Module 8: Chemical Kinetics PDF

Module 8: CHEMICAL KINETICS KNOWLEDGE OBJECTIVES 1. Define chemical kinetics. 2. Differentiate the various rates and orders of decomposition. 3. Compute rate constants, half-life and shelf-life. MODULE OUTLINE A. Orders of Reaction 1. Factors affecting reaction rates 2. Zero-orde...

Module 8: CHEMICAL KINETICS KNOWLEDGE OBJECTIVES 1. Define chemical kinetics. 2. Differentiate the various rates and orders of decomposition. 3. Compute rate constants, half-life and shelf-life. MODULE OUTLINE A. Orders of Reaction 1. Factors affecting reaction rates 2. Zero-order process 3. First-order process B. Half-life C. Shelf-Life and Expiration Dating 1. Decomposition and stabilization of medicinal agents D. Stability Studies 1. Methods of evaluating the stability of pharmaceutical preparations Chemical Kinetics is the study of the rates of reaction and the mechanism by which these reactions occur.  It is used to ascertain pharmaceutical product stability and bioavailability  Proper storage of drug products, providing beyond use dates for prescriptions, and the preparation and storage of sterile products – are some of examples of common scenarios that are dependent on the knowledge of the chemical kinetics of pharmaceuticals. To ensure that the patient receives the correct dose of a drug, whatever form it is carried in, the rate of degradation of a drug must be known. Rate of Reaction (Degradation rate) is the velocity or speed with which a reaction occurs.  Depends on the reactant concentration, temperature and pH.  It is determined by the change in the concentration of the reactants or products as a function of time.  The rate may be determined by the slowest or rate determining step. Orders of reaction:  the number of concentrations that determine rate.  the way in which the concentration of the reactant influences the rate. Law of mass action “The rate of a reaction is proportional to the molar concentrations of the reactants each raised to power equal to the number of molecules undergoing reaction”. aA+bB Product Rate α [A]a. [B]b Rate = K [A]a. [B]b Order of reaction = sum of exponents Order of A = a and B = b Then Overall order = a + b A. Zero Order – is one in which the rate is independent of the concentrations of the reactants. B. First Order – is one where the rate of reaction is directly proportional to the concentration of one of the reactants. The length of time a drug remains stable is determined by: A. Inherent factors - A drug may be changed or decomposed at a molecular level by the changing of energy and the breaking at molecular level.  Solvolysis – the splitting of a drug molecule via a solvent molecule  Oxidation  Photolysis  Dehydration  Racemization B. External factors - pH - pKa - solubility and dissolution - excipient interactions - temperature Half-life (t ½) is the time required for one-half of the material to degrade. Drug Stability The resistance of the drug to the various chemical, physical, and microbiological reactions that may change the original properties of the preparations during transport, storage and use.  Quantitatively it is expressed as shelf life. Shelf life (t90) (expiration dating period) is the period where 90% of the original concentration is left and 10% is already degraded.  The 10% loss criterion is generally based on the negligible clinical consequences of such a loss. 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.  These conditions may include: A requirement that the container remains unopened. 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 within the approved specifications, if stored under defined conditions, and after which it must not be used. Decomposition and Stabilization of Medicinal Agents Pharmaceutical decomposition processes include: - Hydrolysis - Dehydration - Isomerization - Epimerization - Oxidation - Photolysis Stability of a pharmaceutical product may be defined as the capability of a particular formulation in a specific container/closure system to remain within its physical, chemical, microbiological, toxicological, protective and informational specifications.  The extent to which a product retains, within the specified limits, throughout its period of storage and use, the same properties and characteristics possessed at the time of its packaging. Stability testing thus evaluates the effect of environmental factors on the quality of a drug substance or a formulated product which is utilized for prediction of its shelf life, determine proper storage conditions and suggest labeling instructions. The data generated during the stability testing is an important requirement for regulatory approval of any drug or formulation. Factors Influencing the Stability of a Pharmaceutical Product: - stability of the active ingredient(s) - interaction between active ingredients and excipients - manufacturing process followed, - type of dosage form, - container/closure system used for packaging and light, - heat and moisture conditions encountered during shipment, storage and handling STABILITY TESTING METHODS In early stages, accelerated stability testing (at relatively high temperatures and/or humidity) is used in order to determine the type of degradation products which may be found after long- term storage. Testing under less rigorous conditions i.e. those recommended for long-term shelf storage, at slightly elevated temperatures is used to determine a product’s shelf life and expiration dates. A. Real time stability testing  - Normally performed for longer duration of the test period in order to allow significant product degradation under recommended storage conditions. B. Accelerated stability testing - A product is stressed at several high (warmer than ambient) temperatures and the amount of heat input required to cause product failure is determined.  This is done to subject the product to a condition that accelerates degradation.  This information is then projected to predict shelf life or used to compare the relative stability of alternative formulations.  This usually provides an early indication of the product shelf life and thus shortening the development schedule. The concept of accelerated stability testing is based upon the Arrhenius equation lnK= lnA + Δ /  This equation describes the relationship between storage temperatures and degradation rate  According to Arrhenius, for every 10º rise in temperature, the speed of reaction increases about 2-3 times C. Retained sample stability testing - A usual practice for every marketed product for which stability data are required. In this study, stability samples, for retained storage for at least one batch a year are selected. D. Cyclic temperature stress testing Not a routine testing method for marketed products. In this method, cyclic temperature stress tests are designed on knowledge of the product so as to mimic likely conditions in market place storage.  The period of cycle mostly considered is 24 hours since the diurnal rhythm on earth is 24 hours, which the marketed pharmaceuticals are most likely to experience during storage. Protocol for Stability Testing a) Batches - developmental stages are generally carried out on a single batch while studies intended for registration of new product or unstable established product are done on first three production batches, while for stable and well-established batches, even two are allowed. b) Containers and Closures - testing is done on the product in immediate containers and closures proposed for marketing. c) Orientation of storage of containers - samples of the solutions, dispersed systems and semi solid drug products for stability studies must be kept upright and positioned either inverted or on the side to allow for full interaction of the product with the container- closure. d) Sampling time points - frequency of testing should be such that it is sufficient to establish the stability profile of the new drug substance. e) Sampling Plan - sampling plan for stability testing involves, planning for the number of samples to be charged to the stability chambers and sampling out of the charged batch so as to cover the entire study. f) Test parameters - the stability test protocol should define the test parameters that would be used for evaluation of the stability samples. The tests that monitor the quality, purity, potency, and identity which could be expected to change upon storage are chosen as stability tests.