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110 Cards in this Set
- Front
- Back
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Drug Stabilization Approaches
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Store at reduced temperatures
Formulate at stable pH Dry the product Remove/replace oxygen Use antioxidants Use chelators (and minimize metal content) Protect from light |
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silica gel
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a desiccant which adsorbs moisture
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lyophilization
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freeze drying. dehydration process.
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oil-soluble antioxidants
(to stabilize product) |
alpha-tocopherol (vitamin E)
buylated hydroxytoluene (BHT) propyl gallate |
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water-soluble antioxidants
(to stabalize product) |
ascorbic acid (vitamin C)
sodium sulfite (common, allergenic in 0.2% of population) |
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principles of antioxidant action (2)
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1. stop propagation - "chain terminators", "free-radical scavengers"
2. Preferentially oxidized - more easily oxidized |
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chelators
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citric acid, tartaric acid, EDTA
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syrup
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concentrated, aqueous preparations of sugar or sugar substitute with or without added flavoring agents and medicinal substance
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elixir
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clear, sweetened, hydroalcoholic solutions intended for oral use and are flavored to enhance palatability
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advantages of oral solutions
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easy to swallow
flexible dosing immediate drug availability can minimize GI irritation higher physical stability > dispersion |
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disadvantages of oral solutions
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microbial growth
bulky/heavy to transport (compared to tablets) chemical instability (compared to solids) chemical instability (compared to suspensions) pronounced distaste (interact w/taste buds) potential dosing inaccuracies |
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important considerations for oral solutions
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ease of production (dissolution)
dosage uniformity (generally not important for oral) stability (chemical - ph, temperature, antioxidants/ microbiological - preservation) patient acceptance (palatabilty, appearance) Drug release - not important for oral solutions |
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reasons for variability in taste
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children have more tastebuds
children prefer sweet and are more sensitive to bitter elders have less odor sensitivity women are more sensitive |
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flavoring techniques
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blending (flavor + drug flavor)
->citric acid overshadowing (flavor > drug flavor) ->wintergreen oil/glycyrrhiza physical methods ->suspensions, emulsions, effervescence, high viscosity physiological methods ->desensitization, enhancement |
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physical methods of flavoring
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suspensions (drug in crystal form)
emulsions (most of drug in different phase) effervescence (good for salty drugs) high viscosity (slows drug diffusion to taste buds) |
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physiological methods of flavoring
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desensitization (cooling by mannitol or anesthetic action by menthol/peppermint)
enhancement (citric acid or small amounts of vanilla) |
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flavors used to mask sweet
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vanilla, fruit, grape, bubblegum
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flavors used to mask sour
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lemon, lime, orange, cherry, grapefruit, raspberry
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flavors used to mask salty
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nut, butter, butterscotch, spice, maple
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flavors used to mask bitter
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licorice, chocolate, coffee, mint, grapefruit, cherry, peach, raspberry, orange, lemon, lime
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3 methods used to purify water
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reverse osmosis, distillation, ion exchange
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vehicles for oral liquids
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purified water, syrup (acacia, cherry, citric acid, coca cola, glycyrrhiza, ora, orange, raspberry, syrup, wild cherry)
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types of excipients for oral liquids
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co solvents, preservatives, flavorants, colorants, buffers, sweetenrs
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types of cosolvents
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alcohol, glycerin (glycerol), propylene glycol
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types of preservatives
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benzoic acid/sodium benzoate,
methyl-/propyl-/butyl- paraben, sorbic acid (mold and yeast), alcohol has preservative properties |
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Flavorants
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both natural and artificial
are often oils they can be very complex can adsorb to containers or suspended materials (result in flavor challenges) |
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Colorants
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Most regulated by FDA (F, D&C)
Used at very low concentrations Match color with flavor |
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Buffers
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citrate & phosphate
mainly for stability and solubility |
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Sweeteners
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Nutritive (caloric) - all them i've heard of
Nonnutritive (noncaloric) - haven't heard of any of hem ->acesulfame potassium used in hard candy |
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Composition of syrups
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purified water, cosolvents, sucrose, preservatives, flavorants, colorants
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importance of viscosity in liquids
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taste making
soothing irritated tissues stabilizing dispersed systems |
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suspensions
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finely divided solid drug particles in liquid
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colloidal dispersions
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molecular aggregates 0.001 um - 1um
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suspensions
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solid particles greater than 1 um
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emulsions
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liquid particles greater than 1 um
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microemulsions
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liquids less than 0.1 um
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advantages of oral suspensions
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easy to swallow
flexible dosing greater chemical stability (vs solutions) greater poalatabilty (vs solutions) faster onset than oral solids ->tablet disintegration/particle wetting takes time |
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disadvantages of oral suspensions
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relative chemical instability (vs solids)
medium for microbial growth bulky/heavy transport have less physical stability (vs solutions) potential dosing inaccuracies |
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comminuted
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process of particle size reduction
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overview of oral suspension production
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comminuted, wetted, suspended
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3 important issues when producing suspensions
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particle size
partical wetting physical stability |
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micro pulverization
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suspension production tecnique
particle size 10-50 um (largest for industrial) |
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jet milling
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oral suspension production technique, collides particles against eachother <10um
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spray drying
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generally drug is dissolved in solvent then sent into heated chamber as fine spray and it evaporates into fine particles
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3 methods of particle reduction in community pharmacy
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trituration
spatulation electric grinders |
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3 types of physical instability
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particle settling
particle aggregation particle growth |
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electrostatic repulsive forces
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surface charges arising upon dispersal in an aqueous medium
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van der waals attractive forces
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electromagnetic flucuations in surface molecules
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repulsive hydration forces
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structuring of water near interfacial region
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adhesive forces
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arise when particles are in contact
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3 types of physical instability
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particle settling
particle aggregation particle growth |
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3 types of physical instability
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particle settling
particle aggregation particle growth |
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steric repulsive forces
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arise from molecules adsorbed on particle surfaces
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electrostatic repulsive forces
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surface charges arising upon dispersal in an aqueous medium
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electrostatic repulsive forces
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surface charges arising upon dispersal in an aqueous medium
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force of attraction curve
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primary minimum - very strong attractive forces
primary maximum - very strong repulsive forces secondary minimum - this loosely held together |
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van der waals attractive forces
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electromagnetic flucuations in surface molecules
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van der waals attractive forces
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electromagnetic flucuations in surface molecules
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two types of particle aggregation
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coagulation (permanent attraction)
flocculation (weak attraction) |
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repulsive hydration forces
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structuring of water near interfacial region
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repulsive hydration forces
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structuring of water near interfacial region
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coagulation
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"drive together"
primary minimum, difficult to redisperse |
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adhesive forces
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arise when particles are in contact
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caking
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results from coagulation
combination of settling and coagulation non-redispersable |
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adhesive forces
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arise when particles are in contact
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steric repulsive forces
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arise from molecules adsorbed on particle surfaces
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force of attraction curve
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primary minimum - very strong attractive forces
primary maximum - very strong repulsive forces secondary minimum - this loosely held together |
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steric repulsive forces
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arise from molecules adsorbed on particle surfaces
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two types of particle aggregation
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coagulation (permanent attraction)
flocculation (weak attraction) |
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force of attraction curve
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primary minimum - very strong attractive forces
primary maximum - very strong repulsive forces secondary minimum - this loosely held together |
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coagulation
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"drive together"
primary minimum, difficult to redisperse |
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two types of particle aggregation
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coagulation (permanent attraction)
flocculation (weak attraction) |
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caking
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results from coagulation
combination of settling and coagulation non-redispersable |
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coagulation
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"drive together"
primary minimum, difficult to redisperse |
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caking
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results from coagulation
combination of settling and coagulation non-redispersable |
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flocculation
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loose and wooly, weakly held together, second minimum
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particle growth
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growth in crystal, important in the physical stability portion of suspension production
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ostwald ripening
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growth or large particles at expense of small ones
-small particles dissolve/then supersaturate solution and recrystallize to larger crystals -bridges also form larger crystals -accelerated by temperature fluctuations |
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formulation of suspensions
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formulated with excipients that are critical for manufacturing, physical stability, chemical stability, microbiological stability
wetting agents - disperse solids flocculating - hold particles loosely together suspending agents - keep in suspended form |
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wetting agents: surfactants: mechanism
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hydrocarbon chain is adsorbed to hydrophobic particle while polar groups project into aqueous medium (makes surface hydrophilic)
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wetting agents: surfactants: anionic and nonionic
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anionic: docusate sodium
nonionic: polysorbates (tweens) |
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wetting agents: solvents: mechanism
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solvent penetrates loose agglomerates of powder, displacing the air
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wetting agents: solvents: examples
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alcohol, glycerol (glycerin), propylene glycol
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wetting agents: polymers: mechanism
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coat hydrophobic particles with multimolecular layer, become hydrophilic in character
->cellulose derivatives |
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flocculating agents: electrolytes
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reduce the charge (zeta potential), reduces electrical barriers btwn particles
->sodium salts of acetates, phosphates and citrates |
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flocculating agents: surfactants
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ionic - increase charge repulsion
-> docusate sodium nonionic - form a hydration barrier ->tweens (polysorbates) |
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flocculating agent: polymers
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when adsorbed to particle surface they sterically prevent close approach
->cellulose derivatives, PEG, alginate, tragacanth |
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3 agents formulated in suspensions
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wetting, flocculating, suspending
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rheology
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study of flow
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viscosity
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resistance offered when one part of liquid flows by another
->dissolution (bio availability) ->palatability ->stabilizing dispersed dosage forms |
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newton's law
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rate of flow is proportional to applied stress
G = shear rate = reflects rate of flow F = force = reflects force applied |
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n(viscosity) = F/G
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can be plotted shear rate vs shear stress
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Newtonian liquids
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linear function of shear stress (obey Newton's law)
-> water, syrup, alcohol |
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Non-Newtonian Liquids (plastics)
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don't obey Newton's law (viscosity changes with sear stress)
->yield value - no flow occurs until this is overcome ->very viscous, almost appear solid |
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Psuedoplastic liquid
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almost like plastics, but no yield value, high viscosity on shelf but once force is applied
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Thixotropic liquid
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similar to psuedoplastic but there is a time element, when left sitting, returns to viscous state, interacting solutes
*hysteresis* - upon removal of stress, solutes restrict again |
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xanthan gum
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a natural polysaccharide, high molecular weight complex
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cellulose derivatives: hydroxypropylmethylcellulose
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good temperature and pH (4-10) stability
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cellulose derivatives:
sodium carboxylmethylcellulose |
soluble in hot/cold water
precipitates at low pH (stable 4-11) not stable with some salts |
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other viscosity modifiers
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cherry syrup (50-100%)
sorbitol (5-10%) glycerin, glycerol (2-10%) |
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other excipients (suspensions)
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buffers, electrolytes, density modifiers, flavors, colorants, preservatives, sweeteners
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emulsions
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mixture of 2 immiscible liquids, one uniformly dispersed as droplets
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types of single emulsions
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o/w: oral routes
w/o: topical routes |
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applications of emulsions
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topical: creams/foams
parenteral: IV lipid emulsions (can be dangerous) oral: mineral oil emulsions |
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advantages of oral emulsions
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variety of dosing, easier to take
given as minute globules rather than bulk increased palatability of oil improves digestibility (increase surface area) |
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disadvantages of oral emulsions
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preservatives/difference in teaspoon size
limited use compared to oral/easier to make suspension physical instability |
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emulsification and particle-size control
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produce small particles
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industrial production of emulsions
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homogenized
colloid mill |
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extemporaneous emulsification
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blender
hand homogenizer shaking trituration |
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physical stability of emulsions
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altered by droplet aggregation and its result: coalescence (coming together) and creaming (rises to top, less dense)
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