Physical Pharmacy week 8 Flashcards
What is a dispersed and continuous phase?
f.e. in SUSPENSION:
Dispersed phase: particles within the medium
Continuous phase: f.e. water, where particles are dissolved in
Difference between dispersed phase formulations and solutions?
Dispersed phase formulations: particles are not dissolved in single molecules, rather there are chunks dispersed in the continuous phase
Solutions are also seen as dispersed formulations but dissolved in a single molecular form
Describe characteristics, size, and one example of molecular dispersions!
pass through semipermeable membrane and undergo diffusion, < 1 nm, Oxygen molecules and glucose
so well put together that considered as 1 phase
Describe characteristics, size, and one example of colloidal dispersions!
do not pass semipermeable membrane but filter paper, diffuses slowly and visible in electron microscope; 1-500 nm; Colloidal silver sol and polymers
in water, homo or heterogeneous system 1 or 2 phases
Describe characteristics, size, and one example of coarse dispersions!
do not pass membrane or paper filter and no diffusion, > 500 nm, RBC and most pharmac. suspension and emulsion
in water, heterogenous system with 2 phases
Characteristics of LyoPHILIC colloids
Colloidal particles interact with dispersion medium - low interfacial tension
dissolve well and provide stable formulation
often hydrophilic organic: albumin, methylcellulose, gelatin –> viscosifying agents
Why are hydrocolloids used as continuous phase in suspensions?
Because they exhibit sol-gel transition (thixotropy)
Example of hydrocolloids in medicine
Albumin or gelofusine used as plasma expander in critical care patients -> increase volume when in case of blood loss, because the heart keeps pumping blood when blood volume is high enough (circulatory shock)
increase because present in the blood vessel and exter osmotic pressure and draw fluid back from the tissues
(Albumin also prevents adsorption (sticking) of drug to packing material)
Characteristics of LyoPHOBIC colloids
high interfacial tension -> dispersed phase has low affinity to continuous phase, more unstable
inorganic molecules, f.e. colloidal gold/silver in water
specialized methods needed to prepare
LyoPHOBIC applications in medicine
TPN total parental nutrition, for patients in critical care to feed, essential oils in emulsion - the oil molecules may block arteries after long-term care
Megestrol (formulation of progesterol) counters weight loss in chemo and increases appetite
What differences are observed when giving coarse and nanodispersion of Megestrol?
Colloidal VS Coarse dispersion
The Megestrol preparation given in nanosize colloidal dispersion was way more effective in bioavailability than coarse dispersion
Characteristics of amphiphilic colloids
it likes water and oil, and it locates at the interface between water and air, lifting up the tail in the air and hydrophilic head to the water, once the interface is covered and minimum surface tension is reached (critical concentration) micelles are formed
How are amphiphilic colloids used?
used as Liposomes (a bigger form of micelles) to deliver lipophilic drugs
Microemulsion (emulsion with nm particles) increase droplet stability and bioavailability
for very lipophilic drugs with poor bioavailability
What is the function of liposomes?
used to target the drug to a specific area: drugs normally go everywhere
the liver f.e. more likely to take up liposomes, thereby you can target the liver in a therapy
Explain one unique property of colloids
High surface area as a catalyst -> using the bigger sized platinum has no action - because it has not the surface area to catalyze the reaction
bring the small particles together, in a way that works
thermodynamically better
Other properties of colloids: Optical (unique to colloidal dispersions)
Where is it used?
If you pass light through colloidal dispersion it will be scattered –> Tyndall effect
(particles in solutions are too small)
can be used to estimate the molecular weight of the colloid -> Turbidity (a measure of cloudiness)
Property of colloids: Brownian motion
-> Random motion of particles
there is enough kinetic energy to keep the small molecules moving to defy gravity
factors acting against Brownian motion: lower the temperature to take out the kinetic energy, particle size higher than 5 nm, viscosity
What other properties are shared with other dispersed systems?
Brownian motion -> molecular dispersions
electriacl double layers -> coarse dispersion
Explain Sedimentation of suspension
The rate of settling is defined by Stokes Law:
r = particle size radius (larger than 5 nm, it will settle)
p(rho) = particle density - p0 = density of the medium (if the particle is denser than density of the medium it will settle, if it is equal it will neither float nor sink, if its density is lower then it will float
g = gravity
n0 = viscosity
How can Stokes Law be applied to small particle systems?
particles lower than 5 nm don’t obey Stokes Law because Brownian motion keeps particles moving -> you have to increase gravity by centrifuging
added factors: w = angular velocity and x = distance of particle to the center of rotation
if you spin milk, particles will settle although Brownian motion
Kinetic property: Diffusion
Consequence of Brownian motion - Kinetic energy
spontaneously movement of particles from areas of higher concentration to areas of lower concentration
How is diffusion applied in the process of drug delivery?
Drugs first dissolve and go into solution, then they undergo Brownian motion and spread everywhere and bump into the wall of the intestine so that some of those get absorbed to the other side
also filtered this way by kidney
Why do drugs keep getting absorbed, even though equilibrium should be established after a while?
Because blood takes absorbed drugs away and there is a shift in equilibrium that can be established again
What drives diffusion?
The concentration gradient
Ficks Law explained:
Diffusion J is direct propotional to concentratient gradient dc
Ficks Law explained: J = - DS * dc/ dx
Diffusion J is direct propotional to concentratient gradient - dc
directly proportional to the surface area available for diffusion - S
inversly propotional of the thickness of the membrane - dx
D is the constant or coefficient
Explain Einstein’s equation of flow
Viscosity = resistance of a system -> the more viscous the greater the force needed for flow
Kinetic properties: Donnan membrane equilibrium
Electrical property
Macromolecule like Na CMC dissolves: Na will pass the membrane, but CMC cant because it is colloidal (big), so it will aggregate at one side and build an electrical gradient
this gradient can be used to push other negatively charged molecules to the other side to balance the charge of both sides
Explain the instability of colloidal systems and how can it be countered.
It is caused by high surface area and is free energy, it aggregates to reduce the surface area and thereby stabilizes the free energy
Electrical double layers counter aggregation stabilizes colloids
How are electrical double layers built in colloidal dispersions?
Colloids can be + charged (f.e.) to balance the electrical charge exerted by the large surface area of the colloids, negative ions walk there and build the Stern and Gouy-Chapman layer
Which forces act on colloidal particles?
London-type Van der Waals attraction promotes aggregation: energy decreases when two particles come closer
Electrostatic repulsion - barrier of aggregation: due to the double layer (f.e. both negative), repulsion energy increases when they come together
in formulations, a balance between the two needs to be found
What phenomena are considered instability in suspensions and emulsions?
in suspensions: caking -> particles come tight together, because of the amount of van der Waals force it is very hard to resuspend
in emulsions: creaming -> oil in emulsion goes on top and forms a cream layer
How can aggregation be prevented?
-Increase viscosity: slow down the settling of particles - thixotropic
-Flocculation loose aggregation - particles come close but not so close that they form a cake
-adding salt to minimize the double layer, but not too much so they are present in secondary minima state in floccules
-polymer chains on the particle prevent aggregation
-add surfactant to reduce interfacial tension and free energy
Applications of Liposomes
Specific target in anti-cancer therapy - multiple drugs packed in Liposomes
used to deliver drugs and manage their activity to temperature control to kill cancer cells
nanoparticles as an imaging element, contrast medium to visualize areas in the brain
What is the function of Phosphodiesterase inhibitors?
-relax smooth muscle and inhibit inflammatory
-PDE4 is the target
What other receptor is blocked by Methylxanthines (PDE inhibitor)?
-adenosine receptor blocker
-An unwanted effect → Inc HR
Methylxanthines: (not specific to PED4)
-Theophylline
-Aminophylline
(Caffeine)
Selective PED4 inhibtor
-Romflumilast (Daliresp)
-works better against COPD
-no side effect of increased heart rate
How do Muscarinic antagonists (M3) work?
ACh from the vagus nerve binds to muscarinic receptor -> causing bronchoconstriction
Muscarinic antagonists block the muscarinic receptor and prevent the bronchoconstriction, promoting bronchodilation
Examples of Muscarinic blockers
-atropine-like drugs
-Ipratropium
-Tiotropium
-Glycopyrrolate
-Umeclidinium
-Aclidinium
Combination products
SABA/SAMA -> acute (asthma)
-albuterol/ipratropium
LABA/LAMA -> long-term relief (COPD)
-indacaterol/glycopyrrolate
-vilanterol/umeclidinium
-olodaterol/tiotropium
Example of a Combination product:
ANORO ELLIPTA
-umeclidinium, an anticholinergic,
-vilanterol, a long-acting beta2-adrenergic
agonist (LABA)
-long-term, once-daily -> for COPD!!! not asthma
-LABA drugs show an increase in asthma mortality
BREO ELLIPTA (vilanterol + Fluticasone)
BREO ELLIPTA (vilanterol + Fluticasone)
-Vilanterol is a LABA (long-acting beta agonist)
-Fluticasone is an ICS (inhaled corticosteroid)
-special patient population
-LABA increases death in asthma patients
Why are Inhaled corticosteroids (ICS) preferred over oral glucocorticoids?
-less side effects
-Powerful drugs for all type of inflammatory state
Examples of ICSs
-Fluticasone (now OTC)
Prodrugs activated in the lung tissue
-Beclomethasone dipropionate (BDP)
-Ciclesonide
Significant first-pass effect
-Budesonide
-Fluticasone
-Mometasone
What are the side effects of Glucocorticoids?
long-term effects (short-term is OK)
-raised blood glucose
-alter fat metabolism (increased expression in some fat cells, decreased in others -> growth in different parts of the body)
-increased appetite
-May affect skin health
-Capillary fragility
-Gastric ulcers
-May reduce bone metabolism
-Are generally immunosuppressive
Where are Leukotrienes derived from?
Arachidonic acid (22 C fatty acid) from triglyceride out of fat cells
-Arachidonic acid can develop into many different compounds (such as prostaglandins, leukotrienes, many more)
Which enzyme is responsible for the conversion of Arachidonic acid to Cysteinyl-Leukotrienes?
5-Lipoxygenase -> converting Arachidonic acid to Cysteinyl-Leukotrienes (LTC4, LTD4!!!, LTE4)
-blocked by the drug:
5-Leukotrienes synthesis inhibitor Zileuton (Zyflon) !!!
More specific way to block Leukotrienes
1 step downstream
-Leukotrienes Antagonists:
Montelukast
Pranlukast
Zafirlukast
-for long-term therapy, not acute attacks
What would be the effect of Leukotrienes if not inhibited?
-Bronchoconstriction
-Mucus secretion
-Eosinophil recrution
-> inhibited by Leukotriene inhibitor
