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Drug Stability and Degradation Products

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Miky Moheb

on 3 December 2013

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Transcript of Drug Stability and Degradation Products

Made By :
Ebram Ibrahim Nageeb 148

Drug Stability and Degradation products
Stability of pharmaceutical product
The USP defines the stability of a pharmaceutical product as “extent to which a product retains with in specified limits and throughout its period of storage and use i.e. its shelf life, the same properties and characteristics that it possessed at the time of its manufacture”.
What are changes?

Physical changes
Chemical changes
Microbial changes
Therapeutic changes
Toxicological changes
Chemical degradative routes:
1. Solvolysis
2. Oxidation
3. Dehydration
4. Optical isomerization
5. Hydrolysis
6. Photolysis
7. Drug-excipient & drug-drug interaction
Stabilization of Drug Substances against Chemical Degradation By :
Physical factors of degradation
1. Polymorphs
2. Vaporization
3. Water loss
4. Absorption of Water
5. Particle Sedimentation
Microbial degradation
1. Effects of Microbial Instability
2. Prevention of microbial spoilage
3. Containers
It is defined as the time necessary for the drug to decay to 90% of its original concentration.
Ideally any commercial pharmaceutical product should have a shelf life of 5 years.
what is shelf_life ??

1) Quality of a drug substance or drug product
2) shelf life for the drug product
3) Recommended storage conditions


1) Chemical degradation may lead lowering of concentration of drug in dosage form
2) Toxic product may form due to degradation of active ingredients
Stability is used to determine:
Why stability testing is necessary :

In solvolysis the active drug undergo decomposition following reaction with the solvent present.
Usually the solvent is water, but sometimes the reaction may involve pharmaceutical co-solvents such as ethyl alcohol or polyethylene glycol.
These solvents can act as nucleophiles, attacking the electropositive centers in drug molecules.
The most common solvolysis reaction encountered in pharmaceuticals are those involving ‘’labile’’ carbonyl compounds such as esters, lactones and lactams.
* In pharmaceutical dosage forms, oxidation is usually mediated through reaction with atmospheric oxygen under ambient conditions, a process commonly referred to as autoxidation.
* Sensitivity to oxidation of a drug can be ascertained by investigating its stability in an atmosphere of high oxygen tension.
* Oxidation reactions can be catalyzed by oxygen, heavy metal ions and light, leading to free radical formation.
* Aldehydes, alcohols, phenols, alkaloids and unsaturated fats and oil are all susceptible to oxidation.
• The preferred route of degradation for prostaglandin E2 and tetracycline is the elimination of a water molecule from their structures.

• In physical dehydration processes water removal does not create new bonds but often changes the crystalline structure of the drug.

• Since it is possible that anhydrous compounds may have different dissolution rates compared to their hydrates, dehydration reactions involving water of crystallization may potentially affect the absorption rate of the dosage form.
• A change in the optical activity of a drug may result as a change in its biological activity.
• Racemization is the main type of optical isomerization which affects drug molecules and it occurs when the optically active form of the drug is converted into its enantiomer.
• Racemization continues until 50% of the original drug has been converted into its enantiomer. In most cases the enantiomer has less therapeutic effect than the original drug.
• Drugs with functional groups such as esters, amides, lactones or lactams may be susceptible to hydrolytic degradation.

It is probably the most commonly encountered mode of drug degradation in solutions and solid state because of the prevalence of such groups in medicinal agents and the ubiquitous nature of water.



Water can also act as a vehicle for interactions or facilitate microbial growth.
Ultra violet light causes more damage than red/orange light as it has higher energy and shorter wavelength .
•Before a photolytic reaction can occur, the energy from light radiation (in the same spectral region) must be absorbed by the molecules.
•Two way in which photolysis can occur are: the light energy absorbed must be sufficient to achieve the activation energy or the light energy absorbed by molecules is passed on to other molecules which allow degradation to take place.
In this process, light may be the initiator while the reaction may be oxidation, polymerization or ring rearrangement.
•Can be controlled by using:
1.Amber Glass Container
2.Opaque Container
3.Incorporating a Dye
•Drugs are rarely formulated as just the drug substance itself.

•Often, additives or excipients are present in the formulation.

•Quite often, reactions can occur between the drug and one or more additives. Similarly, two drugs might be formulated in the same product and react with each other.
1. Modification of Molecular Structure of Drug Substances

2. Complex Formation between drugs and excipients

3. Formation of Inclusion Complexes with Cyclodextrins

4. Incorporation into Liposomes, Micelles, or Emulsions

5.Addition of Stabilizers Such as Antioxidants and Stabilization through the Use of Packaging
Polymorphs are different crystal forms of the same compound.

Polymorphs differs from one another in the crystal energies, the more energetic ones converting to the least energetic or most stable one.
Different polymorphs of the same drug may exhibit different solubility and melting points.
Many drugs and excipients may be lost from pharmaceutical products at ambient temperature through vaporization.
These drugs and excipients possess a sufficient high vapor pressure that they are volatile at room temperature.
Evaporation of water from liquid preparations will cause concentration of the drug with the possibility of crystallization occurring if the solubility of the drug in the solvent is exceeded.
Water loss from oil- in – water creams may result in a decrease in volume and a surface rubbery feel.
Further evaporation of the water will cause the emulsion to crack.
Some drugs are efflorescent, which mean they will lose water to the atmosphere resulting in a concentration of the drug and overall weight loss.
Water loss to the atmosphere can be prevented by storing the pharmaceutical product in a well closed container.
Water will be absorbed from the atmosphere by some drugs and pharmaceutical products.
For example, some drugs are deliquesecent (calcium chloride and potassium citrate), whereas others are hygroscopic (glycerol and dry plant extracts).
Effervescent powders and tablets will deteriorate if stored in a moist atmosphere.
This is mainly seen as creaming of emulsions when the disperse phase contains large globules as a result of coalescence and aggregation of smaller globules.
• Contamination of a product may sometimes cause a lot of damage and sometimes may not be anything at all.
• Thus it is dependent on the type of microbe and its level of toxicity it may produce.
• If parenteral or ophthalmic formulations are contaminated, it may cause serious harm. But contamination in other non-sterile products is usually not so damaging.
• It results in general spoilage such as discoloration, breakdown of emulsions and the production of gas and other odours. In some cases active drugs may be destroyed without any outward signs.
• Thus, salicylates, phenacetin, paracetamol, atropine, chloramphenicol and hydrocortisone can be degraded to a variety of therapeutically inactive products.
• Preservatives, especially those that are aromatic in structure can themselves act as a ready source of nutrition to microbes.
• Pyrogens which are the metabolic products of bacterial growth are usually lipo-polysaccharides and they represent a particularly hazardous product released by gram negative bacteria. If administered inadvertently to a patient they may cause chills and fever.
A preservative has to be used thus it must have the require oil/water partition coefficient, it must be non-toxic, odourless, stable and compatible with other formulation components while exerting its effects.
• Traditional glass containers do not interact with the preservatives. If the closure is airtight there is no problem of contamination.
• But plastic containers cause problems such as interaction with it.
• Rubber also reacts with preservatives but it is still used for closures. These closures are treated with the preservatives they are to be in contact with, in order to minimize subsequent uptake during storage.
• For sterile preparations there is either a terminal sterilization process or a closely controlled aseptic manufacturing procedure. In every case the final product is so made to protect the product during storage and minimize contamination while the product is in use.
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