Biopharmaceutical Considerations Part 2 Flashcards
The physiochemical properties of a drug has an effect on dissolution and drug product design.
T/F
True
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 and trace elements in excipients 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
Biopharmaceutical considerations
- 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.
- 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
Physiochemical properties for consideration in drug product design and their potential impact.
What is the potential impact of the property pKa and pH profile?
Stability and solubilty of final product.
Physiochemical properties for consideration in drug product design and their potential impact.
What is the potential impact of the property particle size?
impacts surface area of drug and dissolution rate of product.
Physiochemical properties for consideration in drug product design and their potential impact.
What is the potential impact of the property polymorphism?
Solubility and stability of the drug
Physiochemical properties for consideration in drug product design and their potential impact.
What is the potential impact of the property hygroscopicity?
physical structure and stability of the product
Physiochemical properties for consideration in drug product design and their potential impact.
What is the potential impact of the property partition coefficient?
relative affinity of the drug for oil and water.
Physiochemical properties for consideration in drug product design and their potential impact.
What is the potential impact of the property excipient interaction?
stability of the drug product with through interaction with trace element.
Physiochemical properties for consideration in drug product design and their potential impact.
What is the potential impact of the property pH stability profile?
drug product degradation during storage or after administration
Physiochemical properties for consideration in drug product design and their potential impact.
What is the potential impact of the property impurity profile?
choice of synthetic route for active drug
Physiochemical properties for consideration in drug product design and their potential impact.
What is the potential impact of the property chirality?
differences in pharmacodynamic activity.
The solubility-pH is a plot of …………
What must you consider with this plot?
What information does Solubility-pH profile give
….. 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)
e.g Basic excipients (e.g., sodium bicarbonate, meglumine) enhance the solubility of acidic drugs by increasing pH.
T/F
True
Explain how salt formation affects drug physiochemical properties and product design.
Salt formation of the drug may change the drug’s physiochemical properties
e.g. solubility, chemical stability, polymorphism, manufacturability
However you must ensure that the salt converts to unionised form at the site of absorption for optimal drug product design.
What is the stability-pH profile?
How can this help predict degradation of the drug in GIT?
Give an example.
plot of the reaction rate constant for drug degradation versus time.
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.
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)
What does IVIVC stand for?
In vitro in vivo correlation
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
Very soluble
<1
Easily soluble
1-10
Soluble
10-30
Sparingly soluble
30-100
Slightly soluble
100 - 1000
Very slightly soluble
1000 - 10 000
Practically insoluble
> 10 000
What does the Noyes-Whitney equation state?
Explain the relationship between particle size, surface area, drug dissolution and absorption.
surface area of the drug is proportional to the dissolution rate
- Increasing surface area by reducing particle size enhances dissolution rate.
- Geometric Shape (Irregularly shaped particles) increase surface area compared to spherical ones, improving dissolution.
- Note that Surface area constantly changes during dissolution
What is the rate limiting step for BCS class II drugs?
Why?
Dissolution
Because of with low water solubility
So Particle physiochemical properties (hygroscopicity, morphology and size) are important
List examples of drugs with low aqueous solubility.
How can you improve oral absorption of these drugs?
- griseofulvin
- nitrofurantoin
- many steroids
- Reduction of particles by milling
- Disintegrants ensure rapid disintegration and drug release
- Surface-active agents increase wetting and solubility
- Nanosizing produces even smaller drug substance particles
Define polymorphism.
What are the different types or forms of polymorphs?
refers to the arrangement of a drug substance in various crystal forms or polymorphs
- Amorphous forms- noncrystalline forms (not a crystal but more of a variant)
- Solvates – are forms that contain a solvent (solvate) or water (hydrate)
- Desolvated solvates – are forms that are made by removing the solvents from the solvate
- Anhydrous state – drugs existing with no water of hydration
Drug products manufactured with polymorphs have the same chemical structure but different physical properties (different solubility, hygroscopicity, density, hardness, compression characteristics)
T/F
True
Some polymorphic crystals have lower aqueous solubility than the amorphos form. T/F
What can this cause?
A drug existing in the amorphous form generally dissolves more rapidly than the same drug in a crystalline form
T/F
True
Insolubility
True
Which crystal form of chloramphenicol is more soluble and better absorbed?
Beta form
Which is the most stable polymorph?
Why do some polymorphs convert to a more stable form over time?
What can Changing the crystal structure of the drug cause?
The crystal form that has the lowest free energy
Because the polymorph is metastable
cracking in a tablet or prevent granulation from being compressed into a tablet
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, etc
How can excipients influence drug product performance?
- Lubricant e.g magnesium stearate, may repel water and reduce dissolution when used in large quantities
- 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
