The document discusses drug stability and International Conference on Harmonization (ICH) guidelines for stability testing. It provides details on: 1) Chemical kinetics and reaction order (zero, first, second, pseudo-first order) and how they impact degradation rate calculations. 2) Factors that influence drug stability like temperature, solvent, ionic strength, dielectric constant, and acid/base catalysts. 3) Common degradation pathways like hydrolysis, oxidation, photolysis and methods to prevent or minimize degradation through each pathway. 4) ICH guidelines divide stability testing guidelines into quality, safety, efficacy and multidisciplinary categories to ensure drug quality and efficacy globally.

1. B. PHARM 4TH
SEMESTER
PHYSICAL
PHARMACY-II
DRUG STABILITY
Mr. Subhasish Pramanik
Assistant Professor
Mata Gujri College of Pharmacy
Kishanganj, Bihar

2. DRUG STABILITY
 Chemical Kinetics:
It deals with the rate, velocity or rate of reaction at which chemical reaction occurs.
Rate of Reaction =Change in Conc. of reactant/ time = dc/dt
 Order of reaction:
It is define as the number of concentration terms on which the rate of reaction depend when
determined experimentally.
Zero order of reaction:
When the reaction rate does not depend on the concentration of reacting substance (i.e. rate
depends on zero power of reactant).
[A]0 + [B]0
------------ Product
−
𝑑𝑐
𝑑𝑡
= 𝑘
2
Where,
c is the conc. of reactant
k is Rate constant
initial conc. Co time t0
Final conc. C time t
or, 𝐶𝑜
𝑐
−𝑑𝑐 = 𝑡𝑜
𝑡
𝑑𝑡
or, -c + c0 = kt
or, k =
𝐶0 −𝐶
𝑡
Unit of Zero order reaction: mol. L-1.S-1
Integration both side

3. Half life: (50% degradation)
C=C0/2 and t =t1/2
or , k=Co/2t1/2
or , t1/2 = C0/2k
3
Self life: (10% degradation)
t = t0.9 and c = 0.9c0
or , k =
c0−0.9c0
t0.9
or , k =
0.1c0
t0.9
* Because, rate is independent of
reactant concentration, a graph of the
concentration of any reactant as a
function of time is a straight line with
a slope of −k. The value of k is
negative because the concentration of
the reactant decreases with time.

4. First order of reaction:
When the rate of reaction depends on concentration of one reactant.
[A]1 + [B]0
------------ Product
-
𝒅𝒄
𝒅𝒕
∝ 𝒄
or, -
𝑑𝑐
𝑑𝑡
= kc
or, - 0
𝑐 𝑑𝑐
𝑑𝑡
= 𝑘 0
𝑡
𝑑𝑡
or, -ln c + ln c0 = kt
or, log c0 – log c = kt/2.303
or, log
c0
c
= kt/2.303
4
Where,
c is the conc. of reactant
k is Rate constant
initial conc. Co time t0
Final conc. C time t
Integration both side
Unit of First order reaction: S-1
Half life: (50% degradation)
C=C0/2 and t =t1/2
log
c0
C0/2
= k t1/2 /2.303
or, t1/2 = 0.693/k
Self life: (10% degradation)
t = t0.9 and c = 0.9c0
k =
c0−0.9c0
t0.9
k =
0.1c0
t0.9
* The concentration v/s time graph for a first-order reaction is provided
below. For first-order reactions, the equation log c = -kt/2.303+ log c0 is
similar to that of a straight line (y = mx + c) with slope –k/ 2.303. This
line can be graphically plotted as follows

5. Second order of reaction :
The reaction rate of a chemical reaction in which the rate is proportional to the product of
the concentrations (in moles) of two of the reactants (also called bimolecular kinetics), or to
the square of the molar concentration of the reactant.
i. [A]2 + [B]0
------------ Product
ii. [A]1 + [B]1
------------ Product
If (i) a=b
At time = 0
Initial conc. of [A] = a
Initial conc. of [B] = b
At time t,
x = degradation conc.
degradation conc. of [A] = (a-x)
degradation conc. of [B] = (b-x)
5
𝒅𝒙
𝒅𝒕
= k [A] [B]
or,
𝑑𝑥
𝑑𝑡
= k (a-x)(b-x)
or,
𝑑𝑥
𝑑𝑡
= k (a-x)2 (a-x) = (b-x) [a=b]
or,
𝑑𝑥
(a−x)2
= k dt
or, - 0
𝑥 𝑑𝑥
(a−x)2
= 𝑘 0
𝑡
𝑑𝑡
or,
1
(𝑎−𝑥)
-
1
(𝑎−0)
= k(t-0)
or,
𝑥
𝑎−𝑥 𝑎
= kt
or, k =
𝑥
𝑎𝑡(𝑎−𝑥)
Integration both side
Unit of Second order reaction: L. mol-1. S-1

6. If (ii) a≠b
𝑑𝑥
𝑑𝑡
= k (a-x)(b-x)
Integration both side.
kt =
2.303
(𝑎−𝑏)
log
𝑏(𝑎−𝑥)
𝑎(𝑏−𝑥)
6
Half life: (50% degradation)
Degradation conc. x= a/2
(a-x) = a/2 and t =t1/2
k = 1 / at1/2
or, t1/2 = 1/ak
Self life: (10% degradation)
t = t0.9 and (a-x)= (a - 0.1a) = 0.9a
k =
0.1
0.9 a t0.9
or, k = 0.11/a t0.9

7. Pseudo-First order reaction:
It is defined as a second order reaction that is made to behave like first order
reaction. In case one reactant is present in excessive amount or is maintained
at a constant concentration as compare with other one reactant. E.g.:
Inversion of Sugar.
C12H22O11(SUGAR) + H2O → C6H12O6(GLUCOSE) + C6H12O6(FRUCTOSE)
Water use as solvent and reagent. Concentration of H2O is negligible due to
excess amount of water.
7

8. 1. Temperature
2. Solvent
3. Ionic strength
4. Dielectric constant
5. Specific & general acid base catalyst
8

9.  In order for the rate constants or velocity of degradation to be of use in
formulation of pharmaceutical product, it is necessary to evaluate the
temperature dependency of the reaction.
 The most satisfactory method for expressing the influence of temperature on
reaction velocity is expressed by Arrhenius Equation.
 The constant of integration in the Arrhenius equation is a measure of the
frequency of collisions that can be expected between the reacting molecules for a
given reaction.
9

10.  Log taken both side of the equation.
log 𝑘 = log𝐴 −
𝐸𝑎
2⋅303𝑅𝑇
Log A consider as a Constant. From the equation, a plot of log k vs 1/T yields a slop
equal to (−
𝐸𝑎
2⋅303𝑅
) from which the value of activation energy can be determined.
10

11.  The nature of the solvent can also affect the rate of decomposition of drug. The
relation between rate constant and solubility of reactant and product is given by
 If the polarity of the product > polarity of reactant then reaction rate increases
if the solvent is more polar.
 If the polarity of the product < polarity of reactant than reaction rate increases
if the solvent is less polar.
11

12.  The rate of reaction can be influence by ionic strength of the solution is
accordance with the following equation:
 Plotting the log k versus 𝜇 can determine whether an increases the ionic
strength increases, reduces or has no effect on degradation rate.
 If Similar charge, increase Ionic strength and also increase the degradation rate.
 If opposite charge, increase ionic strength but decrease rate of degradation.
12

13.  The dielectric constant (or relative permittivity) of a solvent is a measure of
its polarity.
 Water has a high dielectric constant 78 and Ethanol has low dielectric
constant 24.
 The equation that describes the effect of the dielectric constant, Ɛ,
𝑙𝑜𝑔𝑘 = 𝑙𝑜𝑔𝑘𝜀=∞ − 𝐾𝑍𝐴𝑍𝐵 ×
1
𝜀
 In case of similar charge, if dielectric constant solvent increase rate of
reaction accelerated.
 In case of opposite charge, if dielectric constant solvent increase the reaction
rate retard. 13

14.  A catalyst is a substance that either increase or decrease the rate of reaction but
itself remain unchanged chemically. The catalyst only make the reaction faster,
it dose not affect the yield of the product.
 There are two types acid-base catalyst
1. General acid-base catalyst and 2. Specific acid-base catalyst.
 Buffer are used to maintain pH of a solution. Buffer salt (i.e. acetate Phosphate,
Borates etc.) show catalytic effects on drug degression rate in solution. The
reaction is said to be general acid catalysis if catalytic component is acidic while
the reaction is said to be General based catalytic if the catalyst compound is
basic.
 The evaluation of general acid or general base catalysis can be done by
determining the decrease rate of that drug in a series of buffers having the same
pH, but they should be prepared with increasing concentration of buffer species.
14

15.  Specific acid-base catalyst:
 The number of drugs become posed on the addition of acid alcohol base. When the
rate law for an accelerated decomposition reaction contains a term involving the
concentration of hydrogen ion or hydroxyl ion, the reaction is called specific acid-
base catalyst.
 The general rate law which express the pH dependency Specific acid-base catalyst
reaction.
𝒅𝒙
𝒅𝒕
= 𝒌𝟎 + 𝒌𝟏 𝑯+ + 𝒌𝟐 𝑶𝑯− [𝑺]
 At low pH, 𝑘1 𝐻+ > 𝑘2 𝑂𝐻− and 𝑘0 because the conc. of hydrogen is high, and
specific acid catalysis is observed.
 At high pH, 𝑘2 𝑂𝐻− > 𝑘1 𝐻+ and 𝑘0 because of presence of high conc. of hydroxyl
ion, and specific base catalysis observed.
15

16. STABILIZATION OF MEDICAL
AGENT AGAINST COMMON
CHEMICAL REACTION
Chemical degradation of dosage form occurs through several pathway like hydrolysis,
oxidation, decarboxylation, photolysis, racemization which may lead to lowering the
therapeutic agent in the dosage form, formation of toxic product, decreased the
bioavailability etc.
A. Hydrolysis:
 Most important in system containing suspension, emulsion, solution etc. Also for drugs,
which are affected by moisture from atmosphere.
 It is usually catalyzed by hydrogen ion (acid) or hydroxyl ion (base).
 Main classes of the drugs that undergo hydrolysis are Ester, Amide, alkali, Acid.
 Ester hydrolysis: R.COOH (Ester) + H20 → RCOOH (Acid) + ROH (Alcohol)
 Amide Hydrolysis: RCONHR (Amide) + H2O → RCOOH + NH2R (Amine)
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17.  Protection against Hydrolysis:
1. Avoiding contact with moisture at time of manufacture.
2. Packaging in suitable moisture resistant packs such as strip pack.
3. Partial or full replacement of water with low dielectric solvent (i.e. ethanol).
4. Change in chemical structure.
5. Use of surfactant ( i.e. Anionic, cationic or non-ionic) decrease the rate of degradation.
6. Hydrolysis of certain drugs such as benzocaine and procaine can be decrease by
addition of complex agent like caffeine to drug solution.
7. Hydrolysis of certain drug (i.e. penicillin and derivatives) can be prevented by
formulating them in dry powder form for reconstitution or dispersible tablet.
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18. B. Oxidation:
 Oxidation is the loss of electrons while reduction is the gain of electrons. Either
the addition of oxygen or removal of hydrogen. Occurs when exposed to
atmospheric oxygen ( Example of drug: Vitamin A, B12; Heparin, Morphine).
 Oxidation is controlled by environment i.e. light, trace element, oxygen and
oxidizing agent.
 Step involved oxidation reaction:
R-H → R + H
R + O2 → R-O2
R-O2 + R-H → ROOH + R
ROOH → RO + OH
 Free radicals react with each other resulting in inactive product.
R-O2+X → inactive product
RO2 + RO2 → inactive product
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19.  Protection against oxidation:
1. Use of Anti-oxidants:
 This group antioxidants react with free radicals inhibit the
oxidation. Ex: Tocopherol, Butylated hydroxyl anisole (BHA)
 This group comprising the reducing agents that protect from
oxidation. Ex: Ascorbic acid, iso-sorbic acid
 This group have little antioxidant effect but enhance the action of
true antioxidant. Ex: Citric acid, Lecithin.
2. Use of Chelating agent when heavy metals catalysed oxidation. Ex:
EDTA, Tartaric acid.
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20. C. Photolysis:
 Exposure to light cause substantial degradation of drug molecule.
 When molecules are exposed to electromagnetic radiation, they absorb light at
characteristics wavelength which cause increase in energy which can :
 Cause decomposition; retained or transferred; be converted to heat; result in light at new
wavelength ( Fluorescence).
 Natural wavelength of sunlight 200 nm – 800 nm. Higher energy of UV ( 200 – 400 nm)
cause photo degradation of drug.
 Example: Sodium nitroprusside in aqueous solution (Which is administered by IV infusion
for management acute hypertension). If protected from light it is stable for one year. But if
exposed to normal light it shelf life decrease at 4 hrs.
Protection:
1. Use of amber coloured bottles.
2. Storing the product in dark, packaging in cartons also act as physical barrier to light.
3. Coating of tablets with polymer films.
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21. ICH GUIDELINES (FOR
STABILITY TESTING)
 ICH stands for ‘International Conference on Harmonization’.
 ICH is a joint initiative involving both regulators and research based industry
representative of the European Union, Japan and USA in scientific and technical
discussion of the testing procedure and ensure the quality and efficacy of the
medicines.
 ICH process founded in April 1990. Officially ICH established on 23rd October
2015.
Objectives:
1. Ensure the quality and efficacy of the medicine.
2. To promote public health, prevent duplication of clinical trials in human
3. To developed pharmaceutical in most efficient and cost effective manner.
4. Minimize the use of animal testing
5. To harmonize technical requirement for marketing approval.
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22.  ICH guideline are divided into 4 major parts. These are Q-Quality, S-
Safety, E-Efficacy and M-Multidisciplinary
 Quality: It is relating to chemical and Pharmaceutical quality
assurance (i.e. Stability testing, Impurities testing etc.).
 Efficacy: It is relating to clinical studies in human subject (i.e. Dose
Response Studies, Good Clinical Practices etc.).
 Safety: It is relating to in vitro and in-vivo pre-clinical studies
(Carcinogenicity testing, genotoxicity testing etc.).
 Multidisciplinary: Cross-cutting topic which is not relating with above
categories.
22

23. 23
 Q1: Stability
 Q2: Analytical Validation
 Q3: Impurities
 Q4: Pharmacopoeias
 Q5: Quality of biotechnology product
 Q6: Specification
 Q7: Good Manufacturing Practices
 Q8: Pharmaceutical development
 Q9: Quality Risk Management (QRM)
 Q10: Pharmaceutical Quality system
 Q11: Development and manufacturing of
drug substance
 Q12: Lifecycle Management
 Q13: Continuous manufacturing of drug
substance
 Q14: Analytical procedure development
Class of Quality (Q)

24. CLIMATIC ZONES WITH THEIR TEMPERATURE
& RELATIVE HUMIDITY
Zone Description Climatic Condition Countries
Zone I Moderate temperature 21° C/45% RH
Britain, N. Europe, Canada,
Russia
Zone II
Subtropical &
Mediterranean
25° C/ 60% RH USA, Japan, S. Europe
Zone III Hot and Dry 30° C/ 35% RH Iran, Iraq, Sudan
Zone IV Hot and Humid 30° C/ 70% RH
Brazil, India, Ghana, Indonesia,
Philippines
24
STABILITY STUDIES STORAGE CONDITION
Stability Studies Types Storage Condition Period of times
Long term stability studies
25° C/ 60% RH 12 months
30° C/ 65% RH 6 months
Refrigerator 5 °C; Freeze -20° C 12 months
Intermediate stability studies 30° C/ 65% RH 6 months
Accelerated stability study 40° C/ 75% RH 6 months

25.  Stability study to predict the shelf life of the product by accelerating the rate of
decomposition, preferably by increasing temperature of reaction.
 These are experimental designs.
 Arrhenius equation explain the effect of temperature on the rate of reaction.
 According to Arrhenius, with every 10° C rise in temperature, the rate of reaction
increases by 2-3 times.
 Methodology of Accelerated Stability for prediction shelf life:
1. Drug liquid preparation are stored at elevated temperature i.e. 40, 50,60,70,85,
100 & 121 °C.
2. During different time intervals, samples are withdrawn ( 0, 3, 6 months)
25

26. 3. The order of reaction is determined by plotting the conc. against time and
calculate the K value from the slope.
4. By using Arrhenius equation, log k values are plotted against reciprocal of
temperature.
5. The plot is extrapolated to room temperature, 25 °C to determine k value. This
k value is substituted into shelf life equation to determine shelf life of product.
26

27. 1. This studies are only valid when the breakdown depend on temperature.
2. This method is not used in case of complex reaction.
3. This method is valid only if the energy of activation between 11-30 Kcal/Mole.
4. The product which loose their physical integrity at elevated temperature is not
suitable for accelerated testing.
5. This method is not valid when order changes at higher temperature.
27