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Solid state characterisation of four solvates of R-cinacalcet hydrochloride
Doris E. Braun,a Volker Kahlenberg,b Thomas Gelbrich,a Johannes Ludescherc and Ulrich J. Griesser*a
Received 2nd June 2008, Accepted 7th August 2008
First published as an Advance Article on the web 16th September 2008
DOI: 10.1039/b809219b
The study describes the solid state behaviour, and the thermal and structural features of four
monosolvates of cinacalcet hydrochloride with acetic acid, chloroform, 1,4-dioxane, and
tetrachloromethane, and summarises the transformation and production pathways of the seven crystal
forms of this promising drug compound (calcimimetic). The solvates were identified and characterised
by hot-stage microscopy, differential scanning calorimetry, thermogravimetric analysis, FT-infrared
and Raman spectroscopy, powder diffractometry, and the structure of the acetic acid solvate was
determined by single crystal X-ray diffraction. All solvates are unstable when removed from the mother
liquor and desolvate to form II. To our knowledge, phase pure samples of this metastable but
kinetically stable form are only obtainable via desolvation of one of the solvates.Thermoanalytical data
and a conformation and packing analysis of the acetic acid solvate and the polymorphs indicate that the
desolvation is a destructive process forming an isotropic intermediate state with high molecular
mobility. Therefore the desolvation process results in the kinetic form II, which is structurally less
similar to the solvate than the thermodynamically stable form III . The study demonstrates that in spite
of strong structural similarities between a solvate and a polymorph we can obtain a polymorph with less
structural resemblance to the solvent adduct if the structure collapses during the desolvation process.
which were characterised along with the chloroform solvate in
Introduction
more detail. Since it was also possible to obtain the single crystal
R-Cinacalcet hydrochloride (N-[(1R)-1-(1-naphthyl)ethyl]-
structure of SAC, the structural features of this solvate are
3-[3-(trifluoromethyl)phenyl]propan-1-amine hydrochloride,
discussed and compared with the structures of the metastable
CCCHC, Fig. 1) is the first drug in a new class of therapeutic
form II (structure was solved from powder data2), which is
agents (calcimimetics), which increase the sensitivity of calcium-
exclusively obtained by the desolvation of all solvates, and that
sensing receptors (CaR) to the extracellular calcium ions, thus
of the thermodynamically stable polymorph at room tempera-
lowering the parathyroid hormone (PTH) production and
ture, form III (solved from single crystal data2).
release. This finally results in a decrease of serum calcium and
General thoughts on the nature and importance of solvates
phosphorous concentrations simultaneously.1 The compound is
have been reviewed recently7 including a discussion on whether
marketed as SensiparÒ, MimparaÒ, and PararegÒ.
other terms such as co-crystal or pseudopolymorphism may
CCCHC crystallises in three polymorphic forms, whose
be appropriate appellations of these crystal species, which can
structural and thermodynamic features are described in detail
be broadly defined as crystalline solids where a solvent is
elsewhere.2 These forms have already been popular in different
co-ordinated in or accommodated by the crystal structure. The
patent applications3 6 beside the amorphous form and a chloro-
existence of solvates of industrially relevant materials (such as
form solvate. Within a comprehensive solid state character-
drug compounds)8,9 needs to be considered because of several
isation program of this compound we carried out a large number
reasons. One is the fact that these adducts may show unique
of crystallisation experiments from about 20 different solvents
physical and pharmaceutical properties, as is the case for poly-
(for details see ESI). The experiments confirmed the existence of
morphs.10,11 Solvent adducts often crystallise more easily than
the chloroform solvate and, in addition, we found three new
the solvent-free molecules, because of more efficient packing
solvated forms (acetic acid, dioxane, and tetrachloromethane),
together with the solvent molecules.12 However, often their
stability is low, i.e. they desolvate readily as soon as they are
removed from the mother liquor. Such solvates can be easily
a
Institute of Pharmacy, University of Innsbruck, Innrain 52, 6020
overlooked in polymorph screening programs, and wrong
Innsbruck, Austria. E-mail: [e-mail]; Fax: [phone]
507 2939; Tel: [phone]
b
Institute of Mineralogy and Petrography, University of Innsbruck, Innrain
52, 6020 Innsbruck, Austria
c
Sandoz GmbH, Biochemiestrasse 10, 6250 Kundl, Austria
Electronic supplementary information (ESI) available:
Photomicrographs of a single crystal of SAC (desolvation at higher
heating rates), FT-IR spectra of a heating cycle of the solvates, thermal
ellipsoid plot for SAC, 2D Hirshfeld fingerprint plots for form II and
SAC, details for solvents and conditions used for crystallisation. CCDC
reference number 690028. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/b809219b Fig. 1 Molecular structure of CCCHC (C22H23ClF3N, Mr ź 393.87).
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conclusions concerning the solvent effects on the nucleation of Norwalk, Ct., USA) using the Pyris 2.0 software. Approximately
individual polymorphs may result. The fact that a certain 1 0.0005 mg sample (using a UM3 ultramicrobalance, Mettler,
polymorph can be only produced via a specific solvate13,14 in Greifensee, CH) was weighed into Al-pans (25 ml). Dry nitrogen
a high physical and also chemical purity makes these adducts was used as the purge gas (purge: 20 ml min 1). Heating rates of
particularly appealing for well-controlled manufacturing 10 K min 1 were routinely used. The instrument was calibrated
processes of raw drug materials in pharmaceutical and chemical for temperature with pure benzophenone (mp 48.0 C) and
industry. The technical use of solvates for a purification process caffeine (mp 236.2 C) and the energy calibration was performed
has been reported for dirithromycin15 and is an increasingly with pure indium (purity 99.999%, mp 156.6 C, heat of fusion
disclosed purification strategy in patent applications, e.g. 28.45 J g 1).
the purification of stavudine16 (the purification reaction with
N,N-dimethylacetamide (DMA)). Moreover, the desolvation of Thermal gravimetric analysis (TGA). TGA was carried out
stoichiometric solvates may result in products of small and very with a TGA7 system (Perkin-Elmer, Norwalk, CT, USA) using
homogeneous particle size, which reduces the efforts and prob- the Pyris 2.0 software. Approximately 1 mg of sample was
lems connected to milling.7 Anyway, it is very important to know weighed into a platinum pan. Two-point calibration of the
any existing solid state form including even highly unstable temperature was performed with ferromagnetic materials
solvates for a modern, knowledge based development of chem- (Alumel and Ni, Curie-point standards, Perkin-Elmer). Heating
ical products and pharmaceuticals. Any phase change due to rates of 10 K min 1 were applied and dry nitrogen was used
a phase transition to a more stable polymorph, a desolvation of as a purge gas (sample purge: 20 mL min 1, balance purge:
solvates, the formation of a hydrate, or even a change in the 40 mL min 1).
degree of crystallinity may strongly affect the properties of
the material and subsequently important key parameters of the
Spectroscopy
product such as the bioavailability in the case of drugs.8,9
In order to assess the stability and structural basics of Fourier transform infrared (FT-IR) spectroscopy. FT-IR
the different solvate forms of CCCHC a variety of analytical spectra were recorded with a Bruker IFS 25 spectrometer
techniques were applied, such as hot stage microscopy (Bruker, Ettlingen, D) connected to a Bruker IR microscope I
(HTM), differential scanning calorimetry (DSC), thermogravi- with a 15x-Cassegrain-objective (Bruker). Freshly prepared
metric analysis (TGA), vibrational spectroscopy (FT-IR and single crystals of the solvates were pressed onto a ZnSe disc or for
FT-Raman) as well as powder (PXRD) and single crystal X-ray non ambient temperature spectra the substance was placed in
diffraction. between two ZnSe discs and heated with a Bruker heatable
accessory holder and following measurement conditions were
applied: spectral range 4000 to 600 cm 1, resolution 4 cm 1, 64
Experimental
interferograms per spectrum.
Materials
Fourier transform Raman (FT-Raman) spectroscopy. FT-
CCCHC (purity 99.0%) was obtained from Sandoz GmbH. The
Raman spectra were recorded with a Bruker RFS 100 Raman-
sample consisted of form III (the superscript zero marks the
spectrometer, equipped with a Nd:YAG Laser (1064 nm) as the
stable form at room temperature). All solvents used for the
excitation source and a liquid-nitrogen-cooled, high sensitivity
crystallisations were of p.a. quality and purchased from Sigma-
Ge-detector. The spectra were recorded in aluminum sample
Aldrich.
holders with a laser power of 200 mW (64 scans per spectrum)
and a resolution of 4 cm 1.
Preparation of the individual solvates
Powder X-ray diffractometry (PXRD). XRPD patterns were
CCCHC solvates were obtained by crystallisation from acetic
obtained with a Siemens D-5000 diffractometer equipped with
acid, chloroform, 1,4-dioxane, and tetrachloromethane. Hot
a theta/theta goniometer, a CuKa radiation source, a Göbel
saturated solutions of the compound in the respective solvent
mirror (Bruker AXS, Karlsruhe, D), a 0.15 Soller slit collimator
were filtered, cooled to 0 C in an ice bath, and allowed to crys-
and a scintillation counter. The patterns were recorded at a tube
tallise. The crystals were stable as long as they were surrounded
voltage of 40 kV and a tube current of 35 mA, applying a scan
by the corresponding solvent of crystallisation. Therefore all
rate of 0.005 2q s 1 in the angular range of 2 to 40 2q.
measurements were performed immediately after removing the
crystals from the solution.
Single-crystal X-ray diffractometry. The X-ray data for SAC
were collected on a STOE IPDS-II diffractometer using MoKa
Thermal analysis
radiation. The data collection was performed at 100 C. The
Hot-stage microscopy. For thermomicroscopic investigations program package WinGX17 (SIR9718 and SHELXL9719) was
(HTM) a Reichert Thermovar polarisation microscope equipped used to solve and refine the crystal structure. All H atoms bonded
with a Kofler hot stage (Reichert, Vienna, A) was used. Micro- to carbon and oxygen atoms were generated in idealised geom-
photographs were taken with a digital camera (Olympus DP50). etries using a riding model and their positions were refined with
Uiso(H) ź 1.2 Ueq(C) for aromatic and aliphatic non-terminal
Differential scanning calorimetry (DSC). Differential scanning C H and Uiso(H) ź 1.5 Ueq(C/O) for  CH3 and  OH groups. The
calorimetry was performed with a DSC 7 (Perkin-Elmer, amino H atoms were identified from difference Fourier maps and
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refined without any constraints. The fluorine atoms in the  CF3
group were found to be statistically disordered over two
positions with an occupancy of 0.79:0.21.
Results and discussion
Screening for different solvated forms of CCCHC resulted in
four unstable solvates with acetic acid (SAC), chloroform (SCLF),
1,4-dioxane (SDX), and tetrachloromethane (STCM).
Thermal analysis
Hot-stage microscopy. All four solvates form transparent, thin,
needle-like crystals which lose transparency within hours (SCLF,
SDX, and STCM) or a day (SAC) after their removal from the
Fig. 3 Overlay of the TGA curves of the CCCHC solvates (temperature
mother liquid. The desolvation process (dry preparation) starts
range: 20 120 C, heating rate 10 K min 1).
already at room temperature and shows the highest rate at
approx. 80 C. In silicon oil preparations, the formation of
bubbles in the liquid can be observed on heating. All solvates
desolvation should be performed at lower temperatures if one
desolvate below 100 C. At low heating rates ( 3 K min 1) a loss
aims at the production of pure form II.
of birefringence can be observed in polarized light, as shown
for crystals of the SAC in Fig. 2. This indicates that the solvent
Thermogravimetry and differential scanning calorimetry. The
is released by a diffusion controlled process. Nucleation and
solvent to compound ratios of the adducts were determined with
growth of needle like crystals of the anhydrous phases occur
TGA (Fig. 3). The TGA curves of all solvates exhibit a distinct
between about 90 and 100 C. The original shape of the solvate
step at about 80 C due to the loss of the solvent. The mass loss of
crystals is essentially maintained but the particles (consisting
SAC (13.1 %), SCLF (22.8%), SDX (16.1 %), and STCM (27.8 %)
of many crystals of the anhydrous phase) appear opaque due
corresponds to 0.99 mol acetic acid, 0.98 mol chloroform, 0.86
to light scattering effects. However, at higher heating rates
mol dioxane, and 0.99 mol tetrachloromethane per CCCHC
( 10 K min 1) the isotropic intermediate phase is barely
molecule, respectively. Considering the instability of the solvates,
observable and the nucleation and growth process of the anhy- this result suggests that all of them are monosolvates. Further-
drous phase occurs in the still birefringent solvate crystals. Such
more, the TG experiments indicate that STCM is the least stable
a process is shown for a single crystal of the SAC in the ESI
solvate. SCLF and SDX are equally stable, and SAC shows the
(Fig. S1). From the fact that the crystals grow in all directions
highest thermal stability.
we conclude that the desolvation is not a topotactic reaction but
The DSC curves of the solvates along with the TGA curves are
involves a complete disruption of the original structure at the
given in Fig. 4. Three of the solvates (SCLF, SDX, and STCM) show
reaction interface.
a broad desolvation endotherm, which already starts at the
It was observed that the desolvation of all solvates results
beginning of the heating experiments. The exothermic part of
exclusively in the metastable form II, which melts at 170 C.
the process indicates a crystallisation event and suggests that the
However, when the desolvation product (form II) is kept at
desolvation involves a structural collapse with subsequent
elevated temperature (110 C, for 24 h) a complete solid-solid
nucleation and growth of form II. A desolvation experiment of
transition to the stable form III takes place.2 Therefore the
SDX at 80 C resulted in an amorphous product, which confirms
this conclusion. In contrast, SAC shows a rather sharp inhomo-
geneous melting peak (overlapping processes of desolvation,
melting, and recrystallisation to form II) with an onset temper-
ature of 83 C.
Vibrational spectroscopy
FT-IR spectroscopy. The FT-IR spectra (Fig. 5) of the unstable
solvates were obtained with the aid of a FT-IR microscope.
Frequencies of some characteristic bands of the CCCHC mole-
cule in the different solvates are given in Table 1. According to
these bands a discrimination between all different solid forms
(solvates and polymorphs) is possible.
Additionally the thermal desolvation process of the solvates
was recorded with the aid of the FT-IR microscope and a heating
Fig. 2 Series of photomicrographs of SAC, showing the desolvation
stage. Single crystals (only intact, transparent crystals were used)
process at slowly increasing the temperature. Desolvation is accompanied
were rolled on a ZnSe disc, coverd with a second ZnSe disc, and
by a loss of birefringence before the nucleation of form II and its growth
to small needles of the anhydrous phase begins. the spectra were recorded in 20 C steps on raising the
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Fig. 4 DSC and TGA curves of CCCHC solvates (heating rate 10 K min 1).
presence of acetic acid in SAC can be easily recognised by the
stretch vibrations of the carbonyl group at 1752 and 1723 cm 1
(see Fig. 5) since the CCCHC lacks a carbonyl group.
Additionally the doublet of the aromatic C H deformation
vibrations at around 800 wavenumbers (807, 795 cm 1) is
a striking difference between SAC and the other solvates and
polymorphs. SDX shows the symmetric stretch vibration bands of
the cyclic ether function at 880 cm 1 (medium band at 873, weak
at 888 cm 1) of dioxane. The two halogenated solvates, SCLF and
STCM, exhibit both a characteristic C Cl stretching band in the
spectral range of 740 765 cm 1 (SCLF), and 763 cm 1 (STCM),
respectively. After quickly cooling back to room temperature,
the spectra of all samples showed the presence of form II.
FT-Raman spectroscopy. Fig. 6 shows the FT-Raman spectra
of the four cinacalcet HCl solvates. The characteristic bands for
Fig. 5 FT-IR spectra of CCCHC solvates.
SAC are nC]O (1723 cm 1), and those for SDX are the aromatic
and aliphatic nC H bands (3100 2800 cm 1), indicating differ-
ences in the electronic environments of the alkyl-chain and the
Table 1 Characteristic IR bands for CCCHC solvates
aromatic rings. In particular, the two halogenated solvates can
be distinguished due to differences in the low frequency range
Solvate/ Selected
IR bands SAC SCLF SDX STCM
(250 to 90 cm 1).
n( CH3), ( CH2 ) 2969 2965 2963, 2853 2963, 2864
Powder X-ray diffraction (PXRD). To minimise preferred
n( NH2+ ) 2761 2755, 2713 2752, 2715 2754
n( CF3) 1166, 1122 1165, 1128 1168, 1123 1170, 1129 orientation effects and the risk of desolvation a slurry of the
d( CHar; 1,3-disub) 807, 795 799, 778 799, 779 800, 781
freshly prepared crystals was poured directly onto the sample
holder. The peak positions were unaffected by the irregular
shaped crystal faces in these preparations since an instrument
temperature to 168 C (and in smaller intervals close to the with parallel beam optics was used. The X-ray powder patterns
melting point at 170 C). The results of these experiments of the four solvates (Fig. 7) are quite distinct which alludes to
(spectral range 900 600 cm 1) are shown in ESI (Fig. S2) where prominent structural differences. The following characteristic
the characteristic regions are marked with an arrow. The 2q peak positions can be used to discriminate between the
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Fig. 8 Overlay of the cinacalcet molecules of form II and SAC: SAC 
black, molecule 1 of form II - dark grey, molecule 2 of form II - light grey.
Fig. 6 FT-Raman spectra of CCCHC solvates. orthorhombic space group P212121. Its unit cell consists of four
CCCHC units and four acetic acid molecules (for structural
details see! ). This stoichiometry is consistent with the CCCHC/
acetic acid ratio of 1:1 determined by TG experiments.
Molecular geometry. The cinacalcet molecule consists of two
terminal aromatic groups linked by a flexible methylpropylamine
chain, which can adopt different conformations.2 Fig. 8 shows an
overlay of the cinacalcet molecule of SAC with the two
conformers of form II.2 The torsion angle (C15 C16 C17 C18)
of 80.7 in SAC structure is similar to the corresponding angles
found in the molecule of form III (86.3 , not depicted) and one
conformer of form II (molecule 1, 67.4 ). However, it differs
considerably from the corresponding angle in the second
conformer of form II (molecule 2, 127.3 ).2 Thus, the fact
that the desolvation of SAC results exclusively in form II
seems counterintuitive. Such a transformation requires the
trifluoromethylphenyl (PhCF3) ring of every other molecule to
flip by approximately 150 , whereas only a small conformational
Fig. 7 X-Ray powder diffraction patterns of cinacalcet HCl solvates.
change would be required from the molecule in order to achieve
For SAC the calculated powder diffraction pattern (from single crystal
the conformation of form III . The energy for a rotation of the
data at 100 C) is also shown. Experimental patterns were recorded at
room temperature. PhCF3 ring from the lowest ( 90 ) to the highest energy position
( 0 or 180 ) was calculated2 to be about 6 KJ mol 1.
Considering that the molecules of form II adopt a less
favourable conformation than those of form III , it becomes
different forms. SAC: 15.09, 17.62, 18.30, 18.94, and 19.64 2q;
obvious that the formation of form II upon desolvation is driven
SCLF: 16.32, 17.87, 20.29, 21.49, and 24.67 2q; SDX: 6.49, 13.05,
by kinetics rather than thermodynamics. The formation of form
14.84, 16.52, and 19.43 2q; STCM: 8.31, 13.46, 15.51, 16.70 and
III would be energetically favoured due to both, its lower
21.54 2q. From wet tetrachloromethane we obtained also
samples, whose diffractograms do not match with that of STCM molecular conformation energy2 and its lower lattice energy
(derived from the fact that form III is the thermodynamically
(reflections at 8.33, 17.76, 16.73, and 22.94 2q.) This suggests the
stable form).
existence of an additional, but poorly reproducible TCM solvate.
The calculated powder pattern for SAC is also shown in
Intermolecular Interactions. The cinacalcet molecule contains
Fig. 8. The pattern is in good agreement with the experimental
only one strong H donor group (the quaternary amine) and one
one, except for certain peak shifts due to different recording
temperatures ( 100 C and 25 C of single crystal data and
experimental powder pattern, respectively) and intensity
! Crystal data of SAC: C22H23ClF3N$C2H4O2, Mr ź 453.92,
differences which can be attributed to preferred orientation of
orthorhombic, space group P212121, T ź 173(2) K, size [mm]: 0.32
the needle-shaped crystals of SAC.
0.16 0.12, a ź 7.5434(8), b ź 18.575(2), c ź 16.7756(19) Å, V ź
2350.6(5) Å3, Z ź 4, rcalc ź 1.283 Mg m 3, 13752 reflections measured,
3944 independent reflections, 3393 observed reflections, q range for
Crystal structure analysis
data collection: 1.64 24.68, range of h, k, l: 8 17 < l < 19, data: 3944, parameters: 304, R1 [I >2s(I)] ź 0.0458, wR2
Crystals suitable for a single crystal structure analysis were
(all) ź 0.0845, R int ź 0.048, Goodness of fit on F2 ź 1.070, Drmax ź
obtained only for SAC. This solvate crystallises in the 0.27, Drmin (e Š3) ź 0.19. CCDC reference number 690028.
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Table 2 Geometrical parameters for the intermolecular interactions in
SAC. The sum of the van der Waals radii was used as cut-off parameter.
Distances are given in Å and angles in
Interaction X/H H/A D/A D H A
N1+ H1A/Cl 0.96 2.18 3.12 171
N1+ H2B/Cl 0.86 2.33 3.17 164
O2S H/Cl 0.84 2.26 3.05 157
C4 H/Cl 0.95 2.87 3.78 162
C15 H/Cl 0.99 2.84 3.65 140
a
C6 H/F2 0.95 2.66 3.24 120
a
C16 H/F1 0.99 2.65 3.42 135
C14 H/O2S 0.99 2.64 3.36 130
C18 H/O1S 0.95 2.71 3.57 150
C21 H/O1S 0.95 2.52 3.41 156
b b
C1S H1SA/p 0.98 3.03 3.57 116
b b
C1S H1SC/p 0.98 3.10 3.52 107
a
Fluorine atoms belong to the disordered  CF3 group (occupancy 0.79).
b
Centroid distances.
polymorphs.2 Hence, the molecular packing in these four solid
forms of CCCHC,2 polymorphs I (space group P212121; Z0 ź 1),x
II (P1; Z0 ź 2),x III (P212121; Z0 ź 1),x and SAC (P212121;
Z0 ź 1), were compared using the program XPac.21,22 A set of
corresponding points21,22 was chosen to represent the geometry
of each cinacalcet molecule. This set consisted of 14 non-
hydrogen atomic positions, but no atoms of the PhCF3 moiety
affected by conformational change were included. The obtained
results show that the 1D spatial arrangement of N+ H/Cl
bonded molecules along the respective a-axis is geometrically the
same in all structures except form I. These chains exhibit 21
symmetry. It is worth noting that the two independent and
conformationally slightly different (mainly in the PhCF3 part,
see above) molecules of form II also adopt this arrangement.
This means that there are local pseudo-21 symmetry elements in
Fig. 9 Crystal structures of (a) SAC and (b) form II: strong hydrogen
this structure. Furthermore, a common stacking mode of the
bonds are denoted by dotted lines. H-atoms are omitted for clarity.
H-bonded chains into columns is observed along the crystallo-
Non-hydrogen atoms involved in strong hydrogen-bonds are drawn as
graphic b-axes of forms II and III . Thus, the similarity between
balls.
these two structures is actually 2D. Neighbouring chains in this
2D column are related by translation symmetry and additional 21
axes parallel to those in the H-bonded chains of III (Fig. 10).
strong acceptor group (the chloride anion). In the structures of
Again, there are complementary local pseudo-21 operations in
the three polymorphs2 these two groups form a crankshaft-like
the Z0 ź 2 structure of II. The main difference between these two
chain via N+ H/Cl hydrogen bonds. The same arrangement is
forms lies in the way their common 2D columns are replicated
also present in SAC. The solvent is attached to this unit via
along the c-axis of each structure. In form II, neighbouring
a strong hydrogen bond of the O H/Cl type. Additionally,
columns are related by translation symmetry only. By contrast,
a number of weak, non-standard20 interactions of the C H/Cl,
their counterparts in III are related by two sets of 21 axes which
C H/F, C H/O, and C H/p types can be identified. The
are perpendicular to one another, and they are both perpendic-
extended hydrogen bond schemes of SAC and the desolvation
ular to the internal 21 axes of the H-bonded chains. As a conse-
product, form II, are compared in Fig. 9, and geometrical
quence of the discussed close geometrical relationships, certain
parameters of significant intermolecular interactions in SAC are
unit cell parameters are similar: a of II, III and SAC, and addi-
listed in Table 2. The chain of form II is composed of two kinds
tionally b and g of II and III .x,2 As in form III , the high-
of conformationally distinct cinacalcet molecules (see Fig. 10b),
temperature form I contains N+ H/Cl bonded chains which
and the PhCF3 ring of molecule 2 lies approximately on the
pack in 2D colunms parallel to their 21 axes, and neighbouring
site which would be   occupied  by the solvent molecule in the
columns are related by two additional perpendicular sets of 21
structure of SAC (Fig. 10a).
Packing analysis of SAC and the polymorphs. To gain an insight
x Form I: P212121; Z0 ź 1, a ź 7.2471(4), b ź 11.6772(6), c ź 26.4445(13)
into the packing similarities and differences between all CCCHC
Å; Form II: P1; Z0 ź 2, a ź 7.2615(5), b ź 11.4602(1), c ź 13.9790(11) Å,
forms, we compared the packing of the SAC to that of the
a ź 70.580(5) , b ź 79.217(4) , g ź 88.537(5) ; Form III : P212121; Z0 ź
desolvation product and additionally to those of the other two 1, a ź 7.1731(5), b ź 11.3457(11), c ź 25.313(2) Å.
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III , as every symmetry element would be maintained. However,
since SAC desolvates to form II the process must involve the
complete collapse of the structure resulting in an isotropic phase
with a high molecular mobility from which form II can nucleate.
A formation of form II from SAC is not feasible without the
breaking of the strong hydrogen bonds of CCCHC chains in
every second 2D column parallel to the ac-plane. This would be
followed by a considerable reorientation of one half of the
molecules. Thus, a cooperative transformation process23 can be
excluded. The assumption of a structural collapse (destructive
process23) on desolvation is further supported by the results of
thermoanalytical experiments (see above) and the observation
that only form II but not form III nucleates from the super-
cooled melt.2
Hirshfeld surfaces. Hirshfeld surface analysis is regarded as
a useful tool to assess the packing modes and intermolecular
interactions in molecular crystals. The surfaces are constructed
by partioning the space of crystals into regions where the electron
density from the sum of spherical atoms dominates over the sum
of the electron density of the crystal.24 These calculations were
carried out using the program Crystal Explorer (v.2.1).25 The 2D
fingerprint plots (plots of di versus de)26 of all intermolecular
interactions of the different cinacalcet molecules in the solvate
SAC and the two conformers of its desolvation product (form II)
are shown in Fig. 11. The donor groups of the N+ H/Cl (1b)
and the C H/O interactions (3b) between the cinacalcet and the
solvent molecule in SAC as well as the C H/p interactions
(2a,2b) are marked in the figure. In each case the upper spike
(de > di) corresponds to the donor and the lower spike (di > de) to
the acceptor. From the 2D fingerprint plots, showing the envi-
ronments of the molecules, we can clearly see that the C H/p
interactions (wings, 2), present between the hydrogen-bonded
chains in form II, are not formed between these chains in SAC.
The only C H/p interactions (200) in SAC occur between the
naphthyl as p donor and the acetic acid molecule (C1S H). By
contrast, the neighbouring hydrogen-bonded chains in SAC are
differently orientated against one another due the presence of the
solvent molecule. Thus, one fluorine atom is in close contact
(C6 H/F2) with the adjacent naphthyl group. A second inter-
molecular C H/F interaction (C16 H/F1) is formed along the
1D chains (for geometric details see Table 3). For comparison the
Fig. 10 Molecular packing of (a) SAC, (b) form II, and (c) form III of
H/F contacts for each of the three cinacalcet molecules are
CCCHC; view along the crystallographic a-axis (translation of the
visualised in colour in Fig. 11. C H/F interactions shorter than
N+ H/Cl bonded chains). H-atoms are omitted for clarity. The chain
the van der Waals radii are only present in SAC, where they occur
geometry is the same in all three structures. Additionally, H-bonded
at lower de and di values. The inclusion of the acetic acid molecule
chains are stacked in the same fashion vertically (along the b-axis) in
in the crystal lattice leads to a denser packing, indicated by
forms II (b) and III (c).
a more compact fingerprint plot of SAC (for further fingerprint
plots please see supporting information).
axes. However, despite the presence of the same set of symmetry
elements (i.e. the same space group symmetry), the spatial
Conclusions
arrangement of molecules in these chains and columns is rather
different from polymorph III and indeed from any other Crystallisation of CCCHC from a variety of solvents resulted in
CCCHC form, although all N+ H/Cl bonded 1D chains being monosolvates with acetic acid, chloroform, dioxane, and tetra-
based on a common supramolecular synthon.2 It is also worth chloromethane. From solvent mixtures with n-alkanes, only the
noting that the unit cell parameters of forms I and IIIo are similar chloroform and dioxane solvates are yielded. Crystallisation
despite these fundamental differences in molecular packing. from all other solvents resulted in unsolvated forms, usually the
Not only from the conformational analysis, but also from the thermodynamically stable form III . The solvates show a low
packing diagrams one would assume that SAC desolvates to form stability and survive only at low temperature after harvesting
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Fig. 11 2D fingerprint plots for CCCHC form II and SAC. Highlighted in colour are the F/H contacts. de and di are the distances to the nearest atom
centers exterior and interior to the surface. Hirshfeld surfaces for the SAC were calculated based on the smeared electron distribution of the average
structure (disordered CF3 group).
from the mother liquor. The formation of such unstable solvent exclusively, which implies substantial strong structural changes
adducts is rather common in organic molecules but they are (loss of the 21 symmetry of the 2D columns of CCCHC chains)
frequently overlooked because crystallisation products are and a switch to energetically less favourable molecular confor-
normally dried immediately after harvesting and before further mations, including a rotation of the PhCF3 moiety by 150 in
analytical work is performed.7 However, the formation of every other molecule. These conclusions together with the
a solvate via such   transient  species can be the only gateway to thermal analysis indicate that a complete structural collapse
a particular polymorph, which may not be able to nucleate or occurs on desolvation (destructive process, class I according to
grow fast enough in a solvent to yield a pure phase. This has been the Rouen model23) forming an isotropic phase from which form
reported for example for zanosteron27 and prilocaine hydro- II nucleates as the   kinetic form  . This example demonstrates
chloride.13 CCCHC is another such example, since, to our that concomitant packing and conformational similarities
knowledge, the preparation of a highly pure metastable form II between a solvate and a polymorph (unsolvated form) does not
of CCCHC is only possible via one of the solvates. Form II necessarily imply that the desolvation of the former results in
nucleates also from the melt. It is difficult to obtain pure samples exactly this polymorph. Rather, the outcome of desolvation
of polymorph II from the supercooled melt, since the tempera- depends on the mechanism at work. The structure is either
ture range where its nucleation rate is sufficiently high also completely or to a large extent destroyed, or a cooperative
encompasses the solid-solid transition of form II to the stable rearrangement process to a structurally related product occurs
form III .2 simultaneously with the escape of the solvent molecules.23
Even though SAC and form III show strong similarities in An overview of the interrelations and production pathways of
crystal packing, exhibit nearly identical conformations, and all CCCHC solid state forms is shown in Fig. 12. For more
crystallise in the same space group, the polymorph is not details concerning the structural and thermodynamic properties
obtained from the desolvation process. Instead, form II results of the polymophic forms we refer to another report.2
Acknowledgements
The authors would like to thank Fa. Sandoz GmbH financial
support and for the supply of CCCHC.
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