Solubility and Solution Thermodynamics of Novel Bicyclic Derivatives

Jun 11, 2014 - Drug-like N-substituted 1-selena-3-azaspiro[5,5]undec-2-en-2-amine hydrobromides (1:1) have been synthesized. Phenyl, isopropylphenyl ...
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Solubility and Solution Thermodynamics of Novel Bicyclic Derivatives of 1,3-Selenazine in Biological Relevant Solvents Svetlana V. Blokhina,*,† Tatyana V. Volkova,† Marina V. Ol’khovich,† Angelika V. Sharapova,† Alexey N. Proshin,‡ and German L. Perlovich†,‡ †

Institute of Solution Chemistry, Russian Academy of Sciences, 1 Akademicheskaya Street, 153045, Ivanovo, Russia Institute of Physiologically Active Compounds, Russian Academy of Sciences, 142432, Chernogolovka, Russia

‡

ABSTRACT: Drug-like N-substituted 1-selena-3-azaspiro[5,5]undec-2-en-2-amine hydrobromides (1:1) have been synthesized. Phenyl, isopropylphenyl, and fluorophenyl substituents were used. The solubility of the obtained compounds in pharmaceutically relevant solvents within the temperature range from (298.15 to 318.15) K has been measured using the isothermal saturation technique. All of the compounds studied appear to have poor solubility of ∼10−6 mole fraction in phosphate buffer pH 7.4 and hexane. The solubility values enlarge substantially to ∼10−2 and 10−4 mole fraction, respectively, in octanol and muriatic buffer solution pH 2.0. The solubility of the selenazines in aqueous media was shown to increase as the number of protonated forms grew. The high solubility of the compounds in octanol was found to depend on the formation of intermolecular solvent−solute hydrogen bonds. Thermodynamic solubility functions for the substances in the solvents studied have been calculated. The solubility in all of the systems with the predominant enthalpy term of Gibbs energy was proved to increase as the dissolution enthalpy decreased.

■

INTRODUCTION Drugs based on heterocyclic compounds are widely used in pharmaceutics due to their structural similarity to natural objects with a high biological activity.1 An effective approach to designing new drugs is changing the atoms or molecular fragments in order to give new properties to the synthesized compounds, for example, replacing the carbon atom in the aromatic system with a heteroatom, increasing the number of cycles, and introducing a substituent result in structural and stereochemic shifts in the molecule. The latter, in turn, causes changes in the pharmacokinetic characteristics and specific activity. The solubility is one of the most important properties of drug compounds as it determines the substance concentration on the border layers of the biological membranes, and as a consequence, the diffusion flows across them. This makes it possible to obtain satisfactory bioavailability values, effective therapeutic dosages, and minimal side effects.2,3 As numerous investigations showed, most of the drug substances are ionized in water solution which has a considerable influence on the solubility,4 wherein the degree of ionization and, consequently, the solubility depend largely on the physiologically relevant pH © 2014 American Chemical Society

values. It should be noted that to enhance the solubility and thermodynamical stability in storage, many drugs are produced in the form of salts.5 The previous investigations into isothiourea spiro-derivatives6 neuroprotective properties arouse the interest in the synthesis of the novel compounds of this series having nitrogen- and selenium-containing heterocycles.7 Meanwhile, the selenium-containing heterocyclic derivatives do not only have unique physicochemical properties but also possess antioxidant8 and antibacterial9 biological activity. The aim of the present study was to study the relationship between the molecular structure of the spiroderivatives of 2amino-1,3-selenazine template soluble in pharmaceutically relevant media: muriatic buffer pH 2.0, phosphate buffer pH 7.4, octanol, and hexane. Received: April 21, 2014 Accepted: June 4, 2014 Published: June 11, 2014 2298

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Scheme 1

Table 1. Sample Table N I II III

■

chemical name

source

initial mole fraction purity

method purification

final mole fraction purity

analysis method

N-(1-selena-3-azaspiro[5.5]undec-2-en-2-yl)aniline hydrobromide N-(1-selena-3-azaspiro[5.5]undec-2-en-2-yl)-4-isopropylaniline hydrobromide N-(1-selena-3-azaspiro[5.5]undec-2-en-2-yl)-4-fluoroaniline hydrobromide

synthesis

none

recrystallization

0.98

NMR

synthesis

none

recrystallization

0.98

NMR

synthesis

none

recrystallization

0.98

NMR

EXPERIMENTAL SECTION

7.17 (d, 2 H, Harom, J = 8.6 Hz); 7.26 (d, 2 H, Harom, J = 8.6 Hz); 10.83 (s, 1 H, NH); 11.09 (s, 1 H, NH). N-(1-Selena-3-azaspiro[5.5]undec-2-en-2-yl)-4-fluoroaniline Hydrobromide (III). Yield 80%, light cream-colored crystals, mp 196.3 °C. Found (%): C, 44.35; H, 4.96; N, 6.90. C15H20N2FSeBr. Calculated (%): C, 44.51; H, 4.82; N, 6.81. 1H NMR, δ: 1.32 (m, 3 H, C(9)H2, C(10)HH); 1.62 (m, 5 H, C(11)HH, C(10)HH, C(8)H2, C(7)HH); 2.06 (m, 4 H, C(11)HH, C(7)HH, C(5)H2); 3.63 (m, 2 H, C(4)H2); 7.04 (m, 2 H, Harom); 7.20 (m, 2 H, Harom); 10.88 (s, 1 H, NH); 11.17 (s, 1 H, NH). Octanol (n-octanol, CH 3 (CH 2 ) 7 OH, MW 130.2, lot 11K3688) ARG from Sigma Chemical Co. (USA). Hexane (C6H14, MW 86.18, 99% purity) was received from Aldrich (St. Louis, USA). The buffer solutions were prepared by mixing solutions of muriatic acid and potassium chloride for pH 2.0 and appropriate sodium and potassium salts of phosphoric acid for pH 7.4, as described elsewhere.10 Ionic strength was adjusted by adding potassium chloride. All of the chemicals were of AR grade. The pH values were measured by using an electroanalytical analyzer, type OP-300, Radelkis, Budapest standardized with pH 1.68, 6.86, and 9.22 solutions. The origin, purification method, purity, and method of purity determination of all samples are presented in Table 1. Apparatus and Procedure. Solubility. All of the experiments were carried out by the isothermal saturation method at five temperature points: (293.15, 298.15, 303.15, 310.15, and 315.15) ± 0.1 K. The essence of this method includes the determination of the compound concentration in the saturated solution. Glass ampules containing the tested substance and the solvent were placed into the air thermostat supplied by the stirring device. The point of the solution thermodynamic equilibrium was determined based on the solubility kinetic dependences and averaged 24 h. After the saturation was achieved, the solution aliquot was taken and centrifugated in a

Materials. The synthetic approach to spiro-derivatives of 1,3-selenazine 5 is based on intramolecular cyclization of selenoureas 3 containing a γ,σ-unsaturated fragment (Scheme 1). Reactions of isoselenocyanates 1 with 2-(cyclohex-1enyl)ethylamine 2 (a γ,σ-unsaturated amine) afford 1-aryl-3(2-cyclohex-1-enylethyl)selenoureas 3. They were hydrobrominated at the double bond of the cyclohexene ring in boiling 48% aqueous HBr to give 1-aryl-3-[2-(1-bromocyclohexyl)ethyl]selenoureas 4, which promptly undergo intramolecular Se-alkylation and cyclization into the corresponding Nsubstituted 1-selena-3-azaspiro[5.5]undec-2-en-2-ylamines 5 in total yields of 60−80%. 1 H NMR spectra were recorded by the Bruker CXP-200 instrument (Germany) in CDCl3; the chemical shifts are given in the d scale relative to Me4Si. The solvents were removed using a rotary evaporator under water pump vacuum. N-(1-Selena-3-azaspiro[5.5]undec-2-en-2-yl)aniline Hydrobromide (I). Yield 79%, light brown crystals, mp 144.9 °C. Found (%): C, 46.41; H, 5.45; N, 7.22. C15H21N2SeBr. Calculated (%): C, 46.22; H, 5.33; N, 7.31. 1H NMR, δ: 1.37 (m, 3 H, C(9)H2, C(10)HH); 1.69 (m, 5 H, C(11)HH, C(10)HH, C(8)H2, C(7)HH); 2.14 (m, 4 H, C(11)HH, C(7) HH, C(5)H2); 3.71 (m, 2 H, C(4)H2); 7.28 (m, 2 H, Harom); 7.40 (m, 3 H, Harom); 10.92 (s, 1 H, NH); 11.26 (s, 1 H, NH). N-(1-Selena-3-azaspiro[5.5]undec-2-en-2-yl)-4-isopropylaniline Hydrobromide (II). Yield 75%, light creamcolored crystals, mp 148.5 °C. Found (%): C, 50.24; H, 6.32; N, 6.51. C18H27N2SeBr. Calculated (%): C, 50.02; H, 6.22; N, 6.64. 1H NMR, δ: 1.25 (d, 6 H, CH(CH3)2, J = 6.8 Hz); 1.43 (m, 3 H, C(9)H2, C(10)HH); 1.68 (m, 5 H, C(11)HH, C(10)HH, C(8)H2, C(7)HH); 2.08 (m, 4 H, C(11)HH, C(7) HH, C(5)H2); 2.93 (m, 1 H, CHMe2); 3.69 (m, 2 H, C(4)H2); 2299

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centrifuge under the temperature control Biofuge stratos (Germany) for 5 min under a fixed temperature. The solid phase was removed through isothermal filtration by the filter MILLEXHA 0.45 μm (Ireland). The saturated solution was diluted with the correspondent solvent to the required concentration. The molar solubilities of drugs were measured by means of spectrophotometer Cary-50 (USA) within the UV spectral region λ = (190 to 400) nm with an accuracy from 2 % to 4 %. The experimental results are reported as an average value of at least three replicated experiments. It should be noted that sediment DSC analysis showed that none of the tested compounds have crystallosolvates. Thermal Analyses. Thermogravimetric analysis of the samples was performed with a thermo-microbalance TG 209 F1 (Netzsch, Germany) in an argon flow in the temperature range from (20 to 400) °C. A weighed sample of a compound [∼(4 to 8) mg] was placed in platinum crucible with a pierced lid and heated at a rate of 10 °C·min−1. The weight loss was registered with error of 1·10−6 g. DSC measurements were carried out on a DSC analyzer (DSC 204 F1 “Foenix”, Netzsch, Germany). The experiment was carried out in an atmosphere of flowing (25 mL·min−1) dry argon gas of high purity 99.996 % using standard aluminum sample pans and a heating rate of 10 K·min−1. The DSC was calibrated using five standards: Hg, biphenyl, indium, tin, and bismuth. The sample mass was determined with the accuracy of 1·10−5 g using the balance Sartorius M2P. Background. The standard Gibbs energies of dissolution processes ΔG0sol were calculated using the following equation: 0 ΔGsol = −RT ln a 2

Figure 1. Molecular structure of the studied 1,3-selenazine bicyclic derivatives.

Table 2. Inserting an aromatic substituent in the bicyclic structure is aimed at increasing the lipophilicity of the substances under study. As we estimated earlier, the maximal biological activity among 1,3-thiazines6 is characteristic of the derivatives with a branched alkyl chain. Due to this fact we have synthesized compound (II) with an isopropyl group. The fluorine substituent was chosen for the introduction into compound (III) due to this element’s ability to increase the solubility of the molecules in lipophilic phases.11 Measuring the thermophysical characteristics has shown that the fusion temperatures of the compounds are within an interval from (422.0 to 474.0) K and increase in the following order I > II > III (Table 3). Their fusion enthalpies grow in the same order. On the basis of the results of the DSC and TG, it was estimated that the investigated selenazines have no polymorphic modifications and the compounds are stable up to the fusion temperature. The experimental data exemplified by the DSC and TG curves for compound (III) are represented in Figure 2. The solubility values of the compounds were measured in pharmaceutically relevant solvents: muriatic buffer pH 2.0; phosphate buffer pH 7.4, octanol, and hexane. The buffer solutions simulate the following media: pH 2.0 = the gastric fluid, pH 7.4 = the blood system. Octanol, as an amphyphilic substance capable of forming hydrogen bonds, models the properties of phospholipids of biological membranes.12 Hexane models the blood−brain barrier, which is especially important to the studied compounds as potential neuroprotectors.13 The experimental results about the solubility of the selenazine spiroderivatives are given in Table 2. Based on the obtained data we can make the following conclusions: (a) all of the compounds studied are poorly soluble in buffer pH 7.4 and hexane; (b) the solubility in buffer pH 2.0 and octanol is considerably higher than that in pH 7.4 and hexane; (c) the following trends of solubility decreasing are observed in the investigated solvents: in buffer pH 7.4 and hexane the solubility values are ranged as I > II > III; in buffer pH 2.0, I > III > II; and in octanol, II > I > III; (d) the solubility in hexane and buffer pH 7.4 decreases if the fusion temperature grows. The solubility of organic compounds in aqueous solutions dramatically depends on the molecules being either in the ionized or unionized state. In its turn, the substance ionization degree is determined by the solution pH and the pKa-values. The values of the ionization constants pKa calculated at 298 K and zero ionic strength are given in Table 2. The investigated selenazines belong to the heterocyclic type with the basic properties based on the ability of the uncoupled electrons of the heterocyclic nitrogen atom to attach a proton. All the investigated substances have a single pKa value related to the nitrogen spiro-heterocycle ionization. The pKa values corresponding to the state of the molecules after the most basic position has been protonated were taken for the compounds. Based on the pKa-values we calculated the content of a number of selenazine forms with different protonation degrees in water solution depending on the pH of the media by the Henderson−Hasselbach equation:14

(1)

where a2 = γ2·x is the activity of the solute molecule; x is the compound molar fraction in the saturated solution; γ2 is the activity coefficient of the solute molecule. The standard solution enthalpies ΔH0sol were calculated using the van’t Hoff equation: 0 ∂(ln a 2)/∂T = ΔHsol /RT 2

(2)

The temperature dependences of solubilities within the chosen temperature interval can be described by the linear function: ln x = A − B /T

(3)

This indicates that the change in heat capacity of the solutions with the temperature is negligibly small. The standard solution entropies ΔS0sol were obtained from the well-known equation: 0 0 0 ΔGsol = ΔHsol − T ΔSsol

(4)

To calculate the enthalpy of specific interaction ΔHsp solvent− solute using the following equation:

■

0 0 ΔHsp = ΔHsol (octanol) − ΔHsol (hexane)

(5)

RESULTS AND DISCUSSION The objects of the present study were the heterocyclic spiroderivatives of 1,3-selenazine: a common fragment in the structure of their molecules is connected with the substituents through a secondary amino-group (Figure 1). The studied drug-like substances were used in the form of hydrobromic salts to enhance the solubility in water solutions. Phenyl (I), paraisopropylphenyl (II), and para-fluorophenyl (III) were chosen as the substituents, the structures of which are presented in 2300

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Table 2. Structural Formula of the Substituents, CAS Number, Constant of Ionization, and Solubility at 298.15 K in Buffers, Octanol, and Hexane for the Compounds Studied

a

Calculated using Advanced Chemistry Development (ACD/Laboratories) Software V11.02.

Table 3. Thermophysical Parameters of the Compounds Studied Tm

Δ1crHm ° (T)

Δ1crSm ° (T)

compound

K

kJ·mol−1

J·mol−1·K−1

I II III

417.9 ± 0.2 421.5 ± 0.2 469.3 ± 0.2

18.0 ± 0.5 12.9 ± 0.5 25.1 ± 0.5

42.5 ± 2.5 29.5 ± 2.5 53.0 ± 2.5

Figure 3. Dependence of content of the ionized forms of the studied compounds on the pH of buffer solution at 298 K.

ionized form content on the pH of the water solution for the investigated molecules have been found to be almost identical. According to the obtained data all the studied compounds are ionized at the physiological pH 2.0. If pH reaches 7.4, the content of the protonated forms of selenazines decreases. Figure 4 shows a diagram of the dependence of the compound solubility on the content of the ionized forms. As it follows from the presented data, the uncharged form of the selenazine molecule is less soluble. Under a positive charge, the solubility of the substances increases. These results correspond to the

Figure 2. DSC (a) and TG (b) curves for compound III.

log

[N] = pH − pK a [NH+]

(6)

where N and NH+ correspond to the heterocycle nitrogen atom of neutral and protonated molecular forms, respectively. The ionized/unionized particles distribution as a function of pH was calculated by using ACDLABS version 10.0 and the results are presented in Figure 3. The graphical dependences of the

Figure 4. Histogram of solubility and content of the ionized forms of the studied compounds in buffer solutions at 298 K. 2301

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Table 4. Experimental Mole Fraction Solubility x of Compounds Studied in Buffers pH 2.0 and 7.4 at Temperature T and Pressure p = 0.1 MPaa I

II

III

buffer pH 2.0

buffer pH 7.4

buffer pH 2.0

buffer pH 7.4

buffer pH 2.0

buffer pH 7.4

T/K

x·103

x·106

x·104

x·106

x·104

x·107

293.15 298.15 303.15 308.15 313.15 A Bb Rc σd

1.73 1.87 1.99 2.17 2.40 −1.61 ± 0.16 1415 ± 50 0.9981 0.9·10−2

0.95 1.03 1.12 1.23 1.33 −8.45 ± 0.09 1617 ± 27 0.9996 0.4·10−2

1.59 1.93 2.38 2.80 3.46 3.14 ± 0.28 3483 ± 87 0.9991 1.4·10−2

0.58 0.72 0.98 1.25 1.62 2.09 ± 0.49 4909 ± 151 0.9986 2.5·10−2

6.11 6.85 7.61 8.67 9.68 −0.08 ± 0.17 2184 ± 52 0.9991 0.9·10−2

5.71 6.19 6.61 7.02 7.49 −10.13 ± 0.10 1264 ± 31 0.9991 0.5·10−2

a Standard uncertainties u are u(T) = 0.05 K and ur(x) = 0.02. bParameters of the correlation equation: ln x2 = A − B/T. cR = pair correlation coefficient. dσ = standard deviation.

Table 5. Experimental Mole Fraction Solubility x of Compounds Studied in Octanol and Hexane at Temperature T and Pressure p = 0.1 MPaa I octanol 2

II hexane 6

octanol 2

T/K

x·10

x·10

x·10

293.15 298.15 303.15 308.15 313.15 A Bb Rc σd

1.86 2.29 2.78 3.29 3.85 7.39 ± 0.25 3329 ± 76 0.9992 1.3·10−2

4.94 5.94 7.10 8.46 9.98 −1.14 ± 0.05 3246 ± 15 0.9999 0.2·10−2

4.84 5.51 6.47 7.28 8.31 5.48 ± 0.19 2492 ± 59 0.9992 1.0·10−2

III hexane 6

octanol 2

hexane

x·10

x·10

x·106

4.69 5.82 7.39 8.84 11.11 1.03 ± 0.30 3897 ± 92 0.9992 1.5·10−2

0.30 0.36 0.42 0.48 0.55 3.46 ± 0.17 2713 ± 52 0.9995 0.9·10−2

1.27 1.59 1.90 2.35 2.89 −0.64 ± 0.29 3791 ± 91 0.9991 1.5·10−2

Standard uncertainties u are u(T) = 0.05 K and ur(x) = 0.02. bparameters of the correlation equation: ln x2 = A − B/T. cR = pair correlation coefficient. dσ = standard deviation.

a

hydrogen bonding but also by the structural impact associated with the features of the molecular structure.16 The solubility values of the selenazines measured experimentally in buffer pH 2.0, buffer pH 7.4, octanol, and hexane in the temperature range from (298.15 to 318.15) K are given in Tables 4 and 5. For example, the temperature dependences of the solubility of compound I in all investigated solvents are presented in Figure 5. On the basis of the obtained linear

well-known conceptions: uncharged molecules are better soluble than their charged forms.4 Moreover, a drastic increase of the compounds studied solubility occurs when pH changes from 7.4 to 2.0, while the content of ionized molecules raises unessential. A possible reason for this phenomenon is a considerable difference between the solubility of ionized and unionized selenazine molecular forms. This proposal is confirmed by the solubility values of the protonated forms of the thiazine molecules structurally similar to selenazines. The above values are 2-fold higher than the respective intrinsic solubility.15 Therefore, even a small increase of the charged molecular forms content increases the solubility of the investigated compounds considerably. We should pay attention to the fact that compounds II and III have substituents with different donor and acceptor properties in their structure. Inserting an electrono-donor isopropyl group into the benzene ring increases the negative charge on the heterocyclic nitrogen atom, and vice versa, introducing an electrono-acceptor fluorine atom decreases it. But in spite of the higher basicity the solubility of the isopropylderivative II in buffer pH 2.0 is three times lower than that of compound III with a fluorine atom. In this connection we can conclude that the solubility of the investigated compounds is not only affected by the energy input determined by the interaction of the solute with the solvent analogous to the

Figure 5. Temperature dependencies of compound I solubility in ■, octanol; ▲, hexane; ●, buffer pH 2.0, and ⧫, buffer pH 7.4. 2302

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Analysis of the solubility thermodynamic functions for 1,3selenazine spiro-derivatives in buffer pH 2.0, buffer pH 7.4, octanol, and hexane has shown that excess Gibbs energies in all of the studied binary systems have positive values. This indicates that the selenazines solubility process is thermodynamically complicated. The enthalpy and entropy terms of Gibbs energy are directly connected to the intermolecular forces in the solution and the system regularity. The interaction forces between the solute and the solvent molecules are characterized by the molar solubility heat. The stronger are the intermolecular interactions, the lower the possibility of the transition of the solute molecules in the solution is. The realization of the compensation effect is observed in all the investigated binary systems of selenazines I−III−solvent (Figure 6). The analysis of the results presented in Figure 6

dependences of the solubility on the inverse temperature value, we have calculated the solubility thermodynamic functions of the substances in the investigated solvents (Table 6). The Table 6. Thermodynamic Solubility Functions of the Studied Compounds in Buffers, Octanol, and Hexane at 298.15 K ΔG0sol compound

−1

kJ·mol

I II III

15.7 21.2 18.3

I II III

34.4 35.5 35.6

I II III

9.3 7.2 14.0

I II III

29.8 29.8 33.1

ΔH0sol −1

kJ·mol

Buffer pH 2.0 11.8 ± 0.4 28.9 ± 0.7 18.1 ± 0.4 Buffer pH 7.4 13.4 ± 0.2 40.7 ± 1.2 10.5 ± 0.2 Octanol 27.7 ± 0.6 20.7 ± 0.4 22.5 ± 0.4 Hexane 27.0 ± 0.4 32.4 ± 0.7 31.5 ± 0.2

TΔS0sol −1

ΔS0sol

kJ·mol

J·mol−1·K−1

−3.9 7.7 −0.2

−13.3 ± 0.7 25.9 ± 1.1 −0.7 ± 0.1

−21.0 5.2 −25.1

−70.5 ± 2.5 17.4 ± 1.0 −84.2 ± 3.2

18.4 13.5 8.52

61.7 ± 2.5 45.3 ± 1.7 28.6 ± 1.1

−2.8 2.6 −1.6

−9.4 ± 0.3 8.7 ± 0.3 −5.4 ± 0.1

activity coefficients γ2 = 1 were used in the calculations as the solubility of the studied compounds in buffer solutions and hexane x < 10−2.17 The solubility of the compounds in octanol has been found to equal x ≈ 10−2; therefore, we determined the distribution coefficients between the immiscible phases. The results show that the distribution coefficients in the octanol− buffer system do not depend on the concentration; therefore, the activity coefficients for compounds I to III can be assumed to be equal to 1 as well. To discuss the obtained results we used the 1,3-thiazine spiro-derivatives X-ray analysis18 conducted by us earlier, based on which these compounds can be characterized as molecular crystals with strong hydrogen bonds. The hydrogen bond networks are caused by considerable effective charges on the amino-group (NH+) and heterocyclic nitrogen atom (N−). Therefore, the high solubility of selenoderivatives of a similar structure in octanol can be explained by specific interactions of the solute molecules with the solvent. A hydrogen bond can be formed between the donor amino-group of the studied compounds and the oxygen atom of the acceptor octanol hydroxyl group (N−H···O). The presence of hydrogen bonds is testified by the values of the impacts of the specific solvation term in octanol for the studied 1,3-selenazines calculated by eq 5. Hexane was chosen as an inert solvent interacting with solutes only by van-der-Waals forces, which allows us to assign a specific term of the solvation process. The enthalpies of 1,3selenazine specific interaction ΔHsp with octanol have been determined as positive and equal to (0.7, 11.7, and 9.0) kJ· mol−1 for compounds I to III, respectively. The obtained result is typical of the systems under study in which the molecules of the dissolved substances (pKa = (7.7 to 8.5) have weaker basic properties than the solvent-octanol ones (pKa = 15.27).15 ΔHsp value for the most basic compound I is much lower than those for compounds II and III with lower pKa values. The results show that the hydrogen bond formation plays an important role in the solubility processes of the compounds under study in octanol.

Figure 6. Correlation between the enthalpy and the entropy terms of dissolution Gibbs energy of the studied compounds at 298 K.

has shown that the solubility process in hexane and buffer pH 2.0 is enthalpy determined. The system of isopropyl-derivative (II) in buffer pH 7.4 also belongs to the systems with a dominant enthalpy term influence on the solubility. On the contrary, the dissolution process of compounds I and III in buffer pH 7.4 is entropy determined. It was determined that all of the systems with predominant enthalpy term in Gibbs energy tend to have higher selenazine solubility values if the intermolecular solute−solvent interaction increases (Figure 7). This regularity quite naturally excludes compounds I and III in buffer pH 2.0, in which key role in forming the positive Gibbs energy values is played by the entropy.

■

CONCLUSIONS Three drug-like spiroderivatives of 1,3-selenazine as hydrobromide salts have been synthesized. Phenyl, para-isopropylphenyl, and para-fluorophenyl substituents bonded with spirofragment of the molecule by secondary amino-group were used. The interest in these substances is driven by the diverse biological activity of organoselenium compounds. Investigating the thermophysical properties of the compounds showed that there are no polymorphic modifications and the crystal structures remain stable under heating up to fusion temperatures. The solubility of the studied compounds in muriatic buffer solution pH 2.0, phosphate buffer pH 7.4, octanol, and hexane was measured by the isothermal saturation method. All of the substances were found to have a poor solubility of ∼10−6 mole fraction in phosphate buffer pH 7.4 and hexane. Using the buffer solution pH 2.0 and octanol considerably increases the 2303

dx.doi.org/10.1021/je500363r | J. Chem. Eng. Data 2014, 59, 2298−2304

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Figure 7. Correlation between the solubility and dissolution enthalpy of the studied compounds at 298 K (R = 0.8950).

selenazine solubility to 10−4 and 10−2 mole fraction. To explain the results based on the pKa values, we calculated the content of ionized and unionized molecular forms in accordance with their pH values. It was concluded that the solubility of the selenazines increases when the number of the protonated forms goes up. The comparatively high solubility of the substances in octanol has been explained by the formation of intermolecular bonds with the solvent. Based on the compound solubility dependences on the reverse temperature, the thermodynamic solubility functions of the substances in the investigated solvents have been calculated. The solubility tended to increase if the solution enthalpy decreased in all of the systems with a predominant enthalpy term of the Gibbs energy. A better ordering leads to a solubility decrease in the systems with the entropy-controlled solubility process. The data obtained on the solubility of the biologically active druglike selenazines should be taken into account when drug compounds of the considered group are synthesized and applied.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Phone: 7 (4932)351545; fax: 7 (4932) 336246. Funding

This work was supported by the grant of RFBR No. 13-0300348-a. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Thermal analyses have been performed on the equipment of the Centre for Joint Use of Scientific Equipment “The Upper Volga Region Centre of Physico-Chemical Research”.

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REFERENCES

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dx.doi.org/10.1021/je500363r | J. Chem. Eng. Data 2014, 59, 2298−2304