Tuning of the Cloud Point of Promethazine Hydrochloride with Surfactants and Polymers

Transcription

1 J Surfact Deterg (07) 10:35 DOI /s ORIGINAL ARTICLE Tuning of the Cloud Point of Promethazine Hydrochloride with Surfactants and Polymers Md. Sayem Alam Æ Andleeb Z. Naqvi Æ Kabir-ud-Din Received: 19 July 06 / Accepted: 1 December 06 / Published online: 19 January 07 Ó AOCS 07 Abstract The effect of additives (surfactants and polymers) and ph on the clouding behavior of promethazine hydrochloride (PMT, a phenothiazine drug) was investigated. Cloud point (CP) decreases with increase in ph due to deprotonation of drug molecules. The same trend occurs in the presence of surfactants. However, at constant ph, and depending on their structure and nature, these additives behave differently. Anionic surfactants show peaked behavior, whereas cationic (conventional as well as geminis) and non-ionic surfactants increase the CP, although the mechanisms differ. Cationic surfactants hinder drug association (due to interaggregate repulsion) resulting in an increase in CP, while non-ionic surfactants form mixed micelles with the drug, increasing micelle hydration and CP. Polymers can cause both a decrease as well as an increase in CP, depending on their molecular weight. A large CP increase (with the increase in surfactant concentration) for gemini surfactants suggests they are excellent candidates for drug delivery. Introduction Md. Sayem Alam A. Z. Naqvi Kabir-ud-Din (&) Department of Chemistry, Aligarh Muslim University, Aligarh 02 UP, India kabir7@rediffmail.com Many drugs are amphiphilic and this can cause several problems with respect to their formulation, solubilization in body fluids, and interaction with membranes prior to reaching their final target. Such drugs may aggregate into various structures, most frequently small micellar-type structures [1]. In such cases, the drug aggregate can act as its own carrier at moderate drug loadings. It has been proposed that the formulation of vesicles consisting of pure drug is also feasible [2]. However, most drugs are not sufficiently amphiphilic to easily form vesicles or to act as their own carrier. Over the years, surfactants have been of interest to pharmaceutical scientists either as drug carriers or as targeting systems [3]. In the former application, the surfactant system acts purely as a carrier and takes no part in the biodistribution of the drug it carries, while in the latter case the surfactant system conveys the drug to the desired site and deposits it there. One of the most important properties of non-ionic surfactants is the clouding phenomenon, which can be induced by changing the temperature of the solution. The temperature at which a clear, single phase becomes a cloudy dispersion upon heating is known as the cloud point (CP) temperature [4 7]. Though the mechanism of clouding is still a matter of contention, the removal of interfacial water from the hydrophilic mantle is apparently the main requirement for the clouding phenomenon [8, 9]. The dehydration of the head group area changes the local dielectric constant [10, 11], which also plays a role in the clouding phenomenon. Clouding is rarely observed in ionic surfactants. However, we have observed clouding in anionic surfactant (SDS/SDBS) quaternary ammonium bromide systems. The presence of a CP in these systems is explained in terms of charge neutralization and increased

2 36 J Surfact Deterg (07) 10:35 hydrophobic interactions due to the penetration of the alkyl chains of quaternary bromides inside the micelles [12, 13]. Raghavan et al. [14] also observed clouding in cationic surfactant salt systems. It was also observed that the CP of these systems can be tuned with the use of additives [12, 13, 15, 16]. Since promethazine hydrochloride (PMT), a phenothiazine tranquillizer, is an amphiphilic drug that self-associates in a surfactant-like manner, we explored clouding phenomenon in this drug. The structure of PMT is shown in Scheme 1. PMT possesses a rigid hydrophobic ring system and a hydrophilic amine portion, which becomes cationic at low ph values and neutral at high ph values. Also, the pk a value of this drug is 9.1 [17]. In general, the CP should be greater than 38 C at a ph of approximately 7.4 to allow effective and efficient use of this and other drugs in the human body. Like other surfactants, PMT has a CP which is ph- and concentration-dependent, and the presence of additives can change its value. Since drugs are generally used with surfactants (as drug carriers), an understanding of the phase behavior of drugs, especially in the presence of surfactants, is important in designing effective drug-carrier combinations [18]. As a result, we studied the effect of surfactants and polymers on the CP of PMT. These results will illustrate how, by proper selection of surfactants and/or polymers, a drug-carrier system can be produced that can prevent clouding phenomenon under physiological conditions. Experimental Procedures S N H 3 C N CH 3 CH 3 HCl Scheme 1 Molecular structure of promethazine hydrochloride (PMT) PMT hydrochloride ( 98%), supplied by Sigma (St. Louis, MO), was used as received. Anionic surfactants sodium dodecylsulfate (SDS) ( 99%; Sigma), sodium dodecylbenzenesulfonate (SDBS; 99%; TCI, Tokyo, Japan), and cationic surfactants cetyltrimethylammonium bromide (CTAB; 99%; BDH, Poole, UK) and tetradecyltrimethylammonium bromide (TTAB; 99%; Sigma) were used as received. Nonionic surfactants t- octylphenoxypolyethoxyethanol (TX-100; 99%; Fluka, Buchs, Switzerland), polyethylene glycol dodecylether (Brij 35; BDH), polyoxyethylenesorbitan monolaurate (Tween ; LOBA Chemie, Mumbai, India), polyoxyethylenesorbitan monopalmitate (Tween ; Koch- Light, Haverhill, UK), polyoxyethylenesorbitan monostearate (Tween ) and polyoxyethylenesorbitan monooleate (Tween ; LOBA Chemie) were used as received. PVP 15, PVP 25, PVP, PVP and PVP polymers were obtained from Fluka (Buchs, Switzerland). The gemini surfactants, namely hexanediyl-, pentanediyl-, and butanediyl-a, x-bis(dimethylcetylammonium bromide ( , , and , respectively) were prepared and characterized by methods reported elsewhere [19]. Trisodium phosphate dodecahydrate (TSP) and sodium dihydrogen phosphate monohydrate (SDP) were of reagent grade and obtained from Merck (Mumbai, India). Double-distilled deionized water with specific conductivity Scm 1 was used to prepare the sample solutions. Ten millimolar sodium phosphate (SP) buffer solution, prepared from SP monobasic monohydrate (5.5 mm) and SP tribasic dodecahydrate (4.5 mm) was used throughout as a solvent, except when ph variation was studied. For determining CP, 3 ml of the sample solution was placed in a Pyrex glass tube (15 ml capacity), which was then placed in a controlled heating apparatus. The temperature was raised slowly at a rate of 0.1 C/min near the CP, and the temperature at the onset of sudden clouding in the solution was taken as CP [12, 13]. The reproducibility of the results was ± 0.5 C. Unless mentioned otherwise, the ph and drug concentration of the solutions were fixed at 6.7 and mm, respectively. The ph measurements were made with an ELICO ph meter (model LI 1, Elico, Hyderabad, India) used in conjunction with a combination electrode (CL 51B). Results and Discussion Figure 1 shows the effect of ph on the CP of PMT in the absence and presence of surfactants. With the increase in ph, an increasing number of PMT molecules become deprotonated. This effect reduces the micellar surface charge and electrostatic repulsion among monomers, which, in turn, increases the aggregation number and compactness of micelles. The CP decrease results due to this increased compactness []. Figure 2 shows the effect of added anionic surfactants (SDS and SDBS) on the CP of PMT drug solutions. The ph was fixed at 6.7. At this ph, most of the

3 J Surfact Deterg (07) 10: drug monomers are assumed to be in protonated form, and PMT aggregates would be positively charged. Addition of anionic surfactants was expected to decrease the CP of PMT micelles by interacting electrostatically and hydrophobically. However, the results in Fig. 2 show a different trend: the CP first increases and ph No Surfactant 5 mm SDS 0.5 mm CTAB 0.5 mm TX 100 Fig. 1 Effect of ph on the cloud point (CP) of mm promethazine hydrochloride (PMT) in a 10 mm sodium phosphate (SP) buffer solution containing no or a fixed concentration of surfactant Surfactant Concentration (mm) SDS SDBS Fig. 2 Effect of addition of anionic surfactants on the CP of mm PMT in a 10 mm SP buffer solution (ph 6.7) then decreases with the increase in added surfactant concentration. A possible explanation for this unexpected increase in CP is that surfactant monomers hinder micellar association at low concentrations, causing an increase in CP. Kim and Shah [] observed a similar increase in the CP of amitriptyline in the presence of anionic surfactants. These investigators, however, did not observe the latter part showing a CP decrease. Above a certain added surfactant concentration, the decrease in CP of the system can be explained by taking into account both the charge on the surfactant head group and the nature of the alkyl chain of the surfactant. Addition of surfactant decreases the head head repulsion among drug molecules which, in turn, decreases the surface area per molecule (a o ). Also, interaction of surfactant alkyl chain with the hydrophobic portion of the drug strengthens the hydrophobic interactions among the hydrophobic moieties of PMT. This increases the effective volume of the micelles (v c ). As a result, both the Mitchell Ninham parameter (R p = v c /a o l c )[21] and micellar size increase, leading to a decrease in CP. One can see that CP decrease is more pronounced with SDBS (sulfonate) in comparison to SDS (sulfate). This difference in behavior can be understood in view of their relative basicity, which leads to the following hydrophilic ranking of the head groups [22] --COO --SO 3 [--OSO 3 Another difference in the two surfactant monomers is that SDBS contains a benzene ring. The presence of a benzene ring in SDBS lengthens its hydrophobic chain [23] as compared to SDS and increases its hydrophobic character. This is reflected in a lower cmc value for SDBS [24]. As a result, greater hydrophobic interactions occur between the benzene ring of the SDBS monomer and the hydrophobic portion of the drug molecule. Also, the presence of a benzene ring causes greater electrostatic interaction with cationic drug molecules. All of these factors make SDBS more effective in dehydrating the drug micelles, causing a sharper decrease in CP at higher relative concentrations. The effects of cationic surfactants, conventional as well as geminis, on CP is shown in Fig. 3. CP increases with addition of each of the surfactants. The magnitude of the CP increase was found to be dependent upon the chain length of the alkyl chain present in the conventional surfactant (CTAB or TTAB), with the longer chain lengths increasing the CP to the greatest degree. The presence of a counter-ion (Br ) is responsible for the decrease in surface area occupied per PMT

4 38 J Surfact Deterg (07) 10: CTAB TTAB 100 Cloud Point ( C) Surfactant Concentration (mm) Fig. 3 Effect of addition of various cationic surfactants on the CP of mm PMT in a 10 mm SP buffer solution (ph 6.7) Surfactant Concentration (% w/v) TX 100 Brij Brij 35 Tween Tween Tween Tween headgroup (a o ), with a simultaneous increase in the Mitchell Ninham parameter, R p [21, 25]. An increase in R p results in micellar growth. The added cationic surfactants exist in the PMT solution as monomer, micelles and mixed micelles depending on their cmc values. Addition of CTAB, which forms larger micelles than TTAB, generates stronger electrostatic repulsion between micelles and produces a higher CP. Unlike conventional cationic surfactants, a gemini surfactant of the type 16 m 16 is composed of a hydrophobic polymethylene spacer (CH 2 ) m attached to the two cationic N + Me 2 R head groups. The CP of gemini surfactant drug systems also increase with added surfactant concentration as shown in Fig. 3. Among geminis, the CP increase is least pronounced with m = 4. As the concentration of geminis used in this study is higher than their respective critical micelle concentrations, cationic micelles of the gemini surfactants as well as mixed micelles would be present in the solution along with drug aggregates. This behavior increases interaggregate repulsion, and hence increased CP is observed. It has been shown that the increase in spacer chain length increases the surface charge and significantly influences the aggregation properties of these surfactants [26, 27]. Therefore, repulsion increases with spacer length. This results in a faster increase in CP with added and than with The results of CP variation of PMT solutions with added non-ionic surfactants are depicted in Fig. 4. The CP always increased upon addition of these specific Fig. 4 Effect of addition of nonionic surfactants on the CP of mm PMT in a 10 mm SP buffer solution (ph 6.7) non-ionic surfactants. All of these non-ionic surfactants contain oxyethylene chains and hence are hydrophilic in nature. Therefore, the drug surfactant mixed micelles are more hydrated, and more heating is needed to induce CP in the system. 10 PVP 15 PVP 25 PVP PVP PVP Polyvinylpyrrolidon Concentration (% w/v) Fig. 5 Effect of addition of polyvinylpyrrolidones (PVP) on the CP of mm PMT in a 10 mm SP buffer solution (ph 6.7)

5 J Surfact Deterg (07) 10:35 39 Figure 5 shows the effect of polymers on clouding behavior of PMT solutions. All the polymers show a similar trend: a decrease and then an increase in CP with the magnitudes of increase and decrease depending upon the molecular weight of the polymer. The polymer with the lowest molecular weight, PVP 15, is most hydrophilic and hence, after a small decrease, it increases the CP sharply, whereas PVP, the highest molecular weight polymer, is sufficiently hydrophobic to decrease the CP at almost all concentrations. At intermediate molecular weight, both hydrophobicity and hydrophilicity play a role. Figure 6 shows the effect of CTAB concentration variation at different fixed concentrations of PMT (, 75, 100 mm). The CP-increasing effect of the CTAB is again in evidence. As expected, the values of CP are higher for higher drug concentrations. However, the CP behavior is similar at all PMT concentrations. For a fixed CTAB concentration, an increase in drug concentration increases the number, size, and charge of micelles, which increases both intermicellar and intramicellar repulsions, causing an increase in CP. Effect of CTAB concentration at different fixed ph (6.5, 6.7, 6.9) is shown in Fig. 7. As explained earlier, the PMT molecules in micelles become deprotonated with increasing ph, which reduces intermicellar electrostatic repulsion. This effect may enhance the association of PMT micelles, which leads to a decrease in CP. At any fixed concentration of CTAB, a decrease in ph CTAB Concentration (mm) Fig. 7 Effect of CTAB concentration on the CP of mm PMT solution, prepared in 10 mm SP buffer at different ph CP is observed with increased ph due to deprotonation of PMT micelles/monomers. This causes lowering of the electrostatic repulsion (among micelles) with a concomitant larger decrease in CP. Variation of CP with ph in the presence of different fixed concentrations of gemini surfactant is shown in Fig. 8. A higher concentration of gemini [PMT]/mM [ ]/mM CTAB Concentration (mm) Fig. 6 Effect of cetyltrimethylammonium bromide (CTAB) concentration on the CP of different fixed concentrations ( 100 mm) of PMT solution, prepared in 10 mm SP buffer (ph 6.7) Fig. 8 Effect of ph on the CP of mm PMT in a 10 mm SP buffer solution containing different fixed concentrations of ph

6 J Surfact Deterg (07) 10:35 surfactant hinders drug aggregation and hence clouding appears at a high temperature. Acknowledgments The authors are thankful to the Council of Scientific and Industrial Research, New Delhi, India, for providing a research grant (No. 01(1873)/03/EMR-II). References 1. Attwood D, Florence AT (1983) Surfactant systems: their chemistry, pharmacy and biology. Chapman, New York 2. Vaizoglu MO, Speiser PP (1986) Pharmacopsomes a novel drug delivery system. Acta Pharm Suec 23: Lawrence MJ (1994) Surfactant systems: their use in drug delivery. Chem Soc Rev 23: Schott H (1984) Lyotropic numbers of anions from cloud point changes of nonionic surfactants. Colloids Surf 11: Myers D (1992) Surfactant science and technology, 2nd edn. VCH, New York 6. Gu T, Galera-Gomez PA (1995) Clouding of Triton X-114: the effect of added electrolytes on the cloud point of Triton X-114 in the presence of ionic surfactants. Colloids Surf A 104: Shigeta K, Olsson U, Kuneida H (01) Correlation between micellar structure and cloud point in long poly(oxyethylene) n oleyl ether systems. Langmuir 17: Karlstroem G (1985) A new model for upper and lower critical solution temperatures in poly(ethylene oxide) solutions. J Phys Chem 89: Tasaki K (1996) Poly(oxyethylene) water interactions: a molecular dynamics study. J Am Chem Soc 118: Rao IV, Ruckenstein E (1986) Micellization behavior in the presence of alcohols. J Colloid Interface Sci 113: Cerichelli G, La Mesa C, Luchetti L, Mancini G (00) Role of counterions in the catalytic activity and phase equilibria of phosphonium salts in water. Langmuir 16: Kumar S, Sharma D, Kabir-ud-Din (00) Cloud point phenomenon in anionic surfactant + quaternary bromide systems and its variation with additives. Langmuir 16: Kumar S, Sharma D, Khan ZA, Kabir-ud-Din (01) Occurrence of cloud points in sodium dodecyl sulfate-tetran-butylammonium bromide system. Langmuir 17: Raghavan SR, Edlund H, Kaler EW (02) Cloud-point phenomena in wormlike micellar systems containing cationic surfactant and salt. Langmuir 18: Kumar S, Sharma D, Khan ZA, Kabir-ud-Din (02) Saltinduced cloud point in anionic surfactant solutions: role of the headgroup and additives. Langmuir 18: Kumar S, Sharma D, Kabir-ud-Din (03) Temperature- [salt] compensation for clouding in ionic micellar systems containing sodium dodecyl sulfate and symmetrical quaternary bromides. Langmuir 19: Katzung BG (04) Basic and clinical pharmacology, 9th edn. McGraw Hill, New York 18. Schreier S, Malheiros SVP, de Paula E (00) Surface active drugs: self-association and interaction with membranes and surfactants. Physicochemical and biological aspects. Biochim Biophys Acta 18: Kabir-ud-Din, Fatma W, Khan ZA (06) A 1 H NMR study of 1,4-bis (N-hexadecyl-N,N-dimethylammonium)butane dibromide/sodium anthranilate system: spherical to rodshaped transition. Colloid Polym Sci 284: Kim EJ, Shah DO (03) Effect of surfactants on the cloud point of amphiphilic drug solutions. Colloids Surf A 227: Mitchell DJ, Ninham BW (1981) Micelles, vesicles and microemulsions. J Chem Soc Faraday Trans 1: Laughlin RG (1978) Solvation and structural requirements of surfactant hydrophilic groups. Adv Liq Crystals 3: Lindman B, Wennerstrom H (19) Micelles. Amphiphile aggregation in aqueous solution. Top Curr Chem 87: Mukerjee P, Mysels KJ (1971) Critical micelle concentrations of aqueous surfactant systems. NSRDS-NBS36, Washington DC 25. Kabir-ud-Din, Kumar S, Kirti, Goyal PS (1996) Micellar growth in presence of alcohols and amines: a viscometric study. Langmuir 12: Zana R, Benrraou M, Rueff R (1991) Alkanediyl-.a.,.x.- bis(dimethylalkylammonium bromide) surfactants. 1. Effect of the spacer chain length on the critical micelle concentration and micelle ionization degree. Langmuir 7: De S, Aswal VK, Goyal PS, Bhattacharya S (1996) Role of spacer chain length in dimeric micellar organization. Small angle neutron scattering and fluorescence studies. J Phys Chem 100: Kabir-ud-Din is Professor of Physical Chemistry at Aligarh Muslim University, Aligarh, India. He received his MSc (1965) and PhD (1969) degrees from the same university. He has been a postdoctoral fellow in Prague (Czech Republic), Keele (UK), and Austin (USA), and worked as an Associate Professor in Libya. His research interests are in micellar catalysis, kinetics, electrochemistry, and the solution behavior of surfactants. He has authored over 1 research papers.