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Degradation kinetics

Degradation kinetics

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Degradation kinetics

  1. 1. Presented By: Anvita Jadhav M. Pharm (IP) 1
  2. 2. DRUG STABILITY  Drug stability means the ability of the pharmaceutical dosage form to maintain the physical, chemical, therapeutic and microbial properties during the time of storage and usage by the patient. 2
  3. 3. CRITERIA FOR ACCEPTABLE LEVELS OF STABILITY Type of Stability Conditions maintained throughout the shelf life of the drug product Chemical Each active ingredient retains its chemical integrity and labeled potency within the specified limits. Physical The original physical properties, including appearance, palatability, uniformity, dissolution, & suspendability are retained. Microbiologic Sterility or resistance to microbial growth is retained according to the specified requirements. Antimicrobial agents retain effectiveness within specified limits. Therapeutic The therapeutic effect remains unchanged. Toxicologic No significant increase in toxicity occurs. 3
  4. 4. IMPORTANCE OF DEGRADATION KINETICS  Development of optimum formulation (preformulation studies)  Determine the optimum storage conditions (temperature, light, humidity)  Selecting the proper container for dispensing (glass or plastic, clear or opaque, cap liners)  Predicting the shelf life of the drug  Anticipating drug excipient interactions.  Stabilization of the drugs against degradation 4
  5. 5.  Degradative reactions in pharmaceutical formulations take place at definite rates & are chemical in nature.  Degradation kinetics aims to predict the intrinsic stability of a drug in order to anticipate problems that may arise during development 5
  6. 6. RATE & ORDER OF REACTION  According to the law of mass action:  The rate of a chemical reaction is proportional to the product of molar concentrations of the reactants each raised to a power equal to the number of molecules of the substance undergoing reaction.  aA + bB + ….. Product  The velocity at which a reactant or a product undergoes chemical change is called the rate of a reaction. The rate, velocity or speed of a reaction is given by the expression where dc is increase or decrease of concentration over a time interval dt. 6 ,
  7. 7. ORDER OF REACTION  The order of reaction is defined as the manner in which the rate of a reaction varies with the concentration of reactants. The overall order is the sum of the exponents of concentration terms that afford a linear plot.  For above reaction, order of reaction = a + b 7
  8. 8.  Zero order reaction  First order reaction  Second order reaction  Pseudo order reaction 8 Pseudo zero order reaction Pseudo first order reaction ORDER OF REACTION
  9. 9. ZERO ORDER REACTION  The rate of the reaction doesn't depend on concentration of the reagent(s).  The rate expression for chemical reaction, A B  Rate of reaction = - d[C]/dt = k where, [C] indicates decreasing concentration of reagent & k indicates rate constant.  Integrating of rate equation between initial concentration Ao at t = 0 & At, concentration after t = t we obtain, 9
  10. 10.  The initial concentration corresponding to Co is ordinarily written as ‘a’ & concentration remaining at time ‘t’ as ‘x’. When this linear equation is plotted with x on vertical axis against t on horizontal axis, the slope of the line is equal to – k. 10 Concentration Time Slope = – k
  11. 11. FIRST ORDER REACTION  Rate of the reaction depends on concentration of any one reagent.  The rate expression for chemical reaction, A B  Rate of reaction =  Integrating above rate equation between initial concentration Co at t = 0 & Ct, concentration after t=t, we obtain, 11
  12. 12.  The initial concentration corresponding to Co is ordinarily written as ‘a’ & concentration remaining at time ‘t’ as ‘x’. When this linear equation is plotted with ‘log Ct’ on vertical axis against ‘t’ on horizontal axis, the slope of the line is equal to 12 Time Slope = – kt/2.303 logCt
  13. 13. SECOND ORDER REACTION  The rate of the reaction depends upon concentration of two reactants.  There are two cases,  Case 1: when the initial concentrations of A & B are identical or two molecules of the same reactant are involved in the reaction. A + B products or 2A products  Where, a = initial concentration of the reactant or reactants and x = concentration of the reactant changed in time t. 13
  14. 14. Integrating rate equation between initial concentration ‘a’ at t = 0 & (a-x), concentration after t = t, we obtain,  Case 2: When the initial concentrations of the two reactants are different, i.e., A + B products  Assume the initial concentration of two reactants to be a & b  Integrating above equation,  (a - x) and (b - x) are the concentrations of A and B after time interval, t. 14
  15. 15. PSEUDO ORDER REACTION  Originally of higher order but made to behave like lower order reaction 1. Pseudo zero order reaction: In the solid state, many drugs decompose according to pseudo zero order rates as reactions. It frequently occur in drugs formulated as pharmaceutical suspensions. 2. Pseudo first order reaction: It can be defined as a second order reaction that is made to behave like a first order reaction. 15
  16. 16. DEGRADATION PATHWAYS 16 Hydrolysis Oxidation-Reduction Photolysis Racemization
  17. 17. HYDROLYSIS  Many pharmaceuticals contain ester or amide functional groups, which may undergo hydrolysis in solution.  Examples of drugs that tend to undergo hydrolytic cleavage of an ester or amide linkage are anesthetics, antibiotics, vitamins, & barbiturates. 17
  18. 18. 1. ESTER HYDROLYSIS  The hydrolysis of an ester into a mixture of an acid & alcohol essentially involves the rupture of a covalent linkage between a carbon atom & an oxygen atom.  The alkaline hydrolysis of an ester is irreversible where as acid hydrolysis of an ester is reversible.  The general form of the kinetic equations to express acid or base-catalyzed hydrolysis is as follows: 18
  19. 19.  This is done by keeping the OH- or H- at a considerably higher concentration than the ester concentration or by keeping constant through the use of buffers. This would cause the previous equation reduce to:  Whenever possible, first order kinetics expression have been employed in the study of the degradation of drugs by ester hydrolysis, but at times, second order kinetics expression have been employed. 19
  20. 20. 2. AMIDE HYDROLYSIS  Amides are relatively stable than esters.  Pharmaceuticals such as niacinamide, phenethicillin, barbiturates, & chloramphenicol degrade by amide hydrolysis. 20
  21. 21. 3. RING ALTERATION  A hydrolytic reaction can proceed as a result of ring cleavage with subsequent attack by hydrogen or hydroxyl ion.  Its examples are hydrochlorothiazide, pilocarpine & reserpine. Quite often equilibrium kinetics is associated with such mechanisms. 21
  22. 22. OXIDATION–REDUCTION  The oxidative decomposition of pharmaceutical compounds is responsible for the instability of preparations such as steroids, vitamins, antibiotics, & epinephrine  These reactions are mediated either by free radicals or by molecular oxygen.  Autoxidation is most common form of oxidative decomposition of pharmaceuticals, which involves a free radical chain process. A:B A*+ B*  These radicals are highly unsaturated & readily take electrons from other substances, causing oxidation. 22
  23. 23. FUNCTIONAL GROUP SUSCEPTIBLE TO OXIDATION Functional Group Drugs/Excipients Aldehydes Paraldehyde Amines Clozapine Carboxylic acids Fatty acids Conjugated dienes Vitamin A Ethers Diethyl ether Nitrites Amyl nitrite Phenols Catecholamine, Morphine Thioethers Cholpromazine Thiols dimercaprol 23
  24. 24. PHOTOLYSIS  Photolytic degradation (as it applies to pharmaceutical stability) is the degradation that results from exposure to ultraviolet or visible light in the wavelength range of approximately 300–800 nm.  Photo degradation rates are therefore directly dependent on the amount of incident radiation and on the amount of radiation that is absorbed by the compound or the formulation.  It is important to remember that a compound may undergo photolytic degradation even if it does not itself absorb radiation in the UVA or visible region. 24
  25. 25. o If the molecules absorbing the radiation take part themselves in the main reaction, the reaction is said to be photochemical. o Where the absorbing molecules do not themselves participate directly in the reaction, but pass on their energy to other molecules that do, the absorbing substance is said to be a photosensitizer. o The photodegradation of chlorpromazine through a semiquinone free- radical intermediate follows zero order kinetics. o Alcoholic solutions of hydrocortisone, prednisolone, & methylprednisolone degrade by reactions following first-order kinetics. 25
  26. 26. RACEMIZATION  An optically active substance loses its optical activity without changing its chemical composition  In general, undergo degradation in accordance with first order kinetic principles 26
  27. 27. SHELF LIFE  It can be defined as the period of time during which a pharmaceutical product, if stored correctly, is expected to comply with the specification as determined by stability studies on a number of batches of the product.  The shelf life is used to establish the expiry date of a batch. The shelf-life is the time required for 10% of the material to disappear; it is the time at which concentration has decreased to 90% of its original concentration. Zero order First order 27
  28. 28. Q10 METHOD OF SHELF LIFE ESTIMATION  Q∆T is a factor used to estimate the change in the reaction rate constant with changes in temperature, ∆T. Ea is activation energy established for a reaction. 28 Ea kcal/mole Q5 25o-30o C Q10 25o-35o C Q15 25o-40o C 10 1.32 1.73 2.24 15 1.52 2.27 3.36 20 1.75 2.99 5.04 25 2.01 3.93 7.55 Change in reaction rate constants due to the temperature effects
  29. 29.  The Q10 approach, based on Ea, which is independent of reaction order, is described as  In usable terms, Q10, the ratio of two different reaction rate constants, is defined thus The equation for Q10 shelf life estimates is Where, is the estimated shelf life, is the given shelf life at a given temperature, and ∆T is the difference in the temperatures T1 and T2. 29
  30. 30. ARRHENIUS EQUATION  Arrhenius observed that most reaction rates depend on the following three factors A. Fraction of molecules possessing energy of activation (Ea) or greater B. number of collisions per second C. fraction of molecules having the correct orientation  Arrhenius noted that the increase in reaction rate is not linear with increase in temperature in most reactions. 30
  31. 31.  Svante August Arrhenius (1859–1927) developed a mathematical relationship between k (the rate constant) and Ea (energy of activation).  Therefore, if k is determined experimentally at several temperatures, and ln k vs 1/T is plotted Ea can be calculated from the slope of the plot. 31 Slope = – Ea/R Ink 1/T
  32. 32. 32 Where, k2 & k1 are rate constants at temperature T2 & T1 respectively. The results of Arrhenius analysis can be useful in predicting the impact of changes in storage conditions or climatic zone on expiration dating interval of a given drug-product. In practice, multiple levels of thermal stress are applied to the formulation so that appropriate shelf-life estimates can be made for normally expected marketing conditions. Slope = – Ea/R Ink 1/T
  33. 33. ICH RECOMMENDED EVALUATION  The shelf life of a commercial drug product must be determined in the commercial container closure at the defined storage conditions.  ICH requires at least 12 months stability data at the time of NDA submission.  Most products require at least 24 months to be commercially viable.  The ICH Q1E recommended how the 12 months data may be used to predict long-term stability. 33
  34. 34. CONCLUSION  Degradative reactions (hydrolysis, oxidation- reduction, photolysis, racemization) in pharmaceutical formulations take place at definite rates & are chemical in nature.  Degradation kinetics is important aspect in preformulation studies, determination of the optimum storage conditions, prediction of shelf life, stabilization of the drugs against degradation. 34
  35. 35. REFERENCE:  Lachman/Lieberman’s The Theory and Practice of Industrial Pharmacy, Editors: Roop Khar, SP Vyas, Farhan Ahmad, Gaurav Jain, Chapter 28 Kinetic Principles and Stability Testing, Pg. No. 1036-1072, 2014.  Steven W. Baertschi and Patrick J. Jansen, Chapter 2 Stress Testing: A Predictive Tool, Pharmaceutical Stress Testing (Predicting Drug Degradation), Taylor & Francis Group, LLC, 2005.  Steven W. Baertschi and Karen M. Alsante, Chapter 3 Stress Testing: The Chemistry of Drug Degradation, Pharmaceutical Stress Testing (Predicting Drug Degradation), Taylor & Francis Group, LLC, 2005. 35
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