M.Pharm 1st Semester SeminarSubject : Formulation Development

Topic : Solid State Drug Stability

By:Anindya JanaM.Pharm 1st Year (Pharmaceutics)Regd. No. : 1661611006

IntroductionStability of pharmaceutical product may be defined as the capability of a particular formulation, in a specific container/closure system, to retain its physical, chemical, microbiological, therapeutic & toxicological specification.

Types of Stability & Condition Maintained Throughout The Self Life of The Drug Product

Stability

Chemical

Therapeutical &

Toxicological

Microbiological

Physical

Factors Influencing Drug Stability

The degradation of pharmaceutical product can be treated as zero order reaction, first order reaction or pseudo order reaction.

(1) Zero Order ReactionThe reaction rate is independent of concentration of the reacting substance.Mathematically,Rate of concentration decrease =

-dCa / dt = k (I)Where,Ca = concentration of reacting material.k = Proportionality FactorT = TimeSince Ca is a constant, X, the amount of reacting, is identified asdx / dt = k (II)Integration of equation (II) yieldsx = kt + constant

(2) Pseudo Zero Order Reaction

In solid state, many drug decomposes according to pseudo zero order reaction rates, as reaction occurs between the drug and moisture in the solid dosage form.

The system behaves as a suspension, & because of the presence of excess solid drug, the first order reaction rate becomes a pseudo order reaction rate, & the drug loss rate is linear with time.

(3) First Order ReactionThe rate of reaction is directly proportional to the concentration of the reacting substance.Mathematically,

Rate of concentration decrease = _dCa / dt = kCa (I)

Integrating eq (I) -dCa / Ca = kdt (II)

We obtain,-lnCa = kt + i (III)

Where i is the constant of integration converting from natural logarithm (ln) yields-log Ca = kt/2.303 + constant

(4) Influence of pH on DegradationThe magnitude of rate of hydrolytic reaction catalysed by hydrogen and hydroxyl ions can vary with pH .

Hydrogen ion catalysis predominates at lower pH range.

Hydroxyl ion catalysis at higher pH range.

(5) Influence of Temperature on DegradationIn order for the rate constant or velocity of the degradation to be of use in the formulation of pharmaceutical product, it is necessary to evaluate the temperature dependency of the reaction.The most satisfactory method for expressing the influence of temperature is given by Arrhenius. k = Ae-Ha/RT (I)where,k = specific rate of degradationR = Gas constant (1.987 Calories degree-1 mole-1 T = Absolute TemperatureA = Frequency FactorHa = Activation EnergyAfter integration equation (I) becomeslog k2 / k1 = ∆Ha / 2.303R (1/T2 – 1/T1)

(6) Influence of Dehydration on DegradationIn physical dehydration processes water removal does not create new bonds but often changes the crystalline structure of the drug.

Since anhydrous compounds have different dissolution rates compared to their hydrated, dehydration reaction involving water of crystallization may potentially affect the absorption rate of the dosage form.

(6) Influence of Optical Isomerization on DegradationA Change in the optical activity of the drug may result as a change in its biological activity. Racemization is its main type of optical isomerization which effect drug molecule and it occurs when the optical 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.

(6) Influence of Hydrolysis on Degradation

Drugs with functional group such as ester, amide, lactones may be susceptible to hydrolytic degradation.

It is probably the most commonly encountered mode of drug degradation because of the prevalence of such group in medicinal agents and the ubiquitous nature of water.

(6) Influence of Photolysis on DegradationPhotolysis is the process by which the light sensitive

drug or excipient molecules are chemically degraded by light, room light, or sunlight. The variation of degradation depends on the wavelength of light.

In this process, light may be initiator while the reaction may be oxidation, polymerization or ring rearrangement.

Photolysis followed by a thermal reaction since light energy converted into heat energy.

Stability of Tablet Stable tablet should retained their original size,

shape, weight & colour under normal handling and storage condition throughout their self life.

Excessive powder or solid particle at the bottom of the container, cracks or chips in the face of tablet or appearance of crystal on the surface of the tablet or container walls are indication of physical instability of uncoated tablets.

Tablet hardness or resistance to crushing or fracturing can be assayed by commercially available hardness tester.

Colour stability of tablet can be followed by an appropriate colorimeter or refractometer with heat, sunlight and intense artificial light employed to accelerate the colour deterioration.

For making bioavaibility predictions, dissolution test gives more meaningful results than disintegration test.

Uniformity of water, odour, texture, moisture content and humidity effects also studied during a tablet stability test.

Reference

L. Lachman & H Lieberman; The Theory & Practice of industrial Pharmacy; CBS Publishers & Distributors PVT LTD; 2009; P760-803

J Carstensen, C Rhodes; Drug Stability Principles & Practice; Third Edison; 2008; P145-190

Remington; The Science & Pharmacy Practice; 21st Edition; Volume 1; P 1025-1038

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