DOI: 10.1021/cg100165t
Published as part of a virtual special issue of selected papers presented in celebration of the 40th Anniversary Conference of the British Association for Crystal Growth (BACG), which was held at Wills Hall, Bristol, UK, September 6-8, 2009.
2010, Vol. 10 3879–3886
Solid State Forms of Theophylline: Presenting a New Anhydrous Polymorph Linda Seton,* Dikshitkumar Khamar, Ian J. Bradshaw, and Gillian A. Hutcheon School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Byrom Street, Liverpool L3 3AF, U.K. Received February 2, 2010; Revised Manuscript Received July 7, 2010
ABSTRACT: A previously unreported anhydrous polymorph (Form IV) of theophylline has been crystallized and characterized. Solubility determination, crystallization, and equilibration experiments indicated that Form IV is the most thermodynamically stable anhydrous polymorph. The hydration behavior of theophylline was investigated by three different methods: solubility, crystallization, and slurry experiments. The value of water activity at which the monohydrate form of theophylline becomes the most thermodynamically stable was investigated, and these results help to explain differences reported in the literature. Using solvent mixtures with a range of water activity values, it was demonstrated that the monohydrate, Form M, is produced from mixtures with aw g 0.70 at 25 °C.
*To whom correspondence should be addressed. E-mail: L.Seton@ ljmu.ac.uk. Telephone: þ44 (0) 151 231 2049. Fax: þ44 (0) 0151 231 2170.
material will transform from hydrate to anhydrate depending on the water activity of the solvent environment.10,11 Zhu et al.10 determined that the anhydrous form is most stable in solvent mixtures with aw > 0.25 at 25 °C, and Ticehurst et al.11 determined the value to be 0.64 at 30 °C. Neither study considered the different solid forms of anhydrous theophylline. This paper seeks to present a clear understanding of the influence of water activity on the conversion between the monohydrate and anhydrous forms. Theophylline monohydrate, which will be referred to as Form M, is a monoclinic channel hydrate. The structure was first reported by Sutor in 1958.12 However, the structure by Sun et al. in 2002 presented different positions for the water molecules and is considered to be the correct structure (Figure 1a).7 The space group is P21/n, and the unit cell is a = 4.468 A˚, b = 15.355 A˚, c = 13.121 A˚, β = 97.792°, Z = 4. The theophylline molecules hydrogen bond to form dimers, and water molecules form parallel chains which are crosslinked to the dimers by hydrogen bonding to create layers. Its PXRD pattern can be seen in Figure 2a. Of the three anhydrous forms, I, II, and III reported, the structure of Form II is known.14 Form II is produced by dehydration of the monohydrate15,16 and has an orthorhombic structure (Figure 1b) with space group Pna21. Unlike the dimers in theophylline monohydrate, the packing in the anhydrous structure exhibits hydrogen bonding between N-H 3 3 3 N and two bifurcated hydrogen bonds between C-H 3 3 3 O, forming a bilayer structure. Otsuka et al.16 generated Form I by evaporating a saturated, aqueous solution of theophylline at a temperature of 95 °C over a period of 24 h. The authors presented high quality PXRD patterns of each of the anhydrous forms (Form I and Form II) that had the same peak positions but with
r 2010 American Chemical Society
Published on Web 08/03/2010
Introduction Theophylline is a bronchodilator used to treat asthma. It is known to form cocrystals,1,2 and there have been many studies of its hydration behavior.3-6 Theophylline is known to exist as a crystalline monohydrate,7 and three anhydrous polymorphs have been reported in the literature.8 There has been much interest in the hydration-dehydration behavior of theophylline, and many studies have investigated the processes involved and the influence of environment and conditions on solid state conversion. Despite this, there has been little investigative work into the solid forms of theophylline, and many authors describe anhydrous theophylline, without alluding to which form is present.3-5,9 Further, there is some confusion within the literature, regarding the nature and existence of different anhydrate forms. The hydration behavior of organic compounds was first studied by Shefter and Higuchi in 1963.6 It is known that there is a solubility change associated with the formation of hydrates that leads to changes in dissolution rate and stability of the solid form, which in the case of drug materials can alter bioavailability. The solvent mediated transformation of anhydrate to hydrate can be influenced by factors such as agitation, relative humidity, and water activity. Water activity (aw) is a function of the chemical potential of a solvent and its value depends upon relative humidity, vapor pressure, and solvent composition. It has been previously shown that the equilibrium solid form of theophylline is dependent on the value of the water activity of solvent mixtures in contact with the solid and that
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Figure 1. Crystal packing of published structures of theophylline generated using Mercury:13 (a) Form M;7 (b) Form II.14.
Figure 2. PXRD patterns of (a) Form M and (b) Form I and II.
characteristic patterns of intensities of the three peaks at 7.22°, 12.7°, and 14.4° 2θ. The patterns of intensities are consistent: Form I shows peaks 1 and 3 with high intensity, and Form II shows peak 2 with high intensity, as seen in Figure 2b. Suzuki et al.15 described the isolation of Form I by heating Form II in a glass vial, and they presented PXRD patterns for Forms I, II, and, M. The pattern for Form II agreed with that presented by Otsuka et al.16 and the pattern predicted from the published structure. The pattern for Form I was slightly different from that presented by Otsuka et al., with four peaks between 10 and 15° 2θ; the resolution of the traces was low. The observed differences in intensity between the PXRD patterns of Forms I and II could be due to preferred orientation effects,
since the peaks with high intensity correspond to (200) and (400). The structure of Form I has not been determined, and so it is not clear whether Forms I and II are structurally different. Smith et al. carried out structural prediction calculations of theophylline and, as well as the published structure, predicted a second structure with the same unit cell but a different hydrogen bonding motif and packing arrangement.17 This structure has not been observed experimentally and could be the structure of Form I. There is evidence for a metastable anhydrous form (hereafter known as Form III) which is produced by dehydration of Form M under low pressure or vacuum conditions.8,9,18 The existence of this form was first suggested by
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Figure 3. FTIR spectra: (a) Forms M and II; (b) Forms I and II.
Phadnis and Suryanrayanan in 1997.9 Theophylline monohydrate was dehydrated under a range of conditions, and a new anhydrate form (which they called I* and later N*) was observed which converted readily to Form II. Several studies have subsequently observed this form, but only under low pressure conditions or during high temperature PXRD.8,9,18,19 The PXRD has been presented,8,18 but due to the metastable nature, the structure has not been determined. Method Generation of Anhydrous Forms. Anhydrous theophylline (Form II) was obtained from Sigma-Aldrich (Gillingham, Dorset, U.K.) and used as received. Anhydrous Form I was prepared from a saturated aqueous solution of theophylline by evaporating to dryness at 100 °C. Both anhydrous forms were stored in a desiccator under an environment of anhydrous silica (90% RH at room temperature. Cooling crystallization experiments from methanol, ethanol, acetonitrile, acetone, tetrahydrofuran, and dimethyl sulfoxide were performed to inspect the resultant anhydrous form. Solubility Determination. An excess amount of Form II (≈4 g) was added rapidly to 200 mL of water in a jacketed, circulating flask maintained at 25 °C. The suspension was agitated at constant speed. Samples were withdrawn at every 20-30 s, for the first 5-7 min, and then at longer time intervals over several hours. After filtering through a syringe filter of 0.45 μm size, the concentration was determined by measuring the ultraviolet (UV) absorption at 272 nm using a Thermoscientific Genesys 10 UV spectrophotometer. The solubility of theophylline in methanol at 35 °C was also measured. An excess amount (≈3 g) of theophylline was added rapidly to 200 mL of methanol, maintained at 35 °C. The flask was covered to prevent evaporation of methanol. Samples were taken at
regular intervals, and the concentration was determined gravimetrically. Two milliliters of solution was decanted into a preweighed bottle and dried to constant weight at 50 °C. Determination of the Hydration Profile. The solution mediated transformation of anhydrous forms to the monohydrate was investigated by three different methods to determine the value of water activity, aw, at which anhydrous theophylline converts to the hydrate, Form M. A range of mole fractions of water/methanol and water/2-propanol were prepared (e.g., aw = 0.1, 0.2, 0.3, ..., 0.9), and aw was assigned for each composition using the method described by Zhu et al.10 Slurrying Experiments. To 10 g of each solvent mixture, an excess amount (≈500 mg) of anhydrous Form II was added and agitated at 600 rotations per minute. The solid material was recovered and characterized after 7, 15, and 30 days. This was repeated using Form I as starting material. When the solvent was 100% methanol, material was recovered and characterized each day for 7 days. Crystallization Experiments. Saturated solutions of theophylline were prepared at 50 °C in each of the solvent mixtures. The solutions were filtered immediately with syringe filters (0.45 μm) and cooled to 25 °C, at which temperature crystallization occurred. Solubility Experiments. Theophylline Form II (≈4-5 g) was added to 200 g of solvent at 25 °C and agitated in a covered, jacketed beaker. Samples were withdrawn at regular time intervals up to 24 h, and the concentrations were determined gravimetrically. Sample Characterization. Samples were characterized using optical microscopy, scanning electron microscopy (SEM), powder X-ray diffraction, differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA), and Fourier transform infrared spectroscopy (FTIR). Microscopy. Crystals were observed using an Olympus BH-2 optical microscope fitted with a JVC digital camera (TK-C1381) and a scanning electron microscopic (JSM Jeol 840 SEM) instrument fitted with a Rontec’s image capture system. Powder X-ray diffraction (PXRD). Patterns were obtained using a Rigaku Miniflex X-ray diffractometer. Samples were finely ground,
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Figure 4. Optical and scanning electron microscopy images of different anhydrous forms of theophylline: (a and b) Form I; (c and d) Form II; (e-h) Form IV. and patterns were collected between 5° and 50° 2θ, at increments of 0.02° 2θ, scanning speed 2° min-1, a voltage of 30 kV, and a current of 15 mA using Cu KR (1.54 A˚) radiation. Fourier Transform Infrared Spectroscopy (FTIR). FTIR spectra were collected using a Perkin-Elmer Spectrum BX spectrometer fitted with a PIKE Technologies mIRacle sampling accessory and using spectrum version 5.0.1 for operation. The samples were scanned between 4000 cm-1 and 600 cm-1. Thermal Analysis. DSC data was collected using a Perkin-Elmer Pyris 1 differential scanning calorimeter (DSC). 4-7 mg of sample was placed into a hermetically sealed and crimped pan and scanned at different heating rates (10, 5, 2, and 1 °C min-1) under nitrogen purge. Thermogravimetric analysis (TGA) was carried out using a Thermo Analytical TGA 2050. 15-20 mg of sample was placed in an open pan and heated at 10 °C min-1.
Results and Discussion Characterization of Theophylline Crystal Forms. Crystallization of theophylline from water generated the monohydrate, Form M, which was characterized by its PXRD pattern (Figure 2a) and by the presence of an endotherm at 60-85 °C in the DSC trace due to loss of water. A 9.1% weight loss was observed by TGA, which corresponds to the theoretical weight loss of theophylline monohydrate. The FTIR pattern, shown in Figure 3a, shows a broad peak at 3341 cm-1, which is assigned to the OH of the water molecules. This peak is absent in the FTIR of all the anhydrous forms. The major difference in the IR upon dehydration is seen in the region 40002800 cm-1, shown in Figure 3a. The hydrogen bonded O-H stretch due to the presence of water in the crystalline lattice of Form M can be seen at 3341 cm-1, which is not present in any of the anhydrous samples. The stretch at 2908 cm-1 represents the O-H stretch when the O-H group is involved in a hydrogen bond as in the monohydrate due to dimer formation. The full FTIR patterns of Forms I, II, and IV are available in the Supporting Information.
The PXRD patterns of anhydrous Forms I and II are shown in Figure 2b. They are in agreement with those presented by Otsuka et al.,16 showing the same peak positions and patterns of intensities. The FTIR spectra of Forms I and II, shown in Figure 3b, are indistinguishable and shown here for the region 4000-1800 cm-1. All of the main peaks corresponding to different functional groups remained the same for the two anhydrous samples. No weight loss was observed by TGA, nor was an endotherm corresponding to water loss observed by DSC. The onset of melting observed by DSC was 271-273 °C for both forms. Optical microscope and SEM images of Form I and II are shown in Figure 4. Form I consistently shows a flat, platy morphology, although the shape of the plates can vary between elongated and hexagonal, dependent on solvent. Unlike Form I, Form II crystals are translucent rather than transparent and have a columnar habit. No solid-state transition was observed in Form I and Form II samples kept in a desiccator with anhydrous silica. Slurrying of excess solid in methanol, with either Form I or Form II as starting material, generated a solid form with a hexagonal morphology. The microscopic images and PXRD pattern of this form are shown in Figures 4e-h and 5. The FTIR patterns of Forms I and II are the same (Figure 6); however, it can be seen that the PXRD pattern and the FTIR spectrum of Form IV, shown in Figures 5 and 6, respectively, do not match those of either of the known forms. DSC and TGA did not show any water loss, and therefore, this is considered to be a fourth anhydrous polymorph and will henceforth be referred to as Form IV. Determination of Hydration Profile. Slurrying Experiments. When excess solid was stirred in mixtures of methanol and water, solution mediated phase transitions occurred which were dependent on the water activity of the mixture. In mixtures with aw g 0.69, both Forms I and II converted to
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Figure 5. PXRD pattern of Form IV generated by slurrying Form II in methanol. The powder pattern of Form II is also shown.
Figure 7. Slurrying of Form II in methanol; the change of morphology indicates phase transformation.
Figure 6. FTIR spectrum of Forms II and IV.
Form M. In mixtures with aw e 0.68, both Forms I and II converted to Form IV after around 4 days, as illustrated in Figure 7. Due to continuous agitation during the slurry equilibration method, the crystal size of Form IV was observed to be smaller than when there was no stirring . When water/2-propanol mixtures were used, Form M was obtained when aw g 0.69, and when aw e 0.68, anhydrous material was produced. Up to 14 days, the outcome was inconsistent, with both Forms I and IV being observed. However, when the experiment was repeated with a 30-day time interval, Form IV only was observed. This suggests that the conversion of Form I to Form IV takes longer than in the methanol/water system. Cooling Crystallization. Cooling crystallization from DMSO produced a solvate, as has been reported previously.20 Cooling crystallization from the other organic solvents (acetone, acetonitrile, methanol, ethanol, tetrahydrofuran) resulted in anhydrous Form I. There were variations in crystal
morphology indicating different interactions at the solidsolution interface, but the PXRD pattern of all products agreed with that presented by Otsuka et al.16 for Form I. No solvent loss was observed by either DSC or TGA, and the onset of melting observed by DSC was 272 ( 1 °C. DSC patterns of all forms are available as Supporting Information. Cooling crystallization of theophylline from methanol/ water and 2-propanol/water mixtures produced Form M when aw g 0.66 and Form I when aw e 0.65. When the product was left in its crystallizing liquor for a period of several months, those samples grown from solvent mixtures with a high organic content were observed to convert to Form IV. Solubility Experiments. The dissolution behavior of Forms I, II, and IV in water was investigated, and results are shown in Figure 8a. As stated by Shefter and Higuchi, the maximum concentration measured in solution was taken to be the solubility of the anhydrous form.6 In all cases, the anhydrous forms were converted into Form M, and so a drop in solubility was observed, until after ≈10 min the measured concentration was equal to the solubility of Form M in water. The rapid conversion of the anhydrous material to Form M when added to water reduces the accuracy of the maximum concentration measurement, as the concentration continually changes until equilibrium is reached. There was no phase conversion observed when the anhydrous forms were dissolved in methanol, so equilibrium solubility was established easily and the relative solubilities could be determined accurately, as displayed in Figure 8b. The order of solubility in methanol was observed to be Form II > Form I > Form IV > M, in agreement with the data for water. The solubility behavior of theophylline in organic-aqueous mixtures when aw g 0.69 was similar to that of theophylline in water, with a similar decrease in concentration due to hydrate formation observed (Figure 9). When aw e 0.68, no initial conversion was seen, and excess solid was identified by PXRD as anhydrous Form II after 30 h. The hydration profile in solvent and water mixtures clearly showed a relationship between the organic content and the time taken for hydrate formation, as this increased with increasing organic content. In 100% water, anhydrous material was transformed to Form M within a few minutes (≈10 min), whereas when aw = 0.7, the
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Figure 8. Solubility of different solid forms of theophylline (a) in water at 25 °C and (b) in methanol at 35 °C.
Figure 9. Hydration behavior of theophylline relative to water activity: (a) water/methanol mixtures; (b) water/2-propanol mixtures.
conversion took more than 10 h. This shows that when aw was near to the value at which the equilibrium form changes, the system takes longer to reach equilibrium, and the accuracy of the measured solubility could be highly dependent on the time of sample withdrawal. Results in this study verify that the equilibrium solid phase when in contact with solvent is dependent on the water activity and that the value at which the equilibrium form changes, determined by three different experimental methods, is in the region 0.65-0.70, with slurries higher than this value converting to Form M and slurries lower than this value converting to Form IV, given enough time. According to Ostwald’s Rule,21 Form I and/or II may be observed before conversion to the stable form, Form IV. Results from the slurrying of excess solid, cooling crystallization, and solubility determination all confirm this value, which agrees reasonably with that determined by Ticehurst et al.,11 who reported that Form M is the stable form when aw g 0.64 at 30 °C. The slight variation in the observed values of the water activity threshold could be due to a number of factors. The slightest change of temperature during sample withdrawal
affects the vapor pressure of water above the solvent mixture, which could lead to a change in the water activity value.11 Besides temperature related vapor pressure fluctuations, the amount of theophylline in the solvent mixture also affects the chemical potential of water and in turn will reduce the relative humidity. Zhu et al.10 showed a 6% change in the water activity due to the presence of theophylline in the solvent mixtures. Dette and Ulrich determined aw by different methods and suggested that accuracy varies for different methods.22 Zhu et al.10 reported that when aw g 0.25, Form M is the stable form and, when aw e 0.25, anhydrous forms are more stable at 25 °C. The hydration profile of the anhydrous forms is displayed in Figure 9 and clearly shows that conversion does not occur at the aw value reported by Zhu et al. It is highly possible that some of their samples were Form IV, and the PXRD pattern could have been interpreted as the monohydrate form or a mixture of monohydrate and anhydrous forms. In this study, mixtures of monohydrate and anhydrous forms were never observed; whenever there was sufficient water present, the whole sample converted to Form M.
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Figure 10. DSC thermograph of (1) monohydrate produced by stirring in methanol/water mixtures and (2) its dehydrated form, produced by heating the monohydrate in part 1 in an oven.
Dehydration of Monohydrate. The DSC profiles of Forms I, II, IV, and M show one melting endotherm with an onset of 272 ( 1 °C . Even at different heating rates (1, 2, 5, and 10 °C min-1) and in various pan types (hermetically sealed, semisealed), a single melting endotherm was observed. Form M showed an endotherm at 60-85 °C which corresponds to water loss. Slurrying experiments of Form I or Form II in methanol/water mixtures produced Form IV or Form M depending on the value of aw. Interestingly, the monohydrate form generated by this method showed a different thermal profile. The endotherm at 60-85 °C associated with water loss was the same, but a melting peak at 271.7 ( 1 °C was followed by a recrystallization exotherm and a second melting peak at 277.3 ( 0.5 °C (Figure 10). When the monohydrate sample produced by stirring in methanol/water mixtures was dehydrated in an oven at 120 °C for 1 h, it generated anhydrous Form II, as identified by PXRD. This dehydrated Form II also showed a melting peak at 272.8 °C, followed by a recrystallization endotherm and a second melting peak at 277.6 °C (Figure 10). Form M generated by other methods showed water loss and a single melting peak with an onset of 272 ( 1 °C. PXRD patterns were indistinguishable. None of the other anhydrous samples or freshly grown Form M from water has demonstrated this double melting peak during the course of the study, and the reason for this anomalous DSC pattern in some samples is not clear. Susuki et al.15 reported different melting temperatures for Forms I and II (273 and 269 °C, respectively) and also a separated melting peak that was attributed to a polymorphic phase transition. Legendre and Randzio23 carried out an investigation of the enantiotropic behavior of Forms I and II using a differential scanning transitiometer, and they reported a phase conversion of Form II to Form I on heating. In addition, one of their samples (Form II), which had been stored in air for several days showed a similar double melting, for which an explanation was not offered.
Figure 11. Observed interconversion of solid forms of theophylline. F represents free energy.
It is possible that the solvent mediated phase conversion which takes place in the solvent mixture leads to the presence of a metastable anhydrous form, which during differential calorimetry melts and recrystallizes as another form, which then melts. More detailed thermal studies are planned to investigate this behavior. Suzuki et al. proposed an enantiotropic relationship between Forms I and II, with Form II the most stable anhydrous form at room temperature and Form I stable at high temperatures.15 This was based on thermal studies and was not investigated by experimental means, such as solubility. The Form I pattern presented was of low resolution and does not appear to match with that of Otsuka et al.16 and the current work. Stability and Interconversion of Different Forms. The solubility order of anhydrous theophylline in methanol was observed to be Form II > Form I > Form IV (see Figure 8), indicating that Form IV is the most stable of the anhydrous forms, and Forms I and II are metastable. Both Forms I and
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II were observed to undergo solvent mediated phase transition into Form IV, if allowed enough time in contact with solution. This was true both for samples generated by crystallization and for excess solid stirred in contact with solution. This indicates that the system is following Ostwald’s Rule21 and that Form IV is the most stable anhydrous form. All three anhydrous forms (Forms I, II, and IV) were found to be kinetically stable at room temperature. No solid state transition of any anhydrous form was observed when stored in a desiccator with anhydrous silica. The chart shown in Figure 11 summarizes the conversions between forms observed during the study. The hydration profile of theophylline solid forms has been investigated, and the water activity value at which the monohydrate, Form M, becomes the equilibrium solid form is 0.65-0.7, in agreement with the study by Ticehurst et al.11 The most stable anhydrous form of theophylline is the previously unreported Form IV, to which other forms convert via a solution mediated transformation over a period of between 2 and 30 days. The crystal structure of Form IV is currently under investigation. Detailed thermal studies are planned to further understand the relationship between Forms I and II and to explain the unusual DSC patterns observed from monohydrate samples obtained by slurrying. Acknowledgment. D.K. wishes to acknowledge the School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, for funding. Supporting Information Available: PXRD pattern of Form IV with peak positions, d values, intensities; FTIR spectra of Forms I, II, and IV; and differential scanning calorimetry (DSC) patterns of anhydrous theophylline Forms I, II, IV, and M. This information is available free of charge via the Internet at http://pubs.acs.org/.
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