An introduction to the principles of solubility

Question 1

Most of the drugs pharmacists deal with are in a solid-dosage form- taken orally

When formulating a drug, two essential concepts need to be considered: its solubility and stability

Question 2

Definition of a solution (two):

How must a solution appear?

Answer 2

A solution is a mixture of at least two components one of which is a solute (e.g. drug or Active Pharmaceutical Ingredient (API)) and, the other a solvent (e.g. water).

A solution is a system in which molecules of solutes are dispersed in a solvent vehicle.

Solution must be clear

(Solid particles in water (suspensions) do not match this definition.)

Question 3

What is dissolution?

Answer 3

The transfer of molecules from the solid state to the liquid state is called the dissolution.

Question 4

What is solubility? (2 defiitions)

Answer 4

The extent of which dissolution happens is called the solubility; thus, the solubility can be defined as the amount of a chemical substance that passed in solution at the equilibrium.

(solubilty is the extent to which molecules transfer from solid to liquid state)

(dissolution - transfer of molecules from the solid state to the liquid state)

Question 5

Why is solubility important?

At a given temperature and pressure, when the solubility limit is reached what is the solution said to be?

What happens if you try to add more of the solid drug after this?

Answer 5

Solubility is important because it dictates the rate of dissolution.

At a given temperature and pressure, when the solubility limit is reached: the solution is saturated. Subsequent addition of solid drug will not dissolve and the solution is said to be supersaturated.

Question 6

The solubility of a chemical substance is a concentration.

The British Pharmacopoeia and other pharmaceutical compendia often uses solubility in parts per parts of solvent.
Also find “insoluble”, “poorly soluble” and “soluble”.

The solubility can always be measured and quoted precisely (usually molarity). Other units may be used (percentages, molarity, molality, equivalents, mole fraction):

Question 7

Very soluble
- Approximate volume of solvent (mL) necessary to dissolve 1g of solute (at a temperature between 15 °C and 25 °C)
= Less than 1 mL
- Solubility range= at least 1000

Freely soluble
Approximate volume of solvent (mL) necessary to dissolve 1g of solute
= 1 to 10
- Solubility range= 100 to 1,000

Soluble
Approximate volume of solvent (mL) necessary to dissolve 1g of solute
=10 to 30
- Solubility range= 33 to 100

Sparingly soluble
Approximate volume of solvent (mL) necessary to dissolve 1g of solute
= 30 to 100
- Solubility range= 10 to 33

Slightly soluble
Approximate volume of solvent (mL) necessary to dissolve 1g of solute
= 100 to 1000
- Solubility range 1 to 10
- Parts per million Ppm = 1,000 - 10,000

Very slightly soluble
Approximate volume of solvent (mL) necessary to dissolve 1g of solute
= 1000 to 10,000
- Solubility range= 0.1 to 1
- Ppm = 100 to 1,000

Practically insoluble or insoluble
Approximate volume of solvent (mL) necessary to dissolve 1g of solute
= more than 10,000
- Solubility range= Less than 0.1
- Ppm = <100

(Look at notes for the table)

Question 8

Solubility process:

Describe the solubility process- give the molecular aspects summary

Answer 8

Molecular aspects summary:
- Need to remove a drug molecule from a crystal/solid particle
- Create a hole in the solvent (not favourable- disrupted water molecule network)
- Insert the drug molecule (solute) in the solvent
- Create interaction between solvent and solute

Question 9

Solvent:

Why is water partially organised?

What is created to dissolve a solute and what is required for this?

Discuss the effect of surface area of the compound

Answer 9

Water is partially organised due to H-bonds

A cavity is created (in water) - creating a cavity requires energy

The larger the surface area of the compound, the larger the cavity needed, the lower the solubility i.e., the solubility decreases with the surface area of the compound

Question 10

What is solubility affected by?

Answer 10

Solubility will be affected by:

• Solid state of the drug (amorphous, crystalline)
• Polymorph type (the way molecules are organised in a crystal)
  ○ Molecules can be tight together and it is harder to pull a molecules out from this structure so the solubility is lower
• Salts and counter ions/ common ion effect
• Composition of the aqueous media (composition of buffer)
• pH (buffer components)
• Ionic strength of the solution
• Temperature: an increase in temperature usually results in an increase in solubility but it is not always true

Question 11

Solubility is an essential parameter for drug delivery.

What kind of molecules have larger aqueous solubility?
(which type of molecules are more soluble in water?)

Answer 11

Aqueous solubility is larger with polar, charged molecules.

Ionised species are more soluble in water than unionised species.

Question 12

Solubility of a weakly acidic or basic drug

There are many of these Henderson Hasselbach equations
Don’t need to know/memorise them.
Helpful to know
The Henderson-Hasselbach (already seen for ionisation) equations are defined as:

Answer 12

Acid:
pH − pKa = log((S−S_0)/S_0 )
logS = logS_0 + log⁡(10^(pH−pKa) + 1)

Base:
pH − pKa = log(S_0/(S−S_0 ))
logS = logS_0 + log⁡(10^(pKa−pH) +1)

S is the concentration of the charged and uncharged species of the drug

S0 or (S_0) is the concentration of the uncharged species of the drug

Question 13

Reminder

For acid
If pH is pKa - 2 you have 99% unionised species
If pH is pKa -1 you have 90% unionised species
If pH is equal to pKa you have 50% unionised species
If pH is pKa +1 you have 10% unionised species
If pH is pKa +2 you have 1% unionised species

Question 14

Values to remember

For acid
At pH = pKa - 2
Solubility is about the solubility of ionised species
(logS ≈ logS_0 )

At pH = pKa + 2
logS = logS_0 + 2

For Base
At pH = pKa - 2
logS = logS_0 + 2

At pH = pKa + 2
logS ≈ logS_0

Question 15

Look at notes for diagram

Question 16

What are amphoteric drugs?

Name a few examples.

Answer 16

Amphoteric drugs are drugs that have both positive and negative charges and depending on pH can be zwitterionic.

Zwitterion- molecules contains a positive and negative charge. Charges cancel out to make the substance neutral.

Examples of amphoteric drugs: Acyclovir, Doxycycline, Daunorubicin, Ganciclovir, Sulfadiazine –more and more common with biologics (e.g. mAbs, peptides).

Question 17

What is the isoelectric point?

How do you calculate Isoelectric point (pI)?

Answer 17

The pH at which a molecule has no net electrical charge

pI = (pKa_1 + pKa_2) / 2

Question 18

Ampicillin (2 pKas: 2.66 and 7.25): solubility changes with pH
Isoelectric point, pI:

pI = (pKa_1 + pKa_2) / 2 =
(2.66 + 7.25) / 2 = 4.96

Question 19

For amphoteric drugs, which pH will its solubility be at its lowest?

Answer 19

At its isoelectric point

Question 20

Diagram (in notes)

Question 21

The solubility of amphoteric drugs:

At the isoelectric point what is the overall charge of an amphoteric drug and what would it be called?

At a pH less or more than the isoelectric point, how does the drug behave?

How is solubility determined in each case?

Answer 21

At the isoelectric point (pI) the overall charge is zero, the molecule is called a zwitterion,

At a pH less than the pI, the drug behaves as a base (proton acceptor), BH + H+ –> BH+

At pH more than pI, the drug behaves as an acid (proton donor), HA –> A- + H+

In each case the solubility is determined with the previous formulae.

Question 22

Diagram (in notes)

Question 23

Only uncharged/unionised molecules can cross the membrane however in order for this to happen you need to have your drug in solution.

You only have your drug in solution if it is at a pH at which it will be in solution (so often means pH at which it is ionised).

There needs to be a balance between ionised and unionised.

Question 24

Why are drugs often formulated as salts?

Answer 24

Drugs are often formulated as salts to improve their solubility.

e.g. Sodium naproxate (very soluble) instead of Naproxen (not very soluble)

Question 25

Why can choosing the appropriate salt be a very difficult task?

Answer 25

Choosing the appropriate salt can be a very difficult task, since each salt influences physicochemical properties of the parent compound i.e., dissolution rate, solubility, stability, hygroscopy and, hence, bioavailability.

Hygroscopy- drug can be more prone to attracting water molecules and this can lead to the destabilisation of your drug.

Question 26

Most commonly used salts are:

Anions: hydrochloride> sulfate> bromide> chloride> phosphate> maleate> citrate> acetate (for base)

Cations: Sodium»Potassium~calcium>zinc (for acid)

Question 27

Salting in salting out effect:

What kind of salts is this effect observed in?

Answer 27

• Observed for inorganic salts such as AgCl
• Low solubility of silver
• Solubility product, Ksp, is a constant
  Ksp = [Ag+ ][Cl− ]
• If NaCl is added in the solution, common ion effect.
  (Cl- concentration increases, so Ag+ concentration decreases as Ksp is a constant)

Concept valid for hydrochloride salts of drugs:
the presence of high amount of salts forces out of solution some of the drug (precipitation), e.g. ephedrine hydrochloride – valid for gastric juices but also during preparation when making solutions isotonic.