Journal of Colloid and Interface Science 361 (2011) 42–48

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Journal of Colloid and Interface Science

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Effects of pharmaceutical excipients on cloud points of amphiphilic drugs

Andleeb Z. Naqvi ⇑, Malik Abdul Rub, Kabir-ud-DinDepartment of Chemistry, Aligarh Muslim University, Aligarh 202 002, India

a r t i c l e i n f o a b s t r a c t

Article history:Received 4 February 2011Accepted 14 May 2011Available online 26 May 2011

Keywords:Amphiphilic drugsCloud pointSurfactantsHydrotropesFatty acidsb-Cyclodextrin

0021-9797/$ - see front matter � 2011 Elsevier Inc. Adoi:10.1016/j.jcis.2011.05.037

⇑ Corresponding author.E-mail address: naqviaz@gmail.com (A.Z. Naqvi).

The clouding behavior, i.e., formation of phase separation at elevated temperature (the temperature beingknown as cloud point (CP)), of three amphiphilic drugs, amitriptyline (AMT), clomipramine (CLP) andimipramine (IMP) hydrochlorides in the presence of various additives, like cationic surfactants (conven-tional and gemini), nonionic surfactants, bile salts, anionic hydrotropes, sodium salts of fatty acids andcyclodextrin has been investigated. These additives are generally used as drug delivery systems. Thedrugs used are tricyclic antidepressants. All the surfactants increase the CP of mixed micelles formedby cationic (conventional and gemini) and nonionic surfactants. Hydrotropes, bile salts and fatty acidsalts, when added in low concentrations, increase the CP, whereas at high concentrations, they decreaseit. b-Cyclodextrin behaves as simple sugar and decreases the CP of the drug solutions.

� 2011 Elsevier Inc. All rights reserved.

1. Introduction

One of the most challenging tasks of a pharmaceutical scientistor chemist is to design drugs with good bioavailability. About 40%of the newly developed drugs have poor bioavailability due to pooraqueous solubility [1,2]. This causes a significant economic andtherapeutic loss. Organic solvents, surfactants or complexingagents [3–10] have been widely used to enhance the solubility.However, as the solubilization capacity of the cosolvents is low,their use as excipient is often limited.

Surfactant micelles are the most convenient and efficient drugcarrier systems as they have several advantages over other carriers.Firstly, surfactants form mixed micelles with the drugs, therebyreducing the amount of both the surfactant and the drug to beused. This, in turn, reduces the side effects and toxicity of boththe components. Secondly, it is easy to prepare surfactant micelleson large scale and also they have large shelf-lives. Thirdly, thephysico-chemical properties of drug-carrier systems can be tunedaccordingly simply by changing the structure and type of surfac-tant, without increasing the concentration of surfactant or thedrug. For example, use of dimeric surfactants (with two headgroups and two tails), instead of conventional surfactants (singlehead and single tail), may reduce the amount of carrier as theyform micelles at very low concentrations (around 100 times lowerthan that of conventional ones).

Another class of amphiphilic compounds which can be used assolubilizers or carriers of the drugs is the hydrotropes. These com-pounds also contain a hydrophobic and a hydrophilic part in a sin-

ll rights reserved.

gle molecule. The difference lies in their hydrophobic parts whichare much shorter than that of surfactants: they are generally a ben-zene (or phenyl) ring. Therefore, hydrotropes form aggregates athigh concentrations, in the order of 0.1–0.8 M.

Bile salts are yet another class of surfactants which can be usedas drug carriers. They have a rigid steroidal backbone with polarhydroxyl groups on the concave a-face and methyl groups on con-vex face. These salts are synthesized in the liver, concentrated ingall bladder and discharged through a biliary duct. Bile salt-phospholipid mixed micelles solubilize cholesterol and lipids[11]. It has been reported that the bile salts form mixed micelleswith the drugs also [12].

However, one of the characteristics of amphiphiles which maybe a disadvantage is the phase separation phenomenon. Nonionicsurfactants almost always and ionic surfactants and amphiphilicdrugs in special conditions exhibit phase separation [13–20].When aqueous solutions of these amphiphiles are heated to a cer-tain temperature, they undergo phase separation or clouding. Thetemperature at which phase separation occurs is known as cloudpoint or CP and it is a particular characteristic of the amphiphile.At and above this temperature the amphiphile solution separatesinto two phases: one rich in amphiphile content but small in vol-ume and other large in volume with amphiphile concentrationroughly equal to cmc. The mechanism by which phase separationoccurs is still not clear but the most plausible explanation givenis the decrease in hydration and increase in aggregation numberas the temperature is increased [21–23]. For non-ionic surfactants,although the CP is basically determined by its structure [24,25],presence of additives strongly affects it. The effects of variousadditives on the clouding have been extensively studied[17,19,26–30].

R1

R3

R2

R1 = C; R2 = H; R3 = >CH-CH2-CH2-N(CH3)2 for Amitriptyline Hydrochloride (AMT)

R1 =N; R2 = Cl; R3 = CH3-CH2-CH2-N(CH3)2 for Clomipramine Hydrochloride (CLP)

R1 =N; R2 = H; R3 = CH3-CH2-CH2-N(CH3)2 for Imipramine Hydrochloride (IMP)

Scheme 1. Molecular structure of amphiphilic drugs.

0 10 20 30 40 50

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50

60

70

80

90

CP

(ºC

)

Additive Concentration (mM)

Fig. 1. Effect of addition of cationic surfactants on the cloud point of 50 mM AMT(half filled), 50 mM CLP (open) and 100 mM IMP (full filled); s: DeTAB, h: DTAB, }:14-4-14, 4: 14-5-14, /: 14–6-14. The values for AMT are shifted 5 units on x-axis.

A.Z. Naqvi et al. / Journal of Colloid and Interface Science 361 (2011) 42–48 43

As the amphiphile-rich phase is small in volume and containsalmost all the amphiphile, the concentration of amphiphile in-creases many folds in that volume. Mouritsen and Jorgensen [31]have shown that drugs insert into membranes and affect the orga-nization of lipids. Computer simulations indicated that partitioneddrugs accumulate heterogeneously in the membranes. This accu-mulation may cause a localized high concentration. Such a highconcentration may change the drug’s biological activity due to de-creased ability to pass through biological barriers [32] and mayprove fatal. Therefore, it is necessary to have a good database ofCP variation, effect of various additives on CP and thermodynamicsof CP of amphiphilic drugs. Keeping all these points in mind wehave explored CP behavior of amphiphilic drugs in presence of dif-ferent classes of carriers. For this purpose three amphiphilic drugs,amitriptyline hydrochloride (AMT), clomipramine hydrochloride(CLP), and imipramine hydrochloride (IMP) were chosen. Thesedrugs belong to the class known as tricyclic antidepressants(TCAs). The pKa values of these drugs lie in between 9.1–9.5[33,34] and the structures are shown in Scheme 1. Till date wehave not seen in literature detailed study of the effect of differentclasses of drug carriers on the phase separation of drugs.

Major depressive disorder is a widely distributed illness in thegeneral public. As depression is a chronic disease and the patientsare less likely to remit spontaneously, different treatment strate-gies may be required for successful treatment. Use of TCAs is oneof the strategies. However, TCAs possess anticholinergic, cardiovas-cular and antihistamine effects [35]. To reduce these side effectsthese drugs are generally used with carriers. Use of micelles asdrug carriers presents advantages in comparison to other alterna-tives and makes them cost-effective as well as less toxic.

2. Materials and methods

The amphiphilic drugs, amitriptyline hydrochloride (AMT)(P98%), clomipramine hydrochloride (CLP) (P98%) and imipra-mine hydrochloride (IMP) (P98%) were purchased from Sigma,USA. Cationic surfactants, i.e., decyltrimethylammonium bromide(DeTAB) (P98%) and dodecyltrimethylammonium bromide (DTAB)(P98%) were products of TCI, Japan. Cationic gemini surfactants,alkanediyl – a, x – bis(dimethyltetradecylammonium bromides)with s = 4, 5, 6 were synthesized by the method given in literature[36,37]. Nonionic surfactants (Synperonic P 85 (S85), Synperonic F108 (S108), Triton X 114 (TX-114)) and b-cyclodextrin (99%) werepurchased from Fluka, Germany. Brij 56 and Brij 58 were Merck(Germany) products. Hydrotropes, sodium salicylate (NaSal)(99%), sodium benzoate (NaBenz) (99.5%) and sodium tosylate(NaTos) (75%) were, respectively, Fluka, Merck (India) and Flukaproducts and were used as received. The bile salts used were

sodium cholate (NaC, Sigma, USA) and sodium deoxycholate(NaDC, 97%, Sigma). Fatty acids, sodium myristate (99%), sodiumhexanoate (>99%) and sodium decanoate (P98%) were from Sigma,USA while sodium caprylate ((P98.5%) and sodium palmitate(95%) were from Fluka. Trisodium phosphate dodecahydrate(TSP) and sodium dihydrogen phosphate monohydrate (SDP) wereof reagent grade obtained from Merck (India). 10 mM SP buffersolutions were used throughout as solvent. The pH of the drugsolutions was measured with an ELICO pH meter (model LI 120)using combined electrode. The pH of the drug solutions was fixedat 6.7. The concentrations of the drugs were fixed at 50, 50 and100 mM for AMT, CLP and IMP, respectively.

Stock solution of drug of fixed concentration, prepared in buffer,with a desired concentration of the additive was taken in a se-curely stoppered test tube and placed in a thermostatic water bath,where temperature was increased with the rate of 0.5 �C/min un-der a controlled condition of constant stirring. The point of cloud-ing was noted visually at the start of the phenomenon. The heatingwas then stopped and the system was allowed to cool. The temper-ature at the clearance of turbidity was again noted. The mean of

0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4

30

40

50

60

70

80

90 a

Clo

ud P

oint

(ºC

)

(w/v)%

0.0 0.2 0.4 0.6 0.8 1.0 1.2

40

50

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90

100

b

Clo

ud P

oint

(ºC

)

Additive concentration (w/v)%

0.0 0.2 0.4 0.6 0.8

50

60

70

80

90

c

Clo

ud P

oint

(ºC

)

Additive concentration (w/v) %

Fig. 2. Effect of addition of nonionic surfactants on the cloud point of (a) 50 mMAMT, (b) 50 mM CLP and (c) 100 mM IMP; h: S85, j: S108, s: TX-114, N:Brij 56,4:Brij 58.

0 10 20 30 40 5020

30

40

50

60

70

80

90

CP

(ºC

)

Additive Concentration (mM)

Fig. 3. Effect of addition of anionic hydrotropes on the cloud point of 50 mM AMT(half filled), 50 mM CLP (open) and 100 mM IMP (full filled); 4: NaSal, s: NaBenz,h: NaTos. The values for AMT are shifted 5 units on x-axis.

0 2 4 6 8 10 1220

25

30

35

40

45

50

55

60

65

70

75

CP

(ºC

)

Additive Concentration (mM)

Fig. 4. Effect of addition of bile salts on the cloud point of 50 mM AMT (s), 50 mMCLP (4) and 100 mM IMP (h); filled symbol: NaC, open symbol: NaDC.

44 A.Z. Naqvi et al. / Journal of Colloid and Interface Science 361 (2011) 42–48

the two temperatures was taken as the CP of the system(reproducibility ± 0.5 �C).

3. Results and discussion

3.1. Effect of cationic surfactants

Fig. 1 shows the dependence of CP of the three drugs on theconcentration of added cationic surfactants. The CP of pure drugswas 24, 34 and 49 �C, respectively, for AMT, CLP and IMP. At theexperimental pH the drugs are known to exist in cationic form.As the hydrophobic parts of these drugs are bulky and the hydro-philic heads are charged, the micelles formed would be smalland loose. Hence, head-head repulsions will cause high CPs. Theadded cationic surfactants, due to their hydrophobicity, will form

A.Z. Naqvi et al. / Journal of Colloid and Interface Science 361 (2011) 42–48 45

mixed micelles with the drugs [38]. Their presence in between thetwo drug monomers will increase the already existing repulsionsmaking the micelles looser. Therefore, more water will be presentnear the heads, causing an increase in CP.

It is clear from Fig. 1 that, as the chain length of the surfactantsincreases, their CP boosting effect also increases, i.e., the CP in-crease is sharper with DTAB than with DeTAB. As the surfactant be-comes more hydrophobic with the increase in chain length, moreand more molecules will try to form mixed micelles with the drug(or more molecules will intercalate in the drug micelles) and hencerepulsions within the micelles will increase. This makes it moredifficult for micelles to come closer. Consequently, CP shows sharpincrease [39].

When choosing a surfactant as carrier one point which shouldbe kept in mind is that the surfactant should not decrease the CP

0 5 10 15 2015

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45

50

a

Clo

ud P

oint

(ºC

)

Additive concentration (mM)

0 10

50

55

60

65

70

75

80c

Clo

ud P

oint

(ºC

)

Additive

Fig. 5. Effect of addition of fatty acid salts on the cloud point of (a) 50 mM AMT, (b) 50 mdecanoate, �: sodium tetradecanoate, j: sodium hexadecanoate.

of drug-surfactant mixtures. As is clear from the trend of Fig. 1,the CP boosting effect of surfactant increases with the increase inhydrophobic chain length. Therefore, we tried gemini surfactantswith hydrophobic chains of 14 carbons.

These surfactants are also cationic in nature and should increasethe CP. These surfactants contain two hydrophobic chains and aremuch superior to their monomeric counterparts in all the proper-ties such as lower cmc values [40], greater efficiency in reducingthe surface tension of water [37], better solubilizing power [41],low Kraft point [40,41], and unusual rheological properties [42].Fig. 1 also depicts the effect of 14-s-14 (s = 4–6) gemini surfactantson the CP of drugs. Presence of 14-s-14 gemini surfactants in-creases the CP sharply. Addition of 8–9 mM of 14-4-14 producessame CP boosting effect which was shown by 25 mM of DTAB, indi-cating it to be more effective candidate to use as carrier. As geminis

0 4 8 12 16 20

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60b

Clo

ud P

oint

(ºC

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Additive concentration (mM)

20 30 40

concentration (mM)

M CLP and (c) 100 mM IMP; N: sodium hexanoate, d: sodium octanoate, .: sodium

0 5 10 15 20

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50

Clo

ud P

oint

(ºC

)

Additive concentration (mM)

Fig. 6. Effect of addition of b- cyclodextrin on the cloud point of N: AMT, d: CLP andj: IMP.

46 A.Z. Naqvi et al. / Journal of Colloid and Interface Science 361 (2011) 42–48

contain two charged heads in a single molecule, less concentrationwould be required to increase the electrostatic repulsions amongthe micelles.

This CP enhancing effect increases with the increase in spacerchain length. It is reported in the literature that the presence ofspacer affects the aggregational properties of these surfactants[43]. Increase in chain length of spacer is known to increase thesurface charge of the micelles [44]. Therefore, repulsive interac-tions increase with the spacer chain. This causes a faster increasein CP with added 14-5-14 and 14-6-14 than with 14-4-14.

3.2. Effect of nonionic surfactants

The results of CP variation of the drug solutions with the addi-tion of nonionic surfactants are displayed in Fig. 2. From the abovediscussion it appears that the presence of nonionic surfactantmonomers in between the charged monomers of drugs would re-duce the repulsions and CP should decrease. However, the obtainedresults show increase in CP. These nonionic surfactants are hydro-philic in nature and their intercalation, although decreases theelectrostatic repulsions, also increase the micelle hydration.

3.3. Effect of hydrotropes

Fig. 3 presents the CP variation of drug solutions on addition ofhydrotropes. The amphiphilic moiety of hydrotropes carries a neg-ative charge. By forming mixed micelles with the drugs, these saltsdecrease the repulsions and CP should decrease in their presence.Actually, it happens so, but at high concentration. The two mainfactors which affect the CP are dehydration of head groups andmicellar growth. For ionic amphiphiles micellar growth is opposedby the charge on head groups. Therefore, charge neutralization en-hances micellar growth. In other words, dehydration and chargeneutralization are the two contributing factors for CP phenomenon.Addition of hydrotropes affects both these factors. These salts neu-tralize the micellar charge. At the same time they increase the mi-celle hydration as they contain –COO� and —SO�3 groups. Whenadded in low concentration, second factor dominates and CP showsincrease. As the concentration increases further, first factor startsdominating and (due to charge neutralization) the heads come clo-ser to each other. This causes micellar growth and hence CP showsdecrease. Magnitude and sharpness of increase or decrease de-pends upon the nature of salt and the relative basicity of thegroups attached which leads to the following hydrophilic ranking[45]

—COO� � —SO�3

NaBenz contains a carboxylate whereas NaSal contains a carboxyl-ate and a hydroxyl group attached to benzene ring. NaTos has a sul-fonate group.

The difference in behavior can be explained by taking into ac-count the structures of these hydrotropes. As NaTos has a —SO�3which is less hydrophilic than –COO� group of NaBenz, theincrease and decrease both are slower with NaTos. Presenceof –OH group in NaSal increases its hydrophilicity as compared toNaBenz. Hence, increase is the sharpest with NaSal. Similar peakedbehavior was observed in drugs with anionic surfactants [19,30].

It is well known that among different hydrotropes, NaSal is themost effective in causing micellar growth [46]. The orientationof –COO� group is responsible for the growth. With cationicamphiphiles, Sal� intercalates between the head groups andreduces the repulsions. Also, the –COO� group interacts with thepositive charge of another micelle reducing its surface charge. Inthis way the micelles come closer to each other and CP decreases.

However, the behavior for IMP is different from the other twodrugs: CP increases continuously without a decrease. For IMP,

above certain concentration, the IMP- hydrotrope solutions be-come unstable which hampered the study.

3.4. Effect of bile acids

Fig. 4 depicts the effect of bile salt addition in the drug solu-tions. These salts behave as anionic surfactants [47]. The CP behav-ior is similar to that of hydrotropes. At low concentration CPincreases except for AMT where no decrease was observed at highconcentration. A possible explanation for this increase in CP is thatsurfactant monomers hinder micellar association at low concentra-tions, causing an increase in CP.

3.5. Effect of fatty acids

CP variation of the drug solutions with the addition of fattyacids is shown in Fig. 5. In the body, essential fatty acids (whichcannot be produced in the body) produce hormone-like substanceswhich regulate different functions like blood pressure, blood lipidlevels, and the inflammation response to injury inflection. As fattyacids are essential fuels for mechanical and electrical activities ofthe heart, they have an important role in life and death of cardiaccells. Most of the naturally occurring fatty acids have a chain of 4 to28 carbons. Short and medium chain fatty acids are absorbed di-rectly into the blood via intestine capillaries. Long chain fatty acidsare, however, too large to be directly released into the tiny intes-tine capillaries.

It is clear from Fig. 5 that the behavior of fatty acids is similarwith all the drugs. The fatty acids used contain 6–16 carbons.Sodium hexanoate increases the CP at all concentrations. Otherfatty acids give peaked behavior. The concentration and magnitudeof CP decreases with the increase in chain length of the additive.The trend can be understood in the light of the explanation pro-vided for hydrotropes. These sodium salts of fatty acids in solventgive a moiety with hydrophobic chain attached to carboxyl group.This makes the molecule negatively charged. Their mixed micelli-zation with cationic drug molecules decreases the surface chargeof the micelles, increases the micelle hydration and the hydropho-bic forces. The balance between these factors decides the CP

Table 1Summary of thermodynamic parameters of the three drugs.

Additive DG� for all drugs AMT CLP IMP

DH� TDS� DH� TDS� DH� TDS�

DeTAB Negative Negative Negative Negative Negative Negative NegativeDTAB Negative Negative Positive Negative Positive Negative Positive14-4-14 Negative Negative Positive Negative Positive Negative Positive14-5-14 Negative Negative Positive Negative Positive Negative Positive14-6-14 Negative Negative Positive Negative Positive Negative PositiveS85 Negative Negative Positive Negative Positive Negative PositiveS108 Negative Negative Positive Negative Positive Negative PositiveBrij58 Negative Negative Positive Negative Positive Negative PositiveBrij56 Negative Negative Positive Negative Positive Negative PositiveTX-114 Negative Negative Positive Negative Positive Negative PositiveNaSal Negative Negative/positive Positive Negative/positive Positive Negative PositiveNaBenz Negative Negative/positive Positive Negative/positive Positive Negative PositiveNaTos Negative Negative/positive Positive Negative/positive Positive Negative PositiveNaC Negative Negative Positive Negative/positive Positive Negative PositiveNaDC Negative Negative Positive Negative/positive Positive Negative Positive

A.Z. Naqvi et al. / Journal of Colloid and Interface Science 361 (2011) 42–48 47

behavior. As the chain length of the additive increases, mixed mi-celles of drug- fatty acid will experience stronger hydrophobicinteractions and the micelle will be less hydrated. Hence CPdecreases.

3.6. Effect of cyclodextrin

Cyclodextrins belong to the family of cyclic oligosaccharidescomposed of a-D-glucopyranoside units. a,b,c-cyclodextrins con-tain 6, 7 and 8 glucose units, respectively, in a ring creating a coneshape structure. Recently, cyclodextrins have gained wide atten-tion because of their applications in food, pharmaceuticals andchemical industries [48]. Effect of b-cyclodextrin on the CP of drugsis shown in Fig. 6. b-cyclodextrin is known for its ability to forminclusion complexes with surfactants [49] and increase the CP ofnonionic surfactants [50]. However, in our systems CP decreasesin its presence. May be with the cationic drugs, cyclodextrin actsas water structure maker and does not form inclusion complexes.Water structure makers decrease the cmc by increasing the hydro-phobic interaction. Increase in hydrophobic interactions decreasethe CP also.

3.7. Thermodynamics of CP

The temperature variation of drug solutions in presence of addi-tives can be used to calculate thermodynamic parameters by thefollowing equations

DG� ¼ RT ln x ð1Þ

DH� ¼ @ðDG�=TÞ@ 1=Tð Þ ð2Þ

TDS� ¼ DH� � DG� ð3Þ

where x is the mole fraction of clouding species at CP. Other sym-bols have their usual significance. Values of different parametersare given in Tables S1–S3 (of Supporting Material) for the threedrugs.

At CP, the electrostatic repulsions are minimum and micellescome closer to each. As the two micelles come close to each othertheir hydration spheres overlap and some water molecules arefreed. Hence, entropy increases. At CP, this increase in entropy islarge and the resultant free energy is more negative than thatresulting from repulsion among head groups. Hence, total freeenergy is negative.

Table 1 bears the summary of sign of different parameters. Inour systems also DG� values are negative and the magnitude varies

between 16.5–22 kJ mol�1 and increases with the increase in addi-tive concentration. With DeTAB addition, however, DG� remainsconstant (in fact, it decreases 0.1 kJ mol�1) for all drugs. DeTAB,due to its shorter chain, is less effective in releasing water mole-cules and DG� as well as CP changes slowly.

DG�/T vs 1/T curves have two stages: for all drugs the process ofclouding is entropy controlled, i.e., DH� < TDS�. DH� values are neg-ative for all systems except for AMT – hydrotropes, CLP – bile salts,hydrotropes, and IMP – bile salts at high concentrations where DH�values are positive. The values are always smaller than DG� andTDS� values.

4. Conclusions

In conclusion, the present work reports the effect of variousadditives on the cloud point (CP) of buffered solutions of amphi-philic drugs amitriptyline hydrochloride (AMT), clomipraminehydrochloride (CLP) and imipramine hydrochloride (IMP). Thesedrugs belong to the class of tricyclic antidepressants (TCAs) andare used with carriers. Among drug carriers one can name solublepolymers, microparticles made of insoluble or biodegradable natu-ral and synthetic polymers, microcapsules, cells, liposomes, nio-somes, lipoproteins and micelles. Micelles have an advantage asthat they reduce the amount of both drug and the carrier to a largeextent, making them cost effective and less toxic. Hence, the addi-tives are chosen keeping this in mind. Surfactants (cationics andnonionics) increased the CP by forming mixed micelles with thedrugs. Hydrotropes, bile salts and sodium salts of fatty acidsshowed a peaked behavior. The peak position and magnitude de-pended upon the nature of additive. b-Cyclodextrin decreased theCP. Thermodynamic parameters reveal the process of clouding tobe entropy driven. Thus, it may be concluded that CP of amphi-philic drugs may be changed to required conditions by varyingdrug and/or additive concentrations and a better drug-carrier sys-tem can, thus, be produced.

Acknowledgment

Andleeb Z. Naqvi acknowledges financial assistance under DST’sSERC Scheme (SR/FTP/CS-49/2007).

Appendix A. Supplementary data

Supplementary data associated with this article can be found, inthe online version, at doi:10.1016/j.jcis.2011.05.037.

48 A.Z. Naqvi et al. / Journal of Colloid and Interface Science 361 (2011) 42–48

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