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
What is the equation involved in the rate of dissolution?
D: diffusion coefficient: solvent and solute properties
A: Surface area: Particle size
Cs: solubility
C: concentration
h: thickness of boundary, speed of stirring, visocity
m: mass
t: time
What is involved with the partition coefficient [P] or log P?
Oil/water partition coefficient: measure of molecule’s solubility in oil (e.g. octanol) and water
What is membrane permeability?
After dissolution, drug has to cross biologic membranes
Assessment of passage of drug across biologic membrane
Pharmaceutical Analysis
To control and assess the quality and performance of drug products, numerous analytical methods was selected and used for
- Qualitative analysis
- Semi-quantitative analysis
- Quantitative analysis
What are the considerations for selecting analytical methods?
- When to test?
- How to collect sample? (sampling)
- What to test? (quality, quantity) (chemical, physical)
- What method to use?
- The limits of tests
- Quality of analysis: accuracy, precision, reproducibility, specificity, speed — validation
- How to interpret results?
What are the analytical methods used?
- Physical testing
- Gravimetric – weighting (by balance)
- Conductance methods (electrochemical for ions & pH )
- Spectroscopy (electromagnetic radiation)
- Separation and purification techniques
- Immunoassay and Microbiological assay
What is the physical testing that is involved?>
- Density
- Refractive index
- Optical rotation
- Melting/freezing and boiling point
- Color and color change
- Viscosity and viscosity change
- By eye, by microscope, by thermal analysis,….
What is involved with Spectroscopy and the interactions of electromagnetic radiation?
- Ultraviolet/visible (UV/vis) Spectroscopy
- Fluorescence and Phosphorescence Spectroscopy
- Infrared (IR) Spectroscopy
- Raman spectroscopy
- NMR (nuclear magnetic resonance) Spectroscopy
- X-ray diffraction (XRD)
- Flame emission and atomic absorption (AA) Spectroscopy
- All can be used for qualitative analysis
- Many can be used for quantitative or semi-quantitative analysis
What are the Separation Techniques and Chromatography used?
- As either preparative or analytical methods
- Paper chromatography
- Thin layer chromatography (TLC)
- Column chromatography
- Gas Chromatography (GC)
- High Pressure Liquid Chromatography (HPLC)
What are immunoassays and microbiological tests?
-
Immunoassays: biochemistry test that measures a substance qualitatively or quantitatively based on its specific binding to its antibody
- Enzyme linked immunosorbent assay (ELISA)
- Enzyme multiplied immunoassay techniques
- Fluorescent immunoassay
- Radioimmunoassay
-
Microbiological assay:
- Sterility testing
- Endotoxin testing
- Preservative effectiveness testing
What are the pharmaceutical ingredients?
(Pharmacological) Active pharmaceutical ingredients, API (the drug), is any component that is intended to furnish pharmacologic activity or other direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease or to affect the structure or function of the body of human or other animals. (21 CFR, part 211)
What are excipients?
- Excipients (“Pharmacological” “inactive” and “inert” Pharmaceutical ingredients) are non-medicinal agents given in combination with API that serve varied and specialized pharmaceutical function
- Solubilize, suspend, thicken, dilute, emulsify, stabilize, preserve, color, flavor, fashion
- +Examples of pharmaceutical excipient (Ansel’s Ed9: Table 4.3, page 129-132, Required for Pharmaceutics I & II)
- GRAS (generally regarded as safe)
What are commonly used excipients?
- Solvents
- Chelating agents (EDTA…)
- Flavorant: impart pleasant flavor and/or odor (vanillin, menthol..)
- Sweetening agents (Aspartame, Glycerin, Mannitol, Sucrose..)
- Colorants impart color to liquid and solid (FD&C Red No. 20)
- Antioxidant are used to prevent deterioration of preparations by oxidation (e.g sodium sulfite Na2SO3, BHT, BHA)
- Preservatives (antifungal and/or antimicrobial) is used to preserve the preparations against microbial contamination (methylparaben and propylparaben 0.1~0.2%)
What are preservatives?
- Sterilization vs Preservation
- Sterilization: kill all microorganism during preparation, physically or chemically
- Preservation: using preservatives to inhibit the growth of microorganisms (bacteria, molds, yeast)
- Considerations: soluble as unionized form; safety; comfort; stability; compatibility
- Mode of Actions (next slide)
- Utilization and concentration limit (next slide)
- Can not be used in large volume injections
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