STABILITAS ASAM ASETIL SALISILAT

Sumantri
Daftar Pustaka
Ahuja, S., 1998, Impurities Evaluation of Pharmaceuticals, Marcel Dekker Inc., New York.
Ahuja, S., Scypinski, S., 2006, Handbook of Modern Pharmaceutical Analysis, Academic Press,
New York
Avis, K.E., Lieberman, H.A., Lachman, L., (Ed.), 1992, Pharmaceutical Dosage Forms: Parenteral
Medication, Vol. 1, Second Edition, Marcel Dekker Inc., New York.
Baltes, W., (Ed.), 1990, Rapid methods for analysis of Food and Food Raw Material, Technomic
Publishing Co. Inc., Lancaster.
Carstensen, J.T, Rhodes, C.T. (Ed.), 2000, Drug Stability, Marcel Dekker Inc., New York.
Connors, K.A., Amidon, G.L., Kennon, L., 1986, Chemical Stability of Pharmaceuticals, 2ndEd., John
Wiley & Sons, New York.
Cserhati, T., Forgacs, E., 1999, Chromatography in Food Science and Technology, Technomic
Publishing Co. Inc., Lancaster.
deMan, J.M., 1997, Kimia makanan, Edisi kedua, diterjemahkan oleh Padmawinata, K., Penerbit
ITB, Bandung.
Florence, A.T., Attwood, D., 1994, Physicochemical Principles of Pharmacy, Second Edition, The
MacMillan Press Ltd., Hampshire.
Ketaren, S., 1986, Pengantar teknologi minyak dan lemak pangan, Cetakan Pertama, UI Press,
Jakarta.
Nosoh, Y., Sekiguchi, T., 1991, Protein stability and stabilization through Protein Engineering, Ellis
Horwood, New York.
 ASAM ASETIL SALISILAT

Asam Asetil Salisilat C9H8O4

Asetosal BM 180,16
Aspirin
 Stability
• Aspirin as an acetylation product of salicylic acid which is unstable toward
hydrolysis and other acyl transfer.
• pH-rate profile reveals specific acid and specific base catalysis of
the hydrolysis.
• The hydrolysis of aspirin formed salicylic and acetic acid which can
be detected by its odour.
• The stability of aspirin in formulations is maintained by minimizing
contact with water, with basic substances (e.g., carboxylates salts) and
with nucleophiles (e.g., amines and hydroxy groups).
 DRUG KINETICS

Reactions and Rate Equation

• The hydrolysis reaction of aspirin :

Aspirin Salicylic acid Acetic acid

The kinetics and mechanisms of hydrolysis are affected by the
ionization of the carboxylic acid group of aspirin (pKa = 3.6).
kH
+
RCOOH + H Products
HO2

k’
RCOOH Products
H 2O

- k’’
RCOO Products
H 2O

- - kOH
RCOO + OH Products
H 2O
• The rate equation:
rate = kH [RCOOH] [H+] + k’ [RCOOH]
+ k’’ [RCOO-] + kOH [RCOO-] [OH-]
kH = the second-order rate constant for specific acid
catalysis;
kOH = the specific base second-order constant;
k’ and k’’ = first-order constants for the reaction of
unionized and ionized aspirin.
 pH-Rate profile
- The specific acid catalysis below pH 2
- The specific base catalysis above pH 9
- The sigmoid portion leading to a pH-independent
plateu from pH 5 to 9 (approx.).
- The maximum stability occurs at pH 6.5.
- At pH 7.0 and 250 :
• the rate constant is 3.7 x 10-6 s-1
• Half-life about 52 hours
• Shelf-life (t90) about 8 hours
Activation energies for Aspirin hydrolysis
reaction
Rate constant Ea (kcal/mol)

kH 16.7
k’ 16.4
k’’ 17.6
kOH 12.5
Effect of ethanol on Rate constant in the plateu region

Ethanol 106 k’’ (s-1)

0 3.65
20 5.02
40 9.24
60 14.3
FORMULATION AND COMBINATION
Degradation reactions
- The decomposition reactions of aspirin in
pharmaceutical system are acyl transfers and
hydrolysis (the most important).
- The solid samples of aspirin are decomposed by :
• A route involving physical adsorption of water from the
atmosphere to the solid surface
• Dissolution of aspirin in the adsorbed layer
• Acid-catalyzed hydrolysis of the dissolved aspirin.
- No decomposition in the absence of water.
- Decomposition of aspirin tablets is easily recognized
by the odor of acetic acid.
- Partially degraded aspirin tablets are sometimes seen
with needles of salicylic acid on their surface => as a
result of sublimation of the salicylic acid.
- Several common tablet lubricants affect the stability of
aspirin.
Effect of tablet Lubricants on Aspirin hydrolysis at 300C.
Additivea pH Initial Rateb
None 2.60 0.123
Stearic acid 2.62 0.133
Hydrogenated vegetable oil 2.68 0.123
Talc 2.71 0.133
Aluminium stearate 3.16 0.281
Calcium stearate 3.75 0.986
Magnesium stearate 4.14 1.314

• aAdded in excess of its solubility.

• bIn mg of salicylic acid per hour.
Effect of Additives on Aspirin Tablet Stability at 400C

Additivea Rateb
10% Hexamic acid 0.38
None 0.79
10% Aluminium hydroxide 2.03
5% Calcium stearate 4.73
5% Magnesium stearate 5.93
10% Magnesium trisilicate 38.4

a
• Added in excess of its solubility.
b
• In mg of salicylic acid per hour.
- Aspirin is a acetylating agent (= a substituted phenyl acetate).
- Aspirin can react with amines and hydroxy groups to yield the
corresponding amides and esters.
- Magnesium stearate facilitates this acyl transfer.
- Aspirin and acetaminophen in mixtures give
diacetyl-p-aminophenol in a reaction accelerated by
magnesium stearate.

- Aspirin can acetylate codeine and homatropine.

- Similar reactions might be anticipated with other amino
and hydroxy compounds.
Stabilization methods
- The only effective way to inhibit the hydrolysis aspirin is
to remove it from contact with water.
- Tablets and capsules are the preferred dosage forms.
- A suspension of aspirin is not really a stable dosage form,
although a practical shelf-life may be attained.
- Formulation of aspirin in polyethylene glycol bases leads
to decomposition by acetylation of the hydroxy groups
on the polyethylene glycol.
- Aspirin decomposition is reduced when the hydroxy groups
are blocked by alkylation or acylation.
- Aspirin in nonhydroxylic solvents can undergo decomposition
with the formation of several product, including mixed
anhydrides.