The Effects of Anionic, Cationic, and Nonionic Surfactants on Acid

Article pubs.acs.org/jced

The Effects of Anionic, Cationic, and Nonionic Surfactants on Acid− Base Equilibria of ACE Inhibitors Marija R. Popović,† Gordana V. Popović,‡,* and Danica D. Agbaba† †

Department of Pharmaceutical Chemistry and ‡Department of General and Inorganic Chemistry, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, P.O. Box 146, 11000 Belgrade, Serbia ABSTRACT: The pKa values of ACE inhibitors captopril, cilazapril, enalapril, fosinopril, lisinopril, perindopril, quinapril, ramipril, and zofenopril were determined by potentiometry. Because to the presence of single or several ionizable groups (carboxyl, thiol, primary and secondary amino groups) these substances represent acids and ampholytes. Determinations of pKa values were performed at 25 °C and constant ionic strength of 0.1 M (NaCl), in the absence and in the presence of surfactants, anionic sodium dodecyl sulfate (SDS), cationic cetyltrimethyl ammonium bromide (CTAB), and nonionic 4-octylphenol polyethoxylate (TX 100). A computer program Hyperquad was used to derive pKa values from the data obtained by potentiometric titrations. The observed shift of pKa values from +1.90 to −1.54 pK units demonstrated a significant effect of the surfactants on ionization of ACE inhibitors. It has been observed that the carboxyl group was more susceptible to the effect of the above surfactants than the amino group. Also, among the three surfactants employed, SDS expressed the most prominent effect on acid−base equilibria. On the basis of the shifts of pKa values in the presence of the applied surfactants different ACE inhibitor−micelle interactions were suggested.

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INTRODUCTION ACE (angiotensin-converting enzyme) inhibitors are drugs applied in the treatment of different cardiovascular disorders, primarily in the therapy of hypertension and congestive cardial insufficiency.1 Their pharmacological effects result from the efficient modulation of the system rennin−angiotensin− aldosterone. These drugs act to prevent enzyme-catalyzed conversion of angiotensin I into a potent vasoconstrictor angiotensin II, by reversible competitive inhibition of ACE activity, but they also inhibit degradation of bradykinin, a potent vasodilator. Besides, they inhibit aldosterone and in this way indirectly decrease reabsorption of Na+ and water, as well as K+ ion excretion. The total pharmacological effect of ACE inhibitors on cardiovascular system includes decrease of peripheral pressure and volume of the circulating body liquids leading to decreased blood pressure and improvement of blood and oxygen supply to myocard and other organs. ACE is a relatively unspecific carboxypeptidase, and, keeping in mind characteristics of catalytic activity, the drugs of this category have to fulfill very strict structural demands to interact with this enzyme.1,2 The presence of a peptide bond and free carboxyl group is a common structural feature of the ACE inhibitors (Figure 1). The latter group in ionized form is responsible for the interaction with a protonated amino group of the arginine residue in the cationic active enzyme site. In addition to the carboxyl group, ACE inhibitors can contain some other ionizable groups such as primary and secondary amino groups and sulfhydryl groups, giving them the properties of acids or ampholytes. © 2013 American Chemical Society

The pKa value represents an important parameter in physicochemical characterization of pharmacologically active substances and it is of the utmost importance for the estimation of their behavior in vitro and in vivo. Knowledge of drug pKa values is significant not only for analytical procedures, but also in pharmaceutical industry in the development of novel pharmaceutical dosage forms. Drug absorption, distribution, metabolism, and elimination (ADME) depend on the degree of their ionization. However, other molecules present in body fluids and at the cell membrane surfaces can strongly affect drug ionization under physiological conditions. Since biological membranes are extremely complex structures, much less complex surfactant micelles have been used as model systems for biomembranes in different studies.3−8 Numerous explanations in pharmaceutical (medicinal) chemistry related to drug behavior were obtained by comparative studies of acid−base equilibria in the presence of cationic, anionic, and nonionic surfactants because drug solubilization and absorption from the gastro-intestinal tract, as well as their transport across biological membranes and interaction with biological targets, depend on their ionization extent under physiological conditions.9−12 The pKa values of ACE inhibitors published so far were mostly calculated applying computer programs,13,14 and only in a few cases were these values experimentally determined (captopril,15 enalapril,16−18 lisinopril18−20). However, the data on acid−base equilibria of this group of drugs in micellar media Received: May 9, 2013 Accepted: July 29, 2013 Published: August 13, 2013 2567

dx.doi.org/10.1021/je400397p | J. Chem. Eng. Data 2013, 58, 2567−2573

Journal of Chemical & Engineering Data

Article

Figure 1. Chemical structures of the ACE inhibitors.

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EXPERIMENTAL SECTION Materials. The examined ACE inhibitors (captopril, cilazapril, enalapril maleat, quinapril hydrochloride, perindopril erbumin, ramipril, zofenopril calcium, lisinopril dihydrate, fosinopril sodium) were kindly donated by Medicines and Medical Devices Agency of Serbia (Belgrade, Serbia). Sodium dodecyl sulfate (J.T. Baker, ≥ 95 % purity), cetyltrimethylammonium bromide (Acros Organic, ≥ 99 % purity), 4octylphenol polyethoxilate, Triton X 100 (Acros Organic, ≥ 98 % purity) were used as received. All other chemicals (Merck) used throughout this work were of analytical grade. Double distilled water was used to prepare the solutions. Solutions of HCl and CO2-free NaOH were standardized by potentiometry. Potentiometric titrations were performed on a titration system 798 MPT Titrino with a combined electrode (LL unitrode Pt1000, Metrohm). Constant temperature of the titrated solutions was maintained using a Huber Polistat CC2 thermostat. Potentiometric Titration. The pKa values of the examined ACE inhibitors in the absence and in the presence of the 10−2 M surfactant (SDS, CTAB, and TX 100) were determined by potentiometric titration. The electrode used for the pH measurements was regularly calibrated with standard buffer solutions (pH 4.01, 7.00, and 9.21). Addition of the surfactants in the above concentration expressed a negligible effect on pH of the buffers (under ± 0.02 pH units). Potentiometric titrations were performed at 25 °C and constant ionic strength of 0.1 M (NaCl). To 39 mL of 10−3 M solutions of the ACE inhibitors (in the absence and in the presence of surfactants) 0.5 mL to 1.0 mL of HCl solution (0.1007 M to 0.1024 M) were added and titrated with 0.02 mL aliquots of NaOH solution (0.09920 M to 0.09970 M). The only exception from this protocol was fosinopril titration in the

is still lacking. This prompted us to determine pKa values of nine most frequently prescribed ACE inhibitors, namely, captopril, cilazapril, enalapril, fosinopril, lisinopril, perindopril, quinapril, ramipril, and zofenopril, and to examine the effects of surfactants on their acid−base equilibria. For that purpose sodium dodecyl sulfate (SDS) as an anionic surfactant, cationic cetyl trimethyl ammonium bromide (CTAB), and nonionic 4octylphenol polyetoxylate (TX 100) were employed. The pKa values were determined by potentiometry and the analysis of experimental data was supported by a Hyperquad computer program.21 Structures of the examined ACE inhibitors and the applied surfactants are presented in Figures 1 and 2, respectively.

Figure 2. Chemical structures of the surfactants. 2568



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terminal carboxyl group acting as the only ionizable functional group. In addition to the carboxyl group, captopril contains another acid group, a sulfhydryl group (thiol function). Cilazapril, enalapril, quinapril, perindopril, and ramipril are ampholytes with one acidic (carboxyl) and one basic (secondary amino) group. Lisinopril is an ampholyte with four ionizable groups, two carboxyl (terminal and proximal) and two amino (primary and secondary) groups. Relatively satisfactory solubility of ACE inhibitors enabled pKa determinations in aqueous medium applying a potentiometric titration. Solutions of the ACE inhibitors in the concentration of 10−3 M in the absence and in the presence of 10−2 M surfactants (SDS, CTAB, or TX 100) were titrated with a standard NaOH solution at a constant ionic strength (0.1 M NaCl) and 25 °C. The applied surfactant concentration was significantly above critical micellar concentration (cmc) and thus the influence of other substances in the solution on cmc can be neglected. To prevent dissociation of the carboxyl group of the ACE inhibitors, HCl was added prior to titration with NaOH. Because of a slight fosinopril solubility and its precipitation from 10−3 M acidified solution, its apparent pKa values (pKa*) in the absence of surfactants were determined in different methanol−water mixtures 40 % to 55 % (w/w) (Table 1). Methanol was used as a solvent because its solvation effect is

absence of the surfactants. Because of poor water solubility of fosinopril, this titration was performed in different methanol− water mixtures 40 %, 45 %, 50 %, and 55 %, (w/w). To express the measured pH values as pcH values (pcH = −log [H+]) the relation pcH = pH − A was applied. Correction factor A was determined by titrating HCl solution at an ionic strength of 0.1 M (NaCl) by standard NaOH solution.22,23 The pKa values of the examined ACE inhibitors were calculated with the use of the data obtained by potentiometric titrations that used the computer program Hyperquad.21

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RESULTS AND DISCUSSION Among the examined ACE inhibitors, fosinopril and zofenopril behave as monoprotic acids in aqueous medium with proline Table 1. pKa* (Apparent Dissociation Constant) Values of Fosinopril Determined by Potentiometry in Different Methanol−Water Mixtures at I = 0.1 M (NaCl) and t = 25 °C methanol−water mixture % (w/w)

pKa*

40 45 50 55

4.60 4.66 4.74 4.81

Figure 3. Potentiometric curves of ACE inhibitors solutions in the absence (H2O, 50 % MeOH) and in the presence of 10−2 M surfactant (SDS, CTAB, and TX 100) titrated with standard NaOH solution. I = 0.1 M (NaCl), t = 25 °C. 2569



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Table 2. pKa Values of ACE Inhibitors Determined by Potentiometry and Data from the Literature (Experimentally Determined and Calculated) potentiometric dataa ACE inhibitors

a

pKa1

pKa2

fosinopril

4.03 ± 0.03

zofenopril captopril

4.46 ± 0.03 3.50 ± 0.01

9.99 ± 0.01

cilazapril

3.37 ± 0.01

6.47 ± 0.01

enalapril

2.94 ± 0.02

5.41 ± 0.02

quinapril

3.12 ± 0.04

5.40 ± 0.01

perindopril

3.48 ± 0.02

5.91 ± 0.02

ramipril

3.35 ± 0.02

5.77 ± 0.02

lisinopril

1.43 ± 0.04

3.15 ± 0.01

data from the literature

pKa3

pKa4

pKa1

pKa2

pKa3

pKa4

4.38 3.8

7.20 ± 0.01

10.90 ± 0.01

ref 13 14

4.51 3.90b 3.26 3.3 3.74 3.8 2.85b 2.92b 3.04b 3.71 3.3 3.78 3.7

9.55 10.03b 4.49 5.9 5.15 5.5 5.37b 5.42b 5.49b 5.12 5.4 5.33 5.7

13 15 13 14 13 14 16 17 18 13 14 13 14

3.74 3.7 1.62 2.2 1.40b 1.68b 2.5b

5.15 5.5 3.66 3.8 3.00b 3.29b 4.0b

13 14 13 14 19 18 20

6.07 7.6 7.10b 7.01b 6.7b

10.33 10.5 10.78b 11.12b 10.1b

I = 0.1 M NaCl, t = 25 °C. bExperimentally determined.

close to that of pure water. The aqueous pKa = 4.03 ± 0.03 was deduced by extrapolation of the pKa* values to zero cosolvent.24 Fosinopril titrations in the presence of the surfactants were performed by the same protocol as that used in the case of other examined ACE inhibitors because the solubilizing effect of the surfactants acted to increase the fosinopril solubility. Titration curves of examined ACE inhibitors obtained in the absence and in the presence of the surfactants are shown in Figure 3. A Hyperquad computer program was used to calculate pK a values based on experimental results obtained by potentiometric titrations. In addition to the possibility of overlapping acid−base equilibria of a single substance in solution being evaluated, the Hyperquad program enables determination of equilibrium constants in complex systems containing several components susceptible to protolytic equilibria. This made it possible to determine pKa values of enalapril and perindopril by titrating solutions of enalapril maleate, that is, perindopril erbumin. The obtained pKa values of the ACE inhibitors are listed in Tables 2 and 3 (determinations were performed in surfactant-free and surfactant-supplemented solutions, respectively). The pKa values of the carboxyl group (pKa1 and pKa2 of lisinopril and pKa1 for the other examined ACE inhibitors) ranged from 1.43 to 4.72. Since the lisinopril molecule contains two carboxyl groups (terminal and proximal), the pKa1 of 1.43 can be ascribed to the more acidic proximal carboxyl group. The obtained pKa values of the secondary amino group (pKa2 of cilazapril, enalapril, quinapril, perindopril, and ramipril, and pKa3 of lisinopril) ranged from 5.40 to 7.20. It has been observed that among the examined ACE inhibitors, only lisinopril and captopril participate in protolytic equilibria even at high pH of the media. The pKa4 of the primary amino group

of lisinopril was 10.90 and pKa2 of the thiol function of captopril was 9.99. The data from the available literature on experimentally determined and calculated pKa values of ACE inhibitors are also inserted in Table 2. As seen, pKa values of captopril, enalapril, and lisinopril obtained in the present study are in agreement with experimental data15−20 of the others. Our results are also in relatively good accordance with pKa values calculated by computer programs.13,14 However, the values of captopril pKa1 and cilazapril pKa2 differ from the calculated values, the differences being above 1 pK-unit. pKa values of the examined ACE inhibitors determined in the presence of surfactants (anionic SDS, cationic CTAB, and nonionic TX 100) in the concentration of 10−2 M are given in Table 3, and the shifts of pKa in relation to the values obtained in the absence of surfactants are presented in Table 2. A general observation shows that SDS expressed the most conspicuous effect on the shift of acid−base equilibria of the examined ACE inhibitors. Decreased acidity of carboxyl groups in the ACE inhibitors, with the exception of captopril and increased basicity of the secondary amino groups could be explained in terms of electrostatic interactions at the negatively charged SDS interface (anion repulsion and cation attraction). In the case of acidic functional groups, the negatively charged interfacial SDS layer acts expressing two contradictory effects. Repulsion forces between the negatively charged surface of the micelles and the anions arising by deprotonation of the acidic functional group hinder deprotonation thus leading to acidity decrease. The repulsion of the deprotonated carboxyl group by negatively charged SDS can be mainly discussed for zofenopril, fosinopril, and captopril since amphoteric ACE inhibitors are overall neutral because of amine protonation in acidic solutions. Further, the negatively charged SDS interface acts to increase 2570



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Table 3. pKa Values of ACE Inhibitors Determined by Potentiometry in the Presence of 10−2 M Surfactantsa ACE inhibitor

pKa1

ΔpKa1

ΔpKa2

pKa2

pKa3

ΔpKa3

pKa4

ΔpKa4

7.39 ± 0.05

+0.19

10.52 ± 0.02

−0.38

7.27 ± 0.04

+0.07

11.60 ± 0.03

+0.70

7.24 ± 0.01

+0.04

11.15 ± 0.01

+0.76

SDS

a

fosinopril zofenopril captopril cilazapril enalapril quinapril perindopril ramipril lisinopril

5.37 5.29 3.35 4.96 4.57 5.02 4.75 5.18 3.26

± ± ± ± ± ± ± ± ±

0.07 0.09 0.04 0.04 0.03 0.02 0.08 0.02 0.06

+1.34 +0.83 −0.15 +1.59 +1.63 +1.9 +1.27 +1.83 +1.83

9.67 7.12 5.46 6.27 6.15 6.01 3.89

± ± ± ± ± ± ±

0.03 0.03 0.02 0.02 0.08 0.03 0.07

−0.32 +0.65 +0.05 +0.87 +0.24 +0.24 +0.74 CTAB


3.18 5.27 3.49 3.10 2.99 3.54 3.59 3.39 1.69

± ± ± ± ± ± ± ± ±

0.01 0.03 0.01 0.05 0.09 0.07 0.04 0.05 0.12

−0.85 +0.81 −0.01 −0.27 +0.05 +0.42 +0.11 +0.04 +0.26

10.05 5.03 5.28 3.81 5.63 4.84 3.28

± ± ± ± ± ± ±

0.01 0.05 0.06 0.11 0.04 0.05 0.04

+0.06 −1.44 −0.13 −1.59 −0.28 −0.93 +0.13 TX 100


4.68 5.22 3.55 3.46 3.20 3.27 3.37 3.34 0.51

± ± ± ± ± ± ± ± ±

0.02 0.08 0.01 0.01 0.02 0.02 0.03 0.01 1.03

+0.65 +0.76 +0.05 +0.09 +0.26 +0.15 −0.11 −0.01 −0.92

10.00 6.50 5.55 5.36 5.89 5.88 3.28

± ± ± ± ± ± ±

0.01 0.01 0.01 0.02 0.02 0.01 0.01

+0.01 +0.03 +0.14 −0.04 −0.02 +0.11 +0.13

I = 0.1 M NaCl, t = 25 °C; ΔpKa = differences in relation to pKa values obtained in surfactant-free media (Table 2).

Table 4. Equations for Calculation of Equilibrium Species of ACE Inhibitors as a Function of pH

the pH value in the proximity of micelles via H + stabilization.25,26 As a consequence, stimulation of the acidic

group ionization and thus an increased acidity take place. The shift of pKa values depends on the total sum of all these 2571



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effects.27 In the case of captopril, SDS led to increased acidity of acidic functional groups (carboxyl and thiol), while in other examined ACE inhibitors, SDS decreased carboxyl group acidity. A relatively high increase in pKa value of ACE inhibitors carboxyl group in the presence of SDS also points to the possibility of intramolecular hydrogen bond formation between a carboxyl group hydrogen atom and an amide group oxygen atom. The fact that this hydrogen bond is possible only in cis form, suggests that the reversible cis−trans interconversion, already present in aqueous solution of ACE inhibitors28 is directed toward the cis form in the presence of SDS. Taking into consideration the fact that this interconversion depends on pH,28 dominance of one isomer can be taken as a proof of an increase in the pH value in the proximity of the SDS micelles. This surfactant affected the secondary amino group of all examined ACE inhibitors in the same manner; that is, an increase of basicity due to its negatively charged interface acted to stabilize the protonated amino group. Decreasing basicity of lisinopril primary amino group in the presence of anionic SDS suggested hydrophobic interactions inside the micelles and lipophilic hydrocarbon chain that separates primary amino group from the rest of lisinopril molecule. CTAB strongly stabilizes anionic species.29 However, the effect of CTAB on an amino group (pKa2) of amphoteric ACE inhibitors is more pronounced in relation to the ionization of carboxyl groups (pKa1). This can be explained by a molecular charge which was overall neutral during pKa1 determination (the amino group is protonated). In the case of TX 100, the observed shift of pKa value points to a relatively low influence of this nonionic surfactant on the ionization of ACE inhibitors, except for ionization of the carboxyl group of fosinopril (pKa1 increase of 0.65), zofenopril (pKa1 increase of 0.76), and of lisinopril primary amino group (pKa4 increase of 0.76). Fosinopril and zofenopril in the presence of neutral TX100 show a higher pKa increment than other compounds, probably because their high lipophilicity value allows them to penetrate the neutral form of the drug inside the micelle. No reliable conclusions can be drawn out regarding a decrease of lisinopril pKa1 for 0.92 because of the uncertain determined value of this parameter in the presence of TX 100 in high acidic medium. A decrease of carboxyl group acidity of the examined ACE inhibitors in the presence of TX 100 could support hydrophobic interactions and also, at least partially, result from intermolecular hydrogen bond formation between carboxyl group hydrogen and oxygen atoms in polyoxyethylene groups of TX 100. A high number of these groups in the hydrophilic layer of TX 100 probably influence stabilization of the protonated primary amino group of lisinopril, that is, the increase of basicity of this group. Since the drug bioavailability is directly correlated with distribution of equilibium forms, the percentage of equilibrium forms of the examined ACE inhibitors in the absence and in the presence of the employed surfactants can be calculated on the basis of pKa values (Table 4).

complex interactions in the presence of surfactants. Shifts of pKa values demonstrate a high sensitivity of the carboxyl group of ACE inhibitors to intermolecular interactions. This is especially important because it is known that the carboxyl group plays an important role in drug interaction with the enzyme active site.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Tel.: +381 11 3970379. Fax: +381 11 3972840. Funding

This work was supported by the Ministry of Education, Science and Technological Development of the Republic of Serbia, Contract No. 172033. Notes

The authors declare no competing financial interest.

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CONCLUSION Shifts of pKa values of the examined ACE inhibitors in the presence of anionic, cationic, and nonionic surfactants clearly demonstrate different interactions that include ionizable groups of these drugs. Opposite charges of ionizable acidic and basic groups and partially overlapping acid−base equilibria (close pKa values), as well as reversible cis−trans interconversion of ACE inhibitors in aqueous medium, point to the possibility of rather 2572



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The Effects of Anionic, Cationic, and Nonionic Surfactants on Acid

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