Solid State Transformations Mediated by a Kinetically Stable Form

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Solid State Transformations Mediated by a Kinetically Stable Form Published as part of a virtual special issue of selected papers presented at the 2010 Annual Conference of the British Association for Crystal Growth (BACG), Manchester, U.K., September 5 7, 2010 Dikshitkumar Khamar, Ian J. Bradshaw, Gillian A. Hutcheon, and Linda Seton* School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Byrom Street Liverpool L3 3AF, U.K.

bS Supporting Information ABSTRACT: The anhydrous forms of theophylline and the stability relationships with the monohydrate, Form M, are characterized. Form II, kinetically stable at room temperature and considered as the most stable form during the 70-year history of theophylline usage, is observed to act as an intermediary for conversions between other forms. Form IV, the thermodynamically stable form at room temperature, is shown to be enantiotropically related to Form II and undergoes a solid state transition on heating. The enantiotropic relationship between Forms II and I was investigated, and it was established that a Form II to I transition is observed only in samples generated using specific methods. Form III was found to be a high energy solid form which can only be generated by dehydration of the hydrate. Upon heating, Form III shows an exothermic transition to Form II. Upon rehydration, Form III is extremely hygroscopic and converts initially to Form II and then to Form M. The complexity of anhydrate hydrate relationships is illustrated, and the influence of sample history on batch purity is shown, which in turn may influence solid form transformations.

’ INTRODUCTION Theophylline has been used as a bronchodilator in the treatment of chronic obstructive pulmonary disease (COPD) for over 70 years. Recently, it has been shown that theophylline acts as an anti-inflammatory in patients with asthma and may reverse steroid resistance associated with the treatment of asthma.1 The solid state of theophylline has been extensively studied, and the material is used as a model compound to study hydration, dehydration kinetics, and a number of other aspects of pharmaceutical processing using various analytical techniques.2 7 Theophylline exists as a crystalline monohydrate form or in anhydrous form depending on the storage conditions.5,7 The existence of two anhydrous modifications has been reported in the literature from as early as 1943.8 Form II is commonly obtained at room temperature and has historically been considered to be the stable form; Form I has been reported as stable at higher temperatures.9 Different research groups have reported the generation of Form I by different methods and its identity has been unclear. Until recently, the crystal structures for Form II and monohydrate only were available.10,11 In addition, a number of research groups have documented the existence of a highly metastable form, Form III.12 14 In earlier work, we reported a new, anhydrous polymorph (Form IV) of theophylline and also demonstrated it to be more thermodynamically stable than Form II at room temperature.15,16 The crystal structures for Form IV16 and Form I have now been determined, and these unequivocally cleared the confusion about the identity of Form I.17 r 2011 American Chemical Society

The crystalline packing features of different solid forms of theophylline are shown in Figure 1. Theophylline contains both hydrogen bond donors (imidazole N H and C H) and hydrogen bond acceptors (two carbonyl groups and basic nitrogen). Both Form I and II exhibit orthorhombic structures. The packing of Form II is characterized by N H----N hydrogen bonding and two bifurcated C H----O hydrogen bonds. This arrangement in Form II involves the best donor (the N H) and the best acceptor (basic nitrogen) groups in the theophylline molecule.18 However, in Form I, the network is composed of N H----O hydrogen bonding which forms extended two-dimensional sheets, linked together by short contacts involving the basic nitrogen, C H----N. The monohydrate, Form M, is a monoclinic channel hydrate in which theophylline molecules form dimers. Form IV crystallizes in a monoclinic space group and its crystal structure consists of dimers of theophylline molecules similar to those observed in Form M. The structure of the metastable Form III has not yet been determined due to its rapid conversion into Form II. Thermal and Stability Behavior of Different Solid Forms of Theophylline. Anhydrous Form II has been considered as the stable form and is used in final product formulations.12,19 The enantiotropic relationship between Form II and Form I has been studied by a number of researchers. However, there are Received: July 6, 2011 Revised: October 20, 2011 Published: November 23, 2011 109

dx.doi.org/10.1021/cg2008478 | Cryst. Growth Des. 2012, 12, 109–118

Crystal Growth & Design

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Figure 1. Crystal packing features of theophylline (a) anhydrous Form I,17 (b) anhydrous Form II,10 (c) anhydrous Form IV,16,17 and (d) monohydrate form.11 H atoms are hidden to improve clarity of viewing.

conversion into Form II.14 The research groups who studied metastable Form III, generated Form III by vacuum dehydration.13,14 However, Matsuo and Matsuoka showed the difficulties associated with this method, namely, that there was 0.14 0.15% water content in the final product suggesting that Form III had up to 1.5% monohydrate content.13 The thermal behavior of Form III is not understood, although it is postulated to be monotropically related to Form II.12 The stable polymorph (Form IV) has been shown to be more thermodynamically stable than Form II at room temperature by solubility, crystallization, and slurry equilibration methods.15 This contribution examines its thermal behavior and its thermodynamic relationship with Form II at elevated temperatures. In the case of polymorphism, the control of the solid form during processing and throughout the shelf life of the formulation is crucial as unwanted polymorphic transition during

conflicting reports of the value of the transition temperature (Ttrs) for Form II to I conversion. Burger and Ramberger suggested Ttrs to be 195 231 °C.20 Griesser et al. used a vapor pressure study and showed Ttrs to be 232 °C.21 Legendre and Randzio studied the Form II to Form I transition using scanning transitiometry and showed Ttrs at 263.8 ( 2.2 °C.22 Recently, the Form II to I transition was studied by Szterner et al. using differential scanning calorimetry (DSC); the transition was not observed but using the heat of fusion rule enantiotropy was established.23 By using Yu’s equation,24 Ttrs was proposed at 231.6 °C, which is in agreement with Griesser et al. The polymorphic transition from Form II to Form I has not been directly observed by DSC, and thus its nature is not fully understood. Theophylline monohydrate dehydrates to produce anhydrous Form II. The metastable Form III was reported to be observed only during the dehydration of Form M and subsequent 110

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Table 1. Methods for Generation of Different Solid Forms of Theophylline solid forms of theophylline

method of generation

Form I

Heating of Form II in a sealed glass vial kept in an oven at 265 268 °C for 2 h

Form II

The bulk material obtained from Sigma-Aldrich

Form III

Generated by one step hydration dehydration of Form II in DVS instrument

Form IV

Slurry equilibration experiments of Form II in methanol for 15 days

NM

Aqueous crystallization or keeping Form II in high humidity (>90% RH) environment

SM

Slurry experiments of Form II from methanol: water or cooling crystallization of theophylline from methanol/water mixtures with water activity value> 0.7

processing may lead to a number of consequences including failure in dissolution, shelf life, and manufacturing problems. Theophylline proves to be a highly polymorphic system with four anhydrous forms, a stoichiometric monohydrate form, and a solvate form25 to date. The situation demands clear understanding of the polymorphic transition, stability, and interconversion of different solid forms of theophylline. The aims of this work were (a) to understand the thermal behavior of Form IV and its relationship with the currently used common form, Form II, (b) to investigate the enantiotropic relationship between Form II and Form I, and (c) to examine the overall interconversion between different anhydrous forms of theophylline.

’ EXPERIMENTAL SECTION

camera (TK-C1381). The images and videos were collected by using Studio capture and Studio player software by Studio86 Designs. Dynamic Vapor Sorption (DVS). Data were collected using a DVS-1 instrument from Surface Measurement Systems, UK. 15 20 mg of sample in flat metal pans was subjected to different humidity profiles at 25 °C. Form III was generated by programming the instrument to run at 0% RH for 1 h, 97% RH for 2500 min followed by 0% RH for 1200 min in the first cycle. This material was examined by PXRD. This was compared with samples which were subjected to a similar first cycle followed by a second, stepwise cycle. For this, after the end of first cycle, dehydrated material was rehydrated in a stepwise manner (each step of 300 min at 20, 30, 40, 55, 75% RH and finally 500 min at 97% RH) followed by dehydration using the same steps.

’ RESULTS AND DISCUSSION Characterization of Theophylline Crystal Forms. Anhydrous Form I showed a PXRD pattern in agreement with the pattern reported by Suzuki et al.9 The PXRD pattern was also matched with the simulated pattern generated by Mercury26 using the crystal structure data of Form I.17 Likewise, PXRD patterns of Form II and Form IV were confirmed with the simulated PXRD patterns from the crystal structure data. There was no difference in the PXRD patterns of SM and NM. TGA thermograph showed a 9 9.1% weight loss for both samples, which matches the theoretical value of monohydrate weight loss. No weight loss was observed in TGA thermographs of anhydrous forms. The PXRD patterns of the four anhydrous forms and monohydrate form are shown in Figure 2. Hydration of anhydrous Form II by DVS by keeping at 97% RH resulted in monohydrate formation as expected (Figure 3). During the second cycle, the stepwise rehydration of this dehydrated material showed a hump (mass loss with increasing relative humidity) at 30 50% RH. This type of hydration behavior is normally associated with rehydration of amorphous material, and this characteristic hump was only seen during the second cycle and not in the first cycle. A similar DVS profile was shown earlier for theophylline by Vora et al.2 The authors suggested this behavior could be due to partially amorphous material present in samples or repacking of dehydrated material to give rise to anhydrous material. To inspect this behavior further, PXRD of dehydrated hydrate was taken immediately after removal from the DVS instrument. It was found to be metastable Form III and the PXRD pattern was in agreement with the previous work showing Form III.12 Thus, by using PXRD with DVS, it became clear that the hump seen in the stepwise rehydration was due to the transformation of highly metastable Form III into Form II at 30 50% RH. Unlike previously reported methods,13 Form III generated in DVS did not show any water content.

Generation of Solid Forms of Theophylline. Four different anhydrous forms of theophylline were generated by the methods described in Table 1. Theophylline monohydrate samples were generated by several methods. Monohydrate generated by aqueous crystallization or by keeping Form II in a >90% relative humidity (RH) environment is termed normal monohydrate and hereafter referred to as NM, whereas monohydrate obtained by crystallization from methanol/ water mixtures or slurry equilibration experiments of Form II in methanol/water mixtures with water activity value >0.715 is termed slurry monohydrate and hereafter referred to as SM. Characterization of Solid Forms. Samples were characterized using analytical techniques as described below. Powder X-ray Diffraction (PXRD). PXRD patterns were collected by using a Rigaku Miniflex X-ray diffractometer. The patterns were obtained by using Cu Kα (1.54 Å) radiation. Samples were finely ground and analyzed 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. Patterns obtained experimentally were compared with simulated PXRD generated using the crystal structure visualization software Mercury.26 Thermal Analysis. DSC data were collected using a Perkin-Elmer DSC 8000. A total of 2 4 mg of sample were placed into semisealed pans and scanned at different heating rates (200, 100, 50, 10, 5, 2, and 1 °C min 1) under nitrogen purge of 20 mL min 1. Some samples were also analyzed using hermetically sealed pans. To determine the solid state present after thermal experiments, aluminum pans were opened and the contents were examined using PXRD. Thermogravimetric analysis (TGA) was performed in a TGA 2050 instrument by TA. For this, 15 20 mg of sample was placed in an open pan and heated at 10 °C min 1 under nitrogen purge at 20 mL min 1. Hot stage microscopy (HSM) was performed on different solid samples using a Mettler FP 82 hot stage connected with a Mettler FP 80 central processor. Crystals were mounted on the hot stage with and without paraffin oil while heating at 5 or 10 °C min 1 and were observed using an Olympus BH-2 optical microscope fitted with a JVC digital 111



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Figure 2. PXRD patterns of four anhydrous forms and monohydrate form of theophylline.

Figure 3. DVS plot showing formation of Form III by dehydration of monohydrate form and transformation (crystalline rearrangement) of Form III into Form II.

Enantiotropy between Form II and Form IV. The DSC thermograph of Form II shows the onset of melting at 270.6 ( 1 °C. This is in agreement with that reported by Suzuki et al.9 As can be seen in Figure 4, Form IV shows the same onset of melting as Form II. However, by expanding the baseline scale, a small, broad endotherm corresponding to the Form IVf Form II transition was observed in the region of 210 240 °C. At 5 °C min 1 heating rate, ΔH of transition was found to be 3.4 J g 1 with an onset temperature of 218.38 °C. Form IV was subjected to further DSC analysis at various heating rates: 50, 100, and 200 °C min 1 (provided in Supporting Information). As the conversion of Form IV to II is a kinetic process, the transition temperature (Ttrs) varied according to the heating rate used. With increasing heating rate, Ttrs moves closer to the Form II melting endotherm and at a heating rate of 200 °C min 1, only a shoulder is seen in the melting endotherm of Form II as there is not enough time for Form IV to fully convert into Form II prior to the onset of melting. This suggests that with the use of further higher heating rates, it could be possible to inhibit the kinetic process of Form IV to II conversion, and thus the melting endotherm of Form IV might be observed.

Using the HSM, it was possible to observe directly the single crystal to single crystal transition from Form IV to Form II (Figure 5). Form IV was grown slowly from methanol/water mixtures to get large single crystals for HSM experiments. PXRD of this material matched the Form IV pattern. Upon heating of a single crystal of Form IV from the same sample at 5 °C min 1, no change was observed until 200 °C. Further heating showed darkening of the crystal corresponding to the beginning of Form IV to Form II transition initiated at the cracks and defects in the crystal of Form IV. Heating was stopped at 245 °C at which temperature the crystal had become completely opaque. When examined by PXRD, Form II pattern was obtained. The range of temperatures over which the phase transformation occurred in HSM at 5 °C min 1 agreed with that observed by DSC at the same heating rate. In earlier work, we showed the stability of Form IV over the common form, Form II, at room temperature by solubility, cooling crystallization, and slurry experiments.15 At room temperature, the solid state transformation of Form II to IV is not observed, but Form II undergoes solvent-mediated transformation to generate Form IV. Thermal analysis by DSC and HSM 112



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Figure 4. DSC scans at 5 °C min 1; Form II shows the onset of melting at 271.34 °C and Form IV shows the transition to Form II (expanded baseline scale, inset) in the region of 210 240 °C followed by melting of Form II.

Figure 5. HSM images showing the phase transition between Form IV and Form II.

shows the transition of Form IV into Form II upon heating. Thermal transition of Form IV to Form II occurs over a wide temperature range (210 240 °C) as can be seen from the HSM images and broad endothermic transition in the DSC thermograph (Figures 4 and 5). This seems to be a small endothermic transition compared with the structural difference between Form II and Form IV. In the case of caffeine, which is a structural analogue of theophylline, the enthalpy of transition between the room temperature form and the higher temperature form is much higher at 20.71 J g 1.27 Thermal behavior of theophylline and caffeine however do not represent a good comparison, in spite of having only one methyl group difference in the molecular structure. Caffeine is trimethyl xanthine, and the N7 site is blocked, so it does not present N H---N or N H---O hydrogen

bonding motif as seen in Forms II and IV, respectively. In theophylline, it is likely that at room temperature the dimer motif of Form IV is more thermodynamically stable than the motif in Form II as strong hydrogen bonds are present. However, the dimers are connected with other dimers via short contacts. It seems that upon heating, an increase in molecular motion endeavors to break the short contacts which connect the dimers and to improve packing efficiency, it transforms to Form II, which is stable at elevated temperature. The enantiotropic relationship between Form IV and Form II can be illustrated by an arbitrarily drawn energy temperature diagram (Figure 6). Enantiotropy between Form II and Form I. DSC thermographs of Form II and NM samples did not show any polymorphic transition (Form II f Form I) at the values reported in 113



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the literature.20 23 Form I and Form II were subjected to different heating rates (5, 10, 50, 100, and 200 °C min 1) and in different pan types (semi sealed and hermetically sealed pans) in order to observe the samples in different DSC environments. However, the thermal transition between the two forms was not observed. At various heating rates, in semi sealed pans, Form I showed an onset of melting at 275 ( 1 °C (273 ( 1 °C in crimped pans) and Form II at 270.6 ( 1 °C. In hermetically sealed pans, the melting of Form II and I moved to 2 3 °C higher than that observed in semi sealed pans. This can be explained because as the material begins to sublime, the pressure within the sealed pan increases thus increasing the melting temperature. HSM did not prove to be useful for visualizing the phase transition between Form II and I since both forms sublimed well before the actual melting point of theophylline. As it can be seen from Figure 7a, Form II crystalline material was fully sublimed before 265 °C. In some of the samples, paraffin oil was added before heating began. In these cases, sublimation was minimized and it was possible to see the melting of Form II at 270.5 ( 1 °C which is concordant with DSC observation. Bubbles were seen coming from the sample corresponding to sublimation from 190 °C onward. Also there was no phase transformation seen in the crystalline material at any temperature before the melting of Form II. PXRD patterns of SM and NM showed no difference; however, the DSC behavior was completely different for SM and NM.

Surprisingly, the DSC trace of SM showed melting of Form II at 271.10 °C followed by recrystallization of Form I and finally melting of Form I at 275.95 °C. No such phase transition was observed from NM samples (Figure 8). Initially, it was presumed that the difference in DSC behavior of SM and NM could be due to the role of the solvent used in the generation of SM. To test this hypothesis, both SM and NM were kept in anhydrous silica ( Form II > Form I, whereas Form III is a highly metastable form which spontaneously converts to Form II. At higher than 250 °C the relationships are Form II > Form IV and Form II > Form III. Form I is more stable than Form II above 268 °C. Form II serves as the intermediate for solid state transitions. It is easy to propagate the catemar arrangement of Form II by forming strong and directional hydrogen bonds, and as a result, Form II crystallizes from the melt, cooling crystallization experiments from organic solvents, upon dehydration of monohydrate or via solid state transition from other anhydrous forms. Theopohylline is a clear example of a case in which kinetics surpasses

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thermodynamics as it is not the most stable form which is generated but the form with the lower energy barrier. The thermodynamically stable Form IV needs the presence of solvent to nucleate and propagate dimers. The method of generation of Form III and different thermal behavior of monohydrate form generated by altered methods clearly shows that hydrate to anhydrate is a complex transition especially in the case of a channel hydrate such as theophylline. Besides loosening of water from the lattice, the dehydration of the channel hydrate compound may involve some rearrangement or repacking of the crystal lattice before generating a stable anhydrous compound, and PXRD alone may not be enough to detect small impurities of this kind. This work clearly shows that different methods of generation of hydrate compounds and dehydration procedures may greatly influence the batch purity which may trigger phase transformation.

’ ASSOCIATED CONTENT

bS

Supporting Information. Powder X-ray diffraction patterns showing the characteristic peaks, for Forms I, II, III, IV, and M theophylline; DSC trace of Form IV at high heating rates. This material is available free of charge via the Internet at http://pubs.acs.org.

’ AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected].

’ ACKNOWLEDGMENT D.K. wishes to acknowledge the School of Pharmacy and Biomolecular Sciences, LJMU, for funding. ’ REFERENCES (1) Barnes, P. J. Thorax 2006, 61, 742–744. (2) Vora, K. L.; Buckton, G.; Clapham, D. Eur. J. Pharm. Sci. 2004, 22, 97–105. (3) Otsuka, M.; Kaneniwa, N.; Kawakami, K.; Umezawa, O. J. Pharm. Pharmacol. 1990, 42, 606–610. (4) Shefter, E.; Higuchi, T. J. Pharm. Sci. 1963, 52, 781–791. (5) Ticehurst, M. D.; Storey, R. A.; Watt, C. Int. J. Pharm. 2002, 247, 1–10. (6) Wikstroem, H.; Rantanen, J.; Gift, A. D.; Taylor, L. S. Cryst. Growth Des. 2008, 8, 2684–2693. (7) Zhu, H. J.; Yuen, C. M.; Grant, D. J. W. Int. J. Pharm. 1996, 135, 151–160. (8) Doser, H. Arch. Pharm. Ber. Dtsch. Pharm. Ges. 1943, 281, 251–6. (9) Suzuki, E.; Shimomura, K.; Sekiguchi, K. Chem. Pharm. Bull. (Tokyo) 1989, 37, 493–497. (10) Ebisuzaki, Y.; Boyle, P. D.; Smith, J. A. Acta Crystallogr., Sect. C: Cryst. Struct. Commun. 1997, 53, 777–779. (11) Sun, C. Q.; Zhou, D. L.; Grant, D. J. W.; Young, V. G. Acta Crystallogr., Sect. E: Struct. Rep. Online 2002, 58, O368–O370. (12) Phadnis, N. V.; Suryanarayanan, R. J. Pharm. Sci. 1997, 86, 1256–1263. (13) Matsuo, K.; Matsuoka, M. Cryst. Growth Des. 2007, 7, 411–415. (14) Nunes, C.; Mahendrasingam, A.; Suryanarayanan, R. Pharm. Res. 2006, 23, 2393–2404. (15) Seton, L.; Khamar, D.; Bradshaw, I. J.; Hutcheon, G. A. Cryst. Growth Des. 2010, 10, 3879–3886. (16) Khamar, D.; Seton, L.; Bradshaw, I.; Hutcheon, G. J. Pharm. Pharmacol. 2010, 62, 1333–1334. 117



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Solid State Transformations Mediated by a Kinetically Stable Form

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