Section 3 - Solubility Flashcards
What makes preparation of a solution dose form problematic?
Drugs with limited water solubility
What causes many drugs to have limited water solubility?
Molecules interact with repulsive forces, which prevent molecular interpenetration, and attractive forces, which cause molecules to cohere
What happens when attractive and repulsive forces are in eq’m?
The potential energy between the 2 molecules is minimal and the system is most stable
What is the solubilization theory?
In the process of dissolution, both the solute-solute and solvent-solvent bonds must be broken to allow the formation of solute-solvent bonds
What happens in bond breaking with respect to energy?
- Energy is required
- Breaking of bonds will absorb heat
What happens in bond formation with respect to energy?
Evolution of heat
Most dissolution processes show net effect of _____ heat
Absorbing
How can you increase solubility?
Increase temp.
What is an example of a drug that shows a decrease in solubility with an increase in temp?
Calcium citrate
The solubility of any substance at a stated temperature is _____
Constant
A solubility less than __% is considered insoluble
1%
What does solubility depend on for molecules with ionizable functional groups?
pH of the solvent
What are barbiturates?
- Weak acids with low solubility
- Form water soluble salts at alkaline pH
What situation causes a barbiturate to come out of solution?
If the pH of a solution of one of the water soluble salts is lowered by the addition of acid
The sodium salt of phenobarbital has a solubility of about 1 g in __ mL
1
The free acid phenobarbital has a solubility of about 1 g in ____ mL
1000
How can you predict solubility in a general way?
- Molecular structure
- Functional groups
- Physicochemical properties of the solute and solvent
What does “like dissolves like” mean?
A solvent w/ a chemical structure or functional groups similar to the solute will most likely dissolve it
Organic molecules are generally more soluble in ____ solvents than water
Organic
What will addition of a polar functional group (such as -OH) do to the water solubility of an organic molecule?
It will increase water solubility of an organic molecule
What is the rule for water solubility of an inorganic molecule if both the cation and anion are monovalent and why?
- The compound is soluble
- B/c solute-solute forces are easily overcome
What is the rule for water solubility of an inorganic molecule if one of the ions in a salt is monovalent?
The compound is soluble
What is the rule for water solubility of an inorganic molecule if both the anion and cation are multivalent and why? What are the exceptions?
- The compound will have limited water solubility b/c the solute-solute forces are too great to be easily overcome by solute-solvent interactions
- Exceptions - ZnSO4 and FeSO4
What is the rule for water solubility of an inorganic molecule if it is a salt of alkali metals and ammonia and what is the exception?
- Water soluble
- Exception - Li2CO3
Are nitrates, sulfates, and halides water soluble? What are the exceptions?
- Yes
- Exceptions - AgCl2, BaSO4
Are hydroxides and oxides water soluble? What are the exceptions?
- No
- Exceptions - alkali metals and ammonium salts
Are phosphates, carbonates, silicates, and borates water soluble? What are the exceptions?
- No
- Exceptions - salts of alkali metals and ammonium
What is the rule for water solubility of an organic molecule if the molecule has one polar functional group?
Usually soluble up to a chain length of 5 carbons
What is the rule for water solubility of an organic molecule if the molecule has a branched chain?
More soluble than the corresponding straight chain compound
For organic solubility, what is the relationship between water solubility and molecular weight?
Inverse (solubility decreases with increasing molecular weight)
Generally, a drug must be _____ before it is able to be absorbed into the bloodstream
In solution
What determines how much of a drug is available for absorption?
- Dose
- Solubility
- Dissolution rate
For a liquid dose form, is water solubility desirable?
Yes
For a suspension, is water solubility desirable?
It is desirable to reduce solubility, provided bioavailability is not affected
What is the Biopharmaceutics Classification System (BCS)?
A classification for oral drug products into 4 groups based on solubility and ability to permeate membranes
What is needed for a drug to be considered highly soluble under the BCS?
The highest dose strength must be soluble in less than 250 mL water of a pH range of 1-7.5
What is needed for a drug to be considered highly permeable under the BCS?
When the extent of absorption is over 90% of an administered dose
What are class 1 drugs under BCS?
Highly soluble and highly permeable (present few problems)
What are class 2 drugs under BCS?
Low solubility and high permeability
What are class 3 drugs under BCS?
High solubility and low permeability
What are class 4 drugs under BCS?
Low solubility and low permeability (present problems)
What is the rate-limiting step for bioavailability for class 2 drugs under BCS?
Solubility/dissolution
What is the rate-limiting step for bioavailability for class 3 drugs under BCS?
Crossing biological membranes
What is the required dose:solubility ratio (D:S) for a drug that will enter the stomach?
Under 250 mL b/c the volume of stomach fluid is about 250 mL, so the dose must be soluble in that volume
What is the required dose:solubility ratio (D:S) for a drug that will enter the eye?
Under 0.02 mL b/c the lacrimal fluid volume is about 20 uL
What is the required dose:solubility ratio (D:S) for a drug that will enter the nose?
Under 0.3 mL b/c the volume of nasal fluid is about 0.3 mL
How can solubility be altered for a drug molecule that contains ionizable functional groups?
By altering the pH of the vehicle being used
Most drug products are formulated between pH values of ___ and ___ for ____
4 and 8 for biocompatibility
How is formulation pH determined?
From pH-solubility and pH-rate profiles of the drug
Generally, when a drug is in ionized form it is ____ soluble
Water
What determines the extent a molecule is ionized?
- pH of the medium
- pKa of the drug
What can the Henderson-Hasselbalch equation help you calculate with respect to solubility?
- pH of maximum solubility
- pH at which precipitation occurs
What is generally the target formulation pH?
+/- 1 pH unit from the pH of maximal solubility
What must be considered when buffers are used and why?
- Must consider the stability of the drug
- Some buffer species may accelerate degradation
What is a salt?
The product of an ionizable drug with an ionizable counterion of opposite charge
What can salt formation alter of a drug?
- Physicochemical properties
- Biopharmaceutical properties
- Processing properties
What will salt formation NOT alter?
- Fundamental chemical structure
- Corresponding pharmacology
Salt formation is an easy way to overcome ____
Undesirable properties of the parent drug
Salts will differ from their parent drug and from each other in properties such as ____
- Melting point
- Solubility
- Dissolution rate
- Hydroscopicity
- Stability
- Crystal form
- Solution pH
- Organoleptic properties (like taste)
What is the most common reason for using a salt?
To improve bioavailability
When would reduced solubility be desired?
- Some sustained release products
- Masking an unpleasant taste
What should you consider when choosing a counter-ion for a salt?
The pKa of the conjugate base should be greater than the conjugate acid by at least 3 pKa units
What is Ksp?
The concentration of the drug [A+] times the concentration of the counter-ion [B-]
How can Ksp be kept constant if the counter-ion concentration is increasing?
Drug concentration in solution must decrease
The advantage of increased solubility may be offset if the salt is _____
Hydroscopic
What is polymorphism?
The property where a compound can exist in 2 or more crystalline forms
What is pseudopolymorphism?
Where solvent molecules are incorporated into the lattice, usually when the drug is purified using recrystallization
Is the dissolution rate faster in a salt or its parent molecule and why?
Salt b/c it can act as its own buffer in the diffusion layer
Is the pharmacology of a parent drug usually changed when a salt is formed?
No
What are some examples of atoms that shouldn’t be used as counter-ions and why?
- Lithium, aluminum, bromide, iodides, and salicylates
- They have pharmacologic activities, which may lead to the potential for toxicity
What are examples of products that may be used as cosolvents for parenteral products with limited water solubility and why?
- Glycerin
- Alcohol
- Propylene glycol
- Polyethylene
- May provide exponential increases in solubility and they allow reduction of water content for products susceptible to hydrolysis
Which cosolvents are extremely toxic and shouldn’t be used in pharmaceutical products?
- Ethylene glycol
- Methanol
How is selection and quantity of cosolvent determined?
- Route of administration
- Rate of administration
- Nature of the patient
What happens to solubility when volume fraction of cosolvent is increased?
Solubility increases logarithmically
Solubility is largely a function of ____
The polarity of the solvent
What do polar solvents dissolve?
Ionic and other polar solutes
What do semi-polar solvents do to non polar molecules?
May induce a degree of polarity and improve their water solubility
What is a dielectric constant?
- A measure of the effect of a solvent on the potential energy of interaction between 2 charges
- Measure of how effective the material is as an electrical insulator (its ability to keep two charges separate)
What is the unit for dielectric constants?
No units
How can you determine the dielectric constant of a solvent mixture?
Multiply the volume fraction of each solvent by its respective dielectric constant and sum
Why are there only a few cosolvents that are suitable for use?
Toxicity concerns
What are common side effects of most cosolvents?
- Local irritation
- Hemolysis
- Tissue damage
What is important to note about benzyl alcohol as a cosolvent?
Toxic to neonates
_____ products rarely contain cosolvents
Ophthalmic
For parenterals, the quantity of ethanol rarely exceeds ___%
10%
For parenterals, the quantity of propylene glycol rarely exceeds ___%
40%
For parenterals, the quantity of PEG rarely exceeds ___%
50%
What can result from dilution of a product prepared with cosolvents?
The drug may come out of solution
How can cosolvents stabilize a drug subject to hydrolysis?
Reduce the amount of water present
How do cosolvents affect reaction rates?
Shift the eq’m between reactants and the transition state
What effect will increased polarity of the solvent have on a solution in which the transition state is more polar than the reactants?
Increase reaction rate
What effect does increasing the ionic strength of a solution have on polarity?
Will generally increase polarity
Which dose form are surfactants used to formulate?
Parenteral
What are surfactants?
Molecules w/ distinct polar and non-polar regions
What is normally the non-polar region of a surfactant?
A hydrocarbon segment
What is normally the polar region of a surfactant?
- Anionic (carboxylate or sulfonate)
- Cationic (trialkylammonium or ammonium)
- Non-ionic (PEG, glycerol, sugar)
What happens as concentration of surfactant increases?
The surfactant will associate into soluble structures called micelles
What is the critical micelle concentration?
The concentration at which micelles begin to form
Are micelles soluble?
Yes
What are drawbacks to surfactants?
- Can cause extreme irritation and damage to tissues
- Can cause systemic toxicity in children and newborns
What are the only 3 surfactants used in formulating parenterals?
- Polysorbate-80 (Tween)
- Polyethoxylated fatty alcohol (Cremophor EL)
What is a complexing agent used for?
Drugs are incorporated within a complexing agent so that the outer hydrophilic groups of the agent interact w/ water and make the whole complex soluble
What are cyclodextrins?
Molecules composed of 6, 7, or 8 glucopyranoside units joined through 1-4 bonds
What causes the exterior of a cyclodextrin to be hydrophilic?
Hydroxyl groups
What can complex with the interior of a cyclodextrin?
A lipid-soluble drug molecule
