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122 Cards in this Set

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ability of molecules to stick together to form an elastic layer on the surface of the liquid; this is why a metal pin or clop doesn't sink although denser than water
surface tension
Adhesion
vs
Cohesion
A-2 different materials

C-same material
Wetting
vs
Drier Surfaces
contact angle < 90 degrees

smaller the angle, the wetter the surface
larger the angle, the drier the surface
system containign one or more constitiuents distributed throughout a homogeneous medium
dispersion
3 categories of dispersions
True solutions= less than 0.001 micron
Colloids= 0.001 to 0.5 microns
Coarse Dispersions= greater than 0.5 microns
particles are invisible even with the eletron microscope and pass through filter papter and semi-permeable membranes
True Solution
particles can't be seen with an ordinary microscope but can be seen witht eh eletron microscope; particles pass through filter paper but not semi-permeable membranes; particles diffuse less slowly than do the particles in a true solution
Colloidal Dispersion

ex. Milk
particles often visible with the naked eye; will not pass through filter paper or semi-permeable membranes; particles seldom diffuse; extensively in pharmaceutical products
Coarse Dispersions

ex: emulsions or suspensions
Dispersion Medium:Dispersed Phase
Gas:Gas
Gas:Liquid
Gas:Solid
Dispersion Medium:Dispersed Phase
Gas:Gas- None
Gas:Liquid-Fog
Gas:Solid-Smoke
Dispersion Medium: Dispersed Phase
Liquid:Gas
Liquid:Liquid
Liquid:Solid
Dispersion Medium: Dispersed Phase
Liquid:Gas- Foam
Liquid:Liquid-Emulsion
Liquid:Solid- Suspension
Dispersion Medium:Dispersed Phase
Solid:Gas
Solid:Liquid
Dispersion Medium:Dispersed Phase
Solid:Gas-Pumice
Solid:Liquid- Gel
Surfactant:
Polar Group
Non-polar group
Polar:
Ionic- contains heteratom such as O,S,N,P as carboxylate , sulfate, ammonium, and phosphate
Non-Ionic- contains Oh or -O- as polyalcohol or polyether

Non-polar group:
Hydrocarbon containing 12-20 carbone atoms
2 most important functions of surfactant
1. they locate themselves at the interface of the two phases
2. they tend to make aggregates (micelles)
Lyophilc Colloids
Lyophilic Colloids- react with dispersion medium; solvent loving; essentially one-phase system

Hydrophilic- water loving )mucilages)
Alcophilic- alcohol loving

helps increase viscosity of agents
Major repulsion mechanisms for surfactants
Electrostatic interactions
and
Steric repulsions
Lyophobic Colloids
solvent hating: no attraction between the dispersed particles and the dispersion medium; usually are dispersions of inorganic particles or insoluble drug particles in water
Association Colloids
amphiphilic colloids; have a hydrophilic and lypophilic section; they form monomolecular films on the surface of water to cause a reduction in surface tension
3 types of Colloids
1. Lypophilc Colloids
2. Lyophobic Colliods
3. Association Colloids
Particle Size and Appearance
>1 micro m
0.1-1 micro m
0.05-0.1 micro m
<0.05 micro m
Particle Size and Appearance
>1 micro m- milky
0.1-1 micro m- blue-white (Tyndal effect)
0.05-0.1 micro m- Gray (semi-transparent)
<0.05 micro m- Transparent
any procedure that reduces the size of the particles to colloidal range
Dispersion Method

1. Ultrasonic Generators
2. Colloid Mills
3. Peptidation (addition of 3rd component to help dispersion)
spontaneous disperion of colloidal precipitate on the addition of small amounts of a third substance
Peptization (deflocculation)

3rd substance usually is an electrolyte

ex: sodium citrate added to calamine lotion to promote dispersion and prevent caking
Emulsion Creaming
vs
Suspension Settling
Creaming- Oil particle density < Aqueous medium density
creaming is usually reversible but not desirable

Suspension settling- solid particles density > aqueous medium
Suspension settling is reversible and irreversible
mixture of two substances, one dispersed in the other; particles are visible under microscope and can often be seen with the naked eye
Suspension
challenges with suspensions
desirable particle size
caking of very small particles
fast settling of coarse particles
particle shape (symmetry)
Coagulation
vs
Flocculation
C- strong particle aggregation

F- loose particle aggregation
Equation of Sedimentation Rate
Stoke's Equation

depends on:
particle diameter
particle density
medium density
gravity constant
medium viscosity
rate of settling
Properties of Colloids
1. Kinetic Properties (brownian Movents- random movement)
2. Optical Properties (Tyndal Effect- light is scattered; used to determine size of particles)
3. Diffusion (Fick's Law- high to low conc.)
4. Sedimentation (Stokes law- density and radius are directly proportion to rate of sedimentation)
5. Viscosity (indirectly proportion to rate of sedimentation in stokes law)
6. Electrical Properties (colloids usually have elective charge- affects stability; like charges repel each other causing coagulation or flocculation not to occur)
difference in potential between the true surface of the particle and the area where the particles are uniformly distributed
Nernst potential
difference in potential between the outer edge of the fixed portion and the main body of the liquid
zeta potential

(Most imoortant)
Sedimentation Rate with different in amounts of powder
the more micro m of powder in water of powder in glucering the faster the settling rate
colloids composed of tiny particles suspended in another immiscible (unmixable) marterial; suspension of two liquids that usually do not mix
Emulsion

ex: oil and water
Nature of drug dictates the emulsion type:

W/O preferred when

O/W preferred when
W/O preferred when:
drug is water soluble
skin needs to be softened

O/W preferred when:
drug is oil soluble
easy removal fro the skin by water
Emulsion pros and cons
pros- easy production, dose uniformity, patient acceptability, drug release

cons- instablility, medium for microbial growth, limited use, physical instability (coalescence, creaming)
Emulsion Stabilizers

help prevent flocculation, coalescence, and creaming
1. Surfactants: ionic and non-ionic
2. Hydrocolloids: Acacia, gelatin, lecithin
3. Fine Solid: Colloidal clays (bentonite, magnesium, hydroxide)
Drugs goes to dispered phase
Emulsifyer goes to continuous phase
Just Remember
Hydrophilic Lipophilic Balance (HLB)
Griffin

20x [Mw (hydrophilic portion)/ Mw (whole molecule)]
Range from 0-20

100% hydrophilic: HBL of 20
100% lipophilic: HLB of 0
Emulsion Stability

unstable if:
dispersed phase upon standing tend to form aggregates

large aggregates rise to top or fall to bottom

all or part of liquid of the dispersed phase seperates and forms a layer on the top or bottom of the emulsion as a result of coalescence

microbial contamination and growth

freezing and thawing
Creaming
vs
Coalescence
Creaming-reversible

Coalescence (emulsion breaking)- irreversible
High HLB
vs
Low HLB
high HLB- better for oil in water

low HLB- better for water in oil
HLB values for Emulsifiers

Antifoaming
Emulsifiers (W/O)
Wetting agents
Emulsifiers (O/W)
Typical Detergents
Solubilizer
Antifoaming- 103
Emulsifiers (W/O)- 3-6
Wetting agents- 7-9
Emulsifiers (O/W)- 8-18
Typical Detergents- 13-16
Solubilizer- 15-20
material is resistant to the stomach acid; drug will be released at neutral pH of small intestine
Enteric
material is resistant to neutral pH; drug will be released at lower pH of stomach
Reverse Enteric
the more ____ the stronger th gel
G-Blocks, juction zones

lG-block binds to Ca2+ and looses solubility/turns into gel
4 forces of swelling
Polymer-solvent interaction
Electrostatic Forces
Osmotic Forces
Elastic Forces

Replace H with K or Na to get more swelling; allows more water in
Monothilic
Drug is released by diffusion out of a polymer matrix; release rate depends on initial drug conc. and relaxation of the polymer matrix
Membrane

Drug release is controlled by permeable membrane

Non-Porous
vs
Porous
vs
Filter orientation (Tortuosity)
Non-Porous- drug diffuses through membranes
vs
Porous- drug diffuses through membrane and pores
vs
Filter orientation (Tortuosity)- filler hinders the drug release
Osmotic Tablet
vs
Osmotic Pump
vs
Solvent Evaporation
Osmotic Tablet- constant release because only one outlet for drug
vs
Osmotic Pump- water influx pushes drug out
vs
Solvent Evaporation- ?
Coacervation
the seperation into two liquid phases in colloidal systems. the phase more concentrated in colloidal component is the coacervate, and the other phase is the equilibrium solution
Simple Coacervation
characterized by one polymer component induced by physical or chemical changes

temp
Solubility
pH
Ionic Strength
Conc.
Complex Coacervation
involves more than one component; attraction of oppositely charged oolyelectrolytes
aggregate of surfactant molecules, usually smaller than liposome
Micelle
microscopic phosopholipidbilayer vesicles
liposomes
Gastric Retention
increases the drug absorption and hence its bioavailability; extends the absorption window
Base Case Scenario
Even Absorption
and
Long Half-Life
the addition of a hydrophilic colloid to a hydrophobic colloid will ______ stability
increase
Examples of protective colloids
gelatain, acacia, methylcellulose
relates to the lowest levels of drug that can be measured; practically the smallest amount of drug or metabolite that can be determined
Sensitivity
the ability of an assay to distinguish a drug from its metabolites, other drugs and /or endogenous constituents of biologic fluids
Selectivity
Need for biopharmaceutical Analysis
biovailability and bioequivalence studies
new drug development
drug abuse problems
clinical pharmacokinetics
research in basic biomedical and pharmaceutical sciences
defined as parts-per-million or less concentrations of drugs
Trace Levels
Metabolism reactions

Phase 1
Phase 2
Phase 1-typically involves oxidation, reduction, hydrolysis

Phase 2- entails coupling or condensation of drugs of their phase 1 metabolites with body constituents
an assay must be able to distinguish readily between ___________ and _________
parent compound
and
metabolite
Precision
vs
accuracy
repeatability

degree of closeness of measurement to the actual true value
Limit of detection

Ruggedness

range and Linearity
Limit of detection- only detect within certain range

Ruggedness- ability to reproduce procedures in dif. labratories in different location

range and Linearity- used for comparison
USP-NF
used for pharaceutical testing of official substances; ex: production of new OTC drug
Separation and Purification Techniques
Protein precipitation and denaturation

Biological Samples:
solvent extraction
lyophilization
hydrolysis of conjugates
homogenization
chemical derivatization

Chromatographic methods:
Thin layer chromatogrphy (TLC)
Gas chromatography (GC)
High performance liquid chromatography (HPLc)
Gel permeation chromatography (GPC)
Ion Exchange Chromatography
a seperation technique based on differing affinities of a mixture of solutes between two phases

results in physical separation of the mixture into various components

mixture is separated by distributing the components between a stationary phase and a mobile phase
Chromatography
chromatography that uses a charged stationary phase to separate charged compounds
ion exchange
chromatography that is an elution procedure used in liquid chromatography in which the mobile phase is significantly more polar than the stationary phase
Reversed phase
seperates molecules according to their size

smaller molecules take longer to elute

larger molecules elute faster
Size Exclusion chromatography
aka
gel permeation chromatography or gel filtration chromatography
Detection Methods
Spectrophotometry methodology
Fluoremetry and Phosphometry
Flame Ionization Detector (FID)
Electron Capture detector (ECD)
Mass Spectrometer (Ms)
Qualitative Analysis

Quantitative Analysis
Qualitative Analysis- retention values

Quantitative Analysis- detector responses
External Standard
Internal Standard
Standard Addition
External Standard-spike increasing conc. in fluids; plot responses against conc.

Internal Standard- P-C behavior similar to drug or metabolite; response ratios are determined

Standard Addition- good for quantitation or analyzing compounds close to their sensitivity limit
Note about External Standard
same retention time, but height of peak varies with different concentrations
elution procedure used in liquid chromatography in which the mobile phase is significantly more polar than the stationary phase
Reversed-Phase Chromatography
type of chromatography that uses a charged stationary phase to separate charged compounds
ion exchange chromatography
What is cGMP?
governments quality standards that are intended to protect the public from harmful and unsafe drugs, medical devices, food and cosmetics
cGMP established by
US Food Drug and Cosmetic Act of 1938

applies to domestic and to foreign suppliers and manufacturers
Purpose of cGMP
to make sure food we eat is SAFE
manufactured under SANITARY conditions
medical devises used are SAFE and EFFECTIVE
prepared form APPROPRIATE ingredients
all foods, drugs, medical devices and cosmetics are truthfully and informatively labeled
cGMP code of regulations listed in _____ CFR, Part ___ and _______
cGMP code of regulations listed in 21 CFR, Part 210 and 211
Seven Expectations of all GMPs
1. Protect the product from contamination
2. Prevent Mix-ups
3. Know what you are doing before you do it
4. Strive for consistency and control
5. Document all activities
6. Have an independent group make final decisions on documents, product release and quality issues
7. Learn from mistakes; monitor and continually improve
Dispersed Phase AKA what?

Continuous Phase AKA what?
solute (extermal)/ minor phase

solvent (internal)/ major phase
Manufacturing
vs
Compounding
M- larger scale

C- single prescription
Reason for compounding comeback
-drug doses or forms not commercially available
-acceptable to kids
-some medications are not very stable
-not manufactured/approved yet
-trying products in innovative ways
-veterinary drugs
-home health care
-allergic to excipients
Standards and Regulations For Compounding
Food and Drug Modernization Act of 1997
and
USP/NF
a system containing one or more constituents distributed throughout a homeogeneous medium
dispersion
3 categories of dispersions

True solutions
Colloids
Coarse dispersions
True solutions- less than 0.001 mocrin
Colloids- 0.001 to 0.5 microns
Coarse dispersions- greater than 0.5 microns
particles are invisible even with the electron microscope and pass through filter paper ans semi-permeable membranes
True Solution
Particles can't be seen with an ordinary microscope but can be seen with the electron microscope; passes through filter paper but will not pass through semi-permeable membranes
Colloid Dispersion
particles are visible with the naked eye; will not pass through filter paper nor semi permeable membranes
Coarse Dispersion
Lyophilic Colloids
react with the dispersion medium so solvent loving

strongly attracted to the dispersion medium
Lyophobic Colloids
solvent hating; no attraction between the dispersed particles and the dispersion medium
Association Colloids
amphiphilic colloids; have hydrophilic and lypophilic protion

they form monomolecular films ont he surface of water to cause a reduction in surface tension
Dispersion Methods; any procedure that reduces the size of the particles to the colloidal range
1. Ultrasonic Generators
2. Colloid Mills
3. Peptization
4. Electrolytic disintegration
Peptization (deflocculation)
spontaneous dispersion of a colloidal precipitate on the additions of small amounts of a third substance is known as peptization
Kinetic Properties of Colloids
particles under 0.5 microns which are in the colloidal range will show randome movement in a dispersion medium= BROWNIAN MOVEMENTS
Optical Properties of Colloids
The Tyndal Effect: no visible cone when ligh is shone through a true solution

Light is scattered by colloidal particles
Diffusion of Colloids
Fick's Law: particles have tendency to diffuse from a region of high concentration to a region of low concentration
Sedimentation of Colloids
particle will settle if particles has greater density than that of the dispersion medium

Stoke's Law= relates velocity, radius and viscosity to evaluate sedimentation
Viscosity of Colloids
the measure pf the resistance of a liquid to flow

lyophobic and hydrophobic colloids do not affect the viscosity

lyophilic and hydrophilic colloids do affect viscosity
Electrical Properties of Colloids
usually charged
causes stability
coagulation and flocculation does not occur
ions in solution that surround the colloid particle to balance the charge on the surface are called what?
Gegenions or counterions
potential on the surface of the particle is known as the what?
Nernst potential

= difference in potential between the true surface or the particle and the area where the particles are uniformly distributed
difference in potential between the outer edge of the fixed portion and the main body of the liquid
zeta potential

Most important potential
zeta potential can be lowered by adding what?
adding an ion of opposite charge to that on the colloid particle
Protective Colloids

Examples:
the addition of hydrophilic colloid to a hydrophobic colloid will increase stability

Examples:
Gelatin
Acacia
Methylcellulose
the outer layer of counter ions is called
Gouy-Chapman layer
condition of fixed surface charge surrounded by more loosely held counter ions is known as the what?
Electrical or Helmholtz double layer
stage or process by which the physical, chemical, and mechanical properties of drug substances are determined by themselves and with common excipients
Preformulation
Objectives of preformulation
to demonstrate that the drug product is safe and effective

-selection of most suitable drug
-identifying compatible excipients
Reasons for molecular optimization include:
improvement of stability, solubility, absorption, nd changing crustallinity, taste, odor, etc.
Different Bulk Charactierization
-Crystallinity
-Hygroscopicity
-Fine particle characterization
-Bulk density
-powder flow properties
-mechanical properties
Difference among:
Crystallinity
Polymorphism
Amorphous
Crystallinity-spacing in 3-dimentsional array

Polymorphism- ability to exist as more than one distinct crystalline species

Amorphous- atoms are randomly placed as in a liquid, higher thermodynamic energy
Techniques for determining polymorphism
Thermal Methods (DSC)
X-ray Diffraction
IR spectroscopy
Solid state NMR
Hygroscopicity
vs
Deliquescent
Hygroscopicity- tendency to absorb atm moisture

Deliquescent=- absorb sufficient water to dissolve completely
Parameters and Methods for particle characterization
Parameter:
Size
Shape
Surface Area

Methods:
Microscopy, sieving
Brunauss, Emmett and Teller
(BET)
What is the difference b/w
Bulk density
Apparent/Tap density
True density
Bulk density- total inventory for calculating storage compacity

Apparent/Tap density- mass/volume for capsule preparation

True density- minus the air; smallest density volume of the three
Rationale for Powder Flow
Free flowing
Non-free flowing (cohesive)
Generally, a free flowing material is preferred
Mechanical Properties of powders

Compressiblity vs Compactibility
compress- reduction in volume

compact-pressure w/o chipping; no elasticity
Solubility Analysis
Determination of pKa
Lipophilic nature
solubility in various temperature and media
pH solubility profiles
Stability Analysis needed for what?
Compatibility
Packaging material
usually done at room temperature

vital information for labeling, storage, exp. date, packaging and shipping
Physicochemical properties:
what are the effects on solubility?
-endothermic
-exothermic
-high crystal comp
-low crystal comp

what is the effect on bioavailablitly

-high solubility
Physicochemical properties:
what are the effects on solubility?
-endothermic: increase temp=inc. solubility
-exothermic: increase temp=dec solubilitly
-high crystal comp: inc solubility
-low crystal comp: decreases solubility

what is the effect on bioavailablitly

-high solubility= high bioavailability