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Solid-State Reaction between Sulfadiazine and Acetylsalicylic Acid
Sol id-State Reaction between Sulfadiazine and Acetylsalicylic Acid LI-RONGLlU** AND EUGENEL. PARROlT*' Received January 9, 1990, from the 'Co//egeof Pharmacy, The University of Iowa, Iowa City, /A 52242. July 26, 1990. *Present address: Zenith Laboratories, Inc., Northvale, NJ 07647. Abstract 0 Kinetic data for the solid-state reaction of sulfadiazine and acetylsalicylic acid are presented. A compaction method was used to
observe the influence of applied pressure, particle size, and temperature on the reaction rate.
The stability of a medicinal compound in any dosage form must be considered and characterized before a product is marketed. The pharmaceutical literature abounds with studies of decomposition kinetics of solutions; however, only a limited number of reports are available on solid-state degradation.'-8 The chemistry of solids has been presented in several texts.9-12 The influence of some processing variables-particle size, concentration, applied pressure, and temperature-has been reported13 on a simple addition model (A + B --* AB). This study was initiated to investigate the effect of temperature, applied pressure, and particle size on a more complex reaction model (AB + CD -+ AC + BD), utilizing the transacetylation reaction shown in Scheme I.
Experimental Section The anhydrous sulfadiazine (Sigma, lot 85F-0250) and anhydrous acetylsalicylic acid (Sigma, lot 96F-04433were processed, compressed into 28.57-mm cylindrical compacts, stored, and analyzed by methods previously described.13 The eutectic point was 133 "C as determined by differential scanning calorimetery. The study was conducted at temperatures 37 "C or more below the eutectic temperature to assure the reaction occurred in the solid state. Samples of sulfadiazine sealed under nitrogen showed no degradation detectable by HPLC after 24 h a t 95 "C. Samples of aspirin sealed under nitrogen showed <1% degradation under the same conditions. Thermograms of anhydrous sulfadiazine and anhydrous acetylsalicylic acid did not demonstrate the presence of water. Anhydrous sulfadiazine (ASD) and salicylic
Accepted for publication
acid (SA) were simultaneously determined by HPLC analysis. A mobile phase composed of 28% methanol, 10% 0.1 M phosphate buffer (pH 3.51, and 62% water give good resolution and a reasonably good stability for the aspirin. Samples were weighed on a Cahn microbalance, transferred to a 50-mL volumetric flask, sonificated, and adjusted to volume with the mobile phase. Twenty microliters of solution were injected. The rate of flow of the mobile phase was 1 mL/min, with a C-18 Versapack, 300-mm column at 25 "C. The UV detector was set at 0.02 AUFS and a wavelength of 225 nm. All solutions were analyzed within 30 min of preparation.
Results and Discussion In the reaction between sulfadiazine and acetylsalicylic acid in the solid state, the acetyl group of the acetylsalicylic acid is transferred to the primary amine of the sulfadiazine, forming acetylsulfadiazine and salicylic acid. The observed molar ratios of the reactants and products showed a 1:l stoichiometry for the transacetylation. Influence of Temperature on Reaction KineticeCompacts compressed at 44 MPa from a blend of equal quantities of sulfadiazine and acetylsalicylic acid of a 120/ 140-mesh size fraction were exposed to temperatures of 75,85, and 95 "C. At various intervals of time, samples were taken and analyzed for the four compounds. A typical result in terms of the mole percent in the compact against time is shown in Figure 1 for the mole percent of sulfadiazine, acetylsalicylic acid, acetylsulfadiazine, and salicylic acid after storage at 95 "C. The data indicated a one-exponential term model. If the natural logarithm of the amount of sulfadiazine or acetylsalicylic acid is plotted as a function of time, a linear relationship is obtained, as shown in the example in Figure 2. The linearity or first-order mathematics was observed over the range of temperatures, applied pressures, and sizes of reactants throughout this investigation. From such plots, the T
COOH
60
I
c
t
ASA
SD
aJ
0
40
L
Q
n COOH
Q 0
fi
20
2 10
A SD
SA Scheme I-Transacetylation
salicylic acid.
reaction between sulfadiazine and acetyl-
564 I Journal of Pharmaceutical Sciences Vol. 80, No. 6, June 1991
20
30 Time, hr
40
50
Figure 1-Percent of reactants and products in a compact of 120/140mesh size fraction compressed at 44 MPa as a function of time at 95 "C. Key: (0)SD; (13) ASA; (0)ASD; and (M) SA.
OO22-3549/91/06OO-0564$01.00/0 0 1991, American Pharmaceutical Association
-1.00
Y
-5.00 -6.00 -7.00
f;l
-
t 0
C
O
O
4
8
12
16
Table CRate Constants at 95 "C as a Function of Applied Pressure and Slze
Applied Pressure, MPa 22
44
88
132
kSCJ
0.149 0.147
0.064 0.044
0.036
~ASA
0.032
0.135 0.110
80/100-mesh Size Fraction 1001120-mesh Size Fraction kSD
0.168
0.102
0.103
0.151
kASA
0.134
0.066
0.087
0.129
kS D
0.193
0.122
~ASA
0.123
0.114
0.178 0.137
0.120
0.223 0.155
0.276
0.294
0.301
0.141
0.149
0.136
120/140-mesh Size Fraction 140-200-mesh Size Fraction
1
2.74
Sulfadiazine (SD); acetylsalicylic acid (ASA).
0.208
2.78
2.82
I x 10 T
, hr
rate constants in Table I were evaluated. A typical plot of the natural logarithm of the rate constant against the reciprocal of absolute temperature is shown in Figure 3. Utilizing Arrhenius mathematics the activation energy as gauged from the disappearance of acetylsalicylic acid (ASA) is 44.0 kcal/ mol. Assumptions of the Arrhenius relationship are that the activation energy is independent of temperature, the reaction mechanism is unchanged, and the kinetics is not governed by boundary migration or temperature-dependent equilibria. Although the theoretical assumptions may not be correct for a nonhomogeneous solid compact, in the temperature range studied, the rate constant appears to be representative of the reaction rate so that it may be used to compare the effect of various factors on the transacetylation reaction. Influence of Applied Pressure on Reaction KineticsCompacts of a blend of equal amounts of sulfadiazine and acetylsalicylic acid of' four sizes were prepared at pressures from 22 to 132 MPa. The transacetylation reaction at 95 "C was followed, and the rate constants were calculated. The effect of applied pressure on the rate of reaction is shown for sulfadiazine and acetylsalicylic acid in Figures 4 and 5 for various size fractions and in Table I. In order to determine if the applied pressure had an effect on the reaction rate, a statistically significant difference in the rate must be shown at different pressures.'"16 For compacts of a blend of 80/140-mesh size fraction, the statistical analysis showed the reaction rate decreased when the
Rate Constant, h - ' '
2.70
20
Figure 2-A linear relationship of natural logarithm of amount of reactants in a compact of 1201140-mesh size fraction compressed at 44 MPa against time at 95 "C.Key: (0)sulfadiazine; and (0)acetylsalicylic acid.
~ASA
- 5.00 -6.00!
Tim.
kSD
J
2.86
3
plot of the natural logarithm of reaction rate constants against the reciprocal of absolute temperatures. Key: (0)sulfadiazine; and (0)acetylsalicylic acid. Figure 3-A
0.4 0.5 L
c Oe3
0.1
0
it t I
\ ------30
60
90
120
150
A p p I i e d P r e s s u r e ,M Pa Figure &The relation of reaction rate constants of sulfadiazine to applied pressure for various particle sizes of the reactants at 95 "C.Key: (0)80/100-;(0)100/120-; (A) 120/140-;and (0)140/200-mesh size fraction.
applied pressure increased from 22 to 44 MPa. Then, at applied pressures from 88 to 132 MPa, the reaction rate was faster as the applied pressure was increased. For compacts of a blend of 100/120-mesh size fraction, statistical analysis showed a slowing of the reaction as the applied pressure increased from 22 to 44 MPa, and there was no significant change of reaction rate as the applied pressure increased from 88 to 132 MPa. Statistical analysis failed to show a significant difference in the reaction rate over the range of pressure studied for compacts of blends of 120/140- and 140/200-mesh size fraction. It appears that with fine particles the applied pressure has little or no significant effect on reaction rate. Influence of Size on Reaction Kinetics-Compacts of a blend of equal amounts of sulfadiazine and acetylsalicylic acid having 80/100-, 100/120-, 120/140-, and 140/200-mesh size fractions were compressed at 22, 44, 88, and 132 MPa. The transacetylation reaction at 95 "C was followed, and the calculated rate constants are given in Table I. The effect of particle size on reaction rate is shown for sulfadiazine and acetylsalicylic acid in Figures 6 and 7 at various applied pressures. A reduction of particle size increases the reaction rate. As the particle size is decreased, the specific surface is Journal of Pharmaceutical Sciences I 565 Vol. 80, No. 6, June 7991
0.35
0.2 5T
0 . 2 5 ._
0.20
IL
.
c
O.
1 =
0.05
-0.I 5 .0.10--
0.0 5*
J
I
1
.. Par t l c l e Size,
Flgure !+The
relation of reaction rate constants of acetylsalicylic acid to applied pressure for various particle sizes of the reactants at 95 "C. Key: (3) 80/100-; (c1) 100/120-; (A) 1201140-; and (0)140/200-mesh size fraction.
m m
Figure 7-The relation of reaction rate constants of acetylsalicylic acid at 95 "C to particle size at various applied pressures. Size plotted is average of openings of sieve passed and retained. Key: (0)22; (0) 44; (A)88; and (0)132 MPa.
3. Carstensen, J. T. Theo of Pharmaceutical Systems, Vol. 11; Academic: New York. N?, 1973: D 235. 4. Garrett, E.; Schuman; E. L.; Grosi'c, M. F. J . Am. Pharm. Assoc., Sci.Ed. 1939.48. 684. 5. Carstensen, J. T.; Musa, M. N. J. Pharm. Sci. 1972, 61, 1112. 6. Pothisiri, P.; Carstensen, J. J . Pharm. Sci. 1975, 64, 1931. 7. Kornblum, S. S.;Sciararone, B. J. J. Pharm. Sci. 1964, 53, 935. 8. Carstensen, J. T.; Pothisiri, P. J . Pharm. Sci. 1975. 70, 1095. 9. Gomes, W. P.; Deke ser, W. In Treatise on Solid State Chemistry, Vol. 4; Hannay, B., Ed.; Plenum: New York, NY, 1976; Chapter 2. 10. Jacobs, P. W. M.; Tompkins, F. C. In Chemist oftheSolid State, Garner, W. E., Ed.; Butterworth: London, 19y5;Chapter 7. 11. Galwey, A. K. Chemistry of Solids, Chapman and Hall: London,
d
0.09
0.1I
0.13
0.15
0.17
P a r t i c l e S i z e , mm Figure &The relation of reaction rate constants of sulfadiazine at 95 "C to particle size at various applied pressures. Sue plotted is average of openings of sieve passed and retained. Key: (0)22; (U)44; (A) 88;and (0)132 MPa. increased, resulting in a greater contact between the react a n t s a n d a faster reaction.
References and Notes 1. Carstensen, J. T. J. Pharm. Sci. 1974, 63, 1
2. Byrn,
S.R. J. Pharm. Sci. 19i6,65, 1.
566 I Journal of Pharmaceutical Sciences Vol. 80, No. 6, June 1997
1967.
12. Bamford, C. H.; Tipper, C. F. H. Reactions in the Solid State; Elsevier: Amsterdam, The Netherlands, 1980. 13. Weng, H-L.; Parrott, E. L. J. Pharm. Sci. 1984,73, 1059. 14. Snedecor, G. W.; Cochran, W. G. In Statistical Methods, 7th Ed.; The Iowa State University: Ames, IA,1982;Chapter 18. 15. Draper N. R.;Smith, H. In A p lied Re ressiondnalysis, 2nd Ed.; John diley & Sons: New Yo& NY, f981;Chapter 2. 16. Minitab Reference Manual-Release 6 ; Minitab, Inc.: State College, PA, 1988;pp 104-137.
Acknowledgments This study was abstracted in part from a dissertation submitted by Li-Rong Liu to the Graduate College, University of Iowa, in partial fulfillment of the Doctor of Philosophy degree requirement.
observe the influence of applied pressure, particle size, and temperature on the reaction rate.
The stability of a medicinal compound in any dosage form must be considered and characterized before a product is marketed. The pharmaceutical literature abounds with studies of decomposition kinetics of solutions; however, only a limited number of reports are available on solid-state degradation.'-8 The chemistry of solids has been presented in several texts.9-12 The influence of some processing variables-particle size, concentration, applied pressure, and temperature-has been reported13 on a simple addition model (A + B --* AB). This study was initiated to investigate the effect of temperature, applied pressure, and particle size on a more complex reaction model (AB + CD -+ AC + BD), utilizing the transacetylation reaction shown in Scheme I.
Experimental Section The anhydrous sulfadiazine (Sigma, lot 85F-0250) and anhydrous acetylsalicylic acid (Sigma, lot 96F-04433were processed, compressed into 28.57-mm cylindrical compacts, stored, and analyzed by methods previously described.13 The eutectic point was 133 "C as determined by differential scanning calorimetery. The study was conducted at temperatures 37 "C or more below the eutectic temperature to assure the reaction occurred in the solid state. Samples of sulfadiazine sealed under nitrogen showed no degradation detectable by HPLC after 24 h a t 95 "C. Samples of aspirin sealed under nitrogen showed <1% degradation under the same conditions. Thermograms of anhydrous sulfadiazine and anhydrous acetylsalicylic acid did not demonstrate the presence of water. Anhydrous sulfadiazine (ASD) and salicylic
Accepted for publication
acid (SA) were simultaneously determined by HPLC analysis. A mobile phase composed of 28% methanol, 10% 0.1 M phosphate buffer (pH 3.51, and 62% water give good resolution and a reasonably good stability for the aspirin. Samples were weighed on a Cahn microbalance, transferred to a 50-mL volumetric flask, sonificated, and adjusted to volume with the mobile phase. Twenty microliters of solution were injected. The rate of flow of the mobile phase was 1 mL/min, with a C-18 Versapack, 300-mm column at 25 "C. The UV detector was set at 0.02 AUFS and a wavelength of 225 nm. All solutions were analyzed within 30 min of preparation.
Results and Discussion In the reaction between sulfadiazine and acetylsalicylic acid in the solid state, the acetyl group of the acetylsalicylic acid is transferred to the primary amine of the sulfadiazine, forming acetylsulfadiazine and salicylic acid. The observed molar ratios of the reactants and products showed a 1:l stoichiometry for the transacetylation. Influence of Temperature on Reaction KineticeCompacts compressed at 44 MPa from a blend of equal quantities of sulfadiazine and acetylsalicylic acid of a 120/ 140-mesh size fraction were exposed to temperatures of 75,85, and 95 "C. At various intervals of time, samples were taken and analyzed for the four compounds. A typical result in terms of the mole percent in the compact against time is shown in Figure 1 for the mole percent of sulfadiazine, acetylsalicylic acid, acetylsulfadiazine, and salicylic acid after storage at 95 "C. The data indicated a one-exponential term model. If the natural logarithm of the amount of sulfadiazine or acetylsalicylic acid is plotted as a function of time, a linear relationship is obtained, as shown in the example in Figure 2. The linearity or first-order mathematics was observed over the range of temperatures, applied pressures, and sizes of reactants throughout this investigation. From such plots, the T
COOH
60
I
c
t
ASA
SD
aJ
0
40
L
Q
n COOH
Q 0
fi
20
2 10
A SD
SA Scheme I-Transacetylation
salicylic acid.
reaction between sulfadiazine and acetyl-
564 I Journal of Pharmaceutical Sciences Vol. 80, No. 6, June 1991
20
30 Time, hr
40
50
Figure 1-Percent of reactants and products in a compact of 120/140mesh size fraction compressed at 44 MPa as a function of time at 95 "C. Key: (0)SD; (13) ASA; (0)ASD; and (M) SA.
OO22-3549/91/06OO-0564$01.00/0 0 1991, American Pharmaceutical Association
-1.00
Y
-5.00 -6.00 -7.00
f;l
-
t 0
C
O
O
4
8
12
16
Table CRate Constants at 95 "C as a Function of Applied Pressure and Slze
Applied Pressure, MPa 22
44
88
132
kSCJ
0.149 0.147
0.064 0.044
0.036
~ASA
0.032
0.135 0.110
80/100-mesh Size Fraction 1001120-mesh Size Fraction kSD
0.168
0.102
0.103
0.151
kASA
0.134
0.066
0.087
0.129
kS D
0.193
0.122
~ASA
0.123
0.114
0.178 0.137
0.120
0.223 0.155
0.276
0.294
0.301
0.141
0.149
0.136
120/140-mesh Size Fraction 140-200-mesh Size Fraction
1
2.74
Sulfadiazine (SD); acetylsalicylic acid (ASA).
0.208
2.78
2.82
I x 10 T
, hr
rate constants in Table I were evaluated. A typical plot of the natural logarithm of the rate constant against the reciprocal of absolute temperature is shown in Figure 3. Utilizing Arrhenius mathematics the activation energy as gauged from the disappearance of acetylsalicylic acid (ASA) is 44.0 kcal/ mol. Assumptions of the Arrhenius relationship are that the activation energy is independent of temperature, the reaction mechanism is unchanged, and the kinetics is not governed by boundary migration or temperature-dependent equilibria. Although the theoretical assumptions may not be correct for a nonhomogeneous solid compact, in the temperature range studied, the rate constant appears to be representative of the reaction rate so that it may be used to compare the effect of various factors on the transacetylation reaction. Influence of Applied Pressure on Reaction KineticsCompacts of a blend of equal amounts of sulfadiazine and acetylsalicylic acid of' four sizes were prepared at pressures from 22 to 132 MPa. The transacetylation reaction at 95 "C was followed, and the rate constants were calculated. The effect of applied pressure on the rate of reaction is shown for sulfadiazine and acetylsalicylic acid in Figures 4 and 5 for various size fractions and in Table I. In order to determine if the applied pressure had an effect on the reaction rate, a statistically significant difference in the rate must be shown at different pressures.'"16 For compacts of a blend of 80/140-mesh size fraction, the statistical analysis showed the reaction rate decreased when the
Rate Constant, h - ' '
2.70
20
Figure 2-A linear relationship of natural logarithm of amount of reactants in a compact of 1201140-mesh size fraction compressed at 44 MPa against time at 95 "C.Key: (0)sulfadiazine; and (0)acetylsalicylic acid.
~ASA
- 5.00 -6.00!
Tim.
kSD
J
2.86
3
plot of the natural logarithm of reaction rate constants against the reciprocal of absolute temperatures. Key: (0)sulfadiazine; and (0)acetylsalicylic acid. Figure 3-A
0.4 0.5 L
c Oe3
0.1
0
it t I
\ ------30
60
90
120
150
A p p I i e d P r e s s u r e ,M Pa Figure &The relation of reaction rate constants of sulfadiazine to applied pressure for various particle sizes of the reactants at 95 "C.Key: (0)80/100-;(0)100/120-; (A) 120/140-;and (0)140/200-mesh size fraction.
applied pressure increased from 22 to 44 MPa. Then, at applied pressures from 88 to 132 MPa, the reaction rate was faster as the applied pressure was increased. For compacts of a blend of 100/120-mesh size fraction, statistical analysis showed a slowing of the reaction as the applied pressure increased from 22 to 44 MPa, and there was no significant change of reaction rate as the applied pressure increased from 88 to 132 MPa. Statistical analysis failed to show a significant difference in the reaction rate over the range of pressure studied for compacts of blends of 120/140- and 140/200-mesh size fraction. It appears that with fine particles the applied pressure has little or no significant effect on reaction rate. Influence of Size on Reaction Kinetics-Compacts of a blend of equal amounts of sulfadiazine and acetylsalicylic acid having 80/100-, 100/120-, 120/140-, and 140/200-mesh size fractions were compressed at 22, 44, 88, and 132 MPa. The transacetylation reaction at 95 "C was followed, and the calculated rate constants are given in Table I. The effect of particle size on reaction rate is shown for sulfadiazine and acetylsalicylic acid in Figures 6 and 7 at various applied pressures. A reduction of particle size increases the reaction rate. As the particle size is decreased, the specific surface is Journal of Pharmaceutical Sciences I 565 Vol. 80, No. 6, June 7991
0.35
0.2 5T
0 . 2 5 ._
0.20
IL
.
c
O.
1 =
0.05
-0.I 5 .0.10--
0.0 5*
J
I
1
.. Par t l c l e Size,
Flgure !+The
relation of reaction rate constants of acetylsalicylic acid to applied pressure for various particle sizes of the reactants at 95 "C. Key: (3) 80/100-; (c1) 100/120-; (A) 1201140-; and (0)140/200-mesh size fraction.
m m
Figure 7-The relation of reaction rate constants of acetylsalicylic acid at 95 "C to particle size at various applied pressures. Size plotted is average of openings of sieve passed and retained. Key: (0)22; (0) 44; (A)88; and (0)132 MPa.
3. Carstensen, J. T. Theo of Pharmaceutical Systems, Vol. 11; Academic: New York. N?, 1973: D 235. 4. Garrett, E.; Schuman; E. L.; Grosi'c, M. F. J . Am. Pharm. Assoc., Sci.Ed. 1939.48. 684. 5. Carstensen, J. T.; Musa, M. N. J. Pharm. Sci. 1972, 61, 1112. 6. Pothisiri, P.; Carstensen, J. J . Pharm. Sci. 1975, 64, 1931. 7. Kornblum, S. S.;Sciararone, B. J. J. Pharm. Sci. 1964, 53, 935. 8. Carstensen, J. T.; Pothisiri, P. J . Pharm. Sci. 1975. 70, 1095. 9. Gomes, W. P.; Deke ser, W. In Treatise on Solid State Chemistry, Vol. 4; Hannay, B., Ed.; Plenum: New York, NY, 1976; Chapter 2. 10. Jacobs, P. W. M.; Tompkins, F. C. In Chemist oftheSolid State, Garner, W. E., Ed.; Butterworth: London, 19y5;Chapter 7. 11. Galwey, A. K. Chemistry of Solids, Chapman and Hall: London,
d
0.09
0.1I
0.13
0.15
0.17
P a r t i c l e S i z e , mm Figure &The relation of reaction rate constants of sulfadiazine at 95 "C to particle size at various applied pressures. Sue plotted is average of openings of sieve passed and retained. Key: (0)22; (U)44; (A) 88;and (0)132 MPa. increased, resulting in a greater contact between the react a n t s a n d a faster reaction.
References and Notes 1. Carstensen, J. T. J. Pharm. Sci. 1974, 63, 1
2. Byrn,
S.R. J. Pharm. Sci. 19i6,65, 1.
566 I Journal of Pharmaceutical Sciences Vol. 80, No. 6, June 1997
1967.
12. Bamford, C. H.; Tipper, C. F. H. Reactions in the Solid State; Elsevier: Amsterdam, The Netherlands, 1980. 13. Weng, H-L.; Parrott, E. L. J. Pharm. Sci. 1984,73, 1059. 14. Snedecor, G. W.; Cochran, W. G. In Statistical Methods, 7th Ed.; The Iowa State University: Ames, IA,1982;Chapter 18. 15. Draper N. R.;Smith, H. In A p lied Re ressiondnalysis, 2nd Ed.; John diley & Sons: New Yo& NY, f981;Chapter 2. 16. Minitab Reference Manual-Release 6 ; Minitab, Inc.: State College, PA, 1988;pp 104-137.
Acknowledgments This study was abstracted in part from a dissertation submitted by Li-Rong Liu to the Graduate College, University of Iowa, in partial fulfillment of the Doctor of Philosophy degree requirement.