Kinetics and Drug Stability

Kinetics, Reaction Rates, and Drug Stability

• Kinetics is the study of the rate of chemical change. It involves the rate at which reactants are converted to products, influenced by conditions like reactant concentration, products, other chemical species (e.g., solvents), pressure, and temperature.

Factors Affecting Reaction Rates

• Nature of reactants: A major factor influencing reaction rates.
• Concentration of reactants: Higher reactant concentrations generally lead to faster reaction rates.
• Concentration of catalysts: Catalysts speed up reactions without being consumed.
• Temperature: Higher temperatures typically lead to faster rates.

Drug Stability and Kinetics

• Drug stability is crucial in pharmaceuticals.
• The rate of drug degradation is a key factor in determining shelf life and storage conditions for pharmaceutical products.
• Problems with stability can affect whether a formulation is accepted or rejected.
• Chemical degradation of active ingredients can lead to significant losses.
• Instability of the drug can reduce bioavailability.
• Chemical degradation can create toxic byproducts.

Rates and Orders of Reactions

• Reaction rate (or degradation rate): The velocity at which a reaction occurs.
• Reaction rate is expressed as the ratio of the change in concentration of a reactant (or product) to a change in time. This is often represented as dc/dt.
• The unit of rate is mole/Liter/second (or mol L⁻¹ sec⁻¹).

Order of a Reaction

• The order of a reaction describes how the concentration of a reactant or drug affects the reaction rate.
• The order of a reaction can be determined through experiment; it is not directly apparent from the stoichiometric coefficients in the balanced equation.
• The order (alpha) of a simple A → B reaction can be expressed as rate = α [A]^α.
• The overall order of more complex reactions (e.g., A + B --> C) is the sum of the exponents of the concentration terms (e.g., rate = α [A]^α[B]^β - α + β is the overall order).
• Exponents (a and b) aren't directly related to coefficients in the chemical equation.

Rate Constant (k)

• The rate constant (k) is a numerical expression of the effect of the nature of reactants and temperature on reaction rate.
• k is a proportionality constant

Units of Rate Constants

• The units of the rate constant vary depending on the order of the reaction:
  • For a zero-order reaction: k = mole/L x sec.
  • For a first-order reaction: k = 1/sec.
  • For a second-order reaction: k = L/mole x sec.

Zero-Order Reactions

• In zero-order reactions, the rate of the reaction is constant and independent of the reactant concentrations.
• The equation for zero-order reactions: c= c_o – k_ot.
• This means that the drug concentration decreases linearly over time.
• Half-life is concentration dependent.

First-Order Reactions

• In first-order reactions, the rate of the reaction is proportional to the concentration of a single reactant.
• The equation for first-order reactions is c = c_oe^−kt
  • (c = remaining concentration, c_o= initial concentration, k = reaction rate constant, t = time)
• The graph of the natural log of concentration (ln c) versus time (t) is a straight line.
• The half-life is independent of concentration.

Accelerated Stability Testing

• Accelerated stability testing is a method used to predict drug shelf life by conducting tests at elevated temperatures or conditions.
• The method helps predict the shelf life by calculating rate constants at elevated temperatures, and then extrapolating to the expected storage conditions (room temperature, or other storage temperature).

Catalysis

• Catalysts affect reaction rate without changing chemically.
• Negative catalysts slow down reactions, while inhibitors slow them down and also undergo permanent change.
• Catalysts can speed up reactions by changing the reaction mechanism, hence reducing the activation energy.
• Catalysts can be involved in chain reactions, initiating them via free radicals.

Modes of Pharmaceutical Degradation

• Hydrolysis: The most common mode, hydrolysis is most important with esters and amides. pH influences these reactions, and formulations should be adjusted to optimal pH for stability.
• Oxidation: Substances like ascorbic acid, sodium sulfite/ metabisulfite, and chelating agents can help minimize oxidation reactions.
• Photolysis (Light Degradation): Reactions involving light energy. Photochemical reactions are not dependent on temperature. Photodegradation is NOT a form of catalysis.