PHYSICAL PHARMACY | Chemical Kinetics and Stability

Chemical Kinetics

• The study of the rate or speed of chemical reactions.

• It is important because drugs can degrade over time. Knowing the rate of degradation helps predicts:

  • Drug Stability

  • Expiration Date

  • Shelf-life

  • Storage Conditions

  • Whether the patient still recieves the corect dose

Reaction Rate

The speed of a chemical reaction

Order of Reaction

• The order of reaction describes how drug concentration affects the rate of degradation:

  • Zero Order Reaction

  • First Order Reaction

Zero Order Reaction

• The drug is lost at a constant amount per unit time.

• The rate is independent of drug concentration

• Examples:

  • Warfarin

  • Heparin

  • Alcohol, Aspirin

  • Theophylline

  • Tolbutamide

  • Salicylate

  • Phenytoin

Zero Order Equation

• C_t - C₀ = -kt

• C_t = -kt + C₀

• C_t = C_{0 - kt}

k → is the zero-order rate constant

C₀ → is the initial concentration of the drug

C_t → is the concentration at the time

t → is the time

Zero Order Plot

• A plot of concentration remaining vs time gives a straight line, linear (in regular graphing paper).

  • y-axis → concentration remaining

  • x-axis → time

  • slope → -k

  • y-intercept = C₀

Zero Order Half-Life

• The time required or one-half of the drug to disappear

• t_1/2 or t_0.50

  • t_1/2 = C₀ / 2k₀

Zero Order Kinetics Shelf-life

• The time required for 10% of the drug to disappear, t_0.90

• t_0.90

  • t_0.90 or t_90%= 0.1C₀/ k

First Order Reactions

• The loss of the drug is directly proportional to the concentration remaining with respect to time.

• A constant percentage of fraction of drug is degraded per unit time

• Common for most pharmaceutical products degradation

First Order Equation

C_t = C₀ e^-kt

or

• InC_t - InC₀ = -kt

• InC_t = InC₀ - kt

• logC_t = logC₀ - kt/2.303

  • k → is the first-order rate constant

  • C₀ → is the initial concentration of the drug

  • C_t → is the concentration at the time

  • t → is the time

First Order Plot

• A plot of direct concentration remaining vs time is non liner (in regular graphing paper)

• A plot of log concentration remaining vs time is linear

  • y-axis → log concentration remaining

  • x-axis → time

  • slope = -k/2.303

  • y-intercept - logC₀

First Order Half-Life

t_1/2 = 0.693/k

First Order Shelf-Life

t_0.90 = 0.105/k

Shelf-Life

• The time period during which a drug product is expected to remain within the approved specification for use, provided that it is stored under the conditions defined on the container label.

• The time required for 10% of the material to disappear

Expiration Date

The date place on the concentration label of a drug product designating the time prior to which a batch of the product is expected to remain within the approved shelf-life specification.

Determination of Shelf-Life | Arrhenius Equation

Used to predict temperature stability

Determination of Shelf-Life | Q10 Method

Can estimate the effect of a 10^o rise in temperature on the stability of pharmaceuticals

Evaluation of Stability of Drug Products | Long Term Studies

• Under normal conditions

• Testing Periods: 0, 3 ,6 ,9 ,12 ,15 ,18 ,24 ,36

• Zero Order Kinetics

Evaluation of Stability of Drug Products | Accelerated Studies

• Use exaggerated storage conditions

• Testing Period: 0, 3, 6

• First Order Kinetics

• Passed → 2 years shelf life

Evaluation of Stability of Drug Products | Stress Testing

• Elucidates the intrinsic stability of the drug substance and identify the likely degradation product

• Under more severe conditions

Decomposition and Stabilization of Pharmaceuticals | Hydrolysis

• A chemical bond is split via the addition of water.

• Esters and Amides

• pH buffers, Type of Solvent, Structure modification

Decomposition and Stabilization of Pharmaceuticals | Oxidation

• Transfer of Electrons

• Steroids, Vitamins, Antibiotics

• Low O₂ content, Antioxidants, pH buffers, Type of solvent

Decomposition and Stabilization of Pharmaceuticals | Photolysis

• Absorption of radiant energy in the form of light

• Nifedipine & Hydrocortisone

• Storage Conditions

Antioxidants | True Antioxidants

• Tocopherol (Vitamin E)

• Butylated Hydroxyanisole (BHA)

• Butylated Hydroxytoluene (BHT)

• Alkyl Gallates

Antioxidants | Reducing Agents

• Ascorbic Acid (Vitamin C)

• Sulfates

Antioxidants | Antioxidant Synergist

• EDTA

• Citric Acid

• Tartaric Acid

• Citraconic Acid

• Phosphoric Acid