assessment of solubilization characteristics of different surfactants
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Assessment of solubilization characteristics of different surfactants
for carvedilol phosphate as a function of pH
Subhashis Chakraborty, Dali Shukla, Achint Jain, Brahmeshwar Mishra, Sanjay Singh *
Department of Pharmaceutics, Institute of Technology, Banaras Hindu University, Varanasi 221 005, India
a r t i c l e i n f o
Article history:
Received 14 January 2009Accepted 4 March 2009
Available online 5 April 2009
Keywords:
Carvedilol phosphate
Surfactant
Colloidal drug delivery system
pH dependent solubility
Solubilization characteristics
a b s t r a c t
The effect of surfactants on the solubility of a new phosphate salt of carvedilol was investigated at differ-
ent biorelevent pH to evaluate their solubilization capacity. Solutions of different classes of surfactantsviz., anionicsodium dodecyl sulfate (SDS) and sodium taurocholate (STC), cationiccetyltrimethylam-
monium bromide (CTAB) and non-ionicTween 80 (T80) were prepared in the concentration range of
535 mmol dm3 in buffer solutions of pH 1.2, 3.0, 4.5, 5.8, 6.8 and 7.2. The solubility data were used
to calculate the solubilization characteristics viz. molar solubilization capacity, water micelle partition
coefficient, free energy of solubilization and binding constant. Solubility enhancement in basic pH was
in following order: CTAB > T80 > SDS > STC. CTAB and T80 showed remarkable solubility enhancement
in acidic pH as well. Among the anionic surfactants, solubility in acidic medium was retarded except
at pH 1.2 in case of SDS. Cationic and non-ionic surfactants were found to be suitable for enhancing
the solubility of CP which can be employed for maintaining the in vitro sink condition in the basic dis-
solution medium. While anionic surfactants showed solubility retardant behavior which may be
exploited in increasing the drug entrapment efficiency of a colloidal drug delivery system formulated
by emulsification technique.
2009 Elsevier Inc. All rights reserved.
1. Introduction
The key biopharmaceutical parameters responsible for effective
bioavailability and good in vitro in vivo correlation are the drugs
solubility and permeability [1]. Especially in case of ionizable
drugs, their solubility, dissolution and level of sink condition
(when the saturation solubility is at least three times more than
the drug concentration in the dissolution medium as outlined in
USP) will depend upon the degree of ionization in the dissolution
medium at different pH [24]. Several approaches to achieve the
sink condition in the dissolution medium include increasing the
volume of the aqueous medium or removing the dissolved drug,
solubilization of the drug by co-solvents up to 40%, addition of cat-
ionic, anionic or non-ionic surfactants to the dissolution mediumabove critical micelle concentration (cmc) and use of a hydroalco-
holic surfactant solution[5,6]. Of the above mentioned methods,
the use of media containing surfactants is the most popular meth-
od because of its simulation with various surfactants present in the
gastrointestinal fluid, e.g., bile salts, lecithin, cholesterol and its es-
ters[1,7]. Surfactant monomers above their cmc, aggregate to form
colloidal moieties known as micelles which are capable of encap-
sulating the drug molecules resulting in reduction in the interfacial
tension and improved solubility of the drug in the medium. Ionic
surfactant may preferably solubilize oppositely charged species
than uncharged or similarly charged species. However, there may
be cases where oppositely charged species and surfactant may
interact to form an insoluble salt and result in desolubilization as
reported in case of erythromycin and PG-300995 (an anti-HIV
agent) after addition of sodium dodecyl sulfate due to the forma-
tion of an estolate salt [8,9].
Carvedilol (()-1-(Carbazol-4-yloxy)-3-[[2-(o-methoxyphen-
oxy) ethyl] amino]-2-propanol) is an alpha and beta blocker used
to treat high blood pressure and heart failure. Carvedilol is practi-
cally insoluble in water and exhibits pH dependent solubility. Its
solubility is
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Our interest in CP arose from the finding in our laboratory that
though the salt had a significantly improved aqueous solubility
over the free base, its solubility in the intestinal pH range was
0.999. Absorbance of samples was
measured using blank as distilled water or buffer solutions with/
without the appropriate molar concentration of surfactants as in
the sample. Samples containing surfactants at all concentrationwere scanned everytime to detect any shift in kmax.
2.2.2. Solubility study in water
Drug was added in incremental amount (1060 mg) in six con-
ical flasks each containing 20 ml of distilled water. The flasks were
tightly corked and placed in a thermostated water bath at
37.0 0.5C agitated at 70 rpm for at least 24 h. Samples were ta-
ken at 8, 12, 16 and 24 h to ensure that the equilibrium solubility
had been reached. After this period, aliquots were withdrawn, fil-
tered through 0.45-lm filter, diluted with the medium and thedrug concentration in the final sample solutions was determined
spectrophotometrically. Each solubility value was determined in
triplicate and the results reported are the mean of the three. All
the glassware and filters used were maintained at 37 2.0 C priorto the experiment to avoid precipitation of drug during analysis.
2.2.3. Solubility study in buffer
pH 1.2 hydrochloric acid buffer solution, pH 3.0 acid phthalate
buffer, pH 4.5acetatebuffer andpH 5.8, 6.8and 7.2potassium phos-
phate buffers were prepared as per USP. The buffers were prepared
using freshly prepared double distilled water. The ionic strength
(IS)of the media was adjustedto 0.1 M (representativeof physiolog-
icalIS) withsodiumchloride [18].Thesolubilityofdruginthebuffers
was measured in the similar manner as in water.
2.2.4. Solubility study in buffer with surfactants
Solutions containing different concentration of surfactants at
their respective cmc and in the range of 535 mmol dm
3
wereprepared in above mentioned freshly prepared buffer solutions.
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The solubility study of drug in these solutions was carried out in
similar manner as in buffer solutions using excess amount of the
drug. The solubility data were used to calculate the solubilization
characteristics using their respective equations.
3. Results
3.1. Solubility in distilled water and buffer solutions
Solubility of the drug in distilled water and buffer solutions was
checked to study the impact of excess solids on the apparent solu-
bility[19]. The results indicated a significant and gradual increase
in solubility of drug (0.22.8 mg/ml) in water with increase in the
excess drug quantity (supporting information). At the end of
equilibration (after 24 h), it was found that the pH of water
(7.0) reduced with the increase in amount of excess drug
(approximately by 22.5 U). Higher the amount of drug added,
more was the shift towards lower pH.
In case of buffer solutions, the variation in solubility upon equil-
ibration with similar increase in the drug amount was insignificant
and the reduction in pH was found to be within 0.10.2 U (support-
ing information). Solubility at different pH was in following order:
pH 3.0 > pH 4.5 > pH 1.2 > pH 5.8 > pH 6.8 > pH 7.2, as shown in
Fig. 1.
3.2. Solubility in buffer solutions with surfactant
In order to judge the effect of surfactants on solubility, the buf-
fer solutions used have been divided in two broad groups; acidic
solutions (pH 1.2, 3.0 and 4.5) and basic solutions (pH 5.8, 6.8
and 7.2).
3.2.1. Effect of SDS
The effect of SDS concentration on the solubility of CP at differ-
ent pH is presented inFig. 2. With 5 mmol dm3concentration of
SDS, there was a drastic reduction in solubility in acidic solutions
while an increase in solubility was observed in basic solutions. Atthis concentration, the solubility was almost same at all pH, indi-
cating no effect of variation in pH on drug solubility. Throughout
the pH range studied, the solubility increased gradually with fur-
ther increase in the SDS concentration up to 35 mmol dm3. In
comparison to the drugs solubility at different pH without
surfactant, the solubility with the highest concentration of SDS
was found to be reduced in acidic solutions except at pH 1.2 and
significantly increased in basic solutions. The solubility at
8.1 mmol dm3
(cmc of SDS)[20] concentration was found to liebetween the solubility range of 5 and 10 mmol dm3 solutions.
The difference in solubility due to change in pH was minimal at
all SDS concentrations studied than in absence of SDS.
3.2.2. Effect of STC
The effect of STC concentration on the solubility of CP at differ-
ent pH is presented inFig. 3. The solubility was found to reduce at
all pH on addition of STC at 3 mmol dm3 (cmc of STC is 3
11 mmol dm3) [21] and 5 mmol dm3 concentration. However,
at 10 mmol dm3 concentration, the solubility reduced signifi-
cantly in acidic solutions and no marked change in solubility was
observed in basic solutions. In this case, similar solubility values
at all pH were attained at 10 mmol dm3 concentration. As the
concentration of STC was increased from 10 to 35 mmol dm
3
,the increase in solubility was observed throughout the pH range
studied. Similar pattern of reduced pH dependence of drug solubil-
ity, as in case of SDS, was observed at and above 10 mmol dm3
concentration of STC.
3.2.3. Effect of T80
The effect of T80 concentration on the solubility of CP at differ-
ent pH is presented inFig. 4. The solubility in presence of T80 was
found to increase continuously from 5 to 35 mmol dm3 concen-
Fig. 1. Solubility of CP in buffers of different pH.
Fig. 2. Effect of concentration of SDS on solubility of CP in buffers of different pH.
Fig. 3. Effect of concentration of STC on solubility of CP in buffers of different pH.
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tration at all pH solutions. The increase in solubility at the highest
concentration of T80 was approximately 2.53 times at pH 3.0 and
4.5, 10 times at pH 1.2 and 5.8, 25 times at pH 6.8 and 40 times at
pH 7.2 than the solubility of the drug in the buffer solutions with-
out surfactant. The increase in solubility at cmc level
(0.012 mmol dm3)[17]of T80 was not significant than the solu-
bility without surfactant at all pH.
3.2.4. Effect of CTAB
The effect of CTAB concentration on the solubility of CP at dif-
ferent pH is presented in Fig. 5. Results of solubility study of CP
in presence of CTAB were quiet similar to that of T80. Solubility
was found to increase linearly with increase in surfactant concen-
tration at all pH which was comparatively higher than that
achieved in presence of T80. The increase in solubility at the high-
est surfactant concentration was approximately 34 times at pH
3.0 and 4.5, 1319 times at pH 1.2 and 5.8 and 56 times at pH
6.8 and 75 times at pH 7.2. Unlike anionic surfactants, the solubil-
ity of CP at cmc level of CTAB (0.81 mmol dm3)[12]was higher
than that of its solubility in absence of surfactant and lower than
that observed with higher concentrations of CTAB.
The solubility data were used to calculate the molar solubiliza-
tion ratio (Fig. 6), micellewater partition coefficient (Fig. 7), free
energy of solubilization (Fig. 8) and binding constant (Fig. 9).
Fig. 4. Effect of concentration of T80 on solubility of CP in buffers of different pH.
Fig. 5. Effect of concentration of CTAB on solubility of CP in buffers of different pH.
Fig. 6. Comparison ofv values of the surfactants for CP at different pH.
Fig. 7. Comparison ofPm values of all four surfactants for CP at different pH.
Fig. 8. Comparison ofDGs values of all four surfactants for CP at different pH.
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4. Discussion
4.1. Solubility in water and in buffer without surfactant
It was reported recently that the amount of excess drug added
for solubility studies may have a significant effect on the apparent
solubility, likely to be caused by a competition between the crys-
tallization and dissolution rates [19]. To confirm the same phe-
nomenon in the present work, preliminary solubility studies
were carried out in water and buffer solutions with addition of
incremental quantities of the drug. The increase in solubility of
the drug in water can be attributed to its lack of buffering capac-
ity. As the drug comes in contact with water, it undergoes ioniza-
tion to release phosphate ions. The amount of phosphate ions
released depends on the amount of drug in contact with waterwhich results in increase in acidity. This in turn increases the sol-
ubility of the drug as it exhibits pH dependent solubility and is
more soluble at lower pH (higher solubility at pH 34.5 than
pH 57) as shown in Fig. 1. Thus, the increase in solubility of
the drug as a function of its quantity is a self induced phenome-
non which indicates that the solubility of the phosphate salt of
carvedilol in water cannot be measured exactly. The implication
of the above observation to the salt form of other drugs is yet
to be ascertained.
On the other hand, the buffering capacities of the buffered solu-
tions are sufficient enough to resist the pH change due to release of
phosphate ions, thus preventing significant variations in solubility.
Fig. 1 indicates that CP exhibits pH dependent solubility. The
solubility increases with the decrease in pH up to 3.0 due to in-crease in the ionization of the drug. This may be attributed to the
presence of an alpha-hydroxyl secondary amine functional group,
which has a pKaof 7.8. However, CP undergoes in situ protonation
in the gastric medium of pH 12 to generate its corresponding HCl
salt which has limited solubility in such medium[10].
4.2. Solubility in buffer solutions with surfactant
Anionic surfactants were selected based on the fact that the
electrostatic interactions between the oppositely charged surfac-
tant and drug molecules would cause a decrease in the repulsive
forces between the head groups of the surfactant molecules, con-
tributing to enhanced solubilization[14]. However, the results ob-
tained in both the anionic surfactants (SDS and STC) werecontradictory to the above hypothesis in acidic solutions where
the drug exists predominantly in cationic state except at pH 1.2.
4.2.1. Effect of SDS
The effect of SDS on the solubility profile of CP at different pH is
shown inFig. 2. The profile reflects an increasing trend in solubility
except a drop at 5 mmol dm3(below cmc) concentration in acidic
solutions. In acidic solutions of pH 3 and 4.5, the overall solubility,
even with the highest concentration of SDS used, remains drasti-
cally below the baseline level obtained without surfactant. This
phenomenon can be explained on the basis of the ionic state of
the molecules (Fig. 10). As the drug is basic in nature (pK a 7.8),
its ionization, hence solubility increases with the decrease in pH.
SDS being an anionic surfactant (pKa 1.9) shows its surface active
properties only in ionized state. It is approximately 10% ionized
in 0.1 N HCl and its ionization and hence wetting property in-
creases with pH[22]. Therefore, in acidic solutions, the drug exhib-
its its ionic (cationic) state while SDS is predominantly in the non-
ionic state which is less capable of increasing solubility. The
remaining molecules of SDS in the ionic state (anions) interact with
the cationic species of drug to form an insoluble salt which precip-
itates out resulting in desolubilization of the drug. This phenome-
non, in acidic solutions at low SDS concentration, is responsible for
the overall reduction in solubility. Similar interactions of SDS have
been reported with erythromycin and an anti-HIV agent [8,9]. In
basic solutions, the drug is predominantly in the non-ionic state
which is unsuitable for ionic interaction while the surfactant is in
ionic (anionic) state which is highly suitable for exhibiting surface
active properties. This results in a favorable situation for solubilityenhancement. Increase in basicity results in higher solubilization
due to less ionic interaction and higher surface activity of SDS.
The solubilization capacity of surfactants below cmc is due to their
wetting property which results in increased effective surface area
for solubilization and dissolution by deaggregation of drug parti-
cles while above cmc it is due to micellar solubilization [23]. On
increasing the concentration of SDS above cmc (10 mmol dm3),
a rise in solubility is observed at all pH due to solubilization of
insoluble salt formed, by entrapment in the micelles. Increase in
SDS concentration (1535 mmol dm3) results in increase in the
number of micelles which further enhances the solubility.
4.2.2. Effect of STC
The cmc and pKa of STC has been reported to be 3-11 mmol dm3 and 1.4, respectively[21,24]. At 3 mmol dm3 con-
centration, the solubility of the drug is reduced at all pH solutions
with further reduction at 5 mmol dm3concentration which is
more pronounced in acidic than in basic solutions (Fig. 3). The rea-
sons may be similar to that as explained with SDS as it is also an
Fig. 9. Comparison ofKvalues of all four surfactants for CP at different pH.
Fig. 10. Effect of pH on ionization of CP and SDS.
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anionic surfactant with comparable pKa v alue. Up to
10 mmol dm3 STC concentration, the trend of solubility reduction
continues in the acidic solutions while there was no marked
change in solubility in the basic solutions. With further increase
in the surfactant concentration above the cmc (15 mmol dm3), a
rise in solubility is observed throughout the pH range indicating
micellar solubilization of the insoluble salt formed, which contin-
ues further with increase in the surfactant concentration (25 and35 mmol dm3) due to increased number of micelle available for
solubilization. Like SDS, even with the highest concentration of
surfactant at pH 3.0 and 4.5, the solubility remained well below
that obtained in pure buffer solutions.
The above observation can be extended to explain the pharma-
cokinetic and pharmacodynamic behavior of the drug in the hu-
man body. The bile salt concentration in the duodenum and
upper jejunum are approximately 23 times higher in fed state
(1015 mmol dm3; range 335 mmol dm3), as compared to fast-
ing conditions (5 mmol dm3, range 014 mmol dm3) [2527].
Thus, the absorption of BCS Class II drugs like CP [28]showing dis-
solution rate limited uptake should enhance, when administered in
the fed state, due to the surfactant effects of bile components. This
is in agreement with the result of clinical trials reported in litera-
ture [29]. Administration of extended release capsule of CP with
a high-fat meal resulted in increase in AUC (20%) and Cmax when
compared with administration with a standard meal. This increase
in bioavailability could be explained on the basis of higher STC (a
major bile salt component) concentration in fed state which fur-
ther increases in the presence of high-fat meal [30,31]. Increase
in the bile salt concentration helps in effective colloidal solubiliza-
tion in the intestine which may be the major factor responsible for
faster absorption and enhanced bioavailability of the drug[32]. A
decrease in AUC (27%) and Cmax (43%) were observed when the
capsules were administered in the fasted state compared to admin-
istration after a standard meal. The reason for reduced bioavailabil-
ity could be probably due to interaction between the drug and the
STC molecules below cmc. Therefore, the extended release capsules
of CP have been recommended to be taken with food.One of the less prevalent side effects of CP is increased levels of
serum glutamic pyruvic transaminase and serum glutamic oxaloa-
cetic transaminase enzymes, which are indicative of liver damage
[29]. Such incidences of liver damage may be correlated with the
present findings. CP undergoes extensive first pass metabolism
and is excreted primarily through bile into the feces. Liver releases
the un-metabolized and metabolized drug in the bile duct where
the former could interact with bile salts to cause its precipitation
and block the duct. Owing to bile secretory failure, bile salts and
other biliary constituents are retained in the hepatocyte and this
leads to progressive liver damage [33]. Such cases may occur
where the release of STC is below cmc where micellar solubiliza-
tion of the complex formed is not possible. Similar incidence of bile
secretory failure because of interaction of drug and STC has beenreported for chlorpromazine hydrochloride[34].
4.2.3. Effect of T80
Non-ionic surfactants have the potential to provide a combina-
tion of good molar solubilization capacity and high micellar con-
centration due to their extremely low cmc [13]. The solubility of
CP increases gradually at all concentrations (535 mmol dm3) of
T80, owing to micellar solubilization of the drug (Fig. 4). Being
non-ionic in nature, it does not exhibit any kind of ionic interac-
tion. It was observed that the solubilization effect is greater at high
pH than at low pH indicating better surface activity in the basic pH.
Due to the extremely low cmc level, a higher molar fraction of T80
is available in the micellar form which is responsible for exhibiting
comparatively higher solubility than other surfactants. From thepharmacological perspective, the lower cmc value of T80 is benefi-
cial in improving the stability of the drug incorporated micelles. As
on intravenous administration, large volume of the blood causes
dilution of the administered solution and only micelles of surfac-
tants with very low cmc value can exist, while micelles of surfac-
tants with high cmc value may dissociate into monomers and
their content may precipitate in the blood [35].
4.2.4. Effect of CTABCTAB is a cationic surfactant and it also has low cmc of
0.81 mmol dm3, although it is higher than T80. Being cationic, it
could exert repulsive electrostatic forces on coming in contact with
drug ions and reduce the chances of micellar entrapment of drug. It
was expected that it would show higher solubility enhancement
than anionic surfactant because of lack of ionic interaction, but
lower than non-ionic T80 owing to common ion repulsion between
drug and CTAB. However, to our surprise, the results were contrary
to above mentioned presumption. It yielded highest solubility
enhancement than all the surfactants in all the media (Fig. 5).
The reason can be related to its relatively higher N value (170) than
T80 (60) which is responsible for greater micellar size of CTAB
which helps to accommodate more drug molecules per micelle.
4.3. UVvis spectrum analysis
The possible interaction between CP and the ionic surfactants
was also observed in the UV spectrum (supporting information). A
red shift in theabsorption maxima of CP (240.2 nm) in thepresence
of both SDS and STC (approximately 56 nm and 23 nm shift was
observed with SDS and STC, respectively) is indicative of change in
themicroenvironmental polarityof CP probablydue to ionicinterac-
tion between the head group of SDS and STC and positively charged
alpha-hydroxyl secondary amine moiety of thedrug. Maximumshift
was observedat thecmclevelof thesurfactants.With theincrease in
the surfactant concentration above the cmc, the shiftreducedwhich
may bedue todecreasein polarityas a resultof incorporation ofdrug
molecules or complexesinto themicelles. Similarshift in theabsorp-
tion maximadueto ionicinteractionwasalso reportedby Shahet al.,[36]. The shift inkmax was found to beindependent of pH. No signif-
icant shift was observed in the UV spectrum of CP in the presence of
CTAB and T80indicatingabsenceof anykind of ionic interaction be-
tween the drug and surfactants.
4.4. Solubility characterization
The molar solubilization capacities (v) at the cmc values of the
different surfactants followed the following trend: CTAB > T80 >
SDS > STC (Fig. 6). The maximum v value of the ionic surfactants
is at pH 4.5, probably due to best balance between the ionic and
non-ionic species of the drug and surfactant molecules. The lowv values of STC and SDS in comparison to T80 and CTAB is probably
because of interaction between the cationic species of the drug andthe anionic species of the surfactants resulting in formation of an
insoluble salt. Thus, a part of the molar fraction is utilized in the
interaction while on further addition of these anionic surfactants
above cmc results in micellar solubilization. The involvement of
the surfactant molecules in the interaction causes an overall shift
in its effective cmc towards higher side resulting in reduced solu-
bilization. The relatively low vvalue of STC in comparison to SDS
can be discussed on the basis of their cmc values. It is evident from
Fig. 4 that the solubility of CP in presence of STC increases above
10 mmol dm3concentration, which indicates that this concentra-
tion of STC is insufficient for micelle formation. Therefore, as the
cmc level of STC is higher than SDS, more amount of the former
is required to achieve the same level of solubilization as in the
presence of the latter. Further, the v value of CTAB was lesser thanT80 at pH 3 which can be attributed to the electrostatic repulsion
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between the cations of surfactant and the drug. The increase in v
value of CTAB in comparison to T80 above pH 3 is due to the reduc-
tion in the electrostatic repulsion because of the increase in non-
ionic state of the drug. Another factor contributing to the increase
in v value of CTAB than T80 at higher pH is its Nvalue. Higher the N
value, larger will be the size of micelle and more will be number of
drug molecules per micelle. Therefore, CTAB with high N value
incorporates the maximum number of drug molecules within itexhibiting high solubility. On the other hand, STC with a very
lowNvalue shows very low solubilizing ability. The least solubiliz-
ing capacity of STC can also be explained on the basis of the molec-
ular weights of CP and STC (513.5 and 537.7, respectively). Due to
comparable molecular weight and extremely low Nvalue, the mi-
celle formed will not have adequate space to incorporate the drug
and/or the complex of either equal or larger size, respectively. Sim-
ilar case also exists with SDS of lower molecular weight (288.38)
but due to its larger Nvalue, it dominates over STC in terms of sol-
ubilization capacity.
As can be seen from Fig. 7, the water micelle partition coefficient
(Pm) of CTAB and T80 is higher than SDS and STC in basic pH range.
Further, SDS shows higher Pmthan STC for the same reason as dis-
cussedforv.T80exhibitshigher Pm thanCTAB which couldbe attrib-
uted to its extremely low cmc value for which it initiates micelle
formation at very low concentration. The higher micellar partition-
ingof T80than CTAB canbeexplained onthe basisof theirhydropho-
bic chain length: T80 (oleic acid-C18) and CTAB (hexadecyl group-
C16). Being lipophilic in nature, the drug would have higheraffinity
for a longer chain with higher hydrophobicity and hence higher
micellar partitioning. For all the surfactants, thePmincreases from
pH 3.07.2. This is because of increasing non-ionic nature of drug
at higher pH which causes better partitioning in the micelle, thus
reducing chances of interaction or electrostatic repulsion. In all
cases, the Pmvalue is higher at pH 1.2 than at pH 3.0. At pH 1.2, the
drug tends to form insoluble hydrochloride salt (non-ionic state)
which exhibitshigherpartitioning thanat pH 3.0where drugis max-
imum ionized and has minimumPmvalue.
DGs
is a measureof the interfacial thermodynamicinteractionofthesolubilizate andthe micelles, i.e.the energy utilizedin theforma-
tion of micelles and incorporation of the solute molecules within
them. A greater negative DGs indicates an energetically favorable
condition for the uptake of the solute within the micelles.DGs val-
ues obtained(Fig. 8) arenegative all throughout thesystemsindicat-
ing spontaneous solubilization. The values ofDGs follow exactly
similar trend as that ofPmbut on the negative side. Comparatively
larger negativeDGs values with high solubility data (i.e. v andPm)
were observed forCTAB and T80micellarsystemsin basic solutions,
showing effective solubilizationof CP by cationicand non-ionic than
anionic micellar system. Therefore, CTAB and T80 are the suitable
surfactants to be used to improve thesink condition duringdissolu-
tion study in the intestinal pH range.
Analyses of the binding constant values (Fig. 9) indicate thatirrespective of pH, STC micelles have the minimum affinity for
the drug molecules than the other surfactants as is also evident
from its solubility profile. Thus, STC can be selected as the best sur-
factant, to be used as solubility retardant throughout the pH range
studied. Its application becomes more specific in the development
of colloidal formulations for this drug. In colloidal formulations like
solid lipid nanoparticles, surfactants are essentially added in the
external dispersion medium to reduce the interfacial tension be-
tween the two immiscible phases which results in a thermody-
namically stabilized system [37]. However, the presence of
surfactant increases the solubility of the drug (usually with poor
aqueous solubility) in the external medium, resulting in reduced
drug entrapment into the colloidal particles during the emulsifica-
tion process. Therefore, surfactants capable of reducing the solubil-ity of drug in the external medium may play a significant role in
improving the drug entrapment efficiency of the colloidal particles,
along with stabilization of the system. On the other hand, the bind-
ing constant of SDS is highest among all the surfactants throughout
the pH range indicating the formation of a very stable insoluble
estolate salt[8]. If incorporated within the colloidal particles along
with the drug, its high affinity for the drug would be effective in
controlling the release of the drug.
5. Summary
The solubility of CP in the presence of different types and con-
centrations of surfactants, at different pH has been reported for
the first time in this study. Interestingly, our findings revealed that
the use of anionic surfactants significantly minimized the pH
dependent variation of the drugs solubility. While the micellar sol-
ubilization of the drug in presence of non-ionic and cationic surfac-
tants can be applied for the dissolution method development, the
solubility retarding property of the anionic surfactants may be uti-
lized for the stabilization and enhancing the drug entrapment effi-
ciency of colloidal formulations. Although the data presented in
this work is applicable to CP, we hope that the present investiga-
tion will provide pharmaceutical researchers, adequate insight
concerning the conduct of preformulation studies to select suitable
surfactants for formulation and dissolution method development
of colloidal drug delivery system of other drugs as well which
would save a great deal of valuable time and energy.
Appendix A. Supplementary data
The supporting information contains additional supplementary
material. Fig. S1 shows the chemical structure of CP. Table S1
shows the effect of excess amount of CP on its solubility in water
andTable S2shows the effect of excess amount of CP on its solu-
bility in buffer solutions.Table S3presents the shifts in the wave-
length maxima of CP in various buffer solutions containing
different surfactants at cmc. Supplementary data associated withthis article can be found, in the online version, at doi:10.1016/
j.jcis.2009.03.047.
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