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~ S 0$'
B KINErPIC &~.II'ETHoDSIN STORAGE STABILITY STUDIES
PHARMACEUTICALS
ON DRUGS AND
H. K. KULSHRESHTHA
Defence Research & Developinent Establishment, Gwalior
(Received 14 January 1974; revised 26 September 1975)
Utility of kinetic methods for predicting shelf life of drugs and pharmaceuticals and its importance in our country
with varying conditions of climate ranging from hot and humid to extreme,cold and dry have been brought out in this
review.
As the troops operate under varying conditions of climate, ranging from hot and himid to extreme
cold and dry the shelf life of pharmaceutical preparations intended for storage at room temperature is not
always applicable under the field conditions. Frequently DGAPMS requires information at a very short
notice on the shelf life of certain drugs before purchasing them, or taking a decision on accepting indigenously developed substitute for the existing imported item, or introducing a n&v item in the PVMS list.
In the present report the methods based on kinetic( treatment of experimental data obtained-from
observations spread over from few weeks to few 'months have been reviewed, mentioning in detail where
these have been utilized to predict the shelf life of drugs and pharmaceuticals. No attempt has been made
to enumerate all the references available; they have been selected to demonstrate the wide applicability
and interest of a large number of researeh workers throughout the world.
FACTORS
AFFECTING
STABILITY
A great variety of drugs and pharmaceutical preparations are available in various forms depending
state, route of administration and stiability under normal conditions of room temperaupon their
ture. They are available as solids (powders, tablets, capsules) or liquids such as elixirs, mixtures, parentera1
solutions, biological fluids, etc. A particular preparation is dispensed depending upon the route of administration, which itself depends on its eEcacy, e.g. a drug may not necessarily be as effective if administwed
orally but on being injected via a suitable route may be miraculously effective. The conditions of storage
are specified by the manufacturers and are covered by the various schedules ~f the Drugs and Cosmetics
Act. I n substance, any drug is recommended to be stored in dry cool place protected from direct sunlight.
Due to its chemical characteristics a drug may lose its potency if it is not stored properly as advised,
Drugs and pharmaceuticals have their shelf life for varying periods, from 14 days for human whole blood,
BCG; vaccine, etc. to 3 years for parenteral morphine. preparations. A drug may not be dispensed as liquid,
for in solution deterioration can be rapid, as in the case of ascorbic acid, but stabilizing effect of other themical substance3 is often useful.
Drugs are affected by heat, pH changes, direct sunlight, humidity, other chemicals, metals, preseme
of other drugs as in the mixture of a pharmaoeutioal preparation, presence of fillers as in tablets, preservatives in various liquid preparations, ultrasonic waves, loss of ~olouringdye on storage or exposure to
light.
Effdct of various parameters on the stability of a drug praparation has been brought out in individual
oases.
HISTORY O F DEVELOPMENT OF K I N E T I C METHOD FOR STORAGE
STABILITY
The conventional method for determining the shelf life of pharmaceutical preparations is to study
their stability by actually storing them at desired temperatures or humidity, etc., for the required period
of time, usually one to three years. The obvious disadvantages of such a method are the lobs of time and
i
189
cost. Another method that hag b&n suggested is to study the s&bility of preparations stored in ovens a t
high temperatures and correlating this data with those obtained by actual storage in field conditions. Such
correlations have often been intuitive being base& on an insufflcient data or on empfrical relations found
in supposedly similar preparations'.
.
Prediction of shelf life from accelerated studies has been placed on a quantitative basis by the application of fundamental physicochemical principles 1-4 . A rationale of predicting stability+of pharmaceutical
preparations using chemical kinetics has been presented by Ho and Goeman6 using hydrocortis~nesodium
,
! succinate as an example. Prediction of pharmaceutical stability of parenteral solutions was done by Hoe,
Carstensen and Su7 who found that for preparations having less than 10% degradation, zero order kinetics
was applicable to accelerated test data and by extrapolating it to room temperature, the prediction of
shelf life was possible. Lins proved the efflcacy of the short term data for prediction of shelf life by comparing it with long term storage datag-lo. By the use of a modified form of the Arrhenius equation, and
simultaneous determination of activation energy and rate constant dependence on temperature prediction of stability can be determined from the values of the concentration as shown by Rogers20 and applied
to first order decomposition of sugar and riboflavin; see also Cole and Leadbeater21P2.The Arrhenius
equation can be modifled suitably to formulate non isothermal technique of accelerated testing23-27.
PREDICTION
FOR
A NEW
PRODUCT DURING
,
DEVELOPMENT
By making use of the accelerated test data, the physical stability of a new pharmaceutical prodnct
could be predictedzs-32. Various parameters such as biological contamination,_ container height, age,
temperature, moisture and oxidation, were taken into consideration for studying stability of pharmaceutica1$8 and for emulsions, suspensions and solids33-35. Lintner et aP6 have, shown how the data could be
computerized for predicting shelf life ,of a new ~roduct.
METHODOLOGY
Briefly the method is based on the observation that a suitable metameter of the potency (usually the
potency itself or its logarithm) falls off, at any chosen temperature linearly with time, and the'different
rates of degradation of the potency (or its metameter) obtained a t different temperatures are related to
those temperatures in accordance with Arrhenius equation1,%,
i
k=A.e-
(
~ d/&TI
a
or, log k = - ( @la/2.303R)
+
( l / T ) Constant
/
where is the reaction rate constant, T is temperature in absolute units, B is gas constant (1.987 k~a1.f
mole), AHa is heat of activation, and A is a constant depending on the entropy of the reaction andlor
collision factors.
These relationships can be used to calculate the degradation rate at the required storage temperature
from the experimentally determined degradation rates at elevated temperatures. Thus the shelf life may
he predicted at the required storage temperatures with the aid of determined degradation rates.
-
Alternately, the logarithmic form of the Arrhenius equation shows that any value proportional to the
specificrate (k) would permit slope evaluation of a plot between log k versus 1/T, and also evaluation of the
heat of activation. If such a relation among several values determined at elevated temperatures and the
absolute temperature is reasonably linear, it is possible to predict shelf life at any desired temperatwe.
In stability prediction studies, it is not necessaG to elucidate the mechanism of the reaction and it is
necessary to determine reaction rates, etc. The graphical procedure for predicting thermal stability for
a particular component in a pharmaceutical preparation as enunciated by Garrett and Carper1 is based on
the reproducibility of the degradation rates at the various elevated temperatures and extrapolatio~of the
Arrhenius plot to obtain the rate constants at the desired lower shelf temperatures. The validity of this
method of predicting stability was demonstrated by the agreemsnt of classical assay values from long
term method with the predicted valuesa. A graphical method may also be used to evaluate the order of the
A
&~LSHRESETEA
: $toi%ge%sbil&? ~@%?i&&
bi; hmga and ~hsrmacenticale
.
&action by linearity of a plot of concentration or its logarithm with time, the former giving peudo zerd
o$er reaction and the latter giving pseudo first order reaction3.
\
1n Rogers' methodm Arrhenius equation was modified to evaluate the rate constant and energy of
activa%ionat room temperature from values of the concentration of the reactant. The experiment itself is
designed that the temperature of the reacting sfstem is'raised in accordance with a pre-determined
programme; the temperature of the reactants is allowed to increase from the initial temperature, To, to
the final temperature, Tt both in absolute units, t being time period, say, 6 hours, in accordance with the
equation
80
l / T o-l/Tt = 2-303b log (1
+ t)
e
where b is a constant of proportionality which can be chosen as desired. The whole experiment is finished
in a period of 6-7 hr. The method was applied by Rogers to first order decomposition of riboflavin and inversion of sucrose20, and was critically assessed by Cole and Leadbeater for a number of first order and
second order reactions such as inversion of sucrose, hydrolysis of ethylbernzoate, cholinesterase activity of
horse serum21,22. Here no preliminary experiment is necessary to determine the optimum temperatures
for the method, the linearity of the plots confirm that correct order for the reaction has been assumed,
and deviations from the linearity may therefore be looked k t o 2312&27.,
The statistical method may be utilized as an alternative to a graphical method. In the case of imprecise analytical methods such as microbiological assayw, an ezperimental design based on statistical
method13,31,37-*3 was presented. Lordi and
constructed nomographic charts to facilitate the arialysis of stability data obtained at elevated temperatures. The effects of errors on predictions made by using
the nomogram were described, with particular reference to those arising from faulty assays, timing and
temperature control. Carstensen et aZ46 on the othw hand applied Harnvmett graphs for predicting the
best substituent~for ally1 barbituric acid derivatives to get optimal stability.
The quantitative physico-chemical relationships bermit the rates of degradation to be calculated by
substitution of the appropriate values f%r temperature, concentration, time, pH, light intensity, etc. A
knowledge of mechanism 6f degradative process is necessary to work out stability pattern in the presence of
buffers, vehicles qnd excipihnts.
0 t h parameters
~
followed for the predicting shelf life include solubility analysis46,heats of activationas,
optimufl,"7 pH, melting point depression for pharmaceutical $owders4*, refractornetry48, light reflectante for tabletsm, conductivity measurementss1,. p~larography~~,
microdiffisional study in solid state68,
stirred fiow techniques for developing mathematical equation? for complex kinetic runs6* and N. M. R.
analysi~~~.
- -In addition to usual stability studies, the formulations have also been studied for loss of colour of
dyes66-5B, the effect of fillers on the active ingredients6N1 stability of preservativeslike cholorobutanol,
in parenteral solutions62and effect of vehicle6,.
S T A B I L I T Y S T U D I E S ON V I T A M I N S A N D C O M P L E X V I T A M I N N I X T U R E S
General areas of vitamin stability were reviewed by P a r r a p ; see alsoe6. Vitamins are of varied themical nature, and degrade by photalytic, oxidative and solvolytic mechanisms.
TardiffD used elevated temperature storage tests and a graphical method to determine thermal degradation rates of vitamin A, thiamine and ascorbic acid in three multi-vitamin formulations. The role of
moisture was brought out in this study; if it was maintained below 1% the pseudo first order rate was
reduced considerably for the vitamins separately. Assay of samples stored a t room temperature for
16-38 months confirmed accelerated storage dataB6-68. Accelerated test method was utilized to estimate
the fibelf life of vitamins B,, B,,, and K, by Ebel et aZG9;zero order decomposition for vitamin A jn
organic disper'sion, stabilized with cr---tocopherol acetate was found independent of vitamin A concentration. For vitaminB,, the decomposition was of first order in aqueous solution, and shelf life of
one and three years was predicted from specific rate data, for the two vitaMins70-76.
bag. 801.J., VOL.26, OO*OBERi996
rdscorbic Acid
*
Kinetic method was employed to study the stability of ascorbic acid in a liquid multivitamh emulsiod
by Tingstad et a176. The vitamin was f ~ u n dto degrade initially by a zero order reaction, but other evidences showed the rate to be nearly one. Thus predictions made by making use of the Arrheniu~p b t
were correct77-79. Kinetics of copperion catalyzed auto-oxidatio~
of ascorbic acid-3-phosphate@ have
been reported ; see als078-~8. Investigations on kinetics of ascorbic acid have been reviewed by
Hutterrauchgg.
-
Vitamin A
This vitamin degrades by oxidation and elimination in hydroxylated solvents. Effect of dl - or tocopherol on the stability of vitamin A in aqueous solution was investigated by Klotz at a1100-101. An
hydrovitamin A in preparations, was found to be more stable than the vitamin A itself 102. Solid state
stability of crystalline vitamin A derivatives was studied by Guillory and Higuchilo" Carstensen104 found
that the logarithm of pseudo first order rate was related to water vapour pressure in the case of vitamin A
in tablet; see also1°5-'0%
Thiamine
The main route of destruction is hydrolytic and is catalyzed by buffer salts. Kinetics of hydrolysis
of thiamine was investigated by Windhauser and Higuchi1°9. The hydrolysis followed a first order reaction,
4.
of the vitamin was studied in p'resence of
and was influenced by general base c a t a l y s i ~ l l ~ - ~ ~Stability
dipyroneu5 and in presence of some antibiotics in capsules by accelerated stability test methodslla-120.
Base catalyzed decomposition of riboflavin was found by Guttmanl21 to be of first order a t constant
,.hydroxylion concentration; the kinetic parameters in presence of caffeine, the latter complexing with
the substrate and hence enhancing riboflavin stability, were also evaluated, see alsol22.123.
Cyanocobalamin
x
General acid-base catalysis has been demonstrated for this vitamin. The stability of cyanocobalamin
at different times and pH was studied by Loy et al.124,Marcus and Stanle~12~
and Senlw. Predictions of
stability were made utilizing Arrhenius parameters applied to the apparent first order degradation of the
vitamin in liquid multivitamin preparations127-130.
Other Vitamins
Among studies on other vitamins, photodegradation of vitamin K1,131 hydrolysis of nia~inamidel3~
and kinetic study of pyridoxine hydrochloride in presence of some antibioticsu3 may be mentioned. Tetracycline and chlortetracycline hydrochloride had stabilizing and oxytetracycline and chloramphenicol, had
deleterious effects on pyridoxine. Stability studies on vitamin D have also been reportedl34-136 .
STABILITY STUDIES
ON A N T I B I O T I C S
\
Stability studies and predictions of shelf life have been reported for many of the antibiotics, both
natural and semi-synthetic. Mogt of the antibiotics are thermolabile an4 are effected by pH changes and
presence of metallic ions, etc.
Penicillins
Among the early studies reference may be made to the work of Brodersenl37 who studied the kinetics
of penicillin degradation in various pH ranges, the maximum stability being at about pH 7. Kine3ics of
depadation of penicillin to penicillenic acid was studied =by Krejci 158. In another investigation Swinto&y
et al. 139 found the degradation of saturated solution of procaine penicillin to follow a zero order reaction.
KOLSBRM
:Storage
~ ~ Stability studies on Druga and pharmaoeuticals
Mechanism of catalysis of penicillin degradation in presence of catech0114~, catecholaminesl41 and metallic
ions has been investigated142-148, Kinetics of degradation of 6-aminopenicillanic acid was reported by
Dennenl49; in another study Ra;srnu~senl5~
evaluated kinetic parameters of interaction of penicillinase
with penicillins. Similar w z k led to the theory explaining the penicillin allergyl61-162.
\
/
Semi-Synthetic Penicillzlzs '
4-
Degradation kinetics of phenethicillin and methicillin were evaluated by Schwartqet aZ.153, the rates
being of first order154 ; for aqueous solution of methicillin, the optimum pH was found to be 7.44156 ; see
also?". Kinetics and mechanism of degradation of ampicillin15Fand that of oxacillin in aqueous solution
between the pH range 1.44-10.93 were. studiedll67-161. In solid state stearic acid inactivated sodium
dicloxacillin and sodium oxacillin in tablets; the results were confirmed by accelerated tests on combinationl".
Decomposition of hetacillin leads to a rapid formation of a substance with a characteristic
absorption at 317 nm and ampicillin gives a polymerized prod~ctl63-~66. Recently Hem et all68 found
sucrose*toform 1 : 1 molar complex with various penicillins. the rate being 5-6 times greater than the
uncomplexed penicillin; however, the complexation does not change the degradation pathway.
J
Tetracyclines
\
The C , epimerization of t e t r a c y ~ l i n e ' ~acid
~ - ~base
~ ~ catalyzed and pH dependent. Stability of tetracycline and its derivatives was studied by Zelinka et 01.16' as early as 1961, kinetics of epimerIz*,tios by *
n.m.r. was studied by Schlecht and Prank65- ; see also 168-172.
Major route of degradation in solution is by substitution giving chloride ions. Microbiological kinetics
of chloramphenicol analogues was quantified and shelf life predicted 1739174. In a recent study on effect
of p H on degradation the reaation was found to follow two paths, vie.; oxidation to p-nitrobenzaldehyde,
and reduction to arylamine175-179.
Stability oStzcd!ieson other Antibiotics
3
Stability kinetics of cycloheximide in pharmaceutically useful pH range and temperaturel80, and
degradation. of lin~omycin~~l
in acid medium were reported; see als018~J83..Garrett et al.ls4 studied the
kinetics of effect of erythromycin on lincomycin. Seydells6 found the acid catalyzed hydrolysis of
rifampicin in 0.1 N HCl to be pseudo first, order reaction. The conversion of cephaloglycine esters to
cephaloglycine at pH 7.45 and 37' was studried by 'Binderup186. OesterlingI83 studied the kinetics and
mechanism of aqueous solution degradation of clindamycin and its derivatives in buffered solution. Stability studies on streptorny~in~~7-~8~,
nystatinlgO-lg3, and gramacidinlg4 have bekn reported. Stability studies of other antibiotics, have also been reported by various authors196-206.
\
STABILITY
KINETICS
OF
MISCELLANEOUS
DRUGS
8alicylic Acid Derivatives
Much work has been reported on the stability of aspirin and other salicylic acid derivatives e.g., p-aminosalicylic acid. Fundamental kinetics of aspirin and its solvolysis to salicylic acid was completely studied
by Edwardsao7;specific ac:d base catalysis and a pH independent solvolysis was shown; the rate constants
of hydrogen ion and hydroxyl ion catalyzed reactions varied with the nature of the charge on the molecule.
Garrett208,209 constructed log k-pH profile for the solvolysis of acetyl salicylic acids. Effect of various
tales on acetyl salicylic acid stability as studied by accelerated temperature and hUmidity21G217.
Arrhenius plot for aspirin decomposition in polyethylene glycols at 4,27,45 and '60°C, wae evaluated
by fluorescence measurements43t 2l7-223 , Solid state dtwomposit.ion of benzoic acid derivatives has recently
.
been reported2a4
.
Degradation of PAS acid takes place via decarboxylation the kinetics is pH depeadent, by apparent
attack of hydrdxide ion on the anion225-228, the product is m-aminophenol, the oxidation product6
giving rise to a brown coloration. Decomposition of PAS in solution was found to be of first order while
that of sodium PAS was of zero order"grJ2.
Barbituric Acid Derivatives
The barbiturates are attacked by hydcoxyl ions, the ring being destroyed23S234. Prediction of stability of he no barbital sodium in water, applying the Arrhenius equation to apparent first order rate coqstants obtained a t higher temperat~res23~,
and of ally1 barbituric acids was shown23G-2(3.
Epinephrine
,
,-
The rawmisation of epinephrine in acidic solution is specific hydrogen ion catalyzed. Degradation
kinetics of epinephrine in solution by molecular oxyvgenzi4, and its stabilization by chelation of catechol
nucleue with boric acid245and glutimide2" were studied. Por racemization of the drug in acidic solutions the
log ];--pH profile was found to be linear247 and the data could be used for prediction upto pH 4; see also248-256.
Shbility of this drug in parenteral solutions256 and in tablets containing aspirin257 %havealso been
reported.
L
Arnines and Esters Containing Amino Group
I
Solvolysis of procaine leads to the formation of p-aminobenzoic acid and diethyl aminoethanol258-259
and seems to depend on the hydroxyl ion concentrafion, in the various p H ranges. Accelerated stability
predictions on this drug were conducted by Arancibia et ~1.2~O,
using Arrhenius relation; see also 2fl-nO.
Rates of hydrolysis of benzocaine in cetrimide solutions271and of procaine under different pH and
temperature272 have been calculated.
Among studies on other amines mentioned h a y be made of work on a-chyrnotrypsin27s, chloramine-T
in acid solution 274, chloropyramine274, methionine275; see
Kinetics of solvolysis of urea by Welle~~~O
in concentrated aqueous solution a t 25, 35 and 45°C was
followed by conductometry in another series of experiments. Garrett281 constructed log &-pH profile
and Arrhefius parameters by polarographic and colorimetric assays, solvolysis was catalyzed by hydrogen
ion, hydroxyl ion, solvent and buffer; the maximum stability was demonstrated a t a pH of 4.0.
Similarly stability of phenyl butazone278.2823283 in suppository bases and aminophenaeone279,28&286 in
aqueous solution has been studied; for the former it was found to be dependent on the vehicle used.
Amides and Imides, etc.
-
-
-.
\
Hydrolysis of various amides in both acid and base have been reported, acid hydrolysis having higher
activatioli energy than alkaline h y d ~ o l y s i sFor
~ ~ ~N-acetyl
~ ~ ~ ~ .p-aminophenyl, the overall rate was found
to be due to the catalytic effects of both hydrogen and hydroxyl ions289. Degradation kinetics of glutethimide an,d sodium sulpha~etimide2~~-~~3
were evaluated. Hallzg4 studied the possible reaction9 of
buffered with carboxylic acids; mechanism of degradation of succinamide and other amides and
esters were s t ~ d i e d 2 9 0 ~ 2 9 2 ~ 2 9 5 ~ ~ 9 6111
~~~
6.
another
work stability of cardenolide was investigated by
Lutum$ki291. Garrett et
have studied the stability of N-butyl formamide to acid and enzymic
. ~ ~the~kinetics of hydrolysis of acetaminophen precursors
hydrolysis. Recently, Rattie ed ~ 1investigated
in aqueous buffers; stability of an@otensinamide298,phenoxy-ben~amine~~~
and tolbutamide300was also
reported.
A m o q the aldoximes of the~itrogencontaining compounds work of E h et ~1.~01
and Bernascdni~8
may be mentioned. Chin et al.30Sevaluated comparative hydrolytic rates of thiouracils in acidic and
line medium. Recently Garrett and TsauS04 investigated the solvolysis of cytodine and cytosine to uridine
and uracil, respectively a t all pH values. Kingtics of sydnonimine derivativesSo5, aeetidinoneS8oq
sydnones307 and imidazalidinoness08, have been reported,
Alkaloids and Similar Compounlts
Solvolysis of compounds such as scopo1:amine methylbromide, atropine methylbromide, acetylcholine
chloride, etc., catalysed by hydroxyl ion were studied by Moffet and Garrett309 in alcohol water system a t
96°C; see also310-"5. Accelerated stability study of atropine sulphate over wide range of p H values by
Struhar et ~1.316 and a t elevated temperatures by Simon et a1.a' were done ; see ~2~0318~319.
Hydrolysis of
pilooarpine solution was found to be catalysed both by hydrogen and hydroxyl ions320-322.
I n such cases as atropine where the reaction is different in acidic and alkaline medium, the rate coastant for the hydroxyl ion is Beater when the attack is on the oppositely charged species, i.e., protonated
atropine than when the attack is on the neutral species i.e., unprotonated atropine.
~ ~ ~ been reported. Kirretics
Kinetic parameters for m0rphine"23.3~4apomorphineSz5,d i a m ~ r p h i n ehave
of effect of 10 metal ions on second order auto-oxidation of aqueous papavarine hydrochloride was
studied, the most promi~entbeing for copper bivalent i0nS32~>328.Kinetics of dihydroergotaminemethane-suphonate a t a wide range of pH329 and quinidine sulphate decomposition in aqueous solution3a)
have been reported. Stability of tecamine 331 and taurinophenetidineB2was recently studied; see ~1~0333.3~4
.
,
J
Amongst other alkaloids mention may be made of dpdy on adiphenine and cycloadiphenine335 and
colchicine and related tropolone methyl deri~atives33~>~~~,
decomposition of rneperidine hydrochloride 33s
and idoxyridine339 hydrolysis of khellin340, ergonovine maleates41 and various .quaternary nitrogen
compounds342,343.
Stability kinetics for solutions of aqueous succinyl choline chloride by S u z ~ k i and
~ ~ *recently for acetylcholinesterase inhibition by atropine345and for acetylcholines in acidic and basic splution in presence of
borate buffer were reported346. Recently photoreaction of reserpine in parenteral solutions" and in
stability of atropine and chlorampheniool in aqueous solution have been reported; see alsd48.
Chlorpromaxineand Phenothiazines, etc.
-ties
of photodegradation of chlorpromazine with pH variation m s found to be of zero order by
F(dmeister And Dische9. In a study by Huang and Sandss50, U.V. light catalyzed degradation under
anaerobic conditions was found to be different from aerobic conditions; see also351. Kinetic parameters
were calculated for decomposition of chlorthiazide and its decomposition products and for isoniazid362-360:
l , ~ benzothiadia~~
Effects of pH arid light on the decomposition of several p h e n ~ t h i a z i n e d ~and
zines363 haw recently been studied. Among studies reported on the other azines, hydrolysis of 9-methyl isoalloxazine by Wadke et ~1.364and kinetics of decomposition of a piperazine derivative365 and propionyethyl piperazine derivativ'esss may be mentioned.
Sdfathiazole and Pyrazole Derivatives
In a study of Kostolowska elal.366colour change of aqueous solution of sodium sulphathiazole was
found due tci degradation; kinetics of polymorphic transformation of this compound was followed by
calorimetry by Shamo et ~ 1 .Stability
~ ~ ~ and
. mechanism of a aminopyrazolone compound368 degradation
and alkaline stability of another pyrazolol were reporteda9, the latter being followed spectr~photom~tritally; see ~''~0870. '
Hormones and Steroids
Kinetics of stability prediction has been attempted for many of the steroids and hormones; insulin
stability was predicted by Krogh and H e m n a i n & ~ othe
n ~ ~degradation
~
being apparent first order initially
and half life, for example, in water at 30" was evaluated to be 2 years. Many of the steroids llndergo
photolytic, oxidative or solvolytic degradation.
,
For anterior pituitary growth hormone, the stability appears to be dependent on mode ofproparationWs73. Rates of oxidative destruction and alkali sapo~ificationof some steroidal eskrs were
calculated by Pesez et ~ 1 . Study
~ ~ ~of .factors influencing the stability of prednisolone in agueous solutions75
and that of fluprednisolone acetate aqueous solutiona76by accelerated study were reported; subsKquept
experiments at ambient temperatures also confirmed*the predicted stability. Recently the hydrolytic
behavioyr of corticosteroid derivatives was studied by Yamamuto et ~1.3'~;see aZs0378-38a.
DIP. SOI.J., VOL.26, OCTOB~R
1976
\
Enzymes
Recently acylation of co-enzyme A and pH rate profile for reaction of succinic anhydride with cysteine
have been studied3s3. In another study programme for predicting degradation of lyophilized co-enzyme
Bla was presented384.Kinetics of degradation of amylase in aqueous solution at three pH values385and of
acetylcholinesterase inhibition by atropine 386 have been reported. In another study pH effwt of trypsin
catalysis of an ester was
_
Acids and Esters
Shahass studied the reactions of cxclic acid anhydrides in aqueous solution to understand prediction of
pathways of decomposition. Auto-oxidation of sorbic acid in citric acid was found to be accelerated by
very low concentrations but inhibition by high concentrations of ferric and cupric ions. Stability kinetics
studies on aminoethylesters of phenyl acetic
have been reported; see also395,396.First
order base catalyzed addition reaction of diethyl phosphonate was followed spectrophotometrically by
Hopkins396. Carstensen and Muna397have recently studied decomposition of benzoic acid derivatives in
solid state. Acid catalyzed hydrolysis of sodium dodecyl sulphate and effect of 1-hexadecanol on the
hydrolysis was reported by Barry and S h ~ t t o n ~ ~ ~ .
Sugars
Thermal degradation of glucose exhibited general acid base catalysissg9; the kinetics of degradation
in acid solution were also followed by the initial rate of formation of 6-hydroxymethylfurfural, the
degradation product of gl~cose40~.Accelerated storage tests on 5% glucose and glucose saline sdution have
been conducted in this laboratory by following the formation of 5-hydroxymethylfurfural and Arrhenius
parameters were calculated; however, the high temperature data could not be used to predict storage a t
lower ambient temperature, and pH effect cannot be ruled out (Mitra and Chatterjee, unpublished work).
s
,
The specific rate and other data have been evaluated for the reversible reaction between glucuronoe
lactone and glucuronic acid40'. I n mildly acidic solution, 2-deoxyribose degraded to give a chromdphor' with
a characteristic a b s o r p t i ~ at
n ~261
~ ~nm.
~ ~Alkaline
~~
hydrolysis of sugar404 and rate of inversiou
of sucrose in aqueous solutions of strongly dissociated acid@ have been described ; see also20~21.
Validity of theory and advantages of non isothermal stability method for prediction at any desired temperature for sucrose inversion was brought
In another study acid degradation of aldopentoses to furfural and then further degradation of furfural was found to be a first order reaction with respect to acid and
~ ~studied the h s t order kinetics of hydrolysis of monosterin in
pentose concentration4O7. A r m s t r ~ n @has
aqueous media, the reaction found to decrease with a decrease in the pH. Stability of reconstituted drugs and
intravenous fluids409and that of dextran after prolonged storage410 have been studied. Similar studies on
catalyzed hydrolysis of glyc0sider;41~and fnechanism of hydrolysis of cytosine arabinoside in aqueous
buffer412 were reported.
Miscellaneous Drugs
I n this section various other drugs not covered earlier, have been reported. In a study benzoyl perwas attem$ted. For ecothiophate iodide two pathway&'for degradaoxide stability in phakmaceutical~413
&on depending on p H were found. Kinetics of 4-aminoethane sulphonyl-amino-antippine in differentpH
values414, a sulphone derivative415,stability of levamisole aqueous solution416, and alcoholic fezatione
solution have been p~esented.
Degradation of sodium bisulphite in dextrose solution was investigated by Schumacher and Hull417.
Studies on h;ydrolysis of antioxidants such as paraben418 and chlorobukan01~~~
have been reported. The
hydrolysis of latter was affected by surface active agents but not by polyethylene glycols. Similarly oxi~ " Guth et ~1.~21.
dation reactions of white lotion, paraffin and linoleic acid have been studied by R h ~ d e s ~and
Effect of antioxidants on the stability of hydrated and anhydrous ointment bases was studied by Wisniewski
and Golucki422. I n another investigation stability study of certified dyes was reported by Goodhart et ~1.4~3,
the reaction being followed oolorimetrically; stability of dyes with gelatin was repofled in another paper
by V a l e i r a ~ ~ ~ ~ .
Conclusions and Recommendations
Prediction of shelf life from accelerated studiei has been placed on a quantitative basis by the application of fundamental physico-chemicalprinciplesld. A great volume of literatwe has accumulated sh~wing
K ~ ~ E R E ~ H: Storage
T H A f%bili&y @ubiii C I DGgs
~
"and Pharmaceuticals
the eBcmy of the kinetic method, the short term data bsng oomparabk with long period aata6-13.,
The tmhnique is useful for predicting the physical stability of a new pharmaceutical product during
de~elopment28-~~.
The parameters codd be fed into a computerized unit for-still quicker preZifion~~~5~4a6.
However, for a fairly moderate size manufaoturing research unit, it s h i l d be possibIe td make use of the
~ . a country'like ours with Varying conditions of
empirical procedure enunciated by K e n , n ~ n ~-In
climate ranging from hot and humid to extreme cold and dry, it is imperative on the part'of the drugs man_ufacturers in the country to evolve out stability patterns vis-a-visclimatic/weather cdnditiods. Needbsa to
say this will be in their interest and as such they could modify their production ta<g&s depehding upon)
shelf life pattern round the year or at different areaslzones of such a, vast country.
ACKNOWLEDGEMENTB
The author is extremely grateful to Dr. A. IZ, Chatterjee, Assistant Director and Dr. P.K. Ramachandran, Director, Defence Research and Development Establishment, Gwaliof, for their upeful'suggestions
.
and guidance and enoouragement without which this pzper would not have been possible,
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K n ~ s a ~ E 3 a r r :r Btortge
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Stability Studies on Drugs and Phermeoeutioals
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7
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D E SCI.
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1976
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172. REMZERS,
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174. OLMS, B. & FUERTI~,
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179. GUILLOT,
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180. NOTARI,
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dc
. . .. *
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183. OESTERLING,
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w -a+--*-e-*.s*
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*
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199. GARRETT,E. R. & SCHOEDER,W.,
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202. GARRETT,
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151.
152.
153.
154.
153.
156.
157.
158.
159.
160.
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KWLSERE!S~E~:
Storage Stabiw Sttrdies on, Drugs and Pharmaoeutioals
207. EDWARDS,
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212. PARROTT,
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224. CARBTENSEN,
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241. LARSEN,5, & JENJEN,
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DEE. 801. J., VOL.26, OCTOBER
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r
i
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K U L S H ~ ~ P S:~ Storage
T E A Stability Studies on Drugs and Pharma~euticul~
316.
317.
318.
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374. P ~ S E Z ,M. & BARTOS,6.Atan. Pharm. Franc., 20 (1962), 60.
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375. OESTERLINU,
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376. JENSEN,E. H. & LAMB,D. J., J, Pharm. Sci., 53 (1964), 402. "
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*;
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