Chapter 14 Chemical Kinetics and Stability SKKU Physical

Chapter 14 Chemical Kinetics and Stability SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

Contents “Drug Stability” Introduction Body Conclusion ü The chemical breakdown of drugs ü Kinetics of chemical decomposition in solution ü Factors influencing drug stability ü Stability testing and calculation of shelf-life ü Review & Summarize SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

Introduction The chemical breakdown of drugs are categorized Hydrolysis Oxidation Isomerization Photochemical decomposition Polymerization SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

The chemical breakdown of drug Hydrolysis What is hydrolysis? ! Hydrolysis is a chemical reaction during which molecules of water (H 2 O) are split into hydrogen cations (H+) and hydroxide anions (OH−) in the process of a chemical mechanism * It is the type of reaction that is used to break down certain polymers, especially those made by step-growth polymerization * Compendium of Chemical Terminology, 2 nd ed. (1997). SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

The chemical breakdown of drug Hydrolysis Drugs that contain these functional groups are susceptible to hydrolysis Imide Lactam Lactone Ester Amide * * Physicochemical Principles of Pharmacy 4 th edition Alexander T Florence and David Attwood SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

The chemical breakdown of drug Hydrolysis can be catalyzed by H+ ions or OH- ions Examples of hydrolysis * * * Physicochemical Principles of Pharmacy 4 th edition Alexander T Florence and David Attwood SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

The chemical breakdown of drug Hydrolysis Controlling drug hydrolysis in solution Optimization of formulation ▪ Determine the p. H of maximum stability from kinetic experiments at a range of p. H values ▪ Alteration of the dielectric constants by the addition of nonaqeous solvents ▪ Ex) Alcohol, glycerin or propylene glycol ▪ Suppress degradation by reducing solubility using additives ▪ Ex) Citrates, dextrose, sorbitol , gluconate ▪ Adding a compound that forms a complex with the drug can increase stability ▪ Ex) Addition of caffeine into solution of benzocaine, procaine and tetracaine SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

The chemical breakdown of drug Hydrolysis Controlling drug hydrolysis in solution Modification of chemical structure of drug ▪ The control of drug stability by modifying chemical structure using appropriate substituent ▪ Hammett linear free energy relationship k : The rate constants for the reaction of the substituted compounds k 0 : The rate constants for the reaction of the unsubstituted compounds σ : Hammett substituted constant ρ : Reaction constant SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

The chemical breakdown of drug Oxidation What is oxidation? ! Oxidation is the loss of electrons or an increase in oxidation state by a molecule, atom, or ion. Oxidation process Initiation ▪ X • + RH → R • + XH Propagation ▪ R • + O 2 → ROO • ▪ ROO • + RH → ROOH +R • Termination ▪ ROO • + ROO • → stable product ▪ ROO • + R • → stable product ▪ R • + R • → stable product SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

The chemical breakdown of drug Oxidation Drugs susceptible to oxidation Steroids and sterols Polyunsaturated fatty acids Simvastatin Polyene Antibiotics ▪ Amphotericin B Phenothiazines * Econazole nitrate and miconazole nitrate * * Physicochemical Principles of Pharmacy 4 th edition Alexander T Florence and David Attwood SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

The chemical breakdown of drug Oxidation Stabilization against oxidation Replace Oxygen in pharmaceutical containers with nitrogen or carbon dioxide Avoid contact with heavy-metal ions which catalyze oxidation Storage at reduced temperatures Use of Antioxidant ▪ Interrupt the propagation by interaction with the free radical ▪ More oxidized than the drug ▪ Protect drug from oxidation SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

The chemical breakdown of drug Oxidation Stabilization against oxidation Antioxidant examples * * Physicochemical Principles of Pharmacy 4 th edition Alexander T Florence and David Attwood SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

The chemical breakdown of drug Isomerization What is isomerization? Isomerization is the process by which one molecule is transformed into another molecule which has exactly the same atoms, but the atoms are rearranged * In pharmaceutical aspect, isomerization is the process of conversion of a drug into its optical or geometric isomers, which are often of lower therapeutic activity Examples Racemization Epimerization Base catalyzed isomerization cis-trans isomerization * Compendium of Chemical Terminology, 2 nd ed. (1997) Fast track Physical Pharmacy (2008), Alexander T Florence and David Attwood SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

The chemical breakdown of drug Isomerization Racemization Loss of activity of solutions of adrenaline at low p. H Epimerization In acidic conditions, carbon atom 4 undergo epimerization to 4 -epi-tetracycline, which is toxic and its content in medicines restricted to not more than 3%. * * Physicochemical Principles of Pharmacy 4 th edition Alexander T Florence and David Attwood SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

The chemical breakdown of drug Isomerization Base catalyzed isomerization Biologically inactive * Cis-trans isomerization Decreased activity * * Physicochemical Principles of Pharmacy 4 th edition Alexander T Florence and David Attwood SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

The chemical breakdown of drug Photochemical decomposition What is photochemical decomposition? ! Photochemical decomposition is a chemical reaction in which a chemical compound is broken down by photons produced by light. There are possibilities of loss of potency of drug, changes in the appearance of the product ▪ Ex) coloration, precipitation etc Phenothiazine tranquilizers, hydrocortisone, prednisolone, riboflavin, ascorbic acid, and folic acid degrade when exposed to light. SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

The chemical breakdown of drug Photochemical decomposition Photoreactivity groups Carbonyl, nitro aromatic and N-oxide functions, aryl halides, alkenes, polyenes and sulfides Examples e. g. chlorpromazine e. g. ketoprofen * * * Physicochemical Principles of Pharmacy 4 th edition Alexander T Florence and David Attwood SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

The chemical breakdown of drug Photochemical decomposition may occur not only during storage, but also during use of the product Stabilization against photochemical decomposition The use of coloured glass containers and storage in the dark ▪ Amber glass excludes light of wavelength <470 nm and so affords considerable protection of compounds sensitive to ultraviolet light Coating tablets with a polymer film containing ultraviolet absorbers SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

The chemical breakdown of drug Polymerization What is polymerization? ! Polymerization is the prcoess by which two or more identical drug molecules combine together to form a complex molecule Examples The hydrate of formaldehyde ▪ polymerize in aqueous solutions to form paraformaldehyde which appears white deposit in the solution ▪ Polymerization may be prevented by adding to the solution 10 -15% of methanol *Physicochemical Principles of Pharmacy 4 th edition Alexander T Florence and David Attwood SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

The chemical breakdown of drug Polymerization Examples Dimers of aminopenicillins form higher polymers which is highly antigenic to animals Increase possibilities of polymerization with the increase in the basicity of the side-chain group ▪ Cyclascillin<<Ampicillin<Epicillin<Amoxycillin * *Physicochemical Principles of Pharmacy 4 th edition Alexander T Florence and David Attwood SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

Contents “Drug Stability” Introduction Body Conclusion ü The chemical breakdown of drugs ü Kinetics of chemical decomposition in solution ü Factors influencing drug stability ü Stability testing and calculation of shelf-life ü Review & Summarize SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

Kinetics of chemical decompsition in solution Classifying reactions Rate The rate of a chemical reaction is proportional to the product of the molar concentration of the reactants each raised to a power usually equal to the number of molecules, a and b, of the substances A and B, respectively, undergoing reaction Products Rate SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

Kinetics of chemical decompsition in solution Classifying reactions Molecularity is the number of molecules, atoms, or ions reacting in an elementary process Examples ▪ Unimolecular process ▪ Bimolecular process Specific rate constant The constant, k, appearing in the rate law associated with a single-step reaction SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

Kinetics of chemical decompsition in solution Stability Indicating Assay Method Definition An analytical procedure that measures the active pharmaceutical ingredient (in drug substance and drug product) with accuracy and precision, free from the process impurities, excipients and degradation products. “specific ones, which evaluate the drug in the presence of its degradation products, excipients, and additives” Main Objectives To monitor the impurities and degradation products which affect the safety and efficacy of drug products Examples HPLC, GC SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

Kinetics of chemical decompsition in solution Zero-order reactions The decomposition proceeds at a constant rate and is independent of the concentrations of any of the reactants * * Physicochemical Principles of Pharmacy 4 th edition Alexander T Florence and David Attwood SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

Kinetics of chemical decompsition in solution Half-life and Shelf-life Half –life ( t½ or t 0. 5 ) and Shelf-life(t 0. 9 ) The Half-life is the time taken for half of the reactant to decompose The shelf-life is the time required for 10% of the material to disappear (which is the time require for remaining material is 90%) For example, in zero-order reaction, the half-life and shelf life can be derived 0. 5 A 0= A 0 -kt 0. 5 0. 9 A 0= A 0 -kt 0. 9 0. 5 A 0 t 0. 5 = k 0. 1 A 0 t 0. 9 = k SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

Kinetics of chemical decompsition in solution Apparent zero-order reactions “Apparent”or “pseudo” –order describes a situation where one of the reactants is present in large excess or does not effect the overall reaction and can be held constant Examples (suspensions) SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

Kinetics of chemical decompsition in solution First-order reactions A first-order reaction depends on the concentration of only one reactant (a unimolecular reaction) SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

Kinetics of chemical decompsition in solution First-order reactions Half-life Shelf-life SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

Kinetics of chemical decompsition in solution First-order reactions Examples Conversion to log scale * * Physicochemical Principles of Pharmacy 4 th edition Alexander T Florence and David Attwood SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

Kinetics of chemical decompsition in solution Second-order reactions A second-order reaction depends on the concentrations of one second-order reactant, or two first-order reactants SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

Kinetics of chemical decompsition in solution Third-order reactions are only rarely encountered in drug stability studies involving, as they do, the simultaneous collision of three reactant molecules. Example ▪ Rate of ampicillin breakdown by simultaneous hydrolysis and polymerization ka : p. H-dependent apparent rate constant for hydrolysis kb : uncatalyzed polymerization rate constant kc : general acid–base-catalyzed polymerization rate constant SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

Kinetics of chemical decompsition in solution Determination of the order of reaction Determining the order of a reaction To determine the amount of drug decomposed after various intervals and to substitute the data into the integrated equations for zero-, first- and second-order An alternative method of determining the order of reaction to avoid misleading results of if a fractional order of reaction applies SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

Kinetics of chemical decompsition in solution Determination of the order of reaction Determining the order of a reaction Examples Changing the data log scale SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

Kinetics of chemical decompsition in solution Complex reactions Reversible reaction A reversible reaction is a chemical reaction that results in an equilibrium mixture of reactants and products * * MARTIN’s Physical Pharmacy and Pharmaceutical Sciences 6 th edition Patrck J. Sinko SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

Kinetics of chemical decompsition in solution Complex reactions Parallel reactions The decomposition of many drugs involves two or more pathways, the preferred route of reaction being dependent on reaction condition In other cases decomposition may occur simultaneously by two different processes SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

Kinetics of chemical decompsition in solution Complex reactions Parallel reactions Examples * * Physicochemical Principles of Pharmacy 4 th edition Alexander T Florence and David Attwood SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

Kinetics of chemical decompsition in solution Complex reactions Consecutive reaction The simple consecutive reaction is that described by a sequence where each step is a nonreversible first-order reaction SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

Kinetics of chemical decompsition in solution Complex reactions Consecutive reaction Examples (e. g. chlorodiazepoxide) * * Physicochemical Principles of Pharmacy 4 th edition Alexander T Florence and David Attwood SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

Contents “Drug Stability” Introduction Body Conclusion ü The chemical breakdown of drugs ü Kinetics of chemical decomposition in solution ü Factors influencing drug stability ü Stability testing and calculation of shelf-life ü Review & Summarize SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

Contents Factors influencing drug stability Liquid dosage form • p. H • Temperature • Solvent effect • Oxygen • Light • Surfactant Solid dosage form • Moisture • Excipients • Temperature • Light and Oxygen SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

Factors influencing drug stability Liquid dosage form p. H is the most important parameter which affects the hydrolysis rate of drugs in liquid formulations The Influence of p. H on degradation rate ▪ Different p. H-rate profile obtained using different buffer ▪ Specific acid-base catalysis catalytic effect of hydrogen and hydroxyl ions ▪ General acid-base catalysis accelerating effect of the component of the buffer system SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

Factors influencing drug stability Liquid dosage form p. H Examples * * Physicochemical Principles of Pharmacy 4 th edition Alexander T Florence and David Attwood SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

Factors influencing drug stability Liquid dosage form p. H kobs : experimentally determined hydrolytic rate constant k 0 : uncatalyzed or solvent-catalyzed rate constant k. H+ , k. OH- : specific acid and base catalysis rate constants k. HX , k. X- : general acid and base catalysis rate constants respectively [HX] and [X-] [HX] , [X ] : concentrations of protonated and unprotonated forms of the buffer. 0 SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

Factors influencing drug stability Liquid dosage form p. H Examples ▪ Stable over a wide p. H range except low and high p. H range ▪ Removing the effect of buffer * * Physicochemical Principles of Pharmacy 4 th edition Alexander T Florence and David Attwood SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

Factors influencing drug stability Liquid dosage form p. H Examples * * Physicochemical Principles of Pharmacy 4 th edition Alexander T Florence and David Attwood SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

Factors influencing drug stability Liquid dosage form Temperature Increase in temperature usually causes a very pronounced increase in the hydrolysis rate of drugs in solution Arrehnius equation ▪ The effect of temperature on decomposition ▪ ▪ Ea is the activationb energy A is the frquency factor R is the gas constant T is the temperature in kelvins SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

Factors influencing drug stability Liquid dosage form Temperature Examples * * * Physicochemical Principles of Pharmacy 4 th edition Alexander T Florence and David Attwood SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

Factors influencing drug stability Liquid dosage form Ion strength The ionic strength of a solution is a measure of the concentration of ions in that solution Bronsted-Bjerrum equation ▪ The equation describes the influence of electrolyte on the rate constant ZA , ZB : charge numbers of the two interacting ions A : constant for a given solvent and temperature µ : ionic strength SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

Factors influencing drug stability Liquid dosage form Ion strength Examples * * Physicochemical Principles of Pharmacy 4 th edition Alexander T Florence and David Attwood SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

Factors influencing drug stability Liquid dosage form Solvent effects is the group of effects that a solvent has on chemical reactivity ▪ The equation describes the effect of the dielectric constant, ε, on the rate of hydrolysis K : constant for a particular reaction at a given temperature z. A , z. B : charge numbers of the two interacting ions kε=0 : rate constant in a theoretical solvent of infinite dielectric constant SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

Factors influencing drug stability Liquid dosage form Solvent effects Examples * * Fast track - Physical Pharmacy Alexander T Florence and David Attwood SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

Factors influencing drug stability Liquid dosage form Oxygen Molecular oxygen is involved in many oxidation shemes Particular drug is likely to be affected by oxidative breakdown Stabilization ▪ Replacing the oxygen in the storage containers with nitrogen or carbon oxide ▪ Avoiding contact with heavy metal ions ▪ Adding antioxidants SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

Factors influencing drug stability Liquid dosage form Light Exposure to ultraviolet light is the most usual cause of photodegradation Photolabile drugs are usually stored in containers which exclude ultraviolet light Stabilization ▪ Amber glass is particularly effective ▪ It excludes light of wavelength of less than about 470 nm ▪ Storing photolabile drugs in the dark SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

Factors influencing drug stability Liquid dosage form Surfactants The presence of surfactants in micellar form has a modifying effect on the hydrolysis of drugs k obs , km, kf : observed, micellar and aqueous rate constants fm, fw : fractions of drug associated with micelles and aqueous phase Ionic nature of surfactant have important influence of decomposition rate ▪ Anionic micelle have stabilization effect to base-catalyzed hydrolysis Self-association on stability ▪ Ex) benzylpenicillin- stable 2. 5 times micellar >>monomer SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

Factors influencing drug stability Solid dosage form Moisture Water-soluble drugs present in a solid dosage form ▪ Dissolve in any moisutre which has adsorbed on the solid surface ▪ Influenced by many of the factors as for liquid dosage forms Minimize access of moisture during manufacture and storage * * Physicochemical Principles of Pharmacy 4 th edition Alexander T Florence and David Attwood SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

Factors influencing drug stability Solid dosage form Excipients with particularly high water contents ▪ Affect stability by increasing the water content of the formulation Chemical interactions between the excipients ▪ Lead to a decrease of stability * * Physicochemical Principles of Pharmacy 4 th edition Alexander T Florence and David Attwood SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

Factors influencing drug stability Solid dosage form Excipients Examples * * Physicochemical Principles of Pharmacy 4 th edition Alexander T Florence and David Attwood SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

Factors influencing drug stability Solid dosage form Temperature The effect of temperature change on the stability of solid dosage forms can be complicated for many possible reasons ▪ The drug or one of excipients may melt or change its polymorphic form as temperature is increased ▪ The drug or one of excipients may contain loosely bound water which is lost at high temperatures Arrhenius equation ▪ Predict stability ▪ Calculate Ea SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

Factors influencing drug stability Solid dosage form Temperature Examples * * Physicochemical Principles of Pharmacy 4 th edition Alexander T Florence and David Attwood SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

Factors influencing drug stability Solid dosage form Light and Oxygen Same way as liquid dosage form ▪ Replacing the oxygen ▪ Adding antioxidants ▪ Amber glass Storing under dry condition ▪ Water contains dissolved oxygen and so the presence of moisture on the surface of solid preparations may increase the oxidation of susceptible drugs SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

Contents “Drug Stability” Introduction Body Conclusion ü The chemical breakdown of drugs ü Kinetics of chemical decomposition in solution ü Factors influencing drug stability ü Stability testing and calculation of shelf-life ü Review & Summarize SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

Stability testing and calculation of shelf-life Stability testing * What is stability testing? Testing program designed to assess the stability characteristics of drug products. The results of such stability testing shall be used in determining appropriate storage conditions and expiration dates. The written program shall be followed and shall include 1) 2) 3) 4) 5) Sample size and test intervals Storage conditions for samples retained for testing Reliable, meaningful, and specific test methods Testing of the drug product in the same container-closure system as that in which the drug product is marketed Testing of drug products for reconstitution at the time of dispensing (as directed in the labeling) as well as after they are reconstituted *21 Code of Federal Regulations 211. 166 SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

Stability testing and calculation of shelf-life Stability testing * The purpose of stability testing To provide evidence on how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors To establish a retest period for the drug substance or a shelf life for the drug product and recommended storage conditions * Formal stability studies Long-term and accelerated (and intermediate) studies undertaken on primary and/or commitment batches To establish or confirm the retest period of a drug substance or the shelf life of a drug product *Guidance for Industry, Q 1 A(R 2) Stability Testing of New Drug Substances and Products, ICH, November 2003 SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

Stability testing and calculation of shelf-life Stability testing Long-term testing * Stability studies under the recommended storage condition for the retest period or shelf life proposed (or approved) for labeling Intermediate testing * Studies conducted at 30°C/65% RH and designed to moderately increase the rate of chemical degradation or physical changes for a drug substance or drug product intended to be stored long-term at 25°C *Guidance for Industry, Q 1 A(R 2) Stability Testing of New Drug Substances and Products, ICH, November 2003 SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

Stability testing and calculation of shelf-life Stability testing Accelerated testing * Studies designed to increase the rate of chemical degradation or physical change of a drug substance or drug product by using exaggerated storage conditions as part of the formal stability studies To assess longer term chemical effects at non accelerated conditions To evaluate the effect of short-term excursions outside the label storage conditions Results from accelerated testing studies are not always predictive of physical changes *Guidance for Industry, Q 1 A(R 2) Stability Testing of New Drug Substances and Products, ICH, November 2003 SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

Stability testing and calculation of shelf-life Stability testing The design of the formal stability studies for the drug product at least 3 batches * *Guidance for Industry, Q 1 A(R 2) Stability Testing of New Drug Substances and Products, ICH, November 2003 SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

Stability testing and calculation of shelf-life Stability testing Testing frequency For long-term study, every 3 months over the first year, every 6 months over the second year, and annually thereafter through the proposed shelf life. At the accelerated storage condition, a minimum of three time points, including the initial and final time points (e. g. , 0, 3, and 6 months), from a 6 -month study is recommended. *Guidance for Industry, Q 1 A(R 2) Stability Testing of New Drug Substances and Products, ICH, November 2003 SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

Stability testing and calculation of shelf-life Stability testing In general, significant change for a drug product is defined as one or more of the following (as appropriate for the dosage form) 5 percent change in assay from its initial value Any degradation product’s exceeding its acceptance criterion Failure to meet the acceptance criteria for appearance, physical attributes, and functionality test ▪ Ex) color, phase separation, resuspendibility, caking, hardness, dose delivery per actuation Failure to meet the acceptance criterion for p. H Failure to meet the acceptance criteria for dissolution for 12 dosage units *Guidance for Industry, Q 1 A(R 2) Stability Testing of New Drug Substances and Products, ICH, November 2003 SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

Stability testing and calculation of shelf-life Stress testing to elucidate the intrinsic stability of the drug substance is part of the development strategy and is normally carried out under more severe conditions than those used for accelarated testing The testing typically includes the effects of temperature, humidity where appropriate, oxidation, and photolysis on the drug substance ▪ Temperature – in 10°C increments above that for accelerated testing ▪ Humidity – 75% realative humidity or greater SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

Stability testing and calculation of shelf-life Calculation of Shelf-life Accelerated testing based on the chemical kinetics (by Garrett and Carper) * Accelerated breakdown of a drug in aqueous solution at elevated temperature * MARTIN’s Physical Pharmacy and Pharmaceutical Sciences 6 th edition Patrck J. Sinko * Arrhenius plot for predicting drug stability at room temperature SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

Stability testing and calculation of shelf-life Calculation of Shelf-life Fractional life-period Method (by Free and Blythe and Amirijahe et al ) * Fig. 1. A log plot of t 90 (i. e. , time to 90% potency) on the vertical axis against reciprocal temperature (both Kelvin and centigrade scales are shown) on the horizontal axis * Fig. 2. Time in days required for durg potency to fall to 90% of original value. These times, designated t 90, are then plotted on a log scale in Fig. 1 * MARTIN’s Physical Pharmacy and Pharmaceutical Sciences 6 th edition Patrck J. Sinko SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

Stability testing and calculation of shelf-life Calculation of Shelf-life Nonisothermal kinetics (by Rogers) Enable decomposition rate to be determined from a single experiment Involve raising the temperature of the product with predetermined temperature-time program T 0 : initial temperature a : reciprocal heating rate constant SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

Stability testing and calculation of shelf-life Calculation of Shelf-life is the time period during which a drug product is expected to remain within the approved specification for use, provided that it is stored under the conditions defined on the container label SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

Stability testing and calculation of shelf-life Calculation of Shelf-life Examples ▪ The equations which we can use for 10% loss of activity are obtained by substituting t 0. 5 to t 0. 9 ▪ Extrapolations to 25℃ could predict the * Shelf-life of the drug * MARTIN’s Physical Pharmacy and Pharmaceutical Sciences 6 th edition Patrck J. Sinko Fig. 1. A log plot of t 90 (i. e. , time to 90% potency) on the vertical axis against reciprocal temperature (both Kelvin and centigrade scales are shown) on the horizontal axis SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

Contents “Drug Stability” Introduction Body Conclusion ü The chemical breakdown of drugs ü Kinetics of chemical decomposition in solution ü Factors influencing drug stability ü Stability testing and calculation of shelf-life ü Review & Summarize SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

Review & Summarize Chemical breakdown of drugs Hydrolysis Oxidation Polymerization Chemical breakdown of drugs Isomerization Photochemical decompositon SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

Review & Summarize Chemical breakdown of drugs Hydrolysis Catalyzed by hydrogen ions or hydroxyl ions Ex) Imide, Lactam, Lactone, Ester, Amide groups Optimization ▪ Determine the p. H of maximum stability ▪ Alteration of the dielectric constants ▪ Alteration of the solubility ▪ Adding the compound that form complex with drug Oxidation Removal of an electropositive atom, radical or electron, or the addition of an electronegative atom or radical Ex) Steroids and sterols, polyunsaturated fatty acids, phenothiazines etc Optimization ▪ replaced with nitrogen or carbon dioxide ▪ Storage should be at reduced temperatures ▪ Avoid heavy-metal ions ▪ Addition of Antioxidant SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

Review & Summarize Chemical breakdown of drugs Isomerization is the process of conversion of a drug into its optical or geometric isomers, which are often of lower therapeutic activity Ex) Adrenaline(racemization), tetracycline(epimerization), cephalosporins(base-catalyzed isomerization) and vitamin A(cis-trans isomerization) Photochemical decomposition Degrade when exposed to light Ex) Phenothiazine tranquilizers, hydrocortisone, prednisolone, riboflavin, ascorbic acid Optimization ▪ The use of coloured glass containers and storage in the dark Polymerization Two or more identical drug molecules combine together to form a complex molecule Ex) Amino-penicillins such as ampicillin sodium in aqueous solution, formaldehyde SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

Review & Summarize Kinetics of chemical decompsition Zero-order reactions • The decomposition proceeds at a constant rate and is independent of the concentrations of any of the reactants First-order reactions • First-order reaction depends on the concentration of only one reactant (a unimolecular reaction) Second-order reactions • Second-order reaction depends on the concentration of one second-order reactant, or two first-order reactants SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

Review & Summarize Kinetics of chemical decompsition Reversible reaction A reversible reaction is a chemical reaction that results in an equilibrium mixture of reactants and products Parallel reaction The decomposition of many drugs involves two or more pathways, the preferred route of reaction being dependent on reaction condition Consecutive reaction The simple consecutive reaction is that described by a sequence where each step is a nonreversible first-order reaction SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

Review & Summarize Factors influencing drug stability Liquid dosage form • p. H • Temperature • Solvent effect • Oxygen • Light • Surfactant Solid dosage form • Moisture • Excipients • Temperature • Light and Oxygen SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

Review & Summarize Factors influencing drug stability Liquid dosage form p. H ▪ The most important parameter which affects the hydrolysis rate of drugs in liquid formulations ▪ The rate of reaction is influenced not only by the catalytic effect of hydrogen and hydroxyl ions, but also by the components of the buffer system Temperature ▪ Increase in temperature usually causes a very pronounced increase in the hydrolysis rate of drugs in solution ▪ Arrehnius equation SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

Review & Summarize Factors influencing drug stability Liquid dosage form Ion strength ▪ The ionic strength of a solution is a measure of the concentration of ions in that solution ▪ Bronsted-Bjerrum equation Solvent effects ▪ Solvent effects is the group of effects that a solvent has on chemical reactivity SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

Review & Summarize Factors influencing drug stability Liquid dosage form Oxygen ▪ Molecular oxygen is involved in many oxidation shemes ▪ Particular drug is likely to be affected by oxidative breakdown Light ▪ Exposure to ultraviolet light is the most usual cause of photodegradation ▪ Photolabile drugs are usually stored in containers which exclude ultraviolet light SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

Review & Summarize Factors influencing drug stability Solid dosage form Moisture ▪ Water-soluble drugs present in a solid dosage form will dissolve in any moisutre which has adsorbed on the solid surface Excipients ▪ high water contents and Chemical interactions Temperature ▪ melt or change its polymorphic form Light and Oxygen SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

Review & Summarize Stability testing To ensure the quality, safety, and efficacy of drug products up to their expiration date Formal stability testing ▪ Long-term/Intermediate/Accelerated stability test Stress testing ▪ Temperature – in 10°C increments above that for accelerated testing ▪ Humidity – 75% relative humidity or greater SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

Review & Summarize Calculation of Shelf-life Time period during which a drug product is expected to remain within the approved specification for use, provided that it is stored under the conditions defined on the container label ▪ Extrapolations from high temperature to 25℃ could predict the Shelf-life of * the drug Fig. 1. A log plot of t 90 (i. e. , time to 90% potency) on the vertical axis against reciprocal temperature (both Kelvin and centigrade scales are shown) on the horizontal axis SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실