Solutions I

Dr R.N. Kaali

April, 2022^
 Topic Outline
Introduction: Examples of dispersed systems:
solutions, colloids, suspensions, semisolid (creams and
ointments).

Definition and components of solutions: solvent

(assume to be water), drug, and additives some
additives are mandatory.

Fundamental Properties of solutions

a) Monophasic (free from particles)
b) Stable.

Solution formation and the role of the dissolution

process
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Expected Learning Outcomes

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 Introduction
Based on size of the dispersed phase, dispersed systems
can be classified as:

(a) Solutions (< 1nm) Example: sodium chloride in

water.

(b) Colloids (1-100 nm) Examples: (1) Milk, (2) blood, (3)
iron dextran injection, (4) cod liver oil, (5)
thickening agents like colloidal silica, stearyl alcohol,
magnesium stearate and aluminium monostearate

(c) Coarse dispersions: (>100nm)

-Suspensions Example: (1) antacids, (2) antibiotics
-Emulsions
-Semisolids eg creams and ointments
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 Solutions
 Defined as a homogeneous molecular
dispersions of solutes in a solvents.
 They are pharmaceutical formulations
commonly used to deliver drugs

 Commonly, solutions are liquid-liquid or solid-

liquid. However solid-solid solutions have been
formulated in the pharmaceutical industry.
 Formulation of miscible liquid-liquid
formulations poses few challenges.
 Consequently this presentation will focus on
solid-in-liquid solutions only. 5
 Solid-Liquid Solutions
In order to form a solution the solid drug must
dissolve to form a homogeneous dispersion of
molecules or ions in a solvent- commonly water.

This implies that solutions are single phase liquid

formulations with a minimum of two components
(solute and a solvent)

The process of solid-liquid transformation is

called dissolution.

This presentation presupposes that the solid drug

dissolves in water easily. 6
 Study Question
What is a component?

What is a phase?

What is the component in normal saline?

How many phase in a calcium carbonate

suspension?

What is a formulation?
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 Mechanism of Dissolution
The dissolution process occurs in two steps
namely
(1) interfacial reaction between the drug and
solvent

(2) transfer of drug molecules from the stagnant

layer to the bulk of the solvent

When the drug is highly soluble in water, it

dissolves quickly. 8
 Mechanism
This is because the drug-solvent attraction is
stronger than drug-drug or solvent-solvent
attraction.

The outcome of this rapid reaction is the

formation of a saturated stagnant layer around
the particle.

The molecules must then move away from the

stagnant layer to the bulk of the solvent (How?)
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 The Cavity Creation Theory
Also called the lattice theory

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Solution formation is thus conceptualized as a
three step process which involves:

1) Extraction of a solute (drug) molecule

from its crystal lattice.

2) Cavity creation in a group of solvent

molecules

3) Insertion of the solute (drug) molecule

in the cavity.

All three steps involve work and energy is

spent. (ref. Gibbs free energy equation)
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 Brain Activator
Scenario
Imagine you have two spoonful of sugar
added to each of two cups of tea. The tea in
the cup labelled A is agitated using a spoon
while no agitation is done to the second cup
labelled B.

How will the taste of the tea in these cups

compare? And why?

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 Factors Affecting the Rate of Dissolution
These are summarized by the Noyes Whitney
Equation: DR=K. Sa .ΔC (where ΔC is the concentration
gradient Cs- C), the difference between solubility Cs
and the concentration C of the drug in the bulk of
the solution.

Solubility can be enhanced by various means.

Example: Solubility of the same drug changes due to
•Type of salt
•Type of polymorphs
•Type of suitable complex
•Extent of solvation (monohydrate, dihydrate;
trihydrate) etc. 13
Potential Dissolution “Barrier(s)”
The rate of transfer of molecules to the bulk of
the solvent occurs by passive diffusion according
to Fick’s law of diffusion.

The diffusion process (removal of drug molecules

from the stagnant layer) is often slower than the
rate of dissolution.

The stagnant layer (diffusion layer) is therefore

a potential barrier of the dissolution process.

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 Rate Determining Steps (RDS)
Consequently this slow diffusion process determines
the rate of dissolution of the solid drug and is
accordingly called the “rate determining or rate
liming step” in the dissolution process.

Alternatively the dissolution process is said to be

diffusion rate dependent

Rate determining steps are usually found when there

are “competing” consecutive rate processes.

In this case the two consecutive processes are the

dissolution rate and diffusion rate of drug molecules.15
 Advantages of Solutions
 Easy to swallow and thus convenient to use
in paediatric and geriatrics patients.

 For the same drug the rate and

completeness (extent) of drug absorption
(bioavailability) from such delivery
systems is better compared to all delivery
systems.
 Easier to give accurate and uniform dose
than suspension or emulsion which need
shaking first (Why?).
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 Disadvantages.
 Have the potential for high decomposition
rate resulting in a shorter shelf life
compared to solid delivery systems eg
hydrolysis when water is the solvent.

 Indicators of decomposition: Appear as

colour change, precipitation or gas
formation.

 Microbial growth is also more likely in

solutions than in solid delivery systems
because water supports microbial growth. 17
 High transportation costs because they
are often inherently heavy and bulky.

 Unpleasant taste is more pronounced.

 In case of leakage all contents are lost.

 Accurate dosing depends upon the ability of

the patient to measure volume correctly by
use of a dropper, 5 ml spoon or a medicine cup.

Reason: Most liquid preparations are designed

so that the normal dose is present in 5ml or 18
Instability of drugs In Aqueous
Solutions

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 1. Chemical Instability
 Many different types of chemical instability exist
However, hydrolysis is a common example because
of use of water as the solvent.

 Hydrolysis is defined as water induced molecular

breakdown.

 Significance: Most products of hydrolysis have no

pharmacoactivity.

 Specific functional groups in drug molecules are

known to be prone to hydrolytic reactions.
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 Example I: Acetylsalicylic Acid (Aspirin)

Functional groups prone to hydrolysis include:

1.Carboxylic acid (R-COOH)
2.Ester group (R-O-CO-R’

NOTE: Low PH catalyzes the hydrolytic reaction 21

Example II: Beta Lactam Antibiotics

The amide is susceptible to hydrolysis 22

Functional Groups Prone to Hydrolysis.

Esters (Find more examples)

Carboxylic acid derivatives (Find additional

examples)

Amides (Find more examples)

Imines (Find examples)

Hemiacetals (Find examples)

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 2. Physical Instability

 Precipitation of solutes can occur in solutions.

 Concentrated solutions are particularly prone

to this instability especially when the
concentration is close to the solubility limit
(saturation).
 Triggers include: (1) Temperature drop, (2)
change in pH (cause may be dissolved air or
decomposition products, (3) pH change due to
leaching of chemicals from containers, (4)
Effect of additives like preservatives and (5)
light.
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 Prevention of Instabilities
(1) Add buffer to prevent pH catalyzed instability;

(2) Drugs must be stored at recommended

temperature

(3) Ensure no adverse pharmaceutical interactions

during the formulation process.

(4) Careful study of stability properties of drugs

during formulation stage

(5) Use high quality containers

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 3. Microbial Instability
 Solutions can become contaminated by micro-
organisms due to:

a) Contaminated raw materials Eg sugars and

flavouring agents are often contaminated
because they are good bacterial growth media.

b) Equipment, environment

c) Personnel.

 Microbial contamination justifies the addition of

preservatives in solutions formulations. 26
 Study Question
What is a preservative?

What are the therapeutic and safety

implications of instabilities in
formulations for internal use?

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Common Additives in Solutions.

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 Types Include:

a) Preservatives. f) Tonicity
adjusters. (to be
b) Antioxidants. covered under
sterile products e.g.
c) Flavouring agents injections)
and perfumes.
g) Viscosity
d) Buffers. enhancers. (see
suspensions)
e) Sweeteners
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 Preservatives.
Ideal Properties:

1) Effective against a wide spectrum of micro-

organisms. Combining preservatives is advantageous.

2) Stable during the shelf life of the product.

3) Non toxic, non sensitizing.

4) Compatible with other ingredients.

5) Free of bad taste and odour.

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 Factors Affecting Effectiveness
Concentration: Concentration (mass/volume)
usually specified for each preservative.

The specified concentration of a preservative is

vital because it dictates the effectiveness of
the preservative and the safety to the user, the
patient.

pH: Only non ionized molecules have best

preservative effect. Therefore adjust
formulation to a pH which favours formation of
non-ionized species. 31
 Types and Examples of Preservatives.

 Alcohols
a) Ethanol: a useful preservative and often used
as a solvent.
-High concentration (> 10%) necessary for
effectiveness.
b) Propylene glycol: Also used as a solvent in oral
solutions and topical preparations.
-Has the advantage of being non -volatile. Has
preservative effect in a concentration range of 15
to 30%.
c) Another example is chlorobutanol 0.5%.
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 Type Comment Example Conc. % pH
-
Acids Benzoic acid 0.1 to 0.5 ˃ 4.5
Sorbic acid  
Esters 1. Product of Methyl, ethyl, 0.2 4 to 8
condensation of butyl and  
alcohol & acid propyl
2. Two esters can derivatives of
be combined to benzoic acid
widen spectrum  
of activity and
enhance safety
Quaternary 1. Incompatible Benzalkonium 0.002 to 4 to 10
Ammonium with many Chloride 0.02
Compounds anionic    
compounds
2. Stable at most
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temperatures
Antioxidants.

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 Antioxidants.
 Antioxidants are substances which inhibit
oxidative reactions.

 They are important because some formulations

eg. vitamins, essential oils & almost all fats and
oils are susceptible to oxidation.

 Examples of antioxidants include:

1) Tocopherols (eg vitamin E)

2) Sodium sulphite,

3) Ascorbic acid (vit. C). 35

 Triggers of Oxidative Reactions.

Triggers of oxidative reactions:

1) Heat: Keep oxidizable drugs in a cool place.

2) Light: prevent by use of light- resistant

containers.

3) Heavy metals (e.g. Fe, Cu): Minimized by

using citric acid or sequestering agents eg EDTA.
4) Presence of oxygen in solvent. Remove
oxygen by heating water or bubbling nitrogen)
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 Flavours and Perfumes

 Have the capacity and are usually used to

mask unpleasant taste or odour.

 Source: (1) Synthetic or (2) natural product

like lemon, aromatic oil e.g. peppermint.

 Note: That synthetic perfumes are

cheaper, more readily available and more
stable than natural products.
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 Artificial Sweeteners.
 Certain sweeteners are important for use by
diabetic patients.
 They include syrups containing sodium salts
of saccharin or cyclamate both of which are
many times sweeter than sucrose.
 Both have a bitter taste unless adequately
diluted.
 Aspartame: Concerns have been expressed
about its safety. It may be wise to avoid it.

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 References
 Aulton, M E. (2007), Aulton’s
Pharmaceutics: The design and
manufacture of Medicines, 4th edition,
Churchill Livingstone. Chapter 24
(Solutions)

 https://www.youtube.com/watch?v=T8W
0uZxShvw
(A short video: How to make an
extemporaneous solution)
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