Principles and kinetics of drug stability (PHR 416) Nahla S Barakat, PhD Professor of Pharmaceutics PHR 416 4/22/2017

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. PHR 416 4/22/2017

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 <1191> Stability consideration in dispensing practice PHR 416 4/22/2017

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  PHR 416 4/22/2017

Introduction 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. PHR 416 4/22/2017

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 PHR 416 4/22/2017

For a drug substance, we need to study 3 categories of stabilities- 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 PHR 416 4/22/2017

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. PHR 416 4/22/2017

Importance of stability studies 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 PHR 416 4/22/2017

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. PHR 416 4/22/2017

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 PHR 416 4/22/2017

b. Water promotes microbial growth 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. PHR 416 4/22/2017

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 PHR 416 4/22/2017

PRODUCT TYPE MAX. TIME PERIOD Dosage forms: 5 years 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. : PHR 416 4/22/2017

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. PHR 416 4/22/2017

Five stabilities of drug must be considered:: 1. Physical 2. Chemical 3. Microbiological 4. Toxicological 5. Therapeutic PHR 416 4/22/2017

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Reaction kinetics: “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 PHR 416 4/22/2017

Rate and order of reactions 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. PHR 416 4/22/2017

Rate and order of reactions 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. PHR 416 4/22/2017

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. PHR 416 4/22/2017

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. PHR 416 4/22/2017

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. PHR 416 4/22/2017

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 PHR 416 4/22/2017

Factors that affect the reaction rate: 1- concentration of the reactant 2- solubility of drug 3- pressure (gases) 4- surface area 5- presence of catalyst 6- Nature of the reactant 7- Temperature 8- pH 9- light and humidity PHR 416 4/22/2017

Rate and order of reaction 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 ) PHR 416 4/22/2017

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. PHR 416 4/22/2017

Order of reaction Reactions are classified according to number of reacting species whose concentration determines the rate at which the reaction occurs, i.e. the order of reaction. 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 PHR 416 4/22/2017

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) PHR 416 4/22/2017

Whereas the concentrations of NaOH solution would remain 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. 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 PHR 416 4/22/2017

Zero order reaction: The zero order rate law for the general reaction A P In this type of reaction the decomposition processed at a constant rate and its independent of the concentrations of any of the reactants, the rate equation is : - d [A]= k0 (1) dt Which on integration of both sides gives: When t= 0 the concentration of A is [A]0 [A]t = A0 – k0 t (2) PHR 416 4/22/2017

K0 = A0 – At t A plot of the amount remaining [A] against time is linear with a slope of -k0 (concentration. Time -1) Many decomposition reactions in the solid Phase or in suspensions apparently follow zero-order kinetics. Unit of k0= moles/liter second moles. liter-1 .second-1 PHR 416 4/22/2017

First order reaction A general unimolecular reaction A P where A is a reactant and P is a product is called a first- order reaction. The rate is proportional to the concentration of a single reactant raised to the first power. The decrease in the concentration of A over time can be written as: V = d [A] = k1 [A] (1) d t PHR 416 4/22/2017

- d[A] = k dt (2) [ A] Integrating the equation (2) yield : Ln A- ln A0 = -k (t- 0) Ln A = ln A0 –kt Ln [A] = - k t [A]0 PHR 416 4/22/2017

Plot ln [A] or ln [A] / [A] 0 against time (t) create a straight line with slope – k Log A = log A0 – kt /2.303 K = 2.303 log A0 t A Slope = -k/2.303 k1 has the dimensions of time -1. Equation can be written as [A] = [A]0 e –kt This means that the concentration of A decrease exponentially as a function of time. PHR 416 4/22/2017

Pseudo First Order Reaction Even in the case of a reaction involving more than one reacting species, the rate may still follow first-order kinetics. The most common example of this occurs when one of the reactants is in such a large excess that any change in its concentration is negligible compared with changes in the concentration of the other reactants. This type of reaction is termed a pseudo first-order reaction. Such reactions are often met in stability studies of drugs that hydrolyze in solution, the water being in such excess that changes in its concentration are negligible and hence the rate of reaction is dependent solely on the drug concentration. PHR 416 4/22/2017

Assignment 2 EXAMPLE.1 Calculation of first-order rate constant and half-life The following data were obtained for the hydrolysis of homatropine in 0.226 mol dm-3 HCl at 90°C: Percentage homatropin remaining 93.4 85.2 75.9 63.1 52.5 41.8 Time (h) 1.38 3.0 6.0 8.6 12 17 PHR 416 4/22/2017

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The rate of a second-order reaction is determined by the concentrations of two reacting species. For reactions in which both concentration terms refer to the same reactant we may write: d [A] = k 2 [A] 2 (1) dt and dx = k2 (a-x)2 (2) PHR 416 4/22/2017

Integration of equation 2 between limits of t from 0 to t and of x from 0 to x yield: t = I 1 - 1 = x k2 a-x a k2 a (a-x) k2 t = 1 - 1 A A0 A plot of t against x/a(a-x) yields a linear plot of slope 1/k2 K2 has unit concentration -1 time -1 PHR 416 4/22/2017

Determination of the order of reaction data may be displayed graphically according to the linear equations for the various orders of reactions until a straight-line plot is obtained. Thus, for example, if the data yield a linear graph when plotted as t against log(a- x) the reaction is then taken to be first-order. An alternative method of determining the order of reaction, is based on equation : The half-life of the reaction is determined for a series of initial drug concentrations, C0 , and the order, n, is calculated from the slope of plots of log t0.5 as a function of log C0 . PHR 416 4/22/2017

Assignment 2 Example: The kinetics of decomposition of a drug in aqueous solution were studied using a series of solutions of different initial drug concentrations, C0 . For each solution the time taken for half the drug to decompose (that is, t0.5) was determined with the following results: C0 (mol dm -3) 4.625 1.698 0.724 0.288 t0.5 (min) 87.17 240.1 563.0 1414.4 Determine the order of reaction and calculate the rate constant PHR 416 4/22/2017