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, an additives- not
mandatory.
Fundamental Properties of solutions
a) Monophasic (free from particles)
b) Stable.
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Topic Outline
• Solution formation- Its dependency on the
dissolution process
• Theories of dissolution
• General methods for the preparation of
solutions.
• Enhancing drug solubility: Co-solvents, pH
modification, complexation, choice of
suitable polymorphic forms.
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Expected Learning Outcomes.
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Expected Learning Outcomes.
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Expected Learning Outcomes
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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 to yield low molecular weight chemical
substances.
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 9
Example II: Beta Lactam Antibiotics
The amide is susceptible to hydrolysis 10
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 where 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) Leaching of
chemicals from containers, (4) Effect of
additives like preservatives and (5) light. 12
Prevention of Physical & Chemical
(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. 14
Study Question
• What is a preservative?
• What are the therapeutic and safety
implications of instabilities in
formulations for internal use?
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Solubility.
Defined as the concentration of o solute in a
saturated solution in a specified solvent under
defined conditions of pressure and temperature.
Both the rate of dissolution (how much drug
dissolves per unit time) and the extent of drug
dissolved (the maximum amount of drug which can
dissolve in a specified volume of solvent) depends
on the solubility of the solute in a solvent.
A high solubility of a drug in water is a huge
advantage because the higher the solubility in
water the easier it is to make an aqueous solution
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Solubility (cont.)
From time to time, solvent or drug
properties need to be modified in order to
get desirable solubility.
The use of co-solvents (mixed solvents)
can be used for that purpose.
Drug solubility is higher in combination
solvents than in ONE of the individual
solvent.
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Methods Used to Enhance
Solubility
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Context
• In considering enhancement of solubility, remember
that the solubility of a drug is a constant value.
• EXAMPLE: the solubility of a drug can not be enhances
during the dispensing stage.
• However, pharmaceutical companies which synthesize
pharmaceutical raw material can choose to synthesize
different molecular forms (e.g. salt forms) of the same
drug in order to provide flexibility of solubility of the
drug in water.
• Consequently it is possible for the formulation
scientist to choose a drug with a suitable solubility for
the intended purpose (contrast with bullet 2 above) 19
1. Use of Co-solvents
• A dielectric constant between 25 and 80
corresponds with good aqueous solvent properties.
• Thus water can be mixed with other solvents (eg.
sorbitol, glycerol, propylene glycol, isopropyl
alcohol) in special proportions in order to get a co-
solvent with desirable dielectric constant.
• Again, the solubility of the drug in the co-solvent
will be a constant at the specified conditions of
temperature and pressure.
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2. pH Adjustment.
The solubility of weak acids and bases is pH
dependent.
Generally, bases have higher solubility in acid pH
due to salt formation.
The pH of a solvent may thus be suitably
adjusted in order to get better solubility
properties of a drug in a particular solvent.
Buffers are used in this case.
Note: The solubility of the drug at particular pH
is constant; it cannot change unless the pH is
changed. 21
3. Clatheration.
Clatheration is a means of enhancing the
solubility of organic substances by use of
clathrates (inclusion substances).
It involves the inclusion of an organic drug
“guest” in a cage like crystal structure of
another substance- the host substance.
This is facilitated by the principle of “like
dissolve like.”
Cyclodextrin is a common host substance
used to enhance dissolution by increasing
the solubility. 22
Cyclodextrin Structure.
The outer part is rich in hydrophilic groups
making it freely soluble in water.
However the inside part has abundance of
hydrocarbon groups (-ch2-).
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Example 1: Aspirin in Cyclodextrin
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Examples 2: Methyl α-lipoate in urea
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Clatheration.
Clatheration has been used to enhance the
solubility of some drugs
Example: Retinoic acid has a water solubility of
0.5 mg/ml. However its solubility rises to 160
mg/ml when combined with β-cyclodextrin
Additional examples of drugs formulated by
Clatheration include: oral liquid preparations
containing (1) itraconazole-antifungal (2)
spironolactone and furosemide. - a diuretics; and
(3) multivitamins
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4. Complexation
A water insoluble drug is combined with a water
soluble macromolecule.
Both the water soluble macromolecule and the
complex are usually inactive.
The drug must first be separated from the
macromolecule in order to regain its
pharmacological activity.
Example 1: A complex of iodine and
polyvinylpyrrolidone (a macromolecule).
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Example 2: Solubility of acidic drugs
• The solubility of acidic drugs is improved by
formation of drug-caffein complexes.
• Examples: PABA, Benzocaine and procaine
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5. Chemical Modification
Chemical modification can be done during drug
development (not during the formulation stage)
Many bases (parent compounds) are converted
to their salts forms because their salt forms
have better water solubility properties.
Example: Chloramphenicol has poor water
solubility properties BUT chloramphenicol
sodium succinate salt HAS good water solubility
properties.
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Example II.
Strong Iodine Solution USP also called
Lugol’s Solution. Used in the treatment of
goiter.
The solubility of Iodine in water is low (1:
2950).
However potassium polyiodides (KI.I2,
KI3.I3, KI.4I4) have much higher solubility
in water.
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6. Use of suitable Polymorphs.
Polymorphism: defined as the existence of a
drug as two or more solid state forms
characterised by different molecular
arrangements and/or conformations.
These different forms have different
solubility properties. Eg. Amorphous
substances have high solubility but are
highly unstable.
Suitable metastable forms can be selected
for use subject to their stability properties.
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Varied Molecular Arrangement.
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Drugs with Polymorphic Forms
• Chloramphenicol has three polymorphs (A,B
and C)
• B dissolves faster and has higher solubility
than A which gives lower serum levels
• Other drugs with polymorphic forms include
carbamazepine, ritonavir and rifaximin
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Method for making Solutions
Agitation is the common method used for
water soluble drugs
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2. Agitation Without Heating.
A suitable method if heat sensitive substances are
part of the formulation eg codeine phosphate syrup.
First step involves making the syrup without the
heat sensitive substances (if no stock solution of
syrup).
Cool down the product then transfer the syrup into
a bottle twice the size of the needed syrup. Ensure
the bottle is well stoppered to avoid loss &
contamination.
Add the heat sensitive ingredients and shake until
all solutes dissolve. 35
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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