1. Nahla S Barakat, PhD Professor of Pharmaceutics 8/18/2015 PHR 416 1 Principles and kinetics of drug stability (PHR 416)

2. Course Description: The course deals with different routes of drug degradation principles and kinetics of chemical degradation and stress stability testing. Means of prolonging shelf life of pharmaceutical products are also included. 8/18/2015 PHR 416 2

3. Recommended text books: Martin’s Physical pharmacy & Pharmaceutical Sciences, Fifth Edition, Patrik J. Sinko (ED), Lippincott Williams & Wilkins 2006,( Chapter 15). Modern Pharmaceutics, Fourth Edition, G. S. Banker, C. T, Rhods. Marcl Dekker In., 2002 Physicochemical principles of Pharmacy, Fourth Edition, A.T Florence, D. Attwood, Pharmaceutical Press, 2006, (Chapter 4) Recommended References : US Pharmacopea Stability consideration in dispensing practice 8/18/2015 PHR 416 3

4. This course is a 3 credit hour subject & correspond to 300 marks The marks are divided as follows: 1- Final exam ………………..120 Marks 2- Oral exam ………………… 30 Marks 2- Mid term …………………. 60 Marks 3- Practical…………………... 90 Marks 8/18/2015 PHR 416 4

5. Introduction 8/18/2015 PHR 416 5 Basic requirements of pharmaceutical products Efficacy: Optimum therapeutic level for specified period of time. Safety: Minimum or no side effects. Stability: The products should retain their properties during storage. This should guarantee the efficacy and safety

6. 8/18/2015 PHR 416 6 The USP defines the stability of pharmaceutical product as “extent to which a product retains within specified limits” and throughout its period of storage and use (i.e its shelf life) the same properties and characteristics that it possessed at the time of its manufacturer

7. Stability of drug also can be defined as the time from the date of manufacture and packaging of the formulation until its chemical or predetermined level of labelled potency and its physical characteristics have not changed appreciably. For a drug substance, we need to study 3 categories of stabilities- A. Solid state stability of drug only B. Compatibility studies ( drug+ excipients ) C. Solution phase stability 8/18/2015 PHR 416 7

8. 8/18/2015 PHR 416 8 These stability data involves selected parameters that taken together from the stability profile. Pharmaceutical products are expected to meet their specification for identifying purity, quality and strength throughout their defined storage period at specific storage condition. The stability of pharmaceutical product is investigated throughout the various stages of the development process.

9. Importance of stability studies 8/18/2015 PHR 416 9  Development of optimum formulation (preformulation studies)  Finding 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

10. 8/18/2015 PHR 416 10 In some cases a pharmacist may need to prepare stable compounded preparations from existing dosage form. It is the responsibility of the pharmacist via the information of the manufacture to instruct the patient in the proper storage and handling of the drug product.

11. Factors affecting drug stability: 1. Temperature: high temperature accelerate oxidation, reduction and hydrolysis reaction which lead to drug degradation 2. pH: Acidic and alkaline pH influence the rate of decomposition of most drugs. Many drugs are stable between pH 4 and 8. Weekly acidic and basic drugs show good solubility when they are ionized and they also decompose faster when they are ionized. Sometimes pH can have a very serious effect on decomposition. As little as 1 pH unit change in pH can cause a change of ten fold in rate constant. So when we are formulating a drug into a solution we should carefully prepare a pH – decomposition profile 8/18/2015 11

12. 3. Moisture: a. Water catalyses chemical reactions as oxidation, hydrolysis and reduction reaction b. Water promotes microbial growth 4. Light: affects drug stability through its energy or thermal effect which lead to oxidation 5. Pharmaceutical dosage forms: solid dosage forms are more stable than liquid dosage forms for presence of water. 6. Concentration: rate of drug degradation is constant for the solutions of the same drug with different concentration. So, ratio of degraded part to total amount of drug in diluted solution is bigger than of concentrated solution. 8/18/2015 PHR 416 12

13. 7. Drug incompatibility: reactions between components of pharmaceutical dosage forms it self or between these components and cover of the container. 8. Oxygen: exposure of drug formulations to oxygen affects their stability 8/18/2015 PHR 416 13

14. Expiry date: means that drug can not be used after this date because the concentration of drug is decreased and become lower than therapeutic concentration. In addition, some products of drug degradation are toxic and harmful to patients. NOTE: The expiration date period should begin at the time of manufacture of the lot. PRODUCT TYPE MAX. TIME PERIOD Dosage forms: 5 years Implants, injectables, tablets, capsules, soluble powders, etc. Note! After the opening of the drug container, the expiry date will be shorter as a result of the decreased concentration of drug during usage and the effects of external factors. : 8/18/2015 14

15. Examples: 1. Eye drops: can be used for one month after opening the droppers 2. Syrups and suspension of antibiotics: can be used for one week by storage in room temperature and for two weeks by storage in 4C°. 3. Tablets and capsules remain stable in the package but after removal the expiry date will change 4. Ampoules: must be used immediately but the vials (multidose) are stable for 24 h for the presence of preservatives. 8/18/2015 PHR 416 15

16. Five stabilities of drug must be considered:: 1. Physical 2. Chemical 3. Microbiological 4. Toxicological 5. Therapeutic 8/18/2015 PHR 416 16

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18. Reaction kinetics: 8/18/2015 PHR 416 18 “kinetic” originates fromGreek “kinetikos” that, in turn, originates from Greek “kinetos’ which means “moving”. Kinetics: It is the study of how a system changes as function of time. Reaction kinetics: It is the study of rate of chemical change and the way in which this rate is influenced by conditions of concentration of reactants and products, solvent, ionic strength and temperature

19. Rate and order of reactions 8/18/2015 PHR 416 19 Importance of the rate process:  For drug manufacturer as he must demonstrate that his product is stable and can be stored for reasonable length of time without changing to inactive or toxic form.  The pharmacist must be aware of potential instability of the drug that he handles.  The physician and the patient must be assured that the prescribed drug will reach the site of action in sufficient concentration.

20. Rate and order of reactions 8/18/2015 PHR 416 20 Fields of rate process: Stability and incompatibility: Here the rate process can lead to inactivation of the drug through decomposition or conversion into inactive or toxic form. Dissolution: Here the main concern is the rapidity with which a solid dosage form is changed to molecular solution.

21. 8/18/2015 PHR 416 21 Pharmacokinetics: Concerns with the rate of drug absorption, elimination and metabolism. Drug action at molecular level: Here it is assumed that generation of a response by a drug is a rate process.

22. In general, reaction kinetics is the study of rate of chemical change and the way in which this rate is influenced by conditions of concentration of reactants, products and other chemical species which may be present, and the factors such as solvent, pressure and temperature. Reaction kinetics permits formulation of models for the intermediate steps through which reactants are converted into other chemical compounds and is a powerful tool in elucidating the mechanism by which chemical reactions proceed. 8/18/2015 PHR 416 22

23. It provides a rational approach to stabilization of drug products and prediction of shelf- life and optimum storage conditions. e.g. thiamine HCl is most stable at pH 2-3 and is unstable at pH above 6. If this is combined with a buffered vehicle of say pH 8 or 9 the vitamin is rapidly inactivated. Knowing the rate at which a drug deteriorates at various hydrogen ion concentrations allows one to choose a vehicle that will retard or prevent the degradation. 8/18/2015 PHR 416 23

24. Reaction Rate The rate of reaction is the velocity with which a reactant or reactants undergo chemical change. The rate, velocity or speed of a reaction is given by the expression dc / dt. where dc is increase or decrease of concentration over a time interval dt 8/18/2015 PHR 416 24

25. Rate and order of reaction 8/18/2015 PHR 416 25 Rate: The rate, velocity or speed of reaction is given by:  dc/dt This expression gives the increase (+) or decrease (-) in concentration (C ) within a given time intervals (dt )

26. 8/18/2015 PHR 416 26 Reaction kinetics: Rate Formation of ethyl acetate from ethyl alcohol and acetic acid. CH3COOH + C2H5OH = CH3COOC2H5 + H2O In this reaction the rate of forward reaction (Rf) may be calculated by measuring the concentration of acetic acid or ethanol as the reaction progresses.

27. 8/18/2015 PHR 416 27 Reaction kinetics: Rate CH3COOH + C2H5OH = CH3COOC2H5 + H2O The rate of reverse reaction (Rr) may calculated by measuring the concentration of ethyl acetate or water as the reaction takes place

28. 8/18/2015 PHR 416 28 Reaction kinetics: Rate 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 + ….. = Products Rate = k [A] a [B] b Where k is rate constant.

29. Order of reaction 8/18/2015 PHR 416 29 aA + bB Product Reaction rate = K [A] a [B] b * If a=2 and b=1, the reaction rate = K [A] 2 [B] 1 * The reaction is second order with respect to A and first order with respect to B. * The overall order is the sum of the exponents of concentration terms that afford a linear plot, i.e. third order

30. 8/18/2015 PHR 416 30 Reaction of ethyl acetate with sod. hydroxide in aqueous solution CH3COOC2H5 + NaOHsoln → CH3COONa + C2H5O The rate expression is:

31. 8/18/2015 PHR 416 31 CH3COOC2H5 + NaOHsoln → CH3COONa + C2H5OH The reaction is first order (a = 1) with respect to ethyl acetate and first order (b= 1) with respect to sodium hydroxide solution. The overall reaction is second order (a + b = 2)

32. 8/18/2015 PHR 416 32 CH3COOC2H5 + xss NaOHsoln → CH3COONa + C2H5OH Suppose that NaOH solution is used as solvent (i.e. its conc. is very high) and ethyl acetate were in low concentration. As the reaction proceeds, ethyl acetate would change appreciably from its original concentration, Whereas the concentrations of NaOH solution would remain essentially unchanged because of its presence in great excess

33. 8/18/2015 PHR 416 33 CH3COOC2H5 + xss NaOHsoln → CH3COONa + C2H5OH In this case the reaction rate can be written as where k' = K [NaOH] The reaction is then said to be pseudo-first-order reaction because it depends only on the first power (a = 1) of the concentration of ethyl acetate

34. 8/18/2015 PHR 416 34 In general, when one of the reactants is present in such great excess that its concentration may be considered constant or nearly so, the reaction is said to be of pseudo-order. Apparent or pseudo-order "Apparent" or "pseudo"-order describes a situation where one of the reactants is present in large excess.