3 Stability of drugs (Cont.) Stability: is the capacity of a drug product to remain within specifications established to ensure its identity, strength quality and purity.Instability may cause- Undesired change in performance, i.e. dissolution/bioavailability- Substantial changes in physical appearance of the dosage form- Causing product failures
4 Factors affecting Stability 1- Environmental factors- Temperature Light- Oxygen Moisture- Carbon dioxide2- Drugs or excipients in the dosage formParticle size of drugpH of the vehicle3- Microbial contamination4- Trace metal Contamination5- Leaching from containers
5 Types of stability studies: ۞ Physical۞ Chemical۞ Microbiological
6 Physical stability Physical stability implies that: - The formulation is totally unchanged throughout its shelf life and has not suffered any changes by way of appearance, organoleptic properties, hardness, brittleness, particle size etc.It is significant as it affects:pharmaceutical elegancedrug content uniformitydrug release rate.
7 Physical stability (Cont.) FormulationLikely physical instability problemsEffectsOral solutions1- Loss of flavour2- Change in taste3- Presence of off flavours due to interaction with plastic bottle4- Loss of dye5- Precipitation6- discolorationChange in smell or feel or taste
8 Physical stability (Cont.) FormulationLikely physical instability problemsEffectsParenteral solutions1. Discoloration due to photo chemical reaction or oxidation2. Presence of precipitate due to interaction with container or stopper3. Presence of “whiskers”4. Clouds due to:(i) Chemical changes(ii) The original preparation of a supersaturated solutionChange in appearance and in bio-availability
9 Physical stability (Cont.) FormulationLikely physical instability problemsEffectsSuspensions1- settling2- caking3- crystal growth1-Loss of drug content uniformity in different doses from the bottle2- loss of elegance.
10 Physical stability (Cont.) FormulationLikely physical instability problemsEffectsEmulsions1- Creaming2- coalescence1- Loss of drug content uniformity in different doses from the bottle2- loss of elegance
12 Physical stability (Cont.) FormulationLikely physical instability problemsEffectsSemisolids (Ointments and suppositories)1. Changes in:a) Particle sizeb) Consistency2. Caking or coalescence3. Bleeding1-Loss of drug content uniformity2- loss of elegance3-change in drug release rate.
13 Physical stability (Cont.) FormulationLikely physical instability problemsEffectsTabletsChange in:a) Disintegration timeb) Dissolution profilec) Hardnessd) Appearance (soft and ugly or become very hard)Change in drug release
14 Physical stability (Cont.) FormulationLikely physical instability problemsEffectsCapsulesChange in:a) Appearanceb) Dissolutionc) StrengthChange in drug release
15 Chemical stability: Chemical stability implies: The lack of any decomposition in the chemical moiety that is incorporated in the formulation as the drug, preservatives or any other excipients.This decomposition may influence the physical and chemical stability of the drug
16 Mechanisms Of Degradation 1- Hydrolysis:Hydrolysis means “splitting by water’’
17 Some Functional Groups Subject to Hydrolysis Drug typeExamplesEstersAspirin, alkaloidsDexmethasne sodium phosphateNitroglycerinLactonesPilocarpineSpironolactoneAmidesChloramphenicolLactamsPenicillinsCephalosporins
18 Some Functional Groups Subject to Hydrolysis Drug typeExamplesImidesGlutethimideMalonic ureasBarbiturates
19 Mechanisms Of Degradation 2- OxidationOxidation of inorganic and organic compounds is explained by a loss of electrons and the loss of a molecule of hydrogen.
20 Some Functional Groups Subject to Autoxidation ExamplesCatecholsCatecholamines (dopamine)EthersDiethyletherThiolsDimercaprol (BAL)ThioethersChlorpromazineCarboxylic acidsFatty acids
21 Mechanisms Of Degradation 3- PhotolysisIt means: decomposition by lighte.g. Sodium nitroprusside is administered by intravenous infusion for the management of acute hypertension.If the solution is protected from light, it is stable for at least 1 year; if exposed to normal room light, it has a shelf life of only 4 hours.
22 Mechanisms Of Degradation Relationship between wavelength and associated energy of various forms of light.Type of radiationWavelengthEnergyU.V.VisibleI.r.50 – 400400 – 750750 – 10,000Kcal mol-1287 – 7236 - 1Conventional tungsten filament light bulbs are safe anddo not contribute to photolysis.
23 Mechanisms Of Degradation Photolysis is prevented by:1- suitable packing in amber coloured bottles2- cardboard outers3- aluminium foil over wraps
24 Factors Affecting Rates Of Degradation 1- pHThe acidity or the alkalinity of a solution has a profound influence on the decomposition of drug compound.Aspirin buffered solution is maximum stable at a pH of 2.4, above a pH of 10 the decomposition rate rapidly increases.pH can also influence the rate of oxidation.The system is less readily oxidized when the pH is low.
25 Factors Affecting Rates Of Degradation 2- ComplexationComplex formation reduces the rate of hydrolysis and oxidation.e.g. caffeine complexes with local anesthetics, such as benzocaine, procaine and tetracaime to cause a reduction in their rate of hydrolytic degradation.
26 Factors Affecting Rates Of Degradation 3- SurfactantsNonionic, cationic and anionic surfactants when added to solutions containing drugs form micelle and the drug particles become trapped in the micelle.The hydrolytic groups such as OH cannot penetrate this micelle cover and reach the drug particles, hence hydrolysis rate is decreased.
27 Factors Affecting Rates Of Degradation 4- Presence of heavy metalsHeavy metals, such as copper, iron, cobalt and nickel increase the rate of formation of free radicals and enhance oxidative decomposition.5- Light and humidityLight, especially ultraviolet light enhances photolysis and humidity enhances hydrolytic decomposition.
28 Stabilization of drugs against hydrolysis, oxidation and photolysis 1- TemperatureAll the drug products are stored at suitable temperatures to avoid thermal acceleration of decomposition. Three varieties of temperatures are suggested for storage of drug products. Room temperature, cool storage and cold storage.2- LightLight sensitive materials are stored in ambered colour bottles.
29 Stabilization of drugs against hydrolysis, oxidation and photolysis 3- HumidityPacking materials are chosen (usually glass and plastic) to prevent exposure of drug products to high humid condition.4- OxygenProper packing keeping the oxygen content of the solution less and leaving very little head space in the bottle above the drug products are methods to fight against oxidation.
30 Stabilization of drugs against hydrolysis, oxidation and photolysis Antioxidants commonly used forAqueous systemsOil systemsSodium metabisulfiteSodium thiosulfateAscorbic acidAscorbyl palmitateButylaled hydroxy tolueneButylated hydroxy anisole
31 Stabilization of drugs against hydrolysis, oxidation and photolysis 5- Chelating AgentsChelating agents form complexes with heavy metal ions and prevent them from catalyzing oxidative decomposition.e.g. ethylenediamine tetracetic acid (EDTA) derivatives and salts, citric acid and tartaric acid.6- SolventsBy the addition of a suitable solvent hydrolysis rate may be decreased.
32 Microbiological stability Microbiological stability implies that:The formulation has not suffered from any microbiological attack and is meeting the standards with respect to lack of contamination/sterility.
34 Sources of Microbial Contamination GumsActinomycesAnimal productsSalmonella, ColiformsPersonnelColiforms, Staphylococci, Sterptococci
35 To prevent contamination to the formulation during storage suitably designing the containers(2) usually using single dose containers(3) sticking to proper storage conditions(4) adding an antimicrobial substance as preservative.
36 Preservatives used in pharmaceutical preparations: Concentration% w.vInjectionsPhenolCresolChlorocresol0.50.30.1Eye dropsChlorhexidine acetateBenzalkonium chloride0.01MixturesBenzoic acidMethyl parabenAlcohol12-20
37 Preservatives used in pharmaceutical preparations: Concentration% w.vCreamsParabensChlorocresol0.1TabletsMethylparaben
38 Packaging And Stability : The immediate container and closure are particularly important in affecting product stability.
39 Packaging And Stability: Glass- Glass is resistant to chemical and physical change and is the most commonly used material.LimitationsOvercome1. Its alkaline surfaceuse of Borosilicate glass2. Ions may precipitate insoluble crystals from the glassthe use of buffers3- Permits the transmission of light which may accelerate decomposition.Amber coloured glass
40 Packaging And Stability : PlasticsThe problems with plastic are:1.Migration of the drug through the plastic into the environment.2.Transfer of environmental moisture, oxygen, and other elements into the pharmaceutical product.3.Leaching of container ingredients into the drug.4.Adsorption of the active drug or excipients by the plastic.
41 Packaging And Stability : MetalsVarious alloys and aluminium tubes may be utilized as containers for emulsions, ointments, creams and pastes.Limitation: They may cause corrosion and precipitation in the drug product.Overcome: Coating the tubes with polymers may reduce these tendencies.
42 Packaging And Stability : RubberRubber also has the problems of extraction of drug ingredients and leaching of container ingredients.The pretreatment of rubber vial stoppers and closures with water and steam reduces potential leaching.