Pleconaril Polymorphs: Crystal Structures of Form I and Form III, Evidence of the Enantiotropy, and Assessment of the Structural Purity Servane Coste,† Jean-Marie Schneider,‡ Marie-Noe¨lle Petit,† and Ge´rard Coquerel*,†
CRYSTAL GROWTH & DESIGN 2004 VOL. 4, NO. 6 1237-1244
UC2M2, EA3233, IRCOF, Universite´ de Rouen, 76821 Mont Saint Aignan, France, and PCAS, Site de Seloc France, 78520 Limay, France Received July 10, 2004
ABSTRACT: Form I (HT) and form III (LT) of pleconaril are enantiotropically related with a calculated temperature of transition Tτ ) 35.7 °C (supposing an ideal behavior). Structural data obtained from single crystal X-ray diffraction at 100 K and room temperature show that (i) form I (HT) can be described as a network of dimers and form III can be described as a three-dimensional weakly H-bonded network of monomers. (ii) These two varieties contradict the density rule. (iii) The solid-solid transition (not observed) could only occur via a destructive-reconstructive mechanism. Investigations on the pleconaril-ethanol binary system show that the conversion form I S form III at Tτ ) 31 ( 2 °C is only possible when mediated by a solvent. A favorable set of thermodynamical and kinetic conditions allows quantification of form I in form III down to 0.1% by using differential scanning calorimetry. To assess the structural purity, this method could be applied to other compounds fulfilling five restrictive conditions. Introduction When an organic compound exhibits polymorphism of an enantiotropic type, the knowledge of the different domains of thermodynamic stability for every form is essential in order to obtain the desired form by a robust crystallization process and to define the appropriate storage condition. Up to now, the literature1 reports three polymorphic forms for pleconaril (Figure 1): form I (stable above 40 °C), form II (which transforms into form III at room temperature) and form III (stable at room temperature) already characterized by differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), and Fourier transform infrared. Forms I and III, which appear to be the two solids in competition in almost every process of crystallization, will be the main objects of this study. The aims of the study are (i) to determine the temperature of transition from form III S form I; (ii) to resolve form III and form I structures from single crystals, allowing the unambiguous indexing of the XRPD patterns; and (iii) to perfect a method designed to assess the structural purity of form III, which was chosen in the pharmaceutical formulation. Experimental Section Pleconaril was provided by PCAS Co. (Limay, France) with a high-perfomance liquid chromatography purity higher than 99.5%. Crystal Structure Determinations. Single crystals of form I were obtained from a solution of pleconaril in ethanol (49% mass in solute). After the full dissolution of the solute at 40 °C, the clear solution was cooled to 35 °C and then seeded with pure form I crystals. Thirty minutes after the inoculation, * To whom correspondence should be addressed. Tel and Fax: 33(0)2 35 52 29 27. E-mail:
[email protected]. † Universite ´ de Rouen. ‡ PCAS.
Figure 1. Formula of pleconaril, i.e., 3-{3,5-dimethyl-4-[3(3-methyl-isoxazol-5-yl)propoxy]phenyl}-5-trifluoromethyl[1,2,4]oxodiazole. long and fine needles suitable for X-ray analysis were collected by filtration on a preheated (35 °C) glass filter. Single crystals of form III were obtained by slow evaporation of an ethyl alcohol solution at room temperature. Because of the high thermal motion of CF3 moieties at room temperature, the reflection intensities of both forms were also collected at 100 K on a Bruker SMART APEX X-ray diffractometer using a graphite-monochromatized Mo KR1 radiation (0.71073 Å). Three sets of exposures (1800 frames) were recorded, corresponding to three ω scans, for three different values of φ (φ ) 0, 120, and 180°). Form I and form III structures were solved by means of the direct methods and refined with the SHELXTL (v 6.10) program.2 XRPD. XRPD data were obtained on a Siemens D5005 apparatus (θ-θ set; fixed slits, 1.6 mm) with Cu KR radiation (1.54056 Å) (Ni Kβ filter) under 40 kV and 30 mA and collected on a scintillation detector. The range of measurement lies between 3 and 30° (step, 0.02°; step time, 10 s). Experimental data were processed with EVA (v 9.0) software.3 The θ angle calibrations were carried out by using Siemens slits and a quartz sample (secondary standard). DSC. DSC was performed on a Setaram DSC 141 instrument. Samples (15-20 mg) were put in a 30 µL open aluminum crucible and melted under various heating rates (between 0.5 and 10 °C/min); no purge gas was used. The system was calibrated with indium (mp 156.6 °C) and benzoic acid (mp 122 °C, secondary standard). Solubility Measurements. A suspension composed of saturated solution and crystals was prepared in a thermostated ((0.2 °C) glass tube and stirred with a magnetic rod for 24 h. One hour before sampling, the stirring was stopped and the solid was allowed to settle. A small amount of saturated solution was carefully pipetted in a syringe previously adjusted at the same temperature as the liquid to be sampled. The saturated solution was poured into a tared flask
10.1021/cg049766r CCC: $27.50 © 2004 American Chemical Society Published on Web 10/12/2004
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Table 1. Measurement Conditions and Crystallographic Parameters for Forms I and III at Room Temperature and at 100 K form I (HT temp form) temperature chemical formula formula weight (g mol-1) density (calcd, g cm-3) crystal system space group cell parameters a (Å) b (Å) c (Å) R (°) β (°) γ (°) V (Å3) Z crystal description color crystal size (mm3) linear abs. coeff. (cm-1) no. of measured/independent/ observed reflections [I > 2σ(I)] R1 (obs)a wR2 (obs)a R1 (all)a wR2 (all)a a
100 K
296 K
1.453
1.364
form III (LT temp form) 100 K C18H18F3N3O3 381.35 1.379
296 K 1.325
triclinic P1 h 4.6696(4) 11.9275(10) 15.8830(14) 88.5210(10) 87.4750(10) 80.6750(10) 871.94(13)
monoclinic P21/c 4.8343(9) 11.984(2) 16.206(3) 89.447(3) 88.427(3) 81.715(3) 928.7(3)
9.2526(5) 21.0339(11) 9.6352(5) 90 101.5240(10) 90 1837.38(17)
9.4044(5) 21.0539(11) 9.9067(5) 90 102.9693(10) 90 1911.48(17)
2 rod colorless 0.7 × 0.3 × 0.2 0.121 7044/3523/3089
4 rod colorless 1.0 × 0.4 × 0.2 0.115 14530/3742/3283
0.0379 0.1037 0.0419 0.1069
0.0342 0.0928 0.0385 0.0955
R1 ) ∑(||FO| - |FC||)/∑|FO|, wR2 ) [∑[w(FO2 - FC2) 2]/∑[w(FO2)2]]1/2.
and then evaporated and weighed at room temperature until a constant mass was obtained. The solid remaining in the tube was quickly filtered off, dried, and analyzed by means of XRPD in order to determine the form of the solid in equilibrium with each saturated solution.
Results and Discussion Crystal Structure Determinations. Data Collection. Form I. A rodlike crystal was isolated from the as-prepared sample and glued at the tip of a glass fiber by means of epoxy resin. The Bragg reflections were indexed according to a triclinic cell with a ) 4.8343(9) Å, b ) 11.984(2) Å, c ) 16.206(3) Å, R ) 89.447(3)°, β ) 88.427(3)°, γ ) 81.715(3)°, and V ) 928.7(3) Å3 and with a ) 4.6696(4) Å, b ) 11.9275(10) Å, c ) 15.8830(14) Å, R ) 88.5210(10)°, β ) 87.4750(10)°, γ ) 80.6750(10)°, and V ) 871.94(13) Å3 for room temperature and 100 K data collections, respectively. Form III. The same process as that used for form I was carried out. The Bragg reflections recorded from a rodlike crystal were indexed in a monoclinic system with a ) 9.4044(5) Å, b ) 21.0539(11) Å, c ) 9.9067(5) Å, β ) 102.9693(10)°, and V ) 1911.48(17) Å3 and with a ) 9.2526(5) Å, b ) 21.0339(11) Å, c ) 9.6352(5) Å, β ) 101.5240(10)°, and V ) 1837.38(17) Å3 for room temperature and 100 K data collections, respectively. Structure Refinements. Form I. The initial refinement was performed on the room temperature data set. After the empirical absorption correction, the reflections were merged according to the 1 h point group leading to Rint ) 0.0279. Nonhydrogen atoms were located with initially isotropic and then anisotropic displacement parameters. Hydrogen atoms were located by calculations. The F2 residue factor quickly converged to R1/wR2 ) 0.0889/0.3205 for 2373 observed reflections [I > 2σ(I)] and 248 parameters. At this stage, an important electronic residue was observed in the difference Fourier synthesis around F, C13, and C14 atoms and could be
suppressed by splitting these atoms. The reliability factors converged then to R1/wR2 ) 0.0586/0.1783 for 295 parameters. Analysis of the Uij values of all of the atoms and, more especially, fluorine atoms suggested an important thermal displacement. To improve this result, a data collection at 100 K was performed on the same single crystal. Anisotropic displacement parameters were refined for nonhydrogen atoms. Hydrogen atoms were located from subsequent difference Fourier syntheses (except for the methyl groups C10, C11, and C18) and refined isotropically. The reliability factor converged then to R1/wR2 ) 0.0379/0.1037 for 3089 observed reflections [I > 2σ(I)] and 284 parameters, including a secondary extinction coefficient. No disorder on the F, C13, and C14 atoms was observed, and as expected, all of the anisotropic displacement parameters were significantly reduced. Form III. The initial refinement was performed on the room temperature data set. After the empirical absorption correction, the reflections were merged according to the 2/m point group, leading to Rint ) 0.0246. The conventional space group P21/c was found to be compatible with the observed extinction rules. Anisotropic displacement parameters were refined for nonhydrogen atoms. Hydrogen atoms were located from subsequent difference Fourier syntheses (except for the methyl groups C10, C11, and C18) and refined isotropically. The F2 residue factor quickly converged to R1/ wR2 ) 0.0651/0.1976 for 2599 observed reflections [I > 2σ(I)] and 283 parameters. Once again, a strong disorder was observed on the fluorine atoms. To reduce the thermal motion of the fluorine atoms, a data collection was performed at 100 K. By introducing the atomic coordinates refined previously, the F2 residue factor quickly converged to R1/wR2 ) 0.0342/0.0928 for 3283 observed reflections [I > 2σ(I)] and 283 parameters. Crystallographic data, refinement details, and related results are summarized in the Table 1
Pleconaril Polymorphs: Forms I and III
Crystal Growth & Design, Vol. 4, No. 6, 2004 1239 Table 2. Torsion Angles of the C15-C14-C13-C12-O2-C7 Chain at 100 K C16-C15-C14-C13 C15-C14-C13-C12 C14-C13-C12-O2 C13-C12-O2-C7 C12-O2-C7-C8
Figure 2. ORTEP drawing of form I (upper) and form III (lower) with the adopted numbering scheme for nonhydrogen atoms. All nonhydrogen atoms are represented by their displacement ellipsoids drawn at the 50% probability level. Hydrogen atoms are drawn with an arbitrary radius.
Structure Description (Figure 2). In the following text, the numeric values refer to the structures recorded at 100 K. As expected, the three rings (oxadiazole, phenyl, and isoxazole) have a planar conformation (Figure 3). In form I, the oxadiazole ring plus the phenyl moiety [C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, O1, O2, N1, and N2 (defined as plane π1)] are almost coplanar and the following set of atoms [C14, C15, C16, C17, C18, O3, and N3 (defined as π2)] is also coplanar; π1 and π2 are 15.7° apart. The average RMS deviations are 2.92e-02 and 4.91e-02, respectively, for atoms belonging to π1 and π2 planes. In the molecule of form III, the same structural features are observed except that C12 and C13 atoms can also be considered as belonging to plane π2. Therefore, in form III, every atom lies differently from hydrogen and fluorine atoms whether in plane π1 or in plane π2, which are 10.83° apart. The average RMS deviations are 1.51e-02 and 2.67 e-02, respectively, for atoms belonging to π1 and π2 planes. The difference between both conformations results mainly from the five torsion angles of the propyloxy chain (C15-C14-C13-C12-O2-C7) connecting the two aromatic moieties (Table 2).
form I
form III
139.88(18) -170.24(13) -63.55(17) 170.19(11) -92.23(14)
-0.5(2) 176.82(10) 67.86(14) -167.3(1) -83.50(13)
In form I, the inversion center-related molecules are connected in a head to head fashion forming a four-point hydrogen-bonded synthon involving C-H‚‚‚N and C-H‚‚‚O hydrogen bonds (Figure 4). The C-H‚‚‚N hydrogen bonds are located between the H5 atom of the phenyl group and the N1 atom of the oxadiazole ring, and the C-H‚‚‚O bonds are located between the H10a atom of the C10 methyl group and the O1 atom of the oxadiazole ring. These dimers are themselves related by π-π stacking interactions (dC6-C9 ∼ 3.48 Å) of neighboring phenyl groups (Figure 5a) and by weak C-H‚‚‚F and C-H‚‚‚O hydrogen bonds. Considering the metrical data of the hydrogen bonds in and between the synthons (Table 3), the structure could be considered as a zero-dimensional assembly. The parallel and head to head packing of molecules along the a- and b-axes and the head to tail packing along the c-axis are represented in Figure 5. In form III, the screw axis-related molecules are connected by a two-point hydrogen-bonded synthon with two different C-H‚‚‚N hydrogen bonds. One is located between the H18a atom of the C18 methyl group and the N2 atom of the oxadiazole ring and the other one between the H9 atom of the phenyl moiety and the N3 atom of the isoxazole ring. Adjacent catemer synthons, which are related by a translation along the [101] direction, are connected with C16-H16‚‚‚N1 hydrogen interaction so that a two-dimensional network is formed (Figure 4b). Moreover, the mirror c related molecules are linked through C14-H14a‚‚‚N3 interactions to form chains perpendicular to the layers (Figure 4c). The intra- and interlayer C-H‚‚‚N hydrogen distances being about the same (Table 3), the form III structure can be considered as a three-dimensional structure. Furthermore, the molecules are also connected by C-H‚‚‚F, C-H‚‚‚O, and C-H‚‚‚N hydrogen interactions and by π-π stacking interactions (dC5-C9 ∼ 3.40 Å, and dC3-C7 ∼ 3.36 Å) (Figure 6).
Figure 3. Comparison of molecular conformations of form I (upper) and form III (lower).
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Figure 4. Form I: (a) The four-point synthon. Form III: (b) Layers generated by catemer C-H‚‚‚N synthon (dashed line) connected with C-H‚‚‚N interactions (dotted line). (c) C-H‚‚‚N interactions between the layers. Table 3. Hydrogen Bond Parameters for Forms I and IIIa form I
form III
interaction
d (Å)
ϑ (°)
C-H‚‚‚O C-H‚‚‚N
2.59(1)a 2.70(2)a
167.8(1) 174.2(13)
C-H‚‚‚F
2.68(2) 2.93(1) 2.80(2) 2.81(1) 2.89(2)
129.9(14) 103.3(1) 150.0(17) 112.4(1) 113.0(13)
C-H‚‚‚O
2.80(2) 2.75(2) 2.69(1) 2.87(2) 2.95(2)
107.9(16) 124.6(12) 145.1(1) 145.5(13)
C-H‚‚‚N
d (Å)
ϑ (°)
2.73(1)b 2.69(2)b 2.63(2)c 2.61(1)d 2.93 (1) 2.62(2) 2.95(1) 2.82(2) 2.60(1) 2.59(2) 2.95(1) 2.87(2) 2.92(1) 2.82(1) 2.88(1) 2.93(1) 2.90(1)
161.76(8) 150.2(10) 176.3(12) 156.4(12) 161.9(1) 123.7(10) 112.0(1) 129.7(11) 144.1(1) 155.0(11) 104.3(10) 109.8(10) 123.1(1) 127.6(1) 152.7(1) 114.6(1) 123.7(1)
a Hydrogen bonds (a) in four-point synthon, (b) in two-point synthon, (c) with adjacent catemer synthons, and (d) between layers.
Figure 5. (a) Perspective view of form I showing the π-π stacking interactions symbolized by dashed lines. (b) Projections along the a-axis of form I.
Unexpectedly, at T ) 296 K, the density of form I (d ) 1.364) is significantly greater than that of form III (d ) 1.325), corresponding to a difference of 2.9%, which is in contradiction with the so-called density rule.4 The
evolution of the density toward low temperature even enhances this phenomenon. The densities at 100 K are d ) 1.453 and 1.379, respectively, for forms I and III (∆d ) 5.1%). The temperature lowering led to a 6% volume reduction for form I and 4% for form III. Such similar cases have already been reported.5,6 Face indexing has been carried out by using “faces option” of SMART software7 and are presented on Figure 7. For form I, (001), (010), and (011h ) faces are larger than (110) and (11h 1) faces. Taking into account the poor external quality of the form III crystal, the face
Pleconaril Polymorphs: Forms I and III
Figure 6. (a) Projection along the a-axis and (b) projection perpendicular to the layers of form III. Notice the C14H14a‚‚‚N3 (thick broken lines) and the π-π interactions between these layers (thin broken lines).
determinations could not be completely achieved. Nevertheless, it clearly appears that crystals grow also along the [100] direction. DSC Studies. Melting points and enthalpies of fusion of form I and form III measured under various heating rates are collected in Table 4. Each value corresponds to the mean of the results obtained with three different samples. With 10 and 5 °C/min heating rates, our results are close to Rocco and Swanson’s;1 that is, only a single melting peak is observed for each form, and temperatures and enthalpies are identical. When lower heating rates (1 and 0.5 °C/min) are used, similar results are obtained in the case of form I, but the scans recorded with form III are quite different (Figure 8). First, the metastable fusion of form III occurs (60.2 °C), and then, the supercooled molten liquid recrystallizes into form I, which eventually melts at 63.3 °C. This hypothesis was proved by using hot stage microscopy, i.e., a single crystal of form III undergoing heating at a 1 K min-1 rate (cf. Supporting Information). Study of the Binary System: Pleconaril-Ethanol. In consistency with the structural data (necessity of a destruction-reconstruction process during form III f form I transition), whatever the heating rate, no solid-solid transition has been detected by using DSC. As the use of solvent is beneficial to the fast establishment of thermodynamic equilibria (stable or metastable), solubilities of pleconaril in ethanol at various
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Figure 7. Optical microscopy photographs of form I (upper) and form III (lower). Both crystals preferably grow along the [100] directions. Table 4. Melting Points and Enthalpies of Fusion of Form I and Form III form I Tm (°C) 63.3 ((0.3)
∆Hm (kJ
form III mol-1)
29.3 ((0.5)
Tm (°C)
∆Hm (kJ mol-1)
60.2 ((0.3)
32.7 ((0.5)
temperatures were measured, and the solid phases in equilibrium with the saturated solutions were analyzed by means of XRPD. These data allowed us to establish the pleconaril-ethanol binary phase diagram8 (Table 5 and Figure 9). These data show that form III is stable up to 30.5 °C and form I is stable from 32 to 63.3 °C (stable melting point). It can be noted that between 30.5 and 32 °C (values in italics on Table 5), form I or form III can be obtained, which is usual when the temperature is close to the transition temperature. The experimental transition temperature can thus be estimated to 31 ( 2 °C. Quantification of Form I in Mixtures of Form III Plus Form I. By using an appropriate heating rate (5 K min-1), small amounts of form I can be detected. Figure 10a shows DSC measurements of form I-form III mixtures (5, 1, and 0.1% of form I): A first peak appears at 60.2 °C corresponding to the metastable melting of form III; then, a second phenomenon occurs at 63.3 °C, corresponding to the stable fusion of form I. Figure 10b illustrates the method used for the determination of the enthalpy of fusion of each form in a mixture.
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Figure 9. Binary diagram of the system pleconaril-ethanol (composition expressed in mass fraction).
Figure 8. DSC curves of form I (a) and form III (b) carried out at the heating rates of 5 and 0.5 K min-1. Table 5. Solubility (S) of Pleconaril in Ethyl Alcohol as a Function of Temperature (Experimental Data) and Solid in Equilibrium with the Saturated Solution T (°C)
S (mass %)
solid analysis
T (°C)
S (mass %)
solid analysis
2.1 10.0 20.0 25.0 28.0 29.2 29.5 30.0 30.5
3.1 5.1 11.2 16.2 21.4 24.2 25.0 26.3 28.0
form III form III form III form III form III form III form III form III form III
30.5 31.0 32.3 33.0 34.8 36.0 37.6 40.0 63.3
26.0 29.2 33.0 34.8 42.0 48.9 56.4 67.8 100
form I form III form I form I form I form I form I form I form I
To quantify the amount of form I in a sample, several known mixtures have been carefully prepared by successive solid state dilutions and analyzed by DSC using a 5 K min-1 heating rate. Table 6 displays for each composition: % form I (mass of form I × 100/whole mass of the mixture) and %∆Hform I defined as ∆Hform I × 100/ (∆Hform I + ∆Hform III). In the case of a mixture containing 0.1% of form I, for instance, its value, 23.65% (cf. Table 6), exceeds by far the expected result (0.1%). In fact, by using a 5 K min-1 heating rate, ca. 37 s elapses between the fusion of each polymorphic form. This period of time is not sufficient to allow the primary nucleation of form I. By contrast, if some crystals of form I are present in the molten liquid (therefore in the initial sample), they act as seeds, skipping the primary nucleation, which has
Figure 10. (a) DSC curves on samples containing 5, 1, and 0.1% of form I. (b) Method used for the determination of the enthalpy of fusion of each form in a mixture. Table 6. Percentage of Form I Enthalpy of Melting (% ∆Hform I) as a Function of the Amount of Form I in Various Solid Mixtures (% Form I) % form I % ∆Hform I % form I % ∆Hform I
100 100 40 87.49
99 99.92 20 80.54
95 99.26 10 72.39
90 99.10 5 67.39
80 97.40 1 55.63
60 93.05 0.1 23.65
0 0.00
no time to spontaneously occur, and leading to a fast secondary nucleation and crystal growth. So, a sharp amplification of the initial amount of form I occurs and can be detected by the enthalpy of melting of this high temperature variety. Because of this amplification effect, the quantification of the amount of form I in a form I + form III mixture
Pleconaril Polymorphs: Forms I and III
Figure 11. Percentage of form I enthalpy of melting vs log of percentage of form I.
Crystal Growth & Design, Vol. 4, No. 6, 2004 1243
Figure 12. Exprimental and calculated (Schroeder Van Laar equation) binary diagram of the system pleconaril-ethanol (expressed in molar fraction).
down to 0.1% of form I is feasible. When plotting %∆Hform I vs log(% form I) (Figure 11), a linear curve is obtained. The deviations estimated from three experiments for each composition are (2% for the ratio of the enthalpies, (5 × 10-3% for the composition of the mixtures, i.e., (0.02 on a log scale. Discussion The simulated patterns (calculated by using PowderCell v.2 9) exhibit good fits with experimental patterns in terms of 2θ positions. Nevertheless, intensities are quite different, due to preferential orientation effects; the use of a capillary setting prevents this drawback (cf. Supporting Information). As the structural analyses of the two modifications suggest, no endothermic effect at ca. 31 °C has ever been observed on heating form III samples (experimental heating rates ranging from 0.5 to 10 K min-1). Therefore, the DSC technique is inoperative in the experimental determination of the transition form III S form I. This solid-solid transition would have probably corresponded to a too large activation energy associated with a destructive-reconstructive mechanism. By contrast to the behaviors of pure form I and pure form III (Figure 8), some DSC curves show a very small endotherm at ca. 55 °C (Figure 10a), which might be due to some kind of effect after grinding. In consistency with this interpretation, no other phase than forms III and I (for 5% form I mixture) has been observed by means of temperature-resolved XRPD, after this phenomenon. In a binary system, if an ideal behavior is assumed, the depression of the melting point of each form is independent of the nature of the other component. Thus, by using the Schroeder Van Laar equation,10 the two calculated curves must intersect at the transition temperature. These calculations are sensitive to Tm and ∆Hm; thus, a consistent set of data is necessary. Figure 12 shows that the two curves intersect at 35.7 °C. The curves drawn using a Van’t Hoff plot (Figure 13) show a sheer nonideal behavior of the solutions of pleconaril in ethanol (the experimental temperature of transition is 31 ( 2 °C). The existence of a transition temperature between form I and form III confirms the enantiotropic character
Figure 13. Van’t Hoff plot applied to the experimental and calculated data of pleconaril.
of these two varieties. In addition, none of our experiments could give access to form II, which thus may have a monotropic behavior under normal pressure. When the five restrictive conditions listed below are fulfilled, the study presented here shows that a small amount of the high temperature form can be detected in a dimorphic system by using a differential scanning calorimeter with an appropriate heating rate Ψ. The five restrictive conditions are as follows: (i) chemical stability of the solute (no degradation on melting); (ii) sufficient difference in the melting points (several degrees Celsius); (iii) a slow enough primary nucleation rate of the high temperature form; (iv) no polymorphic transition via a solid-solid mechanism, i.e., the change in polymorphic form occurs via the supercooled molten state resulting from the metastable fusion; and (v) only two polymorphic forms are in competition at high temperature (to avoid multiple overlapping peaks). Ψ must be high enough to prevent the primary nucleation of form I in the supercooled liquid. Considering this prerequisite condition fulfilled, Ψ is advantadeously adjusted as low as possible to promote the maximum secondary nucleation and crystal growth of the high temperature form seeds. Within the frame of these restrictions, this method could be of interest in the difficult problem of structural purity assessment.
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Conclusion In consistency with extensive differences in crystal packings, DSC studies on form III, under various heating rates, have failed to detect any solid-solid transformation (form III f form I) of pleconaril. The stability domains of form I and form III of pleconaril have been determined by establishing a large part of the isobaric binary phase diagram, ethanol-pleconaril. Despite significant deviation from the ideal behavior, the experimental and calculated temperatures of transition (Tτ ) 31 ( 2 and 35.7 °C, respectively) are not very different. A quantitative method for measuring the amount of form I in mixtures form I + form III has been perfected by means of simple DSC measurements using an appropriate heating rate. This example could be applied to other bimorphic systems fulfilling the five conditions detailed in this article. Acknowledgment. Viropharma Inc. (Exton P.A.) is thanked for support of this study. Crystallographic data and fractional coordinates have been deposited at the Cambridge Crystallographic Data Center (CSD) and registered under the deposition numbers CCDC 242978242981. Supporting Information Available: Crystallographic information files, XRPD patterns, and animation of the
Coste et al. thermal behavior. This material is available free of charge via the Internet at http://pubs.acs.org.
References (1) Rocco, W. L.; Swanson, J. R. Int. J. Pharm. 1995, 117, 231236. (2) SHELXTL, Version 6.10, Xshell User’s Manual; Bruker Advanced X-ray Solutions, Inc.: Madison, WI, 2000. (3) EVA, version 9.0.0.02; SOCABIM, 1996-2003. (4) Burger, A.; Ramburger, R. Mikrochim. Acta II (Vienna), 1979a, 259-271. (b) Burger, A.; Ramburger, R. Mikrochim. Acta II (Vienna), 1979a, 27-316. (5) Burger, A. Acta Pharm. Technol. 1982a, 28, 1-20. (6) Maruyama, S.; Ooshima, H.; Kato, J. Chem. Eng. J. 1999, 75, 193-200. (7) SMART for WNT/2000 Version 5.622, Smart Software Reference Manual; Bruker Advanced X-ray Solutions, Inc.: Madison, WI, 2001. (8) (a) Petit, M.-N.; Coquerel, G.; Bouaziz, R. Thermochim. Acta 1986, 97, 177-187. (b) Ricci, J. E. The Phase Rule and Heterogeneous Equilibrium; Dover Publications: New York, 1966. (9) Kraus, N.; Nolze, G. POWDER CELL, version 2.2; Federal Institute for Materials Research and Testing: Berlin, Germany, 2000. (10) (a) Schroeder, I. Z. Phys. Chem. 1893, 11, 449. (b) Van Laar, J. J. Arch. Neerl. 1903, 11 (8), 264.
CG049766R
