Drug Stability Part I - Biopharmaceutics - PDF

UNIVERSITY SCHOOL OF PHARMACY Drug Stability Marshall TM Part I School of Pharmacy Biopharmaceutics I Cynthia B. Jones, Ph.D. © ...

UNIVERSITY SCHOOL OF PHARMACY Drug Stability Marshall TM Part I School of Pharmacy Biopharmaceutics I Cynthia B. Jones, Ph.D. ©  Marshall Learning Outcomes – Part I School of Pharmacy https://corporate.dukehealth.org/sites/ http://www.pharmafile.com/system/files/ corporate.dukehealth.org/files/ThinkstockPhotos- imagecache/news_full/ 152110776%5B1%5D.jpg shutterstock_184341605.jpg Compare and Compare and contrast the contrast the types of drug different types decomposition of protein drug decomposition Cynthia B. Jones, Ph.D. ©  Marshall Why is Chemical Stability Important to Pharmacists? School of Pharmacy Purpose of Stability – provide evidence on how the quality of drug substances or products varies with time under various environmental factors: Temperature Humidity Light Why Should the practicing pharmacist understand drug product stability? Increase in community pharmacy compounding Recognize stability alterations Advise patients on medication storage Cynthia B. Jones, Ph.D. © 10/28/2024  Marshall Why is Chemical Stability Important to Pharmacists? School of Pharmacy Every drug is inherently unstable—the issue is this: to what extent is the drug unstable? Answering this question needs two criteria: (a) what is the sensitivity of how instability is measured; and (b) what is the clinical consequence of the assessed instability? The first of these questions should lead to the understanding that no drug is absolutely stable, but that relative stability is a function of structure and conditions. Why chemical kinetics applications? Allows the production of more stable drug preparations based on sound scientific principles The pharmacist can inform physicians and patients regarding the proper storage and use of medicinal agents. Cynthia B. Jones, Ph.D. © 10/28/2024  Marshall Hydrolysis School of Pharmacy  Hydrolysis is the “splitting of drugs with water  Functional groups that are susceptible to hydrolysis are mostly carboxylic acid derivatives  Other functional groups susceptible to hydrolysis include:  Esters  Lactones  Lactams  Carbamates  Carbonates  Thiol Esters  Imides And  Oxime Cynthia B. Jones, Ph.D. © 10/28/2024  Marshall Hydrolysis Functional Groups School of Pharmacy Esters Lactones Lactams Imide Thiol ester Oxime Carbamate Carbonate Cynthia B. Jones, Ph.D. © 10/28/2024  Marshall Oxidation School of Pharmacy Oxidation is believed to be a chain reaction The mechanism involves formation of a free radical Three Steps 1. Initiation Step: Formation of the free radical drug molecule 2. Propagation Step: free radical takes an electron from another drug molecule, producing another free radical 3. Termination Step: two free radicals find each other. Electrons are now paired, reaction stops Functional groups susceptible to oxidation include: Alkenes, Aldehydes, Thiols, Oxy substitutes on aromatic rings, enols, alpha hydroxy ketones, and cyclic ethers Cynthia B. Jones, Ph.D. © 10/28/2024  Marshall Oxidation Functional Groups School of Pharmacy Alkenes Aldehydes Thiols Oxy Sub on Aromatic Rings Enols Alpha Hydroxy Ketones Cyclic ethers Cynthia B. Jones, Ph.D. © 10/28/2024  Marshall Oxidation School of Pharmacy Oxidation reaction is common and identified by color change in the drug solution Many drug solutions will turn yellow or darken as a result of oxidation The oxidation state of carbon is determined by the number of bonds between carbon and oxygen Cynthia B. Jones, Ph.D. © 10/28/2024  Marshall Initiators of Oxidation School of Pharmacy Environmental oxygen – reaction called auto-oxidation. Extracts electrons from a drug molecule with a susceptible group. R-H + O2 R· + HO·2 Metal cations in trace quantities Fe3+ + ArO- Fe2+ + ArO· Shortwave visible or ultraviolet light ArOH + hv Ar· + ·OH Cynthia B. Jones, Ph.D. © 10/28/2024  Marshall Photolysis School of Pharmacy Photolysis defined as interaction of short wave visible (400-700 nm) and ultraviolet (200-400 nm) light with a drug molecule The functional groups that are affected by photolytic reactants are adjacent to extensive pi systems There are several types of photolysis reactions: 1. Oxidation 2. Isomerization: Light can cause pi bonds to break and subsequent rotation around the single bond that will result in trans-cis conversions 3. Breaking of sigma bonds resulting in the loss of side chains 4. Benzylic halogens that are replaced by hydrogen from a solvent Cynthia B. Jones, Ph.D. © 10/28/2024  Marshall Racemization School of Pharmacy Racemization is conversion of an optically active compound into racemic (optically inactive) form. The racemization reaction can be considered a proton exchange with water, meaning that the preparation of a suspension or a powder for reconstitution will reduce the rate of the reaction Drugs with chiral carbons can experience loss of optical activity (and loss of biological activity) in solution due to proton exchange with the solvent Susceptible functional groups are slightly acidic protons: Drugs with protons on chiral carbons in the benzylic position or Drugs with protons on chiral carbons alpha to the carbonyl group Cynthia B. Jones, Ph.D. © 10/28/2024  Marshall Racemization School of Pharmacy Racemization results in reducing drug activity to half Most vitamins contain chiral centers but because they are built by plant or animal enzymes, they will be single isomers Most drugs with chiral carbons are not affected by racemization because only a small number are single isomers Cynthia B. Jones, Ph.D. © 10/28/2024  Marshall Protein Drug Degradation School of Pharmacy Protein drug molecules contain a number of susceptible functional groups, and as a result, these molecules can be hydrolyzed, oxidized, photolyzed and racemized Protein drugs have additional structural alterations that produce loss of pharmacological activity: Protein denaturation – A change in the spatial arrangement of the polypeptide chain Aggregation – A non-covalent assembly of protein molecules into multiples Fibrillation – An aggregate consisting of protein strands Adsorption – A monomolecular layer of protein molecules accumulated at a surface through unspecified attractive forces Cynthia B. Jones, Ph.D. © 10/28/2024  Marshall Protein Drug Degradation School of Pharmacy Some proteins aggregate naturally while others aggregate only when they begin to unfold due to changes in ionic strength, pH, or shear stress caused by shaking, in which case, aggregation would be considered instability DNA and RNA molecules can also undergo hydrolysis and oxidation reactions that are dependent on pH, temperature and light RNA is less stable than DNA As macromolecules the oligonucleotides are susceptible to conformation changes and aggregation Cynthia B. Jones, Ph.D. © 10/28/2024  Marshall Review Learning Outcomes – Part I School of Pharmacy 8.1 Compare and contrast the types of drug decomposition 8.2 Compare and contrast the different types of protein drug decomposition Cynthia B. Jones, Ph.D. © 10/28/2024  UNIVERSITY SCHOOL OF PHARMACY Drug Stability Marshall TM Part II School of Pharmacy Biopharmaceutics II Cynthia B. Jones, Ph.D. ©  Marshall Learning Outcomes – Part II School of Pharmacy https://accessmedicine.mhmedical.com/data/books/ This Photo by Unknown Author is licensed under This Photo by Unknown Author is licensed 2147/stringer5_ch4_f002.png CC BY-SA-NC under CC BY-SA-NC Classify and Calculate Calculate describe the desired shelf-life with kinetics of variables of changes in chemical decomposition temperature decomposition kinetics Cynthia B. Jones, Ph.D. ©  Marshall Rates of Drug Degradation School of Pharmacy The rate of a chemical reaction is related to the number of collisions and therefore the concentration of reactants in solution. The rate of the reaction can be studied by measuring the concentration of drug over time Drugs will degrade overtime, so it is important to determine the rate at which a particular drug degrades. Cynthia B. Jones, Ph.D. © 10/28/2024  Marshall Rate Constants and Reaction Rates School of Pharmacy Specific rate constant, k - the constant in the rate law associated with an elementary reaction Any change in the conditions of the reaction, for example, in temperature or solvent, or a slight change in one of the reacting species, will lead to a rate law having a different value for the specific rate constant. Variations in the specific rate constant are of great physical significance because a change in this constant represents a change at the molecular level as a result of a variation in the reaction conditions Rate constants derived from reactions consisting of a number of steps of different molecularity are functions of the specific rate constants for the various steps At times, variations in an overall rate constant can be used to provide useful information about a reaction, but quite commonly, anything that affects one specific rate constant will affect another Cynthia B. Jones, Ph.D. © 10/28/2024  Marshall Molecularity School of Pharmacy  A reaction whose overall order is measured can be considered to occur through several steps or elementary reactions  Each of the elementary reactions has a stoichiometry giving the number of molecules taking part in that step  Because the order of an elementary reaction gives the number of molecules coming together to react in the step, it is common to refer to this order as the molecularity of the elementary reaction  Solution reactions, especially in aqueous solutions, generally involve contributions to their reaction mechanisms from solvent molecules, which require specialized techniques to quantify and to understand  Reactions can be unimolecular, bimolecular, or termolecular (rare)  Complex reactions proceed through more than one step Cynthia B. Jones, Ph.D. © 10/28/2024  Marshall Molecularity School of Pharmacy Molecularity is simply the Number of molecules, atoms, or ions coming together to react in an elementary reaction. Unimolecular: Single molecule produces the product e.g. Br2 2Br Bimolecular Two molecules produces the product e.g. H2 + I2 2HI Cynthia B. Jones, Ph.D. © 10/28/2024  Marshall Rates of Drug Degradation Pseudofirst (Apparent) Order School of Pharmacy Most drugs decompose by reacting with other species Because many drugs decompose by reacting with other species, a simplified equation is used to describe the reaction rate as pseudofirst order “Apparent” or “pseudo”-order describes a situation where all but one of the reactants is present in large excess, or do not affect the overall reaction and can be held constant. Drug Products First Order Drug + H2O Products Pseudofirst Order Drug + O2 Products Pseudofirst Order Drug + light Products Pseudofirst Order Cynthia B. Jones, Ph.D. © 10/28/2024  Marshall First Order Reactions School of Pharmacy Log of drug The rate (slope) concentration decreases as the over time tells us concentration of the drug drug increases concentration changes linearly Slope = M over time M= Decline of drug Conc. over time  The slope is negative, the variable y, declines as x increases  The rate is NOT constant in a first order reaction Cynthia B. Jones, Ph.D. ©  First Order Reactions; Concentration dependent 10/28/2024  Marshall Rate of Drug Degradation Zero Order Kinetics School of Pharmacy The rate constant does not change in zero order kinetics Untransformed data The concentration of drug in solution in constant, is linear in a zero order reaction therefore the rate of degradation in suspension is constant Suspensions – drug particles in suspension ensures constant concentration, until all suspended particles have been converted into drug in solution, then changes to first order reaction Drug in Reservoir Drug in Solution Products Formed Cynthia B. Jones, Ph.D. © 10/28/2024  Marshall Rate Constants and Reaction Rates School of Pharmacy Units of Basic Rate Constants  Zero Order – moles liter-1 second-1  First Order – second-1  Second Order – liter second-1 mole-1 The order of a reaction is determined by the number of chemical species participating in the reaction Zero Order Reaction- Concentration independent First Order Reaction – Concentration dependent Cynthia B. Jones, Ph.D. © 10/28/2024  Marshall Methods to Determine Rates of Reaction Order School of Pharmacy The order of a reaction can be determined by several methods. The reaction must be allowed to proceed for an adequate time, typically a minimum of two to three half-lives, with longer periods recommended by some authorities. Substitution Method – Data from kinetic study substituted into the integrated form. Graphic Method – A plot of the data in the form of a graph Half-Life Method – half-life is obtained graphically Cynthia B. Jones, Ph.D. ©  Marshall Review Learning Outcomes – Part II School of Pharmacy 8.3 Classify and describe the kinetics of chemical decomposition 8.4 Calculate desired variables of decomposition kinetics Cynthia B. Jones, Ph.D. © February 14, 2017  UNIVERSITY SCHOOL OF PHARMACY Drug Stability Marshall TM Part III School of Pharmacy Biopharmaceutics II Cynthia B. Jones, Ph.D. ©  Learning Outcomes – Part Marshall III School of Pharmacy This Photo by Unknown Author is https://d2ebzu6go672f3.cloudfront.net/media/content/ This Photo by Unknown Author is licensed licensed under CC BY-SA-NC images/ExpiredDrug_dreamstime_m_20278518.jpg under CC BY Calculate shelf Describe List and life with environmental evaluate the changes in factors that approaches temperature affect shelf-life used to prevent drug stability problems Cynthia B. Jones, Ph.D. ©  Marshall Factors that affect shelf Life - Temp School of Pharmacy Rates of reaction are affected by temperature Collision Theory Reaction rates are expected to be proportional to the number of collisions per unit time. Because the number of collisions increases as the temperature increases, the reaction rate is expected to increase with increasing temperature. Frequency factor Also known as the Arrhenius factor; a constant indicating how many collisions have the correct orientation to lead to products. 10/28/2024 Cynthia B. Jones, Ph.D. ©  Marshall Temperature Effects - Arrhenius School of Pharmacy Arrhenius plot Drug is tested at higher temps, a plot is constructed and the room temperature rate constant is extrapolated from the plot Room temperature shelf life can be calculated from the extrapolated rate constant, k Ea, the energy barrier that the reactants have to climb to become products ranges between 12.2 and 24.5 kcal/mol for drug degradations Cynthia B. Jones, Ph.D. © 10/28/2024 Arrhenius Plot  Marshall Temperature Effects – Q10 School of Pharmacy Simonelli and Dresback designed more convenient method to estimate temperature affect on reaction rates Q10 method designed for determining the change in degradation rates based on temperature Q10 is the ratio of two rate constants for a drug measured at two temperatures that are 10°Celcius apart 10/28/2024 Cynthia B. Jones, Ph.D. ©  Marshall Rate of Drug Degradation Shelf Life and Half-life School of Pharmacy 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 Expiration date is the date placed on the container label of a drug product designating the date after which a batch of the product is not expected to remain with approved specifications, if stored under defined conditions, and after which it must not be used Half-Life - the period of time required for a drug to decompose to one-half of the original concentration 10/28/2024 Cynthia B. Jones, Ph.D. ©  Marshall Half Life and Shelf Life Calculations School of Pharmacy Half-Life Defined – the period of time required for a drug to decompose to one-half of the original concentration. Shelf Life Defined – the time period required for 10% of the material to disappear; it is the time at which the product has decreased to 90% of its original concentration. Manufacturers determine k, because of its relationship to shelf life Drug in solution Drug in suspension Cynthia B. Jones, Ph.D. ©  Managing Chemical Stability Marshall Problems School of Pharmacy Pharmacists must be able to recognize drugs with stability problems and have strategies to prevent those problems. There are three main categories that can be used to overcome chemical instability: Formulation changes Storage conditions Packaging Cynthia B. Jones, Ph.D. © 10/28/2024  Marshall Formulation Changes School of Pharmacy Hydrolyzable drugs Reduce or eliminate water from the formulations Control of pH with Buffers, HCl or NaOH Oxidizable drugs Replace the air in the container’s head space with nitrogen and boil water prior to its use to remove dissolved O2 Control pH: most drugs that oxidize are more stable at acidic pH, in protonated form Addition of chelating agents Addition of antioxidants Drugs that racemize Reduce or eliminate water from formulation Control pH with buffers, HCl or NaOH Cynthia B. Jones, Ph.D. © 10/28/2024  Marshall Storage School of Pharmacy Storage Conditions Store in dry environments for hydrolyzable drugs (ideal humidity 40-60%) Store in low temperatures – Stability of drugs in liquid form can be increased by decreasing temperatures in most cases Key Points to remember Elixirs may precipitate at refrigerator temps The solubility of O2 increases with colder temperatures Freezing protein drugs can cause them to denature Cynthia B. Jones, Ph.D. © 10/28/2024  Marshall Storage School of Pharmacy Oxidizable drugs are generally more stable at lower temps because the activity of metal ions and hydroxyl ion is reduced at lower temps It takes about 3 hours for 500 mL of a solution to reach room temperature after refrigeration. Infusion fluids in lines take about 20 minutes to reach room temp Thawing frozen minibags can take 90 minutes, while thawing 3 liter bags can take 8-10 hours https://thrivedripspa.com/wp-content/uploads/2016/01/ drip-spa-iv-infusion-bag-drip.png Cynthia B. Jones, Ph.D. © 10/28/2024  Marshall Packaging School of Pharmacy Packaging can be chosen to provide protection from oxygen, water vapor and light. It should be selected after the following are considered: Permeability – ability of volatile substances to move through packaging material Leaching – loss of materials from the packaging into the drug solution Adsorption – active or inactive components of drug solution adhere to the surface of packaging materials, which reduces the concentration in solution Cynthia B. Jones, Ph.D. © 10/28/2024  Marshall Packaging School of Pharmacy Other Considerations for packaging Type I glass leaches low levels of metal oxides into waters and drug solutions Other glass types have higher levels of leaching and should be used with caution especially for drug solutions with pH greater than 7 Plastics have a number of additives that are Type I glass potential leachables into drug solutions amber Rubber materials in stoppers and syringe plungers Vial can leach metals, 2-mercaptobenzothiazole and nitrosamines Cynthia B. Jones, Ph.D. © 10/28/2024  Marshall Review Learning Outcomes School of Pharmacy 8.5 Calculate shelf-life with changes in temperature 8.6 Describe environmental factors that affect shelf-life 8.7 List and evaluate the approaches used to prevent drug stability problems Cynthia B. Jones, Ph.D. © 10/28/2024