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The Effect of Nonionic Surfactant Brij 35 on Solubility and Acid−Base Equilibria of Verapamil Marija R. Popović-Nikolić,*,† Gordana V. Popović,‡ and Danica D. Agbaba† †

Department of Pharmaceutical Chemistry, and ‡Department of General and Inorganic Chemistry, University of Belgrade, Faculty of Pharmacy, Vojvode Stepe 450, P.O. Box 146, Belgrade, 11000, Serbia ABSTRACT: Protolytic equilibria and solubility of verapamil were investigated in the presence and in the absence of nonionic surfactant Brij 35 at a constant ionic strength (0.1 mol/L NaCl) and temperature 25 °C. In surfactant free media the intrinsic solubility, S0 = 4.51 × 10−5 mol/L (only the neutral form is present in the solution) and pHdependent solubility, S (neutral and ionized form in solution) of verapamil were determined. On the basis of the solubility data, the apparent pKa value 9.15 of verapamil was indirectly obtained. In micellar media (10−3 mol/L Brij 35) the solubility of verapamil free base (S0,s = 2.76 × 10−3 mol/L) and the apparent pKa,s = 6.35, were determined. The shift in the protolytic equilibria (ΔpKa = −2.80) and the increased solubility of verapamil free base (approximately 60 times) caused by Brij 35 point out to specific interactions between verapamil and the inner part of Brij 35 micelles. The most significant changes in distribution of verapamil equilibrium forms were observed at biopharmaceutically important pH 7.4 which potentially indicates interactions with biomolecules in blood plasma.

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INTRODUCTION Verapamil belongs to the class of calcium channel blockers applied in the treatment of cardiac arrhythmias, angina pectoris, and hypertension. Because of the presence of a single ionizable group, aliphatic tertiary amine, verapamil represents a weak base (Figure 1) and exhibits pH-dependent aqueous solubility.1

the pKa value. Comprehensive understanding of these parameters is necessary for the development of novel drug delivery systems, improvement of existing pharmaceutical formulations, and for the definition of the optimal experimental conditions in drug analysis. Determination of drug solubility and the pKa value is required for the estimation on how the chemical structure influences pharmacological behavior and pharmacokinetic parameters of drugs. The bioavailability of orally administered drugs is directly dependent on the ionization state and solubility in the conditions of the gastrointestinal tract.4−9 Regulatory agencies in the pharmaceutical industry require recognition of the potential drugs solubility issues even in the early stages of discovery and development and in order to find optimal strategies to overcome them.9 It is particularly important to predict the solubility of drugs that may ionize and whose solubility is pH dependent. However, the data on the physicochemical properties of drugs determined in a simple aqueous solution is not sufficient for prediction of solubility and bioavailability in physiological conditions that are significantly more complex. During the transport to the target site of action the drugs have to cross the cell membranes and also interact with biomolecules of different polarity and charge. Potential interactions under physiological conditions can affect the physicochemical properties of drugs and the ionization and solubility profile can differ in a relation to the pure aqueous solution. For this reason, a better understanding of behavior of

Figure 1. Chemical structure of verapamil.

According to the biopharmaceutical classification system of drugs verapamil can be classified into group I/II because after the oral administration a relatively high solubility and permeability is seen, but after the first pass effect in the liver, its solubility is moderate.2 Most of the pharmacologically active compounds behave as weak acids and/or bases which ionize to a small extent in a water solution. The ionized forms are most often more soluble in water, while the molecular forms are more lipophilic with the ability to more easily pass through the cell membranes.3 The physicochemical parameters of primary concern in medicinal chemistry that affect the liberation and the absorption processes of pharmacologically active compounds are the solubility and © XXXX American Chemical Society

Received: October 5, 2016 Accepted: May 16, 2017

A

DOI: 10.1021/acs.jced.6b00864 J. Chem. Eng. Data XXXX, XXX, XXX−XXX

Journal of Chemical & Engineering Data

Article

The concentrations of verapamil in the obtained solutions were determined spectrophotometrically. Verapamil expresses two absorption maxima at 230 and 280 nm. The calibration curve was obtained at 230 nm (higher absorptivity) in 0.01 mol/L HCl within the range of verapamil concentrations 1 × 10−5 to 1 × 10−4 mol/L:

ionizable drugs with pH-dependent solubility in aqueous compartments of a living system separated by lipid membranes could be achieved by investigating their physicochemical properties under conditions more similar to physiological. Micellar solutions of surfactants have been used as the biomembrane mimetic systems which act to increase the solubility of drugs poorly soluble in water and shift the protolytic equilibria of drugs that can ionize.10−12 These interactions between drugs and micelles can affect drug distribution within the body compartments. The aim of this study was to investigate the solubility and ionization of verapamil in micellar solutions of nonionic surfactant, polyoxyethylene (23) lauryl ether (Brij 35) (Figure 2), as biomembrane mimetic system. Only a few values of

A 230 = −0.01228 + 1.511 × 104c ,

(R2 = 0.9996)

(1)

where A230 is the absorbance of the verapamil solution at 230 nm, determined with a 0.01 mol/L HCl as a blank and c is the concentration of verapamil (mol/L). The solubility of verapamil’s molecular form (free base) in the presence of a micellar solution of 10−3 mol/L Brij 35 was examined within the pH range 11.5−12.0 and a constant ionic strength (0.1 mol/L NaCl) by the same procedure applied for determinations in surfactant-free solutions. The filtrates obtained after filtration of the verapamil suspensions supplied with Brij 35 (10−3 mol/L) were diluted 100 times with double distilled water, and HCl was added to a concentration of 0.01 mol/L. The actual concentration of verapamil was determined at 280 nm (the peak with lower absorptivity). This wavelength was chosen to eliminate the influence of Brij 35, which shows a significant absorptivity at wavelengths less than 265 nm. The calibration curve was obtained in 0.01 mol/L of HCl in the range of verapamil concentrations of 1 × 10−5 to 1 × 10−4 mol/ L at 280 nm:

Figure 2. Chemical structure of Brij 35.

verapamil ionization constant are reported in the literature, determined only in a cosolvent system.13,14 However, there are no data on verapamil ionization and solubility in the presence of micelles. In this study, the intrinsic and the pH-dependent aqueous solubility of verapamil have been determined by the shake flask method. The apparent pKa value which defines the ionization of verapamil in surfactant free solution (aqueous media) was calculated based on solubility data. In the presence of Brij 35 micelles the apparent pKa,s value of verapamil was determined potentiometrically.

A 280 = −0.00651 + 5.580 × 103c ,

(R2 = 0.9993)

(2)

The pKa Determination in Micellar Media. The apparent pKa,s value of verapamil, in the presence of 10−3 mol/L micellar solution of Brij 35, was potentiometrically determined. The addition of the surfactant 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 mol/L (NaCl). To 40 mL of 10−3 mol/L solution of verapamil (in the presence of 10−3 mol/L Brij 35) 1.0 mL of HCl solution (0.1027 mol/L) was added in order to achieve total protonation of verapamil and titrated with 0.02 mL aliquots of NaOH solution (0.0984 mol/L). Potentiometric determinations were done in triplicate. On the basis of the measured pH values, pcH values were calculated (pH = −log [H+]) by applying the relation: pcH = pH − A. Correction factor A = 0.05 was determined by titrating 0.1027 mol/L HCl solution at an ionic strength of 0.1 mol/L (NaCl) by a standard NaOH solution (0.0984 mol/L).15,16 On the basis of the data obtained by potentiometric titrations, the apparent pKa,s value of verapamil was calculated using the computer program Hyperquad, the computational approaches of which are based on last-squares curve-fitting procedures.17 For data plotting and creating a distribution diagram OriginPro8 was used. The Acidity Constants Definition. The thermodynamic acid constant (Kaa) describing the ionization of a base (BH+) according the Bronstedt concept:

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EXPERIMENTAL SECTION Apparatus and Reagents. Automatic titrator 798 MPT Titrino (Metrohm, Switzerland) with a combined electrode LL unitrode Pt 1000 (Metrohm, Switzerland) was used for potentiometric determinations. The electrode used for the pH measurements was regularly calibrated with standard buffer solutions (pH 4.01, 7.00, and 9.21). Spectrophotometric measurements were carried out on the UV−vis spectrophotometer Cintra 20 (GBC, Australia). Constant temperature of the titrated solutions was maintained at 25 °C using a Huber Polystat CC2 thermostat. (±)-Verapamil hydrochloride and 5-[N-(3,4dimethoxyphenylethyl)methylamino]-2-(3,4-dimethoxyphenyl)-2-isopropylvaleronitrile hydrochloride were kindly donated from the Medicines and Medical Devices Agency of Serbia (Belgrade, Serbia). The nonionic surfactant, polyoxyethylene (23) lauryl ether (Brij 35) (Sigma−Aldrich, ≥ 99% purity), was used for the preparation of micellar solution. All solutions were prepared in double distilled water. Standard solutions of HCl and carbonate-free NaOH were standardized potentiometrically. Determination of Verapamil Solubility. Saturated solutions of verapamil (pH 7.8 to 12.2) at constant ionic strength (0.1 mol/L NaCl) were prepared by precipitation of verapamil free base from a solution of verapamil hydrochloride (0.25 mg/mL) with 0.1 mol/L NaOH. Suspensions were thermostated at 25 °C, with occasional stirring for 24 h, and then filtered through 0.22 μm membrane filter. The filtrate aliquots were diluted (2.5−8.3 times) by double distilled water with the addition of HCl to reach a 0.01 mol/L concentration.

BH+ + H 2O ⇄ B + H3O+

(3)

is defined by the following equation: a + = K a,BH

a H3O+aBH+ a H2OaB

=

18,19

x H3O+γH O+x B−γB 3

x H2OγH Ox BH+γBH+ 2

= K ac

γH O+γB 3

γH OγBH+ 2

(4) B



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where a is activity, x is the mole fraction, and γ is the activity coefficient. The concentration-based equilibrium constant (Kca) is the apparent constant and depends on the activity coefficient of the ionizable molecule and on the composition of the medium. Considering the fact that γ values are hardly estimable, especially when the surfactants are present in the system, the assumption of an ideal mixture was taken into acount. In that case the activity and activity coefficient are 1 thus the approximation can be made: K aa ≈ K ac

Table 1. pH-Dependent Verapamil Solubility at 25 °C

(5)

pH

S (mol/L)

8.12 8.32 8.41 8.62 8.70 8.84 8.88 9.09

5.34 3.23 2.22 1.46 1.39 8.76 5.06 5.57

× × × × × × × ×

10−4 10−4 10−4 10−4 10−4 10−5 10−5 10−5

Accordingly, in this work the pKa value is termed the apparent pKa, defined as the negative logarithm of Kca.

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RESULTS AND DISCUSSION Solubility Study and the pKa Determination in Pure Aqueous Media. From the chemical point of view verapamil represents the monoprotic base, the molecular form of which is poorly soluble in water. In a saturated aqueous solution of verapamil between the solid phase (Bs) and a solution the following equilibria is established: Bs ⇄ B

K s0 = S0 = [B]

Bs + H+ ⇄ BH+

K s1 =

(6)

[BH+] [H+]

(7)

Figure 3. Linear dependence of verapamil solubility (S) vs [H+] in the pH range from 8.12 to 9.09, eq 8.

where S0 is the intrinsic solubility (solubility of molecular form) of verapamil. The total solubility (S) of verapamil is equal to the sum of the concentrations of the molecular form (B) and of the protonated form (BH+): S = [B] + [BH+]

Table 2 and from five independent determinations a mean value for S0 (4.51 × 10−5 mol/L) was obtained. On the basis of Table 2. Intrinsic Verapamil Solubility at 25 °C

(8)

Combining eqs 6−8 gives the equation:

S = S0 + K s1[H+]

(9)

where the constant Ks1 can be replaced by the relation that connects verapamil’s apparent acidity constant (Kac) and constants in a heterogeneous system: K ac =

K [B][H+] = s0 [BH+] K s1

(10)

⏟ Equation 11 represents linear dependence of the total solubility x

S0 (mol/L) 4.24 × 10−5 2.80 × 10−5 4.23 × 10−5 6.00 × 10−5 5.26 × 10−5 (4.51 ± 1.21) × 10−5

the slope of the curve in Figure 3 (6.38 × 104) and independently obtained the intrinsic solubility S0 (4.51 × 10−5 mol/L), the apparent ionization constant of verapamil Kca = 7.07 × 10−10 (the apparent pKa, 9.15) has been indirectly determined. The most frequently applied methods for the determination of ionization constants in aqueous solution are potentiometry and spectrophotometry.20 These methods are not applicable in the case of verapamil pKa determination. Potentiometric determination in pure aqueous media, without the use of cosolvents, could not be applied due to the low solubility of verapamil. Spectrophotometry cannot be applied due to very small differences in the absorption spectra of molecular and ionized forms. The few published data show that the apparent pKa value of verapamil was determined exclusively by using a cosolvent system (Table 3).13,14 On the basis of determined intrinsic solubility S0, the apparent pKa value, and transformed eq 11 the solubility curve (S vs pH) of verapamil has been defined:

to give the following equation: S S = S0 + 0c [H+] K ⏟y a

pH 11.5 11.7 11.9 12.0 12.2 average

(11)

(S) on [H+]. On the basis of pairs S−[H+] data it is possible to determine the intrinsic solubility (S0) and the ionization constant from the intercept (S0) and slope S0/Kca of the corresponding curve. Experimental data obtained for pHdependent verapamil solubility (S) are listed in Table 1. Linear dependence of verapamil solubility (S) vs [H+] in a pH interval from 8.12 to 9.09 is shown in Figure 3. In the case of very poor soluble compounds, such as verapamil, the ordinate intercept (S0) in eq 11 is often within a statistical error. Reliable results for the S0 of verapamil can be obtained by determining the solubility at pH > (pKa + 2), where total (S) and the intrinsic (S0) solubility are equal because the concentration of verapamil protonated [BH+] form can be neglected (eq 8). Results of S0 determination in the pH range from 11.5 to 12.2 are listed in

S = 4.51 × 10−5 × (1 + 109.15 − pH)

(12)

The Interactions of Verapamil and Brij 35 Micelles. The effect of 10−3 mol/L micellar solution of Brij 35 on C



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Table 3. Apparent pKa Values of Verapamil Determined in This Study and Data from the Literature

Table 4. Intrinsic Solubility of Verapamil Determined in the Presence of 10−3 mol/L Brij 35 at 25 °C

pKa

determination media

method

ref

pH

S0,s (mol/L)

9.15 8.63 8.72 9.07

“pure” water ethanol/dioxane/acetonitrile−water methanol−water cosolvent system

solubility potentiometric potentiometric

this study 13 13 14

11.5 11.7 11.9 12.0 average

2.60 × 10−3 2.98 × 10−3 2.71 × 10−3 2.76 × 10−3 (2.76 ± 0.16)×10−3

solubility of verapamil free base was determined. The influence of verapamil on micelles formation is disabled by selecting the concentration of surfactants much higher than the critical micellar concentration (cmc). Figure 4 shows the absorption spectra of verapamil and Brij 35 separately and of verapamil in the presence of Brij 35. The absorption spectra indicate that the absorbency of the Brij 35 in concentration 10−3 mol/L can be neglected at wavelengths exceeding 265 nm. The intrinsic solubility of verapamil free base (pH > 11.5) determined in the presence of 10−3 mol/L Brij 35 was found to be 2.76 × 10−3 mol/L (Table 4). Obtained results show that the solubility of verapamil free base is increased approximately 60 times in the presence of 10−3 mol/L Brij 35 comparing to the obtained S0 value in surfactant-free media (4.51 × 10−5 mol/L). Because the verapamil is poorly soluble in water, an increase in its solubility in the micellar solution unambiguously points out to the interaction between the verapamil and the Brij 35 micelles. However, the type of interaction cannot be predicted exclusively on the basis of increased solubility, and in the case of compounds which can ionize it is necessary to take into account the influence of micelles on the ionization equilibria for a more detailed assessment. Verapamil can be located in the surface-hydrated layer or in the hydrophobic interior of Brij 35, and the additional determination of the ionization constant can help in estimating which part of the micelles is more appropriate for the retention of the drug. Our previous studies21−23 showed that general prediction about the behavior of ionizable drugs in the presence of surfactants cannot be made even in the case of drugs belonging to the same pharmacological and chemical class. It is necessary to experimentally investigate the ionization and solubility in micellar solutions for every single compound. Since Brij 35 micelles expressed a solubilizing effect on the verapamil that is sparingly soluble in water, it was possible to determine the apparent pKa,s as 6.35 in the presence of 10−3 mol/L Brij 35 by potentiometric titration of 10−3 mol/L verapamil solution.

Potentiometric titrations were done in triplicate, and titration curves for all three probes are shown in Figure 5. The first part

Figure 5. Potentiometric curves obtained for verapamil in the presence of 10−3 mol/L Brij 35 titrated with standard NaOH solution. I = 0.1 mol/L (NaCl) and t = 25 °C: ■, probe 1; red ●, probe 2; blue ▲, probe 3.

of the curve (pH up to 4) represents titration of the strong acid (HCl) added in order to achieve total protonation of verapamil. The second part (pH higher than 4) corresponds to the titration of protonated verapamil. The difference (ΔpKa) between the apparent pKa,s value determined in the surfactant solutions and the apparent pKa value that define the ionization in the surfactant-free solutions demonstrates the shift in protolytic equilibria of verapamil caused by nonionic Brij 35 micelles.24 The estimation of surfactant effect on verapamil ionization demonstrated a significant shift in the ionization constant (ΔpKa = −2.80) which indicates that the ionizable center of verapamil is directly involved in the interactions with micelles and that the equilibrium species are present in a micellar pseudophase.25 This means that the apparent pKa,s represents a kind of a hybrid between drug ionization in the

Figure 4. Absorption spectra: (1) Brij 35 (10−3 mol/L); (2) verapamil 5 × 10−5 mol/L; (3) verapamil (5 × 10−5 mol/L) in the presence of Brij 35 (10−3 mol/L); solutions are prepared in 0.01 mol/L HCl. D



Article

which are responsible for verapamil solubilization. Significant change in the equilibrium forms distribution is observed at pH 6.8, physiologically related to the kidney environment, where the content of verapamil ionized form is 100%, in surfactantfree, and 26%, in surfactant-supplied media. These values can help explain the low verapamil excretion in unchanged form by urine. On the other hand, from Figure 6 it can be clearly seen that the distribution of verapamil equilibrium forms at pH 4.5, which is considered to exist in the proximal part of the small intestine, probably will not be affected by the presence of polar biomolecules with surface activity without charge and will not influence absorption and bioavailability of orally administered verapamil.

aqueous phase and ionization within the micellar pseudophase.26 The micellar pseudophase can be considered as a kind of organic solvent or water−organic mixture, where the equilibria between molecular and ionized form of dissolved compound differs from that in water.27 On the basis of the determined apparent pKa value distribution profiles of verapamil equilibrium forms as a function of pH in surfactant free media and in the presence of Brij 35 micelles were calculated by applying the equations for a monoprotic base: 100 % of ionized form = (13) 1 + 10(pH − pKa) % of molecular form = 100 − (% of ionized form)

■

(14)

CONCLUSION The apparent pKa value of verapamil in aqueous media has been determined without the use of cosolvents for the first time in this study. Significant increase of solubility and decreased ionization of verapamil have been observed in the presence of Brij 35 micelles as a membrane mimicking system. The shift in the ΔpKa value indicates that the verapamil ionizable group is involved in interactions with Brij 35 micelles, and the drug is predominantly retained in the hydrophobic micelle interior. The most significant change in distribution of equilibrium forms can be potentially observed in conditions of blood plasma.

Distribution diagrams are shown in Figure 6 and point to changed ionization in micellar media. Brij 35 caused the

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AUTHOR INFORMATION

Corresponding Author

Figure 6. Distribution of the verapamil equilibrium forms as a function of pH in the presence of Brij 35 and surfactant-free media.

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

reduction in ionization (ΔpKa = −2.80) and shifted protolytic equilibria toward the molecular form of verapamil. On the basis of the shift obtained for the ΔpKa values and solubility, different types of interactions between verapamil and Brij 35 micelles can be described and possible behavior of verapamil in physiological conditions can be predicted. Changes in ionization mode in a relation to surfactant free media can be mainly explained in terms of properties of nonionic Brij 35 micelles. The nonionic micelles of Brij 35 do not have a charge and counterions but they are characterized by a higher degree of hydration in the palisade layer and allows high water penetration.28,29 The simultaneous increase of solubility and content of the lipophilic molecular form led to the conclusion that verapamil is predominantly retained in the hydrophobic interior of Brij 35 micelles. Observed interactions can be transferred to consideration of the potential effect of polar but noncharged biomolecules on the distribution of verapamil equilibrium forms at some physiological conditions. Distribution diagrams (Figure 6) indicate that the most significant shift in ionization of verapamil is observed in the pH range from 6 to 9 which includes some of the biopharmaceutically important values. The percentage of verapamil equilibrium forms, in the absence and in the presence of Brij 35 micelles, can be accurately calculated for pH 6.8 and 7.4 by applying eqs 13 and 14. The most significant shift is observed at pH 7.4 which corresponds to blood plasma where the content of ionized form is 98% and 8%, with and without Brij 35 micelles, respectively. These results can indicate a potential influence of biological molecules present in blood plasma which can shift protolytic equilibria of verapamil toward the more lipophilic nonionized molecular form by interactions

Marija R. Popović-Nikolić: 0000-0002-8902-3211 Gordana V. Popović: 0000-0002-4242-1132 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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REFERENCES

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