Factors affecting drug stability include temperature, pH, buffering species, ionic strength, and dielectric constant. Temperature is an important factor because most reactions proceed faster at higher temperatures according to the Arrhenius equation. pH also affects stability, with most drugs being stable between pH 4-8, as hydrogen and hydroxide ions can catalyze degradation reactions. Buffering species like hydrogen and hydroxide ions participate in formation and breakdown of reaction intermediates. Ionic strength influences rates of reactions between ionic species, while dielectric constant affects rates of ion-dipole and ion-ion reactions. These physicochemical factors must be considered in stability testing and shelf life determination of pharmaceutical products.

1. FACTORS AFFECTING STABLITY
Advanced Pharmaceutical Analysis
MEHUL H JAIN
M. Pharmacy I-I
Pharmaceutical Analysis

2. DRUG STABILITY
Definition:
Drug stability means the ability of pharmaceutical dosage
form to maintain the physical, chemical, therapeutic & microbial
properties during the time of storage & usage by patients.

3. Stability testing is used to:
• Provide evidence as to how the quality of the drug product
varies with time.
• Establish shelf life for the drug product.
• Determine recommended storage conditions.
• Determine container closure system suitability.

4. Factors Affecting Drug Stability
Temperature
pH
Buffering Species
Ionic Strength
Dielectric Constant

5. TEMPERATURE
Temperature is an important parameter because most reactions proceed faster at
elevated temperatures than at lower temperatures.
Arrhenius equation, k = Ae-Ea/RT
In Logarithm form, Log K= log A – (Ea/2.303 RT)
Where K = specific rate constant; A = frequency factor or Arrhenius factor; Ea =
energy of activation; R = Ideal gas constant; T = absolute temp.
According to Arrhenius, for every 10º rise in temperature, the speed of reaction
increases about 2-3 times.
Storage temperatures:
Room temperature: 30-25ºC
Cold temperature: 2-8ºC
Freeze temperature: -20ºC to -10ºC

6. High temperature can drive moisture out of a sample and render the material
apparently stable.
Example: Insulin is sensitive to temperatures that are too high or too low.
Epimerization of tetracycline:
In aqueous solutions, tetracyclines can undergo reversible isomerization in
which the three-dimensional structure is changed to form 4-epi-tetracycline. Epi-
tetracyclines have less antibacterial activity than the corresponding tetracyclines.
Heparin should be stored at controlled room temperature. It should be
protected from freezing and temperatures >40°C.
Temperature Continued….

7. pH
• Most of the drugs are stable at pH 4-8.
• Catalysis of hydrogen ion and hydroxyl ion occurs at lower pH range and higher
pH range respectively.
• The effect of pH on degradation rate can be explained by the catalytic effects that
hydronium or hydroxide ions can have on various chemical reactions.
• These reactions will also be pH dependent because the fraction of any species
present in its acid or base will dependent on dissociation constant.
• If the pH of a drug solution has to be adjusted to improve solubility and the
resultant pH leads to instability then a way out of this tricky problem is to introduce
a water miscible solvent into the product.
Example: 20% propylene glycol is placed in chlordiazepoxide injection for this
purpose.
• 1 unit change in pH can cause a change of ten fold in rate constant.
• Rate of decomposition is critically dependent upon pH. In the case of acid-base
catalyzed hydrolysis at minimum pH the drug stability is maximum.

8. pH Continued….
• The pH-stability profile is essential for understanding how the compound behaves
in different environments and informs formulation development, process
development, drug product stability and the route of administration of the molecule.
Example: Penicillin G is stable at pH range of 4.0–10.0 and temperature range of 0–
52°C.
Pencillin G Penicillonic acid
• Heparin injection B.P., adjusted to a pH between 7.0 and 8.0, preserved with 0.15%
chlorocresol, is a relatively stable biological product.

9. BUFFERING SPECIES
 These buffer species, like H+ and OH-, participates in formation of break down of
activated complexes of various reaction and determine their reaction rate.
 These catalytic species are referred to as general acid-base catalysts.
 In addition to acting as proto donor or accepter, buffer species can also act as Lewis
acid and base through nucleophilic or electrophilic mechanisms.
 Some buffers such as acetate, citrate, lactate, phosphate and ascorbate buffers are
utilized to prevent drastic change in pH.
Example: Studies with phosphate buffer indicates that it enhance the degradation of
various drug substances such as carbenicillin. Carbenicillin is bactericidal antibiotic.
Doripenem is a new parenteral carbapenem and it is antimicrobial agent. Doripenem
undergoes degradation in acetate buffer (pH 4.23–6.04). Doripenem demonstrates the
greatest stability at approximately in borate buffer pH 6.0.

10. IONIC STRENGTH
For drug degradation involving reactions with or between ionic species, the rate is
affected by the presence of other ionic species such as salts of NaCl.
Ionic strength µ is described by
𝝁 =
𝟏
𝟐
𝒊
𝑪𝒊𝒁𝒊
𝟐
Where, Ci = conc. of ionic species; Zi =electric change.
When an ionic species participates in a reaction as a reactant, the reactivity
coefficients(f), for that species is generally described by ɣ.
Log ɣ=QZ2 µ
Rate constant for a reaction between ionic species depends upon on ionic strength
Log K= log K0 + 2 ZAZBѴ µ
Where, ZA and ZB are the charges of A and B; K0 is constant.

11. Ionic Strength Continued….
As ionic strength increases, the rate of reaction between ions of opposite charge
decreases and the rate of reaction between ions of similar charges increases.
Example: An increase in ionic strength resulted in a decrease in the permeation rate of
tryptamine and an increase in the permeation rate of indoleacetic acid. The changes in
the permeation rate with changes in the ionic strength were correlated with the
membrane surface potential monitored by 1-anilino-8-naphthalenesulfonic acid (ANS),
a fluorescent probe. The compound that showed a relatively lower permeation rate was
given relatively stronger effect.
Norfloxacin is most stable in ionic strength of 0.2 if change is occurred then
degradation takes place.

12. DIELECTRIC CONSTANT
It is a measure of substance ability to insulate charges from each other, it is measure of
solvent polarity.
If dielectric constant of solvent is high then it is more polar.
If the reacting ions are of opposite charges then it will result in increased rate of
reaction. If ions of similar charges involve in reaction it will decrease rate of reaction.
Ion dipole reacting rate constant have been related to dielectric constant D.
Log K= log K D=∞
+ 𝒁𝑨 µ𝒄𝒐𝒔ɵ
𝑫𝒌𝑻𝒓𝟐
Where, K D=∞ is the rate constant at infinite dielectric constant; ZA, u and r are ion
charge, dipole moment and the shortest ion dipole distance, respectively; k is
boltzmann constant. The term ɵ represent the alignment of reactant and cosɵ is unity in
the case on alignment.
Thus as the dielectric constant decrease, the rates of anions - dipole reaction decrease
and the rates of cation dipole reaction increases.

13. Dielectric Constant Continued….
Example: Effect of change in solvent dielectric constant on the degradation rate of
chloramphenicol. The hydrolysis rate constant for chloramphenicol in water propyl
glycol mixture increase with decreasing dielectric constant, suggesting a hydronium ion
dipole reaction, whereas in alkali its anionic form is degraded by hydroxide ions.
The dependence of ion-ion reaction rate constants on dielectric constant of solvent
given by
Log K= log K D=∞
−𝒁𝑨 𝒁𝑩
𝑫𝒌𝑻𝒓
Where, r = ion-ion distance; ZA & ZB are charges of A & B
This equation indicates if dielectric constant decrease, the rate of reaction between ions
of similar charge decreases, the rates of reaction between ions of opposite charge
increases.

14. Dielectric Constant Continued….
Example: In its unionized form, morphine is almost insoluble in water (solubility is
about 0.2 mg/ml) but it is most often used in a salt form such as morphine
hydrochloride (solubility is about 40 mg/ml at room temperature). Morphine has two
pKa values: pKa1 8.2 (protonated amino group) and pKa2 9.9 (phenol) at room
temperature. The oxidative degradation pathway of morphine is rather complex in
which the phenol group and the amino group play important roles When only the
protonization of the amino group is considered, then the equation for kobs is (for pH
levels from 2 to 7).
L-Ascorbic acid (vitamin C) is a water-soluble compound frequently used as an
antioxidant in food products due to its mild reducing properties. Ascorbic acid has two
pKa values: pKa1 4.2 and pKa2 11.6 at room temperature. The rate of oxidative
degradation of ascorbic acid is at its maximum pKa value.

15. REFERNCES
• Stability of drugs and dosage forms: Sumic Yoshioka and Valentino T. Stella.
• Theory and Practice of Industrial Pharmacy by Lachman.
• Aulton’s Pharmaceutics, The Design and Manufacture of medicines.
• J.S Patrick; Martins Physical Pharmacy and Pharmaceutical Sciences.
• Physical Pharmaceutics – CVS Subramanyam.

16. THANK YOU