IPS1 - I. Chemical Kinetics and Stability

Chemical Kinetics

____

• is the study of rate of a chemical reaction

• Deals with the stability of drugs and the mode of action of their degradation through the examination of rate of reaction

rate of degradation

To ensure that the patient receives the correct dose of a drug, the rate of _______must be known.

Chemical

Chemical Kinetics degradative reactions are ________[physical/chemical] in nature and take place at definite rates.

chemical kinetics

degradation of drugs is facilitated by ______ ?

Reaction rate

____- refers to the speed of a chemical reaction

Chemical Kinetics

____- can provide predictive information to anticipate stability problems

stability

Chemical kinetics can provide predictive information to anticipate _____________ problems

first order

Majority of drugs = ___[first order/ zero oder]

Order of Reaction

____- is the way in which the concentration of the drug or reactant in a chemical reaction affects the rate.

1) Zero Order Reaction

2) First Order Reaction

Order of Reaction can be ___ [2]

Zero order

[Zero vs. First Order]

• The loss of drugs is independent of the concentration of the reactants and constant with respect to time.

• A constant rate of drug release from a dosage form is highly desirable.

Zero order

• Many decomposition reactions in the solid phase or in suspensions apparently follow ______ [Zero Order / First Order] kinetics

Alcohol

Is the classic example of Zero order reaction

• Warfarin

• Heparin

• Alcohol

• Aspirin

• Theophylline

• Tolbutamide

• Salicylates

• Phenytoin

Zero Order Examples: Zero WHATTS Power

methylxanthine

Drug class of theophylline is ___ ?

anticonvulsant

Drug class of Phenytoin is ___ ?

Half-life

____- is the time required for one-half (50%) of the drug to disappear

Shelf-life

____- is the time required for 10% of the drug to disappear

First Order Reactions

[Zero vs. First Order]

• The loss of the drug is directly proportional to the concentration remaining with respect to time.

First Order Reactions

[Zero vs. First Order]

• The rate depends on the concentration of one reactant

First Order Reactions

[Zero vs. First Order]

• The most common pharmaceutical reactions, e.g. drug absorption and degradation.

First Order Reactions

[Zero vs. First Order]

• Constant Half-Life

First Order Reactions

[Zero vs. First Order]

• Graph of First Order in Normal Graph is Curved

First Order Reactions

[Zero vs. First Order]

• Graph in log paper is Linear

Shelf-life

___-

• is the time period during which a drug product is expected to remain within the approved specification for use, provided that it is stored under the conditions defined on the container label.

• The time required for 10% of the material to disappear

Shelf life

____- is the time a drug would remain to the approved specification for use

Expiration Date

___- is the date placed on the container label of a drug product designating the time prior to which a batch of the product is expected to remain within the approved shelf-life specification

Expiration Date

___- is the date less than 10 % of drugs is present

1. Arrhenius Equation

2. Q10 Method

Methods for Determination of Shelf-life [2]

Arrhenius Equation

[Method for Determination of Shelf-life]

• _____- is used to predict temperature stability for finding shelf life

Q10 Method

[Method for Determination of Shelf-life]

• _____- can estimate the effect of a 10° rise in temperature on the stability of pharmaceuticals in shelf life

Long Term Studies

[Evaluation of Stability of Drug products]

• Under normal conditions

• Testing period: 0, 3, 6, 9, 12, 15, 18, 24, 36

• used for Zero Order Kinetics

Accelerated Studies

[Evaluation of Stability of Drug products]

• Use exaggerated storage conditions

• Testing period: 0, 3, 6 months

• used for First Order Kinetics

• Passed = 2 years shelf life

Stress Testing

[Evaluation of Stability of Drug products]

• Elucidates the intrinsic stability of the drug substance and identify the likely degradation product

• Under more severe conditions

• Hydrolysis

• Oxidation

• Photolysis

Types of Decomposition and Stabilization of Pharmaceuticals [3]

a. Hydrolysis

[Types of Decomposition and Stabilization of Pharmaceuticals]

• A chemical bond is split via the addition of water

a. Hydrolysis

b.Oxidation

c.Photolysis

b.Oxidation

[Types of Decomposition and Stabilization of Pharmaceuticals]

• Transfer of electrons.

a. Hydrolysis

b.Oxidation

c.Photolysis

c.Photolysis

[Types of Decomposition and Stabilization of Pharmaceuticals]

• Absorption of radiant energy in the form of light

a. Hydrolysis

b.Oxidation

c.Photolysis

a. Hydrolysis

Esters and amides are vulnerable to what type of decomposition

a. Hydrolysis

b.Oxidation

c.Photolysis

b.Oxidation

Steroids, vitamins, antibiotics are vulnerable to what type of decomposition

a. Hydrolysis

b.Oxidation

c.Photolysis

c.Photolysis

Nifedipine and hydrocortisone are vulnerable to what type of decomposition

a. Hydrolysis

b.Oxidation

c.Photolysis

• pH buffers

• Type of solvent

• Structure modification

Remedies for Hydrolysis [3]

• Low O₂ content

• Antioxidants

• pH buffers

• Type of solvent

Remedies for Oxidation [4]

Storage conditions

Remedies for Photolysis [1]

light resistant container (e.g. amber bottle)

___- is the official USP container

Calcium channel blocker (CCB)

Drug class of Nefidipine is __ ?

• True antioxidant

• Reducing agents

• Antioxidant synergist

Types of Antioxidant [3]

a. True antioxidant

[Type of Antioxidants] Tocopherol (Vitamin E)

a. True antioxidant

b. Reducing agents

c. Antioxidant synergist

a. True antioxidant

[Type of Antioxidants] Butylated hydroxyanisole (BHA)

a. True antioxidant

b. Reducing agents

c. Antioxidant synergist

a. True antioxidant

[Type of Antioxidants] Butylated hydroxytoluene (BHT)

a. True antioxidant

b. Reducing agents

c. Antioxidant synergist

a. True antioxidant

[Type of Antioxidants] Alkyl gallates

a. True antioxidant

b. Reducing agents

c. Antioxidant synergist

b. Reducing agents

[Type of Antioxidants] Ascorbic acid (Vitamin C)

a. True antioxidant

b. Reducing agents

c. Antioxidant synergist

b. Reducing agents

[Type of Antioxidants] Sulfites

a. True antioxidant

b. Reducing agents

c. Antioxidant synergist

c. Antioxidant synergist

[Type of Antioxidants] EDTA

a. True antioxidant

b. Reducing agents

c. Antioxidant synergist

c. Antioxidant synergist

[Type of Antioxidants] Citric acid

a. True antioxidant

b. Reducing agents

c. Antioxidant synergist

c. Antioxidant synergist

[Type of Antioxidants] Tartaric acid

a. True antioxidant

b. Reducing agents

c. Antioxidant synergist

c. Antioxidant synergist

[Type of Antioxidants] Citraconic acid

a. True antioxidant

b. Reducing agents

c. Antioxidant synergist

c. Antioxidant synergist

[Type of Antioxidants] Phosphoric acid

a. True antioxidant

b. Reducing agents

c. Antioxidant synergist