Stability in Preformulation

8/10/2019 Stability in Preformulation

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STABILITY IN

PREFORMULATION

Presented By

MITHA ANN THAMPY

M PHARM FIRST YEAR

NEHRU COLLEGE OF PHARMACY

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CONTENTS

1. STABILITY

2. OBJECTIVES OF STABILITY STUDIES

3. FACTORS AFFECTING STABILITY

4. STABILITY PROBLEMS AND ITS PREVENTION

5. REFERENCES

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STABILITY

Stability of pharmaceutical product may be definedas the capability of a particular formulation in a

specific container/closure system to remain within its

physical, chemical, microbiological, therapeutic and

toxicological specification. The stability of the drug substance is first assessed in

the preformulation stage.

A drug product must satisfy stability in terms of

chemical, therapeutic, toxicological and physicalcharacteristics

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OBJECTIVES OF STABILITY STUDIES

To gather information during preformulation stage to

produce a stable product.

To determine maximum expiration date.

To get an idea of storage condition.

To determine the packaging components.

To determine the retest period of pharmaceuticals.

To determine transport conditions.

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FACTORS AFFECTING STABILITY

Extrinsic factors- Temperature

- Light

- Gases

- Moisture Intrinsic factors

- pH

- Complexation

- Microbial GrowthBoundary factors

- Container composition

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EXTRINSIC FACTORS

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ENERGY OF ACTIVATION AND

REACTION TYPES

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2-3 kcal/mole----------


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LIGHT

Activate molecules and enhance rate of decompositionPhotochemical decomposition due to absorption of

sunlight ( visible - blue, violet and uv 500 300nm )

Exposure of sunlight colour change of product

- degrade packaging- chemical decomposition of

active ingredient

Test procedure test sample in open petridishes or

clear containers- control sample in light resistantcontainers

- placed into temperature monitoredcabinets for 4 weeks

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Drugs undergo zero order kinetics

eg. Chlorpromazine, reserpine, colchicine

Drugs undergo first order kinetics

eg. Adriamycin, furosemide, nefidipine

Examples of photochemical degradation

- colour fading of tablets and liquids- conversion of ergosterol to vitamin D

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GASES

Oxygen and carbon dioxide affect stability of drug

Oxygen oxidation potency loss / colour change

eg. Ascorbic acid dehydroascorbic acid

CO2 - potency losseg.Sodium hexobarbitone iv injection hydrolysis solution CO2

(basic pH)

hexobarbitone precipitate

(acidic pH )

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MOISTURE

Absorption of moisture increases the weight of product

- dose diluted decreases potency

eg Deliquescent substances CaCl2 ,K2CO3

Gelatin capsules absorb moisture and become soft

Test procedure expose to various range of humidities

- test carried out on final packaged product

and unpackaged product

- To get information regarding formulationadjuvant, type of environment suitable for

a drug & type of package needed

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pH Rate of hydrolytic reactions vary with pH

- Hydrogen ion catalyses predominantly at lower pH- Hydroxyl ion catalysis operates at higher pH range

pH can also influence the rate of oxidation.

- system less readily oxidized when the pH is low.

Test procedure product samples are kept at pH 2 12 at55 90 0c for 2 weeks

- plot pH rate profile ( log k vs. pH )

- point of inflection of such a plot represents

pH of optimum stability

- point is useful in the development of

stable dosage form

eg. Aspirin buffered solution is maximum stable at a pH of 2.4,

above a pH of 10 the decomposition rate rapidly increases.16


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COMPLEXATION

Complex formation reduces the rate of hydrolysisand oxidation.

e.g. caffeine complexes with local anesthetics, such asbenzocaine, procaine and tetracaime - reduction in

rate of hydrolytic degradation.

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MICROBIAL GROWTH

o Threat to stability - degradation of drug dosage

impotency

o Evaluating microbiological stability

chemical assays of preservatives- Microbial challenge tests

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BOUNDARY FACTORS

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CONTAINER COMPOSITION

The container and closure are particularly important in

affecting product stability.

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http://www.inmagine.com/cr15205/cr15205023-photohttp://upload.wikimedia.org/wikipedia/commons/2/22/Risperdal_tablets.jpg


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Glass

- Glass is resistant to chemical and physical change

and is the most commonly used material.

Limitations Overcome

1. Its alkaline surface use of Borosilicate glass

2. Ions may precipitateinsoluble crystals from the glass

the use of buffers

3. Permits the transmission oflight which may acceleratedecomposition.

Amber coloured glass

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Plastics

The problems with plastic are:

1. Migration of the drug through the plastic into the

environment.

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

3.Leaching of container ingredients into the drug.

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

Overcome:1. Minimize by overwrapping

2. Leaching can be reduced by coating with Teflon

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Metals

- Various alloys and aluminium tubes may be utilized ascontainers for emulsions, ointments, creams and pastes.

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

- Overcome: Coating the tubes with polymers may reducethese tendencies.

Rubber

- It 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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STABILITY PROBLEM AND ITS

PREVENTION

Physical instability

Chemical instability

Therapeutic instability

Microbiological instability

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PHYSICAL DEGRADATION

Loss of volatile constituents

Loss of water

Absorption of water

Crystal growth

Polymorphism

Colour changes

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LOSS OF VOLATILE CONSTITUENTS

Medicinal agents such as iodine, camphor, menthol, ethanol,

anaesthetic ether, chloroform tendency to evaporate from

product

Nitroglycerine loose its potency volatilisation of medicament

Prevention

1. keep product in well closed container

2. store in cool place

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LOSS OF WATER

Decrease in weight, rises in concentration andincreases potency

Loss of water depends on temperature and humidity

eg. Efflorescent substances borax, quinidine

sulphate, caffeine

Prevention


2. store in cool place

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ABSORPTION OF WATER

Absorption of moisture increases the weight of product

- dose diluted decreases potency

eg. Deliquescent substances CaCl2 ,K2CO3

Gelatin capsules absorb moisture and become soft

Prevention


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CRYSTAL GROWTH

Fluctuation in temperature causes crystal growth Seen in - supersaturated solution

e.g. 10% w/v Calcium gluconate solution

- suspension

Prevention1. select suitable storage condition to prevent

temperature fluctuation

2. increase the viscosity of the product

3. include surface active agents in formulations

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CHEMICAL INSTABILITY

Hydrolysis

Absorption of CO2Decarboxylation

PolymerizationIsomerization

Oxidation

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HYDROLYSIS

- means splitting by water

Drug type Examples

Esters Aspirin, alkaloids

Dexmethasone sodium phosphate

Nitroglycerin

Lactones Pilocarpine

Spironolactone

Amides Chloramphenicol

Lactams Penicillins

Cephalosporins34


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Prevention

1. By adding Buffers

- maintain pH having maximum stability and

therapeutic activity

- Optimum pH selected should between 3.5 and 5

e.g. Boric acid buffer

2. Complexation3. Suppression of solubility

- achieved by adding

oAdditives e.g. Citrate, dextrose, sorbitol & gluconate

o Converting into salt forme.g. Penicillin Procaine Penicillin

o Converting into water insoluble derivative.

e.g Erythromycin propionate, Erythromycin stearate

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4. Removal of water

- achieved byo Storing drug in dry form

e.g. Streptomycin dry powder for injection

o Use water immiscible vehicle for dispersion of drug

e.g. Aspirin in silicone fluid

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ABSORPTION OF CARBON DIOXIDE

loss potency

eg. Sodium hexobarbitone iv injection

Amphetamine,KOH,NaOH,Ca(OH)2,MgO -

turbid solution

Prevention

- keep product in well closed container

- Manufacture product as dry sterile powder

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DECARBOXYLATION

Elimination of CO2from a compound Encountered when parenteral solutions of NaHCO3

are autoclaved

e.g. Sodium P- amino salicylic acid

Procaine hydrochloride

Prevention

- CO2 gas is passed into the solution for 1 min

prior to sealing

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POLYMERISATION

combination of 2 or more identical molecules to form

larger and more complex molecule

e.g. dextrose inj autoclaving 5 hydroxymethyl furfural

( straw coloured solution)

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OXIDATION

Removal of electropositive atom, radical or electron oraddition of electronegative atom or radical

Functional group Examples

Catechols Catecholamines (dopamine)

Ethers Diethylether

Thiols Dimercaprol (BAL)

Thioethers Chlorpromazine

Carboxylic acids Fatty acids

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Prevention : Oxidation is prevented by

1. Adding antioxidants

- break free radical chain reaction at the step of chain

propagation

2. Adding chelating agents

- form complexes with heavy metal ions and preventthem from catalyzing oxidative decomposition.

e.g. EDTA derivatives and salts, citric acid & tartaricacid.

Aqueous systems Oil systems

Sodium metabisulfite Ascorbyl palmitate

Sodium thiosulfate BHT

Ascorbic acid BHA

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3. Adding Buffers

- impart stability when oxidation catalysed by H+ or

OH- ions

4. Adding reducing agents

- employed at a concentration of .01 - .1 %

e.g. sodium and potassium metabisulphite

5. Adding surfactants- Nonionic, cationic and anionic surfactants when

added to solutions containing drugs form micelle and

the drug particles become trapped in the micelle

6. Environmental control measures- prevent exposure to light

- oxygen free environment

- low temperature storage

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Water gram-negative groups: Pseudomonas,

Xanthamonas, Flavobacterium

Air Mould spores: Penicillium, Aspergillus

Bacterial spores: Bacillus spp. Yeasts

Raw materials Micrococci

Starches Coliforms

Pigments Salmonella

MICROBIOLOGICAL INSTABILITY

Gums Actinomyces

Animal

products

Salmonella, Coliforms

Personnel Coliforms, Staphylococci, Sterptococci44

Prevention:


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Prevention:

(1) Suitably designing the containers

(2) usually using single dose containers

(3) sticking to proper storage conditions

(4) adding an antimicrobial substance as preservative

Preparation Preservative Concentration %w/v

Injections Phenol

CresolChlorocresol

0.5

0.30.1

Eye drops Chlorhexidine

acetate

Benzalkoniumchloride

0.01

0.01

Mixtures Benzoic acid

Methyl paraben

Alcohol

0.1

0.1

12-2045


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THERAPEUTIC INSTABILITY

Due to drug interactions ( effect of one drug is alteredby prior or simultaneous administration of another

drug or food)

Prevention

- proper adjustment of dosage

Generic name Potentiates Decreases Food

Bacampicillin

Beta adrenergic

Birth control pills

Probenicid

Sodium benzoate

Chloramphenicol

Erythromycin

Loperamide

Paromomycin

Tetracycline

Troleandomycin

alcoholic

beverages,acidic

fruits or

juices

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REFERENCES

Leon Lachman et.al, The Theory and Practice of IndustrialPharmacy, Varghese Publishing House, Bombay,3rd editionP. 190

C.V.S Subrahmanyam, Textbook of Physical pharmaceutics,Vallabh Prakashan, Delhi,2ndedition P. 51 - 69

Dr.Shyamala Bhaskaran, Industrial Pharmacy, BirlaPublications, Ist edition, P. 8 - 11

R.M. Mehta, Pharmaceutics ll, Vallabh Prakashan, Delhi,2ndedition P. 58

Conditions for Stability from:http://www.pharmacopeia.cn/v29240/usp29nf24s0c1191.html

Drug interactions from http://en.wikipedia.org/wiki/Listofdrug interactions

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