Drug Stability and Chemical Kinetics

Question 1

What is Stability?

Answer 1

Stability is an essential quality attribute for drug substances and drug products

Definition: the capacity of a drug substance or durg product to remain within the estabilished specifications to maintain its identity, strength, quality and purity through out the retest or expiration dating period.

Question 2

What are the potential adverse effects that the instability of drug products can lead too?

Answer 2

• Decrease or increase in API concentration
• Loss of content uniformity
• Decline of microbiological status
• Formation of toxic degradation products
• Alteration of bioavailability.

Question 3

What are teh reasons for stability testing?

Answer 3

Safety and Efficacy

• Patient’s welfare
• Repuatation of manufacturer
• Requirements of regulatory agencies
• Database for other products & research

Question 4

How does stability play a role in the development of a drug?

Answer 4

Stability plays an important role in the drug development process.

1. Preformulation stage
   
   • API stability, drug stability and excipient compatibility
2. Pre-clinical and clinial long-term stability of the API within the products
   
   • Formulation and process development
   • Packaging development: final packaging stability to support the expiration date.
3. Post-marketing life
   
   • monitoring of newly produced lots

Question 5

What are stability Studies for?

Answer 5

They are to support develop of new drug product

Stability studies are used to provide data to support clinical trials, registration submission or commericialization. Each phase of drug development requires addressing the time period that the drug product continues to maintain its specifications

Question 6

What are the three different modes of drug degradation?

Answer 6

1. Physical
2. Chemical
3. Biological (microbiological)

Question 7

What is Physical degradation?

Answer 7

• The physical changes that can occur in drug substances and excipients
• The physical state of a drug determines its physical properties (dissolution rate)
• Physical properties affect the efficacy and potentially the safety of a drug substance

Question 8

What kind of changes in physical states are there?

Answer 8

• Cyrstallization of amorphous drug
• Formation and growth of crystals
• Transitions between crystalline states
• Vapor-phase transfers including sublimation
• Moisture adsorption
• Liquids and dispersion consistency

Question 9

What is a polymorph and give an example?

Answer 9

The same molecule, different solids

example: 5-methyl-2-[2-nitrophenyl)amino]-3-thiophenecarbonitrile (ROY_ and its polymorph forms

Question 10

What is the formation and growth of crystals?

Answer 10

• Crystals can grow or decrease in size
• Drug substances and excipients in solid dosage forms, may recrystallize or sublime onto the surface of the dosage form during storage.
• Cases: Aspirin tablet, carbamazepine, lactoze,

Molecules in a crystal should not be considered static

Question 11

What is the difference between Crystalline and Amorphous?

Answer 11

Crystalline:

• Crystalline state is thermodynamically the most stable

Amorphous:

• Amorphous state is the less stable; but more soluble

Question 12

Describe Amorphous drugs & their Crystallization

Answer 12

• Pourly water-soluble drugs are often prepared in their amorphous state, due to higher solubility of amorphous materials
• Amorphous state has the lower free energy than the crystalline state, therefore amorphous substances tend to change to their more thermodynamically stable cyrstalline state with time
• Crystallization of amorphous drug substances may occur during long-term storage and may lead to drastic changes in the release characteristics of the drug

Question 13

What is Nifedipine?

Answer 13

• Amorphous nifedipine undergoes partial crystallization during storage under high-humidity conditions
• This transition to a partially crystallized state resulted in altered dissolution and solubility behavior.

Question 14

What are the transitions in crystalline states?

Answer 14

Polymorphs are different crystalline forms of the same drug with different free energy or chemical potential

• Polymorphic transitions during storage may alter critical properties of drugs, such as solubilty and dissolution rate
• Both temperature and humidity affects polymorphic transitions

Question 15

What is involved with chemcial degradation?

Answer 15

Pathways of chemcial degradation:

• Hydrolysis
• Dehydration
• Isomerization and racemization
• Decarboxylation and elimination
• oxidation
• Photodegradation
• Drug-excipient and drug-drug interactions

Question 16

Describe the degradation pathways for pralidoxime

Answer 16

The drug pralidoxime degrades via 2 parallel, pH-sensitive pathways. Under basic pH, the toxic product cyanide is formed.

Question 17

What is dehydration and epimerization of tetracycline?

Answer 17

Dehydration and epimerization of tetracycline, leading to formation of epianhydrotetracycline, known to be associated with Fanconi syndrome

Question 18

What are the factors affecting chemical stability?

Answer 18

Factors that accelerate the decomposition processes:

• Temperature
• pH
• Solvent
• Ionic strength
• Water (moisture)
• Oxygen (oxidization)
• Light (photostability)

Question 19

What are the stabilization strategies against chemical degradation?

Answer 19

• Factors such as pH, ionic strength, and solvent dielectric constant could be controlled
• Buffers and excipients should be excluded or their concentration minimized
• Minimization of moisture content
• Storage under low temperature conditions
• Protection against oxygen and light by using suitable containers and packaging

Question 20

What is Drug photo-reactivity?

Answer 20

• Direct photo-reactivity
  
  • Drug molecules absorb UV or Vis radiation
  • Drug + light –> degradation
• Indirect (sensitized) photoreactivity
  
  • Component other than drug molecules (e.g. additive or impurity in formulation) absorbs UV or Vis radiation resulting in reactive species which react with the drug molecules.

Question 21

What are the drug classes that undergo photo-reaction

Question 22

What are the formulation strategies for stabilization?

Answer 22

• Stabilization by modification of molecular structure of drug substances (development of more stable analogs)
• Addition of antioxidants
• Stabilization by complex formation, e.g. formation of inclusion complexes with cyclodextrins
• Stabilization by incorporation into liposomes, micelles, or emulsions

Question 23

What are the different properities of Chemical Kinetics?

Answer 23

Basic Kinetic Principles

Rate Equations and Kinetic Models

Factors affecting the rate of chemical reaction.

Question 24

What is the Reaction rate?

Answer 24

The change in concentration of a reactant (or a product) in a given period of time.

The period of time: short period anywhere during the reaction or at a certain instant of time.

Rate of reaction = change in concentration/change in time

Question 25

What is the reaction order?

Answer 25

The order of a chemical reaction refers to the way in which the concentration of the reactant influences the rate

Zero order reactions

First order reactions

Second order reactions

Apparrant or pseudo order

Complex reactions

Question 26

What is apparent or pseudo order

Answer 26

Pseudo-order describes a situation where one of the reactants is present in large excess or does not effect the overall reaction and can be held constant

e.g. Many hydrolysis decomposition reactions of drug molecules are second-order. However, the water is usually in excess and these reactions are called pseudo-first order.

Question 27

What are Zero-order rate reactions?

Answer 27

The loss of drug is independent of the concentration of reactant, so that the rate of reaction is a constant (k0). A=>P

Question 28

What is Half-life, shelf-life and expiration date?

Answer 28

Half-life (t1/2) is the time required for one-half of the material to react. It is the time at which A has decreased to 1/2 A

Shelf-life is the time required for 10% of the material to disappear. It is the time at which A has decreased to 90% of its original concentration. Also referred to as expiration dating period.

Expiration date is usually set at the tie when 10% of the initial (labele) dose is degraded at room temp.