Various Factor Affecting Stability of Formulation

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VARIOUS FACTORS

AFFECTING STABILITYOF FORMULATION

Prepared bySANDIP PRAJAPATI

GuidedbyMR.AKSHAY KOLI


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What does stabilitymean for drugs and

pharmaceuticals ?vThe stability of the product isits ability to resist

deterioration. It is alwaysexpressed in terms of shelf life.

vStability: is the capacity of a

drug product to remain withinspecifications established toensure its identity, strength quality

and purity. (USP-NF)


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As per USP there arefive types of stabilitystudies :

Chemical Physical Microbiological

Processingfactors

Toxicological


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1) Chemical

factors:vVarious ways of chemical degradationincludes:hydrolysisdehydrationisomerization & racemizationdecarboxylation & eliminationoxidationphoto degradation

drug excipients & drug drug interactionssuch as a) Reaction of bisulfite, an oxidant

b) Reaction of amines with reducing

sugars3


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o

Hydrolysis causes cleavage of drug molecule

Ex-1)ProcaineOH PABA + Diethyl Amine

ethanol

2)Chloramphenicol

H+CH3COOH

2-amino1-p-nitroPhenyl-1,3-propandiol

+Dichloroaceticacid

oIt is major cause of deterioration of drugs, especiallyfor those in aqueous solution.


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vREMEDIES:

1) Removal of water,storage in dry

form.

2) Using an insoluble derivative in suspensionform.

3) Replacement of water by substantial quantityof some other solvent such as alcohol orpolyhydroxy solvent mixtures.

4) By Micellar formation using anionic & cationicsurfectants.


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qdehydration

Sugars such as glucose and lactose1 are knownto undergo dehydration to form 5-(hydroxymethyl)furural. Erythromycin issusceptible to acidcatalyzed dehydration whereasprostaglandins E1 and E2 undergo dehydrationfollowed by isomerization.

Batanopride undergoes an intramolecular ring-closure reaction in the acidic pH range due to

dehydration whereas streptovitacin A exhibits twosuccessive acid-catalyzed dehydration Reactions.


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qisomerization & racemizationIsomerization

Conversion of active drug into less active orinactive drug.

EX-Vit-A susceptible to isomerization in presence of light.

Racemization

Conversion of optically active drug into itsenantiomer.The best known racemerization reaction ofdrugs are

epinapherine,pilocarpine,ergotamine &tetracycline.


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qDecarboxylation and EliminationDrug substances having a carboxylic acid group aresometimes susceptible to decarboxylation. 4-Aminosalicylic acid is a good example.

Foscarnet also undergoes decarboxylation understrongly acidic conditions,whereas etodolac is

susceptible to decarboxylation by acidcatalysis.Trimelamol eliminates its hydroxymethylgroups and forms formaldehyde. Levothyroxineeliminates iodine.Ditiocarb eliminates carbon disulfide.

Racemization of epinephrine.

This action is minimised by passing CO2 into thesolution for one minute & sealing the container so as to

make it gas-tight prior to autoclaving.

vREMEDIES


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qoxidation

Drugscanbeaffectedbytheavailabilityofoxygen.

Somephotodegradationreactionsinvolvephotooxidativemechanismsthataredependentonconc.ofoxygen.

Oxygenparticipatesasreactantandalsoaltersthedegradationrate.

Oxygenexistsinvariousstatessuchgroundstatetriplateoxygen,etc.

Singlateoxygenishighlyoxidizingandcapableofattackingolfenicbonds.

Superoxidespeciesisamildreductantwhilehydrogen

peroxideisfairlyspecificoxidant.


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The following excipients may have low level residuesfrommanufacture that can lead to oxidative degradation insusceptible compounds.


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vREMEDIES:

1) Minimum oxygen level used which may be achievedby boiling the water & allowing to cool in an atmospherefree from oxygen.2) Hydrogenation ofproduct.3) Incorporation of inert gas incontainers.

4) Use of anti-oxidant.5)Buffering the solution at favourable pH, Use of metalfree solvents.


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qphotolysis

Reactions such as oxidation-reduction, ringalteration and polymerisation can be catalysed oraccelerated by exposure to sun or artificial light.Energy absorption is greater at lower wavelengthsand, as many drugs absorb ultra-violet light,

degradation by low-wavelength radiation is a risk.Photolyticdegradation can be very complex, the products ofsuch degradation being numerous and difficult toidentify. Exposure to light can cause discolourationof both drugs and excipients even when degradationis modest and not even detectable analytically. Thiscan lead to off colour product, perceived by thepatient as a quality deficiency.


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qCATALYSIS

In parentrals, great care is taken to exclude metals,

because only slight decomposition caused by tracemetals may cause sufficient discoloration to theproduct unsatisfactory.

Ex of metal catalysed oxidation in pharmaceuticalsystem are cynocobalamine & erythromycin.


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2) Physical factors

oTEMPERATUREopH AND pH RATE PROFILESo

BUFFERoLIGHToCrystalline state and polymorphism insolid drugsoMOISTURE AND HUMIDITYoEXCIPIENTSoMISCELLANEOUS FACTORS


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q TEMPERATURE

Itisoneoftheprimaryfactorsaffectingdrugstability.Therateconstant/temperaturerelationshiphastraditionallybeendescribedbytheArheniusequation,

k=Aexp(-Ea/RT) whereEa=activationenergy

A=frequencyfactorArheniusequationhastraditionallybeenusedtodescribethetemperaturedependencyforvariouschemicalreactionbyregardingAandEaasindependentoftemperature.

Temperature is obviously an important parameter becausemost reactions proceed faster at elevated temperatures thanat lower temperatures.


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The terms Ea and H are a measure of how sensitive thedegradation rate of a drug is to temperature changes.Quantitation of the temperature Dependency of

degradation rate constants can be done by 3 ways:a) Prediction of Degradation rate by Linear Regression

Analysis of the Arhenius Equationb) Prediction of degradation rate by Nonlinear Regression

Analysis of the Arhenius Equation.

c) Nonisothermal Prediction of Degradation Rate

REMEDIES:-Pharmaceutical product should be stored within the temperature range inwhich they are stable.

They should not be exposed to extremes of temperature.Usually they should be stored at low temperature if they lack sufficientstability at room temperature.There are few drugs on which freezing has an adverse effect, so freezingshould be avoided unless until it is stable at such temperatures.

O S


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qpH AND pH RATE PROFILESSecond most important parameter.

The effect of pH on degradation rate can be explained bythe catalytic effects that hydronium or hydroxide ions canhave on various chemical reactions.

If critical path in a reaction involves a proton transfer orabstraction step, other acids and bases present in solutioncan affect the rate of reaction.

For ionizable drugs, the fraction of drug present in any

particular form will depend on the pH of the solution.

So, if the reactivity of the drug depends on its form, itsreactivity will be pH-dependent.


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A reaction in which hydronium ion, hydroxide ion, and watercatalysis are observed can be described by

Kobs = kH+ aH+ + KH2O + KoH- aOH-

Where Kobs = sum of specific rate constantsaH+ = activities of hydronium ionaOH- =activities of hydroxide ion

This equation is for the case when drug is neutral in the pHrange of study.i.e.where the ionization of drug does not haveto take into account.

BUFFER


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qBUFFERThese buffer species, like H+ and OH-, participates information of break down of activated complexes of

various reaction and determine their reaction rate.

These catalytic species are referred to as generalacid-base catalysts

Studies with phosphate buffer indicates that itenhance the degradation of various drug substancessuch as carbenicillin etc.

In addition to acting as proto donor or accepter, bufferspecies can also act as Lewis acid and base throughnucleophilic or electrophilic mechanisms.

LIGHT


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qLIGHT

The number and wavelength of incident photons

affect the photo degradation rate of drugs.

It is not easy to study the effect of light quantitativelyas the wavelength dependence of degradation variesamong drug substances and because light sources

have different spectral distributions.

Photo degradation for drug strongly dependence onthe spectral properties of the drug substances and thespectral distribution of the light source.


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MOISTURE AND HUMIDITY


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qMOISTURE AND HUMIDITY

Drugdegradationinheterogeneoussystemsuchassolidandsemisolidstatesisaffectedbymoisture.

Moistureplaysimportantroleincatalyzingchemicaldegradation:1)Waterparticipatesinthedrugdegradationprocessitselfas

areactant,leadingtohydrolysis;hydrationetc.Here degradationrateisdirectlyaffectedbytheconcentrationof

water,hydroniumion,hydroxideion.2)Waterabsorbsontothedrugsurfaceandformsamoisture-sorbedlayerinwhichthedrugisdissolvedanddegraded.)Wateradsorptionmayalsochangethephysicalstateofthedrugs,therebyaffectingtheirreactivity.

Ex- ferrous sulphate crystals are more rapidly oxidisedin moist air.

Ex-Sodium ampicillin , potassiumro icillin


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v REMEDIES: Maintenance of controlled humidity condition Moisture proof packaging.

qEFFECT OF SOLUBILITY:-

Applicable to drugs in solution form.Ex:-

Penicillins are very unstable in aqueous solution because of hydrolysis of -lactam ring.

v REMEDIES:Stabilised by using insoluble salts of API.Formulate the drug in suspension dosage form.

EXCIPIENTS


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qEXCIPIENTS

The role that excipients play in drug stability has been

extensively reported-e.g.: accelerating the effect of talc onhydrolysis of thiamine hydrochloride, the accelerating effectof magnesium stearate on tablet containing amines andlactose etc.

Additional informations include reports on compatibility andincompatibility of drugs.

Excipients can affect drug stability via various mechanisms.

The most obvious examples are those in which theexcipients participate directly in degradation as reactants.


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qVaporization

Some drugs & pharmaceutical adjuvants

possess sufficiently high vapor pressures atR.T. that their volatization constitutes a majorroute of drug loss.

Flavors may be lost from the formulation in thismanner.

Ex-Nitroglycerine

A i


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qAging

This is a process through which changes in the

disintegration &/or dissolution characteristics of thedosage form are caused by alteration in the physicochemical properties of the inert ingredient or theactive drug in the dosage form.

Ex-melting point of aminophylline suppositoryincreased from about 20 mins to over an hour

after 24 weeks of storage at 22 c


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qRADIATIONRadiation generally used during gaseous sterilization of

thermolabile drugs.

The exposure also produce deterious changes in theproduct since the procedures also cause ionization in theirradiated material.

The ions joined in the initial stage of the process aresubsequently converted into atoms & radicals becomeinvolved in chemical reactions.

Irradiation of a drug in aq. solution produces greaterchanges than the irradiation of the pure material becauseirradiation of water produces H2O2,free oxidative actionin drug.


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vDrugs affected by radiationare:

1) Alkaloids2) Atropine3) Steroids4) Sulphonamides5) Biological products-Insulin,Heparin.

All the above ex. are irradiated at low level of 2.5 rad.

EFFECT OF PACKAGING COMPONENTS


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qEFFECT OF PACKAGING COMPONENTS:-

Most commonly employed areCONTAINERS:

Glass, Plastic, MetalCLOSURES:-

RubbervCONTAINERS:1) GLASSv PROBLEMS:

a) Release of alkalib) Release of Insoluble flake

v REMEDY FOR PREVENTION OF RELEASE OF ALKALI:- By decreasing soda content

Siliconization of surface. By replacing sodium oxide with other oxides. Surface treatment by sulphur-di-oxide in presence of water-vapour & heat.


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vREMEDY FOR PREVENTION OF RELEASE OF INSOLUBLE FLAKE:-Flake formation can be prevented by using borosilicate glassPretreatment of the container with dilute acid.

2) PLASTIC

HIGH MOLECULAR WEIGHT POLYMERS LIKE POLYETHYLENE, POLYPROPYLENE, POLYSTYRENE,PVC ETC

vPROBLEMS:

Permeation of moistureLeachingADSORPTION OR ABSORPTIONCHEMICAL/PHYSICAL REACTION OF CONTENTS OF CONTAINERSWITH PRODUCTS.

vREMEDY:Lining of the container with an epoxy resin eliminates this problembut

has to be evaluated separately for each product .(epoxy lining does not prevent sorption of phenyl mercuric nitrate).

3) METALS


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3) METALS

Metals commonly used are tin , plastic coated tin , tin-coated lead ,aluminum and coated aluminum .

vPROBLEMS:

a) Reactivity. TIN + CHLORIDE ERROSION

2. ALUMINUM + FATTY ALCHOL WHITEENCRUSTATION

vREMEDY:Application of an epoxy lining to internal surfaces of aluminum tubeswas found to make them more resistant to attack

qCLOSURES:-1)RUBBER

v)PROBLEMS:a) Sorption of API into rubber.b) Extraction of one or more components of rubber into vial solution .


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vREMEDIES:

Epoxy lining applied to rubber stoppers1) reduction results in amount of extractive leached from stopper

but no effect on sorption of preservative from solution .

1) However use of Teflon Coated rubber stoppers essentiallyprevents sorption and leaching of the rubber stopper .

)


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3) PROCESSING FACTORS:-

oBLENDINGoFREEZE-DRYINGPROCESSoPOLYMERIC FILMCOATING PROCESSoMILLING

o

EFFECT OF COMPRESSION:-oEFFECT OF LOCALMOBILITYoWETGRANULATIO

N

qBLENDING:-


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qBLENDING:-

It is most important step for manufacturing of solution dosageform. High speed of mixing may introduce air into the product

and slow mixing may not form a satisfactory product.

For mixing step, both mixing time and speed should beevaluated for API and Excipients.

Mixing might produce particle size reduction or polymorphicconversion.

During mixing some other factors like type of agitator,temperature or vaccum etc. can affect the stability.

Say for example, if during mixing, vacuum is not applied thanair bubble will present into the product that might produceoxidation of product.

v REMEDIES:-Use of optimum time and rate of mixing.Use of optimum and controlled temperature.Application of vacuum.Use of closed system.

qFREEZE-DRYING PROCESS:-


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qFREEZE DRYING PROCESS:

Freeze-drying process also affects the stabilityof product & there are various substances used

for the process of freeze-drying which also leadsto either increase or decrease in the stability.

EX:-1. Freeze drying was found to have destructive effect on the

ordered structure of starch & this effect varied with respect topreparation condition.

2. Impact of bulking agents was studied on the stability of monoclonalantibody.it was found that sucrose acts as a primary stabilizer but whenglycine was added, glycine leads to increase in the stability & whenmannitol was added instead of glycine again there was increase in thestability though to a lesser extent as compared to glycine.

qMILLING


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qMILLING

The milling process results in a reduction in the particle size of a givenmaterial and can be conducted using the mildest conditions possible torender a sample homogeneous, or can use more rigorous milling to reducethe primary particle size.

The formation of a high energy amorphous material is usually undesirableand given the opportunity, will spontaneously transfer either to a crystalline

hydrate or anhydrate

These physical changes in the state of the drug substance can alter thestability, dissolution characteristics and possibly even the bioavailability ofthe drug.

REMEDIES:Use of moderate condition of milling.Optimum time of milling.

EX:-


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EX:1. The phase transformation of chloramphenicol palmitate associated

with grinding and the effect of seed crystals

Form A Form B Form C16min.

150min.

30 min. (1% FormA)

40 min. (1%FormB)

Thus, as we know that with increase in the concentration of form A ofchloramphenicol palmitate the blood level are found to decrease and thereis a detection test for presence of form A in Pharmacopoeias, so whilegrinding no impurity of form A should be present and grinding timeshould not exceed 150 minutes (to prevent conversion of form B to form

A).

qEFFECT OF COMPRESSION:-


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qEFFECT OF COMPRESSION:-It is generally assumed that overall amount of energy input into aformulation during compression is not sufficient to induce a phasetransformation and for many substances this situation is certainly true.There

are numerous examples, for which changes in phase composition doaccompany a compression step.

Carbamazepine is a drug which shows differences in the dissolution ratesthat are associated with production of different polymorphs by tablet mfgprocess.

It has 3 different crystalline form , and Dihydrate form.

Manufacturing process isGrinding (ball mill for 15 and 60 min)Compression (single punch machine).

It was found thatDihydrate - good compressibility but not stable

- best stability but sticking - best stability .

qEFFECT OF LOCAL MOBILITY


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qEFFECT OF LOCAL MOBILITY:-Local mobility in amorphous forms of pharmaceuticals can lead to changesin their glass transition temperature effect of which is such that amorphousform converts to crystalline form.

qWET GRANULATION:-Wet granulation process, the both wetting phase solvent and dryingphase conditions can cause a suitable environment for the transformationto alternate crystalline forms.

API molecule

Polymorph 1Polymorph 2

Polymorphic transformations during wet granulation can be divided to1) Conversion of a metastable form to the stable form;2) Conversion of the stable form to a metastable form; or3) Conversion of an unsolvate form to a solvate form.


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REMEDIES:

Use of granulating liquid which will not produce polymorphic conversion.Moderate/Optimum condition for drying.


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4)MicrobiologicalfactorMicrobial growth in an oral liquid may cause foul

odour and turbidity and adversely palatability andappearance. High titres of micro-organisms may behazardous to especially in very young orimmunocompromised patients. By-products ofmicrobial metabolism may cause a change in the pHof the preparation and reduce the chemical stabilityor solubility of the drug. Microbial contaminationduring preparation must minimised by using cleanequipment, sterile water (Water for Irrigation BP) and

avoiding contaminated raw materials and containers.If sodium benzoate or benzoic acid are antimicrobialpreservatives the final pH must be less than 5 sothat the active unionised ispredominant.Consequently the drug must also be

stable at this pH.(DRUGS STABILITY, by-Jens


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5)Toxicologicalfactor

Water ,vitamins,minerals,enzymes & multitudesof functional groups are present in feed which canseverely reduce the shelf life of a drug.

vREFERENCE


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REFERENCE

1) THE THEORY AND PRACTICE OF INDUSTRIAL PHARMACY BYLEON LACHMAN, HIBERT A. LIBERMAN AND JOSEPH L. KANIG.

2) PHYSICAL PHARMACY BY ALFRED MARTIN.

3) Textbook of Pharmaceutics, by-Bentley, BailliereTindall, 8th edition, Ch-10, Page No:140.

4) Modern Pharmaceutics, by-Banker & Rhodes, MarcelDekker, 4th edition, Ch-6.

5)http://findebookee.com/

6) http://www.slideshare.net/guestd4155c/stability-basic7) PHARMACEUTICS & COSMETICS, by-Gupta & Gupta, Pragati

Prakashan, 1st edition.

8) Stability of Drugs & Dosage forms, Sumie yoshioka& Valentino J. Stella, Kluwer Academic Publishers.

9) DRUG STABILITY, BY-JENS T. CARSTENSEN, MARCELDEKKER, 2nd EDITION.


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Various Factor Affecting Stability of Formulation