Chapter 14 Chemical Kinetics and Stability

Chapter 14 Chemical Kinetics and Stability

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

The chemical breakdown of drugs Review & Summarize Kinetics of chemical decomposition in solution Factors influencing drug stability Stability testing and calculation of shelf-life Body Conclusion

Introduction The chemical breakdown of drugs are categorized
Hydrolysis Oxidation Isomerization Photochemical decomposition Polymerization

Hydrolysis What is hydrolysis?!
The chemical breakdown of drug Hydrolysis What is hydrolysis?! Hydrolysis is a chemical reaction during which molecules of water (H2O) 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, 2nd ed. (1997).

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 4th edition Alexander T Florence and David Attwood

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

Hydrolysis Controlling drug hydrolysis in solution
The chemical breakdown of drug Hydrolysis Controlling drug hydrolysis in solution Optimization of formulation Determine the pH of maximum stability from kinetic experiments at a range of pH 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

Hydrolysis Controlling drug hydrolysis in solution
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 k0 : The rate constants for the reaction of the unsubstituted compounds σ : Hammett substituted constant ρ : Reaction constant

Oxidation What is oxidation?! Oxidation process
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• + O2 → ROO• ROO• + RH → ROOH +R• Termination ROO • + ROO • → stable product ROO • + R • → stable product R • + R • → stable product

Oxidation Drugs susceptible to oxidation Steroids and sterols
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 4th edition Alexander T Florence and David Attwood

Oxidation Stabilization against oxidation
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

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

Isomerization What is isomerization? Examples
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, 2nd ed. (1997) Fast track Physical Pharmacy (2008), Alexander T Florence and David Attwood

Isomerization Racemization Epimerization
The chemical breakdown of drug Isomerization Racemization Loss of activity of solutions of adrenaline at low pH 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 4th edition Alexander T Florence and David Attwood

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

Photochemical decomposition
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.

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 4th edition Alexander T Florence and David Attwood

The chemical breakdown of drug Photochemical decomposition 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

Polymerization What is polymerization?! Examples
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 4th edition Alexander T Florence and David Attwood

Polymerization Examples
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 4th edition Alexander T Florence and David Attwood

Classifying reactions
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

Classifying reactions
Kinetics of chemical decompsition in solution Classifying reactions Molecularity 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

Stability Indicating Assay Method
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

Zero-order reactions Zero-order reactions
Kinetics of chemical decompsition in solution Zero-order reactions 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 4th edition Alexander T Florence and David Attwood

Half-life and Shelf-life
Kinetics of chemical decompsition in solution Half-life and Shelf-life Half –life ( t½ or t0.5 ) and Shelf-life(t0.9 ) 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 A0= A0-kt A0= A0-kt0.9 0.5 A A0 k k t0.5 = t0.9 =

Apparent zero-order reactions
Kinetics of chemical decompsition in solution Apparent zero-order reactions 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)

First-order reactions
Kinetics of chemical decompsition in solution First-order reactions First-order reactions A first-order reaction depends on the concentration of only one reactant (a unimolecular reaction) − 𝑑𝐴 𝑑𝑡 =𝑘[𝐴 ] 1 1 [𝐴] 𝑑𝐴=−𝑘𝑑𝑡 𝐴 0 𝐴 𝑡 1 [𝐴] 𝑑𝐴=−𝑘 0 𝑡 𝑑𝑡 ln 𝐴 𝑡 − ln 𝐴 0 =−𝑘(𝑡−0) ln 𝐴 𝑡 = ln 𝐴 0 −𝑘𝑡 (ln 𝐶 𝑡 = ln 𝐶 0 −𝑘𝑡)

Kinetics of chemical decompsition in solution First-order reactions For example, in First-order reaction, the half-life and shelf life can be derived 𝐴𝑡 𝑡= 𝑡 50% , ln 𝐴 0 = ln 𝐴 0 −𝑘 𝑡 50% , 𝑡 50% = ln 2 𝑘 = 𝑘 𝐴𝑡 𝑡= 𝑡 90% , ln 0.9𝐴 0 = ln 𝐴 0 −𝑘 𝑡 90% , 𝑡 90% = ln 𝐴(0) 0.9𝐴(0) 𝑘 = ln 𝑘 = 𝑘 Half-life Shelf-life

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

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

Third-order reactions
Kinetics of chemical decompsition in solution Third-order reactions Third-order reactions 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 : pH-dependent apparent rate constant for hydrolysis kb : uncatalyzed polymerization rate constant kc :general acid–base-catalyzed polymerization rate constant

Determination of the order of reaction
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

Determination of the order of reaction
Kinetics of chemical decompsition in solution Determination of the order of reaction Determining the order of a reaction Examples Changing the data log scale

Complex reactions Reversible reaction
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 6th edition Patrck J. Sinko

Complex reactions Parallel reactions
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

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

Complex reactions Consecutive reaction
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

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

Factors influencing drug stability
Contents Factors influencing drug stability Liquid dosage form pH Temperature Solvent effect Oxygen Light Surfactant Solid dosage form Moisture Excipients Light and Oxygen

Liquid dosage form pH pH is the most important parameter which affects the hydrolysis rate of drugs in liquid formulations The Influence of pH on degradation rate Different pH-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

Liquid dosage form pH Examples Factors influencing drug stability *
* Physicochemical Principles of Pharmacy 4th edition Alexander T Florence and David Attwood

Liquid dosage form pH kobs : experimentally determined hydrolytic rate constant k0 : uncatalyzed or solvent-catalyzed rate constant kH+ ,kOH- : specific acid and base catalysis rate constants kHX , kX- : general acid and base catalysis rate constants respectively [HX] and [X-] [HX] , [X0] : concentrations of protonated and unprotonated forms of the buffer.

Liquid dosage form pH Examples Stable over a wide pH range
Factors influencing drug stability Liquid dosage form pH Examples Stable over a wide pH range except low and high pH range Removing the effect of buffer * * Physicochemical Principles of Pharmacy 4th edition Alexander T Florence and David Attwood

Liquid dosage form pH Examples Factors influencing drug stability *
* Physicochemical Principles of Pharmacy 4th edition Alexander T Florence and David Attwood

Liquid dosage form Temperature
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

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

Liquid dosage form Ion strength
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

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

Liquid dosage form Solvent effects
Factors influencing drug stability Liquid dosage form Solvent effects 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 zA , zB : charge numbers of the two interacting ions kε=0 : rate constant in a theoretical solvent of infinite dielectric constant

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

Liquid dosage form Oxygen
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

Liquid dosage form Light
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

Liquid dosage form Surfactants
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

Solid dosage form Moisture
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 4th edition Alexander T Florence and David Attwood

Solid dosage form Excipients
Factors influencing drug stability Solid dosage form Excipients 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 4th edition Alexander T Florence and David Attwood

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

Solid dosage form Temperature
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

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

Solid dosage form Light and Oxygen Same way as liquid dosage form
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

Stability testing What is stability testing?
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 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

Stability testing The purpose of stability testing
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, Q1A(R2) Stability Testing of New Drug Substances and Products,ICH, November 2003

Stability testing Long-term testing Intermediate testing
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, Q1A(R2) Stability Testing of New Drug Substances and Products,ICH, November 2003

Stability testing Accelerated testing
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, Q1A(R2) Stability Testing of New Drug Substances and Products,ICH, November 2003

Stability testing and calculation of shelf-life
The design of the formal stability studies for the drug product at least 3 batches * *Guidance for Industry, Q1A(R2) Stability Testing of New Drug Substances and Products,ICH, November 2003

Stability testing Testing frequency
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, Q1A(R2) Stability Testing of New Drug Substances and Products,ICH, November 2003

Stability testing and calculation of shelf-life
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 pH Failure to meet the acceptance criteria for dissolution for 12 dosage units *Guidance for Industry, Q1A(R2) Stability Testing of New Drug Substances and Products,ICH, November 2003

Stress testing Stress testing
Stability testing and calculation of shelf-life Stress testing Stress testing 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

Calculation of Shelf-life
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 * Arrhenius plot for predicting drug stability at room temperature * * MARTIN’s Physical Pharmacy and Pharmaceutical Sciences 6th edition Patrck J. Sinko

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 t90 (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 t90, are then plotted on a log scale in Fig. 1 * * * MARTIN’s Physical Pharmacy and Pharmaceutical Sciences 6th edition Patrck J. Sinko

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 T0 : initial temperature a : reciprocal heating rate constant

Stability testing and calculation of shelf-life Calculation of Shelf-life Shelf-life 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

Stability testing and calculation of shelf-life 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 Fig. 1. A log plot of t90 (i.e., time to 90% potency) on the vertical axis against reciprocal temperature (both Kelvin and centigrade scales are shown) on the horizontal axis * * MARTIN’s Physical Pharmacy and Pharmaceutical Sciences 6th edition Patrck J. Sinko

Chemical breakdown of drugs
Review & Summarize Chemical breakdown of drugs Chemical breakdown of drugs Hydrolysis Isomerization Oxidation Polymerization Photochemical decompositon Isom

Review & Summarize Chemical breakdown of drugs Hydrolysis Catalyzed by hydrogen ions or hydroxyl ions Ex) Imide, Lactam, Lactone, Ester, Amide groups Optimization Determine the pH of maximum stability Alteration of the solubility Alteration of the dielectric constants 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 Isom replaced with nitrogen or carbon dioxide Avoid heavy-metal ions Storage should be at reduced temperatures Addition of Antioxidant

Review & Summarize Chemical breakdown of drugs Isomerization 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 Isom 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

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

Kinetics of chemical decompsition
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

Review & Summarize Factors influencing drug stability Liquid dosage form pH Temperature Solvent effect Oxygen Light Surfactant Solid dosage form Moisture Excipients Light and Oxygen

Review & Summarize Factors influencing drug stability Liquid dosage form pH 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

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

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

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

Stability testing Stability testing Formal stability testing
Review & Summarize Stability testing 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

Review & Summarize Calculation of Shelf-life 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 t90 (i.e., time to 90% potency) on the vertical axis against reciprocal temperature (both Kelvin and centigrade scales are shown) on the horizontal axis *

1st-Order Reaction 𝐶 𝑡 =𝐶(0) 𝑒 −𝑘𝑡 =𝐶(0) 𝑒 − ln 2 𝑡/ 𝑡 1/2
=𝐶(0)( 𝑒 −𝑙𝑛2 ) 𝑡/ 𝑡 1/2 =𝐶(0)( 1 𝑒 ln 2 ) 𝑡/ 𝑡 1/2 =𝐶(0)( 1 2 ) 𝑡/ 𝑡 1/2 =𝐶(0)( 1 2 ) 𝑛 n = 𝑡 𝑡 1/2

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1st-Order Reaction

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Chapter 14 Chemical Kinetics and Stability

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