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Stability of Aspirin in Solid Mixtures
Stability of Aspirin in Solid Mixtures DAVIDJ. AGER*', KENNETHS. ALEXANDER*, ASIF S. BHATTI*, JOHN S. BLACKBURN*, DAVID DOLLIMORE',TIMOTHY S. KOOGAN', KEITHA. MOOSEMAN*, GEORGEM. MUHVIC**,BELINDA SIMS'*, AND VICTORIA J. WEBB* Received June 21, 1985 from the 'Department of Chemistry and the *College of Pharmacy, The University of Toledo, Toledo, OH Accepted for publication September 27, 1985.
43606.
internal standard; IR spectra were recorded on a Pye-Unicam 3-200 either as a thin film or a nujol mull. Ultraviolet spectra were recorded on a Cary 14 spectrophotometer in 95% ethanol solution. employed differential scanning calorimetry and thermal gravimetric Thin-layer chromatography analysis was carried out on silica plates analysis by standard techniques providing simple and rapid analysis for (60FzM, 0.25 mm, Merck Cat. 5765) while preparative TLC was screening the stability of aspirin in mixtures. The degradation was found carried out on silica (60Fna4,2.0 mm, Merck Cat. 5717-7). Thermal to depend on the nature of the additive but, in particular, the presence of studies were carried out with a DuPont 1090 thermal analyzer acidic or basic groups within its structure. equipped with the appropriate DuPont cells. Aspirin (U.S.P. grade, Merck), commercial tablets (Bayer, 325 mg), silica (Mallinckrodt TLC-7G), and alumina (70-230 mesh, Merck Cat. 1077) were used. The degradation of many drugs has been studied in aqueSpectroscopic structural assignments were carried out by comparious media while relatively little is known about the same son with authentic samples.s4 phenomenon in the solid state.' As part of a program to find Oven Heating--Twenty commercial aspirin tablets (containing 5.13 g of aspirin as determined by extraction with chloroform) were suitable techniques t o investigate the decomposition of solid pharmaceutical products, we have examined the decomposi- placed on a watch glass in an oven at 155°C. Samples were taken at -10 min intervals by removing a tablet, crushing it, dissolving a tion of aspirin. This type of investigation is a good prelimismall amount in chloroform, and carrying out TLC analysis (UV nary one because of the difficulties encountered with other detection) with ethanol and ethyl acetate as eluants [aspirin R, analytical techniques. (EtOH) 0.7; R f (EtOAc) 0.5; salicylic acid R, (EtOH) 0.85; R, Compared with the numerous studies which have been (EtOAc)O.8]. Decomposition, as determined by the disappearance of carried out on the hydrolysis of aspirin in relathe aspirin spot on TLC, was shown to be complete within 60 min. tively little has been done with the solid. It has been shown The remaining tablets had t u n e d to a yellow liquid which was that the rate of hydrolysis of solid aspirin is proportional to subjected to extractive work-up (150 mL of chloroform, washing with 2 x 20 mL of saturated aqueous sodium chloride solution and drying the humidity2.8.9 but some of these results have been queswith Na2S04)to give a mixture of salicylic and acetic acids (by NMR tioned because of the complication of the hydrolysis product, and JR). The acetic acid was removed by bulb-to-bulb distillation salicylic acid, subliming from the solid mixture.l0 The effect (bath temperature <4OoC/15mm Hg) and recrystallization (HzO) to of additives on this hydrolysis has been inve5tigated.l'-1' yield 3.74 g (95% of theoretical recovery) of salicylic acid (NMR, IR, The presence of antacids and other tableting additives has W, mp, TLC). been found to affect the rate of decomposition of aspirin.lJ1J6 Repetition of the above with 500 mg samples of powdered aspirin For example, calcium carbonate caused little decomposition resulted in identical findings. (4.4% after 1year) while sodium hydrogen carbonate greatly Thermal Analysia-Under an atmosphere of dry nitrogen, differaccelerated the process (100%after 44 weeks). The decompoential scanning calorimetry (DSC), differential thermal analysis sition of aspirin, in the presence of diluents, has been related (DTA), and thermal gravimetric analysis (TGA) were carried out with the standard techniques. Each of the materials used in these to the moisture content and hardness of the tablet;16 the studies was analyzed in the pure form by these methods. Mixtures of nature of the metal ion may also play a role.16 It has been the ingredients (starch, silica, alumina, stearic acid, cellulose, dexshown to decompose at approximately the same rate whether trose, sodium acetate, sodium acetate hydrate, sodium carbonate, in suspension or tablet form.17 and sodium hydrogen carbonate) in the ratios of 1:1, 15:4, and 1 : l O Tablet formulations of aspirin with other drugs, such as (w/w) were prepared by: (a) mixing the Constituents in the predeterphenylephrine hydrochloride18 and codeine,[email protected] in mined ratio; ( b ) mixing the constituents in the predetermined ratio acylation of the drug.1.2l-26 By contrast, mixtures with other and then compressing into tablets with a Dorsch single punch tablet drugs, for example, caffeine, codeine phosphate, and quinine machine; (c) mixing the constituents in the predetermined ratio, adding chloroform (25 mL per 5 g of mixture) followed by evaporasulfate, were stable.26.27 The reaction, in the phenylephrine tion of the solvent under reduced preesure a t 0°C to constant weight hydrochloride case, could be slowed by the addition of starch and NMR analysis showed no chloroform remained. and magnesium stearate.18 With codeine, the reaction kinetThe samples were stored under reduced pressure, in the absence of ics were complex and did not follow any specific rate order.28 light, a t room temperature (-23"C), and portions were removed The degradation of aspirin in the solid state has been periodically for analysis. In addition to thermal analytical methods, monitored by the detection of salicylic acid, which, in turn, samples were also extracted with chloroform (250 mL per 500 mg of has involved W or visible s p e c t r o s ~ o p y . 2 ~ ~ ~ 1 sample). 1 ~ ~ 3The ~ ~extract ~~~~ ~~ ~ ~ ~ ~ ~ under reduced pressure and was concentrated The assay can, however, be affected by subsequent hydrolyanalyzed by TLC, NMR, and IR spectroscopy. The only hydrolysis s i ~ or 3 ~any additi~e.~.33 It is interesting to note that many of product isolated was salicylic acid. Recovery from degraded samples was usually >go%, confirming the analytical data. The dry silica the degradation studies have monitored product formation, was obtained by heating for 17 h at 850°C in a muffle furnace and i.e., salicylic acid, or acylated drug, rather than loss of cooling in a vacuum desiccator at 2 mm Hg. acetylsalicylic acid.2 With these problems in mind, we undertook a study of the solid-state degradation of aspirin and the Abstrsct 0It has been shown that the degradation of aspirin in mixtures may be monitored by thermal analytical techniques. The methodology
use of thermal analytical methods for following the reaction.
Experimental Section Materials and Reagents-All reagents used in this study were reagent grade. Nuclear magnetic resonance spectra were recorded on a Varian T60A in CDC13 solution with tetramethylsilane as the
OO22-3549/86/0 1OO-ooS7$01. oO/O @ 1986, American Pharmaceutical Association
Results and Discussion It has already been shown that aspirin crystals, when heated on a hot stage, soften and that a liquid appears even below its melting point. These observations have been attributed to the production of acetic acid through hydrolysis.' Our initial experiments were carried out at 155°C in an Journal of Pharmaceutical Sciences / 97 Vol. 75, No. 1, Januaw 1986
oven, that is, above the melting point of aspirin. Complete decomposition to acetic acid and salicylic acid was observed within 1 h. When the experiment was repeated at lOO"C, complete decomposition occurred within 3 h, and the tablets or powder had again turned to liquid. An attempt was made to remove the acetic acid as it was produced by running the experiment in a reduced pressure oven (1OO0C/13mm Hg) but again the liquid formed contained a considerable amount of acetic acid (NMR). The aromatic acid isolated in these experiments was salicylic acid and no evidence of any oligomers was seen by spectroscopic techniques.36 A previous study had detected oligomers of salicylic acid by HPLC, but thermolysis was carried out in the presence of magnesium carbonate.36 In our experiments, little or no magnesium ions were present and, as the heating was carried out in air, the mixture was free to react with atmospheric moisture. Any salicylides formed could, therefore, have been hydrolyzed before detection. Certainly, recrystallization of the product mixture gave salicylic acid (>go% of theoretical recovery). The literature DSC36.37of aspirin showed a sharp endotherm corresponding to melting at 138°C; DTA gave a: similar r e s ~ l t . It ~ 8can, however, be clearly seen that the DSC gave an extra endotherm a t 160°C (Fig. 1). This transition was also apparent in the commercial pharmaceutical aspirin formulation; it is close to the melting point of salicylic acid (158-160°C39;this gave rise to a large endotherm a t 166.8"C on a DSC run). As noted above, the sample was liquid at 160°C and it seems reasonable to suggest that this endot h e m can be attributed to aspirin degradation. Thermal gravimetric analysis (Fig. 2) reinforced this premise as a large weight loss occurred around this temperature. Indeed, this loss was greater than the amount of acetic acid produced and presumably some salicylic acid also evaporated.40 As these reactions were carried out in dry nitrogen, salicylides may have been formed. When the reaction was repeated on a preparative scale, salicylic acid was the only isolated solid product (86%). The sharp endotherm at the melting point of aspirin was
t
t
-24 -284 0
I I
: : : : : : : 100 200 300 400 Temperature, OC Flgure 1-Differential scanning calorimetry thermogram of aspirin. :
98 / Journal of Pharmaceutical Sciences Vol. 75, No. 1, January 1986
I40
/
t 120/
' O Oi
fL+ \ I- -
"
00
100
200
300
400
Temperature,O C Flgure 2-Thermal gravimetric analysis of aspirin. Key: (-) weight remaining; (---) rate of weight loss.
percentage
considered to be a useful tool for the investigation of its degradation in a solid mixture. Although aspirin forms a eutectic with salicylic acidfo it was felt that the interactions between these two compounds would be diminished in the mixtures and would not present any undue problems other than peak broadening. Certainly, the problem, a t worst, would concern interpretation rather than a practical problem. In addition to the eutectic, it has been suggested that aspirin exists in polymorphic f01111~,~~4 the melting points of which can vary greatly. Previous investigators have disputed this.In our hands, prolonged treatment of acetylsalicylic acid with 1-pentanol, the solvent used for the alleged solution-phase transformation of polymorphs, lead to degradation as evidenced by the methyl integral in the NMR. This type of analysis also showed that the acetyl group diminished (-5-10%) when the recrystallization was conducted in a hydrocarbon solvent. This suggests that the changes in melting point are not due to polymorphism44but to degradation. The problem was not pursued because of the difficulty in reproducing the results and characterization of the products. Although GC has been used to differentiate aspirin from salicylic acid,47.48spectroscopic techniques were used in this study to determine the amount of degradation. Thin layer chromatography has also been suggested as a tool to monitor aspirin stability.49.50 When a mixture of salicylic acid and aspirin were separated by this method, eluting with ethanol, ethyl acetate, or 4:1:1 hexane:acetic acid:chloroform,4B light loading had to be used to avoid streaking. When the experiments were repeated on preparative TLC plates, the bands, after removal and extraction, showed the impurities of the other components (by NMR). Although TLC proved useful as a qualitative technique to monitor the degradation, NMR was chosen as the analytical method to confirm the thermal analytical findings. The study on the effects of tablet formulation additives commenced with starch (potato) admixed in the ratios (aspir-
in:starch) of 1:1, 1 5 4 and 1:lO (w/w). The ratio 15:4 was chosen as this approximated the composition of the commercial tablets. The samples were prepared in three separate ways: (a) by grinding the two components together with a mortar and pestle, ( b )by making a tablet, and (c) by adding chloroform to the mixture and then removing this solvent - 2 t under reduced pressure. No attempt was made to assess the pharmacological implications of these formulation^,^^.^^-^^ such as a ~ t i v i t y 5or ~ affects on disintegration of the tab1ets.56.57Even after storage for 3 months, in all cases, no (4%) decomposition was detected in any of the samples by thermal analytical techniques, TLC, or NMR. A representative DSC is shown in Fig. 3; note the peak at 40°C which is due to starch degradation. As the decomposition of aspirin may be catalyzed by acid or base, solid acidic and basic substrates were investigated. Silica was used as the model solid acid and samples were prepared as described above, except that no attempt was made to tablet the mixture. No decomposition was detected in the 154 aspirin:silica sample after 1 month and the aspirin was recovered by chloroform extraction (97%). Some decomposition was detected in the 1:l mixture within 2 d as the DSC curves lost their sharp definition (Fig. 4); little -6 aspirin was detected in the 1:lO aspirin:silica case after a similar time span (Fig. 5). Salicylic acid was isolated when the sample was extracted with chloroform (>go% recovery). To show that water was not the cause of degradation, the -7 silica was dried a t 850°C; the decomposition observed in 0 100 200 300 these mixtures was identical to the samples listed above. Temperature, O C Alumina gave almost identical results to the silica cases as illustrated in Fig. 6. This suggests that the degradation of Flgure 4-Differential scanning calorimetry thermogramof a 1: 7 aspirin: silica mixture. aspirin could be catalyzed by acid or base in solid-state reactions just as it is in solution. Previous studies had been carried out with aluminum hydroxide58and other 8 n t a ~ i d s . l ~ Little decomposition was found by assay for free salicylic acid; in some cases, the metal ion present could have interfered with the colorimetric method employed. It should be noted that 2:l aspirin:additive mixtures were used in the studies and our results, i.e., the 1 5 4 mixtures were stable, are in keeping with these previous findings. One possible explanation is that silica and alumina carry free hydroxyl groups which could interact with the aspirin. The reaction would depend on the concentration of hydroxyl groups; our results show that a relatively high concentration of the additive must be present for rapid degradation to occur. Adjuvants used for aspirin tablet manufacture, such as starch, also contain polyhydroxyl functional groups, but as
I
t
t7
-;I
-10
!O
- 4 4 - 4 - - + + . ~ 0 100 200
300
Temperature,;C Flgure 5-Differential silica:aspirin mixture. C t , : : : : : :
0
)----+-cIc
100200300400500600
Temperature,O C Flgure 3-Differential scanning calorimetry thermogramsof an aged 1: 1 starch:aspirin mixture. Key: (A) I month; (B) 7 week; (C) 3 months.
scanning calorimetry thermogram of a 1O:l
these are neutral the reaction is slow. It is interesting to note that P-cyclodextrin accelerated the basic hydrolysis of aspirin60through formation of a 1:l complex at a pH where the cyclodextrin hydroxides could be deprotonated.60 It seems reasonable to suggest that aspirin degradation in Journal of Phannaceutical Sciences / 99 Vol. 75, No. 1, January 1986
+
solid state could be acid or base catalyzed. The degradation was detected by thermal analysis which was not affected by metal ions as other analytical methods can be. These metal ions could also be important factors in affecting aspirin degradation.63 Although the techniques described in this paper do not allow for the detection of small amounts of aspirin degradation, it is a useful method for the rapid screening of aspirin mixtures to determine stability. The method is simple and may be carried out directly on the mixture, a cheaper alternative to diffuse reflectance spectroscopy.‘O
References and Notes 1.
P* York. J.
-8 ;t N
v
200
100
0
300
Temperature, OC Flgure 6-Differential scanning calorimetry fhermogram of a 103 a1umina:aspirin mixture.
Table CStablllty of Asplrln In the P m n c o of Addltlvm
Additive
Ratio (asp1rin:addltive)(w/w)* 1:1
15:4
1:lO
Starch Silica Silica (dried) Alumina Stearic acid Cellulose Dextrose Sodium acetate Sodium acetate hydrate Sodium carbonate hydrate Sodium hydrogen carbonate
S. R. “Solid-State Chemistry of Drugs”; Academic Press:
1982. 2. Kelly, C. A. Pharm. Sci. 1970,59, 1053. 3. James, K. C. J.Pharm. Pharmacol. 1958,10,363. 4. Tuckel, N.; Antonescu, V.; Gheorghe, V.; Stefanescu, F. F a r m cia 1961.9. 11. 5. Jue, J.; Huych, C. L. J.Am. Pharm. Assoc., Sci. Ed. 1963,3,470. 6. Nogami, H.; Awazu, S.; Nakejima, N. Chem. Pharm.Bull. 1962, 10,503. 7. Komblum, S.S.;Zoglio, M. A. J. Phann. Sci. 1967,56,1569. 8. Leeson, L. J.; Mattock, A.M. J. Am. Phurm. Assoc., Sci. Ed. 1958,47,329. 9. Carstensen, J. T.;Attarchi, F.; Hou, X.-P. J. Pharm. Sci. 1985, 74,741. 10. Gore, A. Y.;Naik K. B.; Kildsig, D. 0.; Peck, G. E.; Smolen, V. F.; Banker, G. 4. J. Pharm. Sci. 1968,57,1850. 11. Trow, D.; Dam, R. Pharm. Pmr. 1966,228. 12. Jaminet, F.;Evrard, G. Phurm.Acta Helv. 1966,41,601. 13. Wisniewski, W.; Piasecka, H. Acta Pol. Pharm. 1967,24,291. 14. Jaminet, F.;Louis, G. Pharm. Acta Helv. 1968,43,153. 15. Bandelin, F.J.; Malesch, W. J. Am. Pharm. Assoc., Sci. Ed. 1953,19,152. 16. Lee, S. T.;Dekay, H. G.; Banker, G. S. J.Pharm. Sci. 1965,54, 1153. 17. Mauldin , H. V.; Zoglio, M. A.; Pigois, F. E.; Wagner, M. J. Pharm. 1969,58,1359. 18. %UD. A. E.: Mitchner. H. J. Phann.Sci. 1964.53.375. 19. Kosh“ K.T.;Troup,’ A. E.; Duvall, R. N.; ’Conwell, R. C.; S h a d e , L. L. J. Pharm. Sci. 1967,56,1117. 20. Jacobs, A. L.;Dilatush, A. E.; Weinstein, S.; Windhauser. J . J. J. Pharm. Sci. 1966.55.893. 21. Ribeiro, D.; Steve’mon, D.; Sam J.; Milosovich, G.; Mattocks, 1955,44,226. A.M. J. Am. Pharm. Sci., Sci. 22. Kral, J.: Bielesmva. H. Drozdova. Z.Farm. Obz. 1960.29.298: Chem. Abstr. 1964,61,2910h. . 23. Nazareth, M. R.; Huyck, C. L. J. Pharm. Sci. 1961,50,608. 24. Nazareth, M. R.; Hu ck, C. L. J. Pharm. Sci. 1961,50,620. 25. Okano, H.;Kawata, Tsutsumi, S.; Umezaki, Y. Yakwaigaku 1963,23,279;Chem.Abstr. 1964,61,537h. 26. Grabowska, I. Gdansk. Tow.Nauk., Rozpr. Wydz. 1964,3,193; Chem.Abstr. 1966. 64. 14029a. 27. Grabowska, I. Gh’nsk: Tow.Nauk., Rozpr. Wydz.1964,3,207; Chem.Abstr. 1966,64, 15678b. 28. Galanta, R. N.; Visalli, A. J.; Patel, D. M. J. Pharm. Sci. 1979. 68, 1494. 29. Strode, C. W.; Stewart, F. N.; Schott, H. 0.; Coleman, 0.J. Anal. Chem.1957,29,1184. 30. DeMarco, J. D.; Marcus, A. D. J.Pharm.Sci. 1962,51,1010. 31. Cullen, L. F.;Packman, D. L.; Papariello, G. J. Ann. N.Y. Acod. Sci. 1968,153,525. 32. Edwards, L.J.; Gore, D. N.; Rapson, H. D. C.; Taylor, hi. P. J. Pharm. P h a r m o l . 1955 7,892. 33. Green, A. R. Austmlus. f.Pharm. 1964,45,588. 34. As obtained by us, but identical with the Aldrich Libraries of IR and NMR spectra. 35. Reepmeyer, J. C. J. Phurm. Sci. 1983,72,322. 36. Daly, K. F.Am. Lab. 1975,75. 37. Wendlandt, W. W.; Collins, L. W. Anal. Chim. Acta 1974, 71, 411. 38. Wendlandt, W. W.; Hoiberg, J . A. Anal. Chim. Acta 1963,29, 539. 39. “Aldrich Catalog,” 1984-85 ed.; Aldrich Chemical Co.: Milwaukee, WI,1984. 40. Monkhow, D. C.; Lach, J. L. Can.J. Pharm. Sci. 1972, 7,29. 41. Tawashi, R. Science 1968,160,76. 42. Tawashi, R. J. Pharm. Pharmacol. 1969,21,701. 43. Summers, M. P.: Carless. J. E.: Enever. R. P. J.Pharm. P h a r m COI. i970,’22, 6i5. 44. Pfeiffer, R. R. J. Pharm.Pharmacol. 1971,23,75. ew
-~ ~ _. _. _ .
83.
B.
I
*Refers to all three methods of mixing (see Experimenfal Section) unless otherwise stated. Key: A, no decomposition detected after 1 month; 8,significant,but not complete decomposition detected after 5 d; C, complete decomposition. bThese mixtures were not prepared in tablet form. other cases may be more complicated than they appear. For example, dilution of phenylephrine hydrochloride and aspirin with starch slowed acetylation of the drug dramatically (vide suprala). This is probably due to the starch acting as a diluent and minimizing aspirin-phenylephrine hydrochloride interactions as well as acting as a pH buffer. In addition, the aspirin could be acylating the starch and the acyl group could then migrate along the starch hydroxyl groups,B1,’32 statistically making interactions less likely. As stated above, many of the degradation processes were monitored by formation of salicylic acid and, therefore, any intermediate would not be detected. Other additives used in this study were sodium acetate, both in the anhydrous and the hydrated form. All samples decomposed within 6 weeks, many of the hydrated samples giving a liquid. Sodium carbonate hydrate also showed decomposition, but sodium hydrogen carbonate did not cause significant decomposition in the 15:4 case, although it did in the others. Stearic acid gave mixtures which were stable as did cellulose and dextrose. It has been shown that the degradation of aspirin in the lo0 / Journal of Pharmaceutical Sciences Vol. 75, No. 1, January 7986
k;
.
I
45. Schwartzman, G. J. Pharm. Pharmacol. 1972,24, 169. 46. Mitchell, A. G.; Milare, B. L.; Saville, D. J.; Griffiths, R. V. J. Phurm. P h u r m o l . 1971,23,534. 47. Crip en, R. C.; Freimuth, H. C. Anal. Chim. Acta 1963,29,539. 48. NikJly, J. G. Anal. Chim. Acta 1964, 36, 2248. 49. Reimers, F. Arch. Pharm. Chem. 1967, 74. 531. 50. Frodyma, M. M.; Lieu, V. T.; Frei, R. W. J. Chromtogr. 1965, 18, 520. 51. Levy, G. J. Phurm. Sci. 1961,50,388. 52. F‘feiffer, C. C.; Goldstein, L.; Murphree, H. B.; Hopkins, M. J. Phurm. Sci. 1967,56, 1338. 53. Wood, J. H. Phurm. Acta Helv. 1967, 42, 129. 54. Levy, G.; Leonards, J. R.; Procknal, J. A. J. Pharm. Sci. 1965, 54, 1719.
55. Levy, G.; Procknal, J. A. J. Phurm. Sci. 1962,51, 294. 56. Chowhan, Z. T.; Chi, L.-H. Phurm. Technol. 1985,9, 84. 57. Bolhuis, G. K.;Smallenbrock, A. J.; Lerk, C. F. J. Pharm. Sci. 1981, 70, 1328. 58. Patel, H. M.; Huyck, C. L. Mtg. Chem. 1963,34, 100. 59. Chin, T.-F.; Chung, P.-M.; Lach, J. L. J. Phurm. Sci. 1968, 57, 44. 60. Lach, J. L.; Cohen, J. J.Pharm. Sci. 1963.52, 137. 61. Dodd, G. H.; Golding, B. T.; Ioannov, P. V. J. Chem. SOC.,Chen. Commun. 1975,249. 62. Houg;h, L.; Richardson, A. C. in “Comprehensive Organic Chem, vol. 5 ; Barton, D. H. R.; Ollis, W. D., Eds.; Pergamon: ord, 1979; p 723. 63. Gold, G.; Campbell, J. A. J. Phurm. Sci. 1964,53, 375.
%?
Journal of Pharmaceutical Sciences / 101 Vol. 75, No. 1, January 1986
43606.
internal standard; IR spectra were recorded on a Pye-Unicam 3-200 either as a thin film or a nujol mull. Ultraviolet spectra were recorded on a Cary 14 spectrophotometer in 95% ethanol solution. employed differential scanning calorimetry and thermal gravimetric Thin-layer chromatography analysis was carried out on silica plates analysis by standard techniques providing simple and rapid analysis for (60FzM, 0.25 mm, Merck Cat. 5765) while preparative TLC was screening the stability of aspirin in mixtures. The degradation was found carried out on silica (60Fna4,2.0 mm, Merck Cat. 5717-7). Thermal to depend on the nature of the additive but, in particular, the presence of studies were carried out with a DuPont 1090 thermal analyzer acidic or basic groups within its structure. equipped with the appropriate DuPont cells. Aspirin (U.S.P. grade, Merck), commercial tablets (Bayer, 325 mg), silica (Mallinckrodt TLC-7G), and alumina (70-230 mesh, Merck Cat. 1077) were used. The degradation of many drugs has been studied in aqueSpectroscopic structural assignments were carried out by comparious media while relatively little is known about the same son with authentic samples.s4 phenomenon in the solid state.' As part of a program to find Oven Heating--Twenty commercial aspirin tablets (containing 5.13 g of aspirin as determined by extraction with chloroform) were suitable techniques t o investigate the decomposition of solid pharmaceutical products, we have examined the decomposi- placed on a watch glass in an oven at 155°C. Samples were taken at -10 min intervals by removing a tablet, crushing it, dissolving a tion of aspirin. This type of investigation is a good prelimismall amount in chloroform, and carrying out TLC analysis (UV nary one because of the difficulties encountered with other detection) with ethanol and ethyl acetate as eluants [aspirin R, analytical techniques. (EtOH) 0.7; R f (EtOAc) 0.5; salicylic acid R, (EtOH) 0.85; R, Compared with the numerous studies which have been (EtOAc)O.8]. Decomposition, as determined by the disappearance of carried out on the hydrolysis of aspirin in relathe aspirin spot on TLC, was shown to be complete within 60 min. tively little has been done with the solid. It has been shown The remaining tablets had t u n e d to a yellow liquid which was that the rate of hydrolysis of solid aspirin is proportional to subjected to extractive work-up (150 mL of chloroform, washing with 2 x 20 mL of saturated aqueous sodium chloride solution and drying the humidity2.8.9 but some of these results have been queswith Na2S04)to give a mixture of salicylic and acetic acids (by NMR tioned because of the complication of the hydrolysis product, and JR). The acetic acid was removed by bulb-to-bulb distillation salicylic acid, subliming from the solid mixture.l0 The effect (bath temperature <4OoC/15mm Hg) and recrystallization (HzO) to of additives on this hydrolysis has been inve5tigated.l'-1' yield 3.74 g (95% of theoretical recovery) of salicylic acid (NMR, IR, The presence of antacids and other tableting additives has W, mp, TLC). been found to affect the rate of decomposition of aspirin.lJ1J6 Repetition of the above with 500 mg samples of powdered aspirin For example, calcium carbonate caused little decomposition resulted in identical findings. (4.4% after 1year) while sodium hydrogen carbonate greatly Thermal Analysia-Under an atmosphere of dry nitrogen, differaccelerated the process (100%after 44 weeks). The decompoential scanning calorimetry (DSC), differential thermal analysis sition of aspirin, in the presence of diluents, has been related (DTA), and thermal gravimetric analysis (TGA) were carried out with the standard techniques. Each of the materials used in these to the moisture content and hardness of the tablet;16 the studies was analyzed in the pure form by these methods. Mixtures of nature of the metal ion may also play a role.16 It has been the ingredients (starch, silica, alumina, stearic acid, cellulose, dexshown to decompose at approximately the same rate whether trose, sodium acetate, sodium acetate hydrate, sodium carbonate, in suspension or tablet form.17 and sodium hydrogen carbonate) in the ratios of 1:1, 15:4, and 1 : l O Tablet formulations of aspirin with other drugs, such as (w/w) were prepared by: (a) mixing the Constituents in the predeterphenylephrine hydrochloride18 and codeine,[email protected] in mined ratio; ( b ) mixing the constituents in the predetermined ratio acylation of the drug.1.2l-26 By contrast, mixtures with other and then compressing into tablets with a Dorsch single punch tablet drugs, for example, caffeine, codeine phosphate, and quinine machine; (c) mixing the constituents in the predetermined ratio, adding chloroform (25 mL per 5 g of mixture) followed by evaporasulfate, were stable.26.27 The reaction, in the phenylephrine tion of the solvent under reduced preesure a t 0°C to constant weight hydrochloride case, could be slowed by the addition of starch and NMR analysis showed no chloroform remained. and magnesium stearate.18 With codeine, the reaction kinetThe samples were stored under reduced pressure, in the absence of ics were complex and did not follow any specific rate order.28 light, a t room temperature (-23"C), and portions were removed The degradation of aspirin in the solid state has been periodically for analysis. In addition to thermal analytical methods, monitored by the detection of salicylic acid, which, in turn, samples were also extracted with chloroform (250 mL per 500 mg of has involved W or visible s p e c t r o s ~ o p y . 2 ~ ~ ~ 1 sample). 1 ~ ~ 3The ~ ~extract ~~~~ ~~ ~ ~ ~ ~ ~ under reduced pressure and was concentrated The assay can, however, be affected by subsequent hydrolyanalyzed by TLC, NMR, and IR spectroscopy. The only hydrolysis s i ~ or 3 ~any additi~e.~.33 It is interesting to note that many of product isolated was salicylic acid. Recovery from degraded samples was usually >go%, confirming the analytical data. The dry silica the degradation studies have monitored product formation, was obtained by heating for 17 h at 850°C in a muffle furnace and i.e., salicylic acid, or acylated drug, rather than loss of cooling in a vacuum desiccator at 2 mm Hg. acetylsalicylic acid.2 With these problems in mind, we undertook a study of the solid-state degradation of aspirin and the Abstrsct 0It has been shown that the degradation of aspirin in mixtures may be monitored by thermal analytical techniques. The methodology
use of thermal analytical methods for following the reaction.
Experimental Section Materials and Reagents-All reagents used in this study were reagent grade. Nuclear magnetic resonance spectra were recorded on a Varian T60A in CDC13 solution with tetramethylsilane as the
OO22-3549/86/0 1OO-ooS7$01. oO/O @ 1986, American Pharmaceutical Association
Results and Discussion It has already been shown that aspirin crystals, when heated on a hot stage, soften and that a liquid appears even below its melting point. These observations have been attributed to the production of acetic acid through hydrolysis.' Our initial experiments were carried out at 155°C in an Journal of Pharmaceutical Sciences / 97 Vol. 75, No. 1, Januaw 1986
oven, that is, above the melting point of aspirin. Complete decomposition to acetic acid and salicylic acid was observed within 1 h. When the experiment was repeated at lOO"C, complete decomposition occurred within 3 h, and the tablets or powder had again turned to liquid. An attempt was made to remove the acetic acid as it was produced by running the experiment in a reduced pressure oven (1OO0C/13mm Hg) but again the liquid formed contained a considerable amount of acetic acid (NMR). The aromatic acid isolated in these experiments was salicylic acid and no evidence of any oligomers was seen by spectroscopic techniques.36 A previous study had detected oligomers of salicylic acid by HPLC, but thermolysis was carried out in the presence of magnesium carbonate.36 In our experiments, little or no magnesium ions were present and, as the heating was carried out in air, the mixture was free to react with atmospheric moisture. Any salicylides formed could, therefore, have been hydrolyzed before detection. Certainly, recrystallization of the product mixture gave salicylic acid (>go% of theoretical recovery). The literature DSC36.37of aspirin showed a sharp endotherm corresponding to melting at 138°C; DTA gave a: similar r e s ~ l t . It ~ 8can, however, be clearly seen that the DSC gave an extra endotherm a t 160°C (Fig. 1). This transition was also apparent in the commercial pharmaceutical aspirin formulation; it is close to the melting point of salicylic acid (158-160°C39;this gave rise to a large endotherm a t 166.8"C on a DSC run). As noted above, the sample was liquid at 160°C and it seems reasonable to suggest that this endot h e m can be attributed to aspirin degradation. Thermal gravimetric analysis (Fig. 2) reinforced this premise as a large weight loss occurred around this temperature. Indeed, this loss was greater than the amount of acetic acid produced and presumably some salicylic acid also evaporated.40 As these reactions were carried out in dry nitrogen, salicylides may have been formed. When the reaction was repeated on a preparative scale, salicylic acid was the only isolated solid product (86%). The sharp endotherm at the melting point of aspirin was
t
t
-24 -284 0
I I
: : : : : : : 100 200 300 400 Temperature, OC Flgure 1-Differential scanning calorimetry thermogram of aspirin. :
98 / Journal of Pharmaceutical Sciences Vol. 75, No. 1, January 1986
I40
/
t 120/
' O Oi
fL+ \ I- -
"
00
100
200
300
400
Temperature,O C Flgure 2-Thermal gravimetric analysis of aspirin. Key: (-) weight remaining; (---) rate of weight loss.
percentage
considered to be a useful tool for the investigation of its degradation in a solid mixture. Although aspirin forms a eutectic with salicylic acidfo it was felt that the interactions between these two compounds would be diminished in the mixtures and would not present any undue problems other than peak broadening. Certainly, the problem, a t worst, would concern interpretation rather than a practical problem. In addition to the eutectic, it has been suggested that aspirin exists in polymorphic f01111~,~~4 the melting points of which can vary greatly. Previous investigators have disputed this.In our hands, prolonged treatment of acetylsalicylic acid with 1-pentanol, the solvent used for the alleged solution-phase transformation of polymorphs, lead to degradation as evidenced by the methyl integral in the NMR. This type of analysis also showed that the acetyl group diminished (-5-10%) when the recrystallization was conducted in a hydrocarbon solvent. This suggests that the changes in melting point are not due to polymorphism44but to degradation. The problem was not pursued because of the difficulty in reproducing the results and characterization of the products. Although GC has been used to differentiate aspirin from salicylic acid,47.48spectroscopic techniques were used in this study to determine the amount of degradation. Thin layer chromatography has also been suggested as a tool to monitor aspirin stability.49.50 When a mixture of salicylic acid and aspirin were separated by this method, eluting with ethanol, ethyl acetate, or 4:1:1 hexane:acetic acid:chloroform,4B light loading had to be used to avoid streaking. When the experiments were repeated on preparative TLC plates, the bands, after removal and extraction, showed the impurities of the other components (by NMR). Although TLC proved useful as a qualitative technique to monitor the degradation, NMR was chosen as the analytical method to confirm the thermal analytical findings. The study on the effects of tablet formulation additives commenced with starch (potato) admixed in the ratios (aspir-
in:starch) of 1:1, 1 5 4 and 1:lO (w/w). The ratio 15:4 was chosen as this approximated the composition of the commercial tablets. The samples were prepared in three separate ways: (a) by grinding the two components together with a mortar and pestle, ( b )by making a tablet, and (c) by adding chloroform to the mixture and then removing this solvent - 2 t under reduced pressure. No attempt was made to assess the pharmacological implications of these formulation^,^^.^^-^^ such as a ~ t i v i t y 5or ~ affects on disintegration of the tab1ets.56.57Even after storage for 3 months, in all cases, no (4%) decomposition was detected in any of the samples by thermal analytical techniques, TLC, or NMR. A representative DSC is shown in Fig. 3; note the peak at 40°C which is due to starch degradation. As the decomposition of aspirin may be catalyzed by acid or base, solid acidic and basic substrates were investigated. Silica was used as the model solid acid and samples were prepared as described above, except that no attempt was made to tablet the mixture. No decomposition was detected in the 154 aspirin:silica sample after 1 month and the aspirin was recovered by chloroform extraction (97%). Some decomposition was detected in the 1:l mixture within 2 d as the DSC curves lost their sharp definition (Fig. 4); little -6 aspirin was detected in the 1:lO aspirin:silica case after a similar time span (Fig. 5). Salicylic acid was isolated when the sample was extracted with chloroform (>go% recovery). To show that water was not the cause of degradation, the -7 silica was dried a t 850°C; the decomposition observed in 0 100 200 300 these mixtures was identical to the samples listed above. Temperature, O C Alumina gave almost identical results to the silica cases as illustrated in Fig. 6. This suggests that the degradation of Flgure 4-Differential scanning calorimetry thermogramof a 1: 7 aspirin: silica mixture. aspirin could be catalyzed by acid or base in solid-state reactions just as it is in solution. Previous studies had been carried out with aluminum hydroxide58and other 8 n t a ~ i d s . l ~ Little decomposition was found by assay for free salicylic acid; in some cases, the metal ion present could have interfered with the colorimetric method employed. It should be noted that 2:l aspirin:additive mixtures were used in the studies and our results, i.e., the 1 5 4 mixtures were stable, are in keeping with these previous findings. One possible explanation is that silica and alumina carry free hydroxyl groups which could interact with the aspirin. The reaction would depend on the concentration of hydroxyl groups; our results show that a relatively high concentration of the additive must be present for rapid degradation to occur. Adjuvants used for aspirin tablet manufacture, such as starch, also contain polyhydroxyl functional groups, but as
I
t
t7
-;I
-10
!O
- 4 4 - 4 - - + + . ~ 0 100 200
300
Temperature,;C Flgure 5-Differential silica:aspirin mixture. C t , : : : : : :
0
)----+-cIc
100200300400500600
Temperature,O C Flgure 3-Differential scanning calorimetry thermogramsof an aged 1: 1 starch:aspirin mixture. Key: (A) I month; (B) 7 week; (C) 3 months.
scanning calorimetry thermogram of a 1O:l
these are neutral the reaction is slow. It is interesting to note that P-cyclodextrin accelerated the basic hydrolysis of aspirin60through formation of a 1:l complex at a pH where the cyclodextrin hydroxides could be deprotonated.60 It seems reasonable to suggest that aspirin degradation in Journal of Phannaceutical Sciences / 99 Vol. 75, No. 1, January 1986
+
solid state could be acid or base catalyzed. The degradation was detected by thermal analysis which was not affected by metal ions as other analytical methods can be. These metal ions could also be important factors in affecting aspirin degradation.63 Although the techniques described in this paper do not allow for the detection of small amounts of aspirin degradation, it is a useful method for the rapid screening of aspirin mixtures to determine stability. The method is simple and may be carried out directly on the mixture, a cheaper alternative to diffuse reflectance spectroscopy.‘O
References and Notes 1.
P* York. J.
-8 ;t N
v
200
100
0
300
Temperature, OC Flgure 6-Differential scanning calorimetry fhermogram of a 103 a1umina:aspirin mixture.
Table CStablllty of Asplrln In the P m n c o of Addltlvm
Additive
Ratio (asp1rin:addltive)(w/w)* 1:1
15:4
1:lO
Starch Silica Silica (dried) Alumina Stearic acid Cellulose Dextrose Sodium acetate Sodium acetate hydrate Sodium carbonate hydrate Sodium hydrogen carbonate
S. R. “Solid-State Chemistry of Drugs”; Academic Press:
1982. 2. Kelly, C. A. Pharm. Sci. 1970,59, 1053. 3. James, K. C. J.Pharm. Pharmacol. 1958,10,363. 4. Tuckel, N.; Antonescu, V.; Gheorghe, V.; Stefanescu, F. F a r m cia 1961.9. 11. 5. Jue, J.; Huych, C. L. J.Am. Pharm. Assoc., Sci. Ed. 1963,3,470. 6. Nogami, H.; Awazu, S.; Nakejima, N. Chem. Pharm.Bull. 1962, 10,503. 7. Komblum, S.S.;Zoglio, M. A. J. Phann. Sci. 1967,56,1569. 8. Leeson, L. J.; Mattock, A.M. J. Am. Phurm. Assoc., Sci. Ed. 1958,47,329. 9. Carstensen, J. T.;Attarchi, F.; Hou, X.-P. J. Pharm. Sci. 1985, 74,741. 10. Gore, A. Y.;Naik K. B.; Kildsig, D. 0.; Peck, G. E.; Smolen, V. F.; Banker, G. 4. J. Pharm. Sci. 1968,57,1850. 11. Trow, D.; Dam, R. Pharm. Pmr. 1966,228. 12. Jaminet, F.;Evrard, G. Phurm.Acta Helv. 1966,41,601. 13. Wisniewski, W.; Piasecka, H. Acta Pol. Pharm. 1967,24,291. 14. Jaminet, F.;Louis, G. Pharm. Acta Helv. 1968,43,153. 15. Bandelin, F.J.; Malesch, W. J. Am. Pharm. Assoc., Sci. Ed. 1953,19,152. 16. Lee, S. T.;Dekay, H. G.; Banker, G. S. J.Pharm. Sci. 1965,54, 1153. 17. Mauldin , H. V.; Zoglio, M. A.; Pigois, F. E.; Wagner, M. J. Pharm. 1969,58,1359. 18. %UD. A. E.: Mitchner. H. J. Phann.Sci. 1964.53.375. 19. Kosh“ K.T.;Troup,’ A. E.; Duvall, R. N.; ’Conwell, R. C.; S h a d e , L. L. J. Pharm. Sci. 1967,56,1117. 20. Jacobs, A. L.;Dilatush, A. E.; Weinstein, S.; Windhauser. J . J. J. Pharm. Sci. 1966.55.893. 21. Ribeiro, D.; Steve’mon, D.; Sam J.; Milosovich, G.; Mattocks, 1955,44,226. A.M. J. Am. Pharm. Sci., Sci. 22. Kral, J.: Bielesmva. H. Drozdova. Z.Farm. Obz. 1960.29.298: Chem. Abstr. 1964,61,2910h. . 23. Nazareth, M. R.; Huyck, C. L. J. Pharm. Sci. 1961,50,608. 24. Nazareth, M. R.; Hu ck, C. L. J. Pharm. Sci. 1961,50,620. 25. Okano, H.;Kawata, Tsutsumi, S.; Umezaki, Y. Yakwaigaku 1963,23,279;Chem.Abstr. 1964,61,537h. 26. Grabowska, I. Gdansk. Tow.Nauk., Rozpr. Wydz. 1964,3,193; Chem.Abstr. 1966. 64. 14029a. 27. Grabowska, I. Gh’nsk: Tow.Nauk., Rozpr. Wydz.1964,3,207; Chem.Abstr. 1966,64, 15678b. 28. Galanta, R. N.; Visalli, A. J.; Patel, D. M. J. Pharm. Sci. 1979. 68, 1494. 29. Strode, C. W.; Stewart, F. N.; Schott, H. 0.; Coleman, 0.J. Anal. Chem.1957,29,1184. 30. DeMarco, J. D.; Marcus, A. D. J.Pharm.Sci. 1962,51,1010. 31. Cullen, L. F.;Packman, D. L.; Papariello, G. J. Ann. N.Y. Acod. Sci. 1968,153,525. 32. Edwards, L.J.; Gore, D. N.; Rapson, H. D. C.; Taylor, hi. P. J. Pharm. P h a r m o l . 1955 7,892. 33. Green, A. R. Austmlus. f.Pharm. 1964,45,588. 34. As obtained by us, but identical with the Aldrich Libraries of IR and NMR spectra. 35. Reepmeyer, J. C. J. Phurm. Sci. 1983,72,322. 36. Daly, K. F.Am. Lab. 1975,75. 37. Wendlandt, W. W.; Collins, L. W. Anal. Chim. Acta 1974, 71, 411. 38. Wendlandt, W. W.; Hoiberg, J . A. Anal. Chim. Acta 1963,29, 539. 39. “Aldrich Catalog,” 1984-85 ed.; Aldrich Chemical Co.: Milwaukee, WI,1984. 40. Monkhow, D. C.; Lach, J. L. Can.J. Pharm. Sci. 1972, 7,29. 41. Tawashi, R. Science 1968,160,76. 42. Tawashi, R. J. Pharm. Pharmacol. 1969,21,701. 43. Summers, M. P.: Carless. J. E.: Enever. R. P. J.Pharm. P h a r m COI. i970,’22, 6i5. 44. Pfeiffer, R. R. J. Pharm.Pharmacol. 1971,23,75. ew
-~ ~ _. _. _ .
83.
B.
I
*Refers to all three methods of mixing (see Experimenfal Section) unless otherwise stated. Key: A, no decomposition detected after 1 month; 8,significant,but not complete decomposition detected after 5 d; C, complete decomposition. bThese mixtures were not prepared in tablet form. other cases may be more complicated than they appear. For example, dilution of phenylephrine hydrochloride and aspirin with starch slowed acetylation of the drug dramatically (vide suprala). This is probably due to the starch acting as a diluent and minimizing aspirin-phenylephrine hydrochloride interactions as well as acting as a pH buffer. In addition, the aspirin could be acylating the starch and the acyl group could then migrate along the starch hydroxyl groups,B1,’32 statistically making interactions less likely. As stated above, many of the degradation processes were monitored by formation of salicylic acid and, therefore, any intermediate would not be detected. Other additives used in this study were sodium acetate, both in the anhydrous and the hydrated form. All samples decomposed within 6 weeks, many of the hydrated samples giving a liquid. Sodium carbonate hydrate also showed decomposition, but sodium hydrogen carbonate did not cause significant decomposition in the 15:4 case, although it did in the others. Stearic acid gave mixtures which were stable as did cellulose and dextrose. It has been shown that the degradation of aspirin in the lo0 / Journal of Pharmaceutical Sciences Vol. 75, No. 1, January 7986
k;
.
I
45. Schwartzman, G. J. Pharm. Pharmacol. 1972,24, 169. 46. Mitchell, A. G.; Milare, B. L.; Saville, D. J.; Griffiths, R. V. J. Phurm. P h u r m o l . 1971,23,534. 47. Crip en, R. C.; Freimuth, H. C. Anal. Chim. Acta 1963,29,539. 48. NikJly, J. G. Anal. Chim. Acta 1964, 36, 2248. 49. Reimers, F. Arch. Pharm. Chem. 1967, 74. 531. 50. Frodyma, M. M.; Lieu, V. T.; Frei, R. W. J. Chromtogr. 1965, 18, 520. 51. Levy, G. J. Phurm. Sci. 1961,50,388. 52. F‘feiffer, C. C.; Goldstein, L.; Murphree, H. B.; Hopkins, M. J. Phurm. Sci. 1967,56, 1338. 53. Wood, J. H. Phurm. Acta Helv. 1967, 42, 129. 54. Levy, G.; Leonards, J. R.; Procknal, J. A. J. Pharm. Sci. 1965, 54, 1719.
55. Levy, G.; Procknal, J. A. J. Phurm. Sci. 1962,51, 294. 56. Chowhan, Z. T.; Chi, L.-H. Phurm. Technol. 1985,9, 84. 57. Bolhuis, G. K.;Smallenbrock, A. J.; Lerk, C. F. J. Pharm. Sci. 1981, 70, 1328. 58. Patel, H. M.; Huyck, C. L. Mtg. Chem. 1963,34, 100. 59. Chin, T.-F.; Chung, P.-M.; Lach, J. L. J. Phurm. Sci. 1968, 57, 44. 60. Lach, J. L.; Cohen, J. J.Pharm. Sci. 1963.52, 137. 61. Dodd, G. H.; Golding, B. T.; Ioannov, P. V. J. Chem. SOC.,Chen. Commun. 1975,249. 62. Houg;h, L.; Richardson, A. C. in “Comprehensive Organic Chem, vol. 5 ; Barton, D. H. R.; Ollis, W. D., Eds.; Pergamon: ord, 1979; p 723. 63. Gold, G.; Campbell, J. A. J. Phurm. Sci. 1964,53, 375.
%?
Journal of Pharmaceutical Sciences / 101 Vol. 75, No. 1, January 1986