Dosage Forms Lecture 3 PDF

 Dr. Dr. Walaa E.Abd El Hady Ghada Ahmed El-Emam Lecturer of Pharmaceutics Lecturer of Pharmaceutics [email protected] [email protected] Dr/ Randa Hanie Awadeen...

 Dr. Dr. Walaa E.Abd El Hady Ghada Ahmed El-Emam Lecturer of Pharmaceutics Lecturer of Pharmaceutics [email protected] [email protected] Dr/ Randa Hanie Awadeen Lecturer of Pharmaceutics [email protected]  Physical stability of different dosage forms Effect of packaging materials on the stability Lecture 3 Stability tests Factors affecting drug stability  1- Solutions:  A stable solution must retain original color, odor, taste, clarity, pH and viscosity throughout its shelf-life.  Any changes in these characteristics indicate the presence of physical instability.  2- Suspension: A stable suspension must retain the following properties throughout its shelf-life: 1- Its original color, odor, taste, and rheological properties. 2- Homogenously redispersed by moderate shaking (no cake). 3- Particle size distribution not affected by storage. 4- No crystal growth. Any changes in these characteristics indicate the presence of physical instability.  3. Emulsions: A stable emulsion must retain the following properties throughout its shelf-life: 1. Its original color, odor, taste, and rheological properties. 2. Homogenously redispersed by moderate shaking. 3. Globule size distribution not affected by storage. 4. No cracking or phase separation. 5. No microbial or fungal growth. Any changes in these characteristics indicate the presence of physical instability. 1. Ointments:  A stable ointment must retain its original: color, odor, homogeneity, and viscosity throughout its shelf life. Any changes in these characteristics indicate the presence of physical instability. 1. Ointments: The main stability problems in ointment are ‘‘bleeding’’, which is the separation of fluid components (oils) on the top of ointment. 2. Creams:  A stable cream must retain its original color, odor, homogeneity and viscosity throughout its shelf-life. Any changes in these characteristics indicate the presence of physical instability. The main stability problems in creams are their drying and cracking. 1. Tablets:  Stable tablets should retain their original color, shape, weight, hardness, disintegration time and dissolution rate throughout their shelf-life. Any changes in these parameters will seriously affect the bioavailability of the drug in such tablets. 1. Tablets: 2. Capsules: The physical instability problems in capsules are:  The capsule shell may soften, and the capsules stuck together  The capsule shell may harden and crack under pressure. Colour, clarity (for solutions), particulate matter, pH, sterility, endotoxins. Stability studies for powders for injection solution should include monitoring for color, reconstitution time and water content. The stability studies for Suspension for injection should include, in addition, particle size distribution, redispersibility and rheological properties. The stability studies for Emulsion for injection should include, in addition, phase separation, viscosity, mean size and distribution of dispersed phase globules. 1. Glass containers: Glass is the container of choice for pharmaceutical dosage forms because of its resistance to decomposition by atmospheric condition or by solid or liquid contents of different chemical composition. Types of glass: Boro-silicate glass. Soda-lime glass. Treated soda-lime glass. 1. Leaching of alkali to the product: Leaching of alkali to the product, especially aqueous preparations, will rise the pH of the product which will lead to precipitation or increase the degradation rate of pH sensitive drugs. Treated soda-lime glass consists of soda-lime glass but the inner surface of the glass is treated with sulfur dioxide, In the presence of water vapor and heat, where the alkaline surface becomes neutral. 2. Formation of insoluble flakes into the formulation: Glass may possess various additives such as oxides of boron, sodium, potassium, calcium, iron, and magnesium, which may add to alter its properties (to be easily shaped). During preparation, a reaction occurs between the ions present in glass and these salts to form insoluble salts as flakes.  To avoid the formation of insoluble flakes: 1. The glass containers should have a minimal amount of these ions. 2. Pretreatment of the containers with hot dilute acid solution.  They include polyethylene, polystyrene, polypropylene, and polyvinyl chloride. Plastic containers are light, less fragile, and not dangerous when subjected to sudden shock. 1. Permeability: The permeability of plastic containers occurs in two directions: a) From the solution in the container into the ambient environment. Examples: 1. Volatile oils, flavor and perfumes. 2. Loss of moisture or water from the formulation. b) From the ambient environment through the plastic wall into the formulation. Examples: 1. Gases such as oxygen or carbon dioxide in the air have been migrate and penetrate the plastic wall to affect the preparation. 2. Moisture penetration from the atmosphere has a deleterious effect on solid dosage forms such as tablets and capsules. 2. Migration through the wall: Component migration of emulsions and creams through the wall of some plastics causes either a deleterious change in the formulation or collapse of the container. 3. Drug-plastic interactions: Many drugs such as insulin, diazepam, isosorbide dinitrate, nitroglycerin, and other are shown to have substantial adsorption when stored in bags or infused via administration set which are made from the plastic-PVC. Rubber is a common component of stoppers, caps, and parts of dropper assemblies. Drug rubber interaction includes: Sorption of the drug, preservative or other formulation ingredients may occur into rubber. How to solve sorption problem? Lining the rubber closures with an epoxy resin reduces the amount of leached extractives but has essentially no effect on the sorption of the active ingredients and others. Teflon coated rubber closures may prevent sorption and leaching. Long term Intermediate stability stability studies studies Accelerated stability studies Types of stability tests I- Stability on pre-formulation batches. II- Accelerated and long-term testing for registration. III- On-going Stability testing. IV- Follow-up Stabilities.  Long term tests Intermediate studies Accelerated studies  25°C ± 2°C / 60% RH ± 5%  30°C ± 2°C / 65% RH ± 5% RH 40°C ± 2°C/75% RH ± RH One year→ every three  Length of study: (min. 6 months, 5% R months max. 12 months) Length of study: 6 Two years → every six  Long term study (refrigerator): 5°C months months Three years → every year ± 3°  Accelerated study once.  Length of study: min. 12 month (refrigerator): 25°C ±  Length of study: min. 1 year, (max. 5 years)  Long term study (freeze): -20°C ± 2°C/60% RH ± 5% RH 5° Length of study: min. 6  Length of study: min. 12 months months  Using exaggerated storage conditions to increase the rate of chemical degradation or physical change of a drug product.  Help identify the likely degradation products.  Useful in establishing degradation pathways.  To evaluate the effect of short-term excursions outside the label storage conditions (e.g., high temperature during shipping).  Temperature: in 10°C increments (e.g., 50°C, 60°C) above that for accelerated testing.  Humidity: ≥75% relative humidity (RH) Methods for storage of pharmaceutical products 1. Storing the products in well-closed containers. 2. Storing the products by protection from light. 3. Storing the products in a cool place. 4. Storing the products by the addition of other substances. Accelerated stability testing in emulsions  An emulsion is stored at elevated temperature. This decreases viscosity of the continuous phase.  If the emulsion withstands this stress it is assumed to be stable at normal conditions of storage.  Creaming and flocculation are slow processes. Centrifugation accelerates rate of creaming and flocculation in emulsions.  The emulsion is subjected to different centrifugal speeds and separation of phases is observed at different time periods.  Bad emulsion separates oil instantly.  Good emulsion does not exhibit detectable separation of oil phase until certain period. Accelerated tests for Suspensions  Cake formation is accelerated by centrifugation. High speed centrifugation is hence not preferred; low speed centrifugation is used to study physical stability.  A Freeze-Thaw cycling technique is one of the stress testing. This cycling treatment promotes particle growth and has primary importance for changes in absolute particle size, particle size distribution and crystal habit.  The equipment used for stability testing is called Stability chamber.  These are specialized environmental chambers that can simulate the storage condition and enable evaluation of product stability based on real-time, accelerated and long-term protocols.  Such chambers or rooms are engineered and qualified to ensure uniform exposure of the set conditions to all the samples in the chamber.  Two types of light sources are usually employed in photo stability chambers, one is the combination of cool white and near UV fluorescent tubes, while second are the artificial daylight lamps, e.g., xenon or metal halide. 1. Batches tested 2. General information 3. Container/closure system 4. Literature and supporting data 5. Stability-indicating analytical methods 6. Testing plan 7. Test parameters 8. Test results 9. Other requirements (post-approval commitments) 10. Conclusion  Drug Temperature Concentration incompatibility Pharmaceutical pH Oxygen dosage forms Moisture Light 1. Temperature: high temperature accelerates oxidation, reduction and hydrolysis reaction which lead to drug degradation. 2. pH: Acidic and alkaline pH influence the rate of decomposition of most drugs. Many drugs are stable between pH 4 and 8. 3. Moisture: a. Water catalyzes chemical reactions as oxidation, hydrolysis and reduction reaction b. Water promotes microbial growth 4. Light: Light affects drug stability through its energy or thermal effect which lead to oxidation. 5. Pharmaceutical dosage forms: Solid dosage forms are more stable than liquid dosage forms for presence of water. 6. Concentration: Rate of drug degradation is constant for the solutions of the same drug with different concentration. 7. Drug incompatibility: Reactions between components of pharmaceutical dosage forms itself or between these components and cover of the container. 8. Oxygen: Exposure of drug formulations to oxygen affects their stability.