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Dr. Gehan Fathy Atia Assistant Prof. (Pharmaceutics)

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Presentation on theme: "Dr. Gehan Fathy Atia Assistant Prof. (Pharmaceutics)"— Presentation transcript:

1 Dr. Gehan Fathy Atia Assistant Prof. (Pharmaceutics)

2 STABILITY OF DRUGS

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 dioxide 2- Drugs or excipients in the dosage form - Particle size of drug - pH of the vehicle 3- Microbial contamination 4- Trace metal Contamination 5- Leaching from containers

5 Types of stability studies: ۞ Physical ۞ Chemical ۞ Microbiological

6 Physical stability Physical stability implies that: 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 elegance pharmaceutical elegance drug content uniformity drug content uniformity drug release rate. drug release rate.

7 Physical stability (Cont.) Formulation Likely physical instability problems Effects Oral solutions 1- Loss of flavour 2- Change in taste 3- Presence of off flavours due to interaction with plastic bottle 4- Loss of dye 5- Precipitation 6- discoloration Change in smell or feel or taste

8 Physical stability (Cont.) Formulation Likely physical instability problems Effects Parenteral solutions 1. Discoloration due to photo chemical reaction or oxidation 2. Presence of precipitate due to interaction with container or stopper 3. Presence of “whiskers” 4. Clouds due to: (i) Chemical changes (ii) The original preparation of a supersaturated solution Change in appearance and in bio- availability

9 Physical stability (Cont.) Formulation Likely physical instability problems Effects Suspensions 1- settling 2- caking 3- crystal growth 1-Loss of drug content uniformity in different doses from the bottle 2- loss of elegance. 2- loss of elegance.

10 Physical stability (Cont.) Formulation Likely physical instability problems Effects Emulsions 1- Creaming 2- coalescence 1- Loss of drug content uniformity in different doses from the bottle 2- loss of elegance

11 Physical stability (Cont.) Coalescence

12 Formulation Likely physical instability problems Effects Semisolids (Ointments and suppositories) 1. Changes in: a) Particle size b) Consistency 2. Caking or coalescence 3. Bleeding 1-Loss of drug content uniformity 2- loss of elegance 3-change in drug release rate.

13 Physical stability (Cont.) Formulation Likely physical instability problems Effects Tablets Change in: a) Disintegration time b) Dissolution profile c) Hardness d) Appearance (soft and ugly or become very hard) Change in drug release

14 Physical stability (Cont.) Formulation Likely physical instability problems Effects Capsules Change in: a) Appearance b) Dissolution c) Strength c) Strength Change in drug release

15 Chemical stability: Chemical stability implies: 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. 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 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 type Examples Esters Aspirin, alkaloids Dexmethasne sodium phosphate Nitroglycerin LactonesPilocarpineSpironolactone AmidesChloramphenicol LactamsPenicillinsCephalosporins

18 Some Functional Groups Subject to Hydrolysis Drug type Examples ImidesGlutethimide Malonic ureas Barbiturates

19 Mechanisms Of Degradation 2- Oxidation Oxidation 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 Functional group Examples Catechols Catecholamines (dopamine) EthersDiethylether Thiols Dimercaprol (BAL) ThioethersChlorpromazine Carboxylic acids Fatty acids

21 Mechanisms Of Degradation 3- Photolysis It means: decomposition by light It means: decomposition by light e.g. Sodium nitroprusside is administered by intravenous infusion for the management of acute hypertension. e.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. Relationship between wavelength and associated energy of various forms of light. Type of radiation WavelengthEnergy U.V. Visible I.r. 50 – – – 10,000 Kcal mol – Conventional tungsten filament light bulbs are safe and do not contribute to photolysis.

23 Mechanisms Of Degradation Photolysis is prevented by: Photolysis is prevented by: 1- suitable packing in amber coloured bottles 2- cardboard outers 3- aluminium foil over wraps

24 Factors Affecting Rates Of Degradation 1- pH The acidity or the alkalinity of a solution has a profound influence on the decomposition of drug compound. The 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. 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- Complexation Complex formation reduces the rate of hydrolysis and oxidation. Complex 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- Surfactants Nonionic, cationic and anionic surfactants when added to solutions containing drugs form micelle and the drug particles become trapped in the micelle. Nonionic, 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. 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 metals Heavy metals, such as copper, iron, cobalt and nickel increase the rate of formation of free radicals and enhance oxidative decomposition. Heavy metals, such as copper, iron, cobalt and nickel increase the rate of formation of free radicals and enhance oxidative decomposition. 5- Light and humidity Light, especially ultraviolet light enhances photolysis and humidity enhances hydrolytic decomposition. Light, especially ultraviolet light enhances photolysis and humidity enhances hydrolytic decomposition.

28 Stabilization of drugs against hydrolysis, oxidation and photolysis 1- Temperature All 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. All 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- Light Light sensitive materials are stored in ambered colour bottles. Light sensitive materials are stored in ambered colour bottles.

29 Stabilization of drugs against hydrolysis, oxidation and photolysis 3- Humidity Packing materials are chosen (usually glass and plastic) to prevent exposure of drug products to high humid condition. Packing materials are chosen (usually glass and plastic) to prevent exposure of drug products to high humid condition. 4- Oxygen Proper 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. Proper 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 for Aqueous systems Oil systems Sodium metabisulfite Sodium thiosulfate Ascorbic acid Ascorbyl palmitate Butylaled hydroxy toluene Butylated hydroxy anisole

31 Stabilization of drugs against hydrolysis, oxidation and photolysis 5- Chelating Agents Chelating agents form complexes with heavy metal ions and prevent them from catalyzing oxidative decomposition. Chelating 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- Solvents By the addition of a suitable solvent hydrolysis rate may be decreased. By the addition of a suitable solvent hydrolysis rate may be decreased.

32 Microbiological stability Microbiological stability implies that: 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.

33 Water gram-negative groups: Pseudomonas, Xanthamonas, Flavobacterium Air Mould spores: Penicillium, Aspergillus Bacterial spores: Bacillus spp. Yeasts Raw materials Micrococci StarchesColiforms PigmentsSalmonella Sources of Microbial Contamination: Microbiological stability

34 Sources of Microbial Contamination GumsActinomyces Animal products Salmonella, Coliforms Personnel Coliforms, Staphylococci, Sterptococci

35 To prevent contamination to the formulation during storage (1) 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: PreparationPreservativeConcentration % w.v InjectionsPhenolCresolChlorocresol Eye drops Chlorhexidine acetate Benzalkonium chloride Mixtures Benzoic acid Methyl paraben Alcohol

37 Preservatives used in pharmaceutical preparations: PreparationPreservativeConcentration % w.v CreamsParabensChlorocresol TabletsMethylparaben0.1

38 Packaging And Stability : The immediate container and closure are particularly important in affecting product stability. The immediate container and closure are particularly important in affecting product stability.

39 Packaging And Stability: Glass Glass - Glass is resistant to chemical and physical change and is the most commonly used material. LimitationsOvercome 1. Its alkaline surface use of Borosilicate glass 2. Ions may precipitate insoluble crystals from the glass the use of buffers 3- Permits the transmission of light which may accelerate decomposition. Amber coloured glass

40 Packaging And Stability : Plastics Plastics The 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 : Metals Metals - Various 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 : Rubber Rubber - Rubber 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.


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