Disperse systems science
traditional pharmacy compounding
complex, multi-disciplinary state of the art science
huge subject area
Dispersed systems
heterogeneous systems in which one phase is dispersed (hopefully with some uniformity) into a second phase
the state of the dispersed phase (gas, solid, liquid) in the dispersion medium can be used to classify the system as foam, aerosol, suspension or em
suspension
insoluble solid particles dispersed in a liquid medium
emulsion
liquid droplets dispersed in a liquid medium. The dispersed liquid is neither soluble or miscible with the dispersion medium
colloid
type of mixture where one substance is dispersed evenly throughout another
the term is often used as a means of classifying the size of the disperse phase (1nm-0.5mcm)
Types of dispersed systems
water is the most widely used dispersion medium
systems can be classified by the characteristics of the disperse phase
hydrophobic (water hating)/Lyophobic (solvent hating)
-water insoluble drugs in a suspension
-oil phase in an oil in water emulsion
-rel
System classifications by particle size
course dispersions-suspensions/emulsions (10-50mcm dispersed phase)
colloidal dispersion or microemulsion (1nm-0.5 mcm)
Most complex dosage forms are?
liquid
Why are liquid dosage forms so complex?
They are thermodynamically unstable
-oil hates water-immiscible
-hydrophobic drug likes to aggregate
There is a reluctance to develop disperse systems when alternatives are available (tablets, solutions)
oils/lipids
formulated as dispersed systems because they are not suitable for formulation as solid or aq dosage forms
intralipid-used for parenteral nutrition
Other drugs that are formulated in dispersed systems
pharmaceuticals that are insoluble in the aq phase
pharmaceuticals that are unstable in water
ex. B-lactam antibiotics
Why deliver drugs in dispersed systems?
to mask the taste
to improve chemical stability
alter the onset of action
improved compliance
flexibility of dosage range
higher doses of drug
Disadvantages of a disperse system
poor physical stability
poor dosing uniformity characteristics
microbial contamination
What is dispersion at the molecular level?
non-equilibrium state
continuously seeking to reach a thermodynamic state
we can stabilize these systems using an understanding of the interfaces between the phases
surface
boundary of 2 phases(one of the phases is gas)
interface
boundary of 2 phases
air-liquid surface
water exposed to the atmosphere
air-solid surface
the surface of a tablet exposed to the atmosphere
liquid-liquid interface
oil in water emulsion droplets
solid-solid interface
powder particle adhering to eachother
surface tension
the surface of any liquid behaves as if it was a stretched membrane
at the surface, molecules are attracted by the molecules below and by the lateral ones. The force is directed inside the liquid
surface molecules pack closer together than the rest of the
cohesive forces
a molecule of a liquid attracts the molecules which surround it
for these molecules inside a liquid, this results in a neutral force and all them are in equilibrium by reacting with eachother
Force definition
surface tension can be defined as the force needed to oppose the pull of the molecules in the surface to minimize the size of that surface
How do we measure surface tension?
the opposing force of detachment of a stainless steel ring is used to measure surface tension with the Du Nouy tensiometer
surface tension equation
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energy definition
surface free energy-this is the more exact definition. It is the work (ergs) done to increase the surface by one unit of area (cm^2)
units of surface free energy
ergs/cm^2
interfacial tension
cohesive forces AND ADHESIVE forces are involved
interfacial tension reflects the imbalance of forces at the interface (between cohesive and adhesive forces)
generally between surface tension values of the two immiscible liquids
measuring interfacial tension
Du nouy tensionometer
wilhelmy plate method
capillary rise method
drop weight and drop volume methods
measurement of solid-liquid interfaces is difficult
spreading
Generally a liquid on liquid term. When a liquid is placed on a surface, it will spread as a film if the force of adhesion between the surface and the liquid is greater than the cohesive forces of the liquid itself
spreading coefficient
S=Wa-Wc
if S is positive, spreading occurs
wetting
Describes the interaction between a solid and a liquid. Drugs cannot be dissolved until they have been wetted.
Theta and wetting
if theta is small (less than 90), surface is wetting by liquid
if theta is large (greater than 90), surface is not wetted
surfactants
surfactants are a group of chemicals that are used to alter the surface and interfacial tension of the disperse phase and the dispersion medium in disperse systems
amphiphilic-so they tend to accumulate on the surface
HLB
hydrophilic lipophilic balance
the lower the HLB number the more lipophilic
the higher the HLB number the more hydrophilic
Surfactant classification (SC)
classified by charge on their hydrophilic group
SC-anionic
hydrophilic gp carries a negative charge
ex. sulfated alcohol
sodium dodecylsulfate-wetting agent and detergent
other things that start with sodium
SC-cationic
hydrophilic gp carries a positive charge
Spans and Tweens
SC-zwitterionic
hydrophilic gp possesses both positive and negative charge groups
SC-nonionic
hydrophilic group carries no charge
Spans
sorbitan esters-insoluble in water
low HLB
used as emulsifying agent and wetting agent
Tween
polysorbates-miscible with water
high HLB
used as emulsifying agent
micelle
an aggregate of surface active particles
can vary in shape dependent upon the characteristics of the surfactant molecule
critical micelle concentration
below CMC only monomers are present
above CMC there are micelles in equilibrium with monomers
solubilization
solubilization of an insoluble compound takes place as it is incorporated into the surfactant micelles
suspensions
refers to 2 phase system consisting of a finely divided solid drug dispersed in a liquid. Contain one or more insoluble medicaments in a vehicle, with other additives such as preservatives, color, buffers and stabilizers
Why formulate a suspension?
drug is insoluble in aq vehicle
allows higher dose
drug is unstable when dissolved
liquid dosage form required
alter absorption kinetics
desired characteristics of a suspension formulation
it should settle slowly
particle size should remain fairly constant
pour readily and evenly
flocculated suspensions
particles form loosely bound flocs that are easily resuspended on shaking
deflocculated suspension
particles remain suspended and settling is retarded by suspending or thickening agents and the dispersion media
van der waals forces (pro-flocculation)
forces of attraction between similar particles
these forces dominate at small and large distances between particles
electrostatic forces (anti-flocculation)
arise from the interaction in the electrical double layer
leads to forces of repulsion for particles with surface charge of the same sign
electric double layer
consists of the fixed surface charge and the more loosely bound counter-ions
zeta potential is the net electrical charge of the electrical double layer- it represents electrical potential difference between the surface charge of the suspended particle and
electrolytes as flocculating agents
they act by modifying the particle zeta potential
the electrolytes carry an electrical charge opposite that of the zeta potential of the particles
the addition of these flocculating agents at some critical concentration, negates the surface charge on the
polymeric flocculating agents
starch, alginates, carbomers
their linear branched chain molecules form a gel like network and become absorbed on the surface of the particles holding them as flocs
Stokes equation
describes the rate of sedimentation
dx/dt=d^2(pi-p)g/18n
suspending/thickening agents
added to dispersion vehicle to increase viscosity and add structure
ensure polymeric agents do not irreversibly bind to the drug particles and alter bioavailability
the amount of suspending agent added is critical, if too much, the liquid will not pour
coarse suspension
particles are larger than 1 mcm
colloidal suspension
particles are less than 1 mcm in diameter
suspension stability
suspended particles are less likely to undergo chemical degradation, however, most drugs do have a finite solubility and its solution stability should be considered
suspension preservatives
added to prevent microbial growth in suspensions
crystal growth
oswald ripening may occur leading to increase in drug particle size
emulsions
a dispersion of 2 immiscible liquids, one of which is finely subdivided and uniformly distributed as droplets throughout the other (continuous phase)
oil in water (o/w) emulsion
oil is dispersed in aq medium
water in oil (w/o) emulsions
water is dispersed in the oil
advantage of emulsions
stable and homogeneous mixture of 2 immiscible liquids
small oil droplet size makes it more digestible and better absorbed in an o/w emulsion
masks the taste
how can emulsions be used?
orally, topically, parenterally
How are emulsions formed?
when the interfacial tension is lowered and an energy source is provided to overcome the surface tension and increase the surface are of the disperse phase by decreasing the droplet particle size
ideal emulsion properties
homogenous system
small droplet size (0.5-2.5 mcm
disperse phase should not aggregate on standing
no creaming of large droplets at surface
no cracking-separation of two phases
emulsion theory
surface tension theory
oriented wedge theory
plastic film theory
surface tension theory
lower interfacial tension-facilitates small droplets (decreases coalescence)
interfacial tension is lowered by surfactants acting as emulsifying agents
selection of the emulsifier
use and HLB number similar to the value assigned to the oil in either the o/w or w/0 emulsion
mixtures of emulsifying agents with hydrophilic and lipophilic properties can be employed to produce the required HLB
Emulsifying agents
carbohydrates
proteins
high molecular weight alcohols
surfactants
colloidal clays
Traditional methods for emulsion preparation
continental or dry gum method
english or wet gum method
bottle method
larger scale methods
homogenization
mechanical stirrers-high speed impellor
colloid miller
ultrasonication
stability of emulsions
phase separation begins with agglomeration
creaming is an example of this and occurs when oil globules aggregate and rise to the surface
the 2nd phase takes place as droplets that are touching begin to merge together, causing a loss of interface between t
antioxidants
incorporated to import the stability of the emulsion
inhibit oxidation
must be compatible with ingredients
emulsion preservatives
important for natural product carb emulsifying agents
combinations of methyl and propyl paraben are frequently employed
high water solubility is desired since growth occurs in aqueous phase