DRUG DEGRADATION PATHWAYSCHEMICAL DECOMPOSITION

1. HYDROLYSISHydrolysis may be due to following reasons: Ester or amide groups react with one molecule

of water and undergoes hydrolysis. Ester groups break faster than amide. Hydrolysis reaction between ionic species

proceeds faster than neutral molecules. It is catalyzed by H+ and OH- ions.

HYDROLYSIS

• A few drugs which decomposes by hydrolytic pathways are,

• Drugs that contain ester groups such as aspirin , procain atropine undergo hydrolysis to give acids and alcohols

Esters Amides

Aspirin Chloramphenicol

Procaine Ampicillin

Atropine Barbituric acids

HYDROLYSIS

• Procaine undergoes decomposition by hydrolysis, conditions for sterilization selected carefully

• Low temp and long period of time (LTLP) or• High temp and short period of time(HTSP) are employed• Sterilization of procaine solution by autoclaving at 120°C

for short period of time preferred to prolonged heating at 100 °C.

HYDROLYSIS

• Atropine, ester undergoes both acid and alkaline hydrolysis

• Optimum pH for maximum stability is 4.1 at 0 °C.• Amide undergoes hydrolysis at a slower rate than esters.• Chloramphenicol decomposition is influenced by acids,

bases, phosphate ions, acidic and citrate buffers.

HYDROLYSIS

• Salicylamide is decomposed by both acid and base catalysis

Protection against Hydrolysis

• A) Buffers:- • Drugs may be stabilized by the use of buffers. • pH of the solution should be adjusted so that the drug

will have maximum stability and therapeutic activity.• Through experimentation type of buffer and the

optimum pH should be established.• Optimal pH will be 3.5 to 5.• Pilocarpine is highly active in alkaline pH but it is

irritating to eye and also decomposes rapidly. • So acidic pH has to be selected.• Boric acid buffer PH 5.0 is used.

Protection against Hydrolysis• B) Complexation:-• Hydrolysis of benzocaine in aq. soln can be inhibited by

the addition of caffeine which forms complex.• The attack of catalytic species on benzocaine may be

reduced due to complexation.• The ion dipole interactions between H+ or OH- ions and

drug molecules will be reduced.• Now rate of hydrolysis depends on the amount of free

uncomplexed benzocaine present in solution.• Increase in caffeine concentration increases

complexation and decreases rate of hydrolysis.• Procaine, Tetracaine may be stabilised by complexation.

Protection against Hydrolysis

• C) Suppression of solubility• Decrease in solubility decreases the concentration of

drug in solution phase and reduces rate of hydrolysis.• Additives:- Citrates, dextrose, sorbitol and gluconates

suppresses the solubility of drug probably due to decreased hydration of drug molecules.

• Salts:- Degradation of penicillin can be prevented by using poorly soluble salt of procaine penicillin in the dosage form. Bezathine penicillin G forms suspension and follows zero order.

Protection against Hydrolysis

• C) Suppression of solubility• Derivatives:- Poorly water soluble derivatives such as

esters of drugs can be used to reduce the tendency of hydrolysis.

• E.g. Erythromycin propionate, chloramphenicol palmitate.

Protection against Hydrolysis

• D) Removal of water• Presence of water is responsible for hydrolysis. This

can be avoided by,• A. Storing drug in dry form. When desired

reconstitute the product. • Eg. Streptomycin dry powder for injection• B. Using water immiscible vehicle for the dispersion • of drug• Eg. Aspirin in silicon fluid.

Oxidation

• It involves the removal of electrons from a molecule.• Reaction between compound and molecular oxygen is

called as auto-oxidation• In fats and oils auto-oxidation of unsaturated fatty

acid proceeds in presence of atmospheric oxygen, light and traces of heavy metals .

• Eg. Oxidation of ascorbic acid increased by factor 105, in presence of 0.002 M copper ions.

Oxidation

• Principle that govern an oxidation reaction are,1. Presence of atmospheric oxygen2. Light provides free energy to initiate oxidation3. Presence of trace elements/ metals 4. Organic peroxides promote chain reaction and accelerates

oxidation5. Oxidation reaction between ionic species proceeds faster

than with neutral molecules.6. Oxidation reactions are catalyzed by H+ and OH- ions. Alkaline solutions are known to react with atmospheric

oxygen and forms oxides.

Oxidation

• Drugs which decompose by oxidation pathways are

Arachis oil Vitamin A

Clove oil Riboflavin

Cinnamon oil Vitamin B12

Epinephrine Ascorbic acid

Autooxidation kinetics of ascorbic acid

• Influence of trace metals:-

Oxidation of ascorbic acid by cupric ionAscorbate ion Cu2+ Semi quinone O2 Dehydro Ascorbic

in solution slow oxidn rapid oxidn acid

Influence of air on oxidation

• The rate of decomposition decreases when higher concentration of ascorbic acid is used.

• Ascorbic acid reacts with oxygen and thus depletes free oxygen.

• If air is bubbled through the mixture the rate of oxidation enhanced.

• When dissolved oxygen is maintained at saturation level the rate of reaction remains constant.

• So oxygen is responsible for auto-oxidation reaction.

Influence of Ionic species of drugs

• Ascorbic acid can exists as singly charged or doubly charged ion.

• In absence of copper ions oxygen is found to react with divalent ions faster compared to its reaction with monovalent ascorbate ion.

• When copper ions are added oxidation of the singly charged ascorbate ion alone is found tobe catalysed.

Influence of acidic and basic ion species

• The acid and base catalysed oxidation on ascorbic acid proceeds as follows.

• Dehydroascorbic acid, degraded product further degrades to give ketogluconic acid which further gives Threonic acid and Oxalic acid

• Auto-oxidation proceeds more readily in alkaline medium than acidic medium.

• Alkaline medium reacts with atmospheric oxygen and form oxides.

Protection against oxidation:• Protective measures should aim at eliminating the

influence of presence of oxygen, trace metals , H+ and OH- ions on drug.

• 1. Use of Antioxidant:- • Eg. Tocopherol, Butylated hydroxy anisole (BHA),

Butylated hydroxy toluene (BHT), Propyl gallate• Oil soluble antioxidants - Acts by breaking the free

radical chain reaction at the step of chain propagation.• Water soluble antioxidants act by preferentially

undergoing oxidation instead of the drug itself.• Ascorbic acid

Protection against oxidation:

• 2. Chelating agents:• Addition of chelating agent useful when traces of

heavy metals catalyse the oxidation.• EDTA (ethylene diamine tetra acetic acid), Citric acid

and tartaric acid forms complexes with heavy metals.• Thus metal ions are not available to catalyze the

oxidation.• Eg. Addition of EDTA to the buffer system prevents

degradation of prednisolone, ascorbic acid.• Boric acid in epinephrine forms one to one chelate

and stabilize it.

Protection against oxidation:

3. Vehicles:

•Replacement of water by other vehicle is often employed as means of stabilizing agent.•Other solvent when used in combination with water have catalyzing effect on oxidation.•Several properties of solvents such as internal pressure, solubility parameter, dielectric constant and ionic strengths are correlated for rate of a reaction.•4. Micellar solubilization:-

Polysorbate 80 enhance the rate of oxidation of ascorbic acid at low conc, but protect above its CMC , entrapping drug in spherical micelles.

Protection against oxidation:

5. Buffers:-

It affects the stability when oxidation is catalyzed by H+and OH- ions. Choose buffer with appropriate pH to maintain maximum stability of the product.

ENVIRONMENTAL CONTROL MEASURES:

6.Prevent the exposure to light:

Use of amber colored bottle or appropriate packaging material for storage of product.

2. Oxygen free environment:

Replace the air with inert gases such as nitrogen and carbon dioxide similarly use oxygen free solvent.

3. Low temp storage:

Store the product in cool and dry place.

Miscellaneous Reactions – Preventive measures

1. Isomerism:

Some drugs shows same structure but different stereochemical configuration. Interconversion of one form into another leads to inactive or less active drugs.

2. Optical Isomerisation:

Adrenaline (-) Adrenaline(+)more active less active/ less potent

Hyocyamine (-) heat or alkali Hyocyamine (+)more active light less active/ less potent

Preventive measures:

Product is protected from light. pH is maintained.

3. Epimerization:

Here compound has more than one asymmetric carbon atoms.

One remains static and other will rotates to give epimer. • Ergometrine Ergometrinine In solution less active

4. Geometric isomerization:

Compounds exist as trans and cis isomers

Vit A palmitate 6 –mono-cis +2,6 di-cis derivative derivative

More active less active

5. Polymerization6. Absorption of carbon dioxide:7. Decarboxylation

Definition of drug stability and drug kineticsStability

It is defined as the study of the extent to which the properties of a drug substance or drug product remain within specified limits at certain temperature. Properties may be physical, chemical, microbiological, toxicological or performance properties such as disintegration and dissolution.

Drug Kinetics

It is defined as how drug changes with time i.e., study of rate of change. Many drugs are not chemically stable and the principles of chemical kinetics are used to predict the time span for which a drug (pure or formulation) will maintain its therapeutic effectiveness or efficacy at a specified temperature.

Importance of studying kineticsIt determines:

Stability of drugs (t1/2)

Shelf life ((t0.9)

Expiration date

Stability of drugs (t1/2)

The half life (t1/2) is defined as the time necessary for a drug to

decay by 50% (e.g., From 100% to 50%, 50% to 25%, 20% to

10%)

Shelf life (t0.9)

It is defined as the time necessary for the drug to decay to 90% of

its original concentration.

Shelf Life:-• Shelf life is the time period during which the dosage

form is supposed to retains its original qualities. It is the time required to reduce the concentration of the reactant to 90% of its initial concentration.

• FIRST ORDER

Let t = t0.9 c = 0.9 co

substitute in ln c = ln co – Kt

t0.9 = 0.105 / K and K = 0.105/ t0.9

• t90 = 2.303 log C0

k1 0.9 C0

• t90 = 2.303 log 10

k1 9

t90 = 0.105 / k1

Shelf Life:-• ZERO ORDER

• Determination of t0.9

Let c = 0.9 co and t= t0.9

substitute in equation;

c = co –k t t90% = t0.9 = 0.1 co / k

ACCELERATED STABILITY STUDIES

A method by which a product is exposed to elevated temperature simulating what would happen over longer periods on the shelf life.

• The stability of pharmaceutical preparations should be evaluated by exposing the product to normal shelf conditions for a year or extended periods. The rate of decomposition is slow at room temperature .Such a method is time consuming and uneconomical.

It is designed to predict stability and hence shelf life of formulation.

OBJECTIVES:-

1. To predict the shelf life of a pharmaceutical product by accelerating the rate of decomposition ,preferably by increasing the temperature.2. Serves as a rapid means of selecting the best formulation from amongst a series of same formulation.3. Serves as a rapid means of Q.C.

ACCELERATED STABILITY STUDIES

1. TEMPERATURE:- Preparation is subjected at elevated temperature

2. HUMIDITY:- Preparation is exposed to high humidity conditions

3. LIGHT: - Preparation is subjected in artificial light of varying intensities.

FACTORS CONSIDERED DURING STABILITY STUDIES

It is based on applying Arrhenius equation, which gives effect of temperature on k of chemical reaction.

Stability can be evaluated by determining some properties of degradation.1. Change in concentration of drug, decrease or increase in concentration of degraded product, color, viscosity, etc.2. Gross stability is studied (Without considering excipients) 3. Mechanism of chemical reaction need not be explored, but such a study is always advantageous to predict stability.4. A stability indicating assay method is essential. Degradation product can also be estimated.5.A linear relationship w.r.t. time should be established as per kinetic principles. The order of reaction is determined.

PREDICTION OF SHELF LIFE:

6. The temperature dependency on the chemical degradation must be established with the help of Arrhenius equation.7. Statistical methods should be employed to predict shelf life.8. Determine stability of products along with container.9. Suitable animal experiments are required to establish its efficacy, safety and toxicity.

PREDICTION OF SHELF LIFE:

Drug preparations are stored at elevated temperatures viz.,50°C, 60°C, 70°C, 80°C, 100°C, 121°C.In addition ,the samples should be studied at 40 °C,75%RH & incubator temperature (35-37°C).To confirm the results obtained from accelerated stability studies, it is necessary to simultaneously conduct experiments at room temperature i.e., 30 °C,70% RH & or refrigerator temperature i.e.,4-5 °C. During different time intervals , samples are withdrawn. The sampling may be done at: 3 month intervals during the 1st year, 6 month intervals during the 2nd year& yearly there after

How to perform stability studies

The drug content is estimated using a stability indicating assay method.In this…..1. Draw a plot by taking any conc. like C or log C against time.

2. Graph is drawn for different elevated temperatures.

3. Linear relationships are obtained & these have different slope.

4. K value for each temperature are calculated.

5. Log k values are then plotted against reciprocal of absolute temperature.

6. Extrapolate the straight line to room temperature(25-30 °C)& read the log k/k25 value on Y axis.

7. Substitute the k25 value in the equation of appropriate order to get shelf life of the product under normal shelf conditions.

Describes regarding sampling times ,storage conditions& specific test parameters for each dosage form.

The FDA & the expert working group of the ICH of technical requirements for the registration of pharmaceuticals for human use have published guidelines for conducting the actual studies.

The ICH guidelines includes 4 batches:batch-Q (quality)batch-S (safety)batch-E (efficacy)batch-M (multidisciplinary)

ICH guidelines:

Q 1A(R2) ) :Stability testing of new drug substances & products.

Q 1B :Photo stability testing of new drug substances & products. Q 1C :Stability testing for new dosage forms.

Q 1D :Bracketing & matrixing designs for stability testing of new drug substances & products.

Q 1E :evaluation for stability data.

ICH guidelines:

These guidelines provide definitions of key terms & principles used in the stability testing of drug substances& drug products.

ICH outlined a combination of temperature & humidities for stability studies for most of the drug products. These include….. -15 °C ±5 °C 5 °C ±3 °C /ambient humidity 25 °C±2 °C /60%RH±5%, 30 °C±2 °C/60% RH±5%, 40 °C±2 °C/75%RH±5%.

ICH guidelines:

For liquid products , stored in semi permeable containers , subject to water loss , exposure to lower humidifies like….. 25 c ±2 c/40% RH±5%, 30 c ±2 c/40% rRH±5%, 40 c ±2 c/15% RH±5% is needed.

Also a high intensity light cabinet& a cycling chamber capable of cycling both temperature and humidity are needed.

ICH guidelines:

STABILITY CABINETS:

STABILITY CABINETS: