3 курс / Фармакология / Синтез_и_изучение_свойств_новых_материалов_с_противоопухолевой
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The thermodynamic characteristics of viscous flow activation (∆G, ∆H, ∆S, Ea) were calculated using the following Eyring theory equations (3.4–3.7) (Table 3.2) [94]:
G = RT ln |
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hNA |
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G = H -T S |
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ln = ln A + |
Ea |
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S |
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R T |
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TA = |
-Ea |
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(3.7) |
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R ln AS |
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where ∆G, ∆H, and ∆S are Gibbs energy, enthalpy and entropy of viscous flow; AS is the pre-exponential entropy factor; Ea is the activation energy of the viscous flow; TA is the activation temperature; R is the universal gas constant; T is absolute temperature.
Table 3.2. Concentration dependence of entropy factor (lnAS), viscous flow activation energy (Ea), Arrhenius temperature (TA), activation enthalpy (ΔH), and entropy (ΔS). C is the concentration of an aqueous solution of compound 1.57.
C / g∙dm−3 |
Ea / J·mol−1 |
lnAs / |
TA / K |
H / kJ·mol−1 |
S / |
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ln[mPa·s] |
J·(mol·K)−1 |
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0.025 |
15118.67 |
−6.21 |
292.94 |
14.81 |
−5.09 |
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0.10 |
15099.15 |
−6.20 |
292.88 |
14.79 |
−5.15 |
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0.25 |
15115.69 |
−6.21 |
292.94 |
14.81 |
−5.10 |
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0.55 |
15108.14 |
−6.20 |
292.94 |
14.80 |
−5.13 |
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1.0 |
15052.56 |
−6.18 |
293.04 |
14.75 |
−5.33 |
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2.5 |
15124.00 |
−6.20 |
293.22 |
14.82 |
−5.12 |
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5.0 |
15187.55 |
−6.22 |
293.87 |
14.88 |
−5.01 |
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10 |
15091.71 |
−6.15 |
295.35 |
14.77 |
−5.62 |
The data obtained allow us to draw the following conclusions:
1)the enthalpy values are almost constant and positive over the entire range of studied concentrations. This fact indicates the presence of specific interactions in solution;
2)the stability of entropy values is observed in the studied range of concentrations. The negative definiteness of entropy indicates ordering in solution associated with the formation of an activated complex.
The temperature dependences of the dynamic viscosity of aqueous solutions of compound 1.57 were described using the empirical van’t Hoff equation (3.8) (Fig. 3.12):
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T |
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10 |
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T - T |
=1, 21 0, 05 |
(3.8) |
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T |
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where γη is van’t Hoff viscosity coefficient.
Analysis of Fig. 3.12 shows that the van’t Hoff temperature coefficient is constant in the studied temperature range.
1.26
1.24
1.22
γ η
1.20
1.18
1.16
0 |
2 |
4 |
6 |
8 |
10 |
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C / gЧdm−3 |
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Fig. 3.12. Dependence of the van’t Hoff viscosity coefficient on the volume
concentration of the compound 1.57: (□) |
278.15 , (○) |
283.15 , ( ) |
288.15 |
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293.15 |
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288.15 |
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293.15 |
298.15 |
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303.15 |
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298.15 |
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303.15 |
, ( ) 308.15 |
, ( ) 313.15 . |
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308.15 |
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313.15 |
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318.15 |
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323.15 |
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Fig. 3.13 presents the results of applying the three-parameter Vogel–Fulcher– Tammann equation [94] to describe the temperature dependences of dynamic viscosity in the binary system compound 1.57 – water:
lg (T ) = lg |
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A |
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0 |
T - B |
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where η0, A, B are correlation parameters; T is absolute temperature.
Table. 3.3 shows the values of the correlation parameters of the Vogel–Fulcher– Tammann equation, as well as the values of the mean absolute deviation (AAD) and standard deviation (SD).
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1.1 |
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1.0 |
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0.9 |
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Чs |
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/ mPa |
0.8 |
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0.7 |
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0.6 |
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0.5 |
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0.4 |
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290 |
300 |
310 |
320 |
330 |
340 |
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T / K |
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Fig. 3.13. Temperature dependences of the dynamic viscosity of aqueous solutions of compound 1.57 ((□) 0.1 g∙dm−3, (○) 0.25 g∙dm−3, ( ) 0.5 g∙dm−3, ( ) 1 g∙dm−3, ( ) 2.5 g∙dm−3, ( ) 5 g∙dm−3, ( ) 10 g∙dm−3) at a shear rate of 100 s−1. Points are experimental data; lines are the result of applying the Vogel–Fulcher–Tammann equation.
Table 3.3. Correlation parameters of the Vogel–Fulcher–Tammann equation.
Parameter |
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C / g∙dm−3 |
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0.025 |
0.1 |
0.25 |
0.55 |
1.0 |
2.5 |
5.0 |
10.0 |
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lgη0 / lg[mPa∙s] |
−1.30 |
−1.32 |
−1.30 |
−1.33 −1.33 −1.32 |
−1.33 |
−1.29 |
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A / K |
160.8 |
165.1 |
159.0 |
167.4 |
166.9 |
165.9 |
168.0 |
161.6 |
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B / K |
170.8 |
168.8 |
171.5 |
167.9 |
167.8 |
168.6 |
168.0 |
170.4 |
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SD / mPa∙s∙104 |
4.8 |
3.2 |
6.2 |
3.9 |
7.1 |
6.4 |
26.4 |
27.7 |
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AAD / % |
0.17 |
0.12 |
0.12 |
0.12 |
0.12 |
0.03 |
0.07 |
0.23 |
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The values of the viscosities of aqueous solutions of compound 1.57 under the selected conditions allow us to draw a conclusion about the alleged haemocompatibility and the possibility of infusion use of aqueous solutions of the compound 1.57.
3.4.3. Refractions of aqueous solutions of the compound 1.57
Table. 3.4 shows experimental data on the concentration (C = 0.01–25 g∙dm−3) and temperature (T = 293.15–333.15 K) dependences of the refractive indices (nD) of aqueous solutions of the compound 1.57.
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Table 3.4. Concentration (C) dependences of the refractive index (nD) of aqueous solutions of compound 1.57 in the temperature range T = 293.15–333.15 K.
nD
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293.15 K |
303.15 K |
313.15 K |
323.15 K |
333.15 K |
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0.01 |
1.33297 |
1.3319 |
1.33057 |
1.32898 |
1.32716 |
0.025 |
1.33298 |
1.33192 |
1.33059 |
1.32899 |
1.32718 |
0.05 |
1.33301 |
1.33194 |
1.33061 |
1.32901 |
1.32721 |
0.1 |
1.33307 |
1.33199 |
1.33067 |
1.32906 |
1.32726 |
0.25 |
1.33313 |
1.33205 |
1.33073 |
1.32914 |
1.32735 |
0.5 |
1.33337 |
1.3323 |
1.33096 |
1.32938 |
1.32759 |
1 |
1.33375 |
1.33269 |
1.33133 |
1.32979 |
1.32801 |
2.5 |
1.33454 |
1.33349 |
1.33213 |
1.33059 |
1.32882 |
15 |
1.33534 |
1.33428 |
1.33294 |
1.33139 |
1.32971 |
25 |
1.33694 |
1.33588 |
1.33459 |
1.33307 |
1.33168 |
The specific and molar refractive indices of solutions were calculated using Eqs. 3.9
and 3.10:
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2 |
-1 |
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1 |
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nD |
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r = |
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n |
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M |
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nD -1 |
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R = |
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where r and R are specific and molar refractions; M is an average molar mass of solution
( M = xH2O Ч M H2O + x1.57 Ч M1.57 ).
Refractive index data at low compound concentrations 1.57 (x1.57 < 1,4∙10−4) were not used for calculations due to the low accuracy of measuring these quantities (Table 3.4).
The specific (r) and molar (R) refractions of aqueous solutions of compound 1.57
were calculated using the equations 3.11 and 3.12: |
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r = (r |
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w |
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H2O |
1.57 |
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1.57 |
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R = R |
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(3.12) |
H2O |
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H2O |
1.57 |
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1.57 |
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where ri, Ri are specific and molar refractions of the components of the solution; wi, xi are mass and molar fractions of solution components. In addition, the molar refraction of
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compound 1.57 was calculated using the additivity rules of Eisenlohr (3.13) and Vogel
(3.14) [95]:
R =14RC + 22RH + RO(OH) + 2RO(R-O-R' ) + RN(R2 NH) + 2RN(R3N) +3RN(C-N=C) |
(3.13) |
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R 83.345 cm3 Ч mol-1 ; |
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R = 20RC-H +11RC-N + 7RC-C +5RC-O +3RC=N + RO-H + RN-H |
(3.14) |
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R 82.262 cm3 Ч mol-1 . |
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The specific refraction of compound 1.57 was calculated using the Eq. 3.15: |
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r = |
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M1.57 |
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The specific values obtained are 0.259 cm3∙g−1 (according to the Eisenlohr rule) and 0.255 cm3∙g−1 (according to the Vogel rule). Comparison of experimental and calculated data on specific (a) and molar refraction (b) is presented in Fig. 3.14.
(a) (b)
3 −1 rсоединения 1.57 / см ∙г
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0.0 |
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0.0 |
0.5 |
1.0 |
1.5 |
2.0 |
2.5 |
w / %
3 −1 Rсоединения 1.57 / см ∙моль
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300
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150
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0.0000 |
0.0002 |
0.0004 |
0.0006 |
0.0008 |
0.0010 |
0.0012 |
0.0014 |
0.0016 |
xсоединения 1.57
Fig. 3.14. Concentration dependence of specific (a) and molar (b) refraction of compound
1.57 at 293.15 K. w is the mass fraction of compound 1.57, x of compound 1.57 is the mole fraction of compound 1.57. The dotted line corresponds to the calculated values of the specific and molar refractions of compound 1.57.
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Based on the obtained values of molar and specific refractions and the obtained equations, we can speak about the possibility of hydrogen bonding and confirm the assumption that, by forming hydrogen bonds with phosphate groups, compound 1.57 can penetrate through the cell membrane.
3.4.4. Mathematical description of T-C dependences of density, viscosity and refractive index of aqueous solutions of compound 1.57
T-C-dependences of density, viscosity and refractive index of aqueous solutions of compound 1.57 were described using the correlation equation (3.16):
M = a + |
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b Ч T i + |
4 |
c |
Ч C j |
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wher M is a physicochemical property of a solution of a compound 1.57, a, bi, cj (i, j = 1– 4) are correlation parameters (Table 3.5).
The results of applying the correlation Eq. 3.16 to the description of the T-C dependences of the physicochemical properties of a solution of compound 1.57 are presented in Fig. 3.15 (a–c).
Thus, thermodynamic studies of the physicochemical properties of aqueous solutions of compound 1.57 in this work provide useful information for predicting the absorption and permeability of compound 1.57 through tumour cell membranes.
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(a)
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Fig. 3.15. T–C dependences of density (a), dynamic viscosity (b), refractive index (c) of aqueous solutions of compound 1.57. Points are experimental data; surfaces are the result of applying the correlation Eq. 3.16.
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Table 3.5. Correlation parameters a, bi, cj (i, j = 1–4) of Eq. 3.16 for the T–C dependences of density (ρ), viscosity (η), and refractive indices (nD) of aqueous solutions of compound 1.57. R2 is a coefficient of determination.
Property |
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b1 |
b2 |
b3 |
b4 |
c1 |
c2 |
c3 |
c4 |
R2 |
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ρ / g∙cm−3 |
−5.12 |
0.076 |
−3.53∙10−4 |
7.32∙10−7 |
−5.76∙10−10 |
3.70∙10−4 |
−1.57∙10−4 |
4.26∙10−5 |
−2.81∙10−6 |
0.99967 |
η / mPa·s |
507.88 |
−6.04 |
0.027 |
−5.46∙10−5 |
4.13∙10−8 |
3.24∙10−3 |
−1.18∙10−3 |
3.07∙10−4 |
−1.84∙10−5 |
0.99960 |
nD |
2.49 |
−0.016 |
8.24∙10−5 |
−1.87∙10−7 |
1.56∙10−10 |
1.64∙10−4 |
−1.32∙10−6 |
1.04∙10−7 |
−2.03∙10−9 |
0.99926 |
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3.4.5. Solubility of compound 1.57 in water
Fig. 3.16 shows the solubility polytherm of compound 1.57 in water in the temperature range T = 293.15–318.15 K. Compound 1.57 is compatible with water: the solubility of compound 1.57 was 26.3–43.0 g dm−3 depending on temperature. The temperature dependence of solubility has a sigmoid course. At the same time, the solubility increases with increasing temperature, which indicates the endothermic effect of the dissolution of compound 1.57 in water. The data of thermogravimetric analysis show that the crystalline hydrate of compound 1.57 (C14H22N6O3∙3H2O) is the equilibrium solid phase with a saturated solution.
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−3 |
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gЧdm |
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C / |
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Fig. 3.16. Temperature dependence of the solubility of compound 1.57 in water.
3.4.6. Distribution of compound 1.57 in the n-octanol – water system
The main factor determining the ability of a drug compound to penetrate to the target and be distributed throughout the body is lipophilicity. The increase in lipophilicity correlates with an increase in biological activity, a decrease in water solubility, an acceleration of metabolism and a slowdown in excretion. Also, high lipophilicity makes it easy to penetrate the skin (transdermal application) [96].
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The distribution of compound 1.57 in the n-octanol – water system was studied at equal volumes of the aqueous and organic phases (25.0 ml), performing 4 parallel experiments. The phases were stirred in a thermostated cell for 4 h, after which an aliquot of the lower aqueous phase was taken. The content of compound 1.57 in the aqueous phase was determined spectrophotometrically.
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w |
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ow |
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where co´ and cw´ are concentrations of compound 1.57 in the organic and aqueous phases, respectively; cw is the initial concentration of compound 1.57 in water.
The value of the logarithm of the distribution coefficient of the compound 1.57 was: lgPow = 0.16. The value obtained shows that compound 1.57 has practically the same affinity for the aqueous and organic phases. An analysis of the literature revealed the presence of a calculated value of the distribution coefficient of the compound 1.57 in the n-octanol – water system, obtained using the XLOGP3-AA atomic additive method: lgPow = 0.1 [97]. One can see a good agreement between the calculated and experimental values of the distribution coefficient.
A lgPow value between −1 and +2 is optimal for substances intended for oral administration. At a low value of lgPow, the compound will be poorly absorbed and, as a result, have low bioavailability. At a high value of lgPow, it will completely linger in the lipid layers. High lipophilicity is necessary only for inhalation anaesthetics (anaesthetics). Therefore, compound 1.57 can be considered suitable for oral administration.
3.4.7. Study of the stability of aqueous solutions of compound 1.57 by NMR
spectroscopy
When studying potential leader compounds, special attention is paid to their stability in aqueous media. One of the important factors affecting the stability of organic compounds is pH. The low stability of drugs, as a rule, is associated with the occurrence
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