VARIOUS FACTORS AFFECTING STABILITY OF FORMULATION

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Guided by Prepared SANDIP PRAJAPATI MR.AKSHAY KOLI by

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The stability of the product is its ability to resist deterioration. It is always expressed in terms of shelf life.
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What does stability mean for drugs and pharmaceuticals ?

Stability: is the capacity of a drug product to remain within specifications established to ensure its identity, strength quality and purity. (USP-NF) 4/28/12
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As per USP there are five types of stability studies : Chemical Physical Microbiological Processing factors Toxicological

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1) Chemical factors: vVarious ways of chemical

includes:
hydrolysis dehydration isomerization & racemization decarboxylation & elimination oxidation photo degradation

degradation

drug excipients & drug drug interactions such as a) Reaction of bisulfite, an oxidant b) Reaction of amines with reducing 4/28/12 sugars3

It is major cause of deterioration of drugs, especially for those in aqueous solution. o Hydrolysis causes cleavage of drug molecule
o

Ex-

OH 1)Procaine

PABA + Diethyl Amine ethanol H+ CH3CO OH 2-amino1-p-nitro Phenyl-1,3propandiol + Dichloro aceticacid

2)Chloramphenic ol

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REMEDIES:

1) Removal of water,storage in dry form. 2) Using an insoluble derivative in suspension form. 3) Replacement of water by substantial quantity of some other solvent such as alcohol or polyhydroxy solvent mixtures.

4) By Micellar formation using anionic & cationic surfectants.

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dehydration

Sugars such as glucose and lactose1 are known to undergo dehydration to form 5(hydroxymethyl)furural. Erythromycin is susceptible to acidcatalyzed dehydration whereas prostaglandins E1 and E2 undergo dehydration followed by isomerization.

Batanopride undergoes an intramolecular ringclosure reaction in the acidic pH range due to dehydration whereas streptovitacin A exhibits two successive acid-catalyzed dehydration Reactions.

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qisomerization & racemization

Isomerization
Conversion of active drug into less active or inactive drug.

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

Racemization

Conversion of optically active drug into its enantiomer. The best known racemerization reaction of drugs are epinapherine,pilocarpine,ergotamine & 4/28/12tetracycline.

Decarboxylation and Elimination

Drug substances having a carboxylic acid group are sometimes susceptible to decarboxylation. 4Aminosalicylic acid is a good example.

Foscarnet also undergoes decarboxylation under strongly acidic conditions,whereas etodolac is susceptible to decarboxylation by acid catalysis.Trimelamol eliminates its hydroxymethyl groups and forms formaldehyde. Levothyroxine eliminates iodine. Ditiocarb eliminates carbon disulfide. Racemization of epinephrine.

REMEDIES This action is minimised by passing CO2 into the solution for one minute & sealing the container so as to 4/28/12 make it gas-tight prior to autoclaving.
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Ionic Strength (Primary Salt Effects)

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For drug degradation involving reactions with or between ionic species, the rate is affected by the presence of other ionic species such as salts like sodium chloride. Ionic strength affects the observed degradation rate constant, k, by its effect on the activityn coefficients, , in Eq. Ionic strength, , is described by

where Ciis the concentration of ionic species i and Zi 4/28/12 is its electric charge.

Drugs can be affected by the availability of oxygen.

Some photo degradation reactions involve photo oxidative mechanisms that are dependent on conc. of oxygen. Oxygen participates as reactant and also alters the degradation rate. Oxygen exists in various states such ground state triplate oxygen, etc. Singlate oxygen is highly oxidizing and capable of attacking olfenic bonds. Super oxide species is a mild reductant while hydrogen peroxide is fairly specific oxidant.

qoxidation

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The following excipients may have low level residues from manufacture that can lead to oxidative degradation in susceptible compounds.

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REMEDIES:

1) Minimum oxygen level used which may be achieved by boiling the water & allowing to cool in an atmosphere free from oxygen. 2) Hydrogenation of product. 3) Incorporation of inert gas in containers. 4) Use of antioxidant. 5)Buffering the solution at favourable pH, Use of metal free solvents.

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Reactions such as oxidation-reduction, ring alteration and polymerisation can be catalysed or accelerated by exposure to sun or artificial light. Energy absorption is greater at lower wavelengths and, as many drugs absorb ultra-violet light, degradation by low-wavelength radiation is a risk. Photolytic degradation can be very complex, the products of such degradation being numerous and difficult to identify. Exposure to light can cause discolouration of both drugs and excipients even when degradation is modest and not even detectable analytically. This can lead to off colour product, perceived by the patient as a quality deficiency.

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qphotolysis

CATALYSIS

In parentrals, great care is taken to exclude metals, because only slight decomposition caused by trace metals may cause sufficient discoloration to the product unsatisfactory.

Ex of metal catalysed oxidation in pharmaceutical system are cynocobalamine & erythromycin.

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2) Physical factors
oTEMPERATURE o pH AND pH RATE PROFILES o BUFFER oLIGHT o Crystalline state and polymorphism in solid drugs o MOISTURE AND HUMIDITY o EXCIPIENTS o MISCELLANEOUS FACTORS

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It is one of the primary factors affecting drug stability. The rate constant/temperature relationship has traditionally been described by the Arhenius equation, k = A exp (-Ea/RT) where Ea = activation energy A = frequency factor Arhenius equation has traditionally been used to describe the temperature dependency for various chemical reaction by regarding A and Ea as independent of temperature.

Temperature is obviously an important parameter because most reactions proceed faster at elevated temperatures than at lower temperatures.
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TEMPERATURE

The terms Ea and H are a measure of how sensitive the degradation 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 Equation b) 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 in which they are stable. They should not be exposed to extremes of temperature. Usually they should be stored at low temperature if they lack sufficient stability at room temperature. There are few drugs on which freezing has an adverse effect, so freezing should be avoided unless until it is stable at such temperatures.
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pH AND pH RATE PROFILES

Second most important parameter. The effect of pH on degradation rate can be explained by the catalytic effects that hydronium or hydroxide ions can have on various chemical reactions. If critical path in a reaction involves a proton transfer or abstraction step, other acids and bases present in solution can 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, its reactivity will be pH-dependent.
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A reaction in which hydronium ion, hydroxide ion, and water catalysis are observed can be described by

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

Where Kobs = sum of specific rate constants aH+ = activities of hydronium ion aOH- =activities of hydroxide ion This equation is for the case when drug is neutral in the pH range of study.i.e.where the ionization of drug does not have to take into account.
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BUFFER

These buffer species, like H+ and OH-, participates in formation of break down of activated complexes of various reaction and determine their reaction rate. These catalytic species are referred to as general acid-base catalysts Studies with phosphate buffer indicates that it enhance the degradation of various drug substances such as carbenicillin etc. In addition to acting as proto donor or accepter, buffer species can also act as Lewis acid and base through nucleophilic or electrophilic mechanisms.

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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 quantitatively as the wavelength dependence of degradation varies among drug substances and because light sources have different spectral distributions. Photo degradation for drug strongly dependence on the spectral properties of the drug substances and the spectral distribution of the light source.

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Crystalline state and polymorphism in solid Drugs in the crystalline state have lower ground state free drugs
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energy and exhibit higher G and so, slow reactivity.

Many drug substances exhibit polymorphism-each crystalline state has a different ground state free energy level and a different chemical reactivity. The stability of drugs in their amorphous form is generally lower than that of drugs In their crystalline form due to higher free energy level of amorphous form decreased chemical stability of solid drugs brought about by mechanical stresses such as grinding is said to be due to change in crystalline state -eg: grinding of aspirin increased degradation rate in suspension form.3
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Drug degradation in heterogeneous system such as solid and semisolid states is affected by moisture. Moisture plays important role in catalyzing chemical degradation: 1) Water participates in the drug degradation process itself as a reactant, leading to hydrolysis; hydration etc. Here degradation rate is directly affected by the concentration of water, hydronium ion, hydroxide ion. 2) Water absorbs onto the drug surface and forms a moisturesorbed layer in which the drug is dissolved and degraded. )Water adsorption may also change the physical state of the drugs, thereby affecting their reactivity.

Ex- ferrous sulphate crystals are more rapidly oxidised in moist air. Ex-Sodium ampicillin , potassium 4/28/12 propicillin

MOISTURE AND HUMIDITY

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.

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EXCIPIENTS

The role that excipients play in drug stability has been extensively reported-e.g.: accelerating the effect of talc on hydrolysis of thiamine hydrochloride, the accelerating effect of magnesium stearate on tablet containing amines and lactose etc. Additional informations include reports on compatibility and incompatibility of drugs. Excipients can affect drug stability via various mechanisms. The most obvious examples are those in which the excipients participate directly in degradation as reactants.

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Vaporization
Some drugs & pharmaceutical adjuvants possess sufficiently high vapor pressures at R.T. that their volatization constitutes a major route of drug loss.

Flavors may be lost from the formulation in this manner.

Ex-Nitroglycerine

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Aging

This is a process through which changes in the disintegration &/or dissolution characteristics of the dosage form are caused by alteration in the physico chemical properties of the inert ingredient or the active drug in the dosage form.

Ex-melting point of aminophylline suppository increased from about 20 mins to over an hour after 24 weeks of storage at 22 c

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RADIATION

Radiation generally used during gaseous sterilization of thermolabile drugs. The exposure also produce deterious changes in the product since the procedures also cause ionization in the irradiated material.

The ions joined in the initial stage of the process are subsequently converted into atoms & radicals become involved in chemical reactions.

Irradiation of a drug in aq. solution produces greater changes than the irradiation of the pure material because irradiation of water produces H2O2,free oxidative action in drug.

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Drugs affected by radiation are: Alkaloids

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1) 2) 3) 4) 5)

Atropine Steroids Sulphonamides Biological products-Insulin,Heparin.

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

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qEFFECT OF PACKAGING COMPONENTS:Most commonly employed are CONTAINERS: Glass, Plastic, Metal CLOSURES:Rubber vCONTAINERS: 1) GLASS v PROBLEMS: a) Release of alkali b) 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 watervapour & heat.
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vREMEDY FOR PREVENTION OF RELEASE OF INSOLUBLE FLAKE:Flake formation can be prevented by using borosilicate glass Pretreatment of the container with dilute acid. 2) PLASTIC
HIGH MOLECULAR WEIGHT POLYMERS LIKE POLYETHYLENE, POLYPROPYLENE, POLYSTYRENE, PVC ETC

vPROBLEMS: Permeation of moisture Leaching ADSORPTION OR ABSORPTION CHEMICAL/PHYSICAL REACTION OF CONTENTS OF CONTAINERS WITH PRODUCTS. vREMEDY: Lining of the container with an epoxy resin eliminates this problem but has to be evaluated separately for each product . (epoxy lining does not prevent sorption of phenyl mercuric nitrate).
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3) METALS Metals commonly used are tin , plastic coated tin , tin-coated lead , aluminum and coated aluminum .
v PROBLEMS:

a) Reactivity
ERROSION ENCRUSTATION WHITE 2. ALUMINUM + FATTY ALCHOL

1. TIN + CHLORIDE

vREMEDY: Application of an epoxy lining to internal surfaces of aluminum tubes was 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 stoppers 1) 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 essentially prevents sorption and leaching of the rubber stopper .

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3) PROCESSING FACTORS:oBLENDING

FREEZE-DRYING oPOLYMERIC FILM PROCESS oMILLING COATING PROCESS

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oEFFECT OF COMPRESSION:-

EFFECT OF LOCAL o MOBILITY WET GRANULATIO N

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qBLENDING:It is most important step for manufacturing of solution dosage form. 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 be evaluated for API and Excipients. Mixing might produce particle size reduction or polymorphic conversion. During mixing some other factors like type of agitator, temperature or vaccum etc. can affect the stability.

v REMEDIES:Use for example, if during mixing. Sayof optimum time and rate ofmixing, vacuum is not applied Use of optimum and controlled temperature. air bubble will vacuum. into the product that might produce Application of present oxidation of product. Use of closed system.
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than

qFREEZE-DRYING PROCESS:

Freeze-drying process also affects the stability of product & there are various substances used for the process of freeze-drying which also leads to 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 to preparation condition.

2.

Impact of bulking agents was studied on the stability of monoclonal antibody.it was found that sucrose acts as a primary stabilizer but when glycine was added, glycine leads to increase in the stability & when mannitol was added instead of glycine again there was increase in the stability though to a lesser extent as compared to glycine.

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qMILLING
The milling process results in a reduction in the particle size of a given material and can be conducted using the mildest conditions possible to render a sample homogeneous, or can use more rigorous milling to reduce the primary particle size. The formation of a high energy amorphous material is usually undesirable and 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 the stability, dissolution characteristics and possibly even the bioavailability of the drug.

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

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EX:1. The phase transformation of chloramphenicol palmitate associated with grinding and the effect of seed crystals
40 min. (1%Form B)

Form A

16 min.

Form B

150 min.

Form C

30 min. (1% Form A)

Thus, as we know that with increase in the concentration of form A of chloramphenicol palmitate the blood level are found to decrease and there is a detection test for presence of form A in Pharmacopoeias, so while grinding no impurity of form A should be present and grinding time should not exceed 150 minutes (to prevent conversion of form B to form A).
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qEFFECT OF COMPRESSION:It is generally assumed that overall amount of energy input into a formulation during compression is not sufficient to induce a phase transformation and for many substances this situation is certainly true.There are numerous examples, for which changes in phase composition do accompany a compression step. Carbamazepine is a drug which shows differences in the dissolution rates that are associated with production of different polymorphs by tablet mfg process. It has 3 different crystalline form , and Dihydrate form. Manufacturing process is Grinding (ball mill for 15 and 60 min) Compression (single punch machine). It was found that Dihydrate - good compressibility but not stable - best stability but sticking - best stability .
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qEFFECT OF LOCAL MOBILITY:qWET GRANULATION:-

Local mobility in amorphous forms of pharmaceuticals can lead to changes in their glass transition temperature effect of which is such that amorphous form converts to crystalline form. Wet granulation process, the both wetting phase solvent and drying phase conditions can cause a suitable environment for the transformation to alternate crystalline forms.

API molecule Polymorph 1 Polymorph 2

Polymorphic transformations during wet granulation can be divided to 1) Conversion of a metastable form to the stable form; 2) Conversion of the stable form to a metastable form; or 3) 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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appearance. High titres of micro-organisms may be hazardous to especially in very young or immunocompromised patients. By-products of microbial metabolism may cause a change in the pH of the preparation and reduce the chemical stability or solubility of the drug. Microbial contamination during preparation must minimised by using clean equipment, sterile water (Water for Irrigation BP) and avoiding contaminated raw materials and containers. If sodium benzoate or benzoic acid are antimicrobial preservatives the final pH must be less than 5 so that the active unionised is predominant.Consequently the drug must also be 4/28/12 at this pH. stable (DRUGS STABILITY, by-Jens

4)Microbiological Microbial growth in an oral liquid may cause foul factor and adversely palatability and odour and turbidity

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

5)Toxicological factor

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REFERENCE

1) THE THEORY AND PRACTICE OF INDUSTRIAL PHARMACY BY LEON LACHMAN, HIBERT A. LIBERMAN AND JOSEPH L. KANIG. 2) PHYSICAL PHARMACY BY ALFRED MARTIN.

3) Textbook of Pharmaceutics, by-Bentley, Bailliere Tindall, 8th edition, Ch-10, Page No:140. 4) Modern Pharmaceutics, by-Banker & Rhodes, Marcel Dekker, 4th edition, Ch-6. 5) 6) http://findebookee.co http://www.slideshare.net/guestd4155c/stabilitym/ basic
7) 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, MARCEL DEKKER, 2nd EDITION.
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Thank you

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