Communication pubs.acs.org/crystal
Screening and Selective Preparation of Polymorphs by Fast Evaporation Method: A Case Study of Aspirin, Anthranilic Acid, and Niflumic Acid Partha Pratim Bag and C. Malla Reddy* Department of Chemical Sciences, Indian Institute of Science Education and Research, Kolkata 741252, West Bengal, India S Supporting Information *
ABSTRACT: We show the preferential formation and scalability of two known polymorphs, I and II, of aspirin from acetone (at 50 °C) and dichloromethane (at 5 °C) solutions, respectively, and two known forms I (from water at 50 °C) and II (from methanol at 50 °C) of anthranilic acid with high purity by fast evaporation (FE) of solvent using rotary evaporation technique. The FE method also provided a means to identify a previously unknown form II of niflumic acid (NFA). The NFA form II, which is characterized by DSC, TGA, IR, and PXRD, could not be detected either by slow evaporation or liquid assisted grinding methods upon screening from a variety of solvents. The results demonstrate the efficiency and complementarity of the FE method to the existing techniques for selective preparation and scale up of API polymorphic forms.
O
utility of the kinetically controlled FE method for obtaining polymorphic forms of two recently well investigated single component model systems, aspirin (ASP) and anthranilic acid (AA), as well as a previously unknown form II of niflumic acid (NFA; Scheme 1).
ne significant challenge currently is the identification of all possible forms of an active pharmaceutical ingredient (API) that can exist as polymorphs, salts, hydrates, solvates, cocrystals etc.1 As the different solid forms can have unique physicochemical properties that may influence the performance of the pharmaceutical product,2 their knowledge is desired for choosing a suitable candidate for development and profitable commercialization.3 Rigorous screening methods practiced today by multiple crystallization techniques are increasingly identifying new solid forms even for the old drugs. Hence there is a growing demand for new and the efficient (in terms of time and/or resources) screening techniques to be able to legally secure all possible drug forms. In this context, the mechanical grinding (both neat and wet) and high-throughput crystallization techniques have been proved very useful.4 Solution based slow evaporation methods are also useful to some extent but not regarded as efficient for screening purposes. Nevertheless, selective preparation and scale up of solid forms, especially in case of concomitant polymorphism, still remains a major concern for many APIs. Fast evaporation (FE) of solvent from solutions, either by nitrogen gas flow or by rotary evaporation, also helps to identify kinetic forms.5,6 But this method has remained relatively obscure, maybe due to the absence of any systematic studies in the literature. On these lines, we have recently shown the utility of the FE method by synthesizing a cocrystal polymorph II of carbamazepin and saccharin (1:1) that was previously obtained only by polymer induced crystallization method, a paracetamol and oxalic acid (1:1) cocrystal, which was known to be obtained only by means of mechanochemical grinding, and some new cocrystals of ascorbic acid with isonicotinic acid, nicotinamide, and carbamazepine.6 Here, we further show the © XXXX American Chemical Society
Scheme 1. Chemical Structures of the APIs Used in This Study
The existence of polymorphism in aspirin has been debated for very long and conclusive proofs for the second form (II) came only very recently.7 It has now been shown that the mysterious metastable form II (ACSALA15)7g has a tendency to grow within the crystals of long known form I (ACSALA14)7g as intergrowths. A very similar crystal structure and powder X-ray diffraction (PXRD) patterns of the forms I and II also contributed to the long delay in identifying of the second form. Reportedly, the aspirin form II crystals (alongside intergrowths) can be obtained by lyophilization (freezedrying)8a from water8b or rapid quenching of hot acetonitrile solution, or slow evaporation at ambient conditions.7g Heating aspirin in organic solvents was reported to increase the aspirin Received: March 27, 2012 Revised: May 2, 2012
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anhydride levels by dehydration process,9 thus possibly leading to increase of form II domains in form I crystals. Recently, Bond et al. have shown that the addition of aspirin anhydride from 2 to 10% to the crystallization solution of aspirin in acetonitrile or tetrahydrofuran enhances the formation of pure form II crystals.10 Here we report the selective preparation of aspirin forms I or II powders starting from a same commercial sample (SigmaAldrich) by optimizing solvent and temperature conditions using the FE method but without the addition or increase in the levels of aspirin anhydride. The commercial sample we used (form I) had only a minimal amount of aspirin anhydride (Supporting Information, Figure S1), as suggested by the PXRD pattern. To identify the suitable conditions for the selective preparation of form I or II, we first screened by drying various dilute solvent solutions of aspirin using the rotary evaporation technique at the appropriate reduced pressure and a temperature of 50 °C (see the Supporting Information, Table S1). The dried solids were analyzed using PXRD, differential scanning calorimetry (DSC), and thermogravimetric (TG) analyses. The analyses showed that the powders obtained from acetone, acetonitrile (MeCN), methanol (MeOH), ethanol (EtOH), tetrahydrofuran (THF), dichloromethane (DCM), diethyl ether (Et2O), iso-propyl alcohol (i-prop) and nitromethane (MeNO2) solvent solutions, all belonged to the pure form I. When the screening experiments were repeated at a lower temperature of 5 (±3) °C, interestingly, the batches from DCM and Et2O showed the preferential formation of form II, while all the other solvents resulted in form I. The DSC of the solids from DCM and Et2O both showed a melting endotherm at 133 °C, while the solids from all the other solvents at 137 °C, supporting the formation of forms II and I, respectively (Figure 1a). Comparison of the experimental and simulated PXRD
patterns of the two polymorphs also confirmed this (Figure 1c). However, it is to be noted that the close similarity of the PXRD patterns of the two forms, except the two additional peaks at 2θ = 20.2° and 25.88° for form II, makes it difficult to rule out the presence of form I in the form II samples. But the intensities of the two additional peaks in form II match well with that of the previously reported experimental PXRD patterns of the pure form II samples, suggesting this as the major phase. Notably, the results on the two forms were also consistent at 2 g batch scales, indicating the scalability and repeatability of the polymorphs by this method. Hence, the present FE method provides an alternate route to obtain the aspirin form II powders, without the addition of the nucleating agent aspirin anhydride. Interestingly, although Bond et al. have obtained the form II crystals from MeCN or THF solvents (in presence of 2−10% of aspirin anhydride), in contrast, the FE method resulted us the form II only from the volatile solvents DCM or Et2O, at 5 °C (but not at 50 °C). According to the Ostwald’s rule of stages, the kinetic polymorphs should crystallize first, then transform successively to more stable polymorphs when left in solution.11 However, in the FE crystallization process, the kinetic forms that crystallize first do not get an opportunity to transform to the more stable polymorphs as the solvent is removed very fast, thus the solution is maintained at the supersaturation level.6 Hence, the results of ASP suggest that the polymorph II should be a kinetic form and the fast evaporation prevents the solvent-mediated transformation. This is also supported by the fact that only the most volatile solvents, DCM and Et2O, achieve this effect, furthermore, only at low temperatures when the conversion rate in solution would be slowest. This is indeed supported by slurry experiments on the two forms in water. The form II converts to form I, while form I remains stable under similar conditions (Supporting Information, Figure S2(a)), proving that the form II is a kinetic phase. It is to be noted that the form II is achieved also by lyophilization8b method, where the similar kinetic effects are expected as this process also involves the (extremely) low temperatures and high evaporation rates.12 Nevertheless, the observations provide some interesting insights into the influence of crystallization conditions on product. The second system, anthranilic acid (AA), is known to exist in three polymorphic forms.13 Ojala and co-workers13 obtained form I (AMBACO07)14 from methanol or ethanol solutions, form II (AMBACO05)15 from water, methanol, ethanol, nitrobenzene, acetic acid, or acetonitrile by slow evaporation technique, and polymorph III (AMBACO08)16 only by sublimation method. Trask et al. showed the interconversion of the three forms depending on the solvent selection in liquid assisted grinding.4 This provided us a platform to evaluate the efficiency of the FE method for selective preparation of polymorphs with high purity. We attempted to prepare the three pure polymorphs of the AA by optimizing conditions in the FE method (Supporting Information, Table S2). The analysis of the resulted solids by PXRD confirmed the selective formation and high purity of the form I from water and form II from MeOH, EtOH, i-prop, chloroform, DCM, MeNO2, MeCN, DMF, or dioxane solutions of AA (Figure 2b). This is also supported by the sharp melting endotherms in the DSC of the two powders (Figure 2a), which are consistent with the form I (149 °C) and II (148.6 °C) of previous reports.12 But, despite several attempts using different solvents, we never obtained the polymorph III, which was previously obtained
Figure 1. (a) DSC, (b) TGA, and (c) PXRD patterns of the aspirin forms I and II. Notice the similarities between the simulated and experimental PXRD patterns of the form II in (c). The ↓ is to indicate the characteristic peaks of form II to distinguish it from form I. B
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Figure 2. Anthranilic acid, AA. (a) DSC and (b) PXRD patterns of the solids obtained from water and nitromethane by FE method confirm the selective formation and high phase purity of the two forms I and II, respectively.
Table 1. Crystallization Conditions for Obtaining Different Solid Forms of Aspirin, Anthranilic Acid and Niflumic Acid from the Fast Evaporation (FE), Slow Evaporation (SE),7,13,17 and Liquid Assisted Grinding (LAG)4 Methodsa ASP
AA
NFA
form
I
II
I
II
III
I
II
FE SE LAG
AcMe MeCN MeOH MeCN n/r
DCM Et2O MeCN (2−10 equiv aa) n/r
H2O hex MeOH EtOH H2O
DCM MeCN MeNO2 H2O, MeOH, EtOH hex
n/o subl chlf
MeCN MeOH THF THF MeOH EtOH i-prop (this work)
EtOH n/o n/o
a
AcMe = acetone, aa = aspirin anhydride, chlf = chloroform, DCM = dichloromethane, hex = n-hexane, i-prop = isopropyl alcohol, subl = sublimation, n/r = not reported, n/o = never obtained.
Figure 3. Niflumic acid (NFA). (a) PXRD, (b) DSC, and (c) TG analysis of the solids prepared from methanol and ethanol by the FE method. Notice the major peaks in PXRD of the new form II (EtOH) at 2θ = 10°, 12.2°, 20.1°, and 27.15° that clearly distinguish it from the form I.
solvents by the FE method (Supporting Information, Table S3) as well as the slow evaporation and LAG methods. The powders obtained from MeOH, MeCN, acetone (AcMe), ethyl acetate (EtOAc), THF, and MeNO2 solutions by the FE method, all resulted in the known form I (Supporting Information, Figure S3a), as confirmed by the PXRD patterns that match well with the simulated pattern of the known form I (Figure 3a). But the PXRD pattern of the solid that was obtained from EtOH, appeared distinct from the form I, with readily distinguishable peaks at 2θ = 10°, 12.2°, 20.1° and 27.15 (indicated with ↓ in Figure 3a). The 1H NMR analysis of the product confirmed the presence of NFA, i.e., the observed changes in the PXRD are not due to a chemical change (Supporting Information, Figure S4). The formation of the new solid phase is also supported by a sharp single melting
only either by sublimation or LAG in presence of chloroform solvent. This observation indicates to a fundamental difference between the operating mechanisms of the FE and LAG methods (Table 1). The two forms I and II of AA could be prepared with high purity also at the 2−5 g scales by the FE method from water and nitromethane solutions, respectively. Having examined the potential of the FE method, we turned our attention to a new API, niflumic acid (NFA), for which only one polymorphic form is currently known. Fenamates, mefenamic acid, meclofenamic acid, flufenamic acid, and niflumic acid, constitute a group of analgesics which act as anti-inflammatory analgesics.17 Murthy et al. obtained the crystals of NFA (thereafter, form I) from THF solvent by slow evaporation method and determined the crystal structure.17 In our polymorphic search, we screened the NFA from different C
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endotherm at 203.6 °C in the DSC, which is distinct from the known form I (204.7 °C). The IR (Supporting Information, Figure S5) and no weight loss before melting temperature in TG analysis, suggest that this is most probably a new crystalline polymorph but not a solvate (Figure 3b). On the other hand, all our attempts to grow the single crystals for structure determination of NFA form II by slow evaporation method from ethanol and the other solvents have failed. We always obtained only form I crystals, but never form II. We further attempted to obtain the new form II solid by the LAG method by grinding the NFA in presence of methanol, acetonitrile, acetone, ethyl acetate, THF, and nitromethane solvent drops (Figure 4). But we could not obtain the form II
AUTHOR INFORMATION
Corresponding Author
*Phone:+91 33 25873118 (Ext. 238). Fax: +91 33 25873020. E-mail:
[email protected]. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank Mr. M. Patni (IIT Guwahati) for assistance with this work. P.P.B. thanks the CSIR for SRF. DST is gratefully thanked by C.M.R. for financial support (SR/FT/CS-074/ 2009).
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REFERENCES
(1) Braga, D.; Grepioni, F.; Maini, L. Chem. Commun. 2010, 46, 6232−6242. (2) (a) Byrn, S. R.; Pfeiffer, R. R.; Stowell, J. G. Solid-State Chemistry of Drugs, 2nd ed.; SSCI, Inc.: West Lafayette, IN, 1999; Chapter 1. (b) Huang, L.-F.; Tong, W.-Q. Adv. Drug Delivery Rev. 2004, 56, 321− 334. (3) Byrn, S. R.; Pfeiffer, R. R.; Ganey, M.; Poochikian, G. Pharm. Res. 1995, 12, 945−954. (4) Trask, A. V.; Shan, N.; Motherwell, W. D. S.; Jones, W.; Feng, S.; Tan, R. B. H.; Carpenter, K. J. Chem. Commun. 2005, 880−882. (5) Hilfiker, R. Polymorphism: In the Pharmaceutical Industry; WileyVCH Verlag GmbH & Co. KGaA: Weinheim, Germany, 2006; p 299. (6) Bag, P. P.; Patni, M.; Reddy, C. M. CrystEngComm 2011, 13, 5650−5652. (7) (a) Wheatley, P. J. J. Chem. Soc. 1964, 6036−6048. (b) Kim, Y.; Machida, K.; Taga, T.; Osaki, K. Chem. Pharm. Bull. 1985, 33, 2641− 2647. (c) Wilson, C. C. New J. Chem. 2002, 26, 1733−1739. (d) Ouvrard, C.; Price, S. L. Cryst. Growth Des 2004, 4, 1119−1127. (e) Vishweshwar, P.; McMahon, J. A.; Oliveira, M.; Peterson, M. L.; Zaworotko, M. J. J. Am. Chem. Soc. 2005, 127, 16802−16803. (f) Bond, A. D.; Boese, R.; Desiraju, G. R. Angew. Chem., Int. Ed. 2007, 46, 615−617. (g) Bond, A. D.; Boese, R.; Desiraju, G. R. Angew. Chem., Int. Ed. 2007, 46, 618−622. (8) (a) Tang, X.; Pikal, M. J. Pharm. Res. 2004, 21, 191−200. (b) Sperger, D.; Chen, B.; Offerdahl, T.; Hong, S.; Schieber, L.; Lubach, J.; Barich, D.; Munson, E.; Characterization of a New Form of Aspirin. AAPS J. 2006, 8, 13961, www.aapsj.org/abstracts/AM_2006/ AAPS2006-002764.pdf. (9) Bundgaard, H. J. Pharm. Pharmacol. 1974, 26, 535−540. (10) Bond, A. D.; Solanko, K. A.; Parsons, S.; Redder, S.; Boese, R. CrystEngComm 2011, 13, 399−401. (11) Ostwald, W. F. Z. Phys. Chem., Stoechiom. Verwandtschaftsl. 1897, 22, 289−302. (12) The lyophilization and FE processes may not be identical, as in the lyophilization, the solvent evaporation is directly from the solid state (where less translational freedom is available for desolvated solute molecules for recrystallization), while in the FE process, it is from the solution state (more translational freedom). These differences are significant, especially considering the fact that a small change in crystallization conditions is enough to lead to a completely different outcome, although this does not seem to matter in this case. (13) Ojala, W. H.; Etter, M. C. J. Am. Chem. Soc. 1992, 114, 10288− 10293. (14) Brown, C. J.; Ehrenberg, M. Acta Crystallogr., Sect. C: Cryst. Struct. Commun. 1985, C41, 441−443. (15) Hardy, G. E.; Kaska, W. C.; Chandra, B. P.; Zink, J. I. J. Am. Chem. Soc. 1981, 103, 1074−1079. (16) Takazawa, H.; Ohba, S.; Saito, Y. Acta Crystallogr., Sect. C: Cryst. Struct. Commun. 1986, C42, 1880−1881. (17) Murthy, H. M. K.; Vijayan, M. Acta Crystallogr., Sect. B: Struct. Sci. 1979, B35, 262−263.
Figure 4. PXRD patterns of the niflumic acid solids obtained by the liquid assisted grinding (LAG) method. Note that all the solids obtained by this method (including that from EtOH assisted grinding) correspond to the known form I. The solvents used in LAG for each case are given in the bracket.
even by the LAG method, which is one of the most efficient methods known today. These observations suggest that this could be a kinetic form. Indeed, this was confirmed from the slurry experiments in that the form II converted to the stable form I (Supporting Information, Figure S3b). These findings not only underline the efficiency of the FE method but also its complementarity to the existing techniques for identifying new solid forms of APIs and other organic materials. Our studies on the well researched APIs, aspirin and anthranilic acid, demonstrate the efficiency of the FE method for identification and selective preparation of new API solid forms, as well as their scale up, by optimizing crystallization conditions. A new form II of NFA is identified successfully by the FE method from ethanol solvent, which could not be obtained by either slow evaporation or the solvent drop grinding methods. The results suggest that the rapid evaporation of solvent enhances the crystallization kinetics, thus improving the chances for detecting new forms, including kinetic forms. The study also demonstrates the complementarity of the FE method to the existing screening techniques and its potential to become a preferred screening tool in solidstate pharmaceutical laboratories.
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ASSOCIATED CONTENT
S Supporting Information *
A detailed procedure for selective preparation of polymorphs by fast evaporation technique and some characterization data (IR, PXRD and 1H NMR) are included. This material is available free of charge via the Internet at http://pubs.acs.org. D
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