Drug Stability

Question 1

What is drug stability?

Answer 1

The extent to which a product retains, within specified limits and throughout it’s period of storage and use, the same properties and characteristics it possessed at the time of manufacture

Question 2

What are the three areas of concern with regards to drug stability?

Answer 2

Chemical (active(s) retain chemical integrity and potency within limits)
Physical (properties like dissolution, appearance are retained)
Microbiological (sterility or resistance to microbial growth retained)

Question 3

Why is chemical stability important?

Answer 3

The degradation of active ingredient(s) can lead to inaccuracy in dosing and possible therapeutic failure
Product specifications have limits usually +/- 2-10% of label
There is tighter control if degradants are toxic

Question 4

Why is physical stability important?

Answer 4

The degradation may lead to reduced bioavailability and reduced efficacy. This may be due to physiochemical changes to active or excipient

Question 5

What are examples of physiochemical changes to active or excipients?

Answer 5

Polymorphs, loss of volatiles, dissolution changes from aging
Changes like mottling, caking or colour change may or may not affect the efficacy but elegance and patient confidence will be lost

Question 6

Why is microbiological stability important?

Answer 6

It refers to the product remaining sterile or resisting microbiological growth (preservatives must retain efficacy over the entire shelf life)

Question 7

Most drugs are organic molecules and degradations involve chemical reactions which follow classical kinetic principles. Chemical reactions are usually done under conditions that promote these reactions, however the conditions in pharmaceutical products are different. Explain.

Answer 7

Low concentrations, neutral room temperature and pH

Question 8

What are four general reaction types considered in chemical stability?

Answer 8

Hydrolysis
Oxidation
Photolysis
Miscellaneous

Question 9

What is hydrolysis? What are the most common functional groups involved?

Answer 9

Decomposition of a drug through reaction with water (important).
Water acts as a nucleophilic agent and attacks electrophilic sites of drug molecule.
Most common functional groups involved are carboxyl derivatives - lactams, esters amides

Question 10

How quick is hydrolysis?

Answer 10

Reaction rates can vary and some molecules like ampicillin can be quite unstable

Question 11

How do other functional groups affect hydrolysis and stability?

Answer 11

Other functional groups on the molecule can affect the stability of the carboxyl group due to inductive, resonance, steric or hydrogen-bonding effects (e.g., lidocaine is much more stable than other amide anesthetics because of the methyl groups)

Question 12

Give examples of products that are often hydrolysed (functional groups)

Answer 12

Amides - acetaminophen
Lactam - penicillin
Ester - atropine
Lactone - warfarin
Acetal - erythromycin
Imine - diazepam

Question 13

Describe oxidation

Answer 13

It is often mediated through atmospheric oxygen. Most are free-radical reactions which occur spontaneously under ordinary conditions (referred to as autoxidative)
Products of oxidative processes are usually electronically more conjugated, which results in colour changes or aroma changes.
They may cause the product to be unfit even though only a small amount is degraded
Oxidation can occur in aqueous and non-aqueous solutions and in solid states

Question 14

What is oxidation?

Answer 14

Oxidation is viewed as a loss or removal of electrons, loss of hydrogen or a gain of oxygen

Question 15

What are redox reactions?

Answer 15

Oxidation/reduction reactions are electron transfer processes where oxidation is a loss of electrons. Electron transfer is accompanied by a change in structure and transfer of protons

Question 16

Describe the steps of oxidation

Answer 16

The first step is initiation, which generates a free radical.
The second step is propagation, where hydroperoxide formation occurs with further release of free radicals.
The final step is termination, which may be two radicals coming together to form a non-radical.

Question 17

Give examples unstable products that are often oxidized

Answer 17

Phenols - steroids
Catechol - isoproterenol
Ether - PEG
Thiols - methimazole
Thioether - chlorpromazine
Aldehyde - paraldehyde

Question 18

What is photolysis?

Answer 18

Light may provide energy (photon) for initiation of an oxidative process. It’s not always oxidative (e.g., conversion of ergosterol to ergocalciferol, degradation of nitroprusside, rearrangement of some steroids). A reaction is initiated and propagated by electromagnetic radiation due to the formation of free radicals.

Question 19

When electromagnetic radiation is absorbed by a molecule, one of the following events may occur:

Answer 19

1. The molecule decomposes with release of free radical
2. Energy retained - chemical change
3. Energy converted to heat and no reaction occurs
4. Absorbing molecules emit light of different wavelengths

Question 20

Explain the decomposition of tetracycline and prostaglandin E2

Answer 20

Degradation of tetracycline and prostaglandin E2 involves the loss of a molecule of water (epidehydrotetracycline and prostaglandin A2)

Question 21

Describe the dehydration of ampicillin trihydrate and threophylline hydate

Answer 21

The loss of water does not cause a chemical change but changes the crystal habit of the drug (pseudopolymorphism) which may result in solubility changes. It may also affect bioavailability and may put the drug into a form where it is more susceptible to chemical decomposition

Question 22

What is racemization? Why is it important?

Answer 22

Change in optical activity may result in significant changes in biological activity

Question 23

Reactions such as hydration, decarboxylation, additions of Schiff’s base formation can occur and result in drug instability when drugs are mixed together. Some of these reactions form the basis for various drug incompatibilities. Some examples are:

Answer 23

Reaction between beta-lactam group of penicillines and cephalosporins with the amino group of aminoglycoside antibiotics cause the formation of an inactive amide
Reaction between a drug containing a primary amine and one with an aldehyde or a ketone group (Schiff’s base formation)
Reaction between a drug with an amine functional group and the hydroxyl group of a sugar (Maillard reaction)

Question 24

What are four examples of physical degradation?

Answer 24

Polymorphism
Vaporization
Aging
Adsorption

Question 25

What is polymorphism?

Answer 25

Polymorphs differ in crystal structure and crystal energies which results in solubility differences This may result in an unusable product e.g., conversion of soluble polymorph of cortisone acetate to stable polymorph results in caking of product when formulated as an injectable suspension

Question 26

What is vaporization?

Answer 26

Some drugs possess high vapour pressure and drug is lost through vaporization Severe changes in tablet content and uniformity may occur

Question 27

What is aging?

Answer 27

Impotant aspect in tablets and changes occur in the disintegration/dissolution properties of the formulation Not easily explained but hardening or softening alters disintegration/dissolution and bioavailability

Question 28

What is adsorption?

Answer 28

Drug loss to packaging materials and well document in IV solutions and PVC plastic Care must be taken with container selection to avoid these problems

Question 29

What are kinetic equations used for in pharmaceutics?

Answer 29

General principles of chemical kinetics is used to determine shelf life for a product. We generally define the shelf life (t90) as the time when the initial concentration of the active has decreased by 10%

Question 30

What is the Order of reaction?

Answer 30

In drug stability, the order of reaction of process is generally treated as "apparent" order. Order determines the shape of the concentration-time profile; the rate constant determines its slope Both must be determined experimentally Zero, first and second order kinetics are the most frequent in drug stability

Question 31

What are factors affecting reaction rate?

Answer 31

``` Temperature Catalysis pH Solvent Solubility ```

Question 32

How does temperature affect reaction rate?

Answer 32

Reaction rates are proportional to the number of collisions, so expect reaction rates to increase with increasing temperature The relationship is known as the Arrhenius equation and a plot of log k as a function of the inverse of absolute temperature gives a straight line with a slope of -Ea/2.303R

Question 33

How can we use Arrhenius to our advantage?

Answer 33

We can speed up the reaction by increasing the temperature to 70ºC, 80ºC, etc. and then extrapolating for 20ºC

Question 34

What is catalysis? Why is it important to drug stability?

Answer 34

Catalyst is a substance which increases rate constant of a reaction but does not change the equilibrium constant The catalyst is not transformed or consumed but interacts with the reactants to facilitate reaction We want to be able to recognize a possible catalyst in a formulation and minimize it's effects on drug stability

Question 35

How does pH affect stability? Why is it important?

Answer 35

Reactions rate in aqueous solutions often dependent on the pH of the solution. The study of pH effects on reaction rates can give insight into the mechanism and provide practical information regarding the stability of the drug. Rate constant determined at a variety of pH values with variables such as temperature, ionic strength and solvent composition held constant. These data presented as plots where rate constant is a function of pH (log k vs pH for first order and k vs pH zero order). Referred to as pH-rate profiles and several characteristic curve shapes can be identified

Question 36

Where do see V-shaped curves?

Answer 36

Seen with non-ionizable substrate subject to hydrolysis

Question 37

Where do we see sigmoid-shaped curves?

Answer 37

Seen when drug molecule can undergo acid/base dissociation so this is the typical curve for an ionizable substrate

Question 38

What does the pH-rate profile look like for aspirin?

Answer 38

It's a combination of the v-shape curve and the sigmoid curve

Question 39

How do solvents affect stability?

Answer 39

Solvent effects on stability are very significant but may be quite complex and difficult to predict. Generally an increase in solvent polarity accelerates the rates when a charge is developed in the activated complex. An increase in solvent polarity will generally decrease the rates when there is less charge in the activated complex compared to the starting materials. A change in solvent polarity will have little or no effect on the rates of reaction when there is little or no difference in charge between the reactants and the activated complex. Solvents may also affect the pKa of the drug by shifting the dissociation equilibrium

Question 40

Why is it important to understand the effects of solvents on stability

Answer 40

It may be necessary to incorporate water miscible solvents into the formulation to solubilize the drug. The range of solvents that can be used is somewhat limited and most common are alcohol, propylene glycol, glycerol and polymeric alcohols (e.g., PEG).

Question 41

How does solubility affect the stability?

Answer 41

Some drug products may be stabilized by preparing insoluble salts and formulating them as suspensions. Reduced solubility in a suspension decreases amount of drug available for reaction. When in solution, drug may undergo apparent first order reaction but when formulated as a suspension, it decomposes through apparent zero order kinetics.

Question 42

Name some stabilization strategies

Answer 42

``` Control of hydrolysis Control of temperature Changes in solvent Formation of complexes Formulation of suspensions Control/prevent oxidation ```

Question 43

A number of factors can affect the rate of hydrolysis. Explain how this can be used as a stabilization strategy

Answer 43

By modifying these variables, some control over rate of hydrolysis can be achieved Drug must be in solution for hydrolysis to occur so exclusion of water will slow the rate May be achieved by formulating product as solid dose form such as a tablet or capsule Note: total exclusion of water is not usually possible

Question 44

How can controlling pH help with stabilization?

Answer 44

Control of pH allows some control over hydrolysis rate and use of pH-rate profile allows determination of pH value where reaction rate is at a minimum. Buffering to optimal pH may not always be possible due to solubility and physiological limitations. Sometimes compromise pH must be used and pH control could be combined with another stabilizing technique such as inclusion of a cosolvent (e.g., diazepam injection)

Question 45

How can controlling the temperature help with stabilization?

Answer 45

Storing at reduced temperature may be used to increase product stability Freezing should not be used unless shown to have no deleterious effects; freezing may be harmful to emulsions, protein drugs and drugs like ampicillin

Question 46

How can formation of drug complexes help with stability?

Answer 46

Formation of complexes may be of value (e.g., benzocaine-caffeine and drug-cyclodextrins) but some complexes may accelerate decomposition and some may alter solubility and bioavailability

Question 47

How can formulating suspensions help with stability?

Answer 47

Formulation of product as a suspension may be a useful tactic since drug will probably degrade through apparent zero order kinetics

Question 48

How can oxidation be prevented?

Answer 48

Protecting from light Exclusion of oxygen Addition of antioxidants Control of pH

Question 49

How can drugs be protected from light?

Answer 49

Statement on the label and package should exclude light | Amber glass, opaque plastics and some come with foil wrapping when given by IV infusion (nitroprusside)

Question 50

How can drugs be excluded of oxygen?

Answer 50

Purged with inert gas (usually nitrogen) and sealed (useful for parenterals)

Question 51

How do we select antioxidants?

Answer 51

Materials which are more easily oxidized than the product or free radical inhibitors Inclusion of a cheating agent such as EDTA to consume trace amounts of metal ions which can function as catalysts may also be useful Selection is important as some may react with product components or there may be physiological issues

Question 52

Why is controlling pH help increase stability?

Answer 52

Usually a pH of 3-4 is useful providing this pH range has no deleterious effect on product and is physiologically acceptable