PHM 213Drug DegradationGroup Members:

Ameenah Khan 09/0509/1391Amrita Hardeo 09/0509/1486Poonam Phagu 09/0509/1114Carissa Bhanedatt 09/0509/1083Smita Tikaram 09/0509/1529Aimara Pierre 08/0509/0632

Introduction• Food has to be well preserved if we want it to retain its

quality. • If raw materials such as rice and wheat grains are not

stored at the proper temperature and humidity they are spoiled by microbial contamination.

• Food is spoiled by three varieties of decomposition; physical, chemical and microbiological.

• Rice grains left alone stay fine for years together; rice made into flour is less stable (with time it develops a musty odor and off color) and rice processed into food is stable only for a few hours.

• “more processing- less stable”; “more contact with water – less stable”.

Introduction cont’d…

• All this is true for drugs also. • Pure drugs, solids, liquids, or gases are usually more stable

than their formulations. • When they are formulated into medicines decomposition

happens faster because of the presence of excipients, and moisture and because of processing.

• So when we say stability, we actually are talking about two varieties of stability; that of the drug and that of the formulation.

• For example a capsule may become soft, an emulsion may break, a suspension may cake and an ointment may bleed.

• Even if solid pure powders of drugs are stored under ideal temperature and humidity conditions –even then there is some degradation.

• For example consider aspirin. • If you take a bottle of an old sample of pure aspirin and smell

it you can clearly feel the unmistakable odor of acetic acid. • If you granulate aspirin and make it into tablets the rate of

decomposition will be faster and if you formulate it into a suspension it will decompose totally into acetic acid and salicylic acid in less than 25 days.

• This is because the breakdown is a chemical reaction involving the collisions of the molecules, collisions having sufficient energy and the molecules having the proper orientation.

• This breakdown is affected by various factors such as presence of oxygen, acidity, alkalinity, moisture and light.

• This breakdown is what we are calling degradation. • This is the reason why the manufacturers of medicines are

bound by rules to put an expiry date on the medicine. In fact if they can not put an expiry date then they have to explain reasons for that.

• So the researchers in charge of the formulation development do extensive studies to understand the mechanism of degradation and the rate of degradation.

• Degradation happens because the molecules are hitting one another (like agitated football players in a big field running madly without looking and hitting one another).But there is a method in this confusion.

• And it is a pharmaceutical technologist’s job to find the factors that enhance or reduce this madness (light? Heat? Air? Acidity? Alkalinity?).

• And it is a pharmaceutical chemistry man’s job to find the mechanism of this madness- how is it triggered and how is it happening? Oxidation? Hydrolysis? Racemisation? Photolysis?

Microbial degradation Effects of Microbial Instability:

• 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 parenterals or opthalmic formulations are contaminated, it may cause serious harm.

• But contamination in other nonsterile 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.

Prevention of microbial spoilage

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.

Containers• Traditional glass containers do not interact with the

preservatives. If the closure is airtight there is no problem of contamination.

• But plastic containers pose problems such as permeation through the container or interaction with it.

• Rubber also reacts with preservatives but it is still used for teats and closures. These teats and 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.

Chemical degradative routes:

1. Solvolysis• 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.

2. Oxidation• 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.

• Oxidative mechanisms are complex, involving removal of an electropositive atom, radical or electron or, conversely, addition of electronegative moiety.

• 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.

3. Dehydration • The preferred route of degradation for prostaglandin E2

and tetracycline is the elimination of a water molecule from their structures.

• The driving force for this type of covalent dehydration is the formation of a double bond that can participate in electronic resonance with neighboring functional groups.

• 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.

4. Optical isomerization

• 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 enantiomorph.

• Racemization continues until 50% of the original drug has been converted into its enantiomorph. In most cases the enantiomorph has less therapeutic effect than the original drug.

5. Hydrolysis

• 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 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.

Photolysis• Photolysis is the process by which light-sensitive drugs or

excipient molecules are chemically degraded by light, room light or sunlight. Ultra violet light causes more damage than red/orange light. The variation of degradation depends on the wavelength of light, shorter wavelengths because more damage than longer wavelengths. Before a photolytic reaction can occur, the energy from light radiation must be absorbed by the molecules. A photosensitizer is the drug or excipient molecule that absorbs light energy. 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.

Photolysis cont’d• In this process, light may be the initiator while the

reaction may be oxidation, polymerization or ring rearrangement. Photolysis may be followed by a thermal reaction since light energy may be converted to heat energy. However, the photolytic reaction may produce a catalyst for the thermal reaction. With the removal of light, the thermal reaction proceeds.

• Several photolytic reactions include: the decomposition of chlorpromazine hydrochloride, and other phenothiazines, the darkening of morphine and codeine, the fading of tartrazine dye and the initiation of numerous auto-oxidation processes.

Physical factors of degradation1. Polymorphs• 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.

2. Vaporization• Many drugs and excipients may be lost from pharmaceutical

products at ambient temperature through vaporization. These drugs and excipients possess a sufficient high vapour pressure that they are volatile at room temperature.

3. Waterloss

• Evaporation of water from liquid preparations will cause concentration of the drug with the possibility of crystilization 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.

4. Absorption of Water• Water will be absorbed from the atmosphere by

some drugs and pharmaceutical products. For example, some drugs are delisquent (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.

5. Particle Sedimentation• This is mainly seen as creaming of emulsions when

the disperse phase contain large globules as a result of coalescence and aggregation of smaller globules.

Formulation Likely physical instability problems

Effects Steps to prevent instability

Oral solutions 1.Loss of flavour2.Change in taste3.Presence of off flavours due to interaction with plastic bottle4.Loss of dye5.Precipitation6.Discoloration

Change in smell or feel or taste

Use of proper excipients and suitable packing materials.

Formulation Likely Physical…. Effect Steps to prevent

Parenteral solutions physical instability occurs due to:(1) Interaction of the contents with the container.(2) Changes in Chemical composition.

1. Discoloration due to photo chemical reaction or oxidation. Ex: thiamine hydrochloride2. Presence of precipitate due to interaction with container or stopper.3. Presence of “whiskers”. If some small pinholes are present in the ampule due to improper sealing the solution wicks out, the liquid evaporates and the solid settles on the outside. It further helps in wicking out more solution and long lines of crystals form on the outside of the vial which are called whiskers. This may happen due too small hole (<0.5 μm) going undetected or the crack developing during storage.

Change in appearance and in bio-availability.Change in appearance and in bioavailability

Use of antioxidants (0.5%) Acetylcystane or 0.02 – 1% Ascorbic acid) or Chelating agents (0.01 – 0.075 sodium edetale) to prevent discoloration.Change in stopper or material of the container will eliminate the problem.

Formulation Likely physical…

Effect Steps to prevent

Parenteral SolutionsCont’d…

4. Clouds: A cloud will appear in the product due to: (i) Chemical changes (an ester eg.: polysorbate may hydrolyse producing an acid which is poorly soluble). (ii) Solubility product may be exceeded. (iii) The original preparation of a supersaturated solution or the use of a metastable form (ex: calcium gluceptate).

Checking of the manufacturing process Increasing solubility by the use of cosolvents (eg: polyethylene glycol) or by other methods such as micellar approach or complexation will reduce clouding.

Formulation Likely physical… Effect Steps to prevent

Suspensions Settling, caking, crystal growth

Loss of drug content uniformity in different doses from the bottle and loss of elegance.

Design of product based on proper pre-formulation studies.

Emulsions 1. Changes in:a) Particle size,b) Polymorphicstate, or hydration or solvation statec) Consistencyd) drug release rate2. Caking or coalescence.3. Bleeding

Loss of drug content uniformity, loss of elegance and change in drug release rate.

Design of product based on proper pre-formulation studies.

Formulation Likely physical instability problem

Effect Steps to prevent

Tablets Change in a) Disintegration time b) Dissolution profile c) Hardness d) Appearance

Change in drug release

Design of product based on proper pre-formulation studies.

Capsules Change ina) Appearanceb) Dissolution, and c) Strength

Change in drug release

Design of product based on proper pre-formulation studies.

Conclusion• Drug degradation- where the breakdown of a drug is a

chemical reaction involving the collision of molecules.

• The reaction routes by which most pharmaceuticals degrade are: hydrolysis, oxidation-reduction, photolysis, racemization and decarboxylation.

• The degradative routes descibed are:chemical- when new chemical entitles are fomed as a

result of drug decomposition.physical- when drug loss does not procedure distinctly

different chemical products.

Reference • Stability of Drugs: Microbial Instability.

PHARMPEDIA; The Free Pharmaceutical Encyclopedia. Last modified 15:39, 17 May 2006 retrieved on 2010-11-06, 11:59 AM http://www.pharmpedia.com/drugstability

• Gilbert S. Banker, Christopher T. Rhodes. Modern Pharmaceutics. Forth Edition, Revised and Expanded. New York, NY 10016: Marcel Dekker, Inc., 2002. (Chapter 6) 

• Patrick Crowley, Dr. Luigi G. Martini. Drug Excipient Interactions. http://www.callumconsultancy.com/articles/DrugExcipientInteractions.pdf

• Stability of drugs- Introduction http://www.pharmpedia.com/Stability_Of_Drugs:Introduction