Structural, Thermodynamic, and Kinetic Aspectsof the Trimorphism of Hydrocortisone

Structural, Thermodynamic, and Kinetic Aspectsof the Trimorphism of Hydrocortisone

Structural, Thermodynamic, and Kinetic Aspects of the Trimorphism of Hydrocortisone VIKTOR SUITCHMEZIAN, INKE JEß, CHRISTIAN NA¨THER Institut fu¨r Ano...

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Structural, Thermodynamic, and Kinetic Aspects of the Trimorphism of Hydrocortisone VIKTOR SUITCHMEZIAN, INKE JEß, CHRISTIAN NA¨THER Institut fu¨r Anorganische Chemie der Christian-Albrechts-Universita¨t zu Kiel, Olshausenstraße 40, D-24098 Kiel, Germany

Received 18 May 2007; revised 16 November 2007; accepted 21 December 2007 Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.21334

ABSTRACT: Hydrocortisone was investigated for polymorphism and pseudopolymorphism and three different polymorphic modifications (I–III) and one 2-propanol solvate were found. Forms I and III crystallize in the orthorhombic space group P212121, whereas form II and the 2-propanol solvate crystallize monoclinic in space group P21. In all the modifications the molecules are connected by intermolecular O–H. . .O hydrogen bonding. In the 2-propanol solvate, channels are formed in which the solvent molecules are embedded. Solvent-mediated conversion experiments reveal that the commercially available form I represents the thermodynamically most stable modification at room temperature, whereas forms II and III are metastable. On heating, form III transforms into form II in an endothermic reaction, which shows that an enantiotropic relationship exists between these forms. Form I exhibits the highest melting point and the highest heat of fusion and thus represents the thermodynamically most stable form over the whole temperature range. DSC measurements indicate that form I behaves monotropic to forms II and III. Desolvation of the 2-propanol solvate at higher temperatures results in a transformation into form II, whereas the removal of 2-propanol at room temperature and in vacuum reduced pressure leads to the formation of form III. ß 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:4516–4527, 2008

Keywords: hydrocortisone; calorimetry (DSC); cocrystals; crystal structure; crystals; desolvation; polymorphism; pseudopolymorphism; X-ray powder diffractometry; thermogravimetric analysis

INTRODUCTION The term polymorphism describes the ability of a chemical compound to exist in different crystalline modifications, whereas pseudopolymorphism refers to chemical compounds, which include additional solvent molecules like, for example, solvates or generally cocrystals. Both phenomena This article contains supplementary material, available at www.interscience.wiley.com/jpages/0022-3549/suppmat. Correspondence to: Christian Na¨ther (Telephone: 49-431880-2092; Fax: 49-431-880-1520; E-mail: [email protected]) Journal of Pharmaceutical Sciences, Vol. 97, 4516–4527 (2008) ß 2008 Wiley-Liss, Inc. and the American Pharmacists Association

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are of extreme importance in industrial and academic research and are for several reasons of special interest in pharmaceutical development.1–4 For drug sterilization an often used method is sterile filtration. In this procedure, the drug is dissolved in a given solvent, filtered off under pressure and afterwards the solvent is vaporized and the residue micronized. By this procedure different polymorphic forms can be obtained directly or by the decomposition of solvates formed as intermediates. However, in the end it must be guaranteed that only that form is produced, which is used in therapy or which is preferred by the manufacturer. This procedure is used for the sterilization of glucocorticoids which

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belong to the most versatile and effective drugs worldwide. Although these compounds are known for several decades their polymorphism has not been investigated in detail and only a few crystal structures are available in the Cambridge structure database (CSD).5 In view of the importance of polymorphism we have started systematic investigations on the polymorphism of glucocorticoids.6–8 In recent investigations our interests focus on hydrocortisone (Scheme 1), which is one of the most effective antiphlogistic and immune-suppressive drugs and exhibits extremely high anti-inflammatory properties. Hence, it is used for a wide range of different applications in medicine. Recent investigations indicated that hydrocortisone exists in two polymorphic modifications. One form was obtained from ethanol or acetone, whereas the other form was prepared by desolvation of the chloroform solvate.9–11 Microscopic investigations indicate that the form, which was obtained from ethanol, crystallizes monoclinic.9 Haner and Norton reported unit cell parameters for hydrocortisone without giving crystallization conditions.12 They found an orthorhombic crystal ˚ system with a ¼ 12.441, b ¼ 30.496, and c ¼ 10.139 A and from systematic extinctions space group P212121 was determined.12 None of these forms were characterized by single crystal X-ray diffraction. However, the form reported by Haner and Norton corresponds to form I, whose structure is reported in this article. Crystal structures were reported only for the solvates of hydrocortisone with pyridine,13 with methanol,14,15 and of a solid solution of hydrocortisone with iodohydrocortisone.16 Interestingly the unit cell parameters reported for the crystal structure of the solid solution are similar to those of the metastable form III, whose structure is also

Scheme 1. DOI 10.1002/jps

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reported here. Both compounds are isotypic and crystallize in space group P212121. In this context it must be mentioned that Petropavlov and coworkers report on investigations on a metastable form of hydrocortisone.17 However, the reported unit cell parameters are in agreement with those published for the methanol solvate of hydrocortisone.14,15 As mentioned above, no crystal structures of the solvent free forms of hydrocortisone are available and it has not been investigated how many forms actually exist and how these forms are thermodynamically related. In view of this we have investigated hydrocortisone for polymorphism. Here we report on these investigations.

EXPERIMENTAL SECTION Chemicals Hydrocortisone is commercially available and was procured from HPP pharmaceuticals. All solvents used for the crystallization experiments were of analytical grade.

Crystal Growth For the preparation of crystals of form I, a solution of hydrocortisone in methanol and L-glutamine in water was mixed and left aside at room temperature. After 1 day, crystals suitable for single crystal structure analysis were obtained. Crystals of form II were obtained by heating a saturated solution of hydrocortisone in acetonitrile to about 708C. On cooling small crystals suitable for single crystal structure analysis were obtained. For the preparation of crystals of form III, a solution of hydrocortisone in acetone and L-phenylalanine in water was mixed and left aside at room temperature. After 1 day, crystals suitable for single crystal structure analysis were obtained. It must be noted that it is not very clear if the additives are actually responsible for the crystal growth of form I or III. However, after a few days when the solvent is completely evaporated, mixtures of the different forms are obtained, or in some cases the thermodynamically most stable room temperature modification form I is obtained exclusively. Experimental and calculated X-ray powder patterns of all forms are given in the supporting information.

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Crystal Structure Determination All data were measured using a STOE Imaging Plate Diffraction system (IPDS-1). Structure solutions were performed with direct methods using SHELXS-97. The structure refinements were performed against F2 using SHELXL-97. All nonhydrogen atoms were refined using anisotropic displacement parameters. The C–H hydrogen atoms were positioned with idealized geometry (methyl H atoms were allowed to rotate but not to tip) and refined with isotropic displacement parameters (Uiso(C) ¼ 1.2  Ueq(Cmethin/methylene) ¼ 1.5  Ueq(Cmethyl) using a riding model with C–Hmethin ¼ ˚ , C–Hmethylene ¼ 0.99 A ˚ , C–Hmethyl ¼ 0.98 A ˚ 0.95 A for hydrocortisone. The O–H hydrogen atoms were located in difference map but positioned with idealized geometry, and allowed to rotate but not to tip with isotropic displacement parameter using a riding model with O–H ¼ 0.84. Since no heavy elements are present the absolute structure and absolute configuration could not be determined. Therefore, Friedel equivalents were merged and the absolute configuration was assigned based on the known absolute configuration of the starting compound. Details on the structure determination can be found in Table 1. Crystallographic data have been deposited with the Cambridge crystallographic data centre, CCDC 633732 (form I), CCDC 633733 (form II), CCDC 633734 (form III), and CCDC 633731 (2-propanol solvate). Copies may be obtained freeof charge on application to the Director, CCDC, 12 Union Road, Cambridge CB2 1E2, UK (Fax: Int. code þ(44) 01223/3 36-033, e-mail: [email protected]). Details on the X-ray powder diffraction, differential thermoanalysis and thermogravimetry (DTA–TG), DSC, and thermomicroscopic measurements are described previously.6–8

RESULTS AND DISCUSSION Solvent-Mediated Conversion Experiments I Crystalline suspensions of commercially available hydrocortisone were stirred in different solvents for 14 days and the residues thus obtained were characterized by X-ray powder diffraction (see supporting information). The powder pattern of nearly all the residues corresponds to that of the commercial available hydrocortisone (form I). Only in 2-propanol powder patterns were obtained

which are different from that of form I. TG measurements reveal that this form represents a solvate (see below). From these conversion experiments there are no evidences for further solvent free modifications of hydrocortisone and hence, it appears that the commercially available form I represents the thermodynamically most stable form at room temperature. In the following single crystals suitable for X-ray structure analysis were prepared. The crystals obtained from acetonitrile surprisingly do not correspond to that of the commercial form and constitutes a new and hitherto unknown modification of hydrocortisone designated as form II (Fig. 1). In further investigations, attempts were made to prepare cocrystals of hydrocortisone with different organic acids. During the course of these investigations single crystals of the commercial drug (form I) and of a third and hitherto unknown modification (form III) were obtained serendipitously (Fig. 1). The exact role played by the additives for the formation of crystals of forms I and III will be the subject of future investigations. Crystals of the 2-propanol solvate were obtained by slow evaporation of the solvent from a saturated solution.

Crystal Structures Form I crystallizes in the orthorhombic space group P212121 with Z ¼ 8 and two crystallographically independent molecules in the asymmetric unit. In the crystal structures the molecules are connected by intermolecular O–H  O hydrogen bonding between the carbonyl oxygen atoms and the hydrogen atoms of the hydroxyl groups as well as between different hydroxyl groups (Tab. 2 and Fig. 2, top). Both crystallographically independent molecules are connected into dimers via O2–H2  O15 and O12–H12  O5 interactions (Fig. 2, top). From this arrangement rings are formed which can be described as N1 ¼ R22 ð18Þ according to the graph set notation.18 The dimers are further connected by O3–H3  O1 and O13–H13  O11 hydrogen bonds into double chains, which are elongated along the b-axis (Fig. 2, top). By this connection N1 ¼ R44 ð30Þ hydrogen bonded rings are formed and each of the single chain is built up only from one of the two crystallographically independent molecules. The double chains are arranged in layers, which are parallel to the b–c plane (Fig. 2, bottom). The double chains are interconnected into tetrameric chains by

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Table 1. Crystal data and results of the structure refinement for the solvent-free forms I, II, and III as well as for the 2-propanol solvate Data Empirical formula MW/g  mol1 Crystal color Crystal system Space group ˚ a/A ˚ b/A ˚ c/A a/8 b/8 g/8 ˚3 V/A Temperature/8C Z Dcalculated mg  cm3 F(000) 2u-Range/8 H/k/l ranges

m (MoKa)/mm1 Reflections collected Rint. Independent refl. Refl. with F0 > 4s( F0) Refined parameters R1 [F0 > 4s( F0)] wR2 [all data] GooF ˚ 3 Minimum/maximum res./e  A

Form I

Form II

Form III

2-Propanol solvate

C21H30O5 362.45 Colorless Orthorhombic P212121 10.0715(6) 12.4240(7) 30.4408(22) 90.000 90.000 90.000 3809.0(4) 53 8 1.264 1568 4.24–49.78 11  h  11 14  k  12 35  l  35 0.089 19135 0.0515 3693 3116 480 0.0367 0.0888 1.011 0.187/0.168

C21H30O5 362.45 Colorless Monoclinic P21 12.4695(14) 12.4629(9) 12.5701(16) 90.000 103.040(14) 90.000 1903.1(4) 103 4 1.265 784 5.22–50.04 14  h  14 14  k  14 12  l  14 0.089 11258 0.1202 3436 2723 476 0.0680 0.1835 1.056 0.306/0.328

C21H30O5 362.45 Colorless Orthorhombic P212121 6.2232(3) 15.7750(10) 18.8776(11) 90.000 90.000 90.000 1853.2(2) 53 4 1.299 784 5.02–56.18 7  h  8 20  k  20 14  l  25 0.091 11972 0.0540 2479 2122 239 0.0377 0.0883 1.026 0.173/0.159

C21H30O5  C3H7OH 422.54 Colorless Monoclinic P21 13.4947(12) 6.1266(4) 13.6844(11) 90.000 98.146(10) 90.000 1119.96(15) 103 2 1.253 460 6.02 to 55.96 17  h  17 7  k  7 18  l  17 0.088 7864 0.0459 2884 2343 272 0.0410 0.1028 0.987 0.226/0.212

O5–H5  O2 hydrogen bonding and the tetrameric chains are elongated along the b-axis (Fig. 3, top). Form II crystallizes in the monoclinic space group P21 with Z ¼ 4 and two crystallographically independent molecules in the asymmetric unit. The crystal structure is very similar to that of form I (see Fig. 2). As in form I the molecules are connected by intermolecular O–H  O hydrogen bonding into dimers via O2–H2  O15 and O12– H12  O5 interactions. This arrangement leads to N1 ¼ R22 ð18Þ rings which are further connected by O3–H3  O1 and O13–H13  O11 hydrogen bonds into double chains which are elongated along the b-axis (see Fig. 2, top).18 In each of the single chains only one crystallographically independent molecule is involved. The double chains are arranged in layers as in form I (see Fig. 2, bottom) and are connected into tetrameric chains by O5–H5  O2 hydrogen bonding (Fig. 3, bottom). The main difference between the crystal structures of forms I and II is found for the DOI 10.1002/jps

arrangement of the tetrameric chain in the direction of the b-axis. In form I the tetrameric chains are closely packed and interlocked. In the direction of the c-axis the two crystallographically independent molecules are related by a 21-screwaxis and therefore, their orientation changes in this direction, which is not the case for form II (Fig. 3, top). In form II, the tetrameric chains are arranged in layers, which are parallel to the b–c plane (Fig. 3, bottom). Form III crystallizes in the orthorhombic space group P212121 with Z ¼ 4 and one crystallographically independent molecule. Two of the molecules are connected by O–H  O hydrogen bonding (O2–H2  O4 and O5–H5  O2) into dimers, which can be described as N1 ¼ R22 ð16Þ ring according to the graph-set notation (Fig. 4, top and Tab. 3).18 The dimers are further connected by (O2–H2  O4 and O5–H5  O2) hydrogen bonding into columns, which are elongated along the a-axis (Fig. 4, top). These columns are interconnected by

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Solvent-Mediated Conversion Experiments II

Figure 1. Microscopic images of crystals of forms I (A), II (B), III (C), and the 2-propanol solvate (D).

additional O–H  O hydrogen bonding between the carbonyl oxygen atom O1 and the hydroxyl hydrogen atom attached to O3 into a threedimensional hydrogen bonded network (Fig. 4, bottom). The 2-propanol solvate crystallizes in the monoclinic noncentrosymmetric space group P21 with Z ¼ 2 and one crystallographically independent molecule. Some structural features are similar to those in the solvent free form III (compare Figs. 4 and 5). As in form III two molecules are connected by O2–H2  O4 and O5–H5  O2 hydrogen bonding into N1 ¼ R22 ð16Þ dimers, which are stacked into columns that are elongated along the b-axis (Fig. 5, top and Tab. 3).18 The molecules within these columns are interconnected by additional O2–H2  O4 and O5–H5  O2 hydrogen bonding. In contrast to form III the columns are not connected via the carbonyl oxygen atom O1 because this atom is involved in O6–H6  O1 hydrogen bonding to the hydroxyl hydrogen atom of a 2-propanol molecule (Fig. 5, mid). The columns are connected by the solvent molecules via O–H  O hydrogen bonding, in which the hydroxyl oxygen atom of the 2-propanol molecule acts as an acceptor for the hydroxyl hydrogen atom attached to O3 (O3–H3  O6). From this arrangement layers are formed which are parallel to the a–c plane and well separated by the solvent molecules (Fig. 5, bottom).

Crystalline suspensions of forms I and II, forms I and III, and forms II and III were stirred for a week in different solvents like acetone, methyl acetate, dichloromethane, and 1-butanol in order to determine definitely which one of the solvent free forms represents the thermodynamically most stable form at room temperature. The residues thus obtained were characterized by X-ray powder diffraction. The patterns of all residues match with that calculated for form I, clearly indicating that form I must represent the thermodynamically most stable form at room temperature. The same experiments were also performed at 408C and no changes were observed in the order of thermodynamic stability. In further experiments crystalline suspensions of forms II, III, and a mixture of II and III were stirred in acetone, methylacetate, dichlormethane, and acetonitrile and the residues were investigated as a function of time by X-ray powder diffraction, to determine if form II transforms into form III or form III into form II before the thermodynamically most stable modification I is formed. However, forms II and III transform directly into form I and therefore the relative stability of forms II and III at room temperature cannot be estimated. For these experiments pure samples of the metastable forms II and III were prepared by the desolvation of the 2-propanol solvate (see below the thermal investigations of the 2-propanol solvate).

DSC Investigations The thermal properties of all modifications were characterized by measurements using differential scanning calorimetry. All measurements were performed with 3 and 208C/min in order to prove that no decomposition takes place before melting or desolvation. On heating, forms I and II display a single endothermic signal, which corresponds to the melting of each form (Fig. 6, top and mid). If the melt is cooled down to room temperature it is amorphous to X-rays and if the experiment is stopped after the exothermic peak at about 2508C a brown residue is obtained. This is in agreement with DTA–TG measurements, which shows a mass loss at higher temperatures. Additional measurements were performed, which were stopped directly before melting to determine if any polymorphic transition occurred

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˚ , 8) for Table 2. Hydrogen bonding interactions (A forms I and II ˚ )
OH  O Form I O2–H2  O15 O3–H3  O1(A) O5–H5  O2(B) O12–H12  O5 O13–H13  O11(C) Form II O2–H2  O15(D) O3–H3  O1(E) O5–H5  O2(F) O12–H12  O5(G) O13–H13  O11(H)

2.003 2.012 1.940 1.975 2.008

155.48 165.57 172.35 169.38 165.57

2.780 2.823 2.764 2.795 2.820

1.970 2.025 2.001 1.981 1.988

159.23 163.82 164.81 165.76 164.69

2.771 2.841 2.820 2.803 2.807

Symmetry codes: A ¼ x, y  1, z; B ¼ x þ 1, y  1/2, z þ 1/2; C ¼ x, y þ 1, z; D ¼ x þ 1, y, z; E ¼ x, y  1, z; F ¼ x þ 2, y1/2, z þ 1; G ¼ x  1, y, z; H ¼ x, y þ 1, z.

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before melting. The powder pattern of the residues is identical to those of the starting materials, which prove that no phase transformation occurred before melting. The DSC thermogram of form III exhibits two endothermic peaks at 187 and 2238C. The second signal is very intense and corresponds to the melting point of the solid, while the first peak is very broad and low in intensity, indicating a polymorphic phase transition (Fig. 6, bottom and Tab. 4). The residue isolated after melting is amorphous to X-rays. To check if a polymorphic phase transition occurs, a second DSC measurement was performed, in which the heating was stopped after the first signal at 1908C. The powder pattern of the residue corresponds to that of form II clearly indicating that form III transforms into form II on heating (Fig. 7). Therefore, the melting point of form III cannot be determined.

Figure 2. Crystal structure of form I with labeling (top) and with view along the c-axis (bottom). Hydrogen bonding is shown as dashed lines (note: the crystal structure of form II looks identical in these directions). DOI 10.1002/jps

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Figure 3. Crystal structure of forms I (top) and II (bottom) with view along the b-axis. Hydrogen bonding is shown as dashed lines.

From the DSC measurements it is evident that form III transforms into form II in an endothermic reaction (Tab. 4). Thus, it can be proposed that above the transition temperature (form III ! form II) form II is thermodynamically more stable than form III and that between both forms II and III an enantiotropic relationship exists. As form III always transforms into form II, the melting point of form III cannot be determined. Because form III is thermodynamically less stable than form II at higher temperatures its melting point is expected to be lower than that of form II. In all measurements no polymorphic transformation of form II or III into form I is observed.

Investigations on the Desolvation of the 2-Propanol Solvate The 2-propanol solvate was investigated by DTA– TG. The solvate displays two mass loss steps in its TG curve, both of which are accompanied with endothermic signals in the DTA curve (Fig. 8). The first TG step corresponds to the desolvation,

whereas the second TG signal corresponds to the vaporization and decomposition of the solvent free modification formed as an intermediate. The experimental mass loss of 13.5% is in good agreement with that calculated for the removal of 2-propanol (Dmcalc ¼ 14.2%). The X-ray powder pattern of the residue formed after the first TG step corresponds to form II, clearly indicating that this modification is formed on the loss of 2-propanol (Fig. 9). The desolvation of the 2-propanol solvate was also investigated at room temperature under a reduced pressure of 4  103 mbar. This experiment clearly shows that under these conditions form III is obtained as a pure phase (Fig. 10). As mentioned earlier, the crystal structures of form III and the 2-propanol solvate are very similar (compare Figs. 4 and 5). Both structures are built up of columns in which the molecules are connected by hydrogen bonding. In the solvate these columns are separated by the 2-propanol molecules, while they are interconnected by additional hydrogen bonding in form III. If the solvent is removed from the solvate only small translational and rotational movements are needed to transform it into form

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Figure 4. Crystal structure of form III with labeling (top) and with view along the a-axis (bottom). Hydrogen bonding is shown as dashed lines.

III. Thus, a smooth reaction pathway can be found for this transformation.

Thermomicroscopy Thermomicroscopic measurements of all three forms were performed to conclusively show that form I exhibits the highest melting point and that form III transforms into form II and will show the same melting point as observed if form II is heated directly. In this experiment the same crystals, which were initially checked by single crystal X-ray diffraction, were used, to be absolutely sure of the identity of each form. All modifications were heated simultaneously in a thermomicroscope. This experiment clearly shows that the polymorphic transformation of form III, which commences at 1908C is complete at 2008C (Fig. 11). Interestingly at about 2108C it appears that a new crystalline phase has formed at the surface of the crystal of form I, showing indications for a polymorphic transformation at higher temperatures. On further heating forms II and III start to melt at 2208C, which is complete at 2228C DOI 10.1002/jps

Figure 5. Crystal structure of the 2-propanol solvate with labeling (top) and with view along the b-axis (mid) and c-axis (bottom). Hydrogen bonding is shown as dashed lines.

(Fig. 11). In this experiment the melting of form I starts at 2268C and is complete at 2288C.

Thermodynamic Aspects Our experiments clearly show that form I represents the thermodynamically most stable form at room temperature, whereas forms II and III are metastable. The melting point of form III cannot be determined, because a transformation of form III into form II occurs below the melting

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2.064 2.041 1.961 2.000

163.11 169.16 173.71 164.61

2.850 2.843 2.764 2.793

Symmetry codes: A ¼ x þ 1/2, y þ 3/2, z þ 1; B ¼ x þ 1/2, y þ 3/2, z þ 1; C ¼ x þ 3/2, y þ 1, z þ 1/2; D ¼ x þ 1, y þ 1/2, z; E ¼ x þ 1, y  1/2, z þ 1.

temperature of form II. Since form III is less stable than form II at high temperatures its melting point must be lower. Form I exhibits the highest heat of fusion and the highest melting point. Following the heat of fusion rule or the entropy of fusion rule form I is the thermodynamically most stable form in the whole temperature range and monotropically related to forms II and III. Although the heat of fusion of form III cannot be determined directly, it must be lower than that

Figure 6. DSC curves for forms I (top), II (mid), and III (bottom) (To ¼ extrapolated onset temperature and Tp ¼ peak temperature; DfusH and DtrsH are given in Tab. 4). JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 10, OCTOBER 2008

220.2 0.3 (493.4 0.3) 222.9 0.2 (496.01 0.2) 223.9 0.3 (497.0 0.3) 40.8 0.4 — 82.69 0.8 —

2.773 2.930 2.864

183 0.2 (456.2 0.2) 186.4 0.2 (459.6 0.2) 191.8 0.3 (465.0 0.3) — 1.1 0.1 — 2.41 0.3

171.97 162.00 174.55

218.9 0.4 (492.1 0.4) 221.6 0.4 (494.8 0.4) 224.2 0.5 (497.35 0.5) 41.25 0.25 — 83.82 0.7 —

1.949 2.130 2.037

221.6 0.3 (494.8 0.3) 224.5 0.5 (497.7 0.5) 225.9 0.3 (499.1 0.3) 44.65 0.4 — 90.23 0.8 —

˚) O  O (A

To/8C (K) Tp/8C (K) Te/8C (K) DfusH/kJmol1 DtrsH/kJmol1 DfusS/Jmol1 K1 DtrsS/Jmol1 K1


Form III (III ! II)

Form III O2–H2  O4(A) O5–H5  O2(B) O3–H3  O1(C) 2–Propanol solvate O2–H2  O4(D) O5–H5  O2(D) O3–H3  O6 O6–H6  O1(E)

˚) H  O (A

Form II

OH  O

Form I

˚ , 8) for Table 3. Hydrogen bonding interactions (A form III and the 2-propanol solvate

Form II

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Table 4. Selected results of the DSC measurements (the average of at least three different measurements is given; To ¼ extrapolated onset temperature; Tp ¼ peak temperature; Te ¼ extrapolated end temperature; for form III the values for the transformation of III into II and the values for the transformation product (form II) are given)

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Figure 7. X-ray powder pattern of the residue isolated at 1908C in the DSC experiment of form III (top) and calculated powder pattern for form II (bottom).

Figure 9. X-ray powder pattern of the residue isolated directly after the first TG step in the thermogravimetric experiment of the 2-propanol solvate (top) and calculated powder pattern for form II (bottom).

of form I, because DfusH (II) þ DtrsH (III ! II) is lower than DfusH (I). From the lower melting points and the lower enthalpies of fusion it is evident that forms II and III are thermodynamically less stable than form I in the whole temperature range. Furthermore, form III shows an endothermic transformation to form II on heating and in accordance with the heat of

transition rule it can be concluded that these forms are enantiotropically related which means that form III is thermodynamically more stable than form II at lower temperatures, whereas at higher temperatures above the transition point form II is more stable. From the thermochemical results a semi-schematic energy temperature diagram can be drawn that displays the thermodynamic relationship between forms I, II, and III (Fig. 12).19,20 However, the results clearly show that form III is less stable than form I in the whole temperature range, which represents an

Figure 8. DTA–TG curves for the 2-propanol solvate (Tp ¼ peak temperature). DOI 10.1002/jps

Figure 10. Calculated X-ray powder pattern for the 2-propanol solvate (1) and III (4) as well as experimental X-ray powder pattern of the 2-propanol solvate (2) and of the residue after the removal of 2-propanol from the solvate under reduced pressure at room temperature (3).

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Figure 11. Results of the thermomicroscopic experiments on forms I (left), II (mid), and III (right) (heating rate 28C/min).

exception to the density rule. Such exceptions are known, and may especially occur when hydrogen bonding is a dominant interaction force in the crystal structure. In this context it should be pointed out that due to kinetic reasons the observed solid–solid transition temperature of form III to form II at 1838C in the DSC measurements must be higher than the true thermodynamic transition point. Though the two forms are enantiotropically related, the back-transformation to III on cooling cannot be observed. This indicates the high kinetic stability of form II which is assumably the least stable form at room temperature. Note that the 2-propanol solvate transforms to pure form II on thermal desolvation (DSC) or when stored at 508C for 30 days, but form III is obtained when the solvent is removed under reduced pressure at room temperature. These results indicate that modification III is formed by kinetic control. From this observation it appears that the true transition point is lower than 508C. In view of the above it is likely that the kinetics strongly governs the phase transition behavior of these polymorphs. Anyway, from the structural similarity one may expect that form III is the favored product when the solvent is removed from the solvate.

CONCLUSIONS

Figure 12. Semi-empirical energy temperature diagram of hydrocortisone forms I, II, and III. Tfus, melting point; G, Gibbs free energy; H, enthalpy; DfusH, enthalpy of fusion; Ttrs, transition point; DtrsH, transition enthalpy; liq, liquid phase (melt). The bold vertical arrows sign the experimentally measured enthalpies.

In the present work we have shown that hydrocortisone exists in three different polymorphic modifications. Form I was found to be the thermodynamically most stable form over the whole temperature range, whereas forms II and III are metastable. The metastable form III can be prepared by the desolvation of the 2-propanol solvate at reduced pressure at room temperature, which can be explained based on a careful analysis of both crystal structures. In this case, it is obvious that the structure of form III is preorganized in the solvate. However, when the same reaction is performed at elevated temperatures in a thermobalance, form II is obtained, which can also be prepared by a polymorphic transformation of form III into II at higher temperatures. These results clearly show the importance of investigations of the desolvation of solvated forms under different conditions. For the preparation of drugs by sterile filtration this knowledge is essential for the selection of the appropriate solvents and to find the conditions for the transformation of a solvate into a special polymorphic modification.

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 10, OCTOBER 2008

DOI 10.1002/jps

TRIMORPHISM OF HYDROCORTISONE

ACKNOWLEDGMENTS We thank Prof. Dr. Wolfgang Bensch for access to his equipment and the State of SchleswigHolstein for financial support. We thank Ulrich Griesser from the Institute of Pharmacy at the University of Innsbruck for helpful discussions concerning the relation of all forms.

11. 12.

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