Lecture 3

Question 1

Preformulation

Answer 1

• characterization studies performed prior to and in support of formulation development
• preformulation prioritizes a drug molecule’s liabilities in relation to a desired dosage form and leads to selection of an appropriate solid-state form of the API

Question 2

Importance of Solubility

Answer 2

1. Binding assays (drug discovery)
2. Drug product performance
3. Analytical method development
4. Chemical reactions
5. Salt screening
6. Polymorph screening
7. Process crystallization
8. Absorption modeling
9. Equipment cleaning

Question 3

Solubility is dependent on equilibration conditions:

Answer 3

– Temperature
– pH (for ionizable compounds)
– State of the solid; relates to the crystal lattice energy
– Composition of the solvent
– Impurities

Question 4

Dissolution Rate

Answer 4

• Permeable drugs dissolved in the GI tract are readily absorbed into the circulatory system
– Creates a sink condition
• In-vivo dissolution rate is proportional to equilibrium solubility for permeable drugs*
• Noyes-Whitney equation for in-vitro dissolution

Question 5

Biopharmaceutics Classification System (BCS) for Oral Immediate Release (IR) Dosage Forms

Answer 5

• Class I: High Solubility, High Permeability
• Class II: Low Solubility, High Permeability
• Class III: High Solubility, Low Permeability
• Class IV: Low Solubility, Low Permeability

Question 6

Ionization Increases…

Answer 6

Aqueous Solubility

Question 7

API Solid-state Forms – 2 general types

Answer 7

• Free Form is the active molecule by itself

* Salt Form is a combination of ionized free acid or free base with an ionized counter-ion

Question 8

Desirable Properties of APIs

Answer 8

1. Crystalline
2. Non-solvated
3. High melting
4. Non-hygroscopic
5. Water soluble

Question 9

Polymorphism

Answer 9

– the ability of one compound to exist in more than one crystal phase

*the thermodynamically most stable crystal phase is almost without exception the desired form of the API due to its superior physical stability

Question 10

Stable-form Screen

Answer 10

A specific type of polymorph screen utilizing solution- mediated phase transformation (SMPT) to identify the most stable crystal form or polymorph of a molecule

Question 11

High solubility in the slurry solvent..

Answer 11

is the most important factor, to ensure identification of the stable form