Polymorphism of Nifedipine: Crystal Structure and Reversible

Article pubs.acs.org/crystal

Polymorphism of Nifedipine: Crystal Structure and Reversible Transition of the Metastable β Polymorph Erica Gunn, Ilia A. Guzei, Ting Cai, and Lian Yu* School of Pharmacy and Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin 53705, United States S Supporting Information *

ABSTRACT: We report the first structural determination of the metastable β polymorph of nifedipine (NIF) by single-crystal X-ray diffraction. Stable, highquality crystals were grown from the melt in the presence of a polymer dopant. Our β NIF structure is characterized by a unit cell similar to that of the structure recently proposed from powder diffraction, but significantly different molecular conformations. Unlike the stable α polymorph, β NIF undergoes a reversible solid-state transformation near 60 °C. The now available β NIF structure clarifies some confusion concerning NIF polymorphs and enables inquiries into the structural basis for the selective crystallization of β NIF from glasses. We report that another polymorph crystallizes concomitantly with β NIF from the supercooled melt and transforms to β NIF at room temperature; this polymorph also undergoes reversible solid-state transformation.

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INTRODUCTION The polymorphism of nifedipine (NIF), a calcium-channel blocker, has been studied for more than three decades,1−14 but confusion still remains in the literature. Three naming systems now exist for NIF polymorphs (I−II−III,1 α−β−γ,7 and A−B−C8), and there is agreement only for the thermodynamically stable polymorph (I = α = A). The confusion around NIF polymorphs has at least two sources. First, there has been insufficient structural data on NIF polymorphs. Prior to this work, only the structure of α NIF has been solved by single-crystal X-ray diffraction,12 and only recently have there been attempts to determine the structures of metastable NIF polymorphs by powder X-ray diffraction.10,13 The lack of reliable structural data makes it difficult to identify phase-pure samples. Second, some NIF polymorphs undergo complex phase transformations, both reversible and irreversible, during thermal treatment,5,8 which may have contributed to the inconsistent naming of polymorphs. As pharmaceutical polymorphism receives greater attention,15,16 the NIF system represents an outstanding unsolved problem. The need to understand the polymorphism of NIF has increased because NIF now serves as a model for studying the crystallization of organic glasses (amorphous solids).5,7,9,14,17−19 Organic glasses are being studied as vehicles for delivering poorly soluble drugs, because amorphous drugs are generally more soluble than their crystalline counterparts. Despite their solidity, organic glasses can crystallize, sometimes surprisingly fast.20−23 In this context, NIF is studied as a relatively fast crystallizer to learn how organic glasses grow crystals in the bulk9 and at the surface,18 and how polymer additives stabilize glasses against crystallization.17,19 It is noteworthy that the crystallization of NIF glasses yields only the β polymorph, in preference to other polymorphs. 9,18 Such polymorphic selectivity is relevant for understanding how glass crystallization depends on the structure being developed.21,24 © 2012 American Chemical Society

During our study of the crystallization of NIF liquid and glasses, we observed that a polymer dopant can stabilize the β polymorph against transformation to the thermodynamically stable α NIF. We took advantage of this effect to grow large single crystals of β NIF for structural determination by X-ray diffraction. The polymer dopant also allowed observation of a reversible phase transformation of β NIF during temperature cycling, without simultaneous conversion to α NIF. Our study found that another metastable polymorph crystallizes from the melt concomitantly with β NIF. We report herein the structure of β NIF determined for the first time by single-crystal X-ray diffraction and the reversible phase transitions of two metastable NIF polymorphs, and discuss the implications of our results for understanding the polymorphism of NIF and the crystallization of NIF glasses.

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EXPERIMENTAL SECTION

Crystals of α NIF were obtained from FWD Chemical. Polyvinylpyrrolidone (Mw ≈ 8 kg/mol; PVP K15) was purchased from ISP Technologies, Inc. (Texas City, TX). NIF and the polymer additive were blended by cryomilling (SPEX CertiPrep model 6750), cooled with liquid nitrogen. One gram of a 10 wt % mixture was cryomilled at 10 Hz for five 2-min cycles, each followed by a 2-min cool down cycle. This mixture was then diluted to 1% and cryomilled again to ensure even blending. Crystals of β NIF were grown from a melt of NIF doped with 1% PVP K15. ∼10 mg of material was melted on a glass coverslip using a Linkam THMS hot/cold stage (±0.1 °C accuracy). A glass fiber spacer was added to ensure a sample thickness of ∼30 μm. A second coverslip was placed on top of the melted material to create a sandwiched sample, which was then quenched to room temperature briefly on an aluminum block while the hot stage was cooled to the 80 °C growth temperature. The sample was protected from light and held at 80 °C Received: January 3, 2012 Revised: February 15, 2012 Published: February 24, 2012 2037

dx.doi.org/10.1021/cg3000075 | Cryst. Growth Des. 2012, 12, 2037−2043

Crystal Growth & Design

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until fully crystallized (∼1.5 h). Crystallization progress was monitored using an Olympus BH2-UMA polarized light microscope. Crystals were also grown at 70 and 95 °C. A single crystal for X-ray structure solution was isolated by peeling off the top coverslip from a sandwiched sample and harvesting the larger crystal domains of the β polymorph. A crystal of adequate size for analysis was selected, and two complete structural data sets were acquired at room temperature and −173 °C. The single-crystal X-ray diffraction experiments were conducted in a routine fashion on a Bruker APEXII diffractometer equipped with a carefully calibrated low temperature device Oxford Cryosystem 700 (see Supporting Information for details). Powder diffraction data were collected at room temperature using a Bruker D8 Advance diffractometer on an as-grown film immediately after crystal growth had completed. The top coverslip was peeled off before measurement. Data were collected from 2 to 40° 2θ with a step size of 0.02° and an integration time of 1 s. Polymorphs were also identified with a Raman microscope (Thermo Scientific DXR; 780 nm laser). Spectra were taken at room temperature. Two polymorphs matched the known Raman patterns of α and β NIF, while a third (hereafter called X) did not. Identifying peaks included the C−C−O stretch (α, 1223 cm−1; β, 1215 cm−1; X, 1211 cm−1), the νs NO2 vibration (α, 1347 cm−1; β, 1345 cm−1; X, 1357 cm−1), and the CC stretch (α, 1647 cm−1; β, 1651 cm−1; X, 1638 cm−1). The spectrum of X is distinct from the spectra reported by Chan et al.7 The thermal behavior of NIF polymorphs was analyzed using a TA Instruments Q2000 differential scanning calorimeter (DSC). Crystals were grown at different temperatures with the aid of a microscope hot stage and their polymorphic identity was determined by Raman and XRD, both before and after DSC measurement. For each DSC run, 4−6 mg of material was loaded in a Tzero pan, hermetically sealed, and analyzed at a heating or cooling rate of 10 °C/min. At least three samples were measured for each polymorph.

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RESULTS Crystal Structure of β NIF. Structural determination of β NIF by X-ray diffraction was performed with single crystals grown at 80 °C from liquid NIF doped with 1 wt % PVP K15. PVP is a melt-miscible25 crystal-growth retarder of NIF.17 Figure 1 shows NIF crystals grown at 80 °C without and with polymer doping. The crystals formed spherulites with sectors that appeared single-crystalline; the largest domains of uniform interference color were isolated at room temperature for X-ray crystallography. The domains labeled “β” were found to be β NIF by Raman microscopy (Figure 1c), according to the naming of Chan et al.7 The PVP dopant had no noticeable effect on the size of single-crystalline domains, but as we describe later, seemed to stabilize β NIF against transformation to α NIF. Besides the domains identified as β NIF, spherulites formed at 80 °C also contained regions that were rougher, finer-grained, and less colorful between crossed polarizers (Figure 1). We will later provide more details on these crystals and speculate that they belong to a different polymorph crystallizing concomitantly with β NIF. Table 1 and Figures 2 and 3 describe the structure of β NIF determined in this work. Additional details are found in the Supporting Information. The unit cell of our β NIF structure differs from that of α NIF [BICCIZ in the Cambridge Structural Database (CSD)26] and resembles that of the β polymorph of Klimakow et al.10 and of Form C of Bortolotti et al.13 We conclude that the latter two structures and our β NIF structure all correspond to the same polymorph (β = C). Note that our structure was determined from analyzing single-crystal diffraction, whereas the other two were from analyzing powder diffraction, and as we show below, our structure differs from

Figure 1. NIF crystals grown at 80 °C in the melt of (a) NIF and (b) NIF + 1 wt % PVP K15. Two domains could be distinguished (labeled β and X), which had different Raman spectra (c). The β domains were more uniform and colorful between crossed polarizers; the X domains were rougher and less colorful. Raman spectra were measured at room temperature. The β spectrum matches that of β NIF of Chan et al. (ref 7) and of the crystal whose structure was solved in this work. The X spectrum does not match any of the spectra reported by Chan et al.

that of Bortolotti et al. in molecular conformation. Klimakow et al. indexed the powder diffraction, but did not fully solve the crystal structure. To see the structural difference between NIF polymorphs, we consider first the spatial distribution of molecules. Figure 2 shows the radial distribution functions (RDF) of molecular centers of mass in various NIF polymorphs. The RDF is one measure of the local molecular environment in a crystal. The α polymorph has one such RDF, for its only symmetryindependent molecule (Z′ = 1). For β NIF (Z′ = 2), the RDF has been calculated for each of the two symmetry-independent molecules using the 23 °C structure. According to this metric, the local environments are similar for the two symmetryindependent molecules in β NIF, but significantly different 2038



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Table 1. Crystal Structures of NIF Polymorphsa form

α

C (β)b

ref CSD T, °C a (Å) b (Å) c (Å) α, deg β, deg γ, deg V, Å3 sp grp ρ, g/cm3 Z

12 BICCIZ 10−30 10.923 10.326 14.814 90 92.7 90 1669.03 P21/c 1.379 4

13 BICCIZ01 25 9.864 13.893 14.287 61.227 79.827 81.782 1685.5 P1̅ 1.364 4

β

β

10c

β

this work

this work

23 9.793 13.897 14.154 61.18 79.89 81.90 1657 n.a. 1.389 4

23 9.840 13.807 14.206 61.39 79.76 81.99 1664.10 P1̅ 1.382 4

−173 9.666 13.701 14.118 61.03 79.63 81.90 1605.89 P1̅ 1.432 4

a

Molecular formula: C17H18N2O6. Molecular weight: 346.34. bThis polymorph is named “C” in ref 13 and judging from its cell parameters is likely the same as the polymorph named “β” in ref 10 and this work. c Cell parameters of ref 10 have been converted to our cell setting.

Figure 3. Comparison of molecular conformations of NIF polymorphs. (a) Structure of NIF and atom numbering (after Triggle et al.12). If the molecule is oriented so that the C4−H bond points away from the reader, the substituents on the 1,4-dihydropyridine ring are designated counterclockwise as ester 1, ester 2, and phenyl ring. (b) The molecule in α NIF and molecule 1 in β NIF. Molecule 2 in β NIF has similar conformation as Molecule 1 (Table 2).

conformations, but as Figure 3 shows, their conformations differ significantly from that of the molecule in α NIF. Table 2 shows a set of torsional angles (θ1, θ2, θ3, θ4) that characterize the conformers in different polymorphs. The first three specify the orientations of the substituents on the 1, 4-dihydropyridine ring (Figure 3a): θ1 (ester 1) = O5′−C5′− C5−C4, θ2 (ester 2) = O3′−C3′−C3−C4, and θ3 (phenyl) = N1···C4−C7−C12. The fourth specifies the torsion of the nitro group relative to the phenyl ring: θ4 = C7−C12−N2−O2. Note that all but θ3 are “proper” torsional angles (tracing consecutive covalent bonds) and that θ3 is defined in such a way that it can report the orientation of the phenyl ring and that upon reflection, no renumbering of atoms is necessary. Table 2 shows that the two molecules in β NIF have similar conformations. Moreover, Table 2 shows that molecular conformations are significantly different between α and β NIF, and between the β NIF structures from this work (determined by single-crystal diffraction) and from Bortolotti et al. (determined from powder diffraction).13 DFT calculation was used to compare the energies of the various conformers reported and the lowest-energy conformer in the gas phase. Computations were performed at the B3LYP/ 6-31G(d) level using Gaussian 03.28 Gas-phase geometry minimizations starting from the experimental conformers in β NIF from this work converged to the same structure within error (Table 2). Relative to this structure, we computed the energies for the five crystal conformers in Table 2 by optimizing each conformer while constraining the four torsion angles in Table 2 to their experimental values. Thus, the α NIF conformer was minimized to +0.46 kcal/mol above the lowestenergy gas-phase conformer; the conformers in the β NIF structure of Bortolotti et al. to +0.24 kcal/mol (Mol. 1) and +2.35 kcal/mol (Mol. 2); the conformers in the β NIF structure of this work to +0.40 kcal/mol (Mol. 1) and +0.20 kcal/mol (Mol. 2). This analysis shows that while most of the crystal conformers have similar energies, Mol. 2 in Bortolotti et al.’s structure has much higher energy and conformational strain. Moderately strong intermolecular hydrogen bonds of the type N−H···O (ester carbonyl) are present in α and β NIF polymorphs. The crystal structure of α NIF was reported

Figure 2. Radial distribution functions (RDF) of molecular centers of mass in α and β NIF at room temperature. For α NIF, only the heavy atoms are used to calculate the molecular center of mass because the hydrogen positions are not reported.

between the molecules in α and β NIF. Despite this difference, the two polymorphs have comparable densities. The packing coefficients for α NIF, β NIF (RT), and β NIF (−173 °C) are 70.8, 68.8, and 72.0%, respectively, as calculated using the PLATON software.27 We next describe the difference in molecular conformation between NIF polymorphs. Both α and β NIF are centrosymmetric and each contains conformers of opposite handedness. We compare only the conformers in one handedness. The two symmetry-independent molecules in β NIF have similar 2039



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Table 2. Torsional Angles of Molecules in NIF Polymorphsa torsional angle, ° θ1 θ2 θ3 θ4

(ester 1) = O5′−C5′−C5−C4 (ester 2) = O3′−C3′−C3−C4 (phenyl) = N1·C4−C7−C12 (nitro) = C7−C12−N2−O2

α

C (β) Mol. 1

C (β) Mol. 2

β Mol. 1

β Mol. 2

gas phaseb

−164.7 7.7 161.5 36.8

177.6 5.0 −171.8 −38.4

−150.0 0.1 −179.7 −16.2

−167.3 17.4 −167.3 −29.5

177.4 21.6 −169.3 −39.4

−179.5 10.5 −165.8 −36.0

a

Conformations are compared at room temperature. bGas-phase conformation obtained by energy minimization by DFT calculation at the B3LYP/ 6-31G(d) level.

While the stable α polymorph of NIF exhibits no thermal transitions at temperatures below its melting point (172 °C), a reversible transformation was observed in β NIF near 60 °C. The crystals used for this experiment were grown at 70 °C from liquid NIF doped with 1 wt % PVP K15; they were confirmed by XRD (Figure 4a) and Raman spectroscopy to be

without H atoms; we used the program Mercury29 to place H atoms at idealized positions to compute the packing coefficient reported above and to examine the hydrogen bonding interactions. In α NIF, the N−H···O bond connects neighboring molecules with the N···O separation being 3.028 Å and the N−H···O angle being 160.3°, to form infinite hydrogen-bonded chains along the crystallographic b axis. This bonding motif is described with a graph set notation C(6). In β NIF (23 °C), the N−H···O bond connects two symmetry-independent molecules A and B to form infinite chains of the type ABAB along the crystallographic [011̅] direction. The graph set notation is C22 (12) due to involvement of two crystallographically independent molecules and hence the presence of two donors and two acceptors. The A → B and B → A hydrogen bonds are described by N···O separations of 3.040(3) and 3.093(3) Å and the respective N−H···O angles of 173(3) and 170(3)°. In β NIF (−173 °C), the hydrogen bonding pattern is the same, and the corresponding bond parameters are N···O separations 2.993(2) and 3.033(2) Å and N−H···O angles 172(2) and 167(2)°. It is noteworthy that the N···O separations in the −173 °C structure are slightly shorter than those in the 23 °C structure, indicating slight strengthening of the hydrogen bonds. This result correlates with the 4% increase in density of β NIF from 23 to −173 °C. The β NIF structure of Bortolotti et. al13 (determined from powder diffraction) shows ABAB hydrogen-bonded chains along [011]̅ similar to those in our β NIF structure (determined from single crystal diffraction). However, their N···O separations for the A → B and B → A hydrogen bonds are significantly longer (3.131 and 3.181 Å or 3% longer than our values) and their N−H···O angles (145 and 152°) deviate more substantially from 180°. To evaluate the structures of β NIF from different sources, it is worth noting that our determination by single-crystal diffraction used a larger number of observations than the previous work by powder diffraction13 (19767 vs 12508), refined a larger number of parameters (467 vs 15), and employed data of higher resolution. For these reasons, the structure from this work is expected to be of higher accuracy and precision. A reanalysis by Dr. Bortolotti, the lead author of ref 13, found that their powderdiffraction data are slightly better fitted (Rwp = 0.156 compared to the original 0.172) if our molecular geometries are used and only the unit-cell parameters and crystallite size are optimized. Knowing the structure of β NIF, one can determine whether previously reported X-ray diffraction patterns are associated with this polymorph. We have compared the XRD pattern expected for β NIF and several patterns from the literature, and confirmed the previous assignment9 that crystals grown in NIF glasses are pure β NIF. We also found that Form C of Groof et al.8,11 is β NIF or β NIF with trace α NIF (their Form A). Phase Transformations of β NIF. Ishida et al. reported that β NIF transforms over time to α NIF at 40 °C.9 Their conclusion is strengthened by this study because their assignment of β NIF, made by Raman spectroscopy, is confirmed here by X-ray diffraction.

Figure 4. (a) XRD patterns of (1) β NIF predicted from its structure, (2) β NIF grown at 70 °C from a melt with 1 wt % PVP K15, and (3) crystals grown at 95 °C from a melt with 1 wt % PVP K15, which are assigned to X NIF on the basis of its subtly different XRD pattern (see vertical lines) and different Raman spectrum. All XRD data were measured at RT. (b) DSC data for β NIF [Sample 2 in (a)], showing a reversible transformation (β ↔ β′). (c) DSC data for X NIF [Sample 3 in (a)], showing a reversible transformation (X ↔ X′). 2040



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at room temperature. Conversion of the cracked region to β was confirmed by Raman microscopy. Crystallizing liquid NIF at 95 °C in the presence of 1 wt % PVP K15 appeared to yield a material that contained a greater amount of X NIF. This conclusion was drawn by visual inspection and Raman analysis. This material had an XRD pattern subtly different from that of β NIF when measured at room temperature (Figure 4a; vertical lines mark differences). We are unsure of the phase-purity of this material. Similar to β NIF, this material showed a reversible transformation (Figure 4c). The transformation temperatures were slightly lower than those for β NIF and the enthalpy of transformation was ca. 4 J/g. XRD analysis found that the material was unchanged after several DSC heat−cool cycles. Polymorphic Selectivity of Crystallization in NIF Liquid and Glasses. The polymorph that grows preferentially in liquid NIF depends on temperature. The thermodynamically stable α NIF was observed to grow only above 120 °C. If a liquid containing actively growing crystals of α NIF was cooled to 110 °C or below, a different polymorph was seen to nucleate and grow on the α NIF growth front. The replacement polymorph, which we tentatively assign as X based on growth temperature and Raman spectra, is less stable than α because over time, the α NIF domain encroached into the new growth, leading to a visible conversion band (Figure 6). The melt crystallization of

phase-pure β NIF. This material showed an endothermic transition on heating and an exothermic transition on subsequent cooling (Figure 4b). The process could be repeated indefinitely. The enthalpy of transition was ca. 5 J/g. XRD showed that the material was still β NIF after several thermal cycles. In Figure 4b, we label the lower- and higher-temperature phases β and β′, respectively. The reversible transformation observed here for β NIF (Figure 4b) is likely that reported by Zhou et al. for Form II5 and that reported by Groof et al. for Form C.8 The presence of polymer dopant probably made our samples less contaminated by the thermodynamically stable α polymorph, and allowed observation of the reversible transformation in repeated heating and cooling. Another Polymorph from Melt Crystallization: X NIF. As stated earlier, crystallization at 80 °C yielded not only crystals of β NIF but also crystals that appeared different (Figure 1). The latter crystals had a distinct Raman spectrum (Figure 1c), which does not match those reported by Chan et al.7 To avoid the wrong association with previously named polymorphs, we shall designate this polymorph as “X”. We now describe preliminary results on X NIF, noting that this polymorph is less well understood than the other polymorphs. Figure 5a shows the photomicrograph of a sample

Figure 6. Stoppage of the growth of α NIF by cross-nucleation. On cooling from 130 to 110 °C, the steady growth of α NIF was terminated because another polymorph (possibly X) nucleated on the α crystals and grew to consume the remaining liquid. The solid-state conversion of the new polymorph to α NIF led to a widening dark band behind the growth front.

ROY30 and D-mannitol31 shows similar temperature-dependent switching of polymorphs owing to cross-nucleation. Below 42 °C, liquid NIF is a glass and its crystallization yields β NIF, in preference to other polymorphs.9 This polymorphic selectivity was further characterized in the present study. First, we tested whether the selectivity results from the slow nucleation of the stable α polymorph. An NIF liquid was allowed to partially crystallize at 130 °C in the α polymorph and cooled to 40 °C (Tg - 2 °C). The preformed α NIF crystals now served as seeds to initiate further growth. We found by Raman microscopy that the new growth from the α seeds was not the α polymorph but the β polymorph. In another experiment, seeds of α NIF were sprinkled on the surface of an NIF glass to induce crystal growth. Here again, the new growth was β NIF. Similar cross-nucleation phenomenon in seeded crystallization has been observed for other systems.30−32

Figure 5. (a, b) Polymorphic conversion at 23 °C. The crystals grew from liquid NIF at 80 °C as two polymorphs distinguishable by Raman spectroscopy. The photographs were taken in reflection and at high resolution, causing the crystals to look different from those in Figure 1. The X polymorph converted over time to the β polymorph with simultaneous formation of cracks.

of pure NIF crystals grown at 80 °C and after spending 2 h at 23 °C. By Raman analysis, the sample contained both X and β NIF and the β region had denser cracks. The image in Figure 5b shows the same sample after 17 h at room temperature. The cracked region grew, which indicates conversion of X to β NIF 2041



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polymorphic system ROY, the polymorphs that grow rapidly in glasses have higher densities and more isotropic molecular packing (as measured by the RDF of molecular centers of mass).21 For further progress, other polymorphic systems are desirable to assess which crystal property  density, isotropic packing, or others  best correlates with fast crystal growth in glasses. The tension-induced-interfacial-mobility model33 predicts that denser polymorphs are favored to grow in glasses. The NIF system, unfortunately, does not provide a sufficiently discerning test because its α and β polymorphs have similar densities (Table 1) and at first glance, similar RDFs of molecular centers of mass (Figure 2). Further work is necessary to understand the polymorphic selectivity of crystallization in NIF glasses. Role of Polymer Dopant in Understanding NIF Polymorphism. Because we grew NIF crystals in the presence of a polymer dopant (1 wt %), it is important to ask whether the β structure is affected in any way by the polymer. We note that crystals grown in the presence of the polymer dopant showed the same X-ray diffraction pattern as those grown from pure NIF. While it is unclear whether the polymer molecules infiltrated the crystal lattice or resided between crystal grains, the X-ray diffraction used for structural determination came mainly from NIF crystals unaffected by the polymer molecules. In this study, we grew crystals of β NIF of sufficient quality for structural determination by single-crystal X-ray diffraction. In contrast, previous attempts to solve the structure of β NIF relied on analyzing powder diffraction patterns.10,13 Because β NIF is an unstable polymorph,8 the condition for growing highquality crystals must allow development of single-crystal domains and avoid simultaneous polymorphic conversion. We speculate that in our crystal growth process, the polymer served as a stabilizer against polymorphic transformation from β to the thermodynamically stable α form, allowing high-quality crystals to develop without simultaneous conversion. Without the polymer, crystallization of liquid NIF would yield some amount of α NIF at our crystal growth temperature (80 °C).8 Our explanation is consistent with the finding that PVP can inhibit the X-to-β polymorphic conversion at room temperature (Figure 5) and crystal growth in NIF glasses.9 While serving as a stabilizer for β NIF, 1 wt % PVP has no obvious effect on the size of single-crystal domains (Figure 1). The presence of a polymer dopant enabled observation of the reversible transformations of β and X NIF during repeated cycles of heating and cooling, without simultaneous conversion to α NIF (Figure 4b,c). In a previous study of D-mannitol polymorphs, the addition of PVP made it possible to observe the congruent melting of the unstable δ polymorph, without simultaneous transformation to the more stable polymorphs.34 It is possible that polymer additives can find similar uses in studies of short-lived polymorphs.

The occurrence of the phenomenon requires that the replacement polymorph grows faster than the initial polymorph.

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DISCUSSION Relationship between NIF Polymorphs. Figure 7 shows a partial phase diagram of NIF polymorphs consistent with the

Figure 7. Phase diagram of NIF polymorphs consistent with results of this study. G is the Gibbs free energy. Kinks in the β and X lines mark reversible transitions. Arrow indicates X to β conversion at 23 °C.

results of this study and our understanding of the literature. The reversible transitions observed for β NIF (Figure 4b) and X NIF (Figure 4c) are indicated as breaks on the relevant lines. The X-to-β conversion observed at room temperature (Figure 5) is indicated with an arrow. We note that the β−β′ and X−X′ transitions occur in seconds to minutes (during DSC heating and cooling at 10 °C/min), whereas the X-to-β conversion occurs more slowly (Figure 5). Although the existence of a 161 °C-melting polymorph of NIF is well established,4,9 it is still unclear whether this polymorph is identified with X′, β′, or some other polymorph (“?” in Figure 7). Besides conversion to the stable α polymorph, the similarity of the XRD patterns of β and X NIF complicates the identification of the polymorph melting at 161 °C. The 161 °C melting endotherm is more clearly seen with NIF crystals formed from melts that have been doped with PVP, presumably a result of retarded polymorphic conversion. Polymorphic Selectivity of the Crystallization of NIF Glasses. The crystallization of organic glasses has been studied to understand the stability and stabilization of amorphous pharmaceuticals. The solidity of glasses might suggest resistance to crystallization, but glasses can crystallize, sometimes surprisingly fast.20−23 Recent studies have found that fast modes of crystal growth can emerge as organic liquids are cooled to become glasses. One such mode occurs in the bulk,20,21 and another at the surface,22,23 both leading to growth rates much faster than predicted by standard theories that assume that diffusion defines the kinetic barrier for crystallization. In this context, NIF has served as a model for understanding crystallization in organic glasses.9,18,19 While several polymorphs are thermodynamically allowed to crystallize from NIF glasses, only β NIF does so, both in the bulk9 and at the surface.18 Even seeding with other polymorphs induces the growth of β NIF. These observations show that β NIF grows much faster in the glasses than the other polymorphs, and it is of interest to understand the structural basis for such polymorphic selectivity. With the now available structure of β NIF, we are better positioned to do so. For the

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CONCLUSIONS Despite decades of study, confusion still surrounds the polymorphism of nifedipine (NIF). The use of NIF as a model for studying the crystallization of organic glasses has increased the need to understand this system. We have determined for the first time the structure of β NIF, the polymorph that grows preferentially from NIF glasses, by single-crystal X-ray diffraction. A polymer dopant was used for growing stable, high-quality single crystals for structural solution. Our structure has a unit cell similar to that of the structure recently proposed 2042



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from the powder pattern, but has significantly different molecular conformations. This polymorph undergoes a reversible solid-state transformation near 60 °C. We report that another polymorph crystallizes concomitantly with β NIF from a supercooled melt and transforms to β NIF at room temperature; this polymorph also undergoes reversible solid-state transformation at a lower temperature. Our results help to clarify some of the confusion concerning NIF polymorphs. To fully understand the polymorphism of NIF, it would be useful to establish the phase relations and transitions of the various polymorphs, to determine the structures of other unstable polymorphs, and to determine the nature of the reversible phase transitions of the β and X polymorphs. In these efforts, polymer additives might prove valuable for stabilizing unstable polymorphs against phase transition.

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ASSOCIATED CONTENT

S Supporting Information *

Full crystallographic information and X-ray crystallographic information files (CIF) for β NIF are included. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the NSF (DMR-0804786 and DMR-0907031) for supporting this work and Dr. Mauro Bortolotti for reanalyzing published powder-diffraction data against structural parameters from this work. E.G. thanks the PhRMA Foundation for a postdoctoral fellowship.

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REFERENCES

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Polymorphism of Nifedipine: Crystal Structure and Reversible

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