dr. gehan fathy atia

Dr. Gehan Fathy AtiaDr. Gehan Fathy Atia

Assistant Prof. Assistant Prof. (Pharmaceutics)(Pharmaceutics)

STABILITY OF STABILITY OF DRUGSDRUGS

Stability of drugs Stability of drugs (Cont.)(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

Factors affecting Factors affecting StabilityStability

1- Environmental factors1- Environmental factors - Temperature - Light - Temperature - Light - Oxygen - Moisture - Oxygen - Moisture - Carbon dioxide- Carbon dioxide

2- Drugs or excipients in the dosage form2- Drugs or excipients in the dosage form - Particle size of drug Particle size of drug - pH of the vehicle pH of the vehicle

3- Microbial contamination 3- Microbial contamination 4- Trace metal Contamination 4- Trace metal Contamination 5- Leaching from containers 5- Leaching from containers

Types of stability Types of stability studies: studies:

۞۞ PhysicalPhysical

۞۞ ChemicalChemical

۞۞ MicrobiologicalMicrobiological

Physical stabilityPhysical stability

Physical stability implies that:Physical stability implies that:

- The formulation is totally unchanged - The formulation is totally unchanged throughout its shelf life and has not suffered throughout its shelf life and has not suffered any changes by way of appearance, any changes by way of appearance, organoleptic properties, hardness, brittleness, organoleptic properties, hardness, brittleness, particle size etc. particle size etc.

- It is significant as it affects: It is significant as it affects:

pharmaceutical elegance pharmaceutical elegance

drug content uniformity drug content uniformity

drug release rate. drug release rate.

Physical stability (Cont.)Physical stability (Cont.)

FormulatioFormulationn

Likely physical Likely physical instability problemsinstability problems

EffectsEffects

Oral Oral solutionssolutions

1- Loss of flavour 1- Loss of flavour

2- Change in taste 2- Change in taste

3- Presence of off 3- Presence of off flavours due to flavours due to interaction with plastic interaction with plastic bottle bottle

4- Loss of dye 4- Loss of dye

5- Precipitation 5- Precipitation

6- discoloration 6- discoloration

Change in Change in smell or smell or feel or feel or taste taste

Physical stability Physical stability (Cont.)(Cont.)FormulatioFormulatio

nnLikely physical Likely physical

instability problemsinstability problemsEffectsEffects

Parenteral Parenteral solutionssolutions

1. Discoloration due to photo 1. Discoloration due to photo chemical reaction or chemical reaction or oxidation oxidation

2. Presence of precipitate 2. Presence of precipitate due to interaction with due to interaction with container or stopper container or stopper

3. Presence of “whiskers”3. Presence of “whiskers” 4. Clouds due to:4. Clouds due to:

(i) Chemical changes(i) Chemical changes (ii) The original preparation (ii) The original preparation

of a supersaturated of a supersaturated

solutionsolution

Change in Change in appearanappearance and in ce and in bio-bio-availabilitavailabilityy



instability instability problemsproblems

EffectsEffects

Suspensions Suspensions 1- settling1- settling

2- caking2- caking

3- crystal growth 3- crystal growth

1-Loss of 1-Loss of drug content drug content uniformity in uniformity in different different doses from doses from the bottle the bottle

2- loss of 2- loss of elegance. elegance.




EffectsEffects

Emulsions Emulsions 1- Creaming 1- Creaming

2- coalescence2- coalescence 1- Loss of 1- Loss of drug content drug content uniformity in uniformity in different different doses from doses from the bottle the bottle

2- loss of 2- loss of eleganceelegance

Physical stability Physical stability (Cont.)(Cont.)

CoalescencCoalescencee




EffectsEffects

SemisolidsSemisolids (Ointments (Ointments and and suppositoriesuppositories) s)

1. Changes in:1. Changes in:

a) Particle sizea) Particle size

b) Consistencyb) Consistency

2. Caking or 2. Caking or coalescencecoalescence

3. Bleeding3. Bleeding

1-Loss of drug 1-Loss of drug content content uniformityuniformity

2- loss of 2- loss of elegance elegance

3-change in 3-change in drug release drug release rate. rate.




EffectsEffects

TabletsTablets Change in:Change in:

a) Disintegration a) Disintegration timetime

b) Dissolution profileb) Dissolution profile

c) Hardness c) Hardness

d) Appearance (soft d) Appearance (soft and ugly or and ugly or become very become very hard)hard)

Change in Change in drug drug release release




EffectsEffects

Capsules Capsules Change in:Change in:

a) Appearancea) Appearance

b) Dissolutionb) Dissolution

c) Strengthc) Strength

Change in Change in drug drug release release

Chemical stability:Chemical stability:

Chemical stability implies:Chemical stability implies: The lack of any decomposition in the chemical The lack of any decomposition in the chemical

moiety that is incorporated in the formulation moiety that is incorporated in the formulation as the drug, preservatives or any other as the drug, preservatives or any other excipients. excipients.

This decomposition may influence the physical This decomposition may influence the physical and chemical stability of the drug and chemical stability of the drug

Mechanisms Of Mechanisms Of DegradationDegradation

1- 1- Hydrolysis:Hydrolysis:

Hydrolysis means “splitting by Hydrolysis means “splitting by water’’ water’’

Some Functional Groups Some Functional Groups Subject to HydrolysisSubject to Hydrolysis

Drug typeDrug type ExamplesExamples

EstersEsters Aspirin, alkaloidsAspirin, alkaloids

Dexmethasne sodium phosphateDexmethasne sodium phosphate

NitroglycerinNitroglycerin

LactonesLactones PilocarpinePilocarpine

SpironolactoneSpironolactone

AmidesAmides ChloramphenicolChloramphenicol

LactamsLactams PenicillinsPenicillins

CephalosporinsCephalosporins

Some Functional Groups Some Functional Groups Subject to HydrolysisSubject to Hydrolysis

Drug typeDrug type ExamplesExamples

ImidesImides GlutethimideGlutethimide

Malonic ureasMalonic ureas

BarbituratesBarbiturates


2- Oxidation2- OxidationOxidation of inorganic and organic compounds is Oxidation of inorganic and organic compounds is

explained by a loss of electrons and the loss of explained by a loss of electrons and the loss of a molecule of hydrogen. a molecule of hydrogen.

Some Functional Groups Some Functional Groups

Subject to AutoxidationSubject to Autoxidation

Functional Functional groupgroup

ExamplesExamples

CatecholsCatechols Catecholamines (dopamine) Catecholamines (dopamine)

EthersEthers DiethyletherDiethylether

ThiolsThiols Dimercaprol (BAL) Dimercaprol (BAL)

ThioethersThioethers Chlorpromazine Chlorpromazine

Carboxylic acidsCarboxylic acids Fatty acidsFatty acids


3- Photolysis3- Photolysis It means: It means: decomposition by lightdecomposition by light

e.g. e.g. Sodium nitroprusside is administered by Sodium nitroprusside is administered by intravenous infusion for the management of intravenous infusion for the management of acute hypertension. acute hypertension.

If the solution is protected from light, it is stable If the solution is protected from light, it is stable for at least 1 year; if exposed to normal room for at least 1 year; if exposed to normal room light, it has a shelf life of only 4 hours. light, it has a shelf life of only 4 hours.


Relationship between wavelength and associated Relationship between wavelength and associated energy of various forms of light.energy of various forms of light.

Type of Type of radiationradiation

WavelengthWavelength EnergyEnergy

U.V.U.V.

VisibleVisible

I.r.I.r.

50 – 40050 – 400

400 – 750400 – 750

750 – 10,000750 – 10,000

Kcal mol-1Kcal mol-1

287 – 72287 – 72

36 - 136 - 1Conventional tungsten filament light bulbs are safe and do not contribute to photolysis.


Photolysis is prevented by:Photolysis is prevented by:1- suitable packing in amber coloured bottles1- suitable packing in amber coloured bottles

2- cardboard outers 2- cardboard outers

3- aluminium foil over wraps 3- aluminium foil over wraps

Factors Affecting Rates Factors Affecting Rates Of DegradationOf Degradation

1- pH1- pH The acidity or the alkalinity of a solution has a The acidity or the alkalinity of a solution has a

profound influence on the decomposition of profound influence on the decomposition of drug compound.drug compound.

- Aspirin buffered solution is maximum stable at Aspirin buffered solution is maximum stable at a pH of 2.4, above a pH of 10 the a pH of 2.4, above a pH of 10 the decomposition rate rapidly increases. 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 The system is less readily oxidized when the

pH is low.pH is low.

Factors Affecting Factors Affecting Rates Of DegradationRates Of Degradation

2- Complexation2- Complexation Complex formation reduces the rate of Complex formation reduces the rate of

hydrolysis and oxidation.hydrolysis and oxidation.

e.g. caffeine complexes with local anesthetics, e.g. caffeine complexes with local anesthetics, such as benzocaine, procaine and tetracaime such as benzocaine, procaine and tetracaime to cause a reduction in their rate of hydrolytic to cause a reduction in their rate of hydrolytic degradation. degradation.

Factors Affecting Factors Affecting Rates Of Degradation Rates Of Degradation

3- Surfactants3- Surfactants Nonionic, cationic and anionic surfactants Nonionic, cationic and anionic surfactants

when added to solutions containing drugs when added to solutions containing drugs form micelle and the drug particles become form micelle and the drug particles become trapped in the micelle.trapped in the micelle.

The hydrolytic groups such as OH cannot The hydrolytic groups such as OH cannot penetrate this micelle cover and reach the penetrate this micelle cover and reach the drug particles, hence hydrolysis rate is drug particles, hence hydrolysis rate is decreased.decreased.

Factors Affecting Factors Affecting Rates Of Degradation Rates Of Degradation

4- Presence of heavy metals4- Presence of heavy metals Heavy metals, such as copper, iron, cobalt and Heavy metals, such as copper, iron, cobalt and

nickel increase the rate of formation of free nickel increase the rate of formation of free radicals and enhance oxidative decomposition.radicals and enhance oxidative decomposition.

5- Light and humidity5- Light and humidity Light, especially ultraviolet light enhances Light, especially ultraviolet light enhances

photolysis and humidity enhances hydrolytic photolysis and humidity enhances hydrolytic decomposition.decomposition.

Stabilization of drugs against Stabilization of drugs against hydrolysis, oxidation and hydrolysis, oxidation and photolysis photolysis

1- Temperature1- Temperature All the drug products are stored at suitable All the drug products are stored at suitable

temperatures to avoid thermal acceleration of temperatures to avoid thermal acceleration of decomposition. Three varieties of decomposition. Three varieties of temperatures are suggested for storage of temperatures are suggested for storage of drug products. Room temperature, cool drug products. Room temperature, cool storage and cold storage.storage and cold storage.

2- Light2- Light Light sensitive materials are stored in Light sensitive materials are stored in

ambered colour bottles.ambered colour bottles.

Stabilization of drugs against Stabilization of drugs against hydrolysis, oxidation and hydrolysis, oxidation and photolysisphotolysis

3- Humidity3- Humidity Packing materials are chosen (usually glass Packing materials are chosen (usually glass

and plastic) to prevent exposure of drug and plastic) to prevent exposure of drug products to high humid condition.products to high humid condition.

4- Oxygen4- Oxygen Proper packing keeping the oxygen content of Proper packing keeping the oxygen content of

the solution less and leaving very little head the solution less and leaving very little head space in the bottle above the drug products space in the bottle above the drug products are methods to fight against oxidation. are methods to fight against oxidation.


Antioxidants commonly used for Antioxidants commonly used for

Aqueous systemsAqueous systems Oil systemsOil systemsSodium metabisulfiteSodium metabisulfite

Sodium thiosulfateSodium thiosulfate

Ascorbic acidAscorbic acid

Ascorbyl palmitateAscorbyl palmitate

Butylaled hydroxy Butylaled hydroxy toluenetoluene

Butylated hydroxy Butylated hydroxy anisoleanisole


5- Chelating Agents5- Chelating Agents Chelating agents form complexes with heavy Chelating agents form complexes with heavy

metal ions and prevent them from catalyzing metal ions and prevent them from catalyzing oxidative decomposition. oxidative decomposition.

e.g. ethylenediamine tetracetic acid (EDTA) e.g. ethylenediamine tetracetic acid (EDTA) derivatives and salts, citric acid and tartaric derivatives and salts, citric acid and tartaric acid.acid.

6- Solvents6- Solvents By the addition of a suitable solvent hydrolysis By the addition of a suitable solvent hydrolysis

rate may be decreased.rate may be decreased.

Microbiological stability Microbiological stability implies that:Microbiological stability implies that:

The formulation has not suffered from any The formulation has not suffered from any microbiological attack and is meeting the microbiological attack and is meeting the standards with respect to lack of standards with respect to lack of contamination/sterility. contamination/sterility.

WaterWater gram-negative groups: Pseudomonas,gram-negative groups: Pseudomonas,Xanthamonas, FlavobacteriumXanthamonas, Flavobacterium

AirAir Mould spores: Penicillium, AspergillusMould spores: Penicillium, AspergillusBacterial spores: Bacillus spp. YeastsBacterial spores: Bacillus spp. Yeasts

Raw Raw materialsmaterials

Micrococci Micrococci

Starches Starches Coliforms Coliforms

PigmentsPigments Salmonella Salmonella

Sources of Microbial Contamination:Sources of Microbial Contamination:

Microbiological stability

Sources of Microbial Sources of Microbial ContaminationContamination

Gums Gums Actinomyces Actinomyces

Animal Animal products products

Salmonella, Coliforms Salmonella, Coliforms

Personnel Personnel Coliforms, Staphylococci, Coliforms, Staphylococci, SterptococciSterptococci

To prevent contamination to To prevent contamination to the formulation during the formulation during storagestorage

(1)(1) suitably designing the containerssuitably designing the containers

(2) usually using single dose (2) usually using single dose containerscontainers

(3) sticking to proper storage (3) sticking to proper storage conditions conditions

(4) adding an antimicrobial substance (4) adding an antimicrobial substance as preservative.as preservative.

Preservatives used in Preservatives used in pharmaceutical pharmaceutical preparations:preparations:PreparationPreparation PreservativePreservative ConcentratioConcentratio

nn

% w.v% w.vInjectionsInjections PhenolPhenol

CresolCresol

ChlorocresolChlorocresol

0.50.5

0.30.3

0.10.1

Eye dropsEye drops Chlorhexidine Chlorhexidine acetateacetate

Benzalkonium Benzalkonium chloridechloride

0.010.01

0.010.01

MixturesMixtures Benzoic acidBenzoic acid

Methyl parabenMethyl paraben

AlcoholAlcohol

0.10.1

0.10.1

12-2012-20

Preservatives used in Preservatives used in pharmaceutical pharmaceutical preparations:preparations:

PreparationPreparation PreservativePreservative ConcentratioConcentrationn

% w.v% w.v

CreamsCreams ParabensParabens

ChlorocresolChlorocresol0.1-0.20.1-0.2

0.10.1

TabletsTablets MethylparabenMethylparaben 0.10.1

Packaging And Packaging And Stability :Stability : The immediate container and closure are The immediate container and closure are

particularly important in affecting product particularly important in affecting product

stability.stability.

Packaging And Packaging And Stability: Stability: GlassGlass- Glass is resistant to chemical and physical change and is - Glass is resistant to chemical and physical change and is

the most commonly used material.the most commonly used material.

LimitationsLimitations OvercomeOvercome1. Its alkaline surface 1. Its alkaline surface use of Borosilicate glassuse of Borosilicate glass 2. Ions may precipitate 2. Ions may precipitate insoluble crystals from the insoluble crystals from the glassglass

the use of buffersthe use of buffers

3- Permits the transmission 3- Permits the transmission of light which may of light which may accelerate decomposition.accelerate decomposition.

Amber coloured glassAmber coloured glass

Packaging And Packaging And Stability :Stability : PlasticsPlastics

The problems with plastic are:The problems with plastic are:1.Migration of the drug through the plastic into 1.Migration of the drug through the plastic into

the environment.the environment.

2.Transfer of environmental moisture, oxygen, 2.Transfer of environmental moisture, oxygen, and other elements into the pharmaceutical and other elements into the pharmaceutical product.product.

3.Leaching of container ingredients into the drug.3.Leaching of container ingredients into the drug.

4.Adsorption of the active drug or excipients by 4.Adsorption of the active drug or excipients by the plastic.the plastic.

Packaging And Packaging And Stability :Stability : MetalsMetals- Various alloys and aluminium tubes may be Various alloys and aluminium tubes may be

utilized as containers for emulsions, utilized as containers for emulsions, ointments, creams and pastes. ointments, creams and pastes.

- Limitation:Limitation: They may cause corrosion and They may cause corrosion and precipitation in the drug product.precipitation in the drug product.

- Overcome:Overcome: Coating the tubes with polymers Coating the tubes with polymers may reduce these tendencies.may reduce these tendencies.

Packaging And Packaging And Stability :Stability : RubberRubber- Rubber also has the problems of extraction of Rubber also has the problems of extraction of

drug ingredients and leaching of container drug ingredients and leaching of container ingredients.ingredients.

- The pretreatment of rubber vial stoppers and The pretreatment of rubber vial stoppers and

closures with water and steam reduces closures with water and steam reduces potential leaching.potential leaching.

dr. gehan fathy atia

Documents

chemical stability

physical appearance

drugs cont

drug product

decomposition rate

drug mechanisms of degradation

decomposition of drug

light oxygen