Crystal structures and physicochemical properties of diltiazem base and its acetylsalicylate, nicotinate and l-malate salts

Article abstract of DOI:10.1039/c5ce01204j

Diltiazem is a drug used as a calcium channel blocker in the treatment of cardiovascular disorders. Because of the poor aqueous solubility of the drug, its hydrochloride salt has been marketed. Due to the short elimination half-life of diltiazem, extended-release formulations were developed. In the present work, the crystal engineering approach has been employed to obtain diltiazem forms with lower water solubility by treating with carboxylic acids. Three molecular salts of diltiazem with aspirin, niacin and l-malic acid were synthesized and characterized by single crystal and powder XRD, DTA, solid state CP-MAS, NMR and UV/vis techniques. The single crystal structure determination allowed us to study the supramolecular structures and proton transfer interactions from the carboxylic acids to diltiazem in the solid state, while the NMR studies showed the interactions in solution. In the crystal, the N,N-(dimethyl)ethylamine fragment of the drug molecule interacts with the carboxylic groups of the acids to form heterosynthons. The maximum 40-fold decrease of the aqueous solubility is achieved for diltiazem acetylsalicylate hydrate in comparison with the solubility of diltiazem hydrochloride.

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Crystal structures and physicochemical properties of
diltiazem base, acetylsalicylate, nicotinate and L-malate
Cite this: DOI: 10.1039/x0xx00000x
D. Stepanovsa,b, M. Jure,b, M. Gosteva,a J. Popelis,a G. Kiselovsa and A. Mishneva,b*
Diltiazem is a drug used as a calcium channel blocker in the treatment of cardiovascular
disorders. Because of poor aqueous solubility of the drug, hydrochloride salt has been marketed.
Due to the short elimination half-life of diltiazem, extended-release formulations were
developed. In the present work, the crystal engineering approach has been employed to obtain
diltiazem forms with lower water solubility by treating with carboxylic acids. Three molecular
Received 00th March 2015,
Accepted 00th March 2015
DOI: 10.1039/x0xx00000x
www.rsc.org/
salts of diltiazem with aspirin, niacin and L-malic acid were synthesized and characterized by a
single crystal and powder XRD, DTA, solid state CP-MAS, NMR and UV/vis techniques. The
single crystal structure determination allowed us to study supramolecular structures and proton
transfer interactions from carboxylic acids to diltiazem in the solid state, while NMR studies –
interaction in solution. In crystal, the N,N-(dimethyl)ethylamine fragment of the drug molecule
interacts with carboxylic groups of the acids to form heterosynthons. The maximum 40-fold
decrease of aqueous solubility is achieved for diltiazem acetylsalicylate hydrate in comparison
with the solubility of diltiazem hydrochloride.
Introduction
The cocrystallization approach has recently found an application
in the preparation of multicomponent pharmaceutical crystals
(MCPC) with improved physicochemical properties.1–6 These
crystals may appear in the form of, e.g., molecular salt or
cocrystal; however, the term cocrystal is currently not well-
defined.7 Both molecular salts and cocrystals in pharmaceutical
development are aimed primarily to improve solubility and
stability8 or to develop multi-drug solids containing two or more
APIs in the same crystal lattice.3,9
diltiazem (dil
)
niacin (nia)
Both solubility and stability are closely related to the
thermal behaviour of the solid. Strong correlations between the
melting points of multicomponent pharmaceutical crystals and
coformers/counter ions (having similar or homological
structures) have been reported in the literature.2,10,11 Disclosure
of such correlations would provide simple rules for rational
choice of coformers in the design of MCPC with desirable
thermal properties. Solubility being an important property can
affect the dissolution rate and, consequently, bioavailability.1,2
The present study describes the design, preparation and
physicochemical properties of diltiazem pharmaceutical molecular
salts with selected carboxylic acids (Scheme 1). Salt formation is
known to be the first-choice method to improve physicochemical
properties of the drug.12,13 Diltiazem (IUPAC name: [(2S,3S)-5-[2-
(dimethylamino)ethyl]-2-(4-methoxyphenyl)-4-oxo-2,3-dihydro-1,5-
benzothiazepin-3-yl] acetate) is a benzothiazepine calcium antagonist
and has been marketed for the treatment of cardiovascular disorders.14
Diltiazem was originally developed as hydrochloride salt and is a
Class I drug according to the Biopharmaceutics Classification System
(BCS). It has high solubility and high permeability.15 Preparation of
the malate molecular salt has been reported,16 but, to the best of our
knowledge, its X-ray single crystal structure has not yet been reported.
aspirin (asa
)
L-malic acid (mal)
Scheme 1 The structures and abbreviations of compounds used
in this study.
The diltiazem base is very slightly soluble17, therefore it is
used in the form of diltiazem hydrochloride, which is freely
soluble in water. Diltiazem is commercially available in the form
of immediate-release 30 mg film-coated tablets, administered
three or four times daily, and 120-240 mg extended-release
capsules administered once daily. Extended-release formulations
compensate for the short elimination half-life of diltiazem
(3.2±1.3h)18 and high solubility of diltiazem hydrochloride,
which is 565 mg/mL.19 There have been other reported attempts
to develop sustained-release tablets of diltiazem hydrochloride
by using polyethylene oxide/polyethylene glycol polymeric
matrices20 or modified guar gum matrix.21 All mentioned facts
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imply that crystal forms of diltiazem with lower solubility would those on the pure dil spectrum. Signals of N-methyl groups are
be preferable to include in the formulation. In the present work, significantly shielded (chemical shifts are given in ESI S3).
we employ the crystal engineering approach22–26 for the
The powder X-ray diffraction (PXRD) patterns of the new
preparation of crystalline diltiazem molecular salts to elucidate compounds are depicted in Fig. 1 in comparison to the PXRD patterns
how far the cocrystallization approach is able to tailor the of the initial compounds. The powder patterns of the products show
solubility of diltiazem. Future work will include investigation of no reflections from initial compounds, indicating complete reactions.
dissolution behaviour, which is related to oral bioavailability.
Results
The diltiazem base
(dil) was obtained from diltiazem
hydrochloride (dil-HCl) and used in molecular salts synthesis,
namely, diltiazem acetylsalycilate hydrate (1:1:1), or dil
-
asa
;
diltiazem nicotinate, or dil nia and diltiazem -malate, or dil
-
L
-
mal (Scheme 2 shows the general formula of molecular salts).
The method reported herein allowed preparing and
characterizing the diltiazem base as a crystalline substance; this
was confirmed by both powder and single crystal X-ray
diffraction. The formation of molecular salts in the solid state has
been proved by powder and single crystal X-ray diffraction,
while in-solution formation was observed by nuclear magnetic
resonance (NMR).
Fig. 1 The experimental PXRD patterns for initial compounds and
products obtained after recrystallization.
The calculated28 X-ray diffraction patterns of dil, dil-asa, dil-nia and
dil-mal solids and experimental patterns collected for samples after
slow solvent evaporation are equivalent (ESI, Fig. 4S–7S), indicating
the formation of pure salts. ORTEP-329 drawings of the asymmetric
units of the structures with atom labelling schemes are given in ESI
(Fig. 8S–11S).
Scheme 2 The chemical structure of diltiazem salt, where A-
represents the organic anion, but the diltiazem is protonated at
nitrogen of the tertiary amine.
Crystal and molecular structure
A decision was made about whether products were cocrystals or
salts depending on the values of C–O and C=O bond lengths in
the carboxylic groups of the acids in the crystal structures. The
pKa [pKa = pKa(base) – pKa(acid)] values ranged from 5.33 to
6.74, implying the formation of salt.27 All the carboxylic groups
are deprotonated, as can be inferred from the similar C-O
distances (1.233(4) to 1.282(4) Å). Furthermore, in all the
molecular structures, hydrogen atoms positions were located
from the difference electron density map, showing the
transference of hydrogen atoms from an acid to tertiary amino
group of a dil. So, these considerations unambiguously
confirmed that all multicomponent solids were molecular salts.
Strong shifts of N-methyl group signals in all molecular salts to
In all crystal structures the seven-membered ring adopts a twisted
boat conformation. The values of the torsion angles in the heterocycle
are listed in ESI, Table S12. Methoxy group are almost co-planar with
average plane of adjacent phenyl ring. The most flexible fragment in
the diltiazem cation is the N,N-(dimethyl)ethylamine group. The C4–
N1–C19–C20 torsion angle characterizing the group’s orientation
with respect to a heterocycle assumes different values: -101.4(4) for
dil, -68.7(5) for dil-asa, 107.4(3) for dil-nia and 107.9(6) for dil-mal.
Crystal packing of dil structure (asymmetric unit is shown in Fig. 2)
is stabilized exclusively by van der Waals interactions.
the weaker fields, as seen in solid state CP-MAS spectra, are a clear
sign of protonation of the amine. Shifts of N-methyl group signals
correlate with Namine∙∙∙Oacid lengths. The bigger is the distance between
Namine and Oacid atoms, the more deshielded is the value of Namine
chemical shift. Namide signals, in contrary, are positioned more to the
stronger fields. Shifts from original positions are not so strong,
because here we don’t have any direct changes for Namide atoms
(spectra is given in ESI, Fig. 1S–2S).
The formation of the salts in solvent was also confirmed by
nuclear magnetic resonance. NMR 1H spectra of dil
-
asa
, dil-nia
Fig. 2 The asymetric unit of the dil crystal structure.
and dil
-mal show the changes in chemical shifts in respect to
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c)
All three salt crystal structures exhibit formation of N–HO–type
hydrogen bonds, and two of them also O–HO–type bonds (Table 1).
Table 1 Hydrogen bond geometry
D–H (Å)
D–HA
HA (Å)
dil-asa
1.74(5)
2.20(6)
1.97(6)
dil-nia
1.52(4)
dil-mal
1.889(3)
2.206(4)
1.93
DA (Å)
 D–HA (°)
N2–H2AO6i
O9–H9AO3ii
O9–H9BO5
0.89(5)
0.96(6)
0.84(6)
2.604(5)
3.113(5)
2.802(5)
161(4)
160(5)
174(6)
N2–H2AO5iii
1.05(4)
2.562(4)
169(4)
0.910(4)
0.910(4)
0.82
2.744(5)
2.820(5)
2.751(5)
3.008(5)
155.7(3)
124.2(3)
177
N2–H2AO6
N2–H2AO7
O7–H7AO5iv
O9–H9O7
0.82
2.52
119.6
Fig. 3 The fragments of crystal structures of a) dil-asa, b) dil-nia
and c) dil-mal. The blue dashed lines indicate hydrogen bonds.
(i) 2 – x, ½ + y, ½ – z, (ii) 1 + x, -1 + y, +z, (iii) x, -1 + y, +z, (iv) -1 + x, y, z
In the structure dil-asa (Fig. 3 a) supramolecular heterosynthon is
made by association of diltiazem cation and acetylsalicylic acid anion
via N–HO type hydrogen bond, acetylsalicylic acid anion with water
molecule via O–HO type hydrogen bond and water molecule with
another diltiazem cation via O–HO type hydrogen bond forming a
30 along unit cell
3
right-handed helix like chain with graph-set
C3 (16)
b axis (Fig. 4). In dil-nia (Fig. 3 b) structure by means of strong
hydrogen bond of O–HO type organic ions are assembled in
D1(3)
supramolecular heterodimers with graph-set
30. Analysis of the
1
packing allowed to identify the presence of the homomolecular layers
in the crystal structure of dil-nia. Thick layers contain bulky diltiazem
molecular cations (depicted in red in Fig. 5 a.) while thin layers consist
of nia anions and are shown in green. The layers are perpendicular to
the unit cell c axis. Within the layers the residues interact by van der
Waals forces. The layers are interconnected together by the O–HO
type hydrogen bonds.
Fig. 4 The fragment of the dil-asa crystal structure showing the right-
handed helix like hydrogen bonded chain along unit cell b axis. Atoms
participating in the chain are highlighted as capped sticks, while other
atoms as wireframes. Hydrogen atoms are shown in light green colour
for clarity. The blue dashed lines indicate hydrogen bonds.
a)
a)
b)
b)
Fig. 5. Crystal structure packing of a) dil-nia and b) dil-mal. The dil
cations are shown in red and anions are green. The blue dashed lines
indicate hydrogen bonds.
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In the structure dil-mal (Fig. 3 c) diltiazem cation with L-malate anion Preparation of diltiazem base
forms heterodimers by means of two bifurcated N–HO type
2
Diltiazem base was prepared from hydrochloride salt. One
gram of diltiazem hydrochloride was dissolved in 50 ml of
distilled water, and saturated Na2CO3 aqueous solution was
added up to pH 7.5. Diltiazem base was precipitated out and then
extracted using diethyl ether. The extraction process was carried
out several times using 50 ml of diethyl ether. Amorphous
diltiazem base was obtained after the solvent evaporated.
Crystalline substance was obtained after amorphous phase
recrystallization from diethyl ether at a temperature of -20C,
giving colourless crystals suitable for a single crystal X-ray
diffraction experiment. Recrystallization at room temperature
results in amorphous substance.
hydrogen bonds with graph-set
. These dimers are further
R1 (5)
linked via O–HO type hydrogen bonds between L-malate moieties
and form chains with graph-set along unit cell a axis (Fig 5
C11(5) 30
b). The conformation of L-malic acid anions is also stabilized by a
week intramolecular hydrogen bond of O–HO type (Table 1).
Physicochemical properties
It is well-established fact that salts have altered
physicochemical properties in comparison with API and salt
former. Table 3 summarizes some physicochemical properties of
diltiazem and its salts. As follows from the table, the melting
point of dil-asa is lower than those of API and salt former. This
Single crystal growth and slow solvent evaporation
may be attributed to the presence of water molecules in the
crystal structure, which are not connected by strong hydrogen
Diltiazem acetylsalicylate hydrate 1:1:1. dil (50 mg, 0.12
bonds to the rest of the structure. The melting point of dil
lies between melting points of API and salt former, but the
melting point of dil mal is higher than those of API and salt
former. This may be explained by the formation of extensive
two-dimensional networks perpendicular to the unit cell axis.
-nia
mmol) and asa (21.7 mg, 0.12 mmol) were dissolved in 5 mL of
diethyl ether under ambient conditions and left for evaporation
of the solvent at -4 °C (freezer). Single crystals were obtained as
colourless blocks in three days.
-
c
Diltiazem nicotinate 1:1. dil (50 mg, 0.12 mmol) and nia (14.8
The melting point of a crystalline solid depends on a number of
factors, including types of intermolecular interactions, symmetry
and flexibility of the moieties, as well as arrangement of the
moieties in the lattice.2 Therefore, the discovery of correlations
between melting points and other physicochemical properties is
not straightforward. Melting points are measured using the DTA
method; thermograms are available in the ESI (Fig. S13–S17).
mg, 0.12 mmol) were dissolved in 5 mL of acetonitrile under
ambient conditions and left for slow evaporation of the solvent
under ambient conditions. Single crystals were obtained as
colourless plates in four days.
Diltiazem L-malate 1:1. dil (50 mg, 0.12 mmol) and mal (16.2
mg, 0.12 mmol) were dissolved in 5 mL of acetonitrile under
ambient conditions and left for slow evaporation of the solvent
under ambient conditions. Single crystals were obtained as
colourless plates in 4 days.
Bulky samples of dil, dil-asa, dil-nia and dil-mal were
obtained using the same procedure as in single crystal growth
and used in further investigations.
Table 2 Physicochemical properties of dil and dil salts
Melting point (ºC)
Water solubility, mg/ml
acid
(salt
acid
(salt
Salt
pKa
dil
salt
dil
salt
dil*
former)
former)
212-
214
dil-HCl
dil-asa
dil-nia
dil-mal
-
-
-
56519
519
Single crystal X-ray diffraction
134-
136
0.48
±
0.02
5.46
6.74
5.33
105-
107
86-89
4.6
18
19.0 ± 0.3 12.8 ± 0.2
35.4 ± 1.1 27.3 ± 0.9
73.3 ± 1.4 55.4 ± 1.0
X-ray diffraction data were collected using a Nonius Kappa
CCD diffractometer (CuKα radiation, λ = 0.71073 Å), equipped
with a low-temperature Oxford Cryosystems Cryostream Plus
device. Data were collected using KappaCCD Server Software,
cell refined by SCALEPACK,31 data reduction performed by
DENZO31 and SCALEPACK,31 structures solved by direct
method using SIR200432 and refined by SHELXL9733 as
implemented in the program package WinGX.29 Software used to
prepare CIF34 files was SHELXL97.33
236-
237
109-
112
128.5-
129.5
152-
155
558
*Concentration of dil in salt solution
As it was already mentioned, the dil as hydrochloride salt is
freely soluble, but dil base is insoluble in water. According to
measured values (Table 2), molecular salts obtained in this work
exhibit much higher water solubility than pure API and lower
than that of dil-HCl. In this work we have varied the solubility,
employing a crystal engineering approach. Molecular salts
exhibit a 27- to 116-fold increase in the aqueous solubility of
diltiazem compared to diltiazem base and a 9- to 40-fold
decrease compared with highly soluble diltiazem hydrochloride.
This promising result makes
a good basis for further
development of extended-release formulations of diltiazem.
Experimental
Materials
All chemicals and solvents were obtained from various
commercial suppliers and were used as received.
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Table3 Selected crystal data, experimental and refinement
parameters for structures dil
,
dil
-
asa
,
dil
-
nia and dil
-
mal
DTA was performed using Seiko Exstar6000 TG/DTA6300
(Seiko Instruments INC., Japan) equipment. The samples (4–10
mg) were heated in open aluminium pans at a rate of 10°C/ min
in nitrogen (flow of 20.0 mL/min).
dil
dil-asa
dil-nia
dil-mal
Empirical
C22H26N2O4S
formula
C31H36N2O9S
C28H31N3O6S
C26H32N2O9S
Formula wt
Crystal shape
Crystal colour
Crystal system
Space group
a (Å)
414.51
Plate
612.68
Plate
Colourless
Orthorhombic
P 212121
9.9411(4)
10.7606(3)
28.593(1)
-
3058.61(19)
4
1.331
173 (2)
0.71073
0.163
537.62
Plate
548.60
Plate
Fourier-transform infrared spectroscopy (FT-IR)
Colourless
Orthorhombic
P212121
9.3387(2)
13.9027(4)
16.5550(5)
-
2149.39(10)
4
1.281
Colourless
Monoclinic
P 21
8.7897(2)
6.1726(1)
25.1531(7)
91.526(1)
1364.21(5)
2
Colourless
Orthorhombic
P 212121
5.8962(1)
9.0320(2)
50.507(1)
-
2689.75(9)
4
1.355
FT-IR was performed at room temperature on Shimadzu Corp.
IRPrestige-21 spectrometer (FT-IR spectra available in the ESI, Fig.
S18–S21).
b (Å)
c (Å)
β (°)
Solubility experiments and UV/vis spectrometry
V (Å3)
Z
Dcalc (g cm-3)
T (K)
1.309
The concentration of salt aqueous solutions was determined by
UV/vis using Camspec M501 UV/vis spectrophotometer. UV/vis
absorption spectra in the 200–400 nm range were recorded for all
samples. One separate linear calibration curve was plotted for (dil).
The absorption maxima at wavelength 237 nm was used to calculate
the concentrations for all samples.
The salt solubility was determined by dissolving excess cocrystal
in 5 mL of deionized water at room temperature (23 ± 1 °C).
Suspensions were mixed for 24 h. The concentration of the cocrystal
in the solution was determined by UV/vis spectrometry, and
composition of the solid phase was analyzed by PXRD. UV/vis
measurements were performed in triplicate.
173 (2)
0.71073
0.181
173 (2)
0.71073
0.165
173 (2)
0.71073
0.176
(MoK) [Å]
(mm-1)
F(000)
No. unique
reflns
No. reflns used
No. parameters
GOF on F2
R1[I > 2(I)]
wR2
880
825
568
1160
6221
1296
7311
5177
4230
266
1.01
0.064
0.113
1056494
4302
405
1.08
0.098
0.150
1056495
4922
351
1.05
0.064
0.119
1056496
1853
346
1.00
0.064
0.124
1056497
CCDC no.
Powder X-ray diffraction
Conclusions
Powder diffraction was used to control the results of slow
solvent evaporation experiments. Powder X-ray data were
collected at room temperature with 0.02° step and scan speed of
0.5 s/step on a Rigaku ULTIMA IV powder diffractometer (CuKα
radiation, λ = 1.5418 Å) equipped with parallel beam geometry.
Diltiazem base has been prepared in crystalline form and used in
synthesis of molecular salts with aspirin (as hydrate), niacin and L-
malic acid. Diltiazem base and its salts have been characterized by
single crystal X-ray diffraction. Diltiazem moiety in all structures is
characterized by seven-membered ring, which adopts a twisted boat
conformation. In all salt crystal structures diltiazem cation is
protonated at the nitrogen atom of the N,N-(dimethyl)ethylamine
group; this allows formation of N–HO–type hydrogen bond with
corresponding carboxylic acid. The preliminary characterization of
new salts has showed a lower solubility as compared with highly
soluble diltiazem hydrochloride. Novel molecular salts exhibit 27–
116 fold increase in the aqueous solubility of diltiazem compared to
diltiazem base and 9–40 fold decrease if compared to highly soluble
diltiazem hydrochloride. These promising results make a good basis
for further development of formulations of diltiazem with improved
bioavailability.
Solid state 13C and 15N CP-MAS
Solid state 13C and 15N CP-MAS spectra were acquired on a 800 MHz
Bruker Avance III HD spectrometer equipped with a 3.2-mm 13C/15N
{1H} E-free MAS probe. The MAS frequency was 15 kHz and the
temperature was regulated to 298 K. The CP from H to 13C was
performed using a linear ramp (50-100%) with maximum radio
frequency (RF) amplitude of 64 kHz on 1H and with 80.6 kHz on 13
for a contact time of 2 ms. The CP from H to 15N was performed
using a linear ramp (50-100%) with maximum RF amplitude of 56
kHz on 1H and with 43 kHz on 15N for a contact time of 2 ms. Spinal64
1
C
1
1
decoupling was applied during acquisition with a H RF of 46.8 kHz
Acknowledgements
and a pulse length of 5 us. The acquisition time was 21 ms. The
recycle delay was 5-10 seconds. The 13C spectra were referenced
externally relative to adamantane. The chemical shift of adamantane
We thank Mārtiņš Balodis (University of Latvia) for solid state 13C
and 15N CP-MAS analysis. D.S. thanks EC seventh Framework
CH2 resonance relative to TMS was 38.48 ppm. The 15N spectra were Programme project REGPOT-CT-2013-316149-InnovaBalt for
financial support and ERASMUS+ mobility project (No. 2014-1-
LV01-KA103-000092) for the opportunity to attend traineeship at
CRS4.
referenced externally relative to glycine. The chemical shift of glycine
relative to liquid NH3 was 33.4 ppm.
Nuclear magnetic resonance (NMR)
Notes and references
a Latvian Institute of Organic Synthesis, 21 Aizkraukles street, Riga, LV-
NMR spectra (1H, 13C) were recorded on Varian 400MR
spectrometers. Samples were dissolved in [d6]-DMSO. Chemical
shifts are measured relative to TMS ( = 0) for 1H, and 13C shifts
1006, Latvia.
b
Faculty of Materials Science and Applied Chemistry, Riga Technical
1
were referenced to the residual carbon signal of the solvent. H
University, 3 Paula Valdena Street, Riga, LV-1007, Latvia.
1
and 13C chemical shifts assignments were supported by 2D H–
13C correlations performed on dil and dil-HCl.
Electronic Supplementary Information (ESI) available: [Solid
state 13C and 15N CP-MAS, NMR chemical shifts, PXRD
Differential thermal analysis (DTA)
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Journal Name
patterns, ORTEP drawings, selected torsion angles, DTA, FT-
IR]. See DOI: 10.1039/b000000x/
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6 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012

Page 7 of 7
CrystEngComm
View Article Online
DOI: 10.1039/C5CE01204J
Crystal structures and physicochemical properties of
diltiazem base, acetylsalicylate, nicotinate and -malate
L
D. Stepanovsa,b, M. Jure,b, M. Gosteva,a J. Popelis,a G. Kiselovs a and A. Mishneva,b*
a Latvian Institute of Organic Synthesis, 21 Aizkraukles street, Riga, LV-1006, Latvia.
b Faculty of Materials Science and Applied Chemistry, Riga Technical University, 3 Paula Valdena
Street, Riga, LV-1007, Latvia.
Molecular salts of diltiazem with aspirin, niacin and -malic acid have been
L
synthesized. Their crystal structures and physicochemical properties have been
investigated