Biopharmaceutical Considerations Part 2 Flashcards
The physiochemical properties of a drug affects dissolution kinetics (refers to how fast and how much of the drug dissolves in body fluids)
and thus is important in drug product design.
List physiochemical properties of drugs
- polymorphism
- Moisture absorption: affects physical structure and stability
- partition coefficient: indicates relative affinity of the drug for oil and water.
- compatibility of the excipients: with drug affects stability
- pH of the vehicle: differing from pH of stomach and gut affects stability
- presence of impurities:depends on route and purification
- Chirality: different isomers have different PD effect
What are the considerations with physiochemical properties of the drug?
- IV solutions are difficult to prepare with drugs that have poor aqueous solubility
- Drugs that are physically or chemically unstable need special excipients, coatings, or manufacturing processes to protect the drug from degradation
- Drugs with potent PD response, such as estrogens, hormones, penicillin antibiotics, cancer chemotherapeutic agents can cause adverse reactions to personnel who are exposed to these drugs during manufacture
Solubility, pH and drug absorption.
The solubility-pH is a plot of …………
What must you consider with this plot?
What information does Solubility-pH profile give
What are factors that impact solubilty?
….. the solubility of the drug at various physiologic pH values
Must consider natural pH of the environment of the stomach or small intestines
a first impression of the challenges to achieve complete dissolution for a dose of a drug in the stomach or in the small intestines.
Solubility improves with a basic or acidic excipient(s)
Converting a drug into a salt form can change the drug’s physiochemical properties. However, once the salt enters the body, it might convert back to the unionized form. This conversion risk must be evaluated to ensure the final product is both effective and safe.
Stability, pH and Drug absorption.
The stability-pH profile is a plot of…..
What information does this plot give?
give an example
plot of the reaction rate constant for drug degradation versus time?
or the rate of drug degradation at various physiological pH.
If drug degradation occurs by acid or base catalysts then you can predict degradation of the drug in GIT.
erythromycin has a pH-dependent stability profile.
Particle size and drug absorption.
What does particle size influence?
What does the Noyes-Whitney equation state?
Explain.
List examples of drugs with low aqueous solubility.
What can you do to improve dissolution and absorption of these drugs?
Particle size influences dissolution rate
According to noyes whitney equation surface area of the drug is proportional to the dissolution rate which means that increasing surface area (reducing particle size) increases dissolution rate.
Geometric shape also influences surface area.
remember that during dissolution the surface area constantly changes.
Particle physiochemical properties (hygroscopicity, morphology and size) are important for drug substances with low water solubility (BCS Class II) because dissolution is the rate limiting step for absorption
griseofulvin, nitrofurantoin and many steroids.
- Reduction of particles by milling to a micronized form.
- Disintegrants ensure rapid disintegration and drug release
- Surface-active agents increase wetting and solubility
- Nanosizing produces even smaller drug substance particles
Polymorphism, solvates and drug absorption.
All forms have the same chemical structure, but different physical properties.
Some of the crystalline forms tend to have lower solubility than the amorphous/non crystalline forms and are therefore insoluble. The amorphous forms generally dissolves more rapidly.
Chloramphenicol is an example of a drug with several polymorphs/crystalline forms. Its β-form or polymorph is more soluble and better absorbed.
The crystal form that has the lowest free energy is the most stable polymorph. A metastable polymorph is less stable and it can change over time into a more stable form.
If the polymorph changes structure, it can cause cracking or prevent granulation.
What is the purpose of dissolution and drug release tests?
- Aid for formulation development and selection
- Confirmation of batch to batch reproducibility
- Demonstrate that the product performs consistently throughout its use period of shelf life
- Establish IVIVC/IVIVR
5.The evaluate the biopharmaceutic implications of a minor/moderate product change (FDA Guidance, 1995)
Explain the biopharmaceutics classification system.
BCS
What law is this classification based on?
Class 1: High solubility-high permeability
Class 2: Low solubility- high permeability
Class 3: High solubility-low permeability
Class 4: Low solubility-low permeability
Fick’s First Law
Compare the dissolution behaviour of erythromycin hydrates and anhydrous forms.
The dihydrate form has the largest % dissolved
The monohydrate is less than the dihydrate
The anhydrous form has the least % dissolved
What is the purpose of adding excipients?
included in the formulation to provide certain functional properties to the drug and dosage form
These are the properties
1. Improve manufacturability of the dosage form
2. Stabilize the drug against degradation
3 Decrease gastric irritation
4. Control the rate of drug absorption from the absorption site
5. Increase drug BA
How can excipients influence drug product performance?
- Large quantities of Lubricant e.g magnesium stearate, may repel water and reduce dissolution.
- Coatings, particularly shellac, will cross link upon aging and decrease the dissolution rate
- Suspending agents that increase the viscosity of the drug vehicle, thereby diminishing the rate of drug dissolution
- Low concentrations of surfactants decrease the surface tension and increase the rate of drug dissolution
What are the PK parameters of oral drug products?
Ka : absorption rate coefficient
T max
AUC
Explain the effect of a lubricant. e.g. magnesium stearate on drug dissolution.
Using a lower % of lubricant increased the % of drug dissolved
