Preformulation Flashcards
What is preformulation?
- 1st phase of drug development
- Begins when a newly chemical entity (NCE) is synthesized, which shows sufficient pharmacological activity in animal models to warrant evaluation in man (before IND)
- Studies physical and chemical characterization of the drug prior to formulation
- Involves learning the physiochemical properties of a drug for designing an ideal dosage form
- Facilitate the decision to “Kill” compound candidates early in the development process
What is the physical description?
- Purity
- Solid, liquid or gas
- E.g: volatile Liquids (propylhexedrine) difficult to formulate as tablets
- heat of fusion & Melting point
- Thermal analysis: methods to determine heat related physical properties
- Heat of Vaporization & B. point
- Phase diagrams: provide information regarding presence of multiple phases
What is heat of vaporization?
- Heat of Vaporization: The amount of heat required to convert unit mass of a liquid into the vapor without a change in temperature.
- Heat of Vaporization of Water Hv = 2260 J /g (540cal/g )
- For water at its normal boiling point of 100 ºC, the heat of vaporization is 2260 J/g. — This means that to convert 1 g of water at 100 ºC to 1 g of steam at 100 ºC, 2260 J of heat must be absorbed by the water.
- Conversely, when 1 g of steam at 100 ºC condenses to give 1 g of water at 100 ºC, 2260 J of heat will be released to the surroundings.
- Vaporization (sublime) of volatile drug from solids
- Vapor pressure of drug and excipients (aerosol)
Describe what particle size affects?
- Particle size affects:
- Particle size => total surface area => dissolution rate
- => Absorption
- Content uniformity, stability, texture, taste
- Sedimentation
- Flow properties of the powder
Decrease particle size increase total surface area increase dissolution rate increase absorption
What is polymorphism?
- Chemical identical substances have more than one crystalline form (polymorph) with different physical properties:
- stabilities, melting point, solubility …
- Polymorphs are usually made by different processes
- Temperature
- Pressure
- Concentration and super-saturation
- Impurity
- Ionic conditions
- Molecular properties
- Meta stable polymorph: the form is less stable than others
What is the polymorphism of cocoa butter?
Tri-glycerin fats derived from stearic, palmitic and oleic acids
Nearly all long chain organic chemicals exhibit polymorphism:
Melting point of Cocoa butter polymorphs
Beta form 35C
Beta’ form 28C
Alpha form 22C
Gama form 18C
What is involved with Crystalline?
What is involved with Amorphouse?
Cystalline:
Crystalline state is organized and the most stable thermodynamically
Amorphous
Amorphous state is not organized, thus less stable; quicker dissolution
What is an Amorphous ‘solid’?
- Amorphous solids can be considered “super-cooled liquids” in which molecules are arranged in somewhat random manner as in the liquid state.
- Amorphous do NOT have definite melting temperature.
- e.g. glass, plastic, beeswax
Summary: Crystalline vs amorphous forms
- Crystalline: greater stability - potential of sustained release
- Amorphous: very often used, amorphous form have greater solubility, quicker dissolution rate, different absorption rates => more therapeutically available
What is Intrinsic solubility?
- Intrinsic solubility is defined in quantitative term as the concentration of a crystalline solid in a saturated solution, at a certain condition of solvent, temperature and pressure, .
- S0 (solubility) indicates the saturated solution concentration (e.g. mol/L)
- Saturated solution of a solid material is in equilibrium between the solute phase and the solid phase — definition of thermodynamic solubility
What is the apparent solubility?
Apparent solubility will change when:
- In different media
- Forming complex
- Adding surfactants
- At different pH
- …
- In a shorter time frame
How do you increase [apparent] solubility?
- Use co-solvents
- Complexation with cyclodextrins
- Formation of ester or salt
- Solubility in water
- Codeine free base: 8.3 mg/mL
- Codeine phosphate salt: 435 mg/mL
- pH adjustment
- Surfactants
- Prepare amorphous form
- Micronization to break down crystalline structure
What is involved with the pKa, pH and buffer capacity?
Ka – dissociate constant (ionization constant)
- Ionization: HA H+ + A-
Influences formulation development
- S0 and apparent solubility
- Stability
Influences absorption – bioavailability of drug
- Ionization and permeability
Accordingly, the pH and Buffer capacity should be optimized for ionization, stability, solubility and other objectives
What are the potential pharmaceutical Salts?
HA
- Hydrochloride
- Sulfate
- Phosphate
- Tartrate
- Citrate
- Mesylate
- Maleate
- Acetate
- Salicylate
- Lactate
- Others
B-
- Potassium
- Sodium
- Lithium
- Calcium
- Magnesium
- Diethanolamine
- Zinc
- Choline
- Aluminum
What is solubility and compare it to the dissolution rate?
Solubility
- How much
- Thermodynamic property
- Measured at equilibrium
- Measured in saturated solution
Dissolution Rate
- How quick
- Kinetic Property
- Measured at any time
- Measured in unsaturated solution
- Closely related to solubility
What is the dissolution and Noyes-Whitney Equation?
- Faster dissolution => faster absorption
- Dissolution: a limiting step of drug delivery and absorption – impact bioavailability, onset, and duration of the effect
