Solubility

Question 1

What is the solubilization theory?

Answer 1

In the process of dissolution, both the solute-solute and the solvent-solvent bonds must be broken to allow the formation of solute-solvent bonds. In bond breaking, energy is required and breaking of bonds will absorb heat. Formation of solute-solvent bonds is usually accompanied by the evolution of heat

Question 2

How does temperature affect solubility?

Answer 2

Most dissolution processes show net effects of absorbing heat, have positive heat of solution and increase solubility with increase in temperature
Some chemicals have a negative heat of solution (e.g., calcium citrate) and show a decrease in solubility with an increase in temperature.
The solubility of any substance at a stated temperature is a constant

Question 3

Besides temperature, what other factors affect solubility?

Answer 3

Physiochemical properties of the solute and the solvent

pH of the solution

Question 4

Many medicinal molecules contain ionizable functional groups and the solubility depends on the pH of the solvent. Explain

Answer 4

Barbiturates are weak acids with low solubility but form water soluble salts at alkaline pH
If the pH of a solution of one of these water soluble salts is lowered by the addition of acid, the free barbiturate will begin to come out of solution
The sodium salt of phenobarbital has a solubility of about 1 g in 1 ml whereas the solubility of the free acid phenobarbital has a solubility of about 1 g in 1000 ml

Question 5

How can solubility be predicted?

Answer 5

It can be predicted in a general way from the molecular structure, functional groups and physiochemical properties of the solute and solvent

Question 6

Explain the term “like dissolves like”

Answer 6

A solvent with a chemical structure or functional groups similar to the solute will most likely dissolve it

Question 7

Describe the water solubility of inorganic molecules

Answer 7

1. If both the cation and anion are monovalent, the compound is soluble (NaCl, LiBr, NH4NO3)
2. If one of the ions in a salt is monovalent the compound is soluble (BaCl2, Na2SO4, Na3PO4)
3. If both the anion and cation are multivalent, the compound will have limited water solubility (CaSO4, BaSO4 - exceptions ZnSO4, FeSO4)
4. Salts of alkali metals (K, Na, Li, Cs) and ammonia are water soluble (Na2CO3, Na2HPO4, LiSO4 - exception Li2CO3)
5. Nitrates, sulfates, and halides are water soluble (exception AgCl2, BaSO4)
6. Hydroxides and oxides except for alkali for metals ammonium salts are not water soluble
7. Phosphates, carbonates, silicates and borates are insoluble except for salts of alkali metals and ammonium

Question 8

Describe the water solubility of organic molecules

Answer 8

1. Molecules having one polar functional group are usually soluble to chain lengths of five carbons
2. Molecules with branched chains are more soluble than the corresponding straight chain compound
3. Water solubility decreases with increasing molecular weight

Question 9

Why is solubility important in pharmaceutics?

Answer 9

Generally a drug must be in solution before it is able to be absorbed into the bloodstream. Solubility is important because the dose, its solubility and dissolution rate determine how much is available for absorption

Question 10

Why is high water solubility desired for liquid dose forms?

Answer 10

So the dose of the drug is in a reasonable volume

Question 11

The FDA introduced a Biopharmaceutics Classification System (BCS) for oral drug products. What does it do?

Answer 11

Drugs are classified into four groups based on solubility and ability to permeate membrane
A drug is considered highly soluble when the highest dose strength is soluble in less than 250 ml of water over a pH range of 1-7.5 and highly permeable when the extent of absorption is more than 90% of an administered dose

Question 12

What are the classes of BCS?

Answer 12

Class I: soluble and permeable (these drugs present few problems)
Class II: permeable (the rate-limiting step is solubility/dissolution)
Class III: soluble (the rate-limiting step is crossing biological membranes)
Class IV: neither soluble nor permeable (these drugs present a problem)

Question 13

BCS is designed for solid oral products but can be applied to other dosage forms. Explain.

Answer 13

Volume of the stomach fluid is about 250 ml so the dose must be soluble in that volume; the dose:solubility ratio (D:S) must be less than 250 ml
For an eyedrop, lacrimal fluid volume is about 20 ul, so the D:S must be less than 0.02 ml
Volume of nasal fluid is about 0.3 ml so D:S must be less than 0.3 ml
With parenteral products or drugs to be given by injection, we may be restricted by practical volumes so SC or IM not reasonable

Question 14

How can pH be used to manage solubility?

Answer 14

If a drug molecule contains ionizable functional groups, solubility may be managed by controlling the pH of the vehicle being used. Most drug products are formulated between pH values of 4-8 for biocompatibility. The pH at which most products are formulated is determined from pH-solubility and pH-rate profiles of the drug

Question 15

How do ionized groups affect solubility? What is ionization dependant on?

Answer 15

Generally when drug is in its ionized form, it is water soluble and when it is in the unionized state, it is insoluble in water. The extent the molecule is ionized is dependant on the pH of the medium and the pKa of the drug

Question 16

How do you calculate the solubility of an acidic compound?

Answer 16

Solubility = the inherent solubility of the unionized form * (1 + 10^pH-pKa)

Question 17

How do you calculate the solubility of a basic compound?

Answer 17

Solubility = the inherent solubility of the unionized form * (1 + 10^pKa-pH)

Question 18

What is a salt?

Answer 18

A salt is the product of an ionizable drug with and ionizable counter ion of opposite charge
Salts will differ from parent drug and from each other in properties such as melting point, solubility, dissolution rate, hydroscopicity, stability, crystal form, solution pH and organoleptic properties like taste

Question 19

How can salt forms be used to manage solubility?

Answer 19

Salt formation can alter physiochemical, biopharmaceutical and processing properties of a drug without modifying its fundamental chemical structure and corresponding pharmacology
It can be an easy way to overcome some undesirable property of the parent drug

Question 20

Why is enhancing solubility important? Why would we not want to enhance solubility?

Answer 20

Often enhanced solubility leads to improved bioavailability. This is the most common reason for using a salt form but sometimes reduced solubility is desirable (sustained release products, helpful for stability or masking unpleasant taste)

Question 21

When selecting the counter-ion, what should the pKa of the base be?

Answer 21

The pKa of the conjugate base should be greater than the conjugate acid (difference of 3 or more pKa units is common)

Question 22

Why can hydroscopicity be problematic?

Answer 22

Hydroscopicity may be a problem in terms of product stability so advantage of increased solubility may be offset if the salt is hydroscopic

Question 23

Is solubility from salt forms sole due to pH effects?

Answer 23

No, often larger than expected, it is due to interactions between drug, counter-ion and solvent

Question 24

What else needs to be considered when selecting salt

Answer 24

Polymorphisms and pseudopolymorphisms

Question 25

Which is quicker: the dissolution rate of the salt or the parent drug?

Answer 25

The dissolution rate of the salt is usually faster than the parent drug because the salt can act as its own buffer in the diffusion layer

Question 26

Does the pharmacology of the parent drug change when it is in a salt form?

Answer 26

Usually pharmacology of the parent drug is unchanged when it’s a salt, but some counter-ions may not be suitable
If it has pharmacologic activities, it may have the potential for toxicity (e.g., lithium, aluminum, bromide, iodides, salicylate)

Question 27

What are cosolvents?

Answer 27

Glycerin, alcohol, propylene glycol and polyethylene glycol may be used as cosolvents for parenteral drug products with limited water solubility
It may provide exponential increases in solubility and they allow reduction of water content for products susceptible to hydrolysis

Question 28

Should ethylene glycol and methanol be used as cosolvents?

Answer 28

Ethylene glycol and methanol are extremely toxic and must never be used in pharmaceutical products

Question 29

How are co-solvents selected?

Answer 29

Selection and quantity of cosolvent is based on experimentation
In most cases, there is a logarithmic increase in solubility with increasing volume fraction of cosolvent
Solubility of drug of a drug is determined for a range of cosovlent fractions and an equation may be written to describe solubility in a binary solvent system

Question 30

Solubility is largely a function of the polarity of the solvent. Explain

Answer 30

It may be polar, semi-polar and non-polar
Polar solvents dissolve ionic and other polar solutes while non-polar solvents will dissolve non polar solutes
Semi-polar solvents like alcohol may induce a degree of polarity in non-polar molecules and improve their water solubility

Question 31

What is the dielectric constant?

Answer 31

The dielectric constant (epsilon) is a measure of the effect of a solvent on the potential energy of interaction between two charges or a measure of how effective the material is an electrical insulator (i.e., it’s ability to keep two charges separate)
There are no units

Question 32

How is the dielectric constant determined?

Answer 32

The dielectric constant of a solvent mixture can be determined by multiplying the volume fraction of each solvent by its respective dielectric constant and summing

Question 33

What is the problem with most cosolvents (with regard to safety)?

Answer 33

Due to toxicity concerns, few cosolvents are suitable for use and there are limitations as to how much can be used.
Most can cause local irritation, hemolysis and tissue damage and benzyl alcohol, which is a preservative with cosolvent properties, is toxic to neonates

Question 34

Do ophthalmic products contain cosolvents?

Answer 34

Ophthalmic products rarely contain cosolvents; otic preparations may contain glycerin, polyethylene glycol (PEG) and propylene glycol

Question 35

Do parenteral products contain cosolvents?

Answer 35

For parenterals, the quantify of ethanol rarely exceeds 10%, propylene glycol 40% and PEG 50%

Question 36

What is an issue with cosolvents?

Answer 36

Dilution of a product prepared with cosolvents may result in the drug coming out of solution.
It has been suggested as a cause for phlebitis when these products are given IV and tissue damage with erratic absorption when given IM

Question 37

What is a benefit of cosolvents?

Answer 37

Cosolvents may stabilize a drug subject to hydrolysis by reducing the amount of water present

Question 38

How do cosolvents affect the reaction rate?

Answer 38

Cosolvents affect the reaction rates by shifting the equilibrium between reactants and the transition state
If transition state or activated complex is more polar (ionized) than the reactants, increasing the polarity of the solvent will increase reaction rates; decreasing polarity of the solvent will slow the reaction rate

Question 39

What are surfactants?

Answer 39

Within limits, they may be used to formulate parenteral dose forms
Surfactants are molecules with polar and non polar regions
Non-polar region is usually a hydrocarbon segment and the polar region may be anionic (carboxylate or sultanate), cationic (trialkylammonium or ammonium) or non-ionic (PEG, glycerol or sugar)
Polar region will interact with water and the non-polar region will interact with the non-polar solute

Question 40

What is the critical micelle concentration?

Answer 40

As concentration of surfactant increases the surfactant will associate into soluble structures known as micelles
The concentration where these begin to form is know as the critical micelle concentration (CMC)

Question 41

What should be considered when using surfactants?

Answer 41

There are practical limits for how much surfactant can be used.
It can cause extreme irritation and damage to tissues and systemic toxicity in children and newborns.
Only polysorbate-80 (Tween) and polyethoxylated fatty alcohol (Cremophor EL) are used in formulating parenterals

Question 42

What are complexing agents?

Answer 42

Involves incorporating drug within the complexing agent so that outer hydrophilic groups of the agent interact with water and make whole complex soluble
Early example: caffeine-benzoic acid mixture, amphotericin-B complex with sodium cholesteryl sulfate (lipid complex)

Question 43

What are cyclodextrines?

Answer 43

Cyclodextrines are molecules of 6, 7 or 8 glucopyranoside units joined through 1-4 bonds
The interior is lipophilic while the exterior is hydrophilic due to hydroxyl groups
Lipid-soluble drug molecule that can complex with the interior of the cyclodextrin and the whole complex is water soluble