Preformulation Flashcards
Purpose of preformulation (3)
- Identifying possible dosage forms
- to use sustainable excipients
- predicting any formulation problems
Contrast between intrinsic properties and derived properties
Intrinsic: inherent to the molecule; affected by CHEMICAL modifications
- solubility, pKa, LogP
Derived properties: related to intermolecular interactions, affected by PHYSICAL shape
- melting point, density, excipient compatibility, particle size
When does preformulation take place
After candidate drugs are identified, and BEFORE dosage form design and optimization
Important physicochemical tests during preformulation
- chemical identity and purity tests
- Solution properties (pKa, solubility)
- Solid state properties: crystal structure, particle size
What are 2 mandatory fundamental solubility parameters for an NCE
intrinsic solubility: solubility when the drug is unionized
Dissociation constant (pKa): ionization of weak bases and weak acids at different pH
What is the acceptable range for aqueous solubility.
What do we need if it is below?
Range is 1-10mg/mL
If less: indicates a need for salt
If cannot be manipulated this way (for weak acids and weak bases) : liquid filling in capsules
What are ways to increase solubility of an NCE (4)
- Salt formation
- Use of solvents, co-solvents (oils)
- Complexation
- Solubilization by surfactants
Define intrinsic dissolution rate
dissolution solely controlled by diffusion
What does Log P = 3 mean
If Log P > 0 : ?
If Lop P < 0: ?
Log P = 3 means that the compounds is 1,000 times more soluble in OCTANOL
0+ = lipid soluble
Below 0 = water soluble
What is the difference between polymorphism and pseudopolymorphism
polymorph: substance exists in more than 1 solid state form
pseudopolymorph: solvents in crystal lattice lead to change in crystal habit
What is the amorphous form
- Non-crystaline materials , possess no long range order
- thermodynamically unstable; tend to revert to a more stable form
- most energetic form
What are the special considerations when selecting salt forms for an NCE (5)
- IV vs oral formulations
- High dose vs low dose
- Excipient compatibility
- Interaction with other actives
- Toxicological consideration
What are the 2 different classifications of polymorphs
- Enantiotropic: can be REVERSIBLY changed into another polymorph by temp. or pressure
- Monotropic: change is IRREVERSIBLE
What are some ways to screen for polymorphism
- Crystallization from different solvents
- Precipitation
- Concentration or evaporation
- Crystallization from the melt
- Grinding and compression
- Lyophilization
- Spray drying
What are 4 common drug degradation pathways
- Hydrolysis
- Oxidation
- Photolysis
- Trace metal catalysis
What does the Arrhenius plot test for?
What is it affected by
Affected by temperature
Test for accelerated stability
What are 3 physical properties that help with stability of solids
Hygroscopic: solids that absorb moisture from environment
Deliquescent: absorb moisture from environment until it becomes liquids
Efflorescent: loses water
What is the relative humidity for solids
55% temperate, 87% tropics
What are some protection that help with stability
- good packaging
- picking best excipients to reduce hydrolytic instability
What are 4 main solid-state characterization properties
- Crystal morphology
- Particle size
- Powder flow properties
- Excipient compatibility
When are small particle size important?
- Low dose is needed
- Using high potency drugs
- Using drugs with poor solubility (dissolution rate is directly prop. to SA)
What are important powder flow properties for tablet and capsule formations (3)
- bulk density (Carr’s index)
- Angle of repose
- Compression properties (elasticity, plasticity)
What is the most common method use to evaluate excipient compatibility
Thermal analysis. Eg DSC (differential scanning calorimetry)
What are the goals of excipient compatibility
- to help select excipients that will result in a stable and effective dosage form
- to identify excipients that are compatible with the API with no effect on its stability
