Nahla S Barakat, PhDProfessor of Pharmaceutics 04/18/23PHR 416 1

Principles and kinetics of

drug stability (PHR 416)

Course Description:The course deals with different routes of drug

degradation principles and kinetics of chemical degradation and stress stability testing.

Means of prolonging shelf life of pharmaceutical products are also included.

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Recommended text books:Martin’s Physical pharmacy & Pharmaceutical

Sciences, Fifth Edition, Patrik J. Sinko (ED), Lippincott Williams & Wilkins 2006,( Chapter 15).

Modern Pharmaceutics, Fourth Edition, G. S. Banker, C. T, Rhods. Marcl Dekker In., 2002

Physicochemical principles of Pharmacy, Fourth Edition, A.T Florence, D. Attwood, Pharmaceutical Press, 2006, (Chapter 4)

Recommended References :US Pharmacopea

<1191> Stability consideration in dispensing practice

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This course is a 3 credit hour subject & correspond to 300 marks The marks are divided as follows: 1- Final exam ………………..120 Marks 2- Oral exam ………………… 30 Marks 2- Mid term ………………….  60 Marks 3- Practical…………………... 90 Marks 

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Introduction

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Basic requirements of pharmaceutical products

Efficacy: Optimum therapeutic level for specified period of time.

Safety: Minimum or no side effects. Stability: The products should retain their

properties during storage. This should guarantee the efficacy and safety

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The USP defines the stability of

pharmaceutical product as “extent to

which a product retains within specified

limits” and throughout its period of storage

and use (i.e its shelf life) the same

properties and characteristics that it

possessed at the time of its manufacturer

Stability of drug also can be defined as the time from the date of manufacture and packaging of the formulation until its chemical or predetermined level of labelled potency and its physical characteristics have not changed appreciably.

For a drug substance, we need to study 3 categories of stabilities-

A. Solid state stability of drug only B. Compatibility studies ( drug+ excipients ) C. Solution phase stability

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These stability data involves selected parameters that taken together from the stability profile.

Pharmaceutical products are expected to meet their specification for identifying purity, quality and strength throughout their defined storage period at specific storage condition.

The stability of pharmaceutical product is investigated throughout the various stages of the development process.

Importance of stability studies

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Development of optimum formulation(preformulation studies) Finding the optimum storage conditions(temperature, light, humidity). Selecting the proper container for dispensing(glass or plastic, clear or opaque, cap liners). Predicting the shelf life of the drug. Anticipating drug excipient interactions. Stabilization of the drugs against degradation

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In some cases a pharmacist may need to

prepare stable compounded preparations

from existing dosage form.

It is the responsibility of the pharmacist

via the information of the manufacture to

instruct the patient in the proper storage

and handling of the drug product.

Factors affecting drug stability:1. Temperature: high temperature accelerate oxidation, reduction

and hydrolysis reaction which lead to drug degradation2. pH:• Acidic and alkaline pH influence the rate of decomposition of

most drugs.• Many drugs are stable between pH 4 and 8.• Weekly acidic and basic drugs show good solubility when they

are ionized and they also decompose faster when they are ionized.

• Sometimes pH can have a very serious effect on decomposition. As little as 1 pH unit change in pH can cause a change of ten fold in rate constant. So when we are formulating a drug into a solution we should carefully prepare a pH – decomposition profile

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3. Moisture:a. Water catalyses chemical reactions as

oxidation, hydrolysis and reduction reactionb. Water promotes microbial growth4. Light: affects drug stability through its energy

or thermal effect which lead to oxidation5. Pharmaceutical dosage forms: solid dosage

forms are more stable than liquid dosage forms for presence of water.

6. Concentration: rate of drug degradation is constant for the solutions of the same drug with different concentration. So, ratio of degraded part to total amount of drug in diluted solution is bigger than of concentrated solution.

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7. Drug incompatibility: reactions between components of pharmaceutical dosage forms it self or between these components and cover of the container .

8. Oxygen: exposure of drug formulations to oxygen affects their stability

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Expiry date: means that drug can not be used after this date because the concentration of drug is decreased and become lower than therapeutic concentration. In addition, some products of drug degradation are toxic and harmful to patients.

NOTE: The expiration date period should begin at the time of manufacture of the lot.

PRODUCT TYPE MAX. TIME PERIODDosage forms: 5 years Implants, injectables, tablets, capsules, soluble

powders, etc. • Note! After the opening of the drug container, the

expiry date will be shorter as a result of the decreased concentration of drug during usage and the effects of external factors. :

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Examples: 1. Eye drops: can be used for one month after

opening the droppers2. Syrups and suspension of antibiotics: can be

used for one week by storage in room temperature and for two weeks by storage in 4C°.

3. Tablets and capsules remain stable in the package but after removal the expiry date will change

4. Ampoules: must be used immediately but the vials (multidose) are stable for 24 h for the presence of preservatives.

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Five stabilities of drug must be considered::

1. Physical2. Chemical3. Microbiological4. Toxicological5. Therapeutic

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Reaction kinetics:

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“kinetic” originates fromGreek “kinetikos” that, in turn, originates from Greek “kinetos’ which means “moving”.

Kinetics: It is the study of how a system changes as function of time.

Reaction kinetics: It is the study of rate of chemical change and the way in which this rate is influenced by conditions of

concentration of reactants and products, solvent, ionic strength and temperature

Rate and order of reactions

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Importance of the rate process: For drug manufacturer as he must

demonstrate that his product is stable and can be stored for reasonable length of time without changing to inactive or toxic form.

The pharmacist must be aware of potential instability of the drug that he handles.

The physician and the patient must be assured that the prescribed drug will reach the site of action in sufficient concentration.

Rate and order of reactions

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Fields of rate process:Stability and incompatibility: Here the rate

process can lead to inactivation of the drug through decomposition or conversion into inactive or toxic form.

Dissolution: Here the main concern is the rapidity with which a solid dosage form is changed to molecular solution.

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Pharmacokinetics: Concerns with the rate of drug absorption, elimination and metabolism.

Drug action at molecular level: Here it is assumed that generation of a response by a drug is a rate process.

In general, reaction kinetics is the study of rate of chemical change and the way in which this rate is influenced by conditions of concentration of reactants, products and other chemical species which may be present, and the factors such as solvent, pressure and temperature.

Reaction kinetics permits formulation of models for the intermediate steps through which reactants are converted into other chemical compounds and is a powerful tool in elucidating the mechanism by which chemical reactions proceed.

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It provides a rational approach to stabilization of drug products and prediction of shelf- life and optimum storage conditions. e.g. thiamine HCl is most stable at pH 2-3 and is unstable at pH above 6. If this is combined with a buffered vehicle of say pH 8 or 9 the vitamin is rapidly inactivated.

Knowing the rate at which a drug deteriorates at various hydrogen ion concentrations allows one to choose a vehicle that will retard or prevent the degradation.

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Reaction Rate The rate of reaction is the velocity with

which a reactant or reactants undergo chemical change.

The rate, velocity or speed of a reaction is given by the expression dc / dt.

where dc is increase or decrease of concentration over a time interval dt

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Rate and order of reaction

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Rate: The rate, velocity or speed of reaction is

given by:

dc/dt This expression gives the increase (+) or

decrease (-) in concentration (C ) within a given time intervals (dt )

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Reaction kinetics: Rate

Formation of ethyl acetate from ethyl alcohol and acetic

acid.

CH3COOH + C2H5OH = CH3COOC2H5 + H2O

In this reaction the rate of forward reaction (Rf) may be

calculated by measuring the concentration of acetic acid

or ethanol as the

reaction progresses.

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Reaction kinetics: Rate CH3COOH + C2H5OH = CH3COOC2H5 + H2O The rate of reverse reaction (Rr) may

calculated by measuring the concentration of ethyl acetate or water as the reaction takes place

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Reaction kinetics: Rate According to the law of mass action: The rate of a chemical reaction is proportional

to the product of molar concentrations of the reactants each raised to a power equal to the number of molecules of the substance undergoing reaction.

aA + bB + ….. = Products Rate = k [A]a [B]b

Where k is rate constant.

Order of reaction

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aA + bB ProductReaction rate = K [A]a [B]b

* If a=2 and b=1, the reaction rate = K [A]2[B]1

* The reaction is second order with respect to A and first order with respect to B.

* The overall order is the sum of the exponents of

concentration terms that afford a linear plot, i.e. third order

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Reaction of ethyl acetate with sod. hydroxide in aqueous solution

CH3COOC2H5 + NaOHsoln → CH3COONa + C2H5O

The rate expression is:

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CH3COOC2H5 + NaOHsoln → CH3COONa + C2H5OH

• The reaction is first order (a = 1) with respect to ethyl acetate and first order (b= 1) with respect to sodium hydroxide solution.

• The overall reaction is second order (a + b = 2)

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CH3COOC2H5 + xss NaOHsoln → CH3COONa + C2H5OH

• Suppose that NaOH solution is used as solvent (i.e. its conc. is very high) and ethyl acetate were in low concentration. As the reaction proceeds, ethyl acetate would change appreciably from its original concentration,

Whereas the concentrations of NaOH solution would remain

essentially unchanged because of its presence in great

excess

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CH3COOC2H5 + xss NaOHsoln → CH3COONa + C2H5OH

• In this case the reaction rate can be written as

• where k' = K [NaOH]• The reaction is then said to be pseudo-first-

orderreaction because it depends only on the first

power (a = 1) of the concentration of ethyl acetate

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In general, when one of the reactants is present in such great excess that its concentration may be considered constant or

nearly so, the reaction is said to be of pseudo-order.

Apparent or pseudo-order "Apparent" or "pseudo"-order describes a

situation where one of the reactants is present in large excess.