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Isothermal and non-isothermal kinetics of hydrolysis of 1-(2-(2- pentyloxyphenylcarbamoyloxy)-(2-methoxymethyl)-ethyl)- perhydroazepinium chloride (BK 129)

Isothermal and non-isothermal kinetics of hydrolysis of 1-(2-(2-... Keywords Kúcové slová: INTRODUCTION The novel potential drug substance BK 129 (Fig. 1) (Búciová et al., 1987) possesses the biological activity up to five times higher than that of lidocaine by the antagonisation of ventricle extrasystoly, fibrilation and mortality, and underwent a detailed pharmacological study (Gibala et al., 1987, 1987). For these reasons, the analytical profile of the substance BK 129 was also elaborated (Sedlárová et al., 1995). The aim of this work was to determine the rate constants of alkaline hydrolysis of substance BK 129 at increased temperature in sodium hydroxide solution c = 0.1 mol/l, as well as the study of its hydrolysis in buffer solutions with the purpose of evaluating its stability. In alkaline media, the basic esters of phenylcarbamic acid undergo the hydrolysis and decompose to substituted aniline, basic * marika.stankovicova@gmail.com © Acta Facultatis Pharmaceuticae Universitatis Comenianae alcohol and carbon dioxide. The studied substance possesses the branched connecting chain which differentiates it from the other derivatives, e.g. heptacaine (Cizmárik et al., 1976). In the preliminary study of alkaline hydrolysis of compound BK 129 at several temperatures, we have observed that the substance was decomposed very quickly up to a certain degree, but later the rate of decomposition reaction slowed down and the reaction rate reached an equilibrium character. At lower temperatures, the alkaline hydrolysis was very slow with identical course. Therefore, we proceeded to solve this problem by a nonisothermal kinetic study also, which is at present successfully used in the study of stability of drugs (Junnakar&Stavchansky, 1995, Lee et al., 1998, Ficara et al., 1999). In the case of non-isothermal processes, the temperature is not constant but changes with time. The first mathematic exact non-isothermal accelerated test of stability was introduced by Rogers (Rogers, 1965) by using the temperature/ time function: If the equation (3) is applied into Arrhenius equation it will be for the 1st order reaction obtained in the relationship: Studied compounds The studied compound was synthesised as hydrochloride by ln (ln / ) = ln - ln (1 + /) + (1 + /) ln (1 + ) + ln [1 - ( / )1+/ ] authors [4] and is depicted in Fig. 1. All other chemicals and solvents were of analytical reagent grade. /) + (1 + /) ln (1 + ) + ln [1 - ( / )1+/ ] (2) where c0 is the concentration of substance in the time t = 0, ct is the concentration in the time t, k0 is the rate constant in the time t = 0, kt is the rate constant in the time t, EA is the activation energy, and R is the universal gas constant (8.315 J/mole/K). The last member of equation may be omitted when kt rises. The graphic expression of function ln (ln c0 /ct ) = f (ln (1 + t)) is the straight line. The slope of this function is equal to (1 + EA B/R). Because the constants B and R are known, it is possible to count the activation energy EA in this way. The line will intersect the ordinate at ln k0 ­ ln (1 + EA B/R). The decomposition rate constant k0 at the temperature T0 can be calculated. In the non-isothermal test by Eriksen and Stelmach during the experiment, the temperature is increased hyperbolically (Eriksen&Stelmach, 1965): where T0 is the thermodynamic temperature in K at the start of experiment, Tt is the temperature in the time t, B is the constant of rate of proportionality which can be chosen as desired, and t is the time. If the equation (1) is applied to Arrhenius equation, it will be for the 1st order reaction obtained in the relationship: 1 1 - = ln (1 + ) ln (ln / ) = ( ) / + ln [ / ( / - 1)] (1) ln (ln / ) = ( ) / + ln [ / ( / - 1 (4) Plotting values of ln (ln c0 /ct ) vs time t obtained a straight line where the slope equals EA B / R and the second summand equal the intercept of ordinate. The equation is dependent on the condition that the intervals between measurements are the same, because the value of t must be constant (Kersten&Göber, 1984). MATERIALS AND METHODS Apparatus The Thermostat Memmert WB 10 (Germany), spectrophotometer Spectronic 20 D, Milton Roy (Germany) and spectrophotometer 8452 A DIODE ARRAY Hewlett Packard (USA). 1 1 - = (3) Kinetics of hydrolysis The hydrolysis of compound BK 129 was carried out in aqueous ethanolic buffer solutions at pH 7.0 and 8.0 (Wells, 1988) as well as in NaOH 0.1 mol/l (pH 13.0) in closed flasks tempered in ultra thermostat. The buffer solutions at pH 7.0 and 8.0 possessed an amount of NaOH in the concentration of 0.029 mol/l and 0.046 mol/l, respectively. The concentration of KH2PO4 in both buffer solutions was 0.05 mol/l. The ionic strength of buffers was 0.1 mol/l; it was achieved by adding the appropriate amount of KCl. The C2H5OH concentration was 50 % (V/V). The concentration of BK 129 was 6.993.10 mol/l in buffers and 4.662.10 mol/l in NaOH solution, respectively. The hydrolysis was carried out at 21.0 °C ± 0.2 °C, 37.0 °C ± 0.2 °C in isothermal study and from 30 °C to 70.0 °C in non-isothermal study with CH 2 NH COO OC 5H 11 CH OCH 3 CH 2 N . HCl Fig. 1. Substance BK 129 BK 129 Fig. 1. Substance Stankovicová, M. et al. rise of temperature 10 °C within 1 h. The hydrolysis at 70.0 °C ± 0.2 °C was carried out after attaining this temperature in nonisothermal study. The concentration of the 2-pentyloxyaniline, produced by the reaction, was determined spectrophotometrically in visible region using the diazotisation reaction with sodium nitrite and copulation with 2-naphthole (Stankovicová et al., 1975). The absorbance of solutions was measured at 492 nm. Calculations The rate constants of hydrolysis were calculated using the kinetic equation of the pseudo 1st order (Treindl, 1990): where A is the preexponential member, R is the molar gas constant, T is the thermodynamic temperature, and EA is the activation energy. Values of EA in the non-isothermal study were determined by the equations (2) and (4), respectively (Rogers, 1965, Eriksen&Stelmach,1965). = - / (8) The half-life t0.5: ln ( - ) = ln - 0.5 = 0.9 = RESULTS AND DISCUSSION In this paper the course of alkaline hydrolysis of substance BK 129 in aqueous ethanolic buffers solutions at equal ionic strength ( = 0.1 mol/l) as well as in aqueous ethanolic sodium hydroxide solution 0.1 mol/l was investigated. As reaction media for stability testing (Wells, 1988), the buffers were chosen with different concentrations of sodium hydroxide, where the presence of ethanol was required because of the low basic solubility of compound. In all cases, the ethanol concentration was equal to 50 % (v/v). The decomposition of substance BK 129 was firstly investigated in aqueous-ethanolic sodium hydroxide solution c = 0.1 mol/l at 40.0 °C and at 60.0 °C. The results of alkaline hydrolysis determined under isothermal conditions are given in Table 1. The substance decomposed very quickly up to a certain degree. The rate constants of pseudo 1st order are calculated from linear part of straight line because later the rate of decomposition reaction slowed down and the reaction rate reached an equilibrium. (5) (6) The time during the stored solution contains 90 % of compound: (7) The values of activation energy EA were determined by the Arrhenius equation: Table 1. Results of kinetics of alkaline hydrolysis study of BK 129 at 40.0 and 60.0 °C in sodium hydroxide solution 0.1 mol/l Temperature °C 40.0 60.0 k [h ] t0.5 [h] 59.6 14.6 n 14 5 r 0.985 0.992 F 385.8 390.3 s 0.00442 0.00651 a0 0.00429 -0.00161 a1 0.01162 0.04733 1.162 × 10-2 ± 5.91 × 10 4.733 × 10 ± 3.38 × 10 -2 -2,75 log k0 -2,80 -2,85 -2,90 -2,95 ,00 ,05 ,10 ,15 7 8 9 10 11 12 13 pH Fig. 2. Dependences of log k of compound BK 129 vs pH at 37 °C determined by isothermal study, the log k ­ pH profile Fig. 2. Dependences of log k of compound BK 129 vs pH at 37 °C determined by isothermal study, the log k ­ pH profile In order to decrease the reaction rate, the course of hydrolysis was observed at the laboratory temperature of 21.0 °C, and by accelerated isothermal stability test at 37.0 °C and at 70.0 °C in buffer solutions. In Table 2, the results of isothermal study are presented. The rate constants of pseudo 1st order rise with concentration of sodium hydroxide in buffers, as well as with temperature. For the study of stability, the values t0.9 in days calculated for hydrolysis at 21.0 °C are important, which express the time during the stored solution that contains 90 % of compound. The results show that substance BK 129 is most stabile in solution with pH 7, where the value t0.9 equals 184 days. Figure 2 shows the dependences of log k of compound BK 129 on pH at 37 °C determined by isothermal study, the log k ­ pH profile. In Table 3 are given the values of activation energy EA of hydrolysis of substance BK 129 in reaction solutions and parameters of straight lines. The reason of relatively high value of deviation of activation energy may be probably caused by too great a difference between temperatures used. The value of activation energy determined in sodium hydroxide solution 89.2 kJ mol is comparable with the values determined for 2-hexyloxy substituted 1-methyl2-piperidinoethyl ester of phenylcarbamic acid (Stankovicová et al., 1999). The hydrolysis of compound BK 129 by non-isothermal conditions was performed in range from 30.0 °C to 70.0 °C, with rate of heating 10 °C within an hour (Stankovicová et al., 2009). The constant B was calculated from equation (1) with rise of temperature 10 °C/h. The calculated value of B was: B = 2.49 × 10 K (Fig. 3). The values of EA were calculated from equation (2), by non-isothermal method of study; in the Table 4 are given the parameters of straight lines. The programmed increase of temperature was carried out from 30 °C to 70 °C and the EA values were calculated from the two parts of straight line, firstly from range of temperatures from 30.0 °C to 50.0 °C and then from range 50.0 °C to 70.0 °C, respectively, because for determination of activation energy it is suitable to use the close interval of temperature. The value of k0 represents the calculated rate constant for starting temperature. In buffers as well as in sodium Table 2. Results of kinetics of isothermal hydrolysis study of stability in buffer solutions of substance BK 129 Temperature °C 21 21 21 37 37 37 70 70 70 7 8 13 7 8 13 7 8 13 pH k [h ] t0.5 [h] -7 -6 t0.9 [d] 184 82 10 8 4.4 2.5 2.2 0.8 0.08 n 6 8 7 12 8 12 5 4 7 r 0.997 0.996 0.988 0.996 0.993 0.984 0.988 0.987 0.968 F 642.2 838.2 196.6 1484 421.0 311.9 124.6 75.71 89.35 s 0.000119 0.000407 0.00546 0.000399 0.000341 0.00251 0.000285 0.000677 0.0186 a0 8.43 × 10-5 1.63 × 10 3.67 × 10 a1 2.37 × 10-5 5.36 × 10-5 4.54 × 10 5.69 × 10 9.92 × 10 1.73 × 10 2.02 × 10 5.27 × 10 5.43 × 10-2 2.373 × 10 ± 9.36 × 10 -5 -5 5.356 × 10 ± 1.85 × 10 5.688 × 10 ± 1.48 × 10 4.537 × 10 ± 3.24 × 10-5 -5 .41 × 10 9.918 × 10 ± 4.83 × 10-5 1.728 × 10 ± 9.79 × 10 -5 4.96 × 10 2.65 × 10 2.015 × 10 ± 1.80 × 10 5.272 × 10 ± 6.06 × 10 -6.80 × 10 .58 × 10 -2 5.428 × 10-2 ± 5.74 × 10 7.76 × 10-2 1/T0 - 1/T0 0,00040 0,00035 0,00030 0,00025 0,00020 0,00015 0,00010 0,00005 0,00000 -0,00005 0,6 0,8 1,0 1,2 1,4 1,6 1,8 2,0 ln(1+t) Fig rise of temperature Fig 3. The 3. The rise of temperature Stankovicová, M. et al. Table 3. Values of activation energy EA of hydrolysis of substance BK 129 determined by isothermal study pH 7.0 8.0 13.0 EA [kJ mol] 71.0 ± 30 74.9 ± 24 89.2 ± 9.6 N 3 3 5 r 0.921 0.951 0.983 F 5.56 9.39 86.57 s 0.5463 0.4438 0.1909 a0 8.265 9.252 8.878 a1 706.4 912.0 658.3 Table 4. Results of non isothermal study of hydrolysis of substance BK 129 determined by Rogers [10] pH 7.0 8.0 13.0 Temperature interval °C 50 ­ 70 30 ­ 50 30 ­ 70 k0 [h] 7.81 × 10 1.284 × 10 1.552 × 10 t0.5 [h] 887 540 446 t0.9 [day] 5.6 3.4 2.8 EA [kJ mol] 31.9 48.1 45.5 n 5 4 12 r 0.999 0.980 0.978 F 14997 47.52 219.8 s 0.00611 0.2362 0.2204 hydroxide solutions, the values of EA are lower than that determined by isothermal kinetics but the calculated rate constants for several temperatures are comparable with rate constants determined experimentally by isothermal kinetics of hydrolysis. The calculated rate constant of hydrolysis by non-isothermal method by Rogers is given in Table 5. In the Fig. 4 is depicted the course of hydrolysis of substance at pH 7 in the range of temperatures from 50.0 °C to 70.0 °C. The results of nonisothermal tests calculated by Eriksen and Stelmach method Eriksen&Stelmach, 1965) are given in Table 6. The calculated value of B was: B = 7.74 × 10-5 K. The values of activation energy determined in this way are comparable with that determined by the non-isothermal study by Rogers, but the rate constant is not in consent with those determined by isothermal study as well as by other method given above. Non-isothermal tests of stability enable to reduce the number of analyses. The necessary data for stability of compound are in this way achieved in a short time but it is necessary to choose the suitable programme for temperature rise. It is also important to calculate the kinetic parameters only from the linear part of straight line of the studied relationship (Kersten&Göber, 1984). The work was supported by grant 1/0055/11 of Ministry of Education of Slovak Republic. Table 5. Calculated rate constant of hydrolysis by non isothermal study of stability pH 7 8 13 -2,8 Temperature interval °C 50 ­ 70 30 ­ 50 30 ­ 70 k25 [h ] k37 [h] 3.37 × 10 4.75 × 10 1.98 × 10 2.33 × 10 9.33 × 10 1.15 × 10 ln[ln(b/b-x)] ,0 ,2 ,4 ,6 ,8 ,0 ,2 ,4 ,6 1,2 1,3 1,4 1,5 1,6 1,7 1,8 ln(1+t) Fig. 4. Non isothermal test ­ the course of hydrolysis of substance BK 129 at pH 7 Fig. 4. Non isothermal test ­ the course of hydrolysis of substance BK 129 at pH 7 Table 6. Results of non isothermal study of hydrolysis of substance BK 129 determined by Eriksen and Stelmach [3] pH 7.0 8.0 13.0 Temperature interval °C 30 ­ 70 50 ­ 70 30 ­ 70 a0 -6.029 -5.619 -5.867 a1 0.3334 0.3058 0.5802 EA [kJ mol] 35.8 × 1.4 32.8 × 1.5 51.2 × 1.9 n 9 4 9 r 0.994 0.998 0.995 F 287.0 461.5 694.7 s 0.0536 0.02362 0.08562 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Acta Facultatis Pharmaceuticae Universitatis Comenianae de Gruyter

Isothermal and non-isothermal kinetics of hydrolysis of 1-(2-(2- pentyloxyphenylcarbamoyloxy)-(2-methoxymethyl)-ethyl)- perhydroazepinium chloride (BK 129)

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de Gruyter
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0301-2298
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Abstract

Keywords Kúcové slová: INTRODUCTION The novel potential drug substance BK 129 (Fig. 1) (Búciová et al., 1987) possesses the biological activity up to five times higher than that of lidocaine by the antagonisation of ventricle extrasystoly, fibrilation and mortality, and underwent a detailed pharmacological study (Gibala et al., 1987, 1987). For these reasons, the analytical profile of the substance BK 129 was also elaborated (Sedlárová et al., 1995). The aim of this work was to determine the rate constants of alkaline hydrolysis of substance BK 129 at increased temperature in sodium hydroxide solution c = 0.1 mol/l, as well as the study of its hydrolysis in buffer solutions with the purpose of evaluating its stability. In alkaline media, the basic esters of phenylcarbamic acid undergo the hydrolysis and decompose to substituted aniline, basic * marika.stankovicova@gmail.com © Acta Facultatis Pharmaceuticae Universitatis Comenianae alcohol and carbon dioxide. The studied substance possesses the branched connecting chain which differentiates it from the other derivatives, e.g. heptacaine (Cizmárik et al., 1976). In the preliminary study of alkaline hydrolysis of compound BK 129 at several temperatures, we have observed that the substance was decomposed very quickly up to a certain degree, but later the rate of decomposition reaction slowed down and the reaction rate reached an equilibrium character. At lower temperatures, the alkaline hydrolysis was very slow with identical course. Therefore, we proceeded to solve this problem by a nonisothermal kinetic study also, which is at present successfully used in the study of stability of drugs (Junnakar&Stavchansky, 1995, Lee et al., 1998, Ficara et al., 1999). In the case of non-isothermal processes, the temperature is not constant but changes with time. The first mathematic exact non-isothermal accelerated test of stability was introduced by Rogers (Rogers, 1965) by using the temperature/ time function: If the equation (3) is applied into Arrhenius equation it will be for the 1st order reaction obtained in the relationship: Studied compounds The studied compound was synthesised as hydrochloride by ln (ln / ) = ln - ln (1 + /) + (1 + /) ln (1 + ) + ln [1 - ( / )1+/ ] authors [4] and is depicted in Fig. 1. All other chemicals and solvents were of analytical reagent grade. /) + (1 + /) ln (1 + ) + ln [1 - ( / )1+/ ] (2) where c0 is the concentration of substance in the time t = 0, ct is the concentration in the time t, k0 is the rate constant in the time t = 0, kt is the rate constant in the time t, EA is the activation energy, and R is the universal gas constant (8.315 J/mole/K). The last member of equation may be omitted when kt rises. The graphic expression of function ln (ln c0 /ct ) = f (ln (1 + t)) is the straight line. The slope of this function is equal to (1 + EA B/R). Because the constants B and R are known, it is possible to count the activation energy EA in this way. The line will intersect the ordinate at ln k0 ­ ln (1 + EA B/R). The decomposition rate constant k0 at the temperature T0 can be calculated. In the non-isothermal test by Eriksen and Stelmach during the experiment, the temperature is increased hyperbolically (Eriksen&Stelmach, 1965): where T0 is the thermodynamic temperature in K at the start of experiment, Tt is the temperature in the time t, B is the constant of rate of proportionality which can be chosen as desired, and t is the time. If the equation (1) is applied to Arrhenius equation, it will be for the 1st order reaction obtained in the relationship: 1 1 - = ln (1 + ) ln (ln / ) = ( ) / + ln [ / ( / - 1)] (1) ln (ln / ) = ( ) / + ln [ / ( / - 1 (4) Plotting values of ln (ln c0 /ct ) vs time t obtained a straight line where the slope equals EA B / R and the second summand equal the intercept of ordinate. The equation is dependent on the condition that the intervals between measurements are the same, because the value of t must be constant (Kersten&Göber, 1984). MATERIALS AND METHODS Apparatus The Thermostat Memmert WB 10 (Germany), spectrophotometer Spectronic 20 D, Milton Roy (Germany) and spectrophotometer 8452 A DIODE ARRAY Hewlett Packard (USA). 1 1 - = (3) Kinetics of hydrolysis The hydrolysis of compound BK 129 was carried out in aqueous ethanolic buffer solutions at pH 7.0 and 8.0 (Wells, 1988) as well as in NaOH 0.1 mol/l (pH 13.0) in closed flasks tempered in ultra thermostat. The buffer solutions at pH 7.0 and 8.0 possessed an amount of NaOH in the concentration of 0.029 mol/l and 0.046 mol/l, respectively. The concentration of KH2PO4 in both buffer solutions was 0.05 mol/l. The ionic strength of buffers was 0.1 mol/l; it was achieved by adding the appropriate amount of KCl. The C2H5OH concentration was 50 % (V/V). The concentration of BK 129 was 6.993.10 mol/l in buffers and 4.662.10 mol/l in NaOH solution, respectively. The hydrolysis was carried out at 21.0 °C ± 0.2 °C, 37.0 °C ± 0.2 °C in isothermal study and from 30 °C to 70.0 °C in non-isothermal study with CH 2 NH COO OC 5H 11 CH OCH 3 CH 2 N . HCl Fig. 1. Substance BK 129 BK 129 Fig. 1. Substance Stankovicová, M. et al. rise of temperature 10 °C within 1 h. The hydrolysis at 70.0 °C ± 0.2 °C was carried out after attaining this temperature in nonisothermal study. The concentration of the 2-pentyloxyaniline, produced by the reaction, was determined spectrophotometrically in visible region using the diazotisation reaction with sodium nitrite and copulation with 2-naphthole (Stankovicová et al., 1975). The absorbance of solutions was measured at 492 nm. Calculations The rate constants of hydrolysis were calculated using the kinetic equation of the pseudo 1st order (Treindl, 1990): where A is the preexponential member, R is the molar gas constant, T is the thermodynamic temperature, and EA is the activation energy. Values of EA in the non-isothermal study were determined by the equations (2) and (4), respectively (Rogers, 1965, Eriksen&Stelmach,1965). = - / (8) The half-life t0.5: ln ( - ) = ln - 0.5 = 0.9 = RESULTS AND DISCUSSION In this paper the course of alkaline hydrolysis of substance BK 129 in aqueous ethanolic buffers solutions at equal ionic strength ( = 0.1 mol/l) as well as in aqueous ethanolic sodium hydroxide solution 0.1 mol/l was investigated. As reaction media for stability testing (Wells, 1988), the buffers were chosen with different concentrations of sodium hydroxide, where the presence of ethanol was required because of the low basic solubility of compound. In all cases, the ethanol concentration was equal to 50 % (v/v). The decomposition of substance BK 129 was firstly investigated in aqueous-ethanolic sodium hydroxide solution c = 0.1 mol/l at 40.0 °C and at 60.0 °C. The results of alkaline hydrolysis determined under isothermal conditions are given in Table 1. The substance decomposed very quickly up to a certain degree. The rate constants of pseudo 1st order are calculated from linear part of straight line because later the rate of decomposition reaction slowed down and the reaction rate reached an equilibrium. (5) (6) The time during the stored solution contains 90 % of compound: (7) The values of activation energy EA were determined by the Arrhenius equation: Table 1. Results of kinetics of alkaline hydrolysis study of BK 129 at 40.0 and 60.0 °C in sodium hydroxide solution 0.1 mol/l Temperature °C 40.0 60.0 k [h ] t0.5 [h] 59.6 14.6 n 14 5 r 0.985 0.992 F 385.8 390.3 s 0.00442 0.00651 a0 0.00429 -0.00161 a1 0.01162 0.04733 1.162 × 10-2 ± 5.91 × 10 4.733 × 10 ± 3.38 × 10 -2 -2,75 log k0 -2,80 -2,85 -2,90 -2,95 ,00 ,05 ,10 ,15 7 8 9 10 11 12 13 pH Fig. 2. Dependences of log k of compound BK 129 vs pH at 37 °C determined by isothermal study, the log k ­ pH profile Fig. 2. Dependences of log k of compound BK 129 vs pH at 37 °C determined by isothermal study, the log k ­ pH profile In order to decrease the reaction rate, the course of hydrolysis was observed at the laboratory temperature of 21.0 °C, and by accelerated isothermal stability test at 37.0 °C and at 70.0 °C in buffer solutions. In Table 2, the results of isothermal study are presented. The rate constants of pseudo 1st order rise with concentration of sodium hydroxide in buffers, as well as with temperature. For the study of stability, the values t0.9 in days calculated for hydrolysis at 21.0 °C are important, which express the time during the stored solution that contains 90 % of compound. The results show that substance BK 129 is most stabile in solution with pH 7, where the value t0.9 equals 184 days. Figure 2 shows the dependences of log k of compound BK 129 on pH at 37 °C determined by isothermal study, the log k ­ pH profile. In Table 3 are given the values of activation energy EA of hydrolysis of substance BK 129 in reaction solutions and parameters of straight lines. The reason of relatively high value of deviation of activation energy may be probably caused by too great a difference between temperatures used. The value of activation energy determined in sodium hydroxide solution 89.2 kJ mol is comparable with the values determined for 2-hexyloxy substituted 1-methyl2-piperidinoethyl ester of phenylcarbamic acid (Stankovicová et al., 1999). The hydrolysis of compound BK 129 by non-isothermal conditions was performed in range from 30.0 °C to 70.0 °C, with rate of heating 10 °C within an hour (Stankovicová et al., 2009). The constant B was calculated from equation (1) with rise of temperature 10 °C/h. The calculated value of B was: B = 2.49 × 10 K (Fig. 3). The values of EA were calculated from equation (2), by non-isothermal method of study; in the Table 4 are given the parameters of straight lines. The programmed increase of temperature was carried out from 30 °C to 70 °C and the EA values were calculated from the two parts of straight line, firstly from range of temperatures from 30.0 °C to 50.0 °C and then from range 50.0 °C to 70.0 °C, respectively, because for determination of activation energy it is suitable to use the close interval of temperature. The value of k0 represents the calculated rate constant for starting temperature. In buffers as well as in sodium Table 2. Results of kinetics of isothermal hydrolysis study of stability in buffer solutions of substance BK 129 Temperature °C 21 21 21 37 37 37 70 70 70 7 8 13 7 8 13 7 8 13 pH k [h ] t0.5 [h] -7 -6 t0.9 [d] 184 82 10 8 4.4 2.5 2.2 0.8 0.08 n 6 8 7 12 8 12 5 4 7 r 0.997 0.996 0.988 0.996 0.993 0.984 0.988 0.987 0.968 F 642.2 838.2 196.6 1484 421.0 311.9 124.6 75.71 89.35 s 0.000119 0.000407 0.00546 0.000399 0.000341 0.00251 0.000285 0.000677 0.0186 a0 8.43 × 10-5 1.63 × 10 3.67 × 10 a1 2.37 × 10-5 5.36 × 10-5 4.54 × 10 5.69 × 10 9.92 × 10 1.73 × 10 2.02 × 10 5.27 × 10 5.43 × 10-2 2.373 × 10 ± 9.36 × 10 -5 -5 5.356 × 10 ± 1.85 × 10 5.688 × 10 ± 1.48 × 10 4.537 × 10 ± 3.24 × 10-5 -5 .41 × 10 9.918 × 10 ± 4.83 × 10-5 1.728 × 10 ± 9.79 × 10 -5 4.96 × 10 2.65 × 10 2.015 × 10 ± 1.80 × 10 5.272 × 10 ± 6.06 × 10 -6.80 × 10 .58 × 10 -2 5.428 × 10-2 ± 5.74 × 10 7.76 × 10-2 1/T0 - 1/T0 0,00040 0,00035 0,00030 0,00025 0,00020 0,00015 0,00010 0,00005 0,00000 -0,00005 0,6 0,8 1,0 1,2 1,4 1,6 1,8 2,0 ln(1+t) Fig rise of temperature Fig 3. The 3. The rise of temperature Stankovicová, M. et al. Table 3. Values of activation energy EA of hydrolysis of substance BK 129 determined by isothermal study pH 7.0 8.0 13.0 EA [kJ mol] 71.0 ± 30 74.9 ± 24 89.2 ± 9.6 N 3 3 5 r 0.921 0.951 0.983 F 5.56 9.39 86.57 s 0.5463 0.4438 0.1909 a0 8.265 9.252 8.878 a1 706.4 912.0 658.3 Table 4. Results of non isothermal study of hydrolysis of substance BK 129 determined by Rogers [10] pH 7.0 8.0 13.0 Temperature interval °C 50 ­ 70 30 ­ 50 30 ­ 70 k0 [h] 7.81 × 10 1.284 × 10 1.552 × 10 t0.5 [h] 887 540 446 t0.9 [day] 5.6 3.4 2.8 EA [kJ mol] 31.9 48.1 45.5 n 5 4 12 r 0.999 0.980 0.978 F 14997 47.52 219.8 s 0.00611 0.2362 0.2204 hydroxide solutions, the values of EA are lower than that determined by isothermal kinetics but the calculated rate constants for several temperatures are comparable with rate constants determined experimentally by isothermal kinetics of hydrolysis. The calculated rate constant of hydrolysis by non-isothermal method by Rogers is given in Table 5. In the Fig. 4 is depicted the course of hydrolysis of substance at pH 7 in the range of temperatures from 50.0 °C to 70.0 °C. The results of nonisothermal tests calculated by Eriksen and Stelmach method Eriksen&Stelmach, 1965) are given in Table 6. The calculated value of B was: B = 7.74 × 10-5 K. The values of activation energy determined in this way are comparable with that determined by the non-isothermal study by Rogers, but the rate constant is not in consent with those determined by isothermal study as well as by other method given above. Non-isothermal tests of stability enable to reduce the number of analyses. The necessary data for stability of compound are in this way achieved in a short time but it is necessary to choose the suitable programme for temperature rise. It is also important to calculate the kinetic parameters only from the linear part of straight line of the studied relationship (Kersten&Göber, 1984). The work was supported by grant 1/0055/11 of Ministry of Education of Slovak Republic. Table 5. Calculated rate constant of hydrolysis by non isothermal study of stability pH 7 8 13 -2,8 Temperature interval °C 50 ­ 70 30 ­ 50 30 ­ 70 k25 [h ] k37 [h] 3.37 × 10 4.75 × 10 1.98 × 10 2.33 × 10 9.33 × 10 1.15 × 10 ln[ln(b/b-x)] ,0 ,2 ,4 ,6 ,8 ,0 ,2 ,4 ,6 1,2 1,3 1,4 1,5 1,6 1,7 1,8 ln(1+t) Fig. 4. Non isothermal test ­ the course of hydrolysis of substance BK 129 at pH 7 Fig. 4. Non isothermal test ­ the course of hydrolysis of substance BK 129 at pH 7 Table 6. Results of non isothermal study of hydrolysis of substance BK 129 determined by Eriksen and Stelmach [3] pH 7.0 8.0 13.0 Temperature interval °C 30 ­ 70 50 ­ 70 30 ­ 70 a0 -6.029 -5.619 -5.867 a1 0.3334 0.3058 0.5802 EA [kJ mol] 35.8 × 1.4 32.8 × 1.5 51.2 × 1.9 n 9 4 9 r 0.994 0.998 0.995 F 287.0 461.5 694.7 s 0.0536 0.02362 0.08562

Journal

Acta Facultatis Pharmaceuticae Universitatis Comenianaede Gruyter

Published: Dec 1, 2013

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