Modification of Crystallization Behaviour of Sertaconazole by Preparing its Solid Dispersions
Sertaconazole is one of the most effective fungicidal and fungistatic agents.
But its practical use is limited due to its extremely low aqueous solubility
and therefore, search for an adequate delivery system is still a challenging
issue. So, the aim of present study was to modify the crystalline behaviour
of sertaconazole by preparing its solid dispersions so as to increase the solubility
of sertaconazole. Some methods have been reported in literature but these methods
require high amount of carrier which can be toxic in such amount. In the present
study, melting method was used to prepare the solid dispersions and these solid
dispersions were characterized by various techniques in solid as well as in
solution state. Solution state studies showed a profound increase in the solubility
and dissolution rate of sertaconazole with nicotinamide in presence of surfactant
and fatty acid and solid state studies showed an absence of chemical interaction
between sertaconazole and nicotinamide. It is concluded that oleic acid and
tween 80 when combined with sertaconazole and nicotinamide in the solid dispersions
results in profound increase in solubility. So, these dispersions can be used
for oral delivery of sertaconazole and can be considered as better choice for
the treatment of dermatological and gynaecological infections.
June 21, 2013; Accepted: September 20, 2013;
Published: February 27, 2014
One of the simplest and easiest ways to administer a drug is by oral drug delivery
system (Anguiano-Igea et al., 1995). Comparing
different oral dosage forms, solid dosage forms have many advantages over other
dosage forms like easy to formulate, greater stability and accurate dosage etc.
Therefore, main focus during the development of New Chemical Entities (NCE)
in these days is to develop their solid dosage (Serajuddin,
1999; Craig, 2002). But, many of these NCE are
poorly water soluble resulting in less absorption after oral administration
(Chiou and Riegelman, 1971; Matsumoto
and Zografi, 1999). Low drug solubility also results in decreased bioavailability,
increased chance of food effect, incomplete release from the dosage form and
higher inter-patient variability. These poorly soluble drugs are also associated
with complex dissolution testing with poor correlation to in vivo absorption.
Their poor solubility and in vivo/in vitro correlations leads to difficulties
in the development on many newly synthesized compounds. Therefore, to overcome
these difficulties, various strategies have been adopted to improve the water
solubility of drugs (Tanaka et al., 2006).
Solid Dispersions (SDs) are one of the most successful strategies to improve
drug release of poorly soluble drugs but very few marketed products are available
based on the solid dispersion strategy. The main reasons for this are poor physical
stability, reproducibility of physicochemical characteristics, cost of production,
difficulty in incorporating into formulation of dosage forms and requirement
of large amount of carrier to achieve the desired dissolution (Dhirendra
et al., 2009).
To overcome these problems, one useful approach is to use surfactant as additional
additive along with hydrophilic carrier for preparing solid dispersions. However,
solid dispersions containing this combination are also very less in market due
to high amount of carrier and surfactant required and toxicity of surfactants
in high concentration.
To overcome these disadvantages, one of the useful methods is to combine one
more excipient (oleic acid) to these solid dispersions so as to decrease the
required amount of carrier and surfactant and having enhanced solubility and
dissolution rate. These solid dispersions can be developed into different solid
dosage forms for oral and parenteral administrations (Tang
et al., 2008). Many advantages are associated with these solid dispersions
like improved solubility and dissolution rate, improved stability, decrease
in production cost and better patient compliance.
The development of antimycotic agents is very essential due to the increased
morbidity and mortality caused by fungal infections in recent years (Ortiz,
1992). Sertaconazole (SER) is one of the effective fungicidal and fungistatic
agents and has a broad-spectrum activity against dermatophytes, opportunistic
filamentous fungi and also gram positive bacteria (Agut
et al., 1992; Carrillo-Munoz et al.,
2008). It has a good profile of security, high cutaneous permanence and
low systemic absorption while using for the treatment of dermatologic and gynaecological
infections (Palacin et al., 2000). Despite these
valuable features, one main problem associated with SER is its extremely low
aqueous solubility (<0.01% w/v) which strongly limits its practical use (Albet
et al., 1992) and therefore, the search for an adequate delivery
system is still a challenging issue. Inclusion complexes of SER with cyclodextrins
(Perdomo-Lopez et al., 2002; Rodriguez-Perez
et al., 2006) are reported but such system needed more than 70% of
cyclodextrins which can be toxic in such amount (Gould
and Scott, 2005).
Therefore, in the present work, solid dispersions of sertaconazole nitrate
were prepared containing Nicotinamide (NIC) along with low content of surfactant
(tween 80) and fatty acid (oleic acid), with the aim to improve the solubility
and dissolution rate of sertaconazole nitrate. The novelty of the present study
lies in the fact that solid dispersions of sertaconazole nitrate with low concentration
of excipients have not been reported previously. The drug-carrier interactions
in the liquid and solid-state were studied by phase solubility studies, saturation
solubility analysis, dissolution studies, Powder X-ray Diffraction (PXRD), Fourier
Transform Infrared spectroscopy (FTIR) and Differential Scanning Calorimetry
MATERIALS AND METHODS
Materials: Sertaconazole nitrate was obtained as gift sample from Glenmark
Pharmaceutical Ltd. (Mumbai, India). Nicotinamide was purchased from Loba chemie
Pvt. Ltd. (Mumbai, India). Tween 80 and oleic acid were purchased from S.D.
Fine Chem. Ltd. (Mumbai, India). All other reagents and solvents used were of
analytical grade. Triple-distilled water was used throughout the experiments.
Preparation of physical mixtures: Physical mixtures of sertaconazole with
nicotinamide in the weight ratios of 90:10 (PMS1), 80:20 (PMS2), 65:35 (PMS3),
50:50 (PMS4), 30:70 (PMS5) and 10:90 (PMS6) were obtained by geometric mixing
and pulverizing accurately weighed amounts of SER and NIC in a glass mortar.
The pulverized mass was then sifted through 100 mesh sieve and stored in a desiccator
till further studies.
Preparation of solid dispersions: Binary solid dispersions containing
SER and NIC in the weight ratios 90:10 (SDS1), 80:20 (SDS2), 65:35 (SDS3), 50:50
(SDS4), 30:70 (SDS5) and 10:90 (SDS6) were prepared by the fusion method. This
method included the melting of NIC in a porcelain dish over a calibrated hot
plate at 145-150°C and addition of drug to the molten carrier to prepare
binary solid dispersions. The fused mass was then placed immediately in a freezing
mixture of ice and salt for solidification. The mass was then placed in a vacuum
desiccator for at least 48 h till complete drying. The dried mass was pulverized
and sifted through 100 mesh sieve and stored in a desiccator till further studies.
Ternary solid dispersions containing SER, NIC and tween 80 in weight ratios
50:50:5 (SDS7) and 65:35:5 (SDS8) were prepared by the same procedure as discussed
above. The only difference is that the drug was mixed in tween 80 and then added
to molten carrier.
Similarly, solid dispersions containing SER, NIC, tween 80 and oleic acid in
the weight ratios 50:50:5:5 (SDS9) and 65:35:5:5 (SDS10) were prepared by mixing
drug with tween 80 and oleic acid and then added to molten carrier. Rest of
the procedure is same as mentioned in the preparation of binary solid dispersions.
Content uniformity analysis: Drug content in all the Solid Dispersions
(SDs) and Physical mixtures (Pms) were evaluated in methanol Using Ultraviolet
(UV) spectrophotometer (Perkin Elmer, Bangalore, India) at 302 nm. The absorbance
was recorded at 302 nm against a blank solution containing equivalent amount
of nicotinamide in methanol to overcome the absorbance of nicotinamide.
Saturation solubility studies: Weighed amounts of each sample (SER,
solid dispersions and physical mixtures) equivalent to 100 mg of drug, were
separately introduced into 25 mL stoppered conical flasks containing 10 mL of
distilled water. All the flasks were shaken on a water bath shaker for 72 h
at 37°C and equilibrated for 2 days. Aliquots were passed through 0.2 micron
filter (Millipore, Bangalore, India) and the filtrates were suitably diluted
with methanol and analyzed on a UV spectrophotometer. The samples were studied
in triplicate for saturation solubility.
Phase solubility studies: The phase solubility studies were conducted
as per the method reported by Higuchi and Connors (1965).
Excess drug was added into 25 mL stoppered conical flasks containing 10 mL of
aqueous solution (0-1% w/v) of NIC. The flasks were shaken on a water bath shaker
at 37°C, for 72 h and equilibrated for 2 days. Preliminary experiments have
been carried out which showed that this time period was sufficient to assure
saturation. After attaining the equilibrium, all the saturated solutions were
filtered through a membrane filter (0.2 micron) and the filtrates were suitably
diluted and analyzed at 302 nm against the blank having same concentration of
NIC as that of sample. All the data were the average of three determinations.
Similarly, phase solubility studies of SER were carried out in NIC solutions
in presence of 1% w/v tween 80 alone and in combination with 1% w/v oleic acid.
Calculation of complexation constants from the phase solubility studies:
The aqueous solubility of pure SER was found to be 16.69 μg mL-1.
The solubility increased in a non-linear fashion in presence of NIC suggesting
the formation of higher order complexes. So, the interaction between the drug
and NIC was studied by assuming that both 1:1 and 1:2 complexes were formed.
The complexation constants and fit parameters multiple R2 and F-values
were calculated as determined by Aggarwal and Jain (2011)
and the method is given below. The closer R2 approaches 1 and the
higher the F-value, the better the fit.
Complexation for a system in which 1: l and 1:2 complexes of a substrate S
with a ligand L are formed is represented by Scheme 1:
In Eq. 1 and 2, where, So is
the equilibrium solubility of the substrate, [L] is the concentration of free
ligand, [SL] is the concentration of the 1:1 complex, [SL2] is the
concentration of the 1:2 complex and K1:1 and K1:2 are
the 1:1 and 1:2 complexation constants, respectively.
Phase solubility profile of SER in aqueous solution of NIC was shown in four
different ways which corresponds to four different conditions as:
||Linear fit assuming [L]~[Lt]
||Linear exact fit
||Parabolic fit assuming [L]~[Lt]
||Exact parabolic fit
where, [Lt] is total ligand concentration.
In vitro dissolution studies: Dissolution tests of the pure drug,
SDs and PMs (equivalent to 0.1 g drug) were performed in vitro using
the dissolution apparatus type II paddle method at 37±0.5°C for 4
h, with a stirring rate of 50 rpm, in 900 mL of a dissolution medium of enzyme-free
simulated intestinal fluid (pH 7.4±0.1). Samples were collected at different
time intervals with replacement of an equal volume of temperature equilibrated
dissolution medium. The samples were filtered through a 0.2 μm membrane
filter and the concentration of the drug was determined by UV spectrophotometry.
Blank experiments with nicotinamide were also performed at the same wavelength
for correction. All samples were analyzed in triplicate.
Fourier transform infrared (FTIR) spectroscopy: FTIR spectroscopy can
be used to study the extent of interactions between drug and NIC by detecting
the variation in the energy distribution of the interactions between drug and
To collect the spectra using FTIR spectrophotometer (Type Spectrum RX 1, California,
USA), small amount of each material (pure drug, NIC, PMs and SDs) was compressed
in KBr pellets. All the samples were dried overnight in a desiccator to avoid
the effect of moisture. The IR spectra were obtained in the spectral region
of 4000-500 cm-1 using a resolution of 2 cm-1 and 4 scans.
Powder X-ray diffraction (PXRD): The crystallinity of the pure drug,
NIC, all PMs and SDs were determined using X-ray diffractometer (XPERT-PRO,
Mumbai, India). Samples were scanned in a 2θ range from 5-50°.
Differential Scanning Calorimetry (DSC): The thermal behavior of pure
drug, NIC, PMs and SDs were investigated using a differential scanning calorimeter
(NETZSCH-204F1 Phoenix, AZ, USA) in the range of 25-600°C (heating rate
Content uniformity analysis: All the solid dispersions exhibited good
content uniformity. The content of SER (data not shown) in PMs and all the SDs
were found to vary from 98.22 to 101.9%.
Phase solubility study: The solubility of SER was enhanced significantly
by NIC in a nonlinear fashion as a function of NIC concentration (Fig.
1c, 2c, 3c) indicating an Ap
type of phase solubility diagram (Higuchi and Connors, 1965).
So, at lower concentrations of NIC, 1:1 complexation occurred between drug and
NIC while at higher concentrations 1:2 complexation occurred. A representation
of the data with the fitted parabola and the linear fit are shown in Fig.
1-3. The apparent stability constants (K1:1 and
K1:2) were calculated along with the fit parameters from the phase
solubility data and are given in Table 1.
An indication of the process of transfer of SER from pure drug to aqueous solution
of NIC was obtained from the values of Gibbs free energy change (ΔGtr°)
(Patel et al., 2008) and was calculated using
the following equation and given in Table 2:
Δgtr° = -2.303RT log (Sc/So)
where, Sc/So is the ratio of molar solubility
of SER in aqueous solution of NIC containing 1% tween 80 alone or in combination
with 1% oleic acid to that in pure water.
||Phase solubility profile of SER in aqueous solution of nicotinamide,
(a) Linear fit assuming [L]~[Lt], (b) Linear exact fit, (c) Parabolic
fit assuming [L]~[Lt] and (d) Exact parabolic fit, where, [L]
is concentration of free ligand, [Lt] is total ligand concentration,
So is the equilibrium solubility of the substrate, St
is total substrate concentration
|| Apparent stability constants along with fit parameters for
the interaction between sertaconazole and nicotinamide
|K1:1: Apparent stability constant for 1:1 complexation between
drug and NIC, K1:2: Apparent stability constant for 1:2 complexation between
drug and NIC, R2: Goodness-of-fit correlation coefficient, F: Ratio of the
regression mean square to the residual mean square, M: Molar, [L]: Concentration
of free ligand, [Lt]: Total ligand concentration
|| ΔGtr° values for the transfer of SER
from water to aqueous solutions of NIC
|kJ: Kilojoules, Δgtr°: Gibbs free energy
||Phase solubility profile of SER in aqueous solution of nicotinamide
containing 1% w/v tween 80 by, (a) Linear fit assuming [L]~[Lt],
(b) Linear exact fit, (c) Parabolic fit assuming [L]~[Lt] and
(d) Exact parabolic fit, where, [L] is concentration of free ligand, [Lt]
is total ligand concentration, So is the equilibrium solubility
of the substrate, St is total substrate concentration
Saturation solubility studies: The solubility of physical mixtures and
the solid dispersions are given in Table 3.
|| Saturation solubility of SER from physical mixtures and solid
|SD: Standard deviation
||Phase solubility profile of SER in aqueous solution of nicotinamide
containing 1% w/v tween 80 and 1% w/v oleic acid by, (a) Linear fit assuming
[L]~[Lt], (b) Linear exact fit, (c) Parabolic fit assuming [L]~[Lt]
and (d) Exact parabolic fit, where, [L] is concentration of free ligand,
[Lt] is total ligand concentration, So is the equilibrium
solubility of the substrate, St is total substrate concentration
|| Summary of wave numbers of different functional groups for
SER, NIC, physical mixtures and solid dispersions
Substantial improvement of 9.9 fold increase in solubility was obtained in
case of solid dispersion (SDS6) whereas 31.3 fold was obtained in solid dispersion
SDS8 and 249.9 fold in SDS10. A remarkably improved solubility of drug was also
seen in the ternary SDs and oleic acid based SDs as compared to the binary systems.
In vitro dissolution studies: The dissolution behavior of SER
from PMs and SDs is shown in Fig. 4. It can be seen from these
figures that the dissolution rates of pure SER were very low with less than
7% drug dissolved after 4 h. It is also demonstrated that NIC enhanced the drug
dissolution rate in binary SDs as compared to PMs. It can also be seen that
dissolution rate was increased further in ternary solid dispersions and in oleic
acid based solid dispersions.
Fourier transform infrared (FTIR) spectroscopy: SER showed IR bands
at (cm-1) 1308 (C-O-C ether stretch), 1461 (C = C aromatic stretch),
1637 (C = N aromatic stretch), 1385 (C-N aromatic stretch), 793 (C-Cl stretch)
and NIC displayed important bands at (cm-1) 3365 and 3160 (N-H stretch)
and 1679 (C = O stretch) (Table 4). Table 4
also showed the various IR bands in different physical mixtures and solid dispersions.
Differential Scanning Calorimetry (DSC): DSC scans of SER, NIC, their
PMs and SDs are shown in Fig. 5. The DSC scan of SER and NIC
showed melting peaks at 156.6 and 136.9°C, respectively with an enthalpy
of fusion 83.23 and 194.63 J g-1.
Powder X-ray diffraction (PXRD): PXRD pattern of SER, NIC, their PMs
and SDs are shown in Fig. 6. The powder X-ray diffractogram
of SER showed 2θ values at 15.5, 17.11, 18.86, 20.94, 23.19, 24.62 and
28.09 indicating a high crystallinity. NIC also exhibited crystallinity as indicated
by distinctive peaks at 2θ values of 11.40, 14.86, 19.56 and 22.28.
Phase solubility study: The nonlinear solubility behavior of SER in
the presence of NIC might be due to the aromaticity (π-system) of the pyridine
ring in NIC (Aggarwal and Jain, 2011; Rasool
et al., 1991).
Comparison of the values of R2 and F statistical fit parameters
shows clearly that the data were best represented by the parabolic regression
method with approximate fit in all the systems.
The negative values of Gibbs free energy change are indicative of the spontaneity
of reaction between SER and NIC.
||Dissolution profile of physical mixtures (PMS1, PMS2, PMS3,
PMS4, PMS5, PMS6), binary solid dispersions (SDS1, SDS2, SDS3, SDS4, SDS5,
SDS6), ternary solid dispersions (SDS7, SDS8) and self emulsifying solid
dispersions (SDS9, SDS10) of sertaconazole
From Table 2, a decrease in Gibbs free energy change was
observed with increase in carrier concentration indicating that reaction became
more favorable with increase in concentration of nicotinamide. The values of
Gibbs free energy change decreased further when 1% w/v tween 80 was added to
the NIC solutions indicating that the reaction was more favorable in presence
of tween 80. The values further decreased when both 1% w/v tween 80 and 1% w/v
oleic acid were added to the NIC solutions indicating that spontaneity further
increased in presence of both tween 80 and oleic acid.
Saturation solubility studies: The solubility enhancement of SER from
the PMs might be due to the solubilization effect of nicotinamide. Whereas,
the solubility enhancement of SER from binary SDs might be due to decrease in
crystallinity of the drug and also due to a highly dispersed state of the drug
in the SDs resulting in its higher wettability (Marin et
al., 2002) as shown by XRD and DSC results.
In ternary SDs, tween 80 might improve the wettability and solubilize the non-molecularly
dispersed or crystalline fraction of SER (Okonogi and Puttipipatkhachorn,
2006). On the other hand, the enhancement in aqueous solubility of SER from
oleic acid based SDs might be due to the microemulsifying effect of oleic acid
when coming in contact with water along with the solubilizing effect of tween
80 (Heo et al., 2005).
In vitro dissolution studies: There might be several factors
for the enhancement of dissolution of SER from binary systems which includes
increased wettability and dispersibility, lack of crystallinity and particle
size reduction (Chaulang et al., 2008; Ford,
1986; Martinez-Oharriz et al., 2002). In
PMs, dry mixing of drug with a hydrophilic carrier probably resulted in reduction
of the electrostatic charges which tend to keep drug particles united together.
||DSC thermograms of, (a) SER, (b) NIC, (c) PMS3, (d) PMS4,
(e) PMS5, (f) SDS3, (g) SDS4, (h) SDS5, (i) SDS8 and (j) SDS10
||PXRD pattern of, (a) SER, (b) NIC, (c) PMS3, (d) PMS5, (e)
SDS3, (f) SDS5, (g) SDS8 and (h) SDS10
Whereas, in binary SDs, drug was dissolved in the melted NIC during the preparation
of the system and fast cooling yielded a very fine dispersion of SER particles
into the NIC matrix (Ahuja et al., 2007).
In ternary SDs, it was supposed that tween 80 decreased the surface tension
of the drug. This led to very high interaction of drug to tween 80 and increased
drug wettability (Okonogi and Puttipipatkhachorn, 2006).
Synergistic effect on drug dissolution was shown when tween 80 and oleic acid
were combined and incorporated into NIC-based SDs. It could be due to the formation
of fine, submicronized emulsion trapping poorly water-soluble drug as very fine
particles or dispersions when exposed to gastrointestinal fluid (Heo
et al., 2005).
Fourier transform infrared (FTIR) spectroscopy: The IR spectra of binary
systems were the addition spectra of both drug and NIC and hence, proved the
absence of any chemical incompatibility between NIC with SER. Addition of tween
80 alone and oleic acid did not appear to affect the solid state characteristics
of SER significantly (Ahuja et al., 2007; Newa
et al., 2008).
Differential Scanning Calorimetry (DSC): Binary systems PMS3 and SDS3
(SER:NIC ratio 65:35) showed sharp peaks at 103.04 and 103.38°C with an
enthalpy of fusion 91.84 and 41.65 J g-1, respectively. In binary
systems PMS4 and SDS4 having more carrier, the DSC scan even showed only one
but slightly broad endothermic peak corresponding to the melting of carrier
at 102.84 and 105.55°C with enthalpy of fusion 106.81 and 33.31 J g-1,
respectively. With further increase in carrier (30:70) in case of PMS5 and SDS5,
the DSC scan showed the endotherms of both the drug and the carrier at 116.8
and 103.5°C with enthalpy of fusion 17.33 and 35.29 J g-1 for
physical mixture and 117.5 and 107.7°C with enthalpy of fusion 49.04 and
27.75 J g-1 for solid dispersion. Therefore, SER was shown to form
eutectics with NIC at around 65% w/w concentration of drug in the mixture.
Almost same thermal behavior as that of binary systems was shown by ternary
solid dispersion (SDS8) and oleic acid based dispersion (SDS10) which further
proves the facts shown by FTIR studies. Only difference is that the incorporation
of tween 80 alone and both tween 80 and oleic acid into drug-NIC system resulted
in more shift in the peak temperature (Tm) of the endotherms displayed
by the carrier as compared to that in the case of binary systems indicating
that the presence of the drug affected the lattice energy of the crystalline
NIC even more in ternary SDs and oleic acid based SDs than in the binary systems.
Similar effect was seen in the solid dispersions of naproxen and polyethylene
glycol containing surfactant (Mura et al., 1999).
Powder X-ray diffraction (PXRD): The PXRD patterns of the binary systems
(Fig. 6) showed the characteristic peaks of both NIC and drug
but the height of the characteristic peaks of the drug decreased extensively
in all the binary systems. Some peaks were even absent in the binary systems.
There was only some physical interaction but no chemical interaction between
drug and the carrier which was suggested by relative reduction of diffraction
intensity and absence of some peaks in binary SDs and further no new peaks were
observed. Similar behaviour was shown by solid dispersions of nifedipine in
Pluronic F68 and Gelucire 50/13 in 1:1 ratio, UC-781 in PEG (polyethylene glycol)
6000 and etoricoxib in PEG (Vippagunta et al., 2002;
Damian et al., 2002; Suhagia
et al., 2006).
PXRD spectra of ternary SDs and oleic acid based SDs (Fig. 6)
further confirmed the study of FTIR and DSC as similar patterns were obtained
in these systems as that of binary systems (Okonogi and
Puttipipatkhachorn, 2006; Mura et al., 1999).
These SDs only caused a further decrease in intensity of the peaks as compared
to binary systems indicating an increase in the amorphous content of drug in
A significantly high dissolution rate was achieved by ternary solid dispersions
and oleic acid based dispersions containing high drug content. Solid state studies
showed that high solubility and dissolution rate from these solid dispersions
might be due to decrease in the crystallization of drug. Solution state studies
showed a profound increase in the interaction between sertaconazole and nicotinamide
in the presence of tween 80 and oleic acid as shown by very high solubility
and dissolution rates in presence of these excipients. So, these oleic acid
based solid dispersions could be considered as better choice of treatment in
dermatological and gynaecological infections with fast release and achieving
good patient compliance.
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