Organic Process Research & Development 2007, 11, 846–860
Characterization of the Polymorphic Behavior of an Organic Compound Using a Dynamic Thermal and X-ray Powder Diffraction Technique David Albers,‡ Michelle Galgoci,† Dan King,‡ Daniel Miller,† Robert Newman,*,‡ Linda Peerey,‡ Eva Tai,† and Richard Wolf† Dowpharma Department, The Dow Chemical Company, 1710 Building, and Department of Analytical Sciences, The Dow Chemical Company, 1897 Building, Midland, Michigan 48674, U.S.A.
Abstract: The crystalline polymorphic forms of several samples of an organic compound produced by Dowpharma were characterized using differential scanning calorimetry (DSC); X-ray powder diffraction (XRPD); combined, simultaneous, and dynamic differential scanning calorimetry/X-ray powder diffraction (DSC/XRPD); and high performance liquid chromatography (HPLC). A total of 10 crystalline polymorphs were identified, six of which are anhydrous. Form l is a heptahydrate that reversibly converts to anhydrous Form I under dry conditions and also undergoes a reversible solid–solid phase transition at about 110 °C to convert to Form II. Form Il is anhydrous and melts at approximately 220 °C. Form III crystallizes as a hexahydrate, which reversibly converts to the monohydrate Form III and then to an anhydrous Form III above 120 °C. Anhydrous Form III melts at approximately 200 °C. Form IV crystallized as a hydrous material, which was converted to the anhydrous Form IV above approximately 60 °C, in a reversible process. Form IV appears to be unstable in high humidity conditions (e.g., 90% relative humidity at 25 °C) and slowly converts to Forms I and III. Form IV also undergoes a nonreversible solid–solid phase transition at approximately 180 °C, to form anhydrous Form V. Form V melts at approximately 245 °C. Form VI is observed only in the anhydrous state and melts at approximately 245 °C. The anhydrous nature of Form VI makes this material the most ideal crystalline material for subsequent formulation work.
1. Introduction The rational control of polymorphs of active pharmaceutical ingredients (API) has been an important goal for the pharmaceutical industry. Differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD) analyses of API solids have been important methods for determining polymorphism for several years. DSC is still used as a stand-alone tool for these determinations.1,2 However, XRPD has become the gold standard method for API polymorphism determinations. Two recent reviews on the importance of XRPD in the pharmaceutical industry have been written.3,4 Other multivariate methods * To whom correspondence should be addressed. Telephone: 989 636-4001. Fax: 989 638-9716 . E-mail:
[email protected]. ‡ Department of Analytical Sciences. † Dowpharma Department.
(1) Park, K; Evans, J. M. B.; Myerson, A. S. Cryst. Growth Des. 2003, 3, 991–995. (2) Hino, T.; Ford, J. L.; Powell, M. W. Thermochimica Acta 2001, 374, 85–92. (3) Byrn, S. R.; Bates, S.; Ivanisevic, I. Am. Pharm. ReV. 2005, 8, 55– 59. 846 • Vol. 11, No. 5, 2007 / Organic Process Research & Development Published on Web 08/17/2007
for quality control of API polymorphism have been developed. These include diffuse reflectance Fourier transfer IR (DRIFT-IR),5,6 focused beam reflectance measurement (FBRM),7 and particle vision and measurement (PVM).7 These latter methods depend, however, on XRPD as a reference and confirmation technique. Recent publications on the use of XRPD for API polymorphism analyses include the characterization of three polymorphic forms of acitretin,8 the study of a stable polymorph of paclitaxel,9 and the study of three polymorphs of sibenadet hydrochloride.10 DSC and XRPD have typically been used as separate techniques to study the polymorphism of the same compound, with XRPD as the confirming methodology. Thus, a combination of separately used DSC and XRPD has been used to study nifedipine (along with the use of FTIR),11 bicifadine (along with the use of thermogravimetric analysis (TGA), attenuated total reflectance (ATR) IR and ATR-near-IR),12 methotrexate (along with TGA),13 carbamazepine (along with FTIR and hot-stage FTIR thermomicroscopy),14 ranitidine hydrochloride,15 terfenadine,16 zanoterone (along with FTIR),17 dehydroepiandrosterone (with IR)18 and 3-[[[3-2[-(7-chloro-2-quinolinyl)-(E)-ethenyl]phenyl][[3-dimethylamino-3-oxopropyl]thio]methyl]thio]propanoic acid.19 Increased use of variable temperature XRPD has been noted in the literature. Polymorphic solid state changes (4) Litteer, B.; Beckers, D. Am. Lab. 2005, 37, 22–24. (5) Poellaenen, K.; Haekkinen, A.; Huhtanen, M.; Reinkainen, S.-P.; Karjalainen, M.; Rantanen, J.; Louhi-Kultanen, M.; Nystoem, L. Anal. Chim. Acta 2005, 544, 108–117. (6) Agatonovic-Kustrin, S.; Rades, T.; Wu, V.; Saville, D.; Tucker, I. G. J. Pharm. Biomed. Anal. 2001, 25, 741–750. (7) O’Sullivan, B.; Barrett, P.; Hsiao, G.; Carr, A.; Glennon, B. Org. Process Res. DeV. 2003, 7, 977–982. (8) Malpezzi, L.; Magnone, G. A.; Masciocchi, N.; Sironi, A. J. Pharm. Sci.s 2005, 94, 1067–1078. (9) Harper, J. K.; Barich, D. H.; Heider, E. M.; Grant, D. M.; Franke, R. R.; Johnson, J. H.; Zhang, Y.; less, P. L.; Von Dreele, R. B.; Scott, B.; Williams, D.; Ansell, G. B. Cryst. Growth Des. 2005, 5, 1737– 1742. (10) Cosgrove, S. D.; Steele, G.; Austin, T. K.; Plumb, A. P.; Stensland, B.; Ferrari, E.; Roberts, K. J. J. Pharm. Sci. 2005, 94, 2403–2415. (11) Song, M.; Liebenberg, W.; de Villiers, M. M. Pharmazie 2006, 61, 336–340. (12) McArdle, P.; Gilligan, K.; Cunningham, D.; Ryder, A. Appl. Spectrosc. 2005, 59, 1365–1371. (13) Nikander, H; Tittanen, S. Res. Disclosure 2004, 486, 1252–1254. (14) Rustichelli, C.; Gamberini, G.; Ferioli, V.; Gamberini, M. C.; Ficarra, R.; Tommasini, S. J. Pharm. Biomed. Anal. 2000, 23, 41–54. (15) Wu, V.; Rades, T.; Saville, D. J. Pharmazie 2000, 55, 508–512. (16) Sheikh, S. M.; Pillai, G. K.; Nabulsi, L.; Al-Kaysi, H. N.; Arafat, T. A.; Malooh, A. A.; Saleh, M.; Badwan, A. A. Int. J. Pharm. 1996, 141, 257–259. (17) Rocco, W. L.; Morphet, C.; Laughlin, S. M. Int. J. Pharm. 1995, 122, 17–25. (18) Chang, L.-C.; Caira, M. R.; Guillory, J. K. J. Pharm. Sci. 1995, 84, 1169–1179. (19) Ghodbane, S.; McCauley, J. A. Int. J. Pharm. 1990, 59, 281–286. 10.1021/op700037w CCC: $37.00 2007 American Chemical Society
Table 1. Summary of methods of preparation of samples for combined DSC/XRD sample no. 8 9
form I and IV I+?
10
I
11
I
26 33
amorphous I
34 35
I III
38 40
I VI
45
I + III
49
III hydrate
50
I
56
III + IV
57
IV hydrate
59
I + III + IV + (VI?)
62
V anhydrous
description of preparationa sample 38 and 95/5 acetone/water held at 52 °C for 2 h sample 11, redissolved into 50/50 acetone/water, then Step 1b; wetcake slurried with 95/5 acetone/water at 52 °C for 4 h, isolated cold solids and dried at 73 °C/25 h 95/5 acetone/water mother liquor from sample 9, after evaporation to leave solids Step 1, but kept 50/50 acetone/water solution at 49 °C and seeded with Form III; solids at 47.5 °C, cooled to 5 °C and isolated solids lyophilized aqueous solution of 1 disodium salt Step 1, then slurried wetcake in 95/5 acetone/water up to 54 °C for 3.2 h, then isolated solids and dried at 69 °C for 15 h Step 1, then dried solids at 50 °C/1.7 h sample 34, heated to reflux as 95/5 acetone/water slurry for 1.5 h; isolated solids and dried at 42 °C/4 h Step 1 with precipitation at 37 °C, and solids dried at 40 °C/3 h sample 38 refluxed with anhydrous acetone (acetone/solids 13.1/1 v/w) for 3.2 h as slurry, then solids isolated and dried in air Step 1, but all processes done in 70/30 acetone/water, with heating to 50 °C to dissolve solids; isolated and dried solids at 38 °C/15 h Step 1, then heated wetcake in 95/5 acetone/water to reflux for 1.3 h, then isolated solids and dried at 48 °C for 15 h Step 1, then slurried wetcake in 95/5 acetone/water up to 52 °C for 2.4 h, then isolated solids and dried at 50 °C for 3 h heated sample 49 to reflux as slurry in 95/5 acetone/water for 2 h; a very thick “milkshake” mixture set up; solids were isolated, washed with acetone, and allowed to dry in air sample 50 was refluxed as slurry in 95/5 acetone/water, isolated solids at 5 °C and allowed to dry in air sample 50, held in 95/5 acetone/water at 50 °C for 1 h; mixture IV + (VI?) set up to make “milkshake” slurry; solids isolated at 5 °C and allowed to dry in air sample 57 was heated to 200 °C in a helium atmosphere and then allowed to cool to ambient temperature
a All drying under vacuum, except as noted. The Step 2 preparation of Form I hydrate involved either stirring the Step 1 wetcake in 95/5 (v/v) acetone/water at ambient temperature for more than 10 h or heating the Step 1 wetcake in 95/5 acetone/water below the reflux temperature for more than 1.5 h. b The Step 1 preparation of 1 dicarboxylate disodium salt involved complete dissolution of 1 dicarboxylic acid into a 50/50 acetone/water (v/v) solution at a temperature of 46–48 °C with a 3–6% excess of sodium bicarbonate to produce the disodium salt. Acetone was then added to make a 70/30 acetone/water solution. The solution was cooled to precipitate and isolate the solids as a wetcake.
using this technique have been reported for sulfathiazole, theophylline, and nitrofurantoin.20,21 The variable temperature XRPD technique has been reviewed recently.22,23 The present manuscript reports the use of a unique Dow-developed combined DSC/XRPD instrument24–26 to dynamically characterize the polymorphic behavior of an organic compound API over a temperature range of hundreds of degrees. This allows the simultaneous measurements of thermochemical and thermophysical events, while following changes in crystalline structure (polymorphism) during these events. (20) Karjalainen, M.; Airaksinen, S.; Rantenen, J.; Aaltonen, J.; Yiruusi, J. J. Pharm. Biomed. Anal. 2005, 39, 27–32. (21) Airaksinen, S.; Karjalainen, M.; Raessaenen, E.; Rantanen, J.; Yiruusi, J. Int. J. Pharm. 2004, 276, 129–141. (22) Brittain, H. G. Am. Pharm. ReV. 2002, 5, 74–76. (23) Brittain, H. G. Spectroscopy 2001, 16, 14–16–18. (24) Fawcett, T. G.; Martin, E. J.; Crowder, C. E.; Kincaid, P. J.; Strandjord, A. J.; Blazy, J. A.; Armentrout, D. N.; Newman, R. A. AdV. X-Ray Anal. 1986, 29, 323–332. (25) Fawcett, T. G.; et al. Chemtech 1987, 564–569. (26) Fawcett, T. G.; Harris, W. C., Jr. Newman, R. A.; Whiting, L. F.; Knoll, F. J. U. S. Patent 4,821,303, 1989.
2. Results and Discussion The compound (1) of this study was a disodium salt of an organic dicarboxylic acid of molecular weight of about 400. Representative sample preparation conditions of various forms of 1 are given in Table 1. Note that a common starting material for the preparation of these samples was the wetcake from Step 1. The Step 1 preparation of 1 disodium salt involved complete dissolution of 1 dicarboxylic acid into a 50/50 (v/v) acetone/ water solution at a temperature of 46–48 °C with a 3–6% excess of sodium bicarbonate to produce the disodium salt. Acetone was then added to make a 70/30 acetone/water solution. The solution was cooled to precipitate and isolate the solids as a wetcake. In the following discussions, generalizations on the conditions found to produce the various crystalline forms of 1 disodium salt are noted, along with discussions on the thermal and XRPD characterization of each form. The ability to simultaneously observe dynamic thermal events (via DSC) and the corresponding structural events (via XRPD) through use of the DSC/XRPD instrument (Figure 1) greatly accelerated Vol. 11, No. 5, 2007 / Organic Process Research & Development
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this), one often re-creates “old” polymorphs during the process of developing control of the system to produce the desired form for development and testing. DSC data, suggested forms, and additional characterizations of representative samples of pure polymorphs of 1 are given in Table 2. Combined DSC/XRPD data, suggested forms, and additional characterizations of representative samples of pure polymorphs of 1 are given in Table 3. Combined DSC/XRPD data, suggested forms, and additional characterizations of representative samples of polymorph mixtures of 1 are given in Table 4. Forms I and II.
Figure 1. Second generation Dow-developed DSC/XRPD instrument. Disruption of the thermal environment of the DSC was minimized by creating a ∼1 mm diameter vertical X-ray beam path through the center of the sample and reference sensors of the DSC cell. Thermal isolation was maintained by using beryllium metal foil to seal the X-ray optical path.
identification and understanding of the thermal behavior of the various polymorphic forms found. It should be noted that throughout this paper there are references to samples with disparate numbering. This is due to the fact that, in a complex multi-polymorph system (such as
Form I has been typically produced during a purification re-slurry of material from Step 1 in a 95/5 (v/v) acetone/water solution between 48 and 54 °C for several hours while being careful to avoid refluxing the sample. This re-slurry process is referred to as Step 2 and has typically produced Form I. The heptahydrate Form I is uniquely identified by DSC analyses, by the presence of a large single endotherm below 80 °C and by a small (4–8 J/g) reversible solid–solid phase transition that occurs with an onset between 100 and 110 °C. Above 110 °C, a new crystalline form, Form II, is produced. Form II melts with an onset of approximately 210–215 °C, with an apparent heat of fusion of 30–45 J/gram. Typical DSC results attributed to Form I are shown in Figures 2 (hydrate) and 3 (anhydrous), and numerical results for representative examples are tabulated in Table 2. The relatively large variation in the heat of fusion may be due to two factors. First, the integration is difficult because an exotherm due to sample degradation immediately follows the melt and creates an uncertain baseline. Second, the varying quantities of water in the starting material (Form I) result
Table 2. Summary of DSC data, suggested results, and additional characterizations sample no. 3b 4 5 7 9 12 17b,c 21c 22 24 25b a
848
peak onsets (°C) 19 178 76 190 107 207 99 189 110 213 106 213 238 242 104 210 2 255 2 258
peak max (°C) 92 186 107 201 111 222 117 202 113 226 111 226 249 252 109 224 36 266 22 266
peak area (J/g) 76 41 81 37 9 47 83 44 8 54 9 56 52 68 5 30 9 41 3 63
Endotherms. b XRPD data obtained separately. c Light microscopy also performed on sample.
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suggested form III monohydrate III monohydrate I III monohydrate I I VI VI I VI hydrate VI hydrate
thermal eventa loss of water melt of Form III? loss of water melt of Form III Form I to Form II melt of Form II loss of water melt of Form III Form I to Form II melt of Form II Form I to Form II melt of Form II melt of Form VI melt of Form VI Form I to Form II melt of Form II loss of water melt of Form VI loss of water melt of Form VI
Table 3. Summary of combined DSC/XRD data, suggested results, and additional characterizations sample no. 11 46 10 33 35 40 26 49 57 62 a
peak onsets (°C) 98 203 110 213 26 188 106 211 5 196 249 1 156 12 21 177 245 246
peak max (°C) 103 213 113 225 60 205 110 225 47-74-113 206 257 50 164 45 59 183 256 257
peak area (J/g) 2 38 8 40 301 15 7 45 110 (total) 37 46 141 2 320 98 9 34 46
suggested form I I I hydrate I I III hydrate VI amorphous III hydrate IV hydrate V anhydrous
thermal event Form I to Form II melt of Form II Form I to Form II melt of Form II loss of water melt of Form I Form I to Form II melt of Form II loss of water melt of Form III melt of Form VI loss of water melt of amorphous loss of water loss of water Form IV to Form V melt of Form V melt of form V
figuresa
5 4 3, 23 3 10, 14 10 22, 23 24, 25 24 11, 12, 13, 14 16, 17, 18, 23 17, 18 17 18, 19
Only selected figures have been included in report to illustrate behavior of the different polymorphs.
Table 4. Mixtures of polymorphs in selected samples as analyzed by DSC and XRPD sample number peak onsets (°C) peak max (°C) peak area (J/g) 2
