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Nov 30, 2007 - of using a salt additive to induce crystallization of the metastable polymorph V of flufenamic acid (FFA). Additionally, it was found t...
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Part of the Special Issue: Facets of Polymorphism in Crystals

Formation and Solid-State Characterization of a Salt-Induced Metastable Polymorph of Flufenamic Acid

CRYSTAL GROWTH & DESIGN 2008 VOL. 8, NO. 1 91–97

Eun Hee Lee, Stephan X. M. Boerrigter, Alfred C. F. Rumondor, Sai P. Chamarthy, and Stephen R. Byrn* Department of Industrial and Physical Pharmacy, Purdue UniVersity, 575 Stadium Mall DriVe, West Lafayette, Indiana 47907 ReceiVed September 8, 2007; ReVised Manuscript ReceiVed NoVember 30, 2007

ABSTRACT: Using additives is one of more recent and special methods to obtain a desirable polymorph. However, for pharmaceuticals, additives are usually limited to structurally related organic compounds. In this study, we have shown the potential of using a salt additive to induce crystallization of the metastable polymorph V of flufenamic acid (FFA). Additionally, it was found that FFA V undergoes a rapid interface mediated polymorphic transformation. Therefore, the slow evaporation method which can decrease the contact of the solvent during crystallization was chosen to delay the polymorphic transformation. It can be concluded that understanding the system is a prerequisite for using additives to obtain the desired polymorph.

1. Introduction Polymorphism occurs when a compound crystallizes in different crystal structures.1 In the pharmaceutical industry, failure to discover the most stable polymorph can create a number of stability problems, the most serious of which is withdrawal of the drug from the market because the metastable form may transform into the stable form. This is because the differences in free energy between a metastable and a stable polymorph can result in differences in solubility and thus in bioavailability. Therefore, efforts are typically made in the early stages of formulation of a drug product to discover as many polymorphs as possible to try to identify the most thermodynamically stable polymorph under ambient conditions. The most catastrophic example is Ritonavir.2 Only one polymorph was discovered during the drug development processes. However, the stable form appeared later as a result of heterogeneous nucleation on a structurally related compound. The Ritonavir example has increased interest in discovering polymorphs using additives. In this paper, we study formation of the metastable polymorph using a salt additive. Conventionally, polymorphs are obtained by modifying the crystallization conditions, such as temperature, supersaturation, solvents, and/or the cooling rate during the crystallization process. A pseudoseed or seed, a single crystal substrate, or a “tailor-made” additive are often used in order to modify the kinetics of crystallization.3–17 In methods using the kinetics of crystallization, polymorphs are obtained via secondary nucleation processes. Since the secondary nucleation process requires less activation energy (requiring smaller critical nuclei and thus less supersaturation) than the primary nucleation process, these methods can promote the formation of the desired form. Sometimes a metastable form can be obtained by modifying the solvent.4 This can be done by choosing a solvent with different properties such as polarity or hydrogen bonding propensity or a combination of solvents. * Corresponding author. E-mail: [email protected]. Fax: (+1) 765494-6545. Tel.: (+1) 765-494-1460.

Figure 1. Molecular structure diagram of flufenamic acid (C14H10F3NO2).

In this study, flufenamic acid (FFA) is used as the model compound and ammonium chloride is used as a salt additive in order to obtain the metastable polymorph, V, of FFA (Figure 1). The effects of salt are frequently studied in biophysics areas including protein folding, protein solubility, and protein crystallization areas.18 Also, salts influence the solubility of small nonpolar molecules in aqueous media19 and extraction of alcohol from aqueous media.20 In the amino acid crystallization field, some studies have shown that salt can induce the metastable polymorphs of glycine by acting as “tailor-made” additives.21–23 Effects of salts have been studied in two ways using computer simulations techniques: by regarding the effect of salts as a mean force24 or as a specific ion effect.10 In a mean force analysis, the effects of salts are limited to the changing ionic strength of the system. In a specific ion effect analysis, the interaction between salt and components are the main factors in determining the effect of salts. The effect of salts are manifested as “saltingin” and “salting-out” processes in which the solubility of a compound can increase or decrease.25 In the presence of salts, favorable interactions between the solute and salt can induce a

10.1021/cg7008607 CCC: $40.75  2008 American Chemical Society Published on Web 01/02/2008

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Figure 2. FFA I crystals in (a) the absence of NH4Cl and (b–d) FFA: NH4Cl ) 5:1.

salting-in process, while favorable interaction between the salt and solvent can induce a salting-out process. It is believed that salts can change the hydrophobic interactions of nonpolar solutes in an aqueous solution.26 Therefore, salts can be used to increase the protein structure stability, increase or decrease the solubility of nonpolar molecules, or improve the extraction of alcohols from aqueous solutions. Here, we are interested in investigating the ability of salt additives to induce formation of a specific polymorph. 2-((3-(Trifluoromethyl)phenyl)amino)benzoic acid, has been named flufenamic acid since 1972. Study of FFA polymorphs was conducted extensively in the late 1970s and early 1980s. Flufenamic acid is a compound with a large number of known polymorphs. At least eight forms are known.27–30 Crystallographic information on only three polymorphs (forms I, II, and III) is available. Other polymorphs could only be obtained by sublimation, fusion, or a boiling solvent method. Polymorphic forms obtained using these methods convert easily into the stable forms and/or can not be isolated easily because concomitant crystallization occurs. Therefore, the information on the other metastable forms is restricted to infrared spectra and/or thermal parameters. Here, we present the method to stabilize metastable form V of FFA using a salt additive, the solid-state characterization, and the structural analysis of molecular interactions in form V using powder X-ray diffraction (PXRD), infrared (IR), differential scanning calorimetry (DSC), and solid state nuclear magnetic resonance (ssNMR) techniques. Finally, the polymorphic transformation behavior was studied.

2. Experimental Section 2.1. Materials. Flufenamic acid (FFA) was purchased from SigmaAldrich (St. Louis, MO). Ethanol was obtained from Pharmco (Brookfield, CT). Ammonium chloride was purchased from Mallinckrodt Baker, Inc. (Phillipsburg, NJ). Water was double-distilled and filtered with a Milli-Q ultrapure water purification system (Billerica, MA). 2.2. Crystallization of Form V of FFA Using Salts as Additives. Method 1. Needle-shaped crystals of FFA were crystallized by cooling a supersaturated solution containing ammonium chloride in a FFA:NH4Cl ) 1:2 molar ratio. The solution was prepared by first dissolving the required amounts of salts in 10 mL of an ethanol–water mixture (80:20 v/v %) and, then, adding FFA powder (1.4 g) to the solution. This solution was kept at 65 °C. The supersaturated solution was transferred to a Petri dish. The Petri dishes were kept undisturbed under the hood at room temperature.

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Figure 3. X-ray diffraction patterns of the FFA crystal face grown in the absence of NH4Cl (1), calculated FFA I (second top), and FFA crystal faces grown in the presence of NH4Cl (1′-4′). The numbers shown in X-ray diffraction correspond to the numbers shown in Figure 2.

j face of FFA I. The molecules Figure 4. Surface topology of the (202) expose all hydrogen bonding sites to the surface, allowing both carboxylic acid and amine moieties to interact with the ammonium chloride.

Figure 5. Pictures of the form V of FFA polymorph (a) grown with salts and (b) grown with salts using a slow evaporation method. Method 2. The needle-shaped crystals can only be isolated when crystals were grown by a slow evaporation method. A 1 mL portion of the solution prepared in method 1 was diluted 15 times with the pure ethanol–water mixture, transferred to a scintillation vial, and kept undisturbed at room temperature. The solution was evaporated where a scintillation vial was half-closed by tilting the cap on top of a vial under ambient conditions. The number of repetitions was 10. 2.3. Powder X-ray Diffraction (PXRD). Powder X-ray diffraction (PXRD) analysis was performed on needle-shaped FFA crystals using a Siemens X-ray diffractometer equipped with Cu KR radiation. Samples were analyzed over a 2θ range of 4–40° at the rate of 4°/min. Reference powder patterns of FFA I and III were calculated with Mercury 1.4 (The Cambridge Crystallographic Data Centre, Cambridge, UK). 2.4. Elemental Microanalysis. Elements C, H, N, and O are analyzed by combustion with a Perkin-Elmer 2400 Series II analyzer. F and Cl were analyzed by suitable wet chemical methods.

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Figure 6. Picture of the crystallization process of FFA V (left) and schematic diagrams of a slow evaporation method (a) form V in solvent, (b) needle-shaped FFA crystals, and (c) solution containing FFA (right). Table 1. Comparison of Elemental Microanalysis Results between Pure FFA and Needle-Shaped FFA Crystals Grown in the Presence of NH4Cl (w/w %)

C

H

O

N

F

Cl

calculated pure FFA FFA V

59.8 59.7

3.6 3.7

11.4 11.6

5 4.9

20.3 20.0

0.1

2.5. Differential Scanning Calorimetry (DSC). The Perkin-Elmer DSC-7 differential scanning calorimeter was used to investigate the thermal behavior of needle-shaped crystals of FFA. The temperature scale was calibrated by measuring the onset temperature of melting of an indium standard. The aluminum pans were hermetically sealed, and the heating rate was 10 °C/min from 40 to 150 °C. Data were acquired and analyzed using Perkin-Elmer’s Pyris software. 2.6. Fourier Transform Infrared Spectroscopy (FT-IR). FT-IR measurements were performed using a Bio-Rad FTS 6000 Spectrometer with a DTGS detector and KBr beam splitter. The scan range was set from 500 to 4000 cm-1 with a 4 cm-1 resolution, and each spectrum was obtained by coadding 256 scans. A Specac ATR sample accessory with a diamond window was used for these measurements. 2.7. Solid State Nuclear Magnetic Resonance (ssNMR). Spectra were obtained using a Chemagnetics CMX-400 spectrometer (Varian, Inc., Palo Alto, CA) equipped with three high-power RF channels and a sample temperature control unit. 13C cross polarization with a double resonance magic angle spinning (MAS) probe was obtained at 100.6 MHz (400.3 MHz ) 1H). The powder sample was placed inside a 4 mm rotor. The spin rate was 8.00 kHz. Spectra were collected using a 90° pulse (4.00 µs) with proton decoupling and a pulse delay of 3.0 s.

3. Results and Discussion 3.1. Stabilization of Form V of FFA. Metastable forms are often not observable because they transform to the stable form quickly. To be able to observe these forms, they have to be stabilized. In the present case, we managed to stabilize the metastable form of FFA, by using a salt additive in an ethanol–water mixture. Without a salt additive, form I or form III is crystallized in the ethanol–water mixture. Four different ratios of FFA:NH4Cl (5:1, 4:1, 3:1, and 2:1 ) FFA: NH4Cl) were selected for crystallization of the metastable form V of FFA crystals. At low concentrations of ammonium chloride in solution, the morphology of FFA I crystals changed showing the specific interactions between salts and FFA. FFA I grows into hexagonal shape crystals (Figure 2a) from the pure ethanol–water mixture. However, when smaller amounts (1:4, 1:5) of ammonium chloride are added to the solution, the morphology of FFA I crystals changes into tablet shaped crystals with rectangular top faces (Figure 2b). This change in morphology can be understood by considering the surface chemistry of each of the crystals. The crystal morphology was indexed using a powder X-ray setup. A number in front of each legend in Figure 3 corresponds to the number on each face of the crystal in Figure 2. On the basis of calculations using unit cell

Figure 7. Powder X-ray diffraction patterns of (a) calculated FFA III, (b) calculated FFA I, and (c) the needle-shaped FFA polymorph.

Figure 8. DSC thermogram of needle-shaped FFA polymorph showing the onset of the exothermal transition at 103.52 °C with an enthalpy of transition of -3.3 kJ/mol.

parameters and morphology predictions using Materials Studio Modeling 4.0 (Accelrys Software Inc. CA), it is found that 1 j face, and and 1′ correspond to the (100) faces, 2′ to the (202) j faces. On the basis of the indexing, we 3′ and 4′ to the (111) j observe that the ammonium chloride strongly favors the (202) face, causing dramatically different crystal morphology. Figure j face of FFA I. In this crystallographic 4 shows the (202) orientation, the molecules are orientated perfectly parallel to the surface, exposing all hydrogen bonding sites. This allows both carboxylic acid and amine moieties to interact with the ammonium chloride, which may explain why this crystal face is strongly inhibited in the presence of ammonium chloride. At even higher concentrations, this inhibition may become so strong as to completely inhibit the growth and/or nucleation of this polymorph. Clearly, at the higher concentrations of ammonium chloride (>1:3), form V becomes the dominant polymorph. Since at the present time the crystal structure of form V is not known, it is impossible to conclude whether and how this effect would also hamper the nucleation of form V. However, it seems very likely that these effects are strongly related. However, any attempt to harvest needle-shaped crystals of FFA in the presence of solvent resulted in a rapid polymorphic transformation. Therefore, a slow complete evaporation method was chosen to avoid polymorphic transformation in the presence of solvent (Figure 5). The concentration of a solution containing FFA and NH4Cl was very low at the beginning (as described in the Experimental Section). Ethanol is a good solvent for FFA, and water is a poor solvent for FFA.

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Figure 9. Comparison of IR spectra of (a) FFA V named by Krc, (b) FFA IV named by Kuhnert, and (c) needle-shaped FFA. Panel a reprinted from ref 27 with permission from McCrone Research Institute. Copyright 1977 Microscope Publications. Panel b reprinted with permission from ref 28. Copyright 1974 Wiley-VCH Verlag GmbH & Co. KgaA.

Figure 11. Crystal packing motifs of flufenamic acid (a) form I and (b) form III, showing intra- and intermolecular hydrogen bondings.

Figure 10. IR spectra of FFA form I, FFA form III, and needle-shaped FFA. The frequency region ranged (a) from 500 to 1000 cm-1 and (b) from 2900 to 3700 cm-1 showing differences in CdO stretching and NsH stretching between polymorphs. Table 2. Infrared Spectra Region and Corresponding Characteristic Absorptions (cm-1) of FFA I, III, and V functional group

FFA I

FFA III

FFA V

CdO (carboxylic acids) NsH stretching

1649.134 3311.769

1652.991 3309.84

1647.205 3325.271

Droplets of solvent containing FFA on the wall of a scintillation vial appeared during evaporation. Evaporation of ethanol–water mixtures, ethanol–water mixtures containing salt, and ethanol–water mixtures containing salt and FFA were conducted under the same condition. The ethanol–water mixture did not produce droplets on the wall of the vial as opposed to both the ethanol–water mixtures containing salt and salt and

FFA. Needle-shaped crystals of FFA seemed to nucleate in the droplets and started growing (Figure 6 left) downward as the solvent evaporated. A gap between crystals (Figure 6b) and the solvent (Figure 6c) in a vial was observed all the time during crystallization (Figure 6). It seems that the gap is a thin film of a solution which contains a high concentration of solutes. As the solvent evaporates, crystals are quickly formed on the wall of the vial. It can not be said that crystals were not exposed to the solvent during crystallization all the time because crystals were exposed to the solution film. However, less exposure of crystals to the solvent was observed at least when crystals nucleated and began to grow. Another important factor leading to the formation of form V was to use a very low concentration of FFA at the beginning of crystallization. Therefore, crystals can be grown on the wall of a vial as the solvent evaporates (see Figure 6). Solution containing a high concentration of FFA produced crystals containing large amounts of solvent between crystals. Therefore, solvents could not be rapidly evaporated during drying, thus inducing a polymorphic transformation. Apparently, in our crystallization method, the metastable form could be isolated because of the rapid evaporation of the solvent from the walls of the vial.

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Figure 12. ssNMR of FFA I, FFA III, and the needle-shaped FFA polymorph. Adapted from ref 33.

3.2. Characterization of Needle-Shaped FFA Crystals. The free energy relationships between the known eight polymorphs were established. However, only powder X-ray patterns of forms I, II, and III and IR spectra of forms I, II, III, IV, and V are available. The crystal structures have only been determined for forms I and III. Therefore, thermal behavior, powder X-ray patterns, and IR spectra must be compared in order to identify the needle-shaped crystals. Elemental microanalysis was conducted to determine the purity of the needles since a high quantity of ammonium chloride was used for crystallization, which may have caused it to have been incorporated within the crystals. The elemental microanalysis results are summarized in Table 1. There is no indication that ammonium is incorporated, but a small amount of chloride (0.1%) was detected. FFA crystals grown by adding a salt additive to a solution were very fine needle-shaped crystals. An attempt to analyze the crystal structure using single crystal X-ray analysis failed because the needles were too thin and grew in close-packed bundles of needles. The powder X-ray pattern of needle-shaped FFA was quite different from the calculated powder patterns of FFA I and III (Figure 7). Needle-shaped FFA shows distinct peaks at 6°, 7.44°, 10.52°, 12.56°, and 14.32° 2θ, whereas form I has peaks at 7.08° and 16.12° and form III shows peaks at 4.48° and 8.88° as determined from the reference structures in the CSD. A separate source reports interplanar distances, or d values (Å), of form II.27 Corresponding peak positions would be at 8.49°, 12.04°, 12.57°, 15.12°, and 16.23°. This shows that our needle-shaped FFA corresponds to none of the forms I, II, or III. DSC was used to compare our crystals with the thermal relationships between known polymorphs of FFA as described by Krc,27 Kuhnert-Brandstäter,28 and Burger.30 The DSC thermogram showed an exothermal transition at 103.52 °C, followed by a melting endotherm at 134 °C (Figure 8). The melting points of form I and form III are 134 and 126 °C, respectively. Therefore, this exothermal transition, according to the “heat of transition rule”, confirms that the needle-shaped FFA crystal is likely to be monotropically related with respect to form I.18 On the basis of the exothermal transition temper-

ature, the needle-shaped crystal is likely to be form V in the nomenclature of Burger and Krc and called form IV by KuhnertBrandstäter. IR spectra of other known polymorphs of FFA were compared with the spectrum of needle-shaped FFA. The spectrum of needle-shaped FFA looks similar to the spectra of FFA form V named by Krc and FFA form VI named by Kuhnert-Brandstater. There are small differences between those three spectra in Figure 9. However, thermal data published by Burger combined with IR spectra confirm that this form is likely to be form V named by Krc.30 Structural Analysis of Molecular Interactions in FFA V. Structural analysis of molecular interactions in FFA V was conducted by comparing FFA I, III, and V in terms of color, morphology, PXRD, FT-IR spectra, and ssNMR spectra. FFA I has four molecules per unit cell and has cell parameters of a ) 12.4329, b ) 7.7790, and c ) 12.7096 Å and β ) 94.76°, while FFA III has eight molecules per unit cell and has cell parameters of a ) 39.589, b ) 5.0568, and c ) 11.981 Å and β ) 92.09°. FFA III has a unit cell with long a axis and crystallizes into long needle-shaped crystals. However, FFA I has a much more isotropic unit cell and crystallized into plateshaped crystals. FFA III powders are yellow, while FFA I powders are white. As shown in Figure 1, the needle-shaped form crystallizes into white long needles. As shown in the PXRD of FFA I, III, and V (Figure 7), FFA V shows its first peak between the peaks of FFA I and FFA III which corresponds to a d value of about 14.72 Å. FT-IR was used to study changes in specific interactions by comparing the spectrum of FFA V to the spectra of FFA I and III. The spectrum of the needle-shaped FFA resembles that of FFA III in area 1, while it resembles form I in area 3 (Figure 10). In area 2, the spectrum of the needle-shaped FFA has a unique appearance, resembling neither. Region 3 corresponds to the CdO stretching of the carboxylic acid dimer. FFA III shows a peak with a shoulder and so does FFA V. However, FFA V is more similar to FFA I in terms of the CdO stretching frequency (see Table 2). In the 3300 cm-1 wavenumber region which is in the NsH stretching frequency region, the spectrum

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Figure 13. Polymorphic transformation of FFA V in the presence of solvent in ambient conditions: (a) before polymorphic transformation occurs, (b) 0 s (starting point), (c) 1 min 20 s, (d) 2 min, (e) 2 min 47 s, (f) 4 min 4 s, (g) 8 min 47 s, and (h) 11 min 47 s.

of the needle-shaped FFA is shifted higher in frequency by about 15 cm-1 with respect to the spectra of form I and form III (Table 2). The differences in the NH stretching region between FFA V and FFA I and III are large as compared to the shift in CdO stretch frequencies. The CdO bonds of FFA I and FFA III are strongly involved in the carboxylic dimerization in the crystalline state. FFA I and III form intermolecular hydrogen bonding forming carboxylic acid dimers and intramolecular hydrogen bonding between the carboxylic acid and the amine (Figure 11). Therefore, the higher frequency of the NH stretches suggests a difference in conformation, where the intramolecular hydrogen bond might be weaker than in the case of FFA I and FFA III. ssNMR confirms this difference in the electronic structure of the carboxylic acid carbon. The peaks around 174 ppm of FFA form I and form III in the ssNMR are assigned to these carboxyl carbons. However, the needle-shaped FFA has the carboxyl carbon peak shifted to 178 ppm (Figure 12). This downfield shift suggests that the carboxylic carbons of FFA V are experiencing less shielding when compared to those in the FFA I and III crystals. Solution NMR of FFA in previous study shows that chemical shifts of carboxylic acid carbon of FFA is around 174 ppm in toluene and cyclohexane and around 171 ppm in ethanol and the ethanol–water mixtures. It was assumed that in toluene or in cyclohexane FFA exists mainly as a dimer and

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in ethanol or in an ethanol–water mixture FFA exists as monomers having strong interactions with the solvent. The particular chemical shift of form V suggests that the electronic structure around the carboxylate carbon of form V is different from that of forms I and III. When NMR data is combined with IR spectra data, it is likely that form V has a carboxylic acid dimer with different intramolecular hydrogen bonding due to a difference in conformation which allows weaker intramolecular hydrogen bonding than those of forms I or III. For example, if there is relatively weak intramolecular hydrogen bonding between carboxylic acid and amine of FFAV when compared to form I or form III, the carboxylic acid carbon of form V can have relatively more deshielding due to the lack of electrons as the amine may act as an electron donating group. However, chains, catemers, or a 2-dimensional network as a hydrogen bonding motif in form V cannot be completely excluded due to the lack of single crystal X-ray data. 3.3. Polymorphic Transformation Behavior of FFA V. As mentioned in earlier, FFA V undergoes rapid polymorphic transformation when crystals are in contact with the solvent. Figure 13 shows this polymorphic transformation of FFA V. The polymorphic transformation from FFA V to FFA III has some characteristic features. The morphology of crystals was not changed during polymorphic transformation. FFA V is completely white at the beginning as shown in Figure 13a. However, instantaneous polymorphic transformation occurs, especially by disturbance of the system, for example, by opening the top of the Petri dish (Figure 13b and c). Once nuclei form, the stable form grows outward throughout the Petri dish. In order to study nucleation by disturbance of the system, crystals of form V were intentionally disturbed. Figure 13d shows a hole which was formed by scooping a small amount of material from the Petri dish. Polymorphic transformation started from this hole and extended outward. Our speculation is that salt may play a role in stabilizing FFA V in the solvent; however, the interaction between FFA and salts are weak, and thus polymorphic transformation can easily occur by disturbance in the system. As described previously, the shape of crystals does not change after the polymorphic transformation. This indicates that the stable form is not formed via complete dissolution of the metastable form and nucleation and crystallization of the stable form in the presence of solvent. However, the rate of polymorphic transformation is higher in the presence of solvent when compared to that in the absence of solvent. Therefore, solvent seems to play a role in the polymorphic transformation. It also seems that the polymorphic transformation occurs via interface mediated polymorphic transformation.31,32 In interface mediated polymorphic transformation, it is proposed that the phase transition occurs via a thin layer of solvent between the stable form and the metastable form in a single crystal. Therefore, it is possible to maintain its original shape after the transformation. This can be extended to crystals in contact in our case. Therefore, the polymorphic transformation proceeds through the contacted crystals and thus for entire crystals in the Petri dish (Figure 13). 3.4. Free Energy Relationships between FFA Polymorphs. There is previously published data on the free energy relationships between FFA polymorphs.27,30 On the basis of a diagram of the free energy relationships between FFA polymorphs, FFA form V is less stable than FFA I, II, and III in the temperature range from 0 °C to its melting point. This explains the difficulty in obtaining this form and of preventing polymorphic transformation of this form.

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4. Conclusions

(8) Staab, E.; Addadi, L.; Leiserowitz, L.; Lahav, M. AdV. Mater. 1990, 2, 40–43. (9) Davey, R. J.; Blagden, N.; Potts, G. D.; Docherty, R. J. Am. Chem. Soc. 1997, 119, 1767–1772. (10) Weissbuch, I.; Zbaida, D.; Addadi, L.; Leiserowitz, L.; Lahav, M. J. Am. Chem. Soc. 1987, 109, 1869–1871. (11) Zbaida, D.; Lahav, M.; Drauz, K.; Knaup, G.; Kottenhahn, M. Tetrahedron 2000, 56, 6645–6649. (12) Miura, H.; Ushio, T.; Nagai, K.; Fujimoto, D.; Lepp, Z.; Takanhashi, H.; Tamura, R. Cryst. Growth Des. 2003, 3, 959–965. (13) Yu, L. J. Am. Chem. Soc. 2003, 125, 6380–6381. (14) Chen, S.; Xi, H.; Yu, L. J. Am. Chem. Soc. 2005, 127, 17439–17444. (15) Mitchell, C. A.; Yu, L.; Ward, M. D. J. Am. Chem. Soc. 2001, 123, 10830–10839. (16) Lee, E.; Byrn, S. R.; Carvajal, M. T. Pharm. Res. 2006, 23, 2375– 2380. (17) Vishweshwar, P.; McMahon, J. A.; Oliveira, M.; Peterson, M. L.; Zaworotko, M. J. J. Am. Chem. Soc. 2005, 127, 16802–16803. (18) Tessier, P. M.; Lenhoff, A. M. Curr. Opin. Biotechnol. 2003, 14, 512– 516. (19) Smith, P. E. J. Phys. Chem. B 1999, 103, 525–534. (20) Comis, V.; Ruiz, F.; Boluda, N.; Saquete, M. D. Ind. Eng. Chem. Res. 1998, 37, 599–603. (21) Bhat, M. N.; Dharmaprakash, S. M. J. Cryst. Growth 2002, 236, 376– 380. (22) Bhat, M. N.; Dharmaprakash, S. M. J. Cryst. Growth 2002, 242, 245– 252. (23) Towlder, C. S.; Davey, R. J.; Lancaster, R. W.; Price, C. J. J. Am. Chem. Soc. 2004, 126, 13347–13353. (24) Ghosh, T.; Kalra, A.; Garde, S. J.Phys. Chem. B 2005, 109, 642–651. (25) van der Vegt, N. F. A.; van Gunsteren, W. F. J. Phys. Chem. B 2004, 108, 1056–1064. (26) Kalra, A.; Tugcu, N.; Cramer, S. M.; Garde, S. J. Phys. Chem. B 2001, 105, 6380–6386. (27) Krc, J., Jr Microscope 1977, 25, 31–45. (28) Kuhnert-Brandstäter, M.; Borka, L.; Friedrich-Sander, G. Arch. Pharm. 1974, 307, 845–853. (29) Galdecki, Z.; Glowka, M. L.; Gorkiewicz, Z. Acta Pol. Pharm. 1978, 35, 77–79. (30) Burger, A.; Ramberger, R. Mikorchim. Acta 1980, 1, 17–28. (31) Sato, K. J. Phys. D: Appl. Phys. 1993, 26, B77–B84. (32) Boerrigter, S. X. M.; van den Hoogenhof, C. J. M.; Meekes, H.; Bennema, P.; Vlieg, E.; van Hoof, P. J. C. M. J. Phys. Chem. B. 2002, 106, 4725–4731. (33) Tishmack, P. A.; Bugay, D. E.; Byrn, S. R. J. Pharm. Sci. 2003, 92, 441–474.

Our studies show that the metastable form V of FFA can be crystallized and stabilized by using ammonium chloride as an additive in a water-ethanol mixture. Form V could not be harvested directly because of interface mediated polymorphic transformation. This transformation was circumvented by using a slow evaporation method, allowing characterization of this form. On the basis of the characterization of needle-shaped FFA crystals using DSC, PXRD, ssNMR, and IR, our needle-shaped FFA crystals are positively identified as the metastable form V named by Krc and Burger.27,30 On the basis of morphology changes as a function of salt concentration, it is likely that the salt additive acts as a tailor-made additive which inhibits the nucleation of more stable polymorph and, thus, induces FFA form V. Salts show the potential to induce the metastable polymorph. However, it is apparent that the crystallization method is also important. Furthermore, choosing the right crystallization method which can inhibit polymorphic transformation can only be possible when the system is well-understood. Acknowledgment. We thank Carl J. Murphy for assistance with ssNMR spectra. The authors are grateful for the financial support from the Purdue-Michigan Program on the Chemical and Physical Stability of Pharmaceutical Solids.

References (1) Byrn, S. R.; Pfeiffer, R. R.; Stowell, J. G. Solid-State Chemistry of Drugs, 2nd ed.; SSCI: West Lafayette, IN, 1999. (2) Bauer, J.; Spanton, S.; Henry, R.; Quick, J.; Dziki, W.; Porter, W.; Morris, J. Pharm. Res. 2001, 18, 859–866. (3) Weissbuch, I.; Lahav, M.; Leiserowitz, L. Cryst. Growth Des. 2003, 3, 125–150. (4) Weissbuch, I.; Torbeev, V. Y.; Leiserowitz, L.; Lahav, M. Angew. Chem., Int. Ed. 2005, 44, 3226–3229. (5) Berkovitch-Yellin, Z.; van Mil, J.; Addadi, L.; Idelson, M.; Lahav, M.; Leiserowitz, L. J. Am. Chem. Soc. 1985, 107, 3111–3122. (6) Addadi, L.; Berkovitch-Yellin, Z.; Weissbuch, I.; van Mil, J.; Shimon, L. J. W.; Lahav, M.; Leiserowitz, L. Angew. Chem., Int. Ed. Engl. 1985, 24, 466–485. (7) Torbeev, V. Y.; Shavit, E.; Weissbuch, I.; Leiserowitz, L.; Lahav, M. Cryst. Growth Des. 2005, 5, 2190–2196.

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