Investigations on the Desolvation Reaction of Pseudopolymorphic Forms of Hydrocortisone Viktor Suitchmezian, Inke Jess, and Christian Na¨ther* Institut fu¨r Anorganische Chemie, Christian-Albrechts-UniVersita¨t zu Kiel, May-Eyth-Str. 2, D-24098 Kiel, Germany
CRYSTAL GROWTH & DESIGN 2009 VOL. 9, NO. 2 774–782
ReceiVed March 17, 2008; ReVised Manuscript ReceiVed NoVember 21, 2008
ABSTRACT: The crystal structures of two pseudopolymorphic modifications of the glucocorticoid hydrocortisone were determined, in addition to the known structures of the 2-propanol (1), methanol (2) and pyridine (3) solvate reported recently. The chloroform solvate (4) and the N,N′-dimethylformamide solvate (5) crystallize in the monoclinic space group P21, with a ) 12.5947 (8) Å, b ) 12.4413 (5) Å, c ) 14.9884 (11) Å, β )90.571 (9)°, V ) 2348.5(2) Å3 for (4) and a ) 13.4186 (10) Å, b ) 6.0878 (3) Å, c ) 14.6595 (11) Å, β ) 104.711 (10)°, V ) 1158.27(14) Å3 for 5. The crystal structures of 1, 3, and 5 are isotypic and are very similar to that of the thermodynamically metastable solvent free modification III of hydrocortisone. The removal of solvents from the pseudopolymorphic forms at elevated temperatures results in the formation of the thermodynamically most stable form I or the metastable form II of hydrocortisone. For the methanol solvate, the desolvation reaction indicates the formation of a new modification of this drug. In contrast, the removal of the solvent from the N,N′-dimethylformamide solvate (5) at room-temperature leads to the formation of the metastable form III of hydrocortisone. These results indicate a smooth reaction pathway for the desolvation reactions of the solvates into the solvent free modifications of hydrocortisone. Introduction Investigations on the polymorphism of drugs constitute a topical area of academic and industrial research.1-10 These studies are very relevant for several reasons which include aspects of the patent law, the influence of a given phase on the chemical, biological, or physical properties of a drug, and special requirements of the authorities responsible for the accreditation of a drug, and so forth.10-14 In this context pseudopolymorphism, which refers to compounds that contain additional solvents like, for example, hydrates or generally solvates is of additional interest. The study of desolvation reactions is very important for solvates, to gain more insight on the formation of the solvent free modification upon solvent removal. Depending on different parameters like the kinetics of the reaction, the thermodynamic relation between all solvent free forms, the nature of the solvate, or the actual condition for the removal of the solvent, different stable and metastable polymorphic modifications can be obtained.15-18 Such investigations can be of interest, for example, for the processing of a drug by sterile filtration, in which a drug is dissolved in a given solvent, filtered off under pressure, and afterward the solvent is vaporized and the residue dried. In several cases this procedure must be optimized so that only one special polymorphic form is obtained. In our research we are interested in the polymorphism and pseudopolymorphism of glucocorticoids which constitute a group of extremely versatile and effective drugs.19-25 During these investigations we have discovered a large number of new polymorphic and pseudopolymorphic forms, which were structurally characterized and investigated for their thermodynamic relation.26-33 Recently we have reported on the polymorphism of hydrocortisone (Structure 1),33 a very effective antiphlogistic and immune-suppressive drug which exhibits extremely high antiinflammatory properties. In these investigations we have obtained three polymorphic forms (I-III) and one 2-propanol * To whom correspondence should be addressed. E-mail: cnaether@ ac.uni-kiel.de. Fax: +49-(0)431-8801520.
solvate (1) (Figure 1).33 The crystal structures of forms I and II are built up of parallel tetrameric hydrogen bonded chains, which are differently packed in the crystal, whereas hydrogen bonded dimers are found in the crystal structure of form III which are stacked into columns (Figure 1). Form I represents the thermodynamically most stable form over the whole temperature range and therefore, it is related by monotropy to the metastable forms II and III.33 Form III can be obtained by desolvation of the 2-propanol solvate at room-temperature, and modification II is obtained by heating form III to about 190 °C.
A detailed analysis of the structures of the 2-propanol solvate and the metastable form III clearly indicates that there is a smooth reaction pathway for the desolvation reaction and that the structure of form III is preorganized in the solvate. To investigate the generality of this reaction, the pseudopolymorphs of hydrocortisone are investigated for structure-property relationships in more detail. In addition to the 2-propanol solvate (1),33 methanol (2),34 pyridine (3), 35-38 and chloroform (4) 39,40 solvates have been reported in the literature, of which 2 and 3 were characterized by single crystal X-ray diffraction. In this contribution, we report on the crystal structures of the chloroform (4), the dimethyl-
10.1021/cg8002838 CCC: $40.75 2009 American Chemical Society Published on Web 12/19/2008
Pseudopolymorphic Forms of Hydrocortisone
Crystal Growth & Design, Vol. 9, No. 2, 2009 775
Figure 1. Crystal structures of form I (top), II (mid), and III (bottom) of hydrocortisone.
formamide solvate (5), and on desolvation experiments on all pseudopolymorphic modifications of hydrocortisone. Experimental Section Chemicals. Hydrocortisone is commercially available and was procured from Acros Organics, NJ, U.S.A. All solvents used were of analytical grade. X-ray Single Crystal Structure Analysis. All data were measured using a STOE IPDS-1 Imaging Plate Diffraction system. Structure
solutions were performed with direct methods using SHELXS-97.41 The structure refinements were performed against F2 using SHELXL97.41 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 to tip) and refined with isotropic displacement parameters [Uiso(C) ) 1.2 × Ueq(Cmethin/methylene) ) 1.5 × Ueq(Cmethyl) using a riding model with C-Hmethine ) 0.95 Å, C-Hmethylene ) 0.99 Å, C-Hmethyl ) 0.98 Å]. The O-H hydrogen atoms were located in difference maps but positioned with idealized geometry, allowed to
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Table 1. Crystal Data and Results of the Structure Refinement for the Chloroform Solvate (4) and the N,N′-dimethylformamide solvate (5) compound formula FW [g/mol] crystal color a/Å b/Å c/Å β/deg V/Å3 temperature/K crystal system space group Z Fcalc [mg m3] µ [mm-1] scan range index range refl. collected independent refl. refl. Fo > 4σ(Fo) Rint [%] parameters R1 (Fo > 4σ(Fo)) wR2 (all refl.) GOF δF [e Å-3]
4
5
C21H31O5 · HCCl3 482.83 colorless 12.5947(8) 12.4413(5) 14.9884(11) 90.571(9) 2348.5(2) 150(2) monoclinic P21 4 1.366 0.421 4.2° e 2θ e 49.9° -14 e h e 14 -14 e k e 14 -15 e l e 17 12025 7701 6583 0.0338 542 0.0449 0.1152 1.027 0.295 and -0.454
C21H30O6 · C3H7NO 435.55 colorless 13.4186(10) 6.0878(3) 14.6595(11) 104.711(10)° 1119.96(15) 170(2) monoclinic P21 2 1.249 0.088 6.0° e 2θ e 56.0° -17 e h e 17 -7 e k e 7 -18 e l e 17 8423 3004 2533 0.0319 281 0.0432 0.1201 1.031 0.295 and -0.371
rotate but not to tip, and 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. The absolute configuration was assigned based on the known absolute configuration of the starting compound. Selected crystal data and details of the structure determinations can be found in Table 1. Crystallographic data have been deposited with the Cambridge Crystallographic Data Centre: CCDC 710231 (4, hydrocortisone chloroform solvate) and CCDC 710232 (5, hydrocortisone N,N′dimethylformamide solvate). Copies may be obtained free of charge on application to the Director, CCDC, 12 Union Road, Cambridge CB2 1E2,U.K.(fax:Int.Code+(44)01223/336-033,e-mail:deposit@chemcrys. cam.ac.uk). X-ray Powder Diffraction Experiments. X-Ray powder diffraction experiments were performed using a STOE STADI P transmission powder diffractometer with an image plate detector using Cu KRradiation (λ ) 1.540598 Å). Differential Thermal Analysis and Thermogravimetry. DTA-TG measurements were performed in Al2O3 crucibles using a STA-409CD thermo balance from Netzsch. Several measurements under nitrogen atmosphere (purity 5.0) and air with heating rates of 4 °C/min were performed. All measurements were performed with a flow rate of 75 mL/min and were corrected for buoyancy and current effects.
Results and Discussion Solvent Mediated Conversion Experiments and Crystal Growth. To determine the existence of additional solvates of hydrocortisone, crystalline suspensions of the drug were stirred in different solvents for 2 weeks. Afterward the residues formed in this procedure were investigated by X-ray powder diffraction. In these experiments one new solvate with N,N′-dimethylformamide (5) was found in addition to the 2-propanol (1), methanol (2), pyridin (3), and chloroform (4) solvate reported previously 32-39 (Table 2). Single crystal growth of the chloroform and the N,N′dimethylformamide solvates were performed by slow evaporation of the solvent from saturated solutions of hydrocortisone in the appropriate solvents. Interestingly, for the chloroform solvate the X-ray powder patterns of the residues obtained by the solvent mediated conversion experiments does not cor-
Table 2. Results of the Solvent Mediated Conversion Experimentsa solvent
form
solvent
form
Acetone Acetonitrile 1-Butanol 2-Butanol Carbon tetrachloride Cyclohexane Ethanol Ethyl acetate Methanol DMF Pyridin Chloroform 2-propanol
I I I I I I I I solvate solvate solvate solvate solvate
Methyl acetate Methylene chloride Methyl isobutyl ketone Ethyl methyl ketone 1-Propanol Tetrahydrofuran Toluene Water HCl (0.1 M) NaCl solution (150 mM) Acetonitrile/Water Acetone/Water Ethanol/Water
I I I I I I I I I I I I I
a I, II, and III refers to the solvent free modifications of hydrocortisone.
Figure 2. Microscopic images of the chloroform (4) and N,N′dimethylformamide (5) solvates of hydrocortisone. Table 3. Hydrogen Bonding Interactions (Å, deg) in the Chloroform Solvate (4)a OH · · · O O2-H2 · · · O15A O3-H3 · · · O1B O5-H5 · · · O2(B) O12-H12 · · · O5 O13-H13 · · · O11(C)
O-H (Å) H · · · O (Å)
