C/min and III at 1°C/mina To in °C Tp in °C ΔHf in kJ/mol

form I

form II

form III

192.6 (192.7) 195.0 (196.6) 32.9 ± 1.1 (31.5 ± 1.0)

182.3 (186.4) 182.6 (187.4) 27.0 ± 1.4 (27.0 ± 1.7)

107.6 113.1 9.0 ± 0.2

The values for I and II given in brackets were determined at 60 °C/ min. The maximum error is given. For the individual values and those measured at additional heating rates, see Table S4−S8 in the Supporting Information. Please note that the ΔH values given in Table S5 were measured for the methanol solvate and, thus, are not comparable because they are based on a different molecular weight.

a

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and the residue obtained was investigated as a function of time by X-ray powder diffraction. In this case only form I was obtained even after about 5 min. Because the speed of the transformation will depend on the solubility, we determined this parameter in 1-butanol (3.955 g/100 mL), 1-propanol (4.641g/100 mL), ethanol (5.771 g/100 mL), and methanol (1.810 g/100 mL) for comparison. The lowest solubility is observed in methanol, but as in this case the solvate always will form, we used 1-butanol as solvent. Unfortunately, even in this case only the transformation into form I is observed within minutes, and therefore we cannot decide if form II or form III will disappear in the beginning (Figure 11). It is noted that the same result is obtained if only a mixture of form II and form III is investigated. However, even if we found no hint for an interconversion of form II into form III in solution our results indicate that form II is more stable than form III and it should be monotropically related to form III. Moreover, the higher stability is also in agreement with the different densities of these two modifications, because the density of form II is higher than the one of form III. This indicates that form II is more stable at low temperatures, even if some exceptions from the density rule are known.11,42−44

and III, are very large and differences in the heating rate will not influence the overall result. For comparison, the same measurements were also performed for form I and some of these values are given in Table 3. From these measurements and those presented before it is proven that form I exhibits the highest melting point and the highest heat of fusion and, therefore, form I and form II as well as form I and form III should be monotropically related (Figure 10).

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CONCLUSION In the present work three modifications of betamethasone valerate as well as one methanol solvate were detected and structurally characterized. Interestingly, two of these forms can only be prepared by solvent removal of the solvate, and because only microcrystalline powders can be obtained by this route, their crystal structures were solved ab initio by a combination of 13C NMR spectroscopy and X-ray powder diffraction. Analysis of the structures clearly shows that a different packing and a different conformation of the molecules are found in the different forms. Moreover, the crystal structure of form III is very similar to that of the methanol solvate, which explains why this form is obtained by solvent removal under kinetic control. This form is clearly metastable and represents one very rare example of a form that exhibits an extremely low melting point compared to its other modifications. Moreover, this modification transforms via melting and crystallization into a third one (form II), which is also metastable and melts at lower temperatures than the stable form I. From our investigations it becomes clear that heating rate dependent DSC measurements are essential, especially in this case, to find optimal condition for the pure preparation of the metastable forms and to determine their thermodynamic parameters as precisely as possible, which is needed for the determination of their thermodynamic relations and for the construction of the energy temperature diagram. From all these investigations it is highly likely that all forms are monotropically related with form I stable over the whole temperature range.

Figure 10. Qualitative energy-temperature diagram for the polymorphic modifications I, II, and III, which shows that they are monotropically related (G = free energy; H = enthalpy; Tm = melting point; ΔHf = enthalpy of fusion).

Moreover, form II exhibits the higher melting point and the higher heat of fusion than form III, and therefore, these forms should also be monotropically related (Figure 11). In this

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Figure 11. Experimental X-ray powder pattern of a mixture of forms I, II, and III (A) and of the residue obtained after stirring this mixture for 5 min (B), as well as calculated pattern for forms I (C), II (D), and III (E).

ASSOCIATED CONTENT

S Supporting Information *

NMR spectra, difference plots of the Rietveld refinement, XRPD pattern, structure plots, DSC curves, IR spectra, microscopic images, and DTA-TG curves. This material is available free of charge via the Internet at http://pubs.acs.org.

context it must be mentioned that some exceptions are possible, if, e.g., the melting point between the two polymorphs is very large, which is the case for these two forms.3 To further confirm this claim, we tried to investigate if form II transforms into form III in solution or if the opposite is the case. Therefore, a mixture of all three forms was stirred in ethanol

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. 372

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Notes

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The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank Professor Dr. Wolfgang Bensch for access to his equipment and the State of Schleswig-Holstein for financial support.

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dx.doi.org/10.1021/cg501464m | Cryst. Growth Des. 2015, 15, 366−373