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A Drug−Drug Salt Hydrate of Norfloxacin and Sulfathiazole:
Enhancement of in Vitro Biological Properties via Improved
Physicochemical Properties
Shanmukha Prasad Gopi, Somnath Ganguly, and Gautam R. Desiraju*
Solid State and Structural Chemistry Unit, Indian Institute of Science, Bangalore 560 012, India
S Supporting Information
*
used antibiotics.13,14 So, attention has shifted to developing new
antimicrobial drug combinations.15,16
The fluoroquinolones17,18 are a family of broad-spectrum
systemic antibacterial agents that have been used in respiratory
and urinary tract infections and are active against a wide range
of aerobic Gram-positive and Gram-negative organisms.
Norfloxacin is a nalidixic acid analogue and one of the most
potent DNA gyrase inhibitors. Generally, it is taken with
antimicrobials like sulfonamides to treat mixed infections and
to reduce resistance.19,20 These mixed drug systems are usually
marketed as physical mixtures formulated by the use of binders.
However, the components of such mixtures could well have
very different physicochemical properties that could result in
inferior biological activity.21 Cocrystals and salts of fluoroquinolones22,23 and sulfonamides24 might be an answer to
compromised physicochemical and biological properties of
these marketed physical mixtures.
Although pharmaceutical cocrystals and salts have been
studied extensively,25−27 only limited work has been done in
the area of crystal engineered multidrug systems with regard to
their physicochemical properties. In this communication, we
use the concepts of pharmaceutical crystal engineering to
design a new dual drug system, namely, the antibacterial/
antimicrobial salt combination of norfloxacin28 (BCS class IV)
and sulfathiazole29 (BCS class II), hereafter NF and ST, and
have studied its physicochemical properties. Biological property
evaluation of the salt with respect to inhibition behavior of
bacterial as well as fungal species is reported. It must be noted
here that enhancement of properties (solubility, dissolution
kinetics, bioavailability, pharmaceutical activity) is a reality in
several salts and cocrystals as compared to the native drugs.7,8
Efficacy as a drug depends on events that take place in solution
or at solution−membrane interfaces. To summarize, there
cannot be a black and white distinction between the crystal and
the solution, for if this were the case, cocrystals would have
exactly the same pharmaceutical effects as mixtures of the
relevant compoundsand this is clearly not the case in many
situations, such as the one described in this communication.
The title salt hydrate was prepared by taking 100 mg of NF
(0.31 mmol) and 79.14 mg of ST (0.31 mmol) in a mortar and
pestle and performing liquid assisted grinding with 5 mL of
ABSTRACT: A new multicomponent solid consisting of
an antibacterial (norfloxacin) and an antimicrobial
(sulfathiazole) was made and characterized with single
crystal X-ray diffraction, PXRD, FTIR, and DSC. The title
salt shows enhanced solubility in different pH buffers and
improved diffusion as well as release and inhibition of
bacterial and fungal species relative to the parent drugs.
The enhanced in vitro biological properties of the drug−
drug salt hydrate may be attributed to the higher extent of
its supersaturation with respect to the individual
components, which leads to higher diffusion rates.
KEYWORDS: solid form, solubility, permeability,
antibacterial, antimicrobial, crystal engineering
P
hysicochemical profiles of lead compounds depend on
basic structural principles of medicinal chemistry.1,2
Improvement of in vitro activity is generally achieved by
incorporating lipophilic groups. Inevitably a number of leads
have poor solubility.3,4 To increase the solubility of lipophilic
compounds, various formulation techniques are employed.5
Pharmaceutical salts and cocrystals, made with coformers, have
also become important.6−8 These multicomponent solids show
enhanced solubility, release, and bioavailability relative to the
parent drugs. A natural and practical extension of such a
strategy would be to substitute the coformer with another drug
in the same therapeutic area9−11 (combination therapy) to
obtain a synergism of the physicochemical properties.
Bacteria are the cause of some of the most deadly diseases
and widespread epidemics in human civilization. Bacterial
infections, with complications of drug resistance from increased
antibiotic use, have increased dramatically in recent times.12
Drug resistant strains, such as vancomycin-resistant enterococci
(VRE) and multidrug-resistant Staphylococcus aureus (MRSA),
are capable of surviving the effects of most, if not all, currently
© 2016 American Chemical Society
Received:
Revised:
Accepted:
Published:
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April 11, 2016
August 26, 2016
August 31, 2016
August 31, 2016
DOI: 10.1021/acs.molpharmaceut.6b00320
Mol. Pharmaceutics 2016, 13, 3590−3594
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Molecular Pharmaceutics
method35 to understand the effect of pH on the solubility
behavior of the parent drugs NF and ST and the NF−ST salt.
These studies were carried out in pH buffers 1.2, 4.0, and 7.4 in
addition to a cosolvent system (ethanol−buffer) (Figure 2).
At pH 7.4 the salt hydrate showed a large enhancement in
the overall solubility (1362 mg/L) with molar equivalent
solubility enhancement being 4× for NF (736 mg/L vs 178
mg/L of pure NF). A marginal decrease was seen for ST (586
mg/L) compared to its original solubility value (703 mg/L,
Figure 2a). At pH 4.0, the overall solubility of the salt is 1198
mg/L, which is slightly lower than at pH 7.4 (Figure 2b).
However, in this case, both NF and ST show comparable
solubilities, namely, NF 3× (647 mg/L vs 221 mg/L) and ST
1.7× ST (515 mg/L vs 316 mg/L). At acidic pH 1.2, which
corresponds to a fasting state of the stomach (Figure 2c), both
components are highly soluble as might be expected, and the
values are presented in Table S3. However, whether a drug is
acidic or basic, most of its absorption occurs in the small
intestine36 (pH 6−8), and hence the solubility at pH 7.4 is
more relevant. In summary, the enhancement of solubility is
due to salt formation between the two drugs as typically seen
for pharmaceuticals,37,38 rather than some pH effect. We also
have studied the effect of ethanol cosolvent on the solubilities
of the salt and the parent compounds. Systems like ethanol−
buffer are used to test the solubilities of poorly soluble
compounds.39 The effect of ethanol cosolvent is to cause a large
increase in the solubility of the salt (6166 mg/L) in which NF
has 12× (3329 mg/L vs 513 mg/L) and ST about 1.5× (2651
mg/L vs 1715 mg/L) enhancements (Figure 2d).
In vitro absorption of molecules is estimated with
permeability measurements, in other words by passive diffusion
through nonliving systems. In this study, we used a Franz
diffusion cell with 0.45 μm cellulose nitrate membranes to
compare the diffusion of solutions of salt hydrate crystals vis-àvis solutions of the parent drugs (Figure 3). The curve shows a
single and steep diffusion curve for the binary salt. The
cumulative amount of material diffusing through the membrane
increases rapidly in the first hour, after which it tapers off, and
after 5 h another small increase is noticed. In contrast, the
parent molecules show much lower diffusion. Diffusion curves
for NF and ST are distinct for a solution of a physical mixture
of the two compounds, indicating different rates of diffusion/
permeation across the barrier. For the salt solution, however,
NF and ST diffuse together (as observed by HPLC). In the
case of the solution of the physical mixture, only ST diffuses for
all practical purposes. No diffusion is seen for NF, and this is
observed at a gross level by the physical appearance of a light
yellow powder (NF) in the donor chamber. The analyte too
does not show any peak corresponding to NF. The enhanced
solubility of the salt hydrate and the improved diffusion of the
dissolved material are indicative of an easier passage through
bacterial fluids and cells compared to the solution of the
physical mixture. The higher solubility of the drug−drug salt is
consistent with its lower melting point. Given the data in Figure
3, and the other data obtained (and depending on pH), one
may say that the drug−drug salt clearly dissolves to give a
solution that has a higher concentration with respect to each
compound, relative to the respective crystalline forms taken
separately (or a physical mixture thereof). Hence, the solution
formed upon dissolution of the drug−drug salt is supersaturated with respect to each of the crystal forms, since
complexation seems to be ruled out by the lack of solubility
increase in a physical mixture of crystalline forms. Super-
EtOH for about 15 min followed by crystallization from the
same solvent at ambient temperature. Well-formed block
shaped crystals (P1, Z = 2) of the 1:1:1 NF·ST·H2O salt
monohydrate appeared after a few days. MeOH and MeCN
solvates of NF−ST are reported in the Supporting Information
(Figures S1 and S2, Table S1). The asymmetric unit contains
one molecule each of the drugs NF and ST along with a
disordered water molecule. A heterodimer is formed between
ST and NF through proton transfer from the N−H group of
the sulfonamide group of ST to the piperazinyl group of NF
(Figure 1). Such dimers form chains via N−H···O hydrogen
Figure 1. Structure of the NF−ST salt hydrate: (a) interactions/chains
of NF and ST; (b) packing diagram to show water channels.
bonds (aniline of ST to carboxyl group of NF), which make a
sheetlike structure through auxiliary interactions involving N−
H···O, C−H···F, and C−H···O bonds. Successive sheets make
channels for disordered water molecules (sustained by O−H···
O and C−H···O interactions) along the b-axis. Water
molecule(s) are disordered about inversion centers and bind
with the carbonyl group of NF (Figure S3).
Differential scanning calorimetry (DSC) of the salt shows a
sharp melting endotherm at 176−178 °C (Figure S4)
indicating a single homogeneous phase of the drug−drug salt.
Generally, desolvation takes place before or at the boiling point
of the solvent, well before melting of the solvate. Nevertheless,
a hydrate/solvate exhibiting desolvation at the melting point is
not unusual.30−32 The melting point shows a shift downward
from the melting points of the parent drugs; the lower melting
point of salt may be due to weaker electrostatic, hydrogen
bonding, and other interactions. Thermogravimetric analysis
(TGA) indicates a monohydrate NF−ST salt and shows water
loss at the same temperature as the DSC melting endotherm
(Figure S4). The FTIR spectrum (Figure S5) of the salt hydrate
shows bands at 1450 cm−1 (ω, strong), 745 cm−1 (r, medium)
and the characteristic stretching band at 3600 cm−1 due to the
NH2+ ion of the salt.33
Solubility is an important preformulation property that has a
direct impact on the absorption of orally administered drugs.
There are numerous methods used to improve the solubility of
poorly soluble drugs, and among these, salt formation is the
most common in industry because of the high solubility and
purity of salts. It is also known that solubility varies as a
function of pH.34 In our solubility studies, we conducted
extensive experiments using the traditional shake-flask
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Figure 2. Solubility comparisons of NF, ST, and NF−ST salt hydrate in (a) pH 7.4 buffer, (b) pH 4.0 buffer, (c) pH 1.2 buffer, and (d) cosolvent
medium (10% EtOH−pH 7.4 buffer). NF (green), ST (purple), and water (orange) are plotted according to their molar equivalents in NF−ST−
H2O (54:43:3).
Figure 3. (a) Cumulative amount of NF, ST, and the salt diffused vs time plot. (b) Plots of flux of the salt with respect to time in pH 7.4 buffer.
and salt) were assayed (using in vitro studies) on antibacterial
and antifungal species of pathogenic bacteria Escherichia coli
(ATCC 25922, hereafter E. coli), Staphylococcus aureus (ATCC
29213, hereafter S. aureus), and fungi (Aspergillus). Table S4
shows the pathogens/microorganism counts on an E. coli strain
that was subjected to a solution containing a mixture of NF and
ST and its salt at a concentration of 1 mg/mL. The inhibition
saturated solutions are well-known to have higher diffusion
rates as compared to their saturated counterparts,40 and this
would appear to rationalize our experimental observations. In
summary, the enhanced flux may be explained by the formation
of a solution that is supersaturated with respect to both species.
In order to test the potency of the salt hydrate, the
compounds (physical mixture, represented hereafter as P.M.
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quantified by HPLC, and it was seen that the ratio of NF
dropped to 36% (Table S6). It is possible that the inhibition by
NF will reduce with time in the P.M. or in the pure form. The
respective HPLC spectra and method details are provided in
Figure S9.
That the initial solubilities of cocrystal/salt systems are
higher than those of the individual components is an actively
researched topic today, and there are different models for the
species which are held in the supersaturated solutions
involved.43−46 In this context, the improved physicochemical
properties of the NF−ST salt hydrate may be rationalized on
the basis of higher supersaturation levels of the salt as
compared to the individual components or a physical mixture
thereof, at the pH of the experiment. The improved
permeability of NF effectively leads to an enhancement of
overall biological activity.
In summary, a novel salt hydrate of norfloxacin and
sulfathiazole has been prepared using crystal engineering
methods. The antibacterial/antimicrobial combination salt
exhibits solubility enhancements in different pH buffers and
also in a cosolvent system. A high single diffusion rate is seen
for the salt compared to independent diffusion behavior seen in
a physical mixture of the two drugs. The salt shows enhanced
inhibition of bacterial and fungal strains, which is a result of
joint diffusion and increased solubility. Such new multidrug
systems are expected to open up new directions in multidrug or
combination therapeutics.
of the salt and the P.M. on bacterial and fungal strains was
compared. In the case of the P.M., broad growth of E. coli was
noticed at 0.8 μg/mL (MIC 1.6 μg/mL), whereas in the salt it
was observed at 0.4 μg/mL (MIC 0.8 μg/mL, Table S4). The
MIC of the NF−ST P.M. matched with the reported MIC
values of NF (0.3−0.12 μg/mL)41,42 which also indicates that
ST in the mixture does not have any additional impact on
inhibition of E. coli by NF (the IR spectrum of P.M. confirms
the presence of both drugs, and their quantitative amounts were
evaluated using HPLC (Figures S5 and S9). This study was
supplemented with the disk diffusion technique of inhibition
zones of the P.M. and salt (Figure S7). The radius of the zone
of inhibition (ZOI) for E. coli was about 10 ± 1 mm at 50 μg/
mL and decreases at lower concentrations to 4 ± 1 mm at 0.4
μg/mL (Figure S7c,d). The radius of the ZOI for the P.M. was
2 mm at 0.8 μg/mL, and for the salt it was 8 mm (Figure S7a−
d). Similarly, the compounds were tested against S. aureus
Gram-positive strain at a concentration of 1.8 μg/mL (Figure
S7e−h). A decreased MIC value was noticed for the salt
compared to the P.M. (MIC for P.M. was 3.1 μg/mL and 1.6
μg/mL for the salt, Table S5). The ZOI was about 5 ± 1 mm at
1.6 μg/mL for the salt whereas there was no clear ZOI at this
concentration for the P.M. (Figure S7e,f). In vitro studies on
Gram-positive and Gram-negative bacteria indicated that in the
salt form MIC was observed on both bacteria at half the MIC of
the P.M. This may arise from enhanced solubility and diffusion.
The above results clearly indicate better inhibition effects from
the salt compared to the P.M. Details are given in the
Supporting Information. The increased inhibition might also
have resulted from the faster release (intrinsic dissolution rate)
of NF in the salt form compared to pure NF (Figure S8). What
is important is the simultaneous presence of both drugs at the
site of action. This is unlikely in the P.M.s because the
difference in solubilities of the individual components is very
high.
The effect of antimicrobial property of NF−ST salt was
tested against an Aspergillus strain using the disk diffusion
method. Figure S7 depicts the disk of the antimicrobial activity
of the salt and its P.M. against concentration of 2.2 mg/mL (a
P.M. of 2.2 mg/mL contains NF and ST in equimolar ratio
NF:ST as 1.2:1.0 mg same for the salt). Fungal growth was seen
for the P.M. at the concentration of 20 μg/mL (ZOI 4 ± 1
mm), but in the case of salt an inhibition zone was noticed even
at 5 μg/mL (disk 2) with the ZOI at about 3 ± 1 mm which
increased to over 10 ± 1 mm at higher concentrations (Figure
S7). In brief, antibacterial and antifungal studies showed a
significant synergistic effect with inhibition by both NF and ST
ions in the salt.
The molar contribution solubility of both the drugs in salt
form as well as the P.M. was determined with HPLC. The
quantification of drugs (salt and P.M.) was carried out by
comparing HPLC peak areas with that of the standards. The
retention times of standard aqueous solutions of NF and ST
were found to be 4.1 and 2.4 min respectively (Table S6). It
was found that both NF and ST contributed in nearly
equimolar ratios (48:52) in the salt solution. However, only
44% of NF contribution to solubility was noticed in the P.M.
solution due to its poor solubility compared to ST (the P.M.
had to be stirred for about 24 h and slightly warmed to dissolve
the components whereas the salt was freely soluble in 5−10
min at room temperature). In the P.M. a mild suspension/
precipitate was noticed over time whereas no such suspension
was seen in the salt solution. The P.M. sample was further
■
ASSOCIATED CONTENT
S Supporting Information
*
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.molpharmaceut.6b00320.
Single crystal and powder XRD, DSC, TGA, FTIR,
HPLC, and in vitro inhibition data and experimental
procedures (PDF)
Crystallographic data (CIF)
■
AUTHOR INFORMATION
Corresponding Author
*Fax: +91 80 23602306. Tel: +91 80 22933311. E-mail:
[email protected].
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS
S.P.G. thanks the University Grants Commission for a Dr. D. S.
Kothari Fellowship. S.G. thanks IISc for a fellowship. G.R.D.
thanks the Department of Science and Technology for a J. C.
Bose Fellowship. The authors are grateful to Dr. S. G.
Ramachandra, M. Shruthi Central Animal Facility, IISc, and Dr.
S. T. Girisha and V. Girish, Dept. of Microbiology &
Biotechnology, Bangalore University, for their help with
biological studies.
■
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