Lecture 2: Solubility Flashcards
Drugs must be in a solution form for
-absorption
-distribution
-reaching site of action
-elimination
Solubility issues
-bodily fluids mostly aqueous
-most drugs hydrophobic
-many drugs hard to solubilize
Factors reducing solubility
= difficulty of dislodging solute molecules from crystal + difficulty of solvating dislodged molecules
Crystal
-strength makes it harder for solute molecules to dislodge
-even if mixed well, this gives difficult solubility
Making a solution
-solid –> liquid by melting
-liquid –> solution by mixing solvent
crystallinity
-solid –> liquid by “melting”
-difficulty of dislodging molecules from crystal
-(∆Hm/2.303RT)((Tm-T)/Tm)
-ideal solubility (log Xideal)
Hydrophobicity
-liquid –> solution by “mixing” solvent
-difficulty of solvating molecules
- -log y
Factors controlling solubility
log Xobs = -(∆Hm/2.303RT)((Tm-T)/Tm) -log y
Graph of Solubility Equation
SLIDE 9
-Log Xobs = horizontal baseline
-Log Xideal= black box above baseline
- -log y = white box on top of black box to 0
Breakdown of solubility contributions
Slide 10
“like dissolves like”
-would be true if everything was liquid INSTEAD:
-higher melting point of solid = lower solubility
Higher melting point
lower solubilty
Dissolution
-end goal for drug
-solubility affects rate
Noyes-Whitney Equation
(dC/dt) = DA/h (Cs-C)
Tablet to tissue
tablet to GI tract to intestinal wall to systemic circulation to target tissue
GI tract
-solubility/dissolution
-stability
sends to intestinal wall
Intestinal wall
-permeability
-stability
sends to circulation
Systemic Circulation
-first-pass
-metabolism/clearance
sends to target tissue
Drug factors that affect dissolution rate
-solubility (change in Cs)
-particle size (change in A)
-pH
-types of solid (salts, hydrates, polymorphs, amorphous)
Dosage form factors that affect dissolution rate
-all the listed drug factors
-disintegration rate
-excipients
-variation in manufacturing conditions
increase solubilizing excipient use (increase Cs)
increase solubility
increase dissolution
Increase surface area (A)
increase dissolution
Combined effect of solubilizing excipient and particle size reduction on bioavailability
dissolves more quicker
Effect of pH on solubility and dissoulution
low until big spike up at pH 8 (or maybe close to pka??) and as pH increases from 8 dissoultion stops and solubility levels off
Salt formation
-over 50% of drugs
-easiest way to increase solubility
salt formation from acidic drug
-made by crystallizing it from a solution where pH>pKa of drug
salt formation from basic drug
-made by crystallizing drug in solution where pH<pKa of drug
Spring and parachute effect
dissolution of salt spikes until converted to free acid then falls until leveled out to solubility of free acid SLIDE 29
Complexation
drug molecule forming complex with cyclodextrin molecule
Complexation equation
Kc = [D-CD] / [D][CD]
-equilibrium
Cosolvents
-affects solubility in a log-linear relationship
-can only change -log y part of solubility equation
-moves the entire box up??
“brick dust” limitation
must disrupt the orderly crystal structure
amorphous form
-more soluble and faster dissolution
-generated by getting drug into liquid form and solidifying quickly so there is no time for crystallization
Drugs need to be ____ in the aqueous bodily fluids in order to work
solubilized
drugs with ___ aqueous solubility are more the rule than the exception
low
Drug solubility dependent on:
- crystallinity (brick dust)
- hydrophobicity (wax)
___ impacts ____ rate but is not the only factor to do so
solubility, dissolution
____ is the simplest way of changing dissolution without changing solubility
Particle size
Solubility can be changes by:
-pH in liquid prep
-pH through salt formation in solids
-complexation
-cosolvents
For really stubborn “brick dust” drugs or when
hitting the brick wall with cosolvents, disrupting the
___________ becomes
necessary
crystal (amorphous formulations)
