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Kinetics and drug stability


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Kinetics and drug stability

  2. 2. INTRODUCTION CHEMICAL KINETICS is the study of rate of chemical changes taking place during chemical reactions. As applied to pharmaceutical formulations, this includes a study of the physical and chemical reactions in drugs and dosage forms, factors influencing the rate of these chemical reactions, accelerated stability testing and prediction of shelf life of formulations.
  3. 3. RATE AND ORDER OF REACTIONS The rate of a chemical reaction is defined as the velocity with which a reactant or reactants undergo chemical change. The rate of a reaction can therefore be measured by measuring the change in the concentration of reactant or product in a particular period of time.
  4. 4. ZERO ORDER REACTION  When the rate of reaction is independent of the concentration of reacting species. The reaction is said to be a Zero-order reaction.  The rate of the zero- order reaction is given by: − 𝑑𝐴 𝑑𝑡 = 𝑘
  5. 5. FIRST ORDER REACTION  When the rate of reaction is directly proportional to the first power of the concentration of a single reactant, the reaction is said to be of first order with respect to the single reactant.  The Rate of the First order reaction is given by: − 𝑑𝑐 𝑑𝑡 = 𝑘𝑐
  6. 6. SECOND ORDER REACTION  A reaction is said to be second order if the experimentally determined rate of reaction is proportional either to the second power of the concentration of a single reactant or to the first power of the concentration if the two reactants.  If A + B = Products then, Rate of Reaction is 𝑑𝑥 𝑑𝑡 = (𝑎 − 𝑥)(𝑏 − 𝑥)
  7. 7. PSEUDO FIRST ORDER REACTION In a second order reaction, if the concentration of one reactant is in such large excess that it virtually remains constant, then the rate of change of concentration follows first order. Hydrolysis reactions ( acid or base catalysed )are common examples of pseudo first order reactions.
  8. 8. PSEUDO ZERO ORDER REACTION A compound decomposing in solution exhibits a first order reaction but if more of it is present as insoluble excess, then an equilibrium is maintained between the compound in solution and that in the solid form. The concentration of the compound in solution, thus, remains essentially constant till any of the insoluble drug material remains. Such a reaction is apparent zero or pseudo zero order reaction.
  9. 9. METHODS FOR DETERMINING ORDER OF REACTION  Substitution Method  Graphical Method  Half Life Method
  10. 10. COMPLEX REACTIONS Many chemical reactions encountered in the pharmaceutical field are not simple reactions of the zero, first, second or third order but consists of a combination of two or more reactions. Such reactions are known as complex reactions. Although the overall reaction can be characterised by the order of the intermediate steps, more often, the rate equation is a complicated function involving first, second or third order intermediate steps. Complex reactions may be classified as :-  Reversible Reactions  Parallel or Side Reactions  Consecutive or Series Reactions
  11. 11. FACTORS AFFECTING RATE OF REACTION  Temperature  Light  Solvent  Ionic Strength  Dielectric Constant of Solvent  Catalysis  Surfactants
  12. 12. STABILITY TESTING A study of drug stability and of stability testing techniques is essential for the following main reasons :-  Patient Safety  Drug Activity  Legal Requirement  Bad Image for the Manufacturer  Patient Economy
  13. 13. CAUSES OF INSTABILITY AND THEIR PREVENTION  Hydrolysis  Oxidation  Photolysis  Isomerisation
  14. 14. ACCELERATED STABILITY ANALYSIS Accelerated stability analysis is designed to predict stability and hence shelf life of formulations under normal or recommended storage conditions by carrying out the study under accelerated conditions of temperature, moisture and light.
  15. 15. STABILITY OF SEMI-SOLID DOSAGE FORMS Stability of active ingredients incorporated into ointments or creams often depends upon the nature of ointment or cream base used in formulation. Cream bases being emulsions containing water are more prone to decomposition of drugs which proceeds via hydrolysis. Incorporation of drugs into gel structure frequently leads to a change in their stability. Penicillin G sodium has been shown to undergo increased degradation in hydrogels of various natural and semi- synthetic polymers. In our country coconut oil or cosmetics creams such as cold cream are sometimes used as a diluent for ointments and creams. However, no data is available to indicate whether such dilutions are safe with respect to the stability of the drug.
  16. 16. STABILITY OF SOLID DOSAGE FORMS The decomposition of drugs in solid dosage forms is more complex than that occurring in the pure drug. The situation is more complex in multi-drug dosage forms. The effects of various factors on the stability in solid dosage forms :-  Temperature  Moisture  Chemical Interactions
  17. 17. ICH AND WHO GUIDELINES FOR STABILITY STUDIES ICH GUIDELINE TITLE Q1A(R2) Stability Testing of New Drug Releases and Products (Second Revision) Q1B Stability Testing: Photostability Testing of New Drugs Substances and Products Q1C Stability Testing for New Dosage Forms Q1D Bracketing and Matrixing Designs for Stability Testing of Drug Substances and Products Q1E Evaluation of Stability Data Q1F Stability Data Package for Registration Application in Climatic Zones III and IV