Lecture 2: Solubility

Question 1

Drugs must be in a solution form for

Answer 1

-absorption
-distribution
-reaching site of action
-elimination

Question 2

Solubility issues

Answer 2

-bodily fluids mostly aqueous
-most drugs hydrophobic
-many drugs hard to solubilize

Question 3

Factors reducing solubility

Answer 3

= difficulty of dislodging solute molecules from crystal + difficulty of solvating dislodged molecules

Question 4

Crystal

Answer 4

-strength makes it harder for solute molecules to dislodge
-even if mixed well, this gives difficult solubility

Question 5

Making a solution

Answer 5

-solid –> liquid by melting
-liquid –> solution by mixing solvent

Question 6

crystallinity

Answer 6

-solid –> liquid by “melting”
-difficulty of dislodging molecules from crystal
-(∆Hm/2.303RT)((Tm-T)/Tm)
-ideal solubility (log Xideal)

Question 7

Hydrophobicity

Answer 7

-liquid –> solution by “mixing” solvent
-difficulty of solvating molecules
- -log y

Question 8

Factors controlling solubility

Answer 8

log Xobs = -(∆Hm/2.303RT)((Tm-T)/Tm) -log y

Question 9

Graph of Solubility Equation

Answer 9

SLIDE 9
-Log Xobs = horizontal baseline
-Log Xideal= black box above baseline
- -log y = white box on top of black box to 0

Question 10

Breakdown of solubility contributions

Answer 10

Slide 10

Question 11

“like dissolves like”

Answer 11

-would be true if everything was liquid INSTEAD:
-higher melting point of solid = lower solubility

Question 12

Higher melting point

Answer 12

lower solubilty

Question 13

Dissolution

Answer 13

-end goal for drug
-solubility affects rate

Question 14

Noyes-Whitney Equation

Answer 14

(dC/dt) = DA/h (Cs-C)

Question 15

Tablet to tissue

Answer 15

tablet to GI tract to intestinal wall to systemic circulation to target tissue

Question 16

GI tract

Answer 16

-solubility/dissolution
-stability
sends to intestinal wall

Question 17

Intestinal wall

Answer 17

-permeability
-stability
sends to circulation

Question 18

Systemic Circulation

Answer 18

-first-pass
-metabolism/clearance
sends to target tissue

Question 19

Drug factors that affect dissolution rate

Answer 19

-solubility (change in Cs)
-particle size (change in A)
-pH
-types of solid (salts, hydrates, polymorphs, amorphous)

Question 20

Dosage form factors that affect dissolution rate

Answer 20

-all the listed drug factors
-disintegration rate
-excipients
-variation in manufacturing conditions

Question 21

increase solubilizing excipient use (increase Cs)

increase solubility

Answer 21

increase dissolution

Question 22

Increase surface area (A)

Answer 22

increase dissolution

Question 23

Combined effect of solubilizing excipient and particle size reduction on bioavailability

Answer 23

dissolves more quicker

Question 24

Effect of pH on solubility and dissoulution

Answer 24

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

Question 25

Salt formation

Answer 25

-over 50% of drugs -easiest way to increase solubility

Question 26

salt formation from acidic drug

Answer 26

-made by crystallizing it from a solution where pH>pKa of drug

Question 27

salt formation from basic drug

Answer 27

-made by crystallizing drug in solution where pH

Question 28

Spring and parachute effect

Answer 28

dissolution of salt spikes until converted to free acid then falls until leveled out to solubility of free acid SLIDE 29

Question 29

Complexation

Answer 29

drug molecule forming complex with cyclodextrin molecule

Question 30

Complexation equation

Answer 30

Kc = [D-CD] / [D][CD] -equilibrium

Question 31

Cosolvents

Answer 31

-affects solubility in a log-linear relationship -can only change -log y part of solubility equation -moves the entire box up??

Question 32

"brick dust" limitation

Answer 32

must disrupt the orderly crystal structure

Question 33

amorphous form

Answer 33

-more soluble and faster dissolution -generated by getting drug into liquid form and solidifying quickly so there is no time for crystallization

Question 34

Drugs need to be ____ in the aqueous bodily fluids in order to work

Answer 34

solubilized

Question 35

drugs with ___ aqueous solubility are more the rule than the exception

Answer 35

low

Question 36

Drug solubility dependent on:

Answer 36

1. crystallinity (brick dust) 2. hydrophobicity (wax)

Question 37

___ impacts ____ rate but is not the only factor to do so

Answer 37

solubility, dissolution

Question 38

____ is the simplest way of changing dissolution without changing solubility

Answer 38

Particle size

Question 39

Solubility can be changes by:

Answer 39

-pH in liquid prep -pH through salt formation in solids -complexation -cosolvents

Question 40

For really stubborn “brick dust” drugs or when hitting the brick wall with cosolvents, disrupting the ___________ becomes necessary

Answer 40

crystal (amorphous formulations)