Structural and Thermodynamic Features of Crystal Polymorphs of R

Structural and Thermodynamic Features of Crystal Polymorphs of R-Cinacalcet Hydrochloride Doris E. Braun,† Daniel M. To¨bbens,‡ Volker Kahlenberg,‡ Johannes Ludescher,§ and Ulrich J. Griesser*,†

CRYSTAL GROWTH & DESIGN 2008 VOL. 8, NO. 11 4109–4119

Institute of Pharmacy, UniVersity of Innsbruck, Innrain 52, 6020 Innsbruck, Austria, Institute of Mineralogy and Petrography, UniVersity of Innsbruck, Innrain 52, 6020 Innsbruck, Austria, and Sandoz GmbH, Biochemiestrasse 10, 6250 Kundl, Austria ReceiVed May 29, 2008; ReVised Manuscript ReceiVed July 16, 2008

ABSTRACT: Three polymorphs of the calcimimetic cinacalcet hydrochloride were characterized by a variety of methods including thermal analysis (hot-stage microscopy and differential scanning calorimetry), vibrational spectroscopy (FT-IR and FT-Raman spectroscopy), and X-ray diffractometry (powder and single crystal). The crystal structures of all polymorphs have been determined either from single crystals (form III°) or from powder data (forms I and II). Forms III° and I both exhibit an orthorhombic cell with space group P212121, whereas form II crystallizes in the triclinic space group P1. All three polymorphs show basically the same hydrogen-bond synthon, and the structural differences are associated with conformational changes. In contrast to form III°, form II shows two conformationally different molecules, and in the high temperature form I the phenyl moiety is dynamically disordered. Among the three enantiotropically related polymorphs, form III° (Tfus: 165 °C) is the thermodynamically stable modification below the transition point of 148.5 °C, and form I (Tfus: 179.5 °C) is stable above this temperature. The phase transition between these forms is reversible, shows a hysteresis of about 30 K, and can be classified as an isosymmetric phase transition. Form II (Tfus: 170 °C) is thermodynamically unstable in the entire temperature range but shows a high kinetic stability at room temperature. Differential scanning calorimetry was identified as the most sensitive method in the evaluation of the phase purity of the polymorphs. The thermal expansion and phase transition behavior (20-170 °C) of the three forms was studied with temperature resolved powder X-ray diffraction. Introduction The phenomenon of polymorphism has been recognized as an important and relevant topic in drug development, and the identification and characterization of the “desired polymorph” are regarded as critical to ensure a reliable and robust manufacturing process of an active pharmaceutical ingredient.1 This requirement emerges from the fact that different polymorphs exhibit more or less distinct material properties which may become noticeable during processing, formulation and stability testing, and particularly in the case of less water soluble compounds in dissolution and bioavailability problems of the drug product.2 The present paper deals with solid-state investigations of cinacalcet hydrochloride (N-[(1R)-1-(1-naphthyl)ethyl]-3-[3(trifluoromethyl)phenyl]propan-1-amine hydrochloride, Figure 1). Cinacalcet hydrochloride (CCCHC) is a novel secondgeneration calcimimetic that modulates the calcium-sensing receptor (CaR) and makes it more sensitive to calcium suppressive effects on parathyroid hormone or parathormone (PTH) secretion. It is orally highly bioavailable and has been chosen for further development in the treatment of primary and secondary hyperparathyroidism as well as hypercalcemia in patients with parathyroid carcinoma.3 The compound has been marketed (Amgen) for a few years under the tradenames Sensipar (USA, Australia) and Mimpara (Europe). So far, no reports on the polymorphism and/or solvate formation of the compound have been published in the scientific literature and also the crystal structure data of this compound are not accessible (e.g., via the Cambridge Structural Database4). Three * Corresponding author: E-mail: [email protected]. † Institute of Pharmacy, University of Innsbruck. ‡ Institute of Mineralogy and Petrography, University of Innsbruck. § Sandoz GmbH.

Figure 1. Molecular structure of cinacalcet hydrochloride (C22H23ClF3N, Mr ) 393.87).

recent patent applications5-7 describe the preparation of two CCCHC polymorphs, a chloroform solvate, and an amorphous form. These crystal forms have been characterized by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and X-ray powder diffraction (XRPD). The aim of our investigation was to comprehensively characterize the solid-state forms of this promising therapeutic agent, and to assess its thermodynamic/kinetic stabilities and structural features. In order to achieve this goal, a number of analytical techniques such as single-crystal and X-ray powder diffraction, thermal analysis (hot-stage microscopy, differential scanning calorimetry), and vibrational spectroscopy (Infrared and Raman spectroscopy) were applied. Since no suitable single crystals of the metastable and the high temperature form could be obtained, structure solutions from powder data were required to assess and understand the structural differences of all individual forms. The structure of one form (III°) was solved from single crystal data. Shortly after the present work including structure solutions from powder data was completed, a new patent application8 appeared which describes the single crystal structures of one metastable form (form II, named “form III”

10.1021/cg8005647 CCC: $40.75  2008 American Chemical Society Published on Web 09/30/2008

4110 Crystal Growth & Design, Vol. 8, No. 11, 2008

in the patent) and gives a short comparison with the structure solution of form III° (named “form I” in the patent). Furthermore, the existence of a third form (form I, named “form II” in the patent) which is unstable at ambient temperature is mentioned in this document. However, in contrast to all recent patent applications our study encompasses the scientific efforts in understanding the solid-state behavior of this promising drug compound. The polymorphs are named according to the Kofler notation using Roman numerals in the order of melting points (the highest melting form is named form I). Since the nomenclature of the forms is not uniform in the individual patents, we did not change our naming system (which we used already before the mentioned patents were published) in this report. The polymorph which is the thermodynamically stable form at room temperature is marked with a superscript zero. Experimental Section Preparation of the Individual Forms. CCCHC was obtained from Sandoz GmbH (purity 99.0%). The sample consisted of form III°. All solvents used for the crystallizations were of p.a. quality. Form I can be produced by heating pure form III° to above 164 °C. However, this transformation is reversible, and at temperatures below 135 °C form III° is reobtained. Pure form II could be produced in small amounts ( 2σs(I)] R indices (all data) absolute structure parameter largest diff. peak and hole Be´rar’s esd correction factor19

form I

Table 2. Physicochemical Data for CCCHC Polymorphsa modification Tfus [°C] TM DSC (onset) ( 95% c.i. ∆fusH [kJ · mol-1] ( 95% c.i. Ttrs [°C] DSC (experimental) XRPD (experimental) thermodynamic ∆trsH [kJ · mol-1] order of thermodynamic stability at 25 °C order of density (highest ) a) selected IR-bands [cm-1] ν(-CH3),ν(-CH2-) ν(-NH2+-) ν(-CF3) δ(-CHar; 1,3-disub)

I 179.5 179.3 ( 0.1 24.4 ( 0.2 20 °C, 148.5, 164 III°fI (heating) 162 ( 1 III°fI (heating) III°/I: 148.5 ( 1 4.7 ( 0.1 (III°fI) a a 2963, 2865 2756, 2712 1167, 1130 805, 797, 777

a Tfus: melting point; Ttrs: transition temperature; ∆fusH: enthalpy of fusion; ∆trsH: transition enthalpy. b Measured by DSC at a heating rate of 200 K min-1. c Calculated: sum of ∆fusHI and ∆trsHIII°-I. d Calculated: difference of ∆fusHI and ∆fusHII. e Calculated: sum of ∆fusHIII° and ∆fusHII.

chlorine ions. The most satisfactory description of the structure resulted from a model with 4-fold disorder of the phenyl group only. Any lower number of disordered groups resulted in significant reduction of the quality of the fit of the powder diffraction pattern; the introduction of additional disorder models resulted in no case in a better fit. In the final Rietveld analysis the occupation of the four disordered fractions of the phenyl group was refined while restraining the total occupation. For further details of the refinement see Table 1. It should be stressed that the limited range in which significant Bragg intensities could be derived allows only for a low-resolution refinement of the crystal structure. Nonetheless, the ordered part of the molecule can be described quite well employing bond restraints. For the disordered moiety, however, this approach is only of limited value. In any case, the atoms in this part of the structure are not characterized by localized physical positions; only the electron density distribution envelope derived from

the refined atom positions should be considered as physically meaningful for this part of the structure.

Results and Discussion Our experimental studies confirm the existence of at least three polymorphic forms (I, II, and III°) and in addition to the known chloroform solvate7,9 and the amorphous form6 we found three new monosolvates with acetic acid, dioxane, and tetrachloromethane, which are described elsewhere.9 Table 2 summarizes the most important thermal and spectroscopic data of the polymorphs for which thermochemical and structural properties are discussed in detail below. Thermal Analysis. Hot Stage Microscopy. Depending on the solvent of crystallization, CCCHC form III° crystallizes in


Braun et al.

Figure 2. Hot stage microscopy of CCCHC forms I and III°: (a) melt film preparation of form III° and (b) form I; (c) single crystals of form III°; (d) form II (dark crystals) and form III° (transparent crystals obtained by sublimation).

thin elongated plates or fine needles (Figure 2c). Upon heating, strong sublimation can be observed at temperatures above 150 °C resulting in transparent rods of form III° (Figure 2d). A reversible solid-solid transition to form I takes place at temperatures above 164 °C. The re-transformation to form III° on cooling occurs below 135 °C. The high temperature form I melts at 179.5 °C. The needle-like crystals of form II melt inhomogeneously at 170 °C to form I (melting and crystallization occur simultaneously). This form also strongly sublimes to needled and elongated plates of form III°. Annealing a pure form II batch at 110 °C for over 24 h induced the transition of form II f III°. Surprisingly, in mixtures of polymorphs II and III° (obtained by crystallization) no solid-solid or inhomogeneous transition to form I was observed, even at heating rates as low as 5 K min-1. Thanks to this circumstance, which obviously denotes the lack of seeds of form I, we were able to determine the melting point of form III° (165 °C) directly. The quench cooled melt does not crystallize spontaneously at room temperature, but nucleation and crystal growth of form II can be induced either by annealing at elevated temperature (preferable above 130 °C) and scratching, or by grinding the glass with a mortar and pestle followed by heating. It should be stressed that in contrast to form II we could never observe the primary nucleation of form III° from the supercooled melt. Nonetheless, we mostly obtain a mixture of the two forms upon annealing the melt at elevated temperatures because form II transforms to form III° under these conditions. However, seeds of form III° show a similar growth rate in the melt as form II. In film preparations the solid-solid transition III° f I is indicated by a clear change in interference colors as shown in Figure 2a,b. The photomicrographs in Figure 2 also show single crystals of form III° (Figure 2c) and a mixture of forms II and III° (Figure 2d). The dark crystals in Figure 2d represent form II, obtained via the chloroform solvate after desolvation. This appearance indicates a typical case of pseudomorphosis, which means that the phase transition results in a splitting of a crystal to an aggregate of small crystals of the new phase, with the

Figure 3. DSC curves of CCCHC polymorphs (heating rate 10 K min-1). Curves 1-3 (from top): solid-solid transition (III° T I); first curve heating, second curve cooling, third curve heating; curve 4: form II; curve 5: mixture of form II and form III°.

same exterior shape.20 The transparent crystals represent sublimates of form III° with the shape of plates and curved needles. Differential Scanning Calorimetry. In Figure 3 the DSC curves of the forms III° (crystallized from water or alcohols) and II (produced by desolvation of the chloroform solvate9), and a mixture of these forms are illustrated. Form III° shows a transition to form I with an onset temperature at 164.5 ( 0.2 °C and an enthalpy of transition of 4.7 ( 0.1 kJ mol-1 (see first curve). Form I melts at 179.3 ( 0.1 °C (enthalpy of fusion 24.4 ( 0.2 kJ mol-1, third and fourth curve of Figure 3). The DSC curve of form II (Figure 3, fourth curve from the top) exhibits an endotherm at 169.6 ( 0.6 °C (onset temperature) followed by an exothermic recrystallization process to form I (inhomogeneous melting process) and the melting peak of form I. The reversibility of the transition III° T I is illustrated in the three upper DSC curves of Figure 3. The first curve shows the endothermic transition III° f I on heating. In the following cooling run (second curve) an exothermic back-transition of

Crystal Polymorphs of R-Cinacalcet Hydrochloride

Crystal Growth & Design, Vol. 8, No. 11, 2008 4113

Figure 4. FT-IR spectra of CCCHC polymorphs (I, II, and III°). The inset shows a characteristic (820-760 cm-1) region which is useful for the discrimination of the two room temperature forms (II and III°).

form I f III° occurs at temperatures below 130 °C. The third curve in Figure 3 shows again the transition of form III° f I on heating, followed by the melting of form I (both endothermic). In coincidence with hot stage microscopy, the DSC curve of a mixture of the two forms II and III° (heating rate 10 K min-1), obtained by crystallization (curve 5), shows only the melting process of form III° followed by the melting process of form II. As mentioned above, it is likely that the transformation to form I did not occur in such mixtures because of the absence of seeds of form I. Surprisingly, such behavior is common for all samples where form II and III° crystallized concomitantly from solvents. This assumption is supported by the observation that a preparation of the two “pure” forms in separate areas in a sample pan, resulted in a DSC curve which displays just the sum of curves 3 and 4 of Figure 3. Spectroscopy. FT-IR Spectroscopy. Because of the spontaneous retransformation of the high temperature form I to form III° below ∼130 °C and the strong sublimation of the substance at elevated temperatures, a special preparation method was required to record the spectrum of this polymorph. The substance was fused between two ZnSe discs on a heating stage, and this sandwich preparation was treated like a conventional microscopic film preparation (between glass slide and coverslip). The spectra were recorded directly in transmission mode with the FTIR microscope. Figure 4 shows the FT-IR spectra of the three polymorphs, recorded at different temperatures (form II and III° at room temperature, form I at 160 °C), and some characteristic frequencies are given in Table 2. The most striking differences between the three polymorphs occur in the stretch vibration range of the -CF3 group (1350-1120 cm-1) and the aromatic adherent C-H out-of-plane deformation vibrations (820-765 cm-1). Form III° shows an additional characteristic band at 805 cm-1 (shoulder, see inset in Figure 4) which allows a fast discrimination between the polymorphs III° and II. With the aid of the FT-IR microscope, a hot-stage, and the above-mentioned sandwich preparation method, we could also monitor the reversible solid-solid transition of form III° to form I and vice versa. The spectra in Figure 5 were recorded in steps of 10 °C during a heating and a subsequent cooling cycle between 120 and 170 °C. Characteristic shifts in the fingerprint area of the aromatic C-H vibrations are marked with dotted lines. Several band shifts indicate that the transformation of form III° to the high temperature form I occurred between 160 and 170 °C in the heating cycle, whereas the reverse transition takes place between 150 and 140 °C. Though the changes are rather

Figure 5. Temperature-resolved FTIR spectra of CCCHC form III° (120 f 170 f120 °C) in the range of 860-650 cm-1. The number on the left side marks the temperature in °C.

Figure 6. FT-Raman spectra of CCCHC polymorphs (I, II, and III°). The insets show characteristic regions to discriminate the two room temperature forms (II and III°) in the spectral range of 1350-1275 cm-1, and 150-100 cm-1, respectively.

weak they demonstrate unambiguously the full reversibility of this phase change, confirming the DSC and HSM data. FT-Raman Spectroscopy. The FT-Raman spectra of the three polymorphs are given in Figure 6. Forms II and III° were recorded at room temperature. These two polymorphs can be distinguished by the stretch vibrations of the -CF3 group whose region is highlighted (inset) in the figure (form III°: 1335 cm-1, form II: 1341 cm-1). Within the low frequency vibration region the two room temperature forms show mainly differences in the band intensities (see inset on the right). Because of its high reproducibility FT-Raman spectroscopy is an adequate technique for identity assays of these forms. The Raman spectrum of the high temperature form was recorded at 160 °C. Differences to the two room temperature forms occur in the


Braun et al. Table 3. Torsion Angles in the Chain, Starting from the Center of the Naphthalene Group C(11) through the Phenyl Group C(18) of the Three CCCHC Polymorphs form form II, form II, III° molecule 1 molecule 2 C(11)-C(3)-C(2)-N(1) -150.2 C(3)-C(2)-N(1)-C(14) 65.9 C(2)-N(1)-C(14)-C(15) 175.2 N(1)-C(14)-C(15)-C(16) 187.9 C(14)-C(15)-C(16)-C(17) -177.2 C(15)-C(16)-C(17)-C(18) 86.3

Figure 7. X-ray powder diffraction patterns of the CCCHC forms I, II, and III°. Form II and III° measured at room temperature; form I at 150 °C.

low frequency region, the symmetric deformation vibrations of the methyl group (form I: 1368 cm-1, forms II and III°: 1371 cm-1) and the combined bend and stretch vibrations of the two aromatic rings (form I: 1580 cm-1, forms II and III°: 1584 cm-1). X-ray Powder Diffractometry. The X-ray powder diffraction patterns of the crystalline solid state forms of CCCHC are illustrated in Figure 7. The powder pattern allow a clear and fast identification of the polymorphs, particularly by the following reflections: form I: 6.63, 14.72, 15.81, 18.15, 18.37, 19.74, and 23.06° 2θ; form II: 6.79, 12.26, 13.65, 16.38, 17.50, 19.42, 20.27, and 23.32° 2θ; form III°: 6.86, 10.35, 13.80, 18.97, 20.79, 21.23, 24.22, and 25.44° 2θ. As a consequence of the plate and needle-like shape of the crystals, texture effects can occur in the powder pattern and the relative intensities of the reflections might vary depending on the preparation. The powder diffraction pattern of the high temperature form I was measured at 150 °C, whereas the other two patterns were recorded at room temperature. Structural Features of the Polymorphs. The cinacalcet molecule consists of two terminal aromatic groups, a (trifluoromethyl)phenyl (PhCF3) moiety and a naphthalene group, linked together by a flexible methyl substituted methyl-propylamine chain. The aromatic groups are rigid, apart from the rotational orientation of the respective methyl and trifluoromethyl group. The flexibility of the molecule concerns only the chain, which has six rotatable bonds. The only strong hydrogenbond acceptor is the Cl- anion, and the only possible donor, which allows the formation of strong standard hydrogen bonds, is the quaternary nitrogen atom. Form III°. In the crystal structure of form III° all four molecules in the unit cell are symmetry equivalent. The alkyl chain of the molecule has all torsion angles close to 180° (see Table 3 for a listing of all torsions). Neighboring molecules are roughly in antiparallel orientation, related by a 21 screw axis. In this arrangement all nitrogen atoms, located in the center of each molecule, fall into the same plane (z ≈ 0, 0.5). Each molecule forms two standard hydrogen bonds of the N-H · · · Cl- type. These strong intermolecular bonds form crankshaft-like chains along the unit cell axis a (Figure 8f), alternating Cl- and N-H, which is the dominating feature of the molecular packing. A number of weak nonstandard hydrogen bonds of the C-H · · · Cl type21 define the coordination around the Cl- ions (see Table 4). It is obvious that the chain structure is the most characteristic feature of the molecular packing, with

148.1 91.5 -151.8 173.8 151.3 67.4

-147.6 77.9 171.1 -177.3 148.2 -127.3

form I -135.6 55.0 136.5 178.8 ≈90 . . . 270

only sparse and weak C-H · · · π, C-H · · · F, and C-F · · · π interactions between parallel chains to constitute a threedimensional network. In form III° one of the fluorine is close enough to the naphthalene group to establish a weak C-F · · · π facial interaction (centroid distances for the two positions of the disordered fluorine atom: 3.307 and 3.202 Å). The extended hydrogen bonding scheme of the strong hydrogen bonds, which build the crankshaft-like chain along a, are shown for all three polymorphs in Figure 8 and is discussed in more detail below (under the subheading Form I). The geometric parameters, including the distances and angles, of all hydrogen bonds of the three polymorphs, are given in Table 4. Form II. Form II of CCCHC is triclinic with a unit cell approximately half the size of form III° and contains two independent formula units. From a comparison of the structures, the close relation is evident, which can be emphasized by a transformation of the unit cell to a nonstandard setting with c′ ) c - 0.5b, resulting in the converted lattice parameters c′ ) 13.228 Å and R′ ) 94.7°. Figure 9a shows an overlay of the two independent cinacalcet molecules of form II together with the conformation of form III°, and in Figure 9b,c the rotation of the PhCF3 moiety is demonstrated in two views by overlaying the C15-C16-C17 chain. The conformational differences concern mainly the orientation of the PhCF3 group. One of the two molecules of form II shows a conformation which is similar to that of form III°, whereas in the other molecule the PhCF3 ring is rotated by 165°. To estimate the energy of this rotation conformational energy calculations were performed using the B3LYP22 functional and the 6-31G* basis set on all atoms, as incorporated in Gaussian 03.23 The results suggest that the CF3 group has only very little influence on the energy of the conformation of the torsion angle C15-C16-C17-C18 (i.e., the rotation of PhCF3) compared to ethylbenzene. The torsion angle in cinacalcet is lowest at about 90°, and by 6.2 KJ mol-1 higher for the planar conformation. This is slightly higher than the rotational energy calculated for a rotation of ethylbenzene24 (albeit with a slightly larger basis set), and this calculated increase in energy is possibly due to the presence of the CF3 group. The 165° rotation of the PhCF3 moiety of molecule 2 (form II) changes the overall polarity of the chain. In an individual chain of the form III° molecule all PhCF3 groups point in the same direction (2-fold symmetry axis along the chain). In form II both conformations alternate in a single chain, breaking the orthorhombic symmetry. The chains are related only by translation in form II but by a set of orthogonal 21 screw axes in form III°. The strong N-H · · · Cl- bonds, as well as the C-H · · · π interactions, are very similar in form II and III°, and the weak nonstandard C-H · · · Cl- bonds show some minor differences (for details see Table 4). The molecular packing of the CCCHC polymorphs is illustrated in Figure 10; for clarity the hydrogen



Figure 8. Strong hydrogen-bond pattern of CCCHC forms I-III°. (a-c) view along the a axis: (a) form I, (b) form II, and (c) form III°; (d-f) view along the c axis: (d) form I, (e) form II, and (f) form III°. Strong hydrogen bonds are denoted with dotted lines. The PhCF3 rings and H-atoms were omitted for clarity. Table 4. Geometrical Parameters for the Weak and Strong Interactions in CCCHC Polymorphs Involving the Cl- anionsa form III° interaction N(1)+-H(1A) · · · ClN(1)+-H(1B) · · · ClC(2)-H(2A) · · · ClC(4)-H(4A) · · · ClC(8)-H(8A) · · · ClC(13)-H(13A) · · · ClC(14)-H(14A) · · · ClC(14)-H(14B) · · · ClC(15)-H(15A) · · · ClC(15)-H(15B) · · · ClC(22)-H(22B) · · · Cl-

D Å θ° 3.13 3.10 3.80 3.74

form II, molecule 1 DÅ

160 3.19 171 2.99 150 165 3.65

θ°

form II, molecule 2 form I DÅ

θ° D Å θ°

144 141

3.16 3.03

172

3.83

148 3.20 120 137 3.60 134 3.51 119 165 3.29 110 3.05 120 139 3.58 130 131 3.16 158

3.73 3.65 157 3.20 106 3.56 3.13, 3.20 116, 108 3.67 131 3.67 140

3.03 162

a

The sum of the van der Waals radii was used as the cut-off parameter.

Figure 9. (a) Overlay of the two independent molecules of CCCHC form II (molecule 1- red, molecule 2 - green) and the molecule of form III° (blue), showing the conformational differences; (b) and (c) demonstrate the rotation of the PhCF3 moiety in CCCHC forms II and III° (molecules were overlaid along the C15-C16-C17 chain, for clarity only the PhCF3 part of the cinacalcet molecule is shown).

atoms are omitted and only the strong intermolecular interactions are shown. The crankshaft-like chains are nearly identical to form III° (see Figure 8). Between the chains of form II only weak interactions of the C-H · · · π type (see Hirshfeld surfaces) exist. The weak C-F · · · π facial bonding and C-H · · · F interactions (cut off parameter: sum of the van der Waals radii) observed in form III° are not present in form II. This might be

Figure 10. Comparison of the molecular packing of CCCHC forms I, II, and III°. (a) Form I along [100], the disordered part of the molecule (PhCF3) is drawn as thin lines, (b) form II along [100], (c) form III° along [100]. Strong hydrogen bonds are denoted with dotted lines. Figures include the unit cells.

one of the reasons for the reduced stability of form II with respect to form III°. Form I. Because of the rather low quality of the data, it was not possible to derive all structural details of the high temperature form I clearly from powder diffraction. The structure of form I shows a high degree of disorder which hampers a straightforward structure solution from powder data. Nonetheless, some major structural conclusions can be drawn from the


Braun et al.

Figure 11. 2D fingerprint plots for CCCHC forms II and III°. de and di are the distances to the nearest atom center exterior and interior to the surface. Spikes labeled with 1, 2, and 5 represent the N-H · · · Cl- H-bonds, wings labeled with 3, 4, and 6 the C-H · · · π interactions; all acceptor groups are denoted with a, all donor groups are denoted with b. The Hirshfeld surfaces for the disordered form III° were calculated based on the smeared electron distribution of the two hypothetical orientations of the CF3 group.

analysis. The most prominent structural difference to form III° is the orientational disorder of the PhCF3 group. The moiety seems to be distributed over a semicircle, with the highest density at the two edges of the distribution. These positions coincide roughly with the two different PhCF3 orientations in the ordered forms. Since the PhCF3 moiety shows only weak intermolecular interactions in the structure of form III° it can be expected that upon heating its thermal motion increases until (above a critical temperature) the moiety starts to switch between the two possible orientations, resulting in a dynamic disorder. To specify this disorder in further detail is not possible on the basis of the available data. In general, form I shows basically the same kind of hydrogen bond synthon along the a axis as the forms II and III° (see Figure 8), but the distance and strength of the N-H · · · Cl- bonds are different (see Table 4). In both ordered forms (II and III°) there is a clear discrepancy between the N-H · · · Cl- distances in the hydrogen bonds and those unbounded intrachain distances across a crank (D ≈ 3.1 and 4.2 Å, respectively). In form I these distances differ only slightly (D ) 3.60 and 3.68 Å) and the order is reversed. This is why the shorter hydrogen bond switches to the opposite site of the Cl- (see Figure 8) compared to the forms II and III°, i.e., the connectivity along a changes. The length of the bonds along b (normal to the chain axis) is 3.20 Å and thus approximately in the same range as for the other forms. Another striking structural difference between form I and the other polymorphs is the orientation of the naphthalene group, which is rotated by about 60°. This is probably a direct consequence of the disorder, i.e., the interference with the phenyl group. 2D Fingerprint Plots of Form II and III°. To compare the strong N-H · · · Cl- bonds, as well as the weak C-H · · · π interactions between the chain moieties, we calculated the Hirshfeld surfaces of the two room temperature polymorphs. The surfaces are constructed by partitioning the space within a crystal structure into regions, where the electron density from a sum of spherical atoms dominates over the sum of the electron density of the crystal.25 For the calculation of the surfaces the program Crystal Explorer26 was used. The 2D fingerprint plots27

give an insight into the overall packing characteristics of the polymorphs. It is a plot of de against di, where di is the distance to the nearest atom center interior to the surface, and de exterior to the surface. In Figure 11, a comparison of the two 2D fingerprint plots of two polymorphs (II and III°) is given. For each of the three conformations (one for form III° and two for form II), the shortest N-H · · · Cl- H-bond appears as a spike in the 2D fingerprint plots. The strongest H-bond is formed in form III° (N(1)-H(1B) · · · Cl-), indicated by the lower de and di value (de ) 1.3 Å - di ) 0.8 Å and de ) 0.8 Å - di ) 1.3 Å) and the sharp narrow spike, marked with 5a, for the acceptor and 5b for the donor. Sharp spikes indicate that the angles are near 180°. The higher de and di values, as well as the broader spikes, illustrate the slightly weaker H-bonds in form II (Figure 11). The N(27)-H(27A) · · · Cl(1)- is labeled with 1 and N(1)H(1B) · · · Cl(2)- with 2. For clarity only the shortest N-H · · · Clbonds are marked in each plot. Characteristic for C-H · · · π interactions are the wings in the 2D fingerprint plots. In both room temperature polymorphs the weak C-H · · · π interactions contribute to the interchain interactions. The naphthalene moiety acts in all these interactions as the acceptor. In polymorph II the C-H · · · π interactions are formed between independent cinacalcet molecules, and the shortest C-H · · · π interaction can be found in this polymorph (4a for the π, and 4b for the C(5)-H(5A), respectively, perpendicular distance d 2.36 Å). The second C-H · · · π interaction in form II involves the C(31)-H(31A) atoms (perpendicular distance d 2.99 Å). For form III° the perpendicular distance d of the C(5)-H(5A) · · · π interaction (6) is 2.77 Å. Thermal Expansion. The isotropic thermal volume expansion (Figure 12, Table 5) is of comparable extent for all three crystalline phases and a strong anisotropy is also a common feature of the polymorphs. However, the anisotropy of the thermal expansion is similar for forms II and III° (high along c and low along a), but for form I the situation for the relative values is reversed. The reason for the thermal expansion differences along a becomes obvious from the structural features of the three forms. The dimension of the unit cell axis a is directly comparable in all three structures. This axis is oriented



Figure 12. Isotropic thermal expansion of CCCHC polymorphs upon heating and cooling. Table 5. Parameters of Thermal Expansion Derived from XRPD, Valid for the Temperature Range Covered Experimentally parameter linear thermal expansion:

absolute value [Å/K, Å3/K or deg/K]

relative value [10-5/K]

form I

V a b c

0.48(4) 0.00063(6) 0.00088(7) 0.00136(17)

21.6(20) 8.7(8) 7.6(6) 5.2(6)

form II

V a b c R β γ

0.20(2) 0.00031(4) 0.00074(9) 0.00155(2) -0.00797(65) 0.01324(121) 0.00249(29)

18.9(17) 4.3(6) 6.5(8) 11.1(2)

V a b c

0.55(2) 0.00050(3) 0.00099(4) 0.00261(5)

25.5(9) 6.9(4) 8.6(4) 10.1(2)

[Å or Å3]

[%]

form III°

discontinuity at transition III° f I

V a b c

66.8(13) -0.035(2) 0.172(3) 0.531(4)

3.03(6) -0.48(2) 1.48(2) 2.03(1)

I f III°

V a b c

-69.0(13) 0.039(2) -0.175(3) -0.569(4)

-3.15(6) 0.54(2) -1.51(2) -2.18(1)

II (x2) f III°

V a

-36.8(6) -0.0055(12)

-1.70(3) -0.08(2)

parallel to the main chain axis, and its length is the repetition period of the chain. Because of the hydrogen bonding along this chain this lattice parameter can thus be expected to be rather rigid for forms II and III°. In the disordered form I the distance between the Cl- ion and the amino nitrogen is increased along the a-axis, resulting in weaker hydrogen bonds than in the other polymorphs. Therefore in form I the thermal expansion is higher along this direction. On the other hand, the strong hydrogen bonds along b are of similar strength in all three forms, leading to a similar thermal expansion along b. Along c only weak intermolecular forces consolidate the framework, which explains the higher thermal expansion of forms II and III° in this direction. However, it is less obvious why the thermal expansion along c is relatively small in form I, but this is presumably an effect of the disorder in this polymorph, which is already associated with a longer (by ∼1 Å) c-axis compared to the isosymmetric form III° (see Table 1).

Figure 13. Temperature-dependent changes of the lattice parameters of CCCHC forms III° and I on heating and cooling. The two-phase regions are indicated by the vertical dotted lines boundaries.

The phase transitions are accompanied by strong anisotropic changes of the lattice dimensions. For the II f III° transformation only a small contraction along a appears, which highlights again the stiffness of the chain direction. The other unit cell dimensions are not directly comparable. However, the strong cell volume contraction must be the result of a cell reduction lateral to the chains. The molecular arrangement of the chains in form III° obviously allows a denser packing, and the transformation to form I is fully reversible. Furthermore, density reduction upon change into the disordered form I is common behavior. The structural reasons for the observed reduction of the lattice parameter a (Figure 13) have been discussed above. Thermodynamic and Kinetic Stability. The DSC and temperature-controlled PXRD experiments reveal that the reversible transformation between the forms III° and I depends strongly on the heating rate, which indicates a considerable kinetic control. DSC experiments were mainly performed with a heating or cooling rate of 10 K min-1, whereas in the temperature controlled XRPD experiments the temperatures were kept constant for 90 min during the individual measurements. The phase transition temperatures of both experiments are listed in Table 2. The DSC curve (see Figure 3) of form II shows the onset of the inhomogeneous melting process to form I at 170 °C. The thermodynamic relationship between the three polymorphs of CCCHC is demonstrated in a semischematic energy/ temperature diagram in Figure 14, which has been constructed based on the measured melting points and transition or fusion enthalpies. According to the heat of fusion rule28 all three polymorphic pairs are enantiotropically related, since in every case the higher melting form has the lower enthalpy of fusion


Braun et al.

Conclusions

rotatable bonds). The observed supramolecular arrangements of the crystal polymorphs are obviously a consequence of these specific molecular features. All three polymorphs show basically the same hydrogen bond arrangement, a crankshaft-like chain, linked by N-H · · · Cl- hydrogen bonds. In addition, C-H · · · Clinteractions are present. Interactions between these strong hydrogen-bonded chains involve weak C-H · · · π (both room temperature forms) and, as discussed for form III°, C-F · · · π and C-H · · · F interactions. The main difference between the polymorphs concerns the orientation of the PhCF3 moiety. The stable form III° shows only one molecular conformation, whereas the structure of form II is based on two different conformations and in the high temperature form I the PhCF3 moiety is dynamically disordered. The orientation of the naphthyl group in the forms II and III° is similar but different from form I. Thus CCCHC is clearly a case of “conformational polymorphism”,29 as it can be expected from its molecular features. Since we were able to determine the melting points and heat of fusions of the three polymorphs we could easily assess the relative thermodynamic stability and relationships of the three polymorphs with the aid of a semischematic energy temperature diagram (see Figure 14) and the Burger-Ramberger rules.28 All forms are enantiotropically related which implies the existence of three transition points. Form III° is stable below the transition point to form I (Ttrs )148.5 °C), and the high temperature form I is stable above this temperature. The data confirm clearly that form II is unstable over the entire temperature range but shows a high kinetic stability at room temperature. This fact enables its use in pharmaceutical solid dosage forms although the stability decreases at elevated temperature (>70 °C) where a transition to form III° occurs. The reversible phase transition III° T I was examined with different analytical techniques. From the structural data we may classify this transition as an isosymmetric phase transition (same space group and similar lattice constants). The study also highlights the strength of thermal analytical techniques in the determination of an “undesired” polymorph. The sensitivity of this technique in the detection of the presence of seeds of a certain polymorph is highlighted by the behavior of mixtures of the two room temperature forms (III° and II). Concomitant crystallization of the two forms from solvents results in samples which lack seeds of form I. This is why they show a completely different thermal behavior to the form II obtained by desolvation of one of the solvates or “pure” form III° crystallized from water. In any case, from our experience, the detection limit of DSC in mixtures of the polymorphs is definitely lower than that of PXRD and vibrational spectroscopy. Because of the observed structural differences it is not surprising that the spectral features of the forms II and III° are also rather similar. Thus a clear identification of the present polymorph in drug products with Raman- or IR-spectroscopy30 is not as straightforward as with powder-X-ray diffractometry, particularly in lower dosed tablets, which contain a higher amount of excipients that may interfere with the characteristic bands. Finally, the study also demonstrates that structure determinations from powder data can provide important key information for the basic understanding of the causes of polymorphism and of observed phase transitions.

CCCHC embodies a halide salt of a linear molecule with only one rather central polar group (secondary amine), which is able to form strong hydrogen bonds, and two hydrophobic (aromatic) terminal groups linked via a flexible aliphatic chain (six freely

Acknowledgment. The authors thank Sandoz GmbH for financial support and the supply of cinacalcet hydrochloride. Thanks also to M. F. Haddow for helpful discussions, comments, and the calculations of the torsion energies.

Figure 14. Semischematic energy/temperature diagram of CCCHC polymorphs (I, II, and III°). Tfus: melting point, G: Gibbs free energy, H: enthalpy, ∆fusH: enthalpy of fusion, Ttrs: transition point, ∆trsH: transition enthalpy, liq: liquid phase (melt). The bold vertical arrows mark the experimentally measured enthalpies.

(see Table 2). Hence, there are three transition points, that is, the free energy curves of all forms intersect below the melting point (Figure 5). The reversible transition of form III° to form I proves directly the enantiotropic relationship between these two forms (heat of transition rule28). The fact that form III° represents the thermodynamically stable polymorph at and below room temperature can be derived from the constructed diagram (lowest free energy). This was also attested by solvent mediated transformation experiments in a 2-PrOH/water mixture starting with mixtures of forms II and III°. Form III° survives in this experiment. The transition point between the forms III° and I lies at 148.5 ( 1 °C, which is calculated from the average of the experimental transition temperatures measured by DSC and temperature controlled XRPD. Form I is the stable form above this temperature and form III° below. The hysteresis of about 30 °C between the experimental transition temperatures indicates a moderate kinetic control of this reversible transition. Form II is thermodynamically unstable over the entire temperature range. A transition of form II to form III° did not take place during storage of samples of pure form II at room temperature in a glass vessel for 18 months, which indicates the high kinetic stability of this polymorph at ∼20 °C. However, at elevated storage temperatures a slow transition to form III° was observed. This transition also happened during the temperature resolved XRPD investigations at 110 °C. The order of the thermodynamic stability of the three polymorphs (III° > II > I) at zero K is in good agreement with the order of calculated densities (III° > II > I, see Table 1), confirming that this polymorphic system obeys the close packing principle, that is, the density rule.28

Crystal Polymorphs of R-Cinacalcet Hydrochloride Supporting Information Available: X-ray powder diffraction pattern and Rietveld fit of CCCHC forms I and II; thermal ellipsoid plot of CCCHC form III°; comparison of the crystal structures of all three polymorphs; structure overlay of forms I and III°. This information is available free of charge via the Internet at http://pubs.acs.org. The crystallographic data of the forms I-III° have been deposited with the Cambridge Crystallographic Data Centre, CCDC Nos. 685307 (form I), 685308 (form II), and 685309 (form III°).

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CG8005647

Structural and Thermodynamic Features of Crystal Polymorphs of R

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