Investigating the Solubilities of the Nitrate and Isomorphous Bromide and Chloride Salts of Dapsone

Article abstract of DOI:10.1021/acs.cgd.9b01467

Dapsone, the major drug for leprosy, has broader application against dermatoses, malaria, and AIDS-related diseases. Besides its antimicrobial/antiprotozoal activity, dapsone has anti-inflammatory properties. However, because of its low aqueous solubility, the high oral doses required and associated side effects limit the tolerability and efficacy of dapsone free base. As a strategy to improve the drug's solubility, new salts of dapsone were prepared. The chloride, bromide, and nitrate salts of dapsone were completely characterized by X-ray diffraction (single and powder), spectroscopic (FT-IR), and thermal (DSC and TGA) techniques. The X-ray results revealed that dapsone chloride and dapsone bromide are isomorphous compounds. Dapsone salts decompose without melting and are thermally less stable than dapsone free base. The equilibrium solubility of dapsone salts was compared to dapsone free base in three aqueous media: HCl buffer pH 1.2, acetate buffer pH 4.5, and phosphate buffer pH 6.8. The highest solubility values were obtained in acid media, and dapsone bromide was found to be slightly more soluble than dapsone free base. The solubility values obtained for the nitrate and chloride salts of dapsone at pH 1.2 cannot be considered real, since the PXRD patterns show their total/partial conversion.

Full text of DOI:10.1021/acs.cgd.9b01467

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Article
Investigating the solubilities of the nitrate and
isomorphous bromide and chloride salts of dapsone
Cristiane Cabral de Melo, Monalisa Bitencourt, Charlane C. Corrêa, and Antonio C. Doriguetto
Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.9b01467 • Publication Date (Web): 20 Feb 2020
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Investigating the Solubilities of the Nitrate and
Isomorphous Bromide and Chloride Salts of
Dapsone
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Cristiane Cabral de Melo*†,‡, Monalisa Bitencourt †, Charlane C. Corrêa §, Antonio C.
Doriguetto*†,‡
†
‡
Faculty of Pharmaceutical Sciences and Institute of Chemistry, Federal University of
Alfenas, 37130-001, Alfenas-MG, Brazil
§Department of Chemistry, Federal University of Juiz de Fora, 36036-900, Juiz de Fora-MG,
Brazil
*Corresponding authors: doriguetto@unifal-mg.edu.br; crisbrizoti@gmail.com
ABSTRACT. Dapsone, the major drug for leprosy, has broader application against
dermatoses, malaria and AIDS-related diseases. Besides its antimicrobial/antiprotozoal
activity, dapsone has anti-inflammatory properties. However, because of its low aqueous
solubility, the high oral doses required and associated side effects limit the tolerability and
efficacy of dapsone free base. As a strategy to improve the drug’s solubility, new salts of
dapsone were prepared. The chloride, bromide and nitrate salts of dapsone were completely
characterized by X-ray diffraction (single and powder), spectroscopic (FT-IR) and thermal
(DSC and TGA) techniques. The X-ray results revealed that dapsone chloride and dapsone
bromide are isomorphous compounds. Dapsone salts decompose without melting and are
thermally less stable than dapsone free base. The equilibrium solubility of dapsone salts was
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compared to dapsone free base in three aqueous media: HCl buffer pH 1.2, acetate buffer pH
4.5 and phosphate buffer pH 6.8. The highest solubility values were obtained in acid media and
dapsone bromide was found to be slightly more soluble than dapsone free base. The solubility
values obtained for the nitrate and chloride salts of dapsone at pH 1.2 cannot be considered
real, since the PXRD patterns show their total/partial conversion.
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Keywords: Leprosy, dapsone salts, isomorphism, thermal behavior, solubility.
1. INTRODUCTION
One of the most important parameters in the process of drug design and pharmaceutical
development, especially for oral-drug delivery systems, is solubility.1 The extensive use of
combinatorial chemistry with high-throughput screening has brought a great number of drugs
with poor solubility into development.2 Together with low permeability, poor solubility is the
main factor behind the incomplete absorption of a drug and therefore of its low or erratic
bioavailability.1,2 To improve drug solubility, several physical or chemical methods have been
used including the reduction of particle size by milling or nanosuspensions, the use of
solubilizing excipients, complexation with cyclodextrins and salt formation, the latter being
most commonly used for drugs containing ionizable groups.1–5 It is well known, and well
documented, that a salt can be prepared in accordance with the pKa rule.6 Although not
formally proven, the pKa rule establishes that when the pKa difference between the salt former
and the drug is greater than 2 or 3 (pKa[protonated base] - pKa[acid] > 2 or 3), salt formation is
expected.6
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Dapsone (4,4’-diaminodiphenyl sulfone, DDS ─ Scheme 1) is a synthetic antibiotic
introduced in the 1940s as a monotherapy for the treatment of Mycobacterium leprae.7,8 Like
other sulfone drugs, dapsone’s mechanism of action involves the interruption of folic acid
synthesis (essential for DNA and RNA synthesis) by inhibition of the bacterial enzyme
dihydropteroate synthase. However, among the sulfone drugs, DDS is the only one which is
effective against M. leprae.7 Currently, leprosy treatment with dapsone alone is contraindicated
and a multi-drug therapy, by combination of dapsone, rifampicin and clofazimine, should be
adopted according to the World Health Organization (WHO) regimen.9 Because of its low
water solubility (0.2 mg.mL-1) and high toxicity, other supramolecular solid forms of DDS,
such as salts and cocrystals, have recently been investigated.8
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DDS is a very weak Lewis base able to form either salts or cocrystals. DDS contains
two ionizable amine groups and can therefore form a monosalt or a disalt compound. The first
acid constant has a pKa of 2.49 for the equilibrium between ammonium (H3N+-aryl) and the
neutral form (H2N-aryl) and the second has a pKa of 1.30 (monosalt-disalt equilibrium).10 It is
curious that besides the potential for salt formation, few salt structures of DDS are known (eight
X-ray structures) and only two have pharmaceutical relevance (the mesylate monohydrate and
the nitrate hemihydrate).11–15 A search for crystallographic forms of DDS in the Cambridge
Structural Database (CSD, v. 5.40, November 2018, update 1, Feb 2019) returned five
polymorphs, one hydrate (with the unusual DDS: water stoichiometry of 3:1), four solvates
with dichloromethane (being two polymorphs), dioxane and tetrahydrofuran and 12 cocrystals
besides the salts structures.16–20
Considering that DDS is a BCS Class II drug, our main interest is the development of
thermally stable and highly soluble DDS salts.21 We chose three acids (HCl, HBr and HNO3)
belonging to the GRAS (generally recognized as safe) category in order to incorporate these
features, and also to synthesize pharmaceutically-acceptable crystalline salts.22 Unfortunately,
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during the course of our experiments, the single-crystal X-ray structure of the nitrate salt was
published.23 Even so, we decided to keep the nitrate salt for comparative purposes and here we
also report, for the first time, the crystal structure of DDS bromide and DDS chloride forms.
The DDS salts were completely characterized using Fourier Transform Infrared Spectroscopy
(FT-IR), Thermogravimetric Analysis (TGA), Differential Scanning Calorimetry (DSC) and
Powder X-ray Diffraction (PXRD) techniques. Finally, this study also presents the equilibrium
solubility of DDS and DDS salts in three different aqueous media.
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Scheme 1. Molecular structure of Dapsone
2. EXPERIMENTAL SECTION
2.1 Samples. DDS was purchased from Sigma-Aldrich Brazil® and used as received. The
solvents (HPLC grade) and the chloride, bromide and nitric acids were obtained from
commercial sources and used as received.
2.2 Synthesis. DDS chloride, DDS bromide and DDS nitrate were prepared by adding 2.0
mL of the corresponding concentrated acid into a saturated ethanolic solution of DDS (20 mL).
The precipitated solid was filtered and recrystallized from an aqueous methanol solution.
2.3 Single crystal X-ray Diffraction. A suitable single crystal of each DDS salt was
selected for processing. Data collection was performed on an Agilent SuperNova
diffractometer, equipped with a dual source of radiation (Cu and Mo) and an Atlas S2 CCD
detector, at room temperature (293 K for DDS bromide and nitrate salts) or low temperature
(200 K for DDS chloride). The data collection routine, unit cell determination and intensity
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data integration were carried out using CrysalisPro software.24 The structures were solved by
direct methods and refined by full-matrix least-squares on F2 using SHELXL-2018/3.25 The
non-hydrogen atoms were refined anisotropically. The hydrogen atoms were placed in
idealized positions and refined using a rigid model, constraining their isotropic displacement
parameters to be equal to 1.2 or 1.5 times the corresponding isotropic displacement parameters
of the bonded atom. The MERCURY (version 3.9) program was used to prepare the artwork
representations for publication.26 The CIFs of these three structures were deposited in the
Cambridge Structural Data Base under the codes CCDC 1963117, CCDC 1963118 and CCDC
1963119.27 Copies of these files may be solicited free of charge via www.ccdc.cam.ac.uk, by
emailing data_request@ccdc.cam.ac.uk or by contacting The Cambridge Crystallographic
Data Centre, CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; Fax + 44 1223-336033.
2.4 Powder X-ray Diffraction (PXRD). To check the authenticity, all samples (DDS and
its salts), as well as the solid residues from the equilibrium solubility measurements, were
subjected to PXRD analysis. The polycrystalline samples were powdered and mounted onto a
sample holder. The milled samples were analyzed using a Rigaku Ultima IV powder
diffractometer with the following experimental conditions: CuK radiation,  = 1.5418 Å; 40
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kV; 30 mA; step scan with a step width of 0.02° over an interval of 3°– 35° in 2; time per step
3s.
2.5 Thermal Analysis. TGA was performed on a TA Instruments Q600. Approximately
10.0 mg of each sample was placed in an open alumina pan and heated from ambient (25 °C)
to 400 °C at a constant rate of 10 °C.min-1 under a N2 flow (50 mL.min-1). A TA Instruments
Q100 model was used to produce DSC curves. The samples (3.00 mg) were heated from room
temperature (30 °C) to the beginning of the decomposition process at a constant rate of 10
°C.min-1 in a closed aluminum pan. The purge gas was N2 under a flow of 50 mL.min-1.
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2.6 Fourier Transform Infrared spectroscopy (FT-IR). The spectra were recorded on a
Shimadzu IR Prestige-21 spectrophotometer, using KBr pellets, in the range of 4000–400 cm-
1, with an average of 64 scans and 4 cm-1 resolution.
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2.7 Equilibrium solubility studies. DDS solubility was determined in three different
aqueous media (HCl buffer pH 1.2, acetate buffer pH 4.5 and phosphate buffer pH 6.8) using
the traditional shake-flask method. The concentrations of DDS and DDS salts were determined
by the UV-Vis method (Shimadzu UV-Vis spectrophotometer, model UV-1800) using a
DDS calibration curve at concentration range 4–13 g.mL-1 (Electronic Supplementary
Information, Figure S1). In all media, DDS and DDS salts showed absorbance maxima at 295
nm (Figure S2). DDS and DDS salts were put into a beaker containing 65 mL of each
dissolution media separately, until saturation was reached (a deposit of DDS free base and DDS
salts not solubilizing). The experiment was performed in triplicate and at room temperature (25
2 °C). The beakers were covered and protected from the light and agitated at 150 rpm using
an orbital shaker, Marconi model MA-830/A (Marconi, Piracicaba, SP – Brazil). After 48 h
of stirring, the solutions were filtered through a 0.45 m pore-size 25 mm PTFE syringe filter
and diluted when necessary in the corresponding medium for further UV-Vis analysis. The pH
variation in each dissolution medium (Table S2, Supplementary Information Section) was
analyzed using a pH meter, Marconi model PA 200 (Marconi, Piracicaba, SP – Brazil).
3. RESULTS AND DISCUSSION
3.1 Structural Description. The asymmetric units of DDS chloride, DDS bromide and
DDS nitrate are shown in Figure S3 with their respective labels. Their crystallographic data are
summarized in Table 1. A diprotonated DDS cation occurs in all the salts, since the two
nitrogen amino atoms (N1 and N2) are protonated. The sulfone group in the DDS cations
assumes a distorted tetrahedron configuration. The large deviation of the angle O1=S1=O2
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(119.9(1) for chloride, 119.6(2) for bromide and 119.7(2) for nitrate) from the ideal
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tetrahedron value of 109.47 is an intrinsic characteristic of the sulfones and can be attributed
to the involvement of the 3d-orbitals of sulfur in the bonding.28 For DDS free base, including
its hydrates and polymorphs, this angle varies from 117.4(1)° (CCDC code: ANSFON02) to
120.6(9)° (CCDC code: TUXDEW). Dapsone molecules can exist in different conformations
because of their free rotation around the C1-S1 and S1-C7 bonds. In dapsone nitrate, two
torsion angles define the cation conformation: C6-C1-S1-C7 = 94.0(3)° and C8-C7-S1-C1 =
92.1(2)°. In the bromide and chloride salts, the conformation is defined by the C6-C1-S1-C1’
torsion angle, which assume the values of 97.0(3)° and 85.1(2)°, respectively.
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Table 1. Crystal data and structure refinement parameters for DDS salts
SALT
DDSNO3
DDSBr
DDSCl
Crystal data
Formula
C12H14N2O2S2+. 2Br- C12H14N2O2S2+. 2Cl-
-
C12H14N2O2S2+. 2NO3
374.33
Formula weight
(g.mol−1)
410.11
321.22
0.71073
Orthorhombic
Pnma
0.71073
Orthorhombic
Pnma
Wavelength (Å)
0.71073
Orthorhombic
Pna21
Crystal System
Space group
293
200
Temperature (K)
293
Unit cell dimensions
a (Å)
7.6701(4)
9.4169(6)
9.2724(5)
b (Å)
c (Å)
9.0611(5)
25.5794(16)
5.9945(4)
1443.95(16)
Z: 8, Z’: ½
5.757
25.0339(14)
5.8561(4)
1359.34(14)
Z: 8, Z’: ½
0.629
21.8546(12)
1518.88(14)
Z: 4, Z’: 1
0.268
Volume (Å3)
Z, Z’
 (mm−1)
Absorption correction
Tmax, Tmin
Crystal size (mm)
multi-scan
1.000, 0.314
0.4 x 0.3 x 0.3
multi-scan
0.178, 0.044
0.9 x 0.5 x 0.3
multi-scan
1.000, 0.630
0.6 x 0.5 x 0.2
Data collection
SuperNova,
AtlasS2
0.0462
SuperNova,
AtlasS2
0.0741
SuperNova,
AtlasS2
0.0407
Diffractometer
Rint
(sin /)max (Å-1)
0.703
0.694
0.7163
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No. of measured,
independent and
observed [I >2(I)]
reflections
31312, 4096, 3577
11304, 1954, 1390 8092,1785, 1529
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Refinement
No. of reflections
No. of parameters
No. of restraints
4096
228
1
1954
92
0
1785
92
0
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Goodness-of-fit on F2
1.026
1.068
1.070
R1 = 0.0384,
wR2 = 0.0881
R1 = 0.0481,
wR2 = 0.0948
0.17, -0.24
R1 = 0.0471,
wR2 = 0.0996
R1 = 0.0761,
wR2 = 0.1148
0.808, -0.776
R1 = 0.0376,
wR2 = 0.0905
R1 = 0.0461,
wR2 = 0.0963
0.312, -0.472
R [I >2(I)]
R (all data)
max, min (e Å-3)
The chloride and bromide salts are isomorphous compounds that crystallize in the
orthorhombic space group Pnma, with the sulfur and oxygen atoms of the drug located on a
crystallographic plane of symmetry, and, therefore, their asymmetric unit consists of one-half
dapsone cation and one bromide anion. The packing analysis shows that DDS molecules are
stabilized by charge-assisted H-bonds (CAHBs) involving the protonated amino N1 atom of
the drug and the corresponding anion (Table S1). Each anion (Cl- or Br-) is attached to two
DDS molecules, related by inversion, via N1-H1B…Cl/Br (D…A = 3.344(2)/3.301(3) Å) and
N1-H1C…Cl/Br (D…A = 3.122(2)/3.305(3) Å) CAHBs (Figure 1).
Figure 1. View of the isomorphous 1D chains of DDS chloride and DDS bromide salts along
the [010] direction
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The combination of these interactions leads to the formation of a ring motif
푅4(8)
along the crystallographic [010] direction (Figure 2). This hydrogen bonded motif propagates
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along the c-axis by unit cell translations to form one-dimensional pleated sheets that are also
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stabilized by CAHBs (N1-H1A…Cl/Br, D…A = 3.160(2)/3.458(3) Å) and, as a result, a fused
푅
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motif is formed along the [001] direction (Figure 2). The 3D-assembly is characterized by
4(8)
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the stacking of these sheets along the [100] direction through van der Waals contacts (Figure
S4).
Figure 2. Pleated sheet structures in the bc plane of the isomorphous DDS chloride and DDS
bromide salts
.
In contrast to the chloride and bromide salts, DDS nitrate crystalizes in the
orthorhombic space group Pna21 with two nitrate anions and one DDS dication in the
asymmetric unit. As the nitrate anion is a conjugate base of a monoprotic acid (HNO3), the 1:2
stoichiometry is necessary to allow the double protonation of DDS, where two acid molecules
transfer their protons to both amine groups of the drug.
The drug molecules propagate along the [001] direction by stronger two- and three-center
hydrogen bonds involving their protonated amine groups and the nitrate anions (Figure 3a).
One of the nitrates acts as a bridge, connecting two crystallographic symmetry-related cations
(related by a 21-screw axis) through three CAHBs with distances from donor (N1 and N2
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atoms) to acceptor (O6, O7, O8 atoms) ranging from 2.8 to 3.3 Å (see Table S1, Figure 3b).
The presence of the screw axis (parallel to the c-axis) and, consequently, of these interactions
leads to the formation of infinite helical chains along the [001] direction (Figure 3a). Here,
also, the nitrate anions serve as a link for the helical chains via the bifurcated three-center
hydrogen bonds. The 2D layer (helix-bound layer) lies parallel to the (100) plane and is
stabilized by the following CAHBs: N1-H1C…O4 (D…A = 3.005(4) Å), N1-H1C…O5 (D…A =
2.909(4) Å), N2-H2C…O5 (D…A = 2.839(4) Å) and N2-H2C…O3 (D…A = 3.117(4) Å) (Figure
3c).
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Figure 3. Packing view of the helical chains (layer A) of DDS nitrate along the bc plane (a).
Representation of the helical chain unit (b). Partial view of layer A highlighting the nitrate
interactions (c).
When viewed along the [100] direction, the 3D assembly can be described by two types
of layers, A and B. In fact, since they are related by symmetry, both layers display the same
pattern of interactions. The A and B helices (or layers) run in opposite directions and
Figure 4. Assembly of type A (right-handed) and type B (left-handed) helical chains. They
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interweave via N1-H1B…O7 (D…A = 2.702(4) Å) CAHB and non-classical C2-H2…π and π…π
hydrogen bonds (Figure 4). The overall 3D structure is characterized by the assembling of these
layers in an “…A-B-A-B…” fashion along the [100] direction (Figure 5). Additionally, the
…
…A-A-A… and B-B-B… helices are also connected to one another along the [100] direction
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through a hydrogen bond involving the sulfonyl oxygen and one of the protonated amine
groups of the drug (N2-H2B…O1, D…A = 3.023(4) Å) (Figure S5).
Figure 5. Representation of the double helical structure. View along the [010] (a) and [100]
(b) directions.
3.2 Thermal and FT-IR results. The TG/DTG/DSC curves of DDS free base and DDS
salts are presented in Figure 6. The DSC curve of DDS is characterized by two endothermic
peaks, one at 81.0 °C and the other one at 180.1 °C. The first peak is ascribed to a polymorphic
transition of DDS17, whereas the second is due to the melting of DDS (polymorph I). This result
is in good agreement with the TG curve, since the sample did not undergo any weight loss in
the interval of 30–190 °C. The TG shows that DDS is stable up to an onset temperature of
353.8 °C; above this temperature, the TG curve is characterized by an abrupt weight loss as the
result of thermal decomposition. The first weight loss for the DDS salts is observed below
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353.8 °C, which shows that they are thermally less stable than DDS. Of the salts analyzed, the
nitrate and chloride are least stable, with an onset temperature of 149.2 °C and 151.5 °C,
respectively, followed by the bromide (Tonset = 232.3 °C) salt. In contrast to DDS, the salts do
not show a DSC peak that could be attributed to melting; in fact, the first endotherms appear
after the beginning of thermal decomposition, i.e. after the onset temperatures extracted from
the TG curves.
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Figure 6. TG/DTG/DSC curves of DDS free base and DDS salts under N2 flow.
FT-IR not only provides information about the molecular conformation, but is also a
powerful and low-cost method of monitoring salt formation.30 Figure 7 presents the FT-IR
spectrum of DDS free base as well as the DDS salts, using KBr pellets. The main changes are
observed in the region 3500–2500 cm-1. The observed bands are assigned in accordance with
data available in the literature, i.e., the experimental and calculated spectra of DDS and
protonated primary amines.30–32 The absorptions associated with the drug’s amine groups are
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essential to distinguish between a protonated and neutral species. The DDS spectrum is
characterized by a series of bands in the region 3460–3340 cm-1 (bands at 3455, 3397, 3369
and 3341 cm-1) related to the antisymmetric and symmetric NH2 stretching modes. The
+
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conversion of NH2 into NH3 (the salt formation) results in the absence of these bands
(suppressed or shifted/overlapped) and the emergence of a set of broad bands in a lower
+
frequency range (3100–2500 cm-1) associated with the antisymmetric and symmetric NH3
stretches and to the combination modes and overtones of the bending and rocking vibrations
+
of NH3 .
Figure 7. FT-IR spectra of DDS free base and DDS salts in KBr
pellets.
3.3 Characterization of DDS salts from the bulk. PXRD (Figure 8) was used not only as
an additional technique to monitor the salt formation but also to ensure that the single-crystal
structure is representative of the bulk obtained by acid precipitation. The experimental
diffractograms of DDS salts are in good agreement with those calculated by the Mercury
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program, using as input the corresponding single-crystal salt structures: DDS chloride (CCDC
code: 1963117), bromide DDS (CCDC code: 1963118) and DDS nitrate (CCDC code:
1963119). The match between the experimental and calculated Bragg peaks confirms the
complete conversion of DDS free base into the salts and the yield of the preparation process.
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Figure 8. Experimental and calculated PXRD patterns of DDS salts.
3.4 Equilibrium solubility studies. The pH-solubility profile of DDS and DDS salts in
three different pH conditions (pH 1.2, pH 4.5 and pH 6.8) is shown in Figure 9. This range was
chosen in order to mimic the acidic gastric medium (HCl buffer pH 1.2) and biological fluids
(acetate buffer pH 4.5 and phosphate buffer pH 6.8). The equilibrium pH values were measured
after the addition of each DDS form and at the end of the equilibrium solubility experiment
(Table S2), and they did not show any significant difference.
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According to the results obtained for pH 4.5 and pH 6.8 (Table 2), the solubility of DDS
and DDS salts is less than 0.500 mgmL-1. At pH 4.5, the solubility of DDS free base is slightly
higher (0.264 0.004 mgmL-1) than that of DDS chloride (0.203 0.001 mgmL-1), DDS
bromide (0.079 0.001 mgmL-1) and DDS nitrate (0.072 0.001 mgmL-1) salts. Also, at pH
6.8 solubility values remain significantly low: 0.167 0.001 mgmL-1 for DDS chloride, 0.108
0.002 mgmL-1 for DDS bromide, 0.091 0.031 mgmL-1 for DDS free base and 0.075 0.001
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mgmL-1 for DDS nitrate. The lower solubility at this pH range can be explained by a possible
0
conversion of the cationic DDS species to its neutral form, i.e. DDS free base (
, which
)
DDS(sol)
is practically insoluble in these media. Since DDS is a weak dibasic compound, its dissolution
and solubility depend on the ionization state that in turn is controlled by the pH of the medium
and the dissociation constant (pKa). As explained in the Introduction, DDS has two pKa values,
+
0
where pK (2.49) is associated with the monosalt-neutral equilibrium (
DDSH(sol) ↔ DDS(sol)
a1
+ H +
DDSH2(sol) ↔ DDSH(sol) + H +
2 +
+
) and pK (1.30) with the monosalt-disalt equilibrium (
).
a2
Therefore, taking into account the calculated pH-dependent acid-base DDS species distribution
0
(insert in Figure 9), the molar fraction of the less soluble
(sol) species will be higher in the
DDS
+
alkaline pH range than the more soluble
species, and vice versa in the acidic pH
DDSH(sol)
+
0
range, where the molar fraction of the
will predominate over the
species.
DDSH(sol)
DDS(sol)
Further, this conversion was confirmed by the PXRD analysis of the solid phase in equilibrium
with the saturated solutions used for measuring the solubility (Figure S6). The PXRD patterns
from the solid residues at pH 4.5 and pH 6.5 clearly show the presence of peaks intrinsic to the
DDS free base pattern.
The highest solubility values are observed for DDS chloride (6.750 0.031 mgmL-1),
followed by DDS bromide (3.669 0.057 mgmL-1), DDS nitrate (3.375 0.013 mgmL-1) and
DDS free base (2.992 0.085 mgmL-1) in HCl buffer pH 1.2. However, the values obtained
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for DDS nitrate and DDS chloride cannot be considered to be real, since the PXRD patterns
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―1
(
)
for DDS free base and DDS salts in three
Table 2. Equilibrium solubility values
푚푔.푚퐿
different conditions. The initial pH (pHi) and final pH (pHf) pH at the equilibrium of each
solution are also given
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DDS free base
2.992  0.085
pHi = 1.20
DDS chloride
6.750  0.031
pHi = 1.20
DDS bromide
3.669  0.057
pHi = 1.20
DDS nitrate
3.375  0.013
pHi = 1.20
HCl buffer pH 1.2
pHf = 1.45
pHf = 1.30
pHf = 1.50
pHf = 1.38
0.264  0.004
pHi = 4.55
0.203  0.001
pHi = 4.55
0.079  0.001
pHi = 4.55
0.072  0.001
pHi = 4.55
Acetate buffer pH 4.5
pHf = 4.48
pHf = 4.45
pHf = 4.16
pHf = 4.30
0.091  0.031
0.167  0.001
pHi = 6.87
0.108  0.002
pHi = 6.87
0.075  0.001
pHi = 6.87
Phosphate buffer pH 6.8 pHi = 6.87
pHf = 6.95
pHf = 6.80
pHf = 6.56
pHf = 6.86
show their total/partial conversion of them to the non-stoichiometric hydrate of DDS (Figure
S7). Nevertheless, DDS bromide salt was found to be slightly more soluble than DDS free base.
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Figure 9. pH-dependent equilibrium solubility values of DDS free base and DDS salts in HCl
buffer pH 1.2, acetate buffer pH 4.5 and phosphate buffer pH 6.8.
4. CONCLUSION
In this study, we present the solubility behavior, in three different pH conditions (pH
1.2, pH 4.5 and pH 6.8), of three salts of the anti-leprosy drug DDS compared with DDS free
base, the marketed form, followed by a complete solid-state investigation of these salts. The
chloride, bromide and nitrate salts were obtained by acid precipitation, whereas the single-
crystals were obtained by the slow evaporation method, in which, for the first time, the single-
crystal X-ray structures of the isomorphous DDS chloride and DDS bromide salts were
determined. Their packing is stabilized by CAHBs between the protonated DDS amino groups
and the respective counterions (Cl-/Br-), generating a pleated sheet structure. In contrast to DDS
free base, which melts at 180.1 °C (Tpeak), the salts decompose without melting; the nitrate
(Tonset = 149.2 °C) and the chloride (Tonset = 151.5 °C) are less thermally stable, i.e. they are the
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salts with the lowest onset temperatures, followed by the bromide salt (Tonset = 232.3 °C ). The
FT-IR and PXRD analysis was congruent with the SCXR results, from the FT-IR it is possible
to confirm the salt formation and from the PXRD, to confirm the isomorphism. DDS salts were
found to be converted into DDS free base in the slightly alkaline-neutral pH range (pH 4.5 to
pH 6.8), which explains their low equilibrium solubility values. The highest values were
obtained in acid medium (pH 1.2) in which DDS bromide (3.669 0.057 mgmL-1) was a little
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more soluble than DDS free base (2.992 0.085 mgmL-1). For the nitrate and chloride salts,
the PXRD patterns of the solid residues showed the appearance of new peaks corresponding to
another crystalline form, the non-stoichiometric hydrate of DDS. Therefore, this total/partial
conversion in acid medium renders the equilibrium solubility results artificial and not adequate
for subsequent (comparative) solubility analyses.
ASSOCIATED CONTENT
Electronic supplementary information (ESI). Figure S1. Calibration curve using standard
solutions of DDS; Figure S2. UV-Vis spectra of DDS free base and DDS salts in three different
conditions; Figure S3. ORTEP view of the asymmetric unit of DDS salts: the isomorphous
chloride and bromide (a) and the nitrate (b) salts. Thermal ellipsoids for non-hydrogen atoms
are drawn at 50% probability level; Figure S4. Crystal packing of the isomorphous DDS
chloride and DDS bromide salts. The 3D assembly is characterized by the stacking of sheets
along the [100] direction; Figure S5. A partial view of DDS nitrate packing. The helical layers
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A (green) and B (pink) are connected along the [100] direction by nitrate-drug (N1-H1B…O7)
and drug-drug (N2-H2B…O1) hydrogen bonds; Figure S6. PXRD data of the solid residues
from the equilibrium solubility assays of DDS salts and DDS free base in three different media
(HCl buffer pH 1.2, acetate buffer pH 4.5 and phosphate buffer pH 6.8). C refers to the control,
i.e. the PXRD of the salt used in the solubility assays; Figure S7. PXRD data of the solid
residues corresponding to the equilibrium solubility of DDS nitrate and DDS chloride at pH
1.2. Both diffractograms show the presence of characteristic peaks related to the non-
stoichiometric hydrate form of DDS (CSD code ANSFON02). For DDS nitrate, it was also
included the calculated PXRD pattern of the mono-protonated salt (CSD code WINFIL).
Unfortunately, there is no structure available for the mono-protonated form of DDS chloride;
Table S1. Geometric parameters of the hydrogen bonds in DDS salts.
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Accession Codes
CCDC codes 963117, 963118 and 963119 contain the supplementary crystallographic data for
this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/getstructures,
or by emailing data_request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223
336033.
AUTHOR INFORMATION
Corresponding author
*(A.C.D.) E–mail: doriguetto@unifal-mg.edu.br
*(C.C.M.) E–mail: crisbrizoti@gmail.com
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
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This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível
Superior – Brasil (CAPES) – Finance Code 001 (C.C.M. and M.B.). Other funding for this
research was provided by FINEP, CNPq (A.C.D. grants 308162/2015-3 and 428475/2018-3)
and FAPEMIG (A.C.D. grants PPM-00533-16 and APQ-01835-18) agencies. The authors
express sincere thanks to NCQ-UNIFAL-MG and LABIQ-UNIFAL-MG for the HPLC,
TG/DSC and FTIR facilities.
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For Table of Contents Use Only
Investigating the Solubilities of the Nitrate and
Isomorphous Bromide and Chloride Salts of
Dapsone
§
Cristiane Cabral de Melo*†,‡, Monalisa Bitencourt †, Charlane C. Correa , Antonio Carlos
Doriguetto*†,‡
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†
‡
Faculty of Pharmaceutical Sciences and Institute of Chemistry, Federal University of
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Alfenas, 37130-001, Alfenas-MG, Brazil
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§Department of Chemistry, Federal University of Juiz de Fora, 36036-900, Juiz de Fora-MG,
Brazil
Pharmaceutical-acceptable salt forms of the anti-leprosy drug dapsone were prepared and
characterized by X-ray diffraction (single and powder), FT-IR and thermal techniques. It was
found that DDS chloride and DDS bromide are isomorphous compounds. The equilibrium
solubility of the nitrate, chloride and bromide salts was investigated and compared to dapsone
free base.
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