Journal of Chemical & Engineering Data
Article
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.
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 corre-
sponding 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
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:
ΔGs0ol = −RT ln a2
(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:
∂(ln a2)/∂T = ΔHs0ol/RT2
(2)
The temperature dependences of solubilities within the chosen
temperature interval can be described by the linear function:
(3)
ln x = A − B/T
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:
ΔGs0ol = ΔHs0ol − TΔSs0ol
(4)
To calculate the enthalpy of specific interaction ΔHsp solvent−
solute using the following equation:
ΔHsp = ΔHs0ol(octanol) − ΔHs0ol(hexane)
(5)
RESULTS AND DISCUSSION
■
The objects of the present study were the heterocyclic spiro-
derivatives 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), para-
isopropylphenyl (II), and para-fluorophenyl (III) were chosen
as the substituents, the structures of which are presented in
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dx.doi.org/10.1021/je500363r | J. Chem. Eng. Data 2014, 59, 2298−2304