Modulating the solubility of sulfacetamide by means of cocrystals

Article abstract of DOI:10.1039/c4ce00103f

Sulfacetamide is a popular antibiotic prescribed for treating ocular infections. However, various physiological constraints are known to reduce its concentration at the site of action, thereby limiting its therapeutic efficacy. In this crystal engineering study, we report novel cocrystals of sulfacetamide with the objective to lower the solubility of the reference drug and improve its residence time at the site of action. Standard cocrystallization methods resulted in cocrystals with caffeine, isonicotinamide, theophylline, bipyridine and a salt with 4-aminopyridine. These crystalline forms were characterized by thermal, spectroscopic and diffraction techniques. In pH 7 phosphate buffer medium, sulfacetamide-caffeine cocrystal exhibited lower solubility (8.64 g L^-1, 0.69 times) than the drug (12.5 g L^-1). The dissolution of sulfacetamide-isonicotinamide and sulfacetamide-caffeine is 0.64 and 0.68 times lower, whereas sulfacetamide-theophylline is comparable to the reference drug. This study highlights a less explored application of pharmaceutical cocrystals to reduce the solubility and dissolution rate of the drug for improved therapeutic action. the Partner Organisations 2014.

Full text of DOI:10.1039/c4ce00103f

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Modulating the solubility of sulfacetamide by
means of cocrystals†
Cite this: CrystEngComm, 2014, 16,
5859
*
N. Rajesh Goud, Ronaq Ali Khan and Ashwini Nangia
Sulfacetamide is a popular antibiotic prescribed for treating ocular infections. However, various physiological
constraints are known to reduce its concentration at the site of action, thereby limiting its therapeutic
efficacy. In this crystal engineering study, we report novel cocrystals of sulfacetamide with the objective to
lower the solubility of the reference drug and improve its residence time at the site of action. Standard
cocrystallization methods resulted in cocrystals with caffeine, isonicotinamide, theophylline, bipyridine and
a salt with 4-aminopyridine. These crystalline forms were characterized by thermal, spectroscopic and
diffraction techniques. In pH 7 phosphate buffer medium, sulfacetamide–caffeine cocrystal exhibited lower
solubility (8.64 g L−1, 0.69 times) than the drug (12.5 g L−1). The dissolution of sulfacetamide–isonicotinamide
and sulfacetamide–caffeine is 0.64 and 0.68 times lower, whereas sulfacetamide–theophylline is comparable
to the reference drug. This study highlights a less explored application of pharmaceutical cocrystals to
reduce the solubility and dissolution rate of the drug for improved therapeutic action.
Received 15th January 2014,
Accepted 10th March 2014
DOI: 10.1039/c4ce00103f
www.rsc.org/crystengcomm
which is often inconvenient to patients and also amounts to
excess drug loading.
Introduction
Sulfacetamide (SACT, hereafter) belongs to the class of sul-
fonamide antibiotics. It is a frontline drug for the treatment
of various ocular infections like trachoma, blepharitis,
conjunctivitis and corneal ulcer.1 It has been investigated as
a therapeutic agent for the treatment of pityriasis versicolor
and rosacea.2 Recent reports indicate that it may also act
Remington's6 pharmacy reference suggests that preparing
a less soluble form of a high solubility drug is a convenient
method for producing extended release dosage forms. Numer-
ous groups have evaluated extended release systems such as
bioadhesive microspheres5a and polymeric nanosuspensions5b
to overcome the limitations of SACT and improve its residence
time and therapeutic efficacy at the site of action. Nonetheless,
these modifications were not suitable for potential marketing.
Entrapment of the drug in a polymeric matrix resulted in poor
bioavailability of the drug.5b Pharmaceutical cocrystallization,7
a process by which a drug molecule and a GRAS coformer
(generally regarded as safe)8 are brought together into a single
crystal lattice, is now an established method to prepare novel
solid-state forms of APIs with tailored physicochemical
properties. The Cambridge Structural Database (CSD, ver. 5.34,
November 2013 update) contains sodium and silver salts of
SACT,9a,b a cocrystal with caffeine,9c and our recent report on
polymorphic cocrystals with acetamide.9d These solid forms
were not investigated for their potential application in address-
ing excessive elimination issues of the drug. We hypothesized
that the hydrogen bonding synthons in the crystal structure of
sulfacetamide (CSD refcode SLFNMG01)9e could be modified
in a graded manner, i.e. the weaker hydrogen bonding interac-
tions in its crystal structure are replaced with stronger hydro-
gen bonds and better crystal packing with coformers to obtain
stable cocrystals. In turn, these cocrystals may be useful to
lower the solubility of the parent drug. These novel cocrystals
were tested in vitro for their potential to lower the solubility
as an antifungal drug through
a CYP51A1-independent
mechanism.3 It is a bacteriostatic agent with a similar activity
against both gram-positive and gram-negative bacteria. SACT
has a high solubility of 12.5 g L−1.4 However, the therapeutic
efficacy of SACT in treating eye infections is severely limited
by physiological constraints such as tear flow and reflex
blinking which results in considerable drug loss. Such a
washout rate reduces the concentration of the drug to one-
tenth of its starting value in 4–20 min after administration.5
As a result, only a few percent of the drug dose is absorbed
by the eye, and therefore, the duration of the therapeutic
action is very short. This necessitates frequent administration
of doses for maintaining optimal therapeutic levels of the drug,
School of Chemistry, University of Hyderabad, Prof. C. R. Rao Road, Gachibowli,
Central University P.O., Hyderabad 500 046, India.
E-mail: ashwini.nangia@gmail.com
† Electronic supplementary information (ESI) available: HPLC plots of SACT
and coformers (Fig. S1), list of compounds used for cocrystal formation (Table S1),
sulfacetamide degradation product (Scheme S1), PXRD of cocrystals (Fig. S2),
IR and Raman spectra (Fig. S3 and S4), IR, Raman and ss-NMR peak values
(Tables S2–S4), PXRD plots of post solubility/dissolution experiments (Fig. S5).
CCDC 981352–981356. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c4ce00103f
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and dissolution rate of the drug, altering its half life, and
improved bioavailability of SACT, akin to a slow release formu-
lation.10 A recent report on the pharmaceutical cocrystals of
epigallocatechin-3-gallate (EGCg)11 lends credence to our
hypothesis. Zaworotko and coworkers11 showed that cocrystals
of EGCg exhibited lower solubility compared to the parent drug
resulting in significant alteration in the pharmacokinetic
profile and improved bioavailability. Similar implications were
echoed by Higuchi and Pitman12 almost four decades ago on
the oral bioavailability of caffeine in low-solubility complexes
with gentisic acid. Mechanochemical grinding,13 slurry
grinding and solution crystallization techniques were used to
screen SACT with various GRAS coformers which resulted in
novel cocrystals with theophylline (THEO), isonicotinamide
(INIC), caffeine (CAF), bipyridine (BIP) and a salt with
4-aminopyridine (4AP) (Scheme 1). The crystallization, charac-
terization, solubility and dissolution rate of SACT cocrystals are
discussed in this article.
and DSC. 30 mg of this material was dissolved in 5 mL EtOH
and left for slow evaporation under ambient conditions.
Single crystals suitable for X-ray diffraction were obtained after
3–4 days. The same cocrystal was also obtained by manual
grinding of SACT and CAF in a 1 : 1 stoichiometric ratio for 30 min.
SACT–INIC cocrystal. SACT (214.2 mg) and INIC (244.24 mg)
in a 1 : 2 molar ratio were slurry ground in 2.5 mL of toluene
and 1.5 ml of EtOAc solvent mixture for 24 h. The formation of
cocrystal was confirmed by PXRD and DSC. 30 mg of this
material was dissolved in 4 mL of 1 : 1 mixture of toluene and
ethyl acetate solvent mixture and left for slow evaporation
under ambient conditions. Single crystals suitable for X-ray
diffraction were obtained after 4–5 days. The same cocrystal
was also obtained by manual grinding of SACT and INIC in a
1 : 2 stoichiometric ratio for 30 min.
SACT–THEO cocrystal. SACT (214.2 mg) and THEO (180.2 mg)
in a 1 : 1 molar ratio were slurry ground in 4 mL of i-PrOH for
24 h. The formation of cocrystal was confirmed by PXRD and
DSC. 30 mg of this material was dissolved in 4 mL of i-PrOH and
left for slow evaporation under ambient conditions. Single crys-
tals suitable for X-ray diffraction were obtained after 4–5 days.
SACT–4AP salt. SACT (214.2 mg) and 4AP (94.11 mg) in a
1 : 1 molar ratio were manually ground for 30 min. Salt
formation was confirmed by PXRD and DSC. 30 mg of this
material was dissolved in 4 mL of EtOH and left for slow
evaporation under ambient conditions. Single crystals suitable
for X-ray diffraction were obtained after 3–4 days.
Experimental section
SACT and coformers (purity > 99.8%) were purchased from
Sigma-Aldrich (Hyderabad, India). Solvents (purity > 99%)
were purchased from Hychem Laboratories (Hyderabad,
India) for crystallization experiments. Water and solvents
(HPLC grade) were purchased from Merck Chemicals (Bangalore,
India) for solubility and dissolution experiments.
Preparation of SACT cocrystals
X-ray crystallography
SACT–BIP cocrystal. SACT (214.2 mg) and 4,4′-BIP (78.0 mg)
in a 1 : 0.5 molar ratio were slurry ground in 5 mL of EtOH for
8 h. The formation of cocrystal was confirmed by PXRD and
DSC. 30 mg of this material was dissolved in 5 mL EtOH and
left for slow evaporation under ambient conditions. Single
crystals suitable for X-ray diffraction were obtained after 3–4 days.
The same cocrystal was also obtained by manual grinding of
SACT and BIP in a 1 : 0.5 stoichiometric ratio for 30 min.
SACT–CAF cocrystal. SACT (214.2 mg) and CAF (194.2 mg)
in a 1 : 1 molar ratio were slurry ground in 4 mL of EtOH for
24 h. The formation of cocrystal was confirmed by PXRD
Crystal structures of SACT–CAF, SACT–4AP and SACT–THEO
were collected on a Bruker SMART APEX-CCD diffractometer.
Mo-Kα (λ = 0.71073 Å) radiation was used to collect X-ray
reflections on a single crystal. While data on SACT–CAF and
SACT–THEO were collected at 100 K, data on SACT–4AP were
collected at 298 K. Data reduction was performed using the
Bruker SAINT software.14a Intensities for absorption were
corrected using SADABS.14b Crystal structures were solved by
direct methods and refined on F2 with SHELXS-97 and
SHELXL-97 programs to give satisfactory R factors.14c,d X-ray
reflections on SACT–BPN and SACT–INIC cocrystals were
collected on an Xcalibur Gemini EOS CCD diffractometer14e
(Oxford Diffraction, Yarnton, UK) using Mo-Kα radiation at
298 K. Data reduction was performed using CrysAlisPro
(version 1.171.33.55). OLEX2-1.014f and SHELX-TL 97 were
used to solve and refine the reflections data. Non-hydrogen
atoms were refined anisotropically. Hydrogen atoms on O
and N were experimentally located in difference electron
density maps. All C–H atoms were fixed geometrically using
HFIX command in SHELX-TL. A check of the final CIF
file using PLATON14g did not show any missed symmetry.
X-Seed14h,i was used to prepare packing diagrams.
Powder X-ray diffraction
Powder X-ray diffraction of the samples were recorded on a
Scheme 1 Sulfacetamide and coformers in this study. Compound
abbreviations are used throughout the paper.
Bruker D8 Focus diffractometer using Cu-Kα X-radiation
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(λ = 1.5406 Å) at 40 kV and 30 mA. Diffraction patterns were
collected over a 2θ range of 5–50° at a scan rate of 1° min−1.
standards. Equilibrium solubility was determined in pH 7
phosphate buffer using
a
shake-flask method.15 Excess
amount of powdered material was added to 5 ml of the buffer
solution, and the resulting suspension was stirred at room
temperature for 24 h. The suspension was filtered through a
0.45 μm syringe filter, and the concentration of the resultant
solution was determined. Intrinsic dissolution rate (IDR)
measurements were carried out on a USP-certified Electrolab
TDT-08L dissolution tester by using the disk intrinsic dissolu-
tion method. For IDR experiments, 500 mg of pure SACT and
the cocrystals were taken in the intrinsic attachments and
compressed to a 0.5 cm2 disk using a hydraulic press at a
pressure of 2.5 ton per inch2 for 5 min. The intrinsic attach-
ments were placed in jars of 900 mL of pH 7 phosphate
buffer preheated to 30 °C and rotated at 150 rpm. 5 ml
aliquots were collected at specific time intervals, and concen-
trations of the aliquots were determined with proper dilution
from the predetermined calibration curves. The linear region
of the dissolution profile (regression > 0.99) was used to
determine the IDR of the compound as [slope of the amount
dissolved ÷ surface area of the pellet] per unit time. There
was no transformation of SACT or cocrystals upon tablet
compression as confirmed by PXRD.
Vibrational spectroscopy
A Nicolet 6700 FT-IR spectrometer with an NXR FT-Raman
and NIR Module was used to record IR and Raman spectra.
IR spectra were recorded on samples dispersed in KBr pellets.
Raman spectra were recorded on samples contained in stan-
dard NMR diameter tubes or on compressed samples
contained in a gold-coated sample holder.
Thermal analysis
DSC was performed on a Mettler Toledo DSC 822e module.
3–5 mg of sample was used for this characterization. Samples
were placed in sealed pin-pricked aluminum pans and char-
acterized at a heating rate of 5 °C min−1 in the temperature
range of 30–250 °C. Samples were purged by a stream of dry
nitrogen flowing at 80 mL min−1.
Solid-state NMR spectroscopy
Solid-state 13C NMR spectra were recorded on a Bruker
Avance 400 MHz spectrometer (Bruker-Biospin, Karlsruhe,
Germany), operating at 100 MHz for 13C nucleus. ss-NMR
measurements were carried out on a Bruker 4-mm double
resonance CP-MAS probe in zirconia rotors with a Kel-F cap
at a 5.0 kHz spinning rate with a cross-polarization contact
time of 2.5 ms and a delay of 8 s. 13C NMR spectra were
recorded at 100 MHz and referenced to the methylene
carbon of glycine and then recalibrated to the TMS scale
(δglycine = 43.3 ppm).
Results and discussion
The supramolecular synthon strategy16 guided by hydrogen
bonding rules17 is the primary design element for the con-
struction of multi-component cocrystals. Based on the nature
of the functional groups in a drug molecule, coformers with
complementary functional moieties were selected so as to
optimize strong and robust synthons.18 The primary func-
tional groups in SACT are amide and amine moieties. In the
literature, functional moieties of COOH, CONH2, N-oxide,
pyridine, etc. have been reported to assemble with amide
containing molecules. Accordingly, SACT was cocrystallized
with GRAS coformers containing the above-mentioned func-
tional groups. A complete list of all the coformers is listed in
Table S1, ESI.† Surprisingly, we did not obtain any cocrystals
with COOH containing coformers which have 48% probability
of heterosynthon formation with the amide functional
group,19 but instead the cocrystals are sustained by hydrogen
bonding with the amide and pyridine coformers, which
have a CSD probability of 35% and 4% for the respective
synthons.19c In addition, the cocrystals contained multiple
molecules in the asymmetric unit and variable stoichiometry:
SACT–CAF (1 : 1), SACT–INIC (1 : 2), SACT–THEO (2 : 2),
SACT–BIP (1 : 0.5) and SACT–4AP (1 : 1). These cocrystals have
different Z″ (Z″ = sum of Z′ values in multi-component
crystals)20 in their crystal structures (Table 1). The X-ray
crystal structure of SACT–CAF was redetermined with better
R-factor. Hydrogen bond parameters are listed in Table 2.
Solubility and dissolution
The solubility and dissolution experiments were performed
using the HPLC method. Prior to estimating solubility and
dissolution rates, calibration curves were determined for each
compound. Various dilutions of a stock solution of SACT and
cocrystals in pH 7 phosphate buffer were made and their
respective retention times were determined using HLPC at
λmax = 254 nm (λmax of SACT). By plotting the known concen-
tration of each dilution vs. the corresponding area, a calibra-
tion curve for each compound was obtained. HPLC was done
on the Shimadzu Prominence model LC-20AD equipped with
a PDA detector and a C-18G column (250 mm × 4.6 mm ID,
5 μm particle size and 120 Å pore size). Elution was achieved
by a mobile phase made up of 85 : 15 ratio of water with 1%
acetic acid: methanol in an isocratic method. The retention
times of standard aqueous solutions of SACT, CAF, THEO
and INIC were found to be 8.2, 41.4, 22.2 and 3.6 min,
respectively, and the same were observed even for the
cocrystals (Fig. S1†). SACT has 73.3, 42.3 and 66.4% contribu-
tion in SACT–CAF, SACT–INIC and SACT–THEO cocrystals.
The quantification of SACT in test solutions obtained from
equilibrium solubility and dissolution experiments was done
by comparison of the HPLC peak area with that of the
Crystal structures
Sulfacetamide–bipyridine (SACT–BPN) cocrystal. This cocrystal
structure contains 1 molecule of SACT and half molecule of
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Table 1 Crystallographic parameters of SACT cocrystals
SACT–BPN (1 : 0.5)
SACT–CAF (1 : 1)
SACT–INIC (1 : 2)
SACT–THEO (2 : 2)
SACT–4AP (1 : 1)
Emp form
Form wt
Cryst syst
Sp gr
C13H14N3O3S
292.33
Monoclinic
P21/n
C16H20N6O5S
408.44
Monoclinic
P21/c
C20H22N6O5S
458.50
Monoclinic
P21/n
C15H18N6O5S
394.41
Triclinic
¯
P1
C13H16N4O3S
308.36
Monoclinic
P21/c
T (K)
a (Å)
b (Å)
c (Å)
α (°)
β (°)
γ (°)
Z
298(2)
11.6469(9)
10.4670(6)
12.4421(9)
90
116.510(10)
90
4
100(2)
7.1821(6)
30.430(3)
8.8188(7)
90
107.6790(10)
90
4
298(2)
10.7667(4)
9.7508(4)
21.1014(7)
90
96.176(3)
90
4
100(2)
298(2)
7.7413(7)
17.8726(16)
11.0065(10)
90
97.8790(10)
90
4
8.6640(7)
14.9675(13)
15.3632(15)
110.234(2)
106.3650(10)
97.2830(10)
4
Z″
1.5
1357.31(17)
1.431
4882
2315
1910
183
0.0404
0.1131
1.035
2
3
4
2
V (Å3)
1836.3(3)
1.477
18 761
3579
3358
269
0.0436
0.1158
1.074
2202.45(14)
1.383
7836
3762
3002
1737.1(3)
1.508
18 179
6823
5929
1508.5(2)
1.358
15 456
2992
2698
211
0.0496
0.1226
1.191
Cryst density (g cm−3
Rflns. collect
Unique rflns.
Obsd. rflns.
Parameters
R1
)
318
525
0.0407
0.1057
1.065
0.0505
0.1297
0.953
wR2
GOF
BPN in the asymmetric unit. SACT molecules are arranged
along the 21 screw axis connected through N–H⋯O hydrogen
bonds (2.44 Å, 124°). Such screw related helices of
SACT molecules are bridged by BPN coformer molecules
through a N–H⋯N interaction (2.10 Å, 153°; Fig. 1a). These
H bonds extend the SACT and BPN molecules in a 2D
arrangement, with a C–H⋯O interaction connecting the
layers (Fig. 1b and c). The hydrogen bonds in this and the
subsequent crystal structure are generally weaker/longer than
standard N–H⋯O/O–H⋯O hydrogen bond distances but
comparable to the previous study on the same system.9d
Sulfacetamide–caffeine (SACT–CAF) cocrystal. This 1 : 1
stoichiometric cocrystal was obtained by slow evaporation
from EtOH. SACT molecules are connected in a chain along
the c-axis through N–H⋯O hydrogen bond (2.18 Å, 172°).
Adjacent layers of SACT molecules are bridged by two CAF
molecules connected through N–H⋯O and N–H⋯N H-bonds
(2.07 Å, 170°; 2.12 Å, 175°; Fig. 2a). Such discrete units are
connected through C–H⋯O interactions (2.28 Å, 163°; Fig. 2b).
Sulfacetamide–isonicotinamide (SACT–INIC) cocrystal.
Initially, single crystals of this 1 : 2 cocrystal were obtained by
crystallizing a 1 : 1 molar ratio of SACT and INIC along with a
few crystals of SACT from toluene–ethyl acetate solvent
mixture. The stoichiometry was optimized by crystallizing
SACT and INIC in a 1 : 2 ratio which resulted in complete
conversion of the starting materials to the cocrystal. The
crystal structure could well have had the expected 1 : 1
stoichiometry. It is as though the second molecule of INIC
resides in the crystal structure as a linear spacer dimer
connecting the SACT–INIC units (symmetry independent
INIC molecules are shaded differently). Unlike previous
structures, SACT molecules in this cocrystal form dimer like
discrete units (2.11 Å, 179°) which are connected through an
INIC dimer N–H⋯O hydrogen bond (2.06 Å, 166°, 2.15 Å, 164°).
SACT molecules self-assemble through an R22(8) ring motif21
(2.06 Å, 166°; Fig. 3a). Such 1D units of SACT and INIC
are connected through a N–H⋯O (2.03 Å, 168°; Fig. 3b)
hydrogen bond.
Sulfacetamide–theophylline (SACT–THEO) cocrystal. This
equimolar stoichiometry cocrystal was obtained when SACT
and THEO in a 1 : 1 ratio were dissolved in i-PrOH and left
for evaporation. SACT molecules extend as a chain along the
a-axis through N–H⋯O H bond in each pair (2.13 Å, 174°;
2.17 Å, 171°). Adjacent chains of SACT molecules are
connected by THEO molecules through N–H⋯O and N–H⋯N
H bonds (Fig. 4). The crystallographically nonequivalent pairs
of SACT and THEO molecules behaving as distinct entities of
1 : 1 cocrystal domains are connected through a C–H⋯O
interaction (2.51 Å, 143°).
Sulfacetamide–4-aminopyridine (SACT–4AP) salt. Solution
crystallization of SACT and 4AP in 1 : 1 stoichiometry resulted
in a salt with proton transfer from the amide N–H of SACT
to the pyridyl nitrogen of 4AP. The amide nitrogen is
sandwiched between the electron-withdrawing carbonyl and
sulfonyl groups and is acidic enough with a pKa of 4.3 to
transfer its proton to the basic nitrogen of 4AP (pKa = 8.95).
The ΔpKa value (ΔpKa = 4.65) is in the normal proton transfer
range according to the ‘rule of three’.22 Screw related SACT
molecules are bonded by N–H⋯O (2.19 Å, 166°) H bonds
which are connected to 4AP by N–H⋯N− (1.87 Å, 178°) and
N–H⋯O (1.97 Å, 164°) H bonds (Fig. 5).
Thermal analysis
DSC analyses of SACT cocrystals showed unique thermal
behavior in comparison to their starting materials (Fig. 6).
The purity of all the cocrystals was indicated by a single,
sharp melting endotherm in DSC. Unlike reported cocrystal
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Table 2 Hydrogen bond distances and angles in SACT cocrystals (neutron-normalized N–H 1.009 Å, O–H 0.983 Å, and C–H 1.083 Å distances)
D–H⋯A
D⋯A (Å)
H⋯A (Å)
D–H⋯A (°)
Symmetry code
SACT–BPN (1 : 0.5)
N1–H1B⋯O3
N2–H2⋯N3
3.008(3)
2.889(3)
2.956(3)
3.399(4)
2.44
2.10
2.60
2.44
124
153
103
178
3/2 − x, −1/2 + y, 1/2 − z
1/2 − x, 1/2 + y, 1/2 − z
a
C2–H2A⋯O1
C8–H8A⋯O2
SACT–CAF (1 : 1)
N1–H1A⋯N5
N2–H2A⋯O1
N2–H2B⋯O5
C6–H6⋯O1
—
1/2 − x, 1/2 + y, 1/2 − z
2.842(2)
2.991(2)
2.941(3)
2.936(2)
3.197(3)
2.755(3)
2.12
2.18
2.07
2.59
2.28
2.29
175
172
170
102
163
108
1 + x, y, 1 + z
x, y, −1 + z
1 − x, −y, −z
a
—
C13–H13⋯O3
C15–H15B⋯O4
SACT–INIC (1 : 2)
N1–H1⋯N3
−1 + x, 1/2 − y, −1/2 + z
a
—
2.852(2)
2.920(3)
3.109(4)
3.092(2)
2.982(2)
2.941(3)
2.961(2)
3.142(3)
3.369(3)
3.299(3)
2.00
2.06
2.49
2.26
2.11
2.03
2.15
2.48
2.44
2.54
177
166
131
169
179
168
164
126
173
139
1/2 − x, −1/2 + y, 1/2 − z
−x, −y, −z
N2–H2A⋯O3
N2–H2B⋯N2
N4–H4A⋯O5
N4–H4B⋯N5
N6–H6A⋯O4
N6–H6B⋯O5
C8–H8A⋯O1
C10–H10⋯O5
C13–H13⋯O2
SACT–THEO (2 : 2)
N1–H1⋯N11
N2–H2A⋯O1
N2–H2B⋯O10
N3–H3A⋯O5
N3–H3B⋯O8
N4–H4⋯N7
−x, 1 − y, −z
1 − x, −y, −z
−1/2 + x, 1/2 − y, −1/2 + z
1 − x, 1 − y, −z
1 − x, −y, −z
1/2 − x, −1/2 + y, 1/2 − z
1 − x, −y, −z
x, 1 + y, z
2.797(3)
3.026(3)
2.868(3)
2.969(3)
2.886(3)
2.812(3)
2.791(3)
2.803(3)
2.896(3)
3.344(3)
2.943(3)
3.184(3)
3.137(3)
3.251(3)
2.739(3)
3.316(3)
3.200(2)
3.307(3)
2.722(3)
2.761(3)
2.00
2.17
2.04
2.13
2.07
2.00
1.95
1.95
2.52
2.51
2.58
2.55
2.37
2.43
2.30
2.49
2.50
2.43
2.37
2.37
165
171
169
174
157
163
174
177
104
143
103
123
137
145
106
142
130
153
100
103
2 − x, −y, 1 − z
−1 + x, y, z
1 − x, 1 − y, 1 − z
1 + x, y, z
2 − x, 1 − y, 1 − z
−1 + x, y, z
N8–H8D⋯O6
N12–H12A⋯O3
C2–H2⋯O2
−1 + x, y, z
1 − x, −y, 1 − z
a
—
C8–H8A⋯O4
C14–H14⋯O4
C16–H16A⋯O4
C21–H21⋯O4
C21–H21⋯O6
C22–H22B⋯O7
C23–H23A⋯O8
C28–H28⋯O2
C28–H28⋯O3
C29–H29B⋯O9
C30–H30A⋯O10
SACT–4AP (1 : 1)
N2–H2A⋯O1
N2–H2B⋯O2
N3–H3A⋯N1
N4–H4A⋯O3
C2–H2⋯O2
x, −1 + y, z
a
—
1 − x, 1 − y, −z
1 − x, 1 − y, −z
1 − x, 1 − y, −z
a
—
1 − x, 1 − y, 1 − z
x, y, 1 + z
x, y, 1 + z
a
—
a
—
3.146(3)
2.999(4)
2.783(3)
2.806(3)
2.914(3)
3.337(3)
2.41
2.19
1.87
1.97
2.54
2.46
153
166
178
164
105
157
1 − x, −1/2 + y, 1/2 − z
x, 1/2 − y, 1/2 + z
1 − x, −1/2 + y, 1/2 − z
1 + x, y, z
a
—
C5–H5⋯O3
x, 1/2 − y, 1/2 + z
a
Intramolecular hydrogen bond.
case studies,7a,23 we did not observe a correlation between
the melting points of SACT cocrystals with those of the
coformers (Table 3). In the DSC thermograms of SACT,
SACT–CAF and SACT–THEO, an extra decomposition hump
after the usual melting endotherm was observed due to
the degradation of SACT to sulfanilamide and acetic
acid (Scheme S1†) at high temperature.6,24 The observed
decomposition peak in the thermograms is probably due to
this degradation.
Powder X-ray diffraction
Powder X-ray diffraction is a reliable technique to establish
the unique diffraction patterns of a novel solid form in
comparison to the starting materials.25a It is the method of
choice for those cases where single crystals are not available
by crystallization. Its application has been diversified with
the detection of polymorphic impurity in a mixture of
polymorphs, bulk purity of polymorphs, cocrystals or salts,
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Fig. 1 a) Screw-axis related SACT molecules are bridged by BPN molecules. b) Adjacent layers connected through C–H⋯O interactions
(highlighted by a circle, top view). c) Adjacent layers connected through C–H⋯O interactions (highlighted by a circle, side view).
amorphous content in a crystalline material and structure
solution of a crystalline material from powder diffraction
data.25 PXRD was used to establish the bulk purity of SACT
cocrystals. The experimental powder patterns of bulk mate-
rials of cocrystals showed excellent match when stacked with
their calculated patterns (Fig. S2†).
Vibrational spectroscopy
The nature of hydrogen bonding and the extent of ionization
can invariably influence the vibrational energy levels of com-
pounds on forming cocrystals or salts. IR and Raman spectra
are sensitive to such changes, being able to identify and dis-
tinguish novel solid forms from their starting components.26a
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Fig. 2 a) Linear chains of SACT molecules bridged through CAF coformer molecules (only one layer of CAF molecules is shown for clarity). b)
Discrete units of SACT and CAF molecules are connected through C–H⋯O hydrogen bonds (marked by a circle). The CH3CO– group of SACT
which blocks the C–H⋯O hydrogen bond (marked by a circle) is deleted for clarity.
In the IR spectrum of SACT, the N–H asymmetric and sym-
metric stretching frequencies appeared at 3471.2, 3380.7 and
3257.0 cm−1. The amide carbonyl stretch was observed at
1685.7 cm−1 and the N–H bending mode at 1596.4 cm−1.
Significant changes in these vibrational modes were observed
upon the formation of the cocrystal/salt (Fig. S3†). In the
Fig. 3 a) SACT molecules are connected through INIC coformers. The crystallographically nonequivalent INIC molecules are distinguished by
cap-stick and ball-stick models. b) N–H⋯O hydrogen bond connects the 1D units of SACT and INIC.
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Fig.
6
Heating curves of SACT cocrystals depicting their unique
melting behavior.
at 3441.7, 3358.1 and 3255.8 cm−1 in SACT–CAF, they showed
up at 3428.4, 3396.6, 3345.9 and 3239.2 cm−1 in SACT–INIC
and 3471.3 and 3380.8 cm−1 in SACT–THEO. The corresponding
carboxamide CO stretch was observed at 1702.0 and
1658.7 cm−1 in SACT–CAF, 1697.2 and 1674.2 cm−1 in
SACT–INIC, and 1716.1 and 1667.8 cm−1 in SACT–THEO.
Larger shifts in the N–H stretching frequencies were observed
in the case of SACT–4AP where proton transfer from amide
N–H to pyridyl nitrogen resulted in salt. The N–H stretching
frequencies here were observed at 3444.4, 3422.9, 3350.3
and 3242.0 cm−1 and the carboxamide –CO stretch at
1656.2 cm−1. Major FT-IR vibrational frequencies of SACT
cocrystals are shown in Table S2.†
Fig. 4 a) Linear chain of SACT molecules are bound through THEO
coformer molecules. The methyl groups of THEO molecules are
deleted for clarity. b) Discrete pairs of SACT and THEO molecules are
connected through a C–H⋯O interaction.
SACT–BPN cocrystal, the N–H stretching modes shifted to
3475.6 and 3375.3 cm−1. While the N–H bending modes
moved to 1594.0 cm−1, the amide –CO stretch appeared at
1704.1 cm−1. On forming cocrystal, the CN stretch of BPN
shifted from 1407.3 cm−1 to 1409.9 cm−1. Similar differences
were also observed in the stretching and bending modes of
other cocrystals. While the N–H stretching frequencies appeared
The complementary Raman spectra26b where the symmetric
stretching frequencies have stronger intensities compared to
the asymmetric modes showed significant shifts in the Raman
intensities on forming the product cocrystal/salt. The Raman
Fig. 5 SACT molecules are connected by 4AP through N–H⋯O and N–H⋯N− H-bonds.
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Table 3 Melting points of SACTa salt/cocrystals and the coformers
SACT cocrystals were performed in pH 7 phosphate buffer
medium and the samples were analyzed by HPLC using a
PDA detector. Equilibrium solubility experiments were
performed for 24 h by making a supersaturated solution of
SACT cocrystals in phosphate buffer medium at pH 7. These
experiments showed that SACT–CAF is stable under equilib-
rium solubility conditions over 24 h, but SACT–INIC and
SACT
Melting
Melting
S. no
cocrystal/salt
point (°C)
Coformer
point (°C)
1
2
3
4
5
SACT–BPN
SACT–CAF
SACT–INIC
SACT–THEO
SACT–4AP
211–213
179–181
119–121
169–171
156–158
4,4′-Bipyridine
Caffeine
Isonicotinamide
Theophylline
4-Aminopyridine
110–114
238–240
155–157
272–274
155–156
a
The M.P. of SACT is 183–185 °C.
intensities for asymmetric and symmetric N–H and CO
stretching frequencies appeared at 3479.5, 3380.7 and
1688.0 cm−1, respectively. These peak positions showed a sig-
nificant shift in the cocrystals/salt. While the N–H asymmetric
and symmetric intensities appeared at 3475.5 and 3377.1 in
SACT–BPN, 3443.3, 3358.2, and 3256.3 in SACT–CAF, 3472.4
and 3381.6 cm−1 in SACT–THEO and 3445.2, 3426.4, 3354.2,
and 3243.8 cm−1 in SACT–4AP, the corresponding –CO
stretch was observed at 1707.1 cm−1 in SACT–BPN, 1703.4 cm−1
in SACT–CAF, 1699.7 cm−1 in SACT–INIC, and 1708.3 cm−1 in
SACT–THEO (Fig. S4†). The important FT-Raman peaks are
shown in Table S3.†
Solid state NMR spectroscopy
ss-NMR is gaining importance as a routine technique for
characterizing pharmaceutical solids because of its sensitivity
to changes in hydrogen bonding interactions and molecular
conformation.27 It is a non-destructive method necessitating
a minimum amount of sample for characterization. 13C
ss-NMR of SACT cocrystals showed significant differences in
chemical shifts in comparison to their individual compo-
nents. The CO carbon of SACT appeared at δ 171.8 ppm,
whereas this peak appeared at 170.7 ppm in SACT–BPN,
171.2 ppm in SACT–CAF, 170.5 ppm in SACT–INIC,
171.3 ppm in SACT–THEO and 170.9 ppm in SACT–4AP due
to changes in hydrogen bonding and local environment.
The remaining carbon nuclei appear at different chemical
shifts to distinguish from the starting components (Fig. 7
and Table S4†).
Solubility and dissolution
The primary objective of developing cocrystals of SACT was to
address the poor residence time of the drug at the site of
action due to its rapid elimination. We reasoned that modu-
lating the hydrogen bonding in the parent drug structure
with appropriate coformers would result in cocrystals with
stronger hydrogen bond synthons and better crystal packing,
and the stable crystal lattice would lower the solubility of
SACT and prolong its residence time at the ocular surface.
In terms of crystal density, which is a good indicator of
molecular packing in the crystal lattice, the density of SACT
cocrystals is higher than that of sulfacetamide (1.377 g cm−3).
Given the high aqueous solubility of 12.5
g
L−1 for
Fig. 7 Overlay of 13C ss-NMR spectra of SACT cocrystals with the
individual components.
sulfacetamide,4 solubility and dissolution experiments on
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SACT–THEO are less stable and dissociated to their individ-
ual components and precipitated SACT out of the solution.
The solubility of stable SACT–CAF cocrystal is 8.64 g L−1
(0.7 times) compared to that of SACT at 12.5 g L−1, indicating
that the thermodynamic solubility of SACT can be lowered by
forming a cocrystal with caffeine.
sulfacetamide (see refcode SLFNMG01 in the CSD). However,
in the case of cocrystals, the molecules propagate through
stronger N–H⋯O and N–H⋯N bonds further stabilized by
C–H⋯O interactions (Table 2). Thus, the cocrystals exhibit
better packing efficiency and stronger crystal lattice which
has lower solubility and dissolution compared to SACT. The
solubility of drugs has been controlled by cocrystals.11,12,29
We did not find any correlation between the melting point of
the cocrystal and its solubility.7a PXRD plots of the residue at
the end of the equilibrium solubility and dissolution experi-
ments are shown in Fig. S5.† In summary, the solubility of
SACT is modulated by forming cocrystals with CAF, INIC and
THEO. SACT–CAF cocrystal showed lower solubility and good
stability by in vitro experiments.
Due to the dissociation of SACT cocrystals in equilibrium
solubility measurements, the dissolution experiment (a kinetic
method) was adopted to determine the rate at which the drug
dissolves in the solution. The intrinsic dissolution rate (IDR)
is particularly useful in determining the solubility of the
metastable forms before they convert to the more stable
polymorph/hydrate, etc. IDR experiments on SACT cocrystals
were performed in pH 7 phosphate buffer media for 4 h by
the rotating disk intrinsic dissolution rate (DIDR) method28 at
30 °C (Fig. 8 and Table 4). SACT–INIC showed 0.64 times the
IDR of SACT followed by SACT–CAF (×0.68) and SACT–THEO
(×1). SACT and SACT–CAF were stable at the end of the disso-
lution experiment, but SACT–INIC and SACT–THEO cocrystals
dissociated into their individual components precipitating
the parent drug. The low solubility and dissolution of
cocrystals may be rationalized based on their stronger hydro-
gen bonding interactions and better packing efficiency as
compared to SACT. The molecules extend through inter-
molecular N–H⋯O hydrogen bonds supported by a single
auxiliary C–H⋯O interaction in the crystal structure of
Conclusions
The primary aim of this study was to lower the solubility of
SACT which in turn was hypothesized to modify its half life
and improve drug residence time. Even though several
research groups have studied different drug delivery strate-
gies to address this issue, the cocrystallization method is
unique to our study. A solid form screen of SACT resulted in
cocrystals with CAF, INIC, THEO and BIP in addition to a salt
with 4AP. Solubility measurements in pH 7 phosphate buffer
media showed that SACT–CAF cocrystal has low solubility
(0.69 times that of drug) and is stable for 24 h in the buffer
slurry medium. Dissolution experiments in the same media
showed that SACT–INIC and SACT–CAF have 0.64 and 0.68
times the IDR of SACT. The low solubility and good stability
of the SACT–CAF cocrystal may be useful in addressing the
poor residence time and faster elimination issues of SACT
similar to extended release formulations.
Acknowledgements
AN thanks DST (JC Bose Fellowship SR/S2/JCB-06/2009), CSIR
(Pharmaceutical Cocrystals Project 01/2410/10/EMR-II), and
DST-SERB (Novel Solid-State Forms of APIs, SR/S1/OC-37/2011)
for research funding. DST (IRPHA) and UGC (PURSE grant)
are thanked for providing instrumentation and infrastructure
facilities at UoH. N.R.G. and R.A.K. thank the CSIR and UGC
for fellowship.
Fig. 8 Intrinsic dissolution rate curves of SACT cocrystals in pH 7
phosphate buffer.
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