3 - Solubility Flashcards
Why is preparation of a solution dose form often problematic?
many drugs have limited water solubility
positive heat of solution = ?
increase solubility with increase in temperature
negative heat of solution = ?
decrease solubility with increase in temperature
solubility of a substance at a stated temp is a _____
constant
If something is very soluble, the amount of solvent required per part of solute = ?
<1
If something is practically insoluble the amount of solvent required per part of solute = ?
<10,000
Acidic drugs don’t ____ in acidic media
ionize
majority will be in unionized form
Basic drugs don’t ____ in basic media
ionize
majority will be in unionized form
Like dissolves ____
like
We would expect organic molecules to be more soluble in ______ solvents than water
organic
Molecules with functional groups like OH will confer ____ solubility to an organic molecule
water
Inorganic molecules - Water solubility:
-If both the cation and anion are ____ the compound is soluble.
monovalent
ex.
NaCl
LiBR
NH4NO3
(all of these have only a charge of +1 or -1)
Inorganic molecules - Water solubility:
If ___ of the ions in a salt is monovalent the compound is soluble.
one
ex.
BaCl2
Na2SO4
Na2PO4
(only one of the ions in a salt needs to be monovalent for it to be soluble)
Inorganic molecules - Water solubility:
If both the anion and cation are _____ the compound will have limited water solubility.
multivalent
ex.
CaSO4
BaSO4
exceptions:
ZnSO4
FeSO4
Inorganic molecules - Water solubility:
Salts of alkali metals (K, Na, Li, Cs) and ____ are water soluble.
ammonia
ex.
Na2CO3
Na2HPO4
LiSO4
exception
Li2CO3
Inorganic molecules - Water solubility:
nitrates, sulfates, and halides are ____ soluble
water
exceptions
AgCL2
BaSO4
Inorganic molecules - Water solubility:
_____ and _____ are not water solbule
hydroxides
oxides
(except for hydroxides and oxides with alkali metals and ammonium salts)
Inorganic molecules - Water solubility:
phosphates, carbonates, silicates, borates are all _____
insoluble
except for those with alkali metals and ammonium
Organic molecules - Water solubility:
Molecules have one POLAR functional group are usually soluble to chain lengths of ___ carbons
five
Organic molecules - Water solubility:
Molecules with ____ chains are more soluble than the corresponding ____ chain compound
branched > straight
Organic molecules - Water solubility:
Water solubility _____ with increasing molecular weight.
decreases
Generally a drug must be in solution before it is able to be ____ into the blood stream
absorbed
For liquid dose form ___ solubility is desirable so a dose of drug is in a reasonable volume.
water
FDA introduced ?? for oral drug products
biopharmaceutics classification system (BCS)
Explain BCS (biopharmaceutics classification system)
drugs are classified into four groups based on solubility and ability to permit membranes
When is a drug considered highly soluble?
When the highest dose strength is:
- soluble in <250 mL water
- soluble over a pH range of 1-7.5
- highly permeable when the extent of absorption is >90% of an administered dose
Explain Class I - IV for BCS
Class I:
- good solubility, good permeability
- few problems
Class II:
- bad solubility, good permeability
- rate-limiting step for bioavailability is solubility/dissolution
Class III:
- good solubility, bad permeability
- rate-limiting step for bioavailability is crossing biological membranes
Class IV:
- bad solubility, bad permeability
- drug has a lot of problems
What must the D:S (dose:solubility) ratio be for an oral dose ?
<250mL
* 100 mL volume would be okay to use as an oral dose form
*because stomach fluid is about 250 mL
What must the D:S (dose:solubility) ratio be for an eye drop dose ?
< 0.02 mL
*because lacrimal fluid is about 20 microL (0.02 mL)
What must the D:S (dose:solubility) ratio be for a nasal dose ?
<0.3 mL
*because nasal fluid is about 0.3mL
What must the D:S (dose:solubility) ratio be for a sublingual dose ?
<5 mL
What must the D:S (dose:solubility) ratio be for a vaginal tablet dose ?
<5 mL
What must the D:S (dose:solubility) ratio be for an inhaled dose ?
<0.5 mL
If a drug molecule contains _____ functional groups the solubility may be managed by controlling the ___ of the vehicle being used.
ionizable
pH
Most drug products are formulated between pH values of ___ for biocompatibility.
4-8
If a drug is ____ it is more water soluble
ionized
worse at crossing membranes
If a drug is more _____ it is insoluble in water
unionized
better at crossing membranes
see slide 26 fo sho
ok gangsta sam
What is a salt?
The product of an ionizable drug with an ionizable counter-ion of opposite charge.
(ionic compound)
Most common reason for using a salt form?
enhanced solubility?
leading to improved bioavailability?
-could be helpful in masking an unpleasant taste
For counter-ion selection, the pKa of the conjugate base should be ___ than the conjugate acid.
greater
difference of 3 or more pKa units is common
Explain the common-ion effect
Its when there is a reduction in solubility of a compound when putting it into a solution that contains one of the same ions as the compound.
ex. putting NaCl into the stomach (where gastric acid HCl is present)
- this reduces solubility of NaCl because there is already a lot of Cl- present.
As counter-ion [Cl-] increases the concentration of [H+] has to decrease to keep Ksp at a constant.
So the solubility of NaCl is decreased to the rate that [H=] is decreasing
When are cosolvents used?
when the parenteral drug product has limited water solubility
Examples of some cosolvents
glycerin
alcohol
propylene glycol
polyethylene glycol
_____ _____ and _____ are extremely toxic and must never be used in pharmaceutical products
ethylene glycol
methanol
Solubility is largely a function of what?
the polarity of the solvent
What do polar solvents dissolve?
ionic and other polar solutes
What do non-polar solvents dissolve?
non-polar solutes
What do semi-polar solvents (like alcohol) do?
they may induce a degree of polarity in non-polar molecules and improve their water solubility
What is the dielectric constant?
no units
a measure of the effect of solvent on potential energy of interaction between two charges
a measure of how effective the material is as an electrical insulator
the ability to keep two charges separate
Water as a very ____ dielectric constant
high
benzyl alcohol is toxic to ??
babies
____ products rarely contain cosolvents
ophthalmic products
too dangerous to use any products even with only small potential toxicity
What are surfactants?
molecules with polar and non-polar regions
Non-polar region of a surfactant is usually a ______ segment
hydrocarbon
Polar region of a surfactant is ??
may be anionic, cationic, or non-ionic
As [surfactant] increases the surfactant will associate into soluble structures known as _______
micelles
What is critical micelle concentration? (CMC)
the concentration where the micelles begin to form
complexing agents
involves incorporating drug within the completing agent so that the outer hydrophilic groups of the agent interact with water and make whole complex soluble
ex. caffeine benzoic acid mixture
ex. amphotericin-B complex with sodium cholesterol sulphate (lipid complex)
What are cyclodextrins?
molecules composed of 6, 7, or 8 glucopyranoside units joined through 1-4 bonds
Cyclodextrins have _____ interior
lipophilic
Cyclodextrins have _____ exterior
hydrophilic (due to hydroxyl groups)
