assessment of solubilization characteristics of different surfactants

8/12/2019 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.

S. Chakraborty et al. / Journal of Colloid and Interface Science 335 (2009) 242249 243


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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.

244 S. Chakraborty et al. / Journal of Colloid and Interface Science 335 (2009) 242249
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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.

246 S. Chakraborty et al. / Journal of Colloid and Interface Science 335 (2009) 242249


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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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