Pharmacy and Biotechnology

Department of Pharmaceutical Technology

Pharmaceutics I
PHTC 311

Lecture 5:
Factors Affecting Drug Solubility and Dissolution Rate
Dr. Mai Rady, Ph.D

Pharmaceutical Technology Department - (PHTC 311) – Winter 2017 1

ILOS
By the end of the theoretical part, the student will be able to:

a. Knowledge & Understanding

a.1. Define liquid pharmaceutical dosage forms and related concepts
a.2. Explain the relation between physicochemical properties of materials (active and inactive) and the design of dosage forms as well as drug bioavailability
a.3. Describe the properties of liquid pharmaceutical dosage forms and its applications
a.4. Discuss the principles of rheology, Newtonian and non-Newtonian flow, colligative properties, adsorption, interfacial phenomena, types of surfactants, distribution
coefficient, phase equilibrium, buffers, solubility and their effects on the correct design of pharmaceutical formulations.

Professional and Practical skills

b.1. Recognize the correct pharmaceutical terms, symbols, measuring units and abbreviations.

Intellectual skills
c.1. Compute pharmaceutical calculations based on different systems of weighing and measuring units.
c.2. Analyze information and data specific to pharmaceutical solutions and factors affecting solubility.
c.3. Solve problems related to pharmaceutical calculations.
c.4. Compare between different types of solution dosage forms
c.5. Justify some pharmaceutical techniques and the incompatibilities occurring during dispensing of solution dosage forms
c.6. Formulate independently a formulae of solution pharmaceutical dosage forms
c.7. Distinguish the factors affecting rheology, phase equilibrium, colligative properties, adsorption and Interfacial phenomena

d. General and transferable skills

d.1. Retrieve information from different sources to improve professional competencies.
d.2. Demonstrate critical thinking and decision- making abilities

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Outline /

• The Difference between Solubility and Dissolution.

• Factors affecting drug solubility and dissolution rate.

• Some approaches to enhance drug solubility.

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 Important Definitions

• Solution:
A mixture of two or more components that form a single phase
which is homogenous down to molecular level.
Dissolution:
The transfer of molecules or ions from a solid state into
solution.
Solubility:
The extent to which the dissolution proceeds under a given set
of experimental conditions.
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 How dissolution Occur?
Solids: The intermolecular cohesive
forces between solid materials are very
high, spaces between molecules are the
least and molecules only vibrate.

Solute Solvent Gases: The intermolecular cohesive

A molecule from the surface of the solute forces are the least, spaces between
is removed, reallocated into cavities of molecules are wide and molecules move
solvent.
freely in space.

Liquids: They are intermediate between

solids and gasses.
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 Factors Affecting Solubility
1. Temperature: Important Definitions:

According to Gibbs Law: ∆G: Gibbs free energy: is a

measure of energy available
∆Hcl the change in heat absorbed when molecules of solutes detached to to the system to do work.
dissolve.

∆Hsolv is the heat absorbed when solute molecule are allocated between ∆H: Change to enthalpy to the
the solvent molecules (mostly have –ve charge). system.

T: is the absolute temperature

The dissolution process is either:
of the system.

Endothermic Process: Heat Exothermic Process: Heat

∆S: The Entropy change.
absorbing (Most Common) absorbing (less Common)
Always possitive, involves
∆Hcl >> ∆Hsolv ∆Hcl << ∆Hsolv
mixing of two components
Therefore ∆H is negative during dissolution.
Therefore ∆H is positive
e.g: CaOH2
e.g: K nitrate
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 Factors Affecting Solubility
1. Temperature (cont.):
In spontaneous dissolution processes ∆G is negative,
∆G is negative in these cases:
• The dissolution process is exothermic ( ∆H is negative as well as –T∆S.
• The dissolution is endothermic (∆H is +ve) but –T∆S is a higher value than ∆H
by
1. Increase temperature of the system (T).
2. Increase ∆S by increasing agitation speed.

Finally, solubility increase by increasing temperature in endothermic dissolution

processes and decrease by increasing temperature in exothermic dissolution
processes .

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 Factors Affecting Solubility
2. Chemical structure of the drug
• Ionic drugs like salts dissolve with great extent in water than
non-electrolytes.

• Drugs having polar groups that are capable of forming

hydrogen bonds with water dissolve at greater extent in water.
Hydrophilic Groups like:
OH- – NH3+ – COOH- - NH2 – CHO……

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 Factors Affecting Solubility
3- Polarity of the solvent
• Water has the highest polarity among other solvents-
highest DEC-, Polar solvents dissolve ionic compounds and
polar compounds(like dissolves like).
• Mixing water with other solvents like ethyl alcohol, glycerol,
propylene glycol, polyethylene glycol decreases its polarity (
DEC), and this is known as co-solvency.

Pharmaceutical Technology Department - (PHTC 311) – Winter 2017 9

 Dissolution Rate
Dissolution rate: The rate of mass transfer to solution (dm/dt)
Noyes-Whitney Steps of dissolution:
Equation:
1. Molecules from the surface of the solid crystal
dissolve in the solvent surrounding the surface
of the crystal forming ‘’stagnant layer of
saturated solution’’.

Saturated solution 2. Diffusion of solute molecules to the bulk of

solution.

Cs D is the diffusion coefficient.

A is the surface area of the solid crystal.
Cs is the saturated concentration of solute in the
Bulk solution C stagnant layer.
C is concentration of solute in the bulk solution.
h is the thickness of the stagnant layer..

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 Dissolution Rate
Dissolution rate: The rate of mass transfer to solution (dm/dt)
Noyes-Whitney
Equation:
The solubility of sucrose: 2g/ml water

While NaCl solubility: 0.36g/ml

But sucrose dissolves slowly and NaCl dissolves at faster

rates.

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 Factors Affecting Dissolution Rate

1. Surface Area of Un-dissolved Solid:

• When particle size decrease area increase and dissolution is faster.

• When powder of small particles is dispersed in dissolution media is better than a large particle of
same mass.

• Porous drug particles dissolve faster as they allow solvent penetration to the surface.

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 Factors Affecting Dissolution Rate
2. Saturated solubility of solid particle (Cs)

•Temperature: increasing temperature increases CS (endothermic processes).

•Nature of dissolution medium.

•Molecular structure of solute.

•Crystalline form of the Solute.

Drugs may exist in different crystalline forms (polymorphs) that exhibit different solubility.

Different arrangement of molecules in the crystal lattice (polymorphism). Some polymorphs have weaker
intermolecular bonds than others, therefore have faster dissolution

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 Factors Affecting Dissolution Rate
2. Saturated solubility of solid particle (Cs) (Cont.)

•Presence of other compounds:

This can affect Cs by:

1. Common ion effect: e

AgCl [Ag]+ + [Cl]-

Cl-
The presence of Cl- in the solution shifts the ionization process backward to the unionized form
AgCl.

2. Salting Out:
e.g. The presence of ions in the solution decreases the solubility of some drugs in water due to
higher affinity of ions to water.

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 Factors Affecting Dissolution Rate
3. Concentration of Solute in The Bulk solution:
As the concentration of solute in the bulk decreases the dissolution rate increases.

•The volume of the dissolution medium affect this. (increasing the volume of dissolution medium increases
the rate).

•If the solute is removed from the dissolution medium ( Absorption of drugs inside the body).

4. The diffusion Coefficient (D)

Diffusion coefficient is affected by:

•Thickness of stagnant layer (h) ( decreases by agitation).

•Viscosity of the dissolution medium (as viscosity increase dissolution rate decrease).

•The molecular weight of the diffusing solute.

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 Roman
Different
Numbers Approaches to Enhance Solubility of Drugs
Metrology

Drug solubility should be enhanced during drug formulation

because it is an important parameter when:

The drug should be formulated in a Increasing the bioavailability of the

solution form: drug, where drug should be dissolved
in the dissolution medium to the
e.g. Pediatric oral solutions, eye molecular level before absorption
drops, Injections…etc through biological membranes.

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Pharmaceutical Technology Department - (PHTC 311) – Winter 2017
 Roman
Different
Numbers Approaches to Enhance Solubility of Drugs
Metrology

1. Micronization: (Decreasing Particle size of drug):

This equation studies the effect of particle size decrease on the solubility of drugs.

S is the solubility of small particles having small radius r (reduced radius).

S0 is the normal solubility of the drug.

γ is the interfacial energy

M is the molecular weight of the drug.

R is gas constant
T is the absolute temperature of the system .
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Pharmaceutical Technology Department - (PHTC 311) – Winter 2017
 Roman Numbers
Different Approaches to Enhance Solubility of Drugs

2. Changing The structure of drugs:

•Adding hydrophilic groups to the drug enhances drug solubility.

Addition of OH group to drug structure may increase drug solubility 100 folds.

• Conversion of weak acid or weak base to a salt form increases water solubility markedly.

e.g. Na salt of salicylic acid has higher water solubility than salicylic acid.

Na salicylate solubility is 1:1 in water in comparison to 1: 550 of salicylic acid.

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Pharmaceutical Technology Department - (PHTC 311) – Winter 2017
 Roman Numbers
Different Approaches to Enhance Solubility of Drugs

3. Nature of the solvent

Like dissolves like

•Mixing water with other solvents like ethyl alcohol, glycerol, propylene glycol, polyethylene glycol
decreases its polarity ( decreases DEC), and this is known as co-solvency.

e.g. solubility of metronidazole was enhanced from 100mg in 10 ml to 500mg in 10ml. by addition
of co-solvent for parentral formulation.

• Dissolving some hydrophobic drugs in oils as sesame oils and formulated as oily IM injections (e.g.
Vitamin E).

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Pharmaceutical Technology Department - (PHTC 311) – Winter 2017
 Roman Numbers
Different Approaches to Enhance Solubility of Drugs

4. Crystal characteristics:

Drugs may exist as amourphous powder, crystalline, polymorphic forms.

Amorphous: molecules has random arrangement in the particles.

Crystals: molecules have repeated arrangement in the crystal lattice, have strong intermolecular
bonds between molecules.

Polymorphs: different crystalline form of the same compounds.

Upon formulation we can use amorphous forms of drugs to enhance the solubility, also we can
choose the polymorphic forms of higher solubility.
e.g. of drugs exhibit polymorphism, steroids, barbiturates, sulphonamides.

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Pharmaceutical Technology Department - (PHTC 311) – Winter 2017
 Roman Numbers
Different Approaches to Enhance Solubility of Drugs

5. pH.

If the pH of the solution of weakly acidic drugs or their salts decreases the proportion of unionized
form of the drug is increased. The opposite will occur with weak bases and their salts.

Also these drugs when pass through intestinal tract of different pH values, their solubility will
vary.

For acidic drugs the relationship between pH and pKa can be described by the modified Henderson
Hasselbalch equation:
S is the overall solubility of drug
Su is the solubility of unionized form

For basic drugs the relationship between pH and pKa can be described by the modified Henderson
Hasselbalch equation:

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Pharmaceutical Technology Department - (PHTC 311) – Winter 2017
 Roman Numbers
Different Approaches to Enhance Solubility of Drugs

6. Hydrotropy (Salting In)

Some salts of weak acids like Na Citrate enhances the solubility of some drugs by unknown
mechanism. It was assumed that the drug and the hyrotopic agent forms weak interaction,
therefore enhances their solubility.

7. Complex formation:
Some compounds are used to form complex with dugs (e.g. cyclodextrin, caffeine) to enhance their
solubility. These complexing agents forms weak hydrogen bonds, electrostatic bonds or vanderwal
forces with drugs enhancing their wettability and solubility.

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Pharmaceutical Technology Department - (PHTC 311) – Winter 2017
 Roman Numbers
Different Approaches to Enhance Solubility of Drugs

8. Solubilizing Agents:

Surface active agents (SAA) has a unique structure with polar hydrophilic head and lipophilic tail,
they align themselves according to the nature of the solvent to form micelles that solubilize drugs
in its core.

Drug

Micelle formation
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Pharmaceutical Technology Department - (PHTC 311) – Winter 2017
 Roman Numbers
Different Approaches to Enhance Solubility of Drugs

9. Solid Dispersion:

The term “solid dispersions” refers to the dispersion of one or more active ingredients in an inert
carrier (usually hydrophilic) in a solid state to enhance water solubility.

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 References

1- Sinko, Patrick J., and Yashveer Singh. Martin's physical pharmacy and pharmaceutical sciences: physical
chemical and biopharmaceutical principles in the pharmaceutical sciences. Walter Kluer, 2011.

2- M.E. Aulton, Aulton's pharmaceutics, Second Ed. ed., Elsevier, Amsterdam, 2007.

Thank you
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