Synthesis and Characterization of a Series of Sulfamethazine Multicomponent Crystals with Various Benzoic Acids

Article abstract of DOI:10.1021/acs.cgd.9b01209

Nine multicomponent crystals consisting of sulfamethazine (sz) with benzoic acid and its derivatives were synthesized and characterized. Eight of the nine multicomponent crystals are cocrystals, while one is a molecular salt. The coformers used to form multicomponent crystals with sz include 2-chloro-4-nitrobenzoic acid (2c4n), 2-chloro-5-nitrobenzoic acid (2c5n), salicylic acid (2hba), 3-hydroxybenzoic acid (3hba), 4-hydroxybenzoic acid (4hba), 4-bromobenzoic acid (4Brba), benzoic acid (ba), cinnamic acid (ca), and toluic acid (ta). These multicomponent crystals were characterized by single-crystal X-ray diffraction (SC-XRD), powder X-ray diffraction (PXRD), and differential scanning calorimetry (DSC). SC-XRD showed that eight of the coformers that interacted with sz formed the amidine-carboxyl synthon; the only exception to this was sz + 4hba, which formed the imidine-carboxyl synthon formed instead. PXRD confirmed that the single crystals were representative of the bulk material. DSC showed most of the multicomponent crystals to have only a melting phase transition, which differed from the melting points of the coformers. The only exceptions were sz + 4brba and sz + ca, where an additional endothermic peak was observed, which corresponds to an amorphous phase transition before melting.

Full text of DOI:10.1021/acs.cgd.9b01209

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Article
Synthesis and characterization of a series of sulfamethazine
multi-component crystals with various benzoic acids
Matthew Clarke Scheepers, and Andreas Lemmerer
Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.9b01209 • Publication Date (Web): 18 Dec 2019
Downloaded from pubs.acs.org on January 1, 2020
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Crystal Growth & Design
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Synthesis and characterization of a series of
sulfamethazine multi-component crystals with various
benzoic acids
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Matthew C. Scheepers and Andreas Lemmerer*‡
‡Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand, 2050,
Johannesburg, South Africa
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
To whom correspondence should be addressed:
Dr. Andreas Lemmerer, Molecular Sciences Institute, School of Chemistry, University of the
Witwatersrand, Private Bag 3, 2050, Johannesburg, South Africa.
E-mail: andreas.lemmerer@wits.ac.za. Fax: +27-11-717-6749. Tel: +27-11-717-6711.
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ABSTRACT:
Nine multi-component crystals consisting of sulfamethazine (sz) with benzoic acid and its derivatives
were synthesized and characterized. Eight of the nine multi-component crystals are co-crystals, while
one is a molecular salt. The co-formers used to form multi-component crystals with sz include: 2-
chloro-4-nitrobenzoic acid (2c4n), 2-chloro-5-nitrobenzoic acid (2c5n), salicylic acid (2hba), 3-
hydroxybenzoic acid (3hba), 4-hydroxybenzoic acid (4hba), 4-bromobenzoic acid (4Brba), benzoic acid
(ba), cinnamic acid (ca) and toluic acid (ta). These multi-component crystals were characterized by
single-crystal X-ray diffraction (SC-XRD), Powder X-ray diffraction (PXRD) and Differential Scanning
Calorimetry (DSC). SC-XRD showed that eight of the co-formers that interacted with sz formed the
amidine-carboxyl synthon; with the only exception to this were sz+4hba which formed the imidine-
carboxyl synthon formed instead. PXRD confirmed that the single crystals were representative of the
bulk material. DSC showed most of the multi-component crystals to have only a melting phase
transition, which differed from the melting points of the co-formers. The only exceptions were
sz+4brba and sz+ca, where an additional endothermic peak was observed, which corresponds to an
amorphous phase transition before melting.
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Crystal Growth & Design
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KEYWORDS:
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sulfamethazine, sulfadiazine, co-crystal, salt, multi-component crystal
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Introduction
The need for designing new crystal forms of potentially useful Active Pharmaceutical Ingredients
(API’s) has been rising in the past few decades. Promising drug candidates often have poor
physiochemical properties, especially poor water solubility and dissolution rates 1 2. One common
approach to altering the poor physiochemical properties of an API is to incorporate them into multi-
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component crystals . Multi-component crystals often have different properties, if not superior
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properties, in respect to its co-formers . Therefore there is a great interest in exploring new multi-
component crystals of various APIs.
Sulfamethazine (sz), also referred to as sulfadimidine, is an anti-bacterial drug used to treat urinary tract
infection, chlamydia, malaria, rheumatoid fever and toxoplasmosis in humans as well as for veterinary
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5, 6
purposes. Sz is also known to be tautomeric,
consisting of an amidine form and an imidine form
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(
Scheme 1). Both forms have been reported to appear in the solid state. 5, 6, 7 However, the amidine form
tends to be the more dominant form, appearing more frequently than the imidine form. In its pure form
sz is able to crystallise into several different crystal habits, but has only one crystal structure. 8 In
addition to the amidine/imidine group, an amino group is present to act as an additional hydrogen bond
donor, and the sulfoxide and second nitrogen of the pyrimidine ring can act as an additional hydrogen
bond acceptor. This provides a wide variety of possible hydrogen bond interactions to occur.
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Several different co-crystals and solvates of sulfamethazine have already been reported in the literature.
The major synthon that forms between sz and the corresponding co-formers involves the
amidine/imidine functional group. Several multi-component crystals of sz containing a co-former with a
carboxylic acid usually interact with the amidine/imidine group as seen in synthon (i) and (ii) (Scheme
2
). In such case, this should leave the amino and sulfoxide groups free to interact with each other
(Synthon (iii), Scheme 2).
In this work we present the synthesis of 9 multi-component crystals of sulfamethazine, with eight co-
crystals and one molecular salt. Six of these multi-component crystals are novel while three have been
previously reported but produced under slightly different conditions. The benzoic acids chosen for this
work were either structural isomers of each other (2hba, 3hba, 4hba etc.) or did not contain any
additional hydrogen bonding groups (e.g. ca, ba, ta). These multi-component crystals were
characterized by Single Crystal X-ray Diffraction (SC-XRD), Powder X-ray diffraction (PXRD) and
Differential Scanning Calorimetry (DSC).
Scheme 1. Sulfamethazine showing the amidine form (left) and imidine form (right).
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Crystal Growth & Design
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Scheme 2 Some of the synthons expected for this work: (i) amidine-carboxyl synthon, (ii) imidine-
carboxyl synthon, (iii) sulfoxide-amino chains, (iv) amino-carboxyl synthon, (v) Hydroxyl-amino
synthon.
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Experimental Section
Crystal Preparation
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All reagents used were purchased from Sigma-Aldrich and were used without further purification.
Most of the co-crystals presented here have been prepared almost exclusively by solvent evaporation
methods. Equimolar amounts of SZ and the respective co-former were dissolved together in a 1:1 v/v
ratio of ethanol: acetonitrile, which was allowed to stir for an additional 10 minutes with some heating.
Afterwards samples were left slightly open at room temperature to allow solvent evaporation. Crystals
were grown from this solution after several days.
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For the case of sz+2c5n and sz+ca, ball milling followed by solvent evaporation methods was deployed.
Equimolar amounts of sz and the respective co-former were placed in Teflon-coated milling jar (18mm
diameter, 65 mm length) with two steel balls (5mm diameter). A few drops of acetonitrile were added to
this mixture. The jars were then placed on a Retsch MM200 vibratory mill and were milled at 20 Hz for
2
0 minutes. Afterwards the solvent evaporation methods described previously was used, with some of
the powder from the ball milling used as seeds.
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Crystal Growth & Design
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Scheme 3: Co-formers used for this work: (i) cinnamic acid (ca), (ii) 2-chloro-4-nitrobenzoic acid
(2c4n), (iii) 2-chloro-5-nitrobenzoic acid (2c5n), (iv) 4-nitrobenzoic acid (4nba), (v) 4-bromobenzoic
acid (4brba), (vi) 2-hydroxybenzoic acid/salicylic acid (2hba), (vii) 3-hydroxybenzoic acid (3hba), (viii)
4-hydroxybenzoic acid (4hba), (ix) toluic acid (ta).
Powder X-ray Diffraction (PXRD)
Powder X-ray diffraction is done to determine the phase purity of the bulk material. PXRD data for all
compounds were measured at 293 K on a Bruker D2 Phaser diffractometer which employs a sealed tube
Co X-ray source (λ = 1.78896 Å), operating at 30 kV and 10 mA, and LynxEye PSD detector in Bragg-
Brentano geometry. Powder patterns for each sample are presented in the supporting information, where
the experimentally obtained data are compared to the calculated patterns obtained from the SC-XRD
data.
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Single Crystal X-Ray Diffraction (SC-XRD)
The Bruker D8 VENTURE PHOTON CMOS area detector diffractometer, equipped with a graphite
monochromated Mo Kα sealed tube (50 kV, 30 mA), was used to collect all the intensity data. The
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program SAINT+, vers. 6.02 was used to integrate the data and the program SADABS 10 was used to
make empirical absorption corrections. Space group assignments were made using XPREP 10 on all
compounds. In all cases, the structures were solved in the WinGX Suite of programs 11 by direct methods
using SHELXS-97 10 and refined using full-matrix least-squares/difference Fourier techniques on F2
using SHELXL-97. 10 All non-hydrogen atoms were refined anisotropically. Thereafter, all hydrogen
atoms attached to N or O atoms, except where otherwise stated, were located in the difference Fourier
map and their coordinates and isotropic thermal displacement parameters were refined freely. All C-H
hydrogen atoms were placed at idealized positions and refined as riding atoms with isotropic parameters
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.2 or 1.5 times those of the ‘heavy’ atoms to which they are attached. Diagrams and publication
material were generated using ORTEP-3, 11 and Mercury 12.
Differential Scanning Calorimetry (DSC)
e
Differential scanning calorimetry data were collected using a Mettler Toledo 822 with aluminium pans
under nitrogen gas (flow rate = 10 L/min). Exothermic events were shown as peaks. Co-crystals were
heated and cooled to determine melting points as well as any additional phase transitions. The
temperature and energy calibrations were performed using pure indium (purity 99.99%, m.p 156.6°C,
heat of fusion: 28.45 J g-1).
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Crystal Growth & Design
Infrared Spectroscopy
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Infrared spectra were collected on a Bruker Tensor 27. Samples were used as is without further
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processing. Spectra were collected in the range of 4000-600 cm and band intensities were expressed as
transmittance %.
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Results and Discussion
Nine multi-component crystal forms containing sulfamethazine are reported. Six of these crystal forms
are new. These crystal forms were characterized by SC-XRD. PXRD was used to confirm that the bulk
material matched the calculated pattern in order to ensure purity. DSC was used to determine the
melting points as well as any other potential phase transitions.
SC-XRD Results
Sz formed nine multi-component crystals which were characterized by SC-XRD. For most of these
crystal systems the intermolecular interactions are similar, and possess some structural and packing
similarities. For the purpose of this work, several multi-component crystals are grouped and discussed
together below. Table 1 gives a list of which multi-component crystals are grouped together and reasons
for such grouping. In addition, Table 4 contains a list of the bond lengths of the carboxyl group
obtained from each of the multi-component crystals as well as if a salt or co-crystal was formed. The
ratios of the C-O bond lengths indicate that most of the crystals systems are co-crystals, with the
exception of sz+2c4n and sz+3hba which show incomplete proton transfer.
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Table 1 The grouping of the multi-component crystals as well as the motivation for such
groupings.
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Group
Motivation for grouping together
sz + 4Brba
sz + 4Brba is in its own group since it does not fit
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in with the other three group list below.
The co-formers consist of a carboxylic acid group
which acts as the sole source for hydrogen
bonding.
sz + ca, sz + ba, sz + ta
sz + 2hba, sz + 3hba, sz + 4hba
sz + 2c4n, sz + 2c5n
The co-formers are structural isomers of each
other.
The co-formers are structural isomers of each
other, in particular it is the shift of the nitro group
from the 4’ position to the 5’ position.
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Crystal Growth & Design
Table 2 Crystallographic Data and Structure Refinement Data for sz multi-component crystals.
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sz+2c4n
sz+2c5n
sz+2hba
sz+3hba
sz+4hba
Empirical formula
C
19
H18ClN
5
O
6
S
C
19
H18ClN
5
O
6
S
C
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H
20
N
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O
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H
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N
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O
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S
19 20 4 5
C H N O S
Formula weight/ g·mol-1
479.89
173(2)
0.71073
479.89
173(2)
0.71073
416.45
173(2)
0.71073
416.45
173(2)
0.71073
416.45
173(2)
0.71073
triclinic
P-1
Temperature / K
Wavelength / Å
Crystal system
Space group
a / Å
Orthorhombic
Pbc2
monoclinic
P2
orthorhombic
Pbca
orthorhombic
Pbca
1
1
19.2999(6)
6.96450(10)
19.3894(3)
15.7238(2)
90
10.1289(3)
15.7422(4)
25.0535(7)
90
9.9985(3)
15.7375(4)
24.6844(7)
90
7.9638(9)
9.3601(10)
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6
7
8
9
0
b / Å
7.7198(2)
c/ Å
13.9038(4) Å
13.2882(14)
74.123(4)
75.616(4)
85.727(4)
α /°
90
90
90
β /°
90.7000(10)
90
90
90
γ /°
90
90
3
2071.55(10)
4
2123.14(5)
4
3994.81(19)
8
3884.12(19)
8
922.85(18)
2
V / Å
Z
Density (calculated)/
1.539
1.501
1.385
1.424
1.499
Mgm-3
μ/ mm-1
F(000)
0.335
992
0.326
992
0.201
0.207
0.218
1744
1744
436
0
0
.214 x 0.248 x
.317
0.349 x 0.189 x
0.130
0.441 x 0.284 x
0.238
0.315 x 0.257 x
0.129
0.163 x 0.146 x
0.052
Crystal size / mm3
Theta range for data/°
collection
2
.110 to 28.238.
1.295 to 28.215.
3.057 to 28.334.
2.924 to 28.360.
3.126 to 28.334.
Reflections collected
24549
58621
58505
47634
36343
5046 [R(int) =
0.0545]
10439 [R(int) =
0.0482]
4953 [R(int) =
0.0405]
4831 [R(int) =
0.0748]
4592 [R(int) =
0.0511]
Independent reflections
2
1.030
1.059
1.021
1.072
1.046
Goodness-of-fit on F
Final R indices
[I>2sigma(I)]
R
1
= 0.0366
wR = 0.0707
= 0.0560
wR = 0.0785
R
1
= 0.0392
wR = 0.0854
= 0.0595
wR = 0.0935
R
1
= 0.0373
wR = 0.0926
R1 = 0.0484
wR = 0.0999
R
1
= 0.0452
wR = 0.1134
= 0.0693
wR = 0.1250
R
1
= 0.0416
wR = 0.0977
= 0.0555
wR = 0.1039
1952596
2
2
2
2
2
R
1
R
1
R
1
R
1
R indices (all data)
CCDC Number
2
2
2
2
2
1952592
1952593
1952594
1952595
sz+4brba
sz+ba
sz+ca
sz+ta
Empirical formula
C
19
H19BrN
4
O
4
S
C
19
H
20
N
4
O
4
S
C
21
H
22
N
4
O
4
S
20 22 4 4
C H N O S
Formula weight/ g·mol-1
479.35
400.45
426.48
414.47
173(2)
0.71073
Temperature / K
Wavelength / Å
Crystal system
Space group
a / Å
173(2) K
0.71073
173(2) K
0.71073
173(2) K
0.71073
Monoclinic
P2 /n
8.5979(7)
orthorhombic
Pbca
monoclinic
P2 /n
monoclinic
P2
1
1
1
15.1817(3)
14.0288(3)
17.9844(4)
90
a = 8.3614(2)
14.6091(4)
16.9318(5)
90
a = 7.3454(6)
13.3001(11)
11.2172(10)
90
b / Å
11.8215(10)
19.5587(16)
90
c / Å
α /°
β /°
102.009(3)
90
90
98.2910(10)
90
107.585(3)
90
γ /°
90
3
V / Å
1944.4(3)
4
3830.34(14)
8
2046.65(10)
4
1044.65(15)
2
Z
Density (calculated) /
1.637
1.389
1.384
1.318
Mg m-
3
μ / mm-1
F(000)
2.257
976
0.203
0.195
0.188
1680
896
436
0
0
.365 x 0.086 x
.066
0.347 x 0.248 x
0.160
0.514 x 0.317 x
0.254
0.325 x 0.258 x
0.136
Crystal size / mm3
Theta range for data
collection
2.983 to 28.356°.
2.265 to 30.749°.
2.899 to 28.315°.
2.909 to 28.356°.
Reflections collected
26446
46609
40194
19104
4
840 [R(int) =
5970 [R(int) =
0.0892]
5084 [R(int) =
0.0413]
5182 [R(int) =
0.0224]
Independent reflections
0.0864]
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11

Crystal Growth & Design
Page 12 of 41
2
1.050
= 0.0485
wR = 0.0748
= 0.0889
wR = 0.0840
1952597
1.011
= 0.0465
wR = 0.1101
= 0.0917
wR = 0.1314
1952598
1.081
1.064
= 0.0336
wR = 0.0932
= 0.0375
wR = 0.1025
1952600
Goodness-of-fit on F
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Final R indices
R
1
R
1
R
1
= 0.0372
wR = 0.0955
= 0.0478
wR = 0.1011
1952599
R
1
[I>2sigma(I)]
2
2
2
2
R
1
R
1
R
1
R
1
R indices (all data)
2
2
2
2
CCDC Number
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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12

Page 13 of 41
Crystal Growth & Design
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 1 Ortep diagram for (i) sz+2c4n, (ii) sz+2c5n, (iii) sz+2hba, (iv) sz+3hba, (v) sz+4brba, (vi)
sz+4hba, (vii) sz+ba and (viii) sz+ca
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Crystal Growth & Design
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1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 2 Ortep diagram for sz+ta
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Page 15 of 41
Crystal Growth & Design
Table 3 Hydrogen bond table for the multi-component crystals represented in this work.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
D-H···A
d(D-H)
d(H···A)
d(D···A)
<(DHA)
sz+2c4n
N1-H1A···O4(a)
N1-H1B···O5(b)
N2-H2A···O4
N4-H4A···O3
0.89(5)
0.78(5)
0.83(5)
0.88
2.40(5)
2.30(5)
1.91(5)
1.68
3.083(4)
3.032(5)
2.731(4)
2.560(4)
134(4)
156(5)
176(5)
173
sz+2c5n
N1-H1A···O8(c)
N1-H1B···O7
N2-H2A···O3
O4-H4A···N4
N6-H6A···O2(d)
N6-H6B···O1(e)
N7-H7A···O10
O9-H9A···N9
0.90(4)
0.80(5)
0.73(4)
0.88(5)
0.84(5)
0.87(4)
0.85(5)
0.90(6)
2.20(4)
2.15(5)
2.06(4)
1.80(5)
2.36(5)
2.14(4)
1.92(5)
1.74(6)
3.067(5)
2.899(4)
2.793(4)
2.647(4)
3.021(4)
2.976(4)
2.762(4)
2.631(4)
159(4)
156(4)
172(4)
159(5)
136(4)
162(3)
173(4)
172(6)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
sz+3hba
N2-H2A···O3
N1-H1A···O1(f)
N1-H1A···S1(f)
N1-H1B···O2(g)
O4-H4···N3
0.88
1.93
2.751(2)
3.124(2)
3.7743(18)
3.039(2)
2.722(2)
2.878(2)
2.722(2)
155
0.88(2)
0.88(2)
0.88(2)
0.84
0.89(3)
0.88
2.24(2)
2.95(2)
2.26(2)
1.89
2.01(3)
1.86
177(2)
155(18)
148(2)
171
165(3)
166
O5-H5A···N1(h)
N3-H3A···O4
sz+4brba
sz+4hba
N1-H1A···O1(c)
N1-H1B···O2(i)
N2-H2A···O3
O3-H3A···N4
0.85(4)
0.82(3)
0.80(3)
0.78(4)
2.27(4)
2.36(3)
3.12(3)
1.93(4)
3.103(4)
3.166(4)
3.706(4)
2.693(3)
169(3)
168(3)
132(3)
168(4)
N1-H1A···O2(c)
N1-H1A···S1(c)
N1-H1B···N4(j)
N1-H1B···O2(j)
N3-H3A···O3
O3-H3B···N2
O3-H3B···S1
0.85(2)
0.85(2)
0.88(2)
0.88(2)
0.91(2)
0.93(3)
0.93(3)
0.85(3)
2.23(3)
2.95(3)
2.56(2)
2.63(2)
3.06(2)
1.86(3)
2.76(3)
1.97(3)
3.0697(19)
3.7585(16)
3.430(2)
3.1212(18)
3.7433(19)
2.7765(19)
3.5270(14)
2.800(2)
168(2)
158(19)
168(19)
116(17)
133(17)
173(3)
141(2)
165(2)
O5-H5A···N1(k)
sz+ba
sz+ca
N1-H1A···O3(g)
N1-H1B···O2(l)
N2-H2A···O3
O4-H4···N4
0.83(3)
0.92(3)
0.80(3)
0.94(3)
2.40(3)
2.04(3)
2.00(3)
1.70(3)
3.084(3)
2.955(3)
2.792(2)
2.640(2)
140(2)
172(2)
174(3)
174(2)
N2-H2···O3
0.84(2)
0.97(2)
0.85(2)
0.83(2)
3.04(2)
1.71(2)
2.27(2)
2.27(2)
3.6632(15)
2.6757(15)
3.0828(18)
3.0859(18)
134(16)
171(2)
159(18)
168(2)
O3-H3A···N4
N1-H1A···O2(c)
N1-H1B···O1(i)
sz+2hba
N2-H2···O4
0.88(2)
0.85(2)
0.91(2)
0.91(2)
0.99(3)
0.99(3)
1.90(2)
2.14(2)
2.99(2)
2.16(2)
1.64(3)
3.56(3)
2.7789(16)
2.9478(19)
3.8674(18)
3.057(2)
2.6283(15)
4.1468(17)
175(18)
160(2)
164(17)
168(19)
171(3)
N1-H1A···O2(a)
N1-H1B···S1(b)
N1-H1B···O1(b)
O3-H3A···N4
O5-H5A···O3
120(19)
sz+ta
N1-H1A···O1(o)
N1-H1B···O2(n)
N2-H2A···O4
O3-H3A···N4
0.87(3)
0.83(3)
0.86(3)
0.94(4)
2.08(3)
2.19(3)
1.90(3)
1.81(4)
2.896(3)
2.961(3)
2.759(2)
2.732(2)
155(3)
154(3)
177(3)
168(4)
Symmetry transformations used to generate equivalent atoms:
(a) –x + 1, -y + 2, z - 1/2; (b) x - 1/2, -y + 2, z – 1; (c) x + 1, y, z; (d) x, y, z + 1; (e) x - 1, y, z + 1;
(f) –x + 1/2, y + 1/2, z; (g) –x + 1, y + 1/2, -z + ½; (h) –x + 1/2, -y + 1, z + ½; (i) –x + 3/2, y - 1/2, -z + ½;
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Crystal Growth & Design
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(j) –x + 2, -y + 1, -z; (k) –x + 1, -y, -z + 1; (l) –x + 3/2, y + 1/2, z; (m) –x + 1, y - 1/2, -z + 3/2;
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(n) –x + 1, y - 1/2, -z + 2; (o) -x, y - 1/2, -z + 2.
Table 4 Comparison of the bond lengths of the carboxyl group of the co-former.
Long C-O bond of
Short C-O bond of
Ratio (long over
short)
respective co-former
in native crystal
structure/ Å
1.247 (Form I)
1.288 / 1309 / 1.301 /
respective co-former
in native crystal
structure/ Å
Compound
sz+2c4n
C19-O3 / Å
C19-O4 / Å
1
.233 (Form I) 1.221 /
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
.266(4)
1.237(4)
1.023
1.216 / 1.214 / 1.222
(salt/cc)
1.313 (Form II) 13
Form II) 13
(
*
**
sz+2c5n*
cc)
sz+3hba
salt/cc)
1.202(4) / 1.197(4)
1.285(4) / 1.279(4)
1.284(2)
1.069 / 1.068
1.027
1.295 14
1.317 15
1.309 16
1.220 14
1.208 15
1.223 16
(
1
1
1
1
.250(2)
.311(4)
.318(2)
.306(2)
(
sz+4brba
(cc)
1.227(4)
1.069
sz+4hba
1.227(2)
1.074
1.278 17
1.267 17
(
cc)
sz+ba
cc)
sz+ca**
cc)
sz+2hba
cc)
1.275 18
1.264 18
1.228(2)
1.064
(
1.3127(17)
.2921(19)
.311(3)
1.2299(16)
1.2476(18)
1.224(3)
1.067
1.292 19
1.311 20
1.302 21
1.254 19
1.245 20
1.248 21
(
1
1.036
(
sz+ta
(cc)
1
1.053
*
For the case of sz+2c5n the second molecule of 2c5n is also included, as C38-O10 and C38-O9 respectively, separated by a slash. ** For the case of sz+ca
it is the C21-O3 and C21-O4 bond respectively instead. ***2c4n is polymorphic, with Form I having one 2c4n molecule in the asymmetric unit while
Form II has four 2c4n molecules.
Crystal Structures of sz+4brba
The co-crystal of sz+4brba crystalizes in the P2 /n space group with the asymmetric unit consisting of
1
one molecule of each sz and 4brBA. Sz forms in the amidine tautomer, forming the expected amidine-
carboxyl synthon. Sz adopts a v-conformation, which forms wave-like columns along the c-axis (Fig. 3
(i)), with 4brba sitting in between adjacent columns. However, the pyrimidine rings of sz and 4brba
forms a layered structure, with layers separated from each other via the aniline ring of sz.
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Crystal Growth & Design
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 3 The crystal structure of sz+4brba showing (i) the packing viewed down the b-axis, (ii) the
layers of the pyrimidine of sz and 4brba separated by the aniline rings.
Crystal Structures of sz+ba, sz+ca and sz+ta
The crystal structure of sz+ba has been previously reported 22; while sz+ca and sz+ta are novel to this
work. Co-crystals of sz+ba, sz+ca and sz+ta are described and compared together since the co-formers
only consists of one hydrogen bond donor/acceptor – the carboxyl group. From this it should be
reasoned that differences in the crystal structures should arise due to the unique aspects of the respective
co-former. Co-crystals of sz+ba, sz+ca and sz+ta crystallise in the Pbca, P2 /n and P2 space groups
1
1
respectively. In each case the asymmetric unit is made up of one molecule of sz and one molecule of the
respective co-former. The co-formers ta, ba and ca contain only one functional group that can form
hydrogen bonds – the carboxyl group. In each case, the amidine-carboxyl synthon (Synthon (ii), See
Scheme 2) formed. Sz+ca and sz+ta formed the sulfoxide-amino chain synthon (Synthon (iii) see
Scheme 2), while sz+ba did not. Instead, in sz+ba the amino group forms a hydrogen bond to one of the
oxygen atoms of the sulfoxide group while the other hydrogen bonds to the carboxyl group of ba
(Synthon (iv) see Scheme 2).
In the packing of the co-crystal of sz+ba (Fig 4 (ii)), the pyrimidine ring of sz and rings of ba form rows
of the aniline ring of sz in the b-axis direction separating clusters of sz+ba apart. Adjacent dimers of
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Crystal Growth & Design
Page 18 of 41
sz+ba running in the a-axis appear T-shaped, with rows interlocking together. In the packing of sz+ca,
molecules of sz lie in rows down the b-axis, alternating between the aniline and pyrimidine rings. This
results in the sz molecules forming parallel zig-zag formations, with molecules of ca filling in the gaps
between the sz-rows.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 4 The crystal structure of sz+ba showing the hydrogen bonding patterns (i) and its packing (ii).
The packing diagrams for sz+ca (iii) and sz+ta (iv).
Crystal structures of sz + hydroxybenzoic acids
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Crystal Growth & Design
The co-crystals of sz+2hba and sz+3hba both crystallise in Pbca space group, while the co-crystal of
sz+4hba crystalizes in the P-1 space group. In each case, the asymmetric unit is composed of one
molecule of sz and each respective conformer. The crystal structures of sz+4hba and sz+2hba have
been previously reported in the literature. 5, 23 Despite using slightly different crystallising conditions
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(sz+2hba used acetone as the solvent, while sz+4hba used pure acetonitrile), the same crystal structures
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
were obtained. The co-crystal of sz+3hba is novel, hence the synthesis of the former were to prove
useful in comparing the changes that may occur due to the shift of the hydroxyl group. In the co-crystal
of sz+3hba, it was observed that the carboxylic acid proton had only partially transferred to the sz. In
the difference Fourier map, there were two clear areas of electron density near O3 and N4.
Subsequently, we decided to place a hydroxyl (H3A) and aromatic (H4) hydrogen atom geometrically
and give each one a site occupancy of a half. This behaviour is reflected in the ratio of the C-O bonds
given in Table 3. For a typical carboxylic acid, the ratio should be greater than 1.5. For a carboxylate,
the value should be close to 1.0. In this case, the ratio was found to be 1.027. Hence, we will refer to
sz+3hba as a mixed salt/co-crystal. sz+2hba and sz+3hba form the amidine-carboxyl synthon while
sz+4hba formed the imidine-carboxyl synthon instead. sz+2hba and sz+3hba form the sulfoxide-amino
chains, while Sz+4hba do not. Instead only one of the oxygen atoms of the sulfoxide group forms a
hydrogen bond with the amino group (N1-H1A···O2). The hydroxyl group for sz+2hba forms an
intramolecular hydrogen bond as expected. For both sz+3hba and sz+4hba the hydroxyl group forms a
hydrogen bond interaction with the amino group of sz (Synthon (v) see Scheme 2).
The packing of the crystal structures of sz+2hba and sz+3hba are isomorphous, as seen in Fig 5 (i) and
(ii). Like many of the other crystal structures reported in this work, sz adopts a v-shaped conformation.
Both sz+2hba and sz+3hba form long chains of sz connected by the sulfoxide-amino hydrogen bond,
which essentially forms long columns with the hydroxybenzoic acid attached. These columns overall
appear in a wave-like structure.
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The packing of sz+4hba deviates from the previous two. Two molecules of each sz and 4hba form
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
tetramers, which stack together to form a ladder. This ladder is made up of the pyrimidine rings of sz
and 4hba making up the steps, while the aniline ring makes up the rail. This description matches the one
previously reported. 5
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 5 Packing diagram for (i) sz+2hba as viewed down the a-axis, (ii) sz+3hba as viewed down the
a-axis and (iii) sz+4hba as viewed down the b-axis and (iv) two tetramers of sz+4hba stacked to show
the ladder.
Crystal Structures of sz+2c4n and sz+2c5n
The multi-component crystals of sz+2c4n and sz+2c5n form a molecular salt and a co-crystal
respectively. Sz+2c4n and sz+2c5n crystalize in the Pca2 and P2 space groups respectively. The
1
1
asymmetric unit for sz+2c4n consists of one molecule of each sz and 2c4n, while the one for sz+2c5n
consists of two molecules of sz and 2c5n. As was the case for sz+3hba, sz+2c4n was observed to have a
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Crystal Growth & Design
positional disorder of the carboxylic H atom. In the difference Fourier map, there were two clear areas
of electron density near O3 and N4. Subsequently, we decided to place a hydroxyl (H4) and aromatic
(H3a) hydrogen atom geometrically and give each one a site occupancy of a half. The bond lengths of
C19-O3 and C19-O4 for sz+2c4n are 1.266(4) and 1.237(4) respectively, giving a ratio of 1.023 and
indicating again a mixed salt/co-crystal. Despite being close isomers of each other, 2c4n and 2c5n will
exhibit different acid strengths. One approach to determining if a co-crystal or a molecular salt will form
is to use the pK of the co-formers. If the ΔpK (ΔpK = pK (Conjugate acid of base) - pK (acid)) is
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
a
a
a
a
greater than 2-3, a molecular salt will form. 24 Anything less than 1 will almost always indicate the
formation of a co-crystal. Values between 0-3 are an intermediate case where either a molecular salt or
2
5
co-crystal could form. For water the pK ’s for sz, 2c4n and 2c5n respectively are 2.07 , 1.96 and 2.17,
a
and give ΔpK ’s for sz+2c4n and sz+2c5n as 0.11 and -0.10 respectively. Although this ΔpK could
a
a
only be truly valid if these crystals were grown from water solution, it still correlates well for the case of
sz+2c5n.
In addition to being different in being a salt and a co-crystal, some hydrogen bonding patterns are
different. The co-crystal of sz+2c5n is comparable to many of the other co-crystals presented in this
work: the formation of the amidine-carboxyl and the amino-sulfoxide synthons. The nitro group of 2c5n
is involved in some weak hydrogen bonding with a neighbouring 2c5n molecule (C16-H16···O12-N10
and C35-H35···O6-N6). In contrast, the sulfoxide group of sz in the salt of sz+2c4n does not form the
sulfoxide-amino chains that are observed in the other crystal structures. Instead, the amino group of sz
forms hydrogen bonds with the carboxylate group and nitro group of 2c4n (N1-H1B···O5 and N1-
H1A···O4 respectively). The sulfoxide group forms only weak hydrogen bonds (C11-H11···O1 C14-
,
H14···O2, and C6-H6···O2).
The packing of the crystal structures of sz+2c4n and sz+2c5n is similar. In both cases sz adopts a v-
shaped conformation that has been observed in the other crystal structures. The packing of sz molecules
forms channels formed by four sz molecules, which the molecules of 2c4n and 2c5n occupy.
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1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 6 The packing diagrams of the multi-component crystals of sz+2c4n as viewed down the c-axis
(left) and sz+2c5n with the a-axis coming out of the plane (right).
Infrared Spectroscopy
Infrared spectroscopy can be used to determine the formation of molecular salts or co-crystals by
comparing the spectrum of the multi-component crystal with the spectra of the parent co-formers. A
shift of a peak between the spectrum of the parent co-former and the spectrum of the multi-component
crystal is typically expected. For this work, FT-IR spectra were obtained and are presented in Fig. 7.The
stretching frequencies of the primary amino group of sz (-NH ) and the sulfonamide group (-NH) are
2
then compared to that of the parent co-former. Table 7 contains the wavenumbers associated with the
sym and asym stretching frequencies of the primary amino group and the stretching frequency of the
sulfonamide group. It is clear that for most of the multi-component crystals, there is a shift in the
expected stretching frequencies.
In particular it should be noted that for the spectrum of sz+2c4n a broad band is observed over the 1500-
-1
1650 cm region, which is not observed for the other multi-component crystals presented in this work.
This broad band is typically associated with a carboxylate, which infers that the multi-component
crystal of sz+2c4n is indeed a molecular salt, in contrast to the refinement model we used in the crystal
structure.
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Crystal Growth & Design
1
2
3
4
5
6
7
8
9
sz+4Brba
sz+ta
sz+ca
sz+ba
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
sz + 4hba
sz+3hba
sz+2hba
sz+2c5n
sz
sz + 2c4n
4
000
3500
3000
2500
2000
1500
1000
500
-
1
Wavenumber /cm
Figure 7 The FTIR spectra obtained for the sz and the multi-component crystals of sz.
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Table 5 Peak shift assignments for the IR spectra of sz and the multi-component crystals of sz. Note,
values in brackets indicate the shift of the peak compared to pure sz.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Peak Assignment
Wavenumber /cm-1
sz
Amine ν(NH ) sym
3346
3445
3238
2
Amine ν(NH ) asym
2
Sulfonamide (NH)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
sz+2c4n
3396 (+50)
Amine ν(NH ) sym
2
Amine ν(NH ) asym
3488 (+43)
3094 (-144)
2
Sulfonamide (NH)
sz+2c5n
Amine ν(NH ) sym
3388 (+42)
3483 (+38)
3247 (+9)
2
Amine ν(NH ) asym
2
Sulfonamide (NH)
sz+2hba
Amine ν(NH ) sym
3380 (+34)
3485 (+40)
3251 (+13)
2
Amine ν(NH ) asym
2
Sulfonamide (NH)
sz+3hba
Amine ν(NH ) sym
3352 (+6)
3419 (-26)
3230 (-8)
2
Amine ν(NH ) asym
2
Sulfonamide (NH)
sz+4hba
Amine ν(NH ) sym
3359 (+13)
3376 (-69)
3283 (+45)
2
Amine ν(NH ) asym
2
Sulfonamide (NH)
sz+4Brba
Amine ν(NH ) sym
3384 (+38)
3486 (+41)
3241 (+3)
2
Amine ν(NH ) asym
2
Sulfonamide (NH)
sz+ba
Amine ν(NH ) sym
3373 (+27)
3460 (+15)
3271 (+33)
2
Amine ν(NH ) asym
2
Sulfonamide (NH)
sz+ca
Amine ν(NH ) sym
3371 (+25)
3477 (+32)
3265 (+29)
2
Amine ν(NH ) asym
2
Sulfonamide (NH)
sz+ta
Amine ν(NH ) sym
3381 (+35)
3480 (+32)
3247 (+9)
2
Amine ν(NH ) asym
2
Sulfonamide (NH)
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Crystal Growth & Design
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Differential Scanning Calorimetry Results
The multicomponent crystals were analysed by DSC. Samples were heated at a rate of 10 °C/min from
2
5 °C to 250 °C, which were then cooled back to 25 °C at a rate of 10 °C/min. In each case, upon
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
cooling, no further thermal events were observed. With the exception of sz+4brba and sz+ca, the DSC
curve for each sample showed only one single endothermic peak, which corresponds to melting. These
curves are plotted in Fig. 8, with thermodynamic data in Table 2. The DSC curves for sz+4brba and
sz+ca were plotted separately and are in Fig. 9. sz+4brba show two endothermic peaks: one broad peak
occurring at 125 °C and one peak at 204 °C. sz+ca show two peaks occurring at 188 °C and 209 °C
respectively.
In order to determine what the additional peaks observed in the crystals of sz+4Brba and sz+ca are,
crystals were mounted on a glass fibre and heated in situ in the diffractometer. These crystals were
heated from 25 °C up to the temperature at which the first thermal event were observed. The unit cell
parameters were collected at every 10 °C interval to monitor if any significant change occurs. In both
cases, as soon as the crystal reached the temperature at which the first thermal event occurs, no
diffraction spots were observed in the diffraction image. These crystals were observed to have changed
from being transparent to being opaque. This implies that the phase change associated with the first
thermal event of the DSC curves for both cases is a phase change from being crystalline to being
amorphous.
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1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Sz + ta
Sz + ba
Sz + 4hba
Sz + 3hba
Sz + 2hba
Sz + 2c5n
Sz + 2c4n
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
0
50
100
150
200
250
300
Temperature /°C
Figure 8 DSC curves for co-crystals which only show melting.
sz + 4Brba
sz + ca
0
50
100
150
200
250
300
Temperature /°C
Figure 9 DSC curves for sz+4brba and sz+ca showing the additional endothermic peaks.
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Crystal Growth & Design
Table 6 Thermodynamic data for the endothermic peaks of the multi-component crystals.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Enthalpy / kJ mol-1
Co-crystal/salt
sz+2c4n
Onset / °C
192.1
Peak / °C
193.8
72.5
72.6
64.1
75.3
57.5
sz+2c5n
200.8
201.6
sz+2hba
198.0
199.2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
sz+3hba
184.8
187.4
sz+4hba
214.2
217.6
Sz+4Brba (crystalline

amorphous phase
126.1
132.8
208.8
192.7
211.2
10.5
58.3
2.3
transition)
sz+4Brba (Melting phase
transition)
2
06.6
sz+ca (crystalline

amorphous phase
188.7
transition)
sz+ca (Melting phase
transition)
sz+ba
2
09.8
51.2
217.4
203.9
220.5
208.0
66.4
54.0
sz+ta
Conclusions
Nine multi-component crystals were synthesised and characterized. Among sz+ba, sz+ca and sz+ta,
structural feature varied widely despite having the same set of hydrogen bond synthons. sz+2hba and
sz+3hba were found to be isomorphous and favoured the amidine-carboxyl synthon, while sz+4hba
differed from the previous two both in terms of packing as well as the imidine-carboxyl synthon.
sz+2c4n and sz+2c5n formed a salt and co-crystal respectively and showed vast differences between the
two in terms of packing and synthons despite being isomers of each other. Finally the DSC showed that
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Page 28 of 41
the multi-component crystals have different melting points from each other and the co-formers that
make it up. Thus, co-formers containing the carboxyl group have great potential for forming a multi-
component crystal with sz. Therefore sz could prove useful as a potential co-former itself for
compounds or even other API’s which feature carboxylic acid functional groups.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
References
(
1) Blagden N., de Matas M., Gavan P.T., York P., Crystal engineering of active pharmaceutical
ingredients to improve solubility and dissolution rates., Advanced Drug Delivery Reviews, 2007, 59,
17 – 630
6
(2) Pouton C.W., Formulation of poorly water-soluble drugs for oral administration: Physicochemical
and physiological issues and the lipid formulation classification system, European Journal of
Pharmaceutical Sciences, 2006, 29, 278-287
(3) Schultheiss N., Newman A., Pharmaceutical Cocrystals and Their Physicochemical Properties
Crystal Growth & Design, 2009, 9, 2950–2967
(4) Vishweshwar P., Mcmahon J., Bis J.A., Zaworokto M.J., Pharmaceutical co-crystals., J. Pharm Sci,
2
006, 95, 499-516
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