Exploring the Crystal Landscape of 3-Methyl-2-phenylbutyramide: Crystallization of Metastable Racemic Forms from the Stable Conglomerate

Article abstract of DOI:10.1021/acs.cgd.8b00348

In the solid state, (±)-3-methyl-2-phenylbutyramide 1 spontaneously resolves into a conglomerate (Form I) that crystallizes in a racemic form (Form II) upon melting followed by vapor crystallization, a rarely reported phenomenon. An additional racemic pol

Full text of DOI:10.1021/acs.cgd.8b00348

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Exploring the crystal landscape of 3-methyl-2-phenylbutyramide:
crystallization of metastable racemic forms from the stable conglomerate
Udaya Bhaskara Rao Khandavilli, Declan Gavin, Anita R. Maguire, Michael Nolan, and Simon E. Lawrence
Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.8b00348 • Publication Date (Web): 24 Apr 2018
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Exploring the crystal landscape of 3ꢀmethylꢀ2ꢀ
phenylbutyramide: crystallization of metastable
racemic forms from the stable conglomerate
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U. B. Rao Khandavilli,† Declan P. Gavin, ‡ Anita R. Maguire,‡ Michael Nolan§ and Simon E.
Lawrence*,†
† School of Chemistry, Analytical and Biological Chemistry Research Facility, Synthesis and Solid State
Pharmaceutical Centre, University College Cork, Ireland. Eꢀmail: simon.lawrence@ucc.ie
‡ School of Chemistry and School of Pharmacy, Analytical and Biological Chemistry Research Facility, Synthesis
and Solid State Pharmaceutical Centre, University College Cork, Cork, Ireland.
§
Tyndall National Institute, University College Cork, Lee Maltings, Prospect Row, Cork, Ireland
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if
required according to the journal that you are submitting your paper to)
KEYWORDS: Conglomerate, Polymorphism, DFT calculations and crystallization.
Abstract:
In the solid state (±)ꢀ3ꢀmethylꢀ2ꢀphenylbutyramide 1 spontaneously resolves into a conglomerate
(Form I) that crystallizes in a racemic form (Form II) upon melting followed by vapor
crystallization, a rarely reported phenomenon. An additional racemic polymorph, Form III, has
been characterized, and the thermodynamic relationship between the three forms established by a
variety of computational and experimental methods including grinding, slurry crystallization and
seeding techniques. Both racemic Forms II and III are metastable and readily convert to the more
stable conglomerate, Form I. Density Functional Theory calculations of the different polymorphs
of 1 show that the enantiomers of 1 (R & S) are more stable than both racemic forms.
Introduction:
The racemic and enantiopure forms of a pharmaceutical compound often display distinct
physiological and pharmacological properties in living organisms.1ꢀ3 Many chiral pharmaceutical
compounds in the market were historically developed as racemates.4 Specific guidelines for the
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marketing of the bioꢀactive enantiomer of an active pharmaceutical ingredient (API) have been
provided by the FDA since 1992, to ensure safety.5ꢀ6 These directives stipulate that each isomer
and racemic form of an API should be studied separately to understand their pharmacological
activity and metabolic pathways. Therefore, obtaining enantiopure compounds has received
tremendous attention from both academic and industrial researchers over the last few decades.7
This has provided a strong stimulus for the development of methodologies for the asymmetric
synthesis of organic compounds.8 From the solidꢀstate perspective, a racemic mixture can
crystallize in three ways: a racemic compound (hereafter called a ‘racemate’), a racemic
conglomerate (hereafter called a ‘conglomerate’) or a solid solution.9 A racemate contains an
equal ratio of both enantiomers in its crystal lattice with its molecules in a regular, usually
centrosymmetric, arrangement.10 A conglomerate is a physical mixture of both enantiomers that
crystallize separately during the crystallization process; this is also referred to as spontaneous
resolution.11 A solid solution has both enantiomers present in the lattice in an unordered manner.
It often happens when the two enantiomers compete for the same position in its crystal lattice,
and the term “pseudo racemates” has also been used to describe this phenomenon.12
Conglomerates are relatively rare, with this behavior observed for organic molecules about 5ꢀ
10% cases in the Cambridge Structural Database, whereas racemates predominate and solid
solutions occur rarely.13ꢀ15 The importance of understanding the interaction between enantiomers
of chiral compounds used as pharmaceuticals16ꢀ17 has been highlighted through a recent report of
a more stable racemic form of Pioglitazone Hydrochloride, which has been marketed as a
conglomerate for many years.18
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One of the common inexpensive methods to resolve the enantiomers of a compound on an
industrial scale is the entrainment procedure, where the desired enantiomer is used as a seed in
the crystallization step to obtain a pure product consisting only of the same enantiomer.19ꢀ22
However, this method can only be used for chiral resolution when the compound crystallizes as a
conglomerate.23 Diastereomeric salt formation is a related method that has been used to
crystallize the preferred enantiomer from a racemic mixture.24
Understanding the interconversion and stability relationships between racemic and conglomerate
forms is an important step in the crystallization of an API.25ꢀ31 In this context, we have examined
the crystallization behavior of 3ꢀmethylꢀ2ꢀphenylbutyramide, 1, an antimitotic compound that
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displays racemic and conglomerate forms, Figure 1. Notably, the solidꢀstate properties of 1 have
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not been described previously.
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Figure 1. Structure of 3ꢀmethylꢀ2ꢀphenylbutyramide, 1.
Experimental
Materials and methods. Racemic 3ꢀmethylꢀ2ꢀphenylbutyric acid was purchased from Alfa
Aesar. (R)ꢀ3ꢀMethylꢀ2ꢀphenylbutyric acid was purchased from SigmaꢀAldrich and (S)ꢀ3ꢀmethylꢀ
2ꢀphenylbutyric acid was purchased from Fluorochem. All solvents were purchased from Sigmaꢀ
Aldrich and used directly, without any further purification.
(±)-3-Methyl-2-phenylbutyramide, (±)-1. This was synthesized from (±)ꢀ3ꢀmethylꢀ2ꢀ
phenylbutyricic acid using the reported procedure.32 1H NMR: δH (300 MHz, CDCl3) : 7.38ꢀ7.23
(m, 5H), 5.47 (br s, 2H), 2.91 (d, J = 10.2 Hz, 1H), 2.48ꢀ2.30 (m, 1H), 1.08 (d, J = 6.5 Hz, 3H),
0.71 (d, J = 6.7 Hz, 3H). Anal. Calcd for C11H15NO: C, 74.54; H, 8.53; N, 7.90; Found: C, 74.29;
H, 8.62; N, 7.98, mp: 105ꢀ107 ⁰C. All spectroscopic details for 1 agreed with those previously
reported.32 Crystals suitable for single crystal analysis were grown from ethanol and called Form
I.
(R)-3-Methyl-2-phenylbutyramide, (R)-1. To a flask containing (R)ꢀ3ꢀmethylꢀ2ꢀphenylbutyric
acid (0.15 g, 0.842 mmol) was added thionyl chloride (0.8 mL, 1.1 mmol, 1.3 equiv.) while
maintaining the temperature at 0 °C. The solution was let warm to room temperature and stirred
for 20 h. The excess thionyl chloride was removed under reduced pressure at room temperature
to give a yellow liquid. This was dissolved in CH2Cl2 (1 mL) and the solution was added
dropwise to aqueous ammonia solution (32%, 0.15 mL). This gave a white precipitate which was
dissolved in CH2Cl2 (30 mL) and washed with water (3 x 20 mL) and brine (30 mL). The solvent
was removed under in vacuo to give pure (R)ꢀ1 as a white solid (0.140 g, 93%) with identical
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spectroscopic characteristics to (±)ꢀ1. 1H NMR: δH (300 MHz, CDCl3): 7.38ꢀ7.23 (m, 5H), 5.47
(br s, 2H), 2.91 (d, J = 10.2 Hz, 1H), 2.48ꢀ2.30 (m, 1H), 1.08 (d, J = 6.5 Hz, 3H), 0.71 (d, J = 6.7
Hz, 3H), 13C NMR δ (75 MHz, CDCl3): 175.6, 139.1, 128.6, 128.3, 127.2, 61.1, 31.2, 21.6, 20.3.
Anal. Calcd for C11H15NO: C, 74.54; H, 8.53; N, 7.90; Found: C, 74.64; H, 8.49; N, 7.83, m.p.:
138ꢀ140 °C.
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(S)-3-Methyl-2-phenylbutyramide, (S)-1. This was synthesized from (S)ꢀ3ꢀmethylꢀ2ꢀ
1
phenylbutyric acid following the procedure for (R)ꢀ1 to give 0.143 g (95%) of pure (S)ꢀ1. H
NMR: δH (300 MHz, CDCl3): 7.38ꢀ7.23 (m, 5H), 5.47 (br s, 2H), 2.91 (d, J = 10.2 Hz, 1H),
2.48ꢀ2.30 (m, 1H), 1.08 (d, J = 6.5 Hz, 3H), 0.71 (d, J = 6.7 Hz, 3H). Anal. Calcd for C11H15NO:
C, 74.54; H, 8.53; N, 7.90; Found: C, 74.61; H, 8.48; N, 7.70, m.p.: 138ꢀ140 °C. Analysis
matches the reported literature.33
Crystallization of conglomerate, Form I.
A wide variety of different crystallization conditions were examined. For all experiments Form I
(~50 mg) was placed in a sample vial, solvent (10 mL) added and the sample vial heated gently
until dissolution occurred. The resulting clear solution was filtered using a 0.45 micron filter
fitted to a 10 mL syringe. A variety of different solvents and solvent mixtures were investigated:
methanol, ethanol, acetonitrile, tetrahydrofuran, dichloromethane, water / methanol (50:50) and
hexane / chloroform (50:50). For cooling crystallization experiments, the solutions were either
allowed to cool to room temperature, or placed directly into the freezer compartment of a fridge
(−4 °C). For solvent evaporation experiments, samples were left to stand at room temperature, or
−4 °C, until dry. In certain instances, a rotary evaporator was used.34,35
Crystallization of (±)-Form II. The synthesized (±)-1 (2.00 g, 11.3 mmol) was placed in the
outer vessel of a sublimation apparatus, which was heated to 150 °C, and the internal cold finger
was cooled with water circulating at ~10 °C. (At these conditions, (±)-1 was in its liquid phase
and vapors of (±)-1 crystallized on the cold finger surface. No decomposition of (±)-1 was
observed) The outer vessel was maintained at 150 °C for 3 h, producing needle crystals of pure
racemic Form II on the cold finger (1.86 g, 93% yield). Anal. Calcd for Form II crystals
C11H15NO: C, 74.54; H, 8.53; N, 7.90; Found: C, 74.50; H, 8.55; N, 8.10, m.p.: 110ꢀ112 °C.
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Crystallization of (±)-Form III. Crystals of Form II (1.00 g, 5.64 mmol) were placed in a
25 mL conical flask which was placed on a hot plate (~120 ºC) until all the solid had melted.
Acetonitrile (10 mL) was added dropwise over 15 min. [Alternatively, the first step, heating until
the solid melted, can be replaced by simply dissolving Form II in acetonitrile (10 mL)]. The
resulting clear solution was removed from the hot plate, filtered using a 0.2 micron filter fitted to
a 10 mL syringe, cooled to room temperature and placed into a fridge (−4 °C) for 2 d. Crystals of
racemic Form III (blocks) and the conglomerate Form I (needles) crystallized concomitantly and
were manually separated. Anal. Calcd for Form III crystals, C11H15NO: C, 74.54; H, 8.53; N,
7.90; Found: C, 74.58; H, 8.60; N, 8.12, m.p.: 112ꢀ114 °C.
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Mechanical grinding. Mechanical grinding was carried out in a Retsch MM−00 Mixer mill,
equipped with two stainless steel 5 mL grinding jars and one 2.5 mm stainless steel grinding ball
per jar. The mill was operated at a rate of 30 Hz for 30 min and the typical sample size was 150ꢀ
200 mg.
Slurry experiments. Slurry experiments were carried out with typically 150ꢀ200 mg of the
sample placed in a 25 mL round bottomed flask, to which was added 2ꢀ3 mL of a solvent. After
stirring for ~10 min at room temperature, 2ꢀ4 mg of seed crystals were added and the mixture
stirred for a further 24 hours at room temperature. A detailed list of solvent, type of seed and the
experimental outcomes are presented in Table 3 in the Supporting Information.
Manual grinding. Manual grinding was undertaken using a mortar and pestle with the typical
sample size of 200ꢀ250 mg for 20 min. for both dry grinding and solvent drop grinding (using 2ꢀ
3 drops of solvent).
Infrared Spectroscopy. Infrared spectra were recorded on a Bruker Tensor 37 attenuated total
reflection (ATR)ꢀIR spectrophotometer interfaced with Opus software version 7.2.139.1294 over
a range of 400 – 4000 cmꢀ1. An average of 16 scans was taken for each spectrum obtained.
Powder X-Ray Diffraction. PXRD data were collected using a D2 phaser diffractometer using
Cu Kα (λ = 1.5406 Å) radiation. Samples were analyzed over a 2θ range of 3.5−45° with
increments of 0.05° at a rate of 2° minꢀ1. Data were evaluated using the DIFFRAC.Eva (Bruker
AXS Inc.) software.
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Nuclear Magnetic Resonance. 1H (300 MHz) and 13C (75.5 MHz) NMR spectra were recorded
on a Bruker Avance 300 MHz NMR spectrometer. All spectra were recorded at room
temperature (20 ºC) in deuterated chloroform (CDCl3), using tetramethylsilane (TMS) as an
internal standard. Chemical shifts (δH & δC) are reported in parts per million (ppm) relative to
TMS and coupling constants are expressed in Hertz (Hz).
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High Performance Liquid Chromatography (HPLC). Chiral HPLC analysis was conducted
on a Waters Alliance 2690 separations module with a PDA detector. The enantiomeric purities
were determined by analysis on a Chiralcel ODꢀH column (5 x 250 mm), purchased from Daicel
Chemical Industries, Japan. The mobile phase was a 90:10 mixture of hexane:2ꢀpropanol, the
flow rate was 1 mL min−1 and the detection wavelength was at 209.8 nm. The experiments were
carried out at 25 °C.
Differential Scanning Calorimetry (DSC). All melting points were obtained from a TA Q1000
instrument. Samples (2–6 mg) were crimped in nonhermetic aluminum pans and scanned from
30 to 160 °C at a heating rate of 10 °C min−1 under a continuously purged dry nitrogen
atmosphere.
Elemental analysis. An Exeter Analytical CE440 was used for elemental analysis.
Single Crystal X-ray Diffraction. Single crystal Xꢀray data was collected on a Bruker APEX II
DUO diffractometer,36 using graphite monochromatized Mo Kα (λ = 0.7107 Å) radiation for the
racemic forms and Incoatec montel multilayer mirror monochromatized Cu Kα (λ = 1.5418 Å)
radiation for the R and S enantiomers. The APEX suite of programmes,37 incorporating the
SHELX suite of programs,38 were used. The structures were solved using direct methods and
refined by fullꢀmatrix leastꢀsquares on F2. All nonꢀhydrogen atoms were located and refined with
anisotropic thermal parameters. Hydrogen atoms were either placed in calculated positions or
located and refined with isotropic thermal parameters. Diagrams were prepared with Mercury
3.8.39 The crystallographic data are summarized in Table 1.
Table 1. Crystallographic data for both enantiomers and the two racemic forms
Compound
R Form
S Form
Form II
Form III
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Formula
MW
C11 H15 N1 O1 C11 H15 N1 O1C11 H15 N1 O1 C11 H15 N1 O1
177.24
monoclinic
P21, 4
177.24
177.24
177.24
monoclinic
P21/n, 8
9.1071(10)
24.498(3)
10.49(2)
112.545(2)
2141.2(4)
1.100
crystal system
space group, Z
a, Å
monoclinic monoclinic
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P21, 4
P21/c, 4
12.017(6)
5.158(3)
17.526(9)
15.0554(16)
5.2629(2)
15.1388(6)
15.0331(4)
5.26050(10)
15.1573(4)
b, Å
c, Å
β, °
116.996(2) 116.9520(10) 93.757(13)
V, Å3
1068.82(7)
1.101
1.5418
0.552
3.28ꢀ67.12
296
1068.47(5) 1084.0(10)
Dc, g cm−3
Wavelength, Å
ꢁ, mm−1
1.102
1.5418
0.552
1.086
0.7107
0.069
0.7107
0.069
θ range, deg
T, K
3.27ꢀ66.49 1.70ꢀ25.09
1.66ꢀ26.40
296
296
10451
3643
0.0205
3570
255
296
12380
1896
0.0423
1226
152
total reflns
unique reflns
Rint
10337
3655
33023
4390
0.0353
3530
0.0287
3647
obs. refns, I > 2σ(I)
no. parameters
no. restraints
R1 [I > 2σ(I)]
255
255
1
1
0
0
0.0862
0.0320
0.0431
0.0448
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wR2 [all data]
S
0.2252
0.0877
1.052
0.1254
1.010
ꢀꢀ
0.1175
1.082
ꢀꢀ
1.135
Flack parameter
0.06(12)
0.08(6)
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ρ
max, ρmin, e Å−3
0.893, ꢀ0.250 0.158, ꢀ0.129 0.221, ꢀ0.159 0.179, ꢀ0.169
Density Functional Theory Modelling
Density functional theory (DFT) simulations were applied to analyze the relative stability of the
the different crystal forms of 1 and understand their energetic ordering. The initial crystal and
atomic structures were taken from the experimental *.cif. DFT simulations were carried out
using the VASP5.340 simulation code – the valence electrons were described in a periodic plane
wave basis set with a cut off energy of 450 eV. The interaction between the core and valence
electrons were described by the projector augmented wave approach41 with 6, 5, 4 and 1 valence
electron for O, N, C and H, respectively. The PerdewꢀBurkeꢀErnzerhof (PBE) GGA
approximation to the exchangeꢀcorrelation functional was applied.42 Two hybrid DFT
functionals were also applied, namely HSE06 and PBE0.43,44 The HSE06 and PBE0 calculations
use the default parameters of 25% exact HF exchange and, in HSE06, a screening length of 5 Å.
Grimme’s D2 and D3 models were used to include two different descriptions of the vdW
interactions,45,46 giving PBEꢀD2/PBEꢀD3, HSE06ꢀD2/HSE06ꢀD3 and PBE0ꢀD2/PBE0ꢀD3
theoretical models.
Initially, all atomic positions were relaxed with no symmetry imposed with convergence criteria
in the energy and ionic relaxations of 1x10−5 eV and 0.01 eV Å−1, respectively. Then the lattices
were relaxed, with both lattice dimensions and angles being allowed to vary. We used direct
lattice relaxations and an iterative procedure in which atomic positions are relaxed, followed by
cell relaxation and repeating this process. The latter procedure avoids any issues arising from an
incomplete plane wave basis set during simultaneous ion and cell relaxations; however, similar
results were obtained for the lattice parameters in both approaches. MethfesselꢀPaxton Fermi
level smearing was applied with a value of σ = 0.1 eV. The quasiꢀNewton relaxation algorithm
was applied for the atomic relaxations.
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Results and discussion
Conglomerate, Form I
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(±)ꢀ3ꢀMethylꢀ2ꢀphenylbutyramide 1 was synthesized from (±)ꢀ3ꢀmethylꢀ2ꢀphenylbutyric acid
and crystallized from a variety of solvents. Crystals of Form I suitable for single crystal
diffraction were obtained as needles by slow evaporation from ethanol and analysis revealed the
S enantiomer had crystallized in the Sohncke space group P21 with Z′ = 2. The experimental
PXRD pattern of the synthesized amide matches the theoretical PXRD pattern based on this
single crystal analysis, suggesting spontaneous resolution during crystallization and the
formation of a conglomerate.
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Analysis of 6 randomly picked crystals of Form I obtained from the ethanol crystallization batch
revealed that they had all spontaneously resolved into the conglomerate, with no evidence of any
other crystal form. This approach allowed both R and S enantiomers to be successfully
characterized (both in P21 with Z′ = 2). Difficulties were experienced in finding good quality
single crystals, particularly for the R enantiomer, because most of the crystals stick to each other
along the needle axis. By applying pressure with a needle, it was possible to separate the crystal,
albeit with much smaller crystallites remaining adhered to the main needle. However, the
absolute configurations of both enantiomers, (R)ꢀ1 & (S)ꢀ1, have been established basing on the
anomalous dispersion effects.
Crystal structure analysis of each enantiomer shows two crystallographically unique molecules
in the asymmetric unit which interact with each other through infinite NꢀH···O=C hydrogen
bonding. One of the amide hydrogen atoms forms R22(8) dimers, while the other amide hydrogen
atom forms C(4) chains of the same symmetry molecules, also via NꢀH···O=C hydrogen
bonding, leading to the wellꢀknown 1ꢀD infinite ribbons, Figure 2.
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Figure 2. Crystal packing in S enantiomer (left) and R enantiomer (right).
To investigate further the formation of the conglomerate, the synthesis of the individual
enantiopure enantiomers (R)ꢀ1 and (S)ꢀ1 was undertaken. While crystallization of either the R or
S enantiopure material was attempted using a variety of solvents and crystallization techniques,
crystals suitable for single crystal analysis could not be obtained in either case. However, the
experimental PXRD pattern for samples of each enantiomer from these crystallization
experiments match the calculated diffraction patterns generated from the single crystal data of
Form I. The chiral HPLC analysis also confirms the spontaneous resolution during crystallization
of (±)ꢀ1 to form the conglomerate, Form I (see Supporting Information).
Racemic Polymorphs, Forms II and III
Crystallization of the amide was examined using a variety of methods including: fast and slow
solvent evaporation in different organic solvents at different temperatures, crystallization from
the melt by cooling to RT, mechanical grinding using either a mortarꢀpestle or a mixer mill, fast
evaporation using a rotatory evaporator and melting followed by vapor crystallization.47ꢀ49
Further details are provided in Table 3 in the Supporting Information. All these approaches
yielded the conglomerate, except for evaporation from the melt, which gave rise to needle
crystals of a new form that single crystal analysis revealed adopted the racemic space group
P21/c with Z′ = 1, termed Form II. Subsequently, a third form, Form III, was obtained as block
crystals concomitantly with Form I by crystallizing from acetonitrile and placing in a fridge at −4
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°C (see Experimental). This was determined to be a second racemic form, crystallizing in P21/n
with Z′ = 2. Different Z′ values50 are seen in Forms II and III.
In both Forms II and III, the amides interact via NꢀH···O=C hydrogen bonding by the formation
of R22(8) dimers and C(4) chains to form the familiar ladder motif. For Form II, all the R
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enantiomers are located on one side of the ladder motif and the S enantiomers located on the
opposite side due to inversion centers present in the middle of both the R22(8) dimers and the
binary level R24(8) tetramers (Figure 3, left). In Form III, the inversion centers are only present in
the middle of the R22(8) dimer, leading to an alternating arrangement of R and S enantiomers
along each side of the ladder motif (Figure 3, right). The infinite ribbons are packed further in a
parquet pattern in both forms.
Figure 3 Comparison between the two racemic forms: Form II, left, and Form III, right. [R and S
enantiomers, are colored blue and green, respectively, and the orange dots indicate the inversion
centres.]
There are small, but significant, differences in the hydrogen bonding and IR data for the different
forms, Table 2 (The IR data for the R and S Form are identical, so only the S Form is presented).
The IR data for Form II for the C=O stretch (1699 cm−1) and the NꢀH stretch (3161 cm−1) are
notably different to the corresponding data for Forms I, (1650 cm−1, 3187 cm−1) and III (1651
cm−1, 3184 cm−1). While this observation is not readily rationalized by analysis of bond lengths,
angles, torsion angles and planarity of the nitrogen in the different forms, superimposition of the
molecules indicate the conformation of the amides differ slightly across the three forms,
presumably impacting on the IR data (see Figure 12 in the Supporting Information).
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Table 2. Comparison of the different forms of 1
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S Form
Form II
2.07(2)
Form III
1.985(2)
2.08(2)
NꢀH···O=C, Å
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150.50(2)
142.97(2)
152.55(2)
NꢀH···O, °
νC=O, cm−1
1650
1699
1651
νNꢀH, cm−1
3403, 3186
1.228(2)
3393, 3161
1.242(2)
3399, 3184
1.234(2)
C=O Bond length, Å
1.326(3)
1.324(2)
1.325(2)
CꢀN Bond length, Å
Interconversion experiments between conglomerate and racemates
In general, racemic compounds are thermodynamically more stable in comparison with the
conglomerates.51 Sublimation of racemic material can result in the formation of
conglomerates.52ꢀ55 It is rare for a conglomerate to convert to the racemate upon sublimation and
we found only one report with such behavior.56 Notably, in this reported case the conversion is a
solidꢀtoꢀsolid process while in our work the racemate is formed by evaporation, i.e. melting
followed by crystallization. Repeated experiments were undertaken to obtain sufficient quantities
of the racemic Forms II and III. Both racemic forms readily reconvert to the conglomerate upon
melting or recrystallization from solvents, suggesting that the conglomerate is more stable than
either racemic form (see Table 3 in SI for details). As described earlier, Form II can be converted
to a mixture of Forms I and III through low temperature crystallization from acetonitrile.
Differential scanning calorimetry (DSC) revealed sharp melting endotherms and no high
temperature transitions were seen for any of the forms. It has been reported that if the melting
point of an enantiopure material is higher than that of the corresponding racemic material by 25
°C or greater, then that compound is expected to show spontaneous resolution behavior.57 For 1
the differences in melting point between the R (or S) Form and Forms II and III are 28 °C and 26
°C, respectively, Table 3; spontaneous resolution is observed, in agreement with this empirical
rule. A range of slurry experiments in different solvent media, both with and without seeding,
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were performed to investigate the relative stability of the different forms. Form I was obtained
exclusively in all the experiments, indicating that it is the most stable form in the conditions
examined.
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Table 3. Melting point for solid forms of 1
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Type of solid form
Melting point, °C
Form I a
R enantiomer
S enantiomer
Form II
105ꢀ108
138ꢀ140
138ꢀ140
110ꢀ112
112ꢀ114
Form III
a conglomerate of R and S
Mechanical grinding, an environmentally friendly method,58,59 has been used to study the
interconversion between polymorphs and establish their relative stabilities, although it does not
necessarily yield the thermodynamically stable form.60 Both manual (mortarꢀpestle) and
mechanical (ball mill) methods were utilized for investigating the stability of the conglomerate
and racemic forms of 1. In all cases the conglomerate was the product obtained from the grinding
experiments. Slurry crystallization and crystallization by seeding experiments also resulted in the
transformation of the racemic forms to the conglomerate. The relationships between all the forms
and routes to obtain them are summarized in Figure 4.
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Figure 4. Schematic representation of the behavior of the solid forms of 1.
DFT results on the stability of the crystal structures.
We have used density functional theory (DFT) simulations to examine the stability and structure
of the crystal forms of 1 produced in the experiments. The DFT derived atomic structure of the S
enantiomer, the R enantiomer and the two racemic forms, racemic FormꢀII and racemic FormꢀIII
that are derived from atomic and lattice relaxations are available in the SI. Table 4 gives the
computed lattice vectors and angles from the following DFT setꢀups: PBE+vdW, HSE06+vdW
and PBE0+vdW cell relaxations. The vdW interactions are the D2 and D3 and these are used for
each exchangeꢀcorrelation functional.
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Comparison of the lattice parameters with the experimental data in Table 1 reveals that the PBE
functional gives the smallest deviations from the experimental lattice parameters. By contrast,
the HSE exchangeꢀcorrelation functional can give very large deviations of up to 10% while the
PBE0 functional can give deviations of ca. 5%, which is still significant. The crystal form that is
most sensitive to the DFT setꢀup is the R form which shows the very strong deviations just
described. This finding is robust to the choice of input structure, e.g. whether the relaxation
begins from the experimental lattice or the PBEꢀD2 lattice. The cell angle β is much less senstive
to the choice of DFT functional for each crystal form. Finally, the effect of the form of the vdW
correction on the compuated lattice vectors and angles is much smaller and so the performance
of both vdW corrections appears to be similar and, thus, it is the underlying exchangeꢀcorrelation
functional that gives the most significant differences.
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Table 4. Computed lattice vectors and cell angle β for the enantiomers and racemic forms of 1.
The theoretical methods are explained as follows: PBE-D2: atomic and cell relaxations using
PBE with Grimme D2 van der Waals correction. PBE-D3: atomic and cell relaxations using PBE
with Grimme D3 van der Waals correction. HSE06-D2: atomic and cell relaxations using HSE06
with Grimme D2 van der Waals correction. HSE06-D3: atomic and cell relaxations using HSE06
with Grimme D3 van der Waals correction. PBE0-D2: atomic and cell relaxations using PBE0
with Grimme D2 van der Waals correction. PBE0-D3: atomic and cell relaxations using PBE0
with Grimme D3 van der Waals correction
PBE-D2
S Form
14.603
4.623
R Form
14.556
4.619
Racemic Form II
11.398
Racemic Form III
8.932
a, Å
b, Å
c, Å
β, °
4.593
24.266
14.691
117.33
14.598
117.4
17.453
10.016
92.970
112.041
PBE-D3
S Form
R Form
Racemic Form II
Racemic Form III
a, Å
14.696
14.629
11.740
8.937
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b, Å
c, Å
β, °
4.649
14.791
117.359
4.656
14.675
117.237
4.604
24.219
10.034
112.08
17.616
93.021
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HSE06-D2
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S Form
14.143
4.547
R Form
13.64
Racemic Form II
11.122
Racemic Form III
8.861
a, Å
b, Å
c, Å
β, °
4.446
4.526
24.135
14.217
116.623
13.681
117.823
17.309
9.943
92.761
112.028
HSE06-D3
S Form
14.168
4.575
R Form
12.778
4.975
Racemic Form II
10.968
Racemic Form III
8.854
a, Å
b, Å
c, Å
β, °
4.547
24.150
14.242
116.294
12.8365
109.826
17.236
9.946
92.954
112.024
PBE0-D2
S Form
14.304
4.963
R Form
13.071
4.693
Racemic Form II
11.216
Racemic Form III
8.881
a, Å
b, Å
c, Å
β, °
4.489
24.118
14.405
116.041
13.111
114.925
17.362
9.962
92.706
112.061
PBE0-D3
S Form
14.553
4.787
R Form
13.6004
4.508
Racemic Form II
11.223
Racemic Form III
8.906
a, Å
b, Å
4.5001
24.209
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c, Å
β, °
92.525
13.638
17.381
92.672
9.965
117.013
117.403
112.018
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Table 5 provides the relative energies of each crystal form in kJ mol−1, where the structure with
zero energy is the most stable form. Together with the crystal structure data, this allows us to
explore the suitabilitiy of, and any dependencies on, the choice of DFT exchangeꢀcorrelation
functional. From the energy data in Table 5, it appears that the S enantiomer and the R
enantiomer are generally very close in energy, with a maximum difference of less than 1 kJ
mol−1 with PBEꢀD2 or PBEꢀD3. This suggests that both enantiomers are equally likely to be
formed. Considering the racemic forms, with PBE and both vdW correactions, these are both less
stable and racemic Form III is by far the least stable.
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However, with the hybrid DFT exchangeꢀcorrelation functionals, there is a very strong effect on
the relative energetics of the crystal forms, similar to the crystal structure. For example, with
HSE06, the R enantiomer is now less stable than the racemic Form II, with the S enantiomer
continuing to be the most stable. This is found with both vdW corrections so it appears to be
attributable to the hybrid functional. With the PBE0+vdW hybrid functional, the qualitative trend
in stability is the same as PBE+vdW, although we note that the relative energies from
PBE0+vdW indicate that the racemic Form II is close in stabilty to the R enantiomer. Thus, it
appears that there is a significant sensitivity in the crystal structure and, thus, stability to the DFT
setꢀup and the standard hybrid DFT functionals appear to perform less well than the PBE GGA
functional, irrespective of the vdW corrections used. This may be due to the contribution of exact
exchange (25%) in PBE0 and HSE06 and, in addition, HSE06 has a screening length of 5 Å,
which can influence the computational results. However, given the high cost of hybrid DFT
calculations within the VASP code (ca. 50 times that of a GGA functional calculation), it is not
practical to test hybrid DFT to obtain a an exact exchange contribution for each system .
However, the PBEꢀGGA functional together with vdW corrections does appear to provide a
reasonable description of the structure and stability of the MPBA system.
Table 5. Relative DFT energies in kJ mol−1 for the crystal forms of 1 studied. The energy of the
most stable crystal form for a given DFT approach is set to 0 kJ mol−1. The theoretical methods
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are explained as follows: PBE-D2: atomic and cell relaxations using PBE with Grimme D2 van
der Waals correction. PBE-D3: atomic and cell relaxations using PBE with Grimme D3 van der
Waals correction. HSE06-D2: atomic and cell relaxations using HSE06 with Grimme D2 van der
Waals correction. HSE06-D3: atomic and cell relaxations using HSE06 with Grimme D3 van der
Waals correction. PBE0-D2: atomic and cell relaxations using PBE with Grimme D2 van der
Waals correction. PBE0-D3: atomic and cell relaxations using PBE with Grimme D3 van der
Waals correction
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PBEꢀD2
E relative
PBEꢀD3
E relative
HSE06ꢀD2 HSE06ꢀD3 PBE0ꢀD2 PBE0ꢀD3
E relative E relative E relative E relative
/
/
/
/
/
/
Crystal Structure
kJ mol−1
kJ mol−1
kJ mol−1
kJ mol−1
kJ mol−1
kJ mol−1
Racemic Form II
Racemic Form III
R enantiomer
17
137
0.2
0
28
114
0
28
234
188
0
30
210
173
0
86
229
17
0
27
117
35
0
S enantiomer
0.96
To help understand the differences in stability of the crystal forms we have examined the atomic
structure and focused on the interactions between molecules of 1 in each crystal form. As
discussed earlier, each structure has two NꢀH···O=C hydrogen bonds. The computational data
using the PBEꢀD2 level of theory gave similar O···H distances of 1.98 Å in Form III, 2.08 Å in
Form II, 1.96/2.02 Å in the R enantiomer and 2.07/2.09 Å in the S enantiomer. Thus, this cannot
be the origin of the different stabilities observed. When we examine the different orientations of
1 in each form we note that the R, S, and racemic form II structures have adjacent aromatic rings,
with typical H···H distances of 3.15 – 3.6 Å (typical benzene dimer distances are around 2.5 –
3.5 Å). However, the racemic Form III is the only structure with no adjacent aromatic rings. It is
possible that this structure is less stable than the other forms of 1 because the stabilisation
induced by the aromatic ring interactions is missing.
Conclusion:
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In the antimitotic amide 1, the most stable form in the solid state is a conglomerate, Form I. Two
metastable racemic polymorphs have been identified, Forms II and III, notably with Form II
isolated by melting Form I followed by vapor crystallization. The DFT energy calculations
which include vdW corrections support our hypothesis that the individual enantiomers are more
energetically favorable than the racemic polymorphs Form II and III. However, it appears that
hybrid DFT in the guise of the HSE06 and PBE0 functionals with standard exchange
contributions can have difficulty in describing these systems and, thus, care must be taken in
applying hybrid DFT. Slurrying experiments revealed that the most stable form was the
conglomerate in all conditions examined, in agreement with both the initial experimental results
that identified the different forms and the computational results. This example highlights the
need to explore as fully as possible the crystal landscape of conglomerates for potential
polymorphs and the stability behavior of any polymorphs identified.
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Electronic Supplementary Information (ESI) available. Detailed IR, PXRD, DSC data, and
additional figures. The crystallographic data have been deposited with the Cambridge
Crystallographic Data Centre, CCDC deposition numbers 1562052ꢀ1562055. This material is
available free of charge via the Internet at http://pubs.acs.org.
Acknowledgment:
This publication has emanated from research conducted with the financial support of Science
Foundation Ireland under Grant Numbers 12/RC/2275, 05/PICA/B802/EC07, 14/US/E2915 as
well as the UCC 2012 Strategic Research Fund.
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ripening: a reliable crystallisation method to reach single chirality Chem. Soc.
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12. Oliveira, M. A.; Peterson, M. L.; Klein, D. Continuously Substituted Solid Solutions of
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Publishing Company, Malabar, FL, 1994.
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Exploring the crystal landscape of 3ꢀmethylꢀ2ꢀ
phenylbutyramide: crystallization of metastable
racemic forms from the stable conglomerate
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U. B. Rao Khandavilli, Declan P. Gavin, Anita R. Maguire, Michael Nolan, Simon E. Lawrence
Three polymorphs have been identified for the antimitotic amide (±)ꢀ3ꢀmethylꢀ2ꢀ
phenylbutyramide: a stable conglomerate and two metastable racemates, as evidenced by both
experimental and theoretical studies. The more stable racemate is obtained by melting the
conglomerate and crystallizing from the vapor, a rare phenomenon.
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