E3 Flashcards
1-88 Pt1; 89-139 Pt2; 140-205 pt3; 206-253 pt 4
What does the skin do?
enables the body to interact most intimately with its environment and provides a hydrophobic barrier
What are the four layers of the skin?
stratum corneum, rest of the epidermis (viable and below), dermis, and subcutaneous tissues
What are the associated appendages of the skin?
hair follicles, sweat ducts, apocrine glands, and nails
What are the main functions of the skin classified as?
Protection, Homeostatic, and Sensing
What does the skin protect us from?
bacteria and viruses, toxic substances, UV radiations, and dehydration
What are cosmetic products?
no defined active pharmaceutical ingredient
Why are there different forms of topical transdermal delivery?
some are more hydrophobic; some will stick on the skin longer; some absorbed faster
Why is the skin being so large (2 m^2) so important?
this gives a lot of room to deliver drugs across the body even multiple
What is the stratum corneum?
only nonviable, live tissue, outermost layer
How thick is the stratum corneum
10-20 mcm (very thin) of 15-25 flattened and stacked cornified cells
What is each stratum corneum cell composed of?
insoluble bundled keratins (70%), and lipids(20%) encased in a cell envelope
What does the intercellular region of stratum corneum cells consist of?
lipids
What happens every 2-3 weeks?
continuous desquamation or shedding of the outermost layer of the stratum corneum
What is the most important function of the viable epidermis?
generation of the stratum corneum
What are some other functions of the epidermis?
metabolism; making melanin from melanocytes for pigment and protections
Where do the cells of the stratum corneum come from?
viable epidermis where they undergo many changes before shedding (desquamation)
What does the epidermis consists of ?
several cell strata at varying levels of differentiation
What specialized cells are in the epidermis?
melanocytes, Langerhans cells, Merkel Cells
What are Langerhans cells?
prominent antigen-presenting cells of the skin’s immune system
What are melanocytes?
cell type of the epidermal basal layer to produce melanin creating skin pigments
What are Merkel cells?
closely associated with nerve endings; sensory receptors
How does the stratum corneum develop?
from keratinocytes of basal layer involving several steps of cell differentiation
What does the dermis do?
provide support to the epidermis; plays a role in regulating temperature, pressure, and pain
What does the dermis consist of?
mainly collagen fibers and elastic connective tissues and also extensive vascular network
What are collagen fibers for?
to provide support
What are elastic connective tissues for?
provide elasticity in a semi-gel matrix of mucopolysaccharides
What does the extensive vascular network provide?
arteriovenous anastomoses
What are arteriovenous anastomoses for?
functions of heat regulation and blood vessel control
What is found in the dermis?
hair follicles and sweat glands
Is there live tissue in the dermis?
Yes, there is a channel at the hair follicle and sweat glands coming from the stratum corneum
How do drugs permeate through the skin?
through the channels of the hair follicle and sweat glands to be absorbed
What is the major route drugs permeate the skin?
the intercellular region between keratinocytes of stratum corneum
What is the problem with the intercellular pathway?
very hydrophobic environment
What does permeation depend on, then?
proper drug properties and base of the carrier (gel,ointment base), conc of permeant applied(more drug), partition coefficient of permeant between stratum corneum lipids and vehicle, diffusivity of compound within stratum corneum, surface area of application
What is another way topical drugs can permeate the skin?
transcellular where it is jumping through the corneocytes
What does the rate of permeation depend on?
physicochemical characteristics of penetrant and more importantly the relative ability to partition into the intercellular lamellae
What is the octanol water partition coefficient?
log P{oct/wat}=log([solute] unionized octanol/ [solute] unionized water)
What does the octanol water partition coefficient indicate?
how hydrophilic or hydrophobic a molecule is
What does the partition coefficient indicate?
drug levels between the skin and the vehicle
What is the ideal drug property?
amphiphilic so can jump from hydrophilic and hydrophobic environments without difficulty
What characteristics of drugs can permeate the skin?
molecular weight of 100-800 (ideally 400 of less), adequate lipids, and aqueous solubility
What is more favored hydration of the skin or percutaneous absorption?
hydration
What else does permeation depends on?
duration the formulation remains in contact with the skin
What are the 3 basic steps associated with percutaneous absorption?
- permeant has to escape from the vehicle and penetrate into the stratum corneum
- diffusion across the stratum corneum
- clearance from the epidermis/dermis
What is the most important factor in the 1st step of percutaneous absorption?
the ability to partition from the formulation into the intercellular lipid lamellae
How can the partition coefficient (K) of a drug between the skin and vehicle be written as?
Csc (conc in stratum corneum) / Cv (conc of drug in the vehicle)
What is the steady-state flux (Js) across the skin expressed as?
Js= ADKCv/h
What does A, D, and h stand for in the formula?
A-area of application
D-apparent diffusion coefficient
h-diffusional path length or the thickness of membrane
T or F: If there’s more surface area, this will increase the amount of drug entering the skin.
T
T or F: If there is a thinner skin layer, more drug will enter the skin.
T
What is the permeability coefficient (kp)?
steady-state flux per unit area divided by the conc of drug applied in solution
What is the formula for the permeability coefficient?
kp=Js/ACv=D/h
What is the diffusion coefficient (D)?
expressed by the Stokes-Einstein equation as:
D=kT/6𝝅nr
What is k, T, r, and h in the diffusion coefficient equation?
k-Boltzmann constant
T-Temp in Kelvin
r-size (MW)
n-viscosity
T or F: The larger the D value, the more flux of the drug.
T
T or F: Increase viscosity of sample, the more difficult it will be to enter the skin.
T
What is the amount of drug penetrating per unit time in a steady state skin crossing?
constant
Why is there a lag time?
products do not penetrate skin immediately
What is emphasized when considering the therapeutic activity following dermal application?
quantifying the extent of absorption of a drug through the skin or on some relevant pharmacodynamic response
How can the amount absorbed (Q) be expressed by?
kpACv(T-lag)
What does T stand for in the amount absorbed equation?
exposure time
What is lag in the amount absorbed equation?
diffusional lag time across the barrier
What are some assumptions under Q equation?
No appreciable accumulation of the drug on the distal side of the barrier (sink conditions).
No depletion of the drug on the application side.
What is another factor that affects percutaneous absorption?
Anatomical site variations
What can different application sites cause?
different drug penetration associated with stratum corneum, skin thickness, and corneocyte diameter
What else can affect percutaneous absorption?
sex, age, and race and skin metabolism
Why does skin metabolism affect percutaneous absorption?
potential for biotransformation of molecules within the skin; some enzymes in the skin have high activity (reductive), where usually low activity of metabolic processes in the skin compared to liver
What kind of application can be either local effects or systemic absorption?
Topical
What is a topical dermatological product for?
deliver drug into the skin in treating dermal disorders, with skin as target organ
What is a transdermal product for?
deliver drugs through skin (percutaneous absorption) to the general circulation for systemic effects, with the skin not being the target organ
Why are solution and powders aren’t use on the skin?
lack staying power (retention time)
can only afford transient relief
Why are semisolid formulations preferred for dermatological therapy?
they remain in situ and deliver their drug payload over extended periods
What are the most common formulations?
ointments, creams, gels
What do the formulations consists of?
active compound or drug and the base or body of the dosage form
What are some common ingredients in bases?
hydrocarbons and paraffin wax
What are hydrocarbons?
organic compounds made of hydrogen and carbon molecules
What are saturated hydrocarbons?
only single bonds between carbons in a chain
What are unsaturated hydrocarbon?
there is at least one double bond in the chain
What is an aromatic hydrocarbon?
ring with double bonds
What are diolefins?
hydrocarbon ingredient with 2 double bonds
What are Polyenes?
hydrocarbon ingredients with 2 or more double bonds
How many carbons in a hydrocarbons to be solid?
18 or more
What is the major origin for hydrocarbons?
crude oil
What is fossil fuel aka crude oil?
mix of hydrocarbons of different lengths
How is pretolatum made?
through distillation and other purification processes with specific hydrocarbon contents
What are other hydrocarbon ingredients?
bee wax and fat
What is mineral oil (Paraffin oil or liquid petrolatum)?
of various colorless, odorless, light mixtures of higher alkanes from a mineral source, particularly a distillate of petroletum; thick, oily
What is paraffin wax?
mix of solid hydrocarbons from petroleum; very hydrophobic; colorless/white translucent, solid, greasy to touch, insoluble in water, alcohol and acetone
What is alcohol?
organic compound in which the hydroxyl functional group (–OH) is bound to a saturated carbon; hydrogen bonding
What are some more common ingredients in bases?
Alcohols and Fatty Alcohols
How does increasing the aliphatic chain affect other aspects?
increases boiling point and decreasing miscibility
What are fatty alcohols?
high molecular weight, straight chain primary alcohols; can have as few as 4-6 carbons to as many as 22-26; can be saturated or unsaturated
What are glycols or diols?
compound containing 2 hydroxyl groups; ethylene glycol is most common
What is propylene glycol or propane-1,2-diol?
3 carbons, 2 hydroxyl groups; viscous colorless liquid, nearly odorless, faintly sweet; miscible with many solvents like water, acetone, and chloroform; accommodates hydrophobic and hydrophobic molecules; less viscous than glycerol
What is glycerol or glycerin? (know structure)
3 carbons connected to a respective hydroxyl group (3); colorless, odorless, viscous liquid, sweet tasting, non toxic; soluble in water, ethanol, and propylene glycol
Why is glycerol a versatile molecules?
can dissolve hydrophilic molecules and can accommodate dissolution in non polar solvent, etc
What are fatty acids?
common ingredient in bases; a carboxylic acid with a long aliphatic (hydrophobic) chain;
-COOH; can be saturated or unsaturated
T or F: Melting point for saturated is much higher than the respective exact molecules of the unsaturated. This means saturated are going to be more solid or harder.
T.
What can saturated chains do?
move around as much as they want and entangle with each other more easily thus allowing a high melting point
What is stearic acid or octadecanoic acid?
common ingredient in bases; a saturated fatty acid with an 18-carbon chain; one of the most common fatty acids in nature following palmitic acid
What is oleic acid?
common ingredient in bases; odorless, colorless oil (may be yellowish in commercial samples); commonly present in triglycerides (ester form); 18 C but has double bond
What makes oleic acid important?
can accommodate drug either hydrophilic and hydrophobic; can enhance delivery thru the skin; permeation enhancer; nice, stable formulations
What are esters?
common ingredient in bases; made of the reaction between an (carboxylic) acid and an alcohol; e.i.: triglycerides of fatty acids and glycerin; happens during dehydration
T or F: Alcohol esterification on the glycerin molecules can only be complete.
F. Alcohol esterification on the glycerin molecules can be complete or partial. one out of 3, 2 out of 3, or 3 out of 3 alcohols substituted by fatty acids potentially different fatty acids
What is glyceryl monostearate?
fatty material that will react with stratum corneum; hydrophobic material and hydrophilic material; non-ionic emulsifier
What are waxes?
common in bases; blends of esters of long-chain alcohols and acids; hydrophobic; melting point above 40C; produced from plant or animal
What is needed to achieve the required therapeutic drug levels through the stratum corneum?
increasing the intrinsic rate of dermal or transdermal drug delivery
How to enhance and retard skin permeation?
using particular formulation strategies
incorporating specific chemicals into the formulation that alter the stratum corneum barrier function
What will using super-saturated formulations do?
increase drug content, more drug that is available; along with increasing surface area will increase more; not stable and is short stable; hydroxypropyl methyl cellulose (HPMC)
What are penetration/permeation enhancers’ purpose?
work as carriers for drugs that cannot enter into the skin easily like hydrophilic drugs; increase drug absorption by increasing the skin permeability
How do penetration/permeation enhancers work?
reversibly damaging or altering the physicochemical nature of the stratum corneum to reduce its diffusion resistance
What are some alterations that is done to the stratum corneum?
increase hydration of the stratum corneum
change in the structure of the lipids and lipoproteins in the intercellular channels
What are penetration/permeation enhancers?
chemicals that render an otherwise impenetrable substance useful in transdermal drug delivery; over 275 chemicals; anything that can accommodate the drug to penetrate; even water; acetone; azone-can be toxic; ethanol; oleic acid; isopropyl palmitate and myristate
What are ideal enhancers?
non toxic, non irritating, non allergenic, no pharmacological activity, no damage to skin, cosmetically acceptable; temp disrupt skin and not leave anything behind
What is iontophoresis and sonophoresis for?
physical methods used to enhance transdermal drug delivery and penetration
What is iontophoresis?
delivery of a charged chemical across the skin membrane using an electrical field; lidocaine, insulin; big molecules
How does iontophoresis work?
electrochemical method that enhances the transport of some solute molecules by creating a potential gradient thru the skin with an applied electrical current or voltage
What does iontophoresis do?
induces increased migration of ionic drugs into the skin by electrostatic repulsion at the active electrode. negative ions by the cathodes and positive ions by the anode
What does a typical IP device consists of?
battery, microprocessor controller, drug reservoir, and electrodes
What is iontophoresis used for?
compounds that oral administration is not suitable for but bc of their large size, cannot permeate naturally thru the skin
What are the advantages of IP?
control of the delivery rates by variations of current density, pulsed voltage, drug conc, and ionic strength;
eliminates GI incompatibility, erratic absorption, and first pass metabolism (like all transdermal systems);
reduces side effects and variation among patients (active method depending on surface area and thickness of skin);
avoids the risks of infection, inflammation, and fibrosis associated with continuous injection or infusion;
enhances compliance with a convenient and noninvasive therapeutic regimen;
deliver higher quantities of drug per time and deliver molecules that would not be penetrable thru the skin
What is the main disadvantage of IP?
skin irritation at high current densities
What is sonophoresis or phonophoresis?
high-frequency ultrasound to disrupt the stratum corneum and produce physical air pressure; lidocaine again
How is sonophoresis product applied?
applied to the skin and allow for drug to begin absorption into skin then apply ultrasound unit; disrupts stratum corneum and adds heat that helps with solubility and mobility
T or F: The ultrasound emitted are not within the sound range of humans’ hearing
T
What are the 3 effects of ultrasound?
cavitation
microstreaming
heat generation
What is cavitation?
formation and collapse of very small air bubbles in a liquid in contact with ultrasound waves
What is microstreaming?
closely associated with cavitation; results in efficient mixing by inducing eddies in small volume elements of a liquid
What is heat in sonophoresis?
results from the conversion of ultrasound energy to heat energy and can occur at the surface of the skin and deeper layers
How to select a drug that is appropriate to deliver thru the skin?
needs to have a therapeutic rationale for why we want to treat something and compound efficacy/safety; needs drug stability through other roots of administration; high drug lipophilicity and molecular volume
What is therapeutic efficacy dependent on?
ability of the compound to cross biological barriers to reach the target site
What does higher drug lipophilicity mean?
higher possibility for skin penetration or at least thru sc bc epidermis is hydrophilic
What does molecular volume mean?
bigger molecules will remain in sc for longer periods
T or F: A larger lipophilic molecule will stay in sc.
True
What is added for sunscreen formulations that stays on the skin?
medium length alkyl chain to UV reflective molecule (big and hydrophobic)
What do molecules need to do for transdermal application?
partition into relatively lipophilic sc;
diffuse rapidly across sc;
and partition easily into more hydrophilic viable epidermis and dermis prior to vascular removal
What are some properties of transdermal formulations?
low dose; half life 10 hours or less; <400-500 MW; be rather hydrophobic but still a bit hydrophilic; absorbed fast enough; non irritating and non sensitizing; low oral bioavailability; low therapeutic index
What are the advantages of transdermal system?
avoid first pass metabolism; non invasive; topical application; drug therapy can be terminated easily and rapidly; can be self administered; well accepted; can be used for long term therapies; easy to prepare
What are the disadvantages of transdermal system?
not all drugs can be utilized; unsuitable for skin irritating compounds; drug candidate must demonstrate strong effect in low doses; can develop dermatitis at site; discomfort to long term application; large molecules may not be suitable
What do topical delivery systems deliver?
corticosteroids, acne products, antibiotics, antifungals, antiseptics, local anesthetics, emollients
What are ointment?
a common topical system; classified as either Oleaginous bases (hydrocarbon bases), absorption bases, water-removable bases (O/W emulsion), or water-soluble bases
What are oleaginous bases?
have an emollient effect; protect against the escape of moisture; effective as occlusive dressings; remain on the skin for long periods without drying out; more difficult to wash off
How are water and aqueous preparations incorporating water?
in small amounts with some difficulty since they are hydrophobic bases
What are some examples of oleaginous bases?
petrolatum, white petrolatum, white ointment, and yellow ointment
What is Petrolatum or yellow petrolatum or petroleum jelly?
purified mixture of semisolid hydrocarbons obtained from petroleum; unctuous mass, varying in color from yellowish to light amber; may be used alone or in combo with other agents as an ointment base; yellow soft paraffin
What is white petrolatum or white petroleum jelly?
purified mixture of semisolid hydrocarbons from petroleum that has been entirely or kind of decolorized; more esthetically pleasing; white soft paraffin
What are some characteristics of petrolatum and white petrolatum?
tasteless, odorless, greasy, melts between 38C to 60C, soluble in most oils but practically insoluble in water, alcohol, acetone, and glycerin
What is yellow wax?
purified wax from honeycomb; slightly greater viscosity than plain petrolatum; more solid, more hydrophobic, very greasy
How is an ointment or simple ointment prepared with yellow wax?
by melting the yellow wax on a water bath, adding the petrolatum until the mixture is uniform then cooling and stirring until congealed
How is white ointment prepared?
instead of yellow wax use white wax (bleached and purified yellow wax) and white petrolatum; for aesthetic purposes
What are the two types of absorption bases?
- those that permit the incorporation of aqueous solutions resulting in the formation of W/O emulsions like hydrophilic petrolatum
- those that are W/O emulsion (emulsion bases) that permit the incorporation of additional quantities of aqueous solutions like lanolin
What are absorption bases?
W/O emulsions; useful as pharmaceutical adjuncts to incorporate small volumes of aq soln into hydrocarbon bases; external phase is oleaginous so not water washable
What is an example of absorption bases?
hydrophilic petrolatum
How is hydrophilic petrolatum prepared?
by melting stearyl alcohol and white wax on a steam bath, adding the cholesterol with stirring until dissolved, adding the white petrolatum, and allowing mixture to cool while stirring until congealed
What is lanolin?
absorption base from the wool of sheep that is a purified waxlike substance; no more than 0.25% of water
What is modified lanolin?
same as lanolin but reduced alcohols, detergents, and pesticide residues
What are water-removable bases?
in O/W emulsions called creams; external phase is aq so easily washable from skin; can be diluted with water or aq soln and absorb serous discharges
What is an example of water removable base?
hydrophilic ointment
How is hydrophilic ointment prepared?
stearyl alcohol and white petrolatum melt together at about 75C; other agents dissolved in purified water are added with stirring until the mix congeals
What are the other agents in hydrophilic ointment?
sodium lauryl sulfate-emulsifying agent; stearyl alcohol and white petrolatum-oleaginous phase of emulsion; other ingredients-aq phase; methylparaben and propylparaben-antimicrobial preservatives
What are water-soluble bases?
completely water-washable and greaseless that do not contain oleaginous components; used for incorporation of solid substances
What is an example of water soluble bases?
polyethylene glycol ointment (PEG)
What is PEG?
polymer of ethylene oxide and water; the greater the molecular weight, the greater the viscosity
What are PEGs with an average molecular weight below 600?
clear, colorless liquids
What are PEGs with an average molecular weight above 1000?
waxlike white materials
What are PEGs with an average weight between 600 and 1000?
semisolids
What can make a very pliable semisolid ointment?
combining PEG 3350, a solid, with PEG 400, a liquid
What are some decision factors of the appropriate base?
release rate of drug substance from the ointment base, topical or percutaneous drug absorption, occlusion of moisture from the skin, stability of the drug in the ointment base, effect of drug on the consistency or other features of base, ease of removal by washing with water, characteristics of surface applied to
Where is an ointment generally applied to?
dry, scaly skin
Where is a cream generally applied to?
weeping or oozing surfaces
Where is a lotion generally applied to?
where friction may occur or intertriginous areas
What 2 methods are ointments prepared by?
incorporation and fusion depending on nature of ingredients
What is incorporation?
mixing components (base and drug) until uniformity; needs a very very fine powder preferable if API is going to dissolve in base
What can be used for incorporation?
hand mortar and pestle, ointment slab, ointment mill/Unguator
How are solids incorporated?
ointment base and powder placed on different sides; small portion of fine powder is mixed with a portion of base until uniform while performing geometric dilution
What is desirable in incorporation of solids?
to reduce the particle size of a powder or crystalline material before incorporating into ointment base done by levigating or mixing the solid material in an insoluble vehicle to make a smooth dispersion
What is the levigating agent in the incorporation of solids?
mineral oil for bases in which oils are the external phase or glycerin for bases in which water is the external phase so should be physically and chemically compatible with the drug and base
What does the levigating agent allow?
both reduction of particle size and dispersion of the substance in the vehicle
What happens after levigation?
dispersion is incorporated into ointment base by spatulation or mortar and pestle until uniformity
What method is used to incorporate a gummy material (camphor)?
pulverization by intervention
How does pulverization by intervention happen?
material dissolved in solvent and spread out on pill tile; solvent can evaporate, leaving a thin film of material onto which other ingredients are spread; material is then worked into ingredients by trituration with a spatula
When are solids and liquids added to ointment
solids-to dissolve in the solve then ointment base
liquids-to ointment after considering volume required due to ointment base’s capacity
T or F: Only very small amounts of an sq soln may be incorporated into an oleaginous ointment whereas hydrophilic ointment bases readily accept aq soln. All bases even hydrophilic have a limit, though.
T
How can a aq preparation be added to a hydrophobic base?
soln first incorporated into minimum amnt of hydrophilic base then that mixture is added to hydrophobic base
Are alcoholic solns of small volume added easily or difficultly to oleaginous vehicles or emulsion bases?
easily
How are natural balsams (Peru balsam) mixed?
with an equal portion of castor oil before incorporation into a base
What are ointment roller mills used for?
to force coarsely formed ointments thru stainless steel or ceramic rollers to produce ointments uniform in composition and smooth in texture; after congealing
What is fusion?
all or some of ointment are combined by being melting together and congealed
What happens to components not melted during fusion?
added to the congealing mixture as it is being cooled and stirred
What is added last during fusion?
heat-labile substances and any voltaile components, naturally, when the temperature of mix is low enough not to cause decompositon or volatilization of these
What can be added to congealing mixtures?
solution or insoluble powders levigated with some base
What can be prepared by fusion?
medicated ointments and ointment bases containing beeswax, paraffin, stearyl alcohol, and high molecular weight PEGs
How does fusion produce a melt?
materials with highest melting points are heated to the lowest required temp
How else can fusion be performed?
melting the component with the lowest melting pt first and adding remaining components in order of their melting pts or simply melting all of the components together under slowly increasing temp
What methods does fusion use in preparation of ointments having an emulsion base?
both melting and emulsification
What is melted together in a steam bath to 70C to 75C?
water immiscible components like oil and waxes
What is prepared and heated to the same temp as the oleaginous components?
aq soln of heat stable and water soluble components
What happens after heating the aq soln?
it is slowly added with mechanical stirring to the melted oleaginous mixture where temp is maintained for 5-10 minutes and slowly cooled and stirred until congealed
What tests do ointments and other semisolid dosage forms must meet for?
microbial content; minimum fill; packaging; storage; labeling; sterility
T or F: There are no sterility requirements for ointments.
True bc the skin is a good barrier
What must ointments contain? Why?
antimicrobial preservatives except ophthalmics because contain water to support growth (O/W, water soluble)
Why does Betamethasone Valerate Ointment must meet the requirements of the tests for absence of Staphylococcus aureus and Pseudomonas aeruginosa?
they have a capacity to infect the skin and patients using this are already compromised
What is the minimum fill test?
net weight or volume of the contents of filled containers to ensure proper contents compared with the labeled amount
What are ointments and semisolid preps usually packing and stored in?
large mouth ointment jars and metal tubes and plastic tubes that are well closed in a cool place(not fridge usually!); when required, in opaque or light resistant containers
What are some additional standards of ointments and semisolid preps?
viscosity and in vitro drug release including diffusion cell studies
What are creams?
semisolid preps containing one or more medicinal agents dissolved or dispersed in a W/O emulsion or O/W emulsion
What are vanishing creams?
O/W emulsions containing large percentages of water and stearic acid or other oleaginous components where after application the water evaporates and leaves behind a thin residue film of the stearic acid or oleaginous component
Ointments vs cream texture?
ointment-more viscous, thicker
cream-softer
How are creams in a two-phase prep?
one phase (dispersed or internal phase) is finely dispersed in the other (continuous or external phase)
What makes a cream O/W or W/O?
the properties of the system used to stabilize the interface between the phases
What is an emulsion-stabilizing system aka an emulsifier required to do?
maintain the two incompatible phases in an emulsion state
What are emulsifiers comprised of?
surfactants (ionic and/or nonionic), polymers (nonionic polymers, polyelectrolytes, or biopolymers), and a mixture of there
What is an emulsion?
a dispersion of two immiscible liquids stabilized by an emulsifier
What is a W/O emulsion?
oil is continuous phase having a stabilized suspension of water droplets
What is an O/W emulsion?
water is continuous phase having a stabilized susp of oil droplets
What is the purpose of emulsifiers?
to lower interfacial tension and form a thin film at the water/oil interface and prevent or minimize flocculation; amphiphilic with hydrophilic head and hydrophobic tail
How can repulsion when droplets approach each other be generated?
electrostatically by the establishment of an electric double layer on the droplet surface and sterically by adsorbed nonionic surfactant or polymeric material
T or F: If it is a hydrophilic-dominated emulsifier, it is going to create an O/W emulsion. If it is a hydrophobic-dominated emulsifier, it is going to create a W/O emulsion
T
What is electrostatic repulsion?
provided by ionic surfactants; occurs when 2 similarly charged droplets approach each other; extremely sensitive to additional electrolytes
What is used for steric repulsion to beproduced?
produced using nonionic surfactants or polymers like polyvinyl alcohol or poloxamers
What forms a thick hydrophilic shell of polyoxyethylene chains around the droplet?
special distribution of the polyethoxylated nonionic surfactants blocking copolymers
How is repulsion made?
by mixing interaction (osmotic repulsion) and entropic interaction (volume restriction)
What is adsorption energy?
critical to the generation of steric repulsion for polymeric materials without definitive hydrophobic and hydrophilic regions; should neither be so low to result in no polymer adsorption nor so high to result in complete polymer adsorption to the droplet
What can ionic and nonionic surfactants be used for?
ionic-O/W emulsions
nonionic- both O/W and W/O emulsions
What generates an arbitrary number (usually between 0 and 20) that is assigned to a particular surfactant(oil)?
hydrophilic-lipophilic balance (HLB) value
What will have high HLB values?
hydrophilic surfactants
What will have low HLB values?
lipophilic
What kind of emulsifiers have a surfactant with HLB of 4-6?
W/O
What kind of emulsifiers have a surfactant with HLB of 8-18?
O/W
What is the formula for the overall HLB of a surfactant mixture (HLBM)?
HLBM=f x HLBA+(1-f)HLBB where f is the weight fraction of surfactant A
T or F: When we’re making a system we have an oil in water that will have an interface that is fixed and creates a required fixed HLB value. You can put emulsifying agents specifically a combo of them in an oil phase. Adjust the amount of emulsifying agents to get HLB value within range.
T
What are the most commonly used surfactants/ emulsifiers?
sodium alkyl sulfates (anionic), alkylammonium halides (cationic), polyoxyethylene alkyl ethers, and polysorbates (nonionic)
What emulsions are often used alone or in conjunction with nonionic polymerics?
polyvinyl alcohol, poloxamer block copolymers, polyelectrolytes, polyacrylic/polymethacrylic acids
What are polysorbates?
hydrophilic surfactants that tend to form o/w emulsions; tweens and spans; highly viscous yellowish liquids; groups of sorbitol to sorbitan
What is a polysorbate span?
hydrophilic sorbitan group and hydrophobic tail no PEG groups; hydrophobic group is dominant; water in oil emulsions
What is a polysorbate tween?
has polyethylene glycols (hydrophilic) and carboxylic ester and hydrophobic tail in oil in water emulsions
What is another type of emulsifier?
Cremophors and Cremophor EL
What is Cremophor EL?
has glycerol connected to 3 polyethylene glycol (hydrophilic center) connected thru carboxyl ester bonds to fatty acids (hydrophobic portion)
How is Cremophor EL prepared?
by reacting 35 moles of ethylene oxide with each mole of castor oil
What is the resulting product of Cremophor EL?
mixture where the major component is the material in which the hydroxyl groups of the castor oil triglyceride have reacted with ethylene oxide and the minor components are the polyethylene glycol esters of ricinoleic acid, polyethylene glycols and polyethylene glycol ethers of glycerol
What are more complex types of emulsion?
water in oil in water or oil in water in oil which are difficult to formulate and have somewhat variable stability issues
What are some advantages of multiple emulsion systems over conventional emulsions?
control of drug release and kinetics of skin distribution
Where are creams typically applied?
topically on skin; rectally and vaginally on mucous membranes; easier to spread and remove
How are creams generally described?
either nonwashable or washable reflecting that an emulsion with an aq external continuous phase (O/W) is more easily removed than one with a nonaq external phase (W/O emulsion); usually water washable
What are creams formulated from?
a variety of oils, both mineral and vegetable, and from fatty alcohols, fatty acids, and fatty esters; while these are being prepped solid excipients are being melted
What are some emulsifying agents?
nonionic surfactants, detergents, and soaps
How are soaps usually formed?
from a fatty acid in the oil phase hydrolyzed by a base dissolved in the aq phase in situ during the prep of creams
What does the preparation of creams involve?
separating the formula components into two portions: lipid and aqueous
What do the lipid portion and aq portion of the cream contain?
lipid portion-all water-insoluble components
aq portion-water-soluble components
What is done with both the lipid and aq phases?
heated to a temp above the melting pt of the highest melting component then mixed and stirred until reaching ambient temp or congealed; continue mixing during cooling process to promote uniformity
What is high-shear homogenization used for?
to reduce particle or droplet size and improve physical stability of the resultant dosage form
When can the APIs be added?
to the phase in which it is soluble at the beginning of process or added after the cream is prepared by a suitable dispersion process such as levigation or milling with a roller mill
Are preservatives needed in creams?
Yes, unless they were compounded immediately before use and used for a short period
What is rheology?
science studying the deformation and flow of matter for: liquids, semisolids, solutions, suspensions, and emulsions
What is flow?
relationship between viscosity and the applied force
What is viscosity?
measure of resistance of a fluid to deformation due to shear stress (force) or tensile stretch; water is less viscous, easily flows; honey is high viscosity difficult flow; associated with internal friction of moving fluid and interaction among the fluid’s molecules
What is Newtonian flow?
when viscosity stays constant as the applied force change; simplest type of flow like with water
What is non-Newtonian flow?
viscosity changes as some function of applied force
What is shear stress?!
application of horizontal force (F) over a unit area (A)
What is directly proportional to the applied shear stress?
velocity (𝛥v) of the material over the small distance (𝛥x) it travels
F/A∝∆v/∆x»F/A=n(∆v/∆r) aka (rate of shear)
n is coefficient of viscosity and r is the distance from the stationary surface
What is strain rate?
how fast material start moving bc of force applied to them
What does slope (ø) give us?
fluidity or 1/viscocity
What is an important feature of Newtonian rheology?
viscosity is independent of shear stress and remains constant except temperature
What is kinematic viscosity?
absolute viscosity divided by the density of the substance
What happens to the viscosity of Newtonian fluids as temperature increases?
it decreases
n=A exp^Ev/RT
A-constant
Ev-activation energy required to initiate flow of molecules
R-universal gas constant
T- temp
What is non-Newtonian flow shown in?
creams, ointments, or suspensions; in complex heterogenous systems in which the relationship between the shear stress and rate of strain is nonlinear
What are the 3 common types of non-Newtonian rheological profiles?
plastic flow, pseudoplastic flow, dilatant flow
What is plastic flow?
no flow occurs in response to shear stress until a certain transition point is reached (mayo)
What is the yield value of plastic flow?
minimum shear stress required by system before it deforms and begins to flow; how much to be shaken
What is pseudoplastic flow?
deform and flow instantaneously with applied stress (ketchup); highly viscous until shaken when 3d structure collapses; becomes thinner and less viscous
What exhibits pseudoplastic rheological profile?
aq solutions of certain polymers like some of polysaccs
What form are polymers in at rest or low shear stress?
coiled or globular conformation bc of intramolecular stabilizing forces but untangle once flow initiates
What is dilatant flow?
opposite to pseudoplastic systems; deformation and flow occur instantaneously upon application of stress; becomes thicker like whipping cream; more viscous
In what suspensions is dilatant flow observed in?
ones that contain a very high (>40% to 50% w/w) solid content; solid particles are loosely aggregated at rest, results in low viscosity
What is thixotropy or shear thinning?
time dependent change of viscosity; longer apply a force, the viscosity of liquid drops but once force is removed, viscosity gradually increases back; needed! in creams
What is shear thinning?
desirable property that should have high viscosity upon standing to prevent settling and aggregation but should pour easily from container once shaken
What is viscoelasticity?
both viscous flow and elastic deformation when stressed like silly putty and polyethylene oxide
