Lecture 1 and 2

Chapter I: Pharmaceutical solutions
Pharmaceutical solutions defined as:

liquid preparations in which the therapeutic agent and the
various excipients (known as solutes) are dissolved in
aqueous or non aqueous solvent (known as solvent).
Or it may be defined as a mixture of two or more components
that form a single phase which is homogenous down to the
molecular level.
The solvent system (vehicle), is likely to be liquid
The solute will be either a liquid, gas or a solid.
Solutions of gases in liquids are characteristic of aerosols, in
which the propellant gas is dispersed or dissolved in the
solvent under pressure.

Advantages of pharmaceutical solutions for oral administration
Easily administered orally to individuals who have difficulty in
swallowing, e.g. elderly patients, infants.
The therapeutic agent is dissolved in the formulation
And therefore is therefore immediately available for
absorption.
Providing the drug does not precipitate within the
gastrointestinal
tract,
the
bioavailability
of
pharmaceutical solutions is greater than that of oral soliddosage forms.

Dis-advantages of pharmaceutical solutions for oral administration
They are unsuitable for therapeutic agents that are chemically
unstable in the presence of water.
The poor solubility of certain therapeutic agents may prohibit their
formulation as pharmaceutical solutions. However, certain
techniques are available to improve drug solubility (will be discussed
later)
Pharmaceutical solutions are expensive to ship and are bulky for
the patient to carry due to the associated mass of the product.

Dis-advantages of pharmaceutical solutions for oral administration
Difficult to mask bad taste or odour.
They are liable to deterioration faster than solid dosage forms.
Has high possibility of bacterial growth.

Manufacture of solutions:
For small and large scale manufacture all what we need is dissolving
all ingredients in the solvent.
Equipment required for solutions preparation are: mixing vessels, a
means of agitation and a filtration system to ensure clarity of the
final solution.
During manufacture, ingredients (solutes) are added to the solvent
in the mixing vessel and stirring is continued until dissolution is
complete.

If solute is more soluble at elevated temperature, it may be
advantageous to apply heat. However, caution should be taken
especially if there are volatile or thermo-labile materials..
Size reduction is advantageous as it will increase the surface area
and speed up the solution process.
Solutes present in low concentrations particularly dyes are dissolved
in a small volume of the solvent then added to the bulk.

Volatile materials should be added last and after cooling to reduce
loss due to evaporation.
Finally it is essential to make sure that there is no significant amount
of any of the ingredients is adsorbed irreversibly onto the filter
medium used for final clarification

Pharmaceutical solutions may contain a range of excipients, each with
a defined pharmaceutical purpose such as:
The vehicle, usually purified water
Co-solvents, e.g. propylene glycol, glycerin, alcohol
Agents specifically to enhance the solubility of the therapeutic agent
in the vehicle, e.g. surface-active agents
Preservatives, e.g. parahydroxybenzoate esters
(methylhydroxybenzoate and propylhydroxybenzoate), boric acid
and borate salts, sorbic acid and sorbate salts, phenolics

Pharmaceutical solutions may contain a range of excipients, each with
a defined pharmaceutical purpose such as:
Sweeteners, e.g. glucose, saccharin, aspartame
Rheology (viscosity) modifiers, e.g. hydrophilic polymers (cellulose
derivatives, alginic acid, polyvinylpyrrolidone)
antioxidants, e.g. sodium formaldehyde sulphoxylate, butylated
hydroxyanisole, butylated hydroxytoluene
Colours
Flavours
Buffers to regulate the pH of the formulation, e.g. citrate buffer.

Classification of solution according to method of preparation:
Simple solution: prepared by dissolving solutes in solvent, it may
contain additives that help in solubilisation and stability of active
medicaments. E.g. calcium hydroxide topical solution, Iodine
solution
Solution by chemical reaction: formed by reacting 2 or more
solutes with each other in a suitable solvent. E.g. Aluminium subacetate topical solution
Solution by Extraction: Drugs or pharmaceutics obtained from
vegetables or animal source are extracted with a suitable solvent
such as water or water containing substances.

Classification of solution according to vehicle:
Aqueous solution
Non-aqueous solution
Aqueous solution: Water is the most widely used as a solvent.
Advantages:
Inert (has no pharmacological effect).
Palatable.
Inexpensive.
Safe (non-toxic when used internally and non-irritant when used
externally)
Physiological compatible.

Disadvantages of Aqueous solution:
Some drugs form unstable solutions when dissolved in water.
Types of pharmaceutical water:
(1) Potable water:
It is water suitable for drinking.
Salts often dissolve in potable water are undesirable.
Contains less than 0.1% of total solids as dissolved and undissolved
organic matter and micro-organisms.
N.B. hard water contains calcium and magnesium cations.

(2) Purified water B.P.
Has been freshly boiled and cooled immediately before use to
destroy any vegetative microorganisms that might be present.
Purified Water is normally prepared by
Distillation of potable water: e.g Distilled water
Deionization of potable water: e.g demineralized water or deionized.
Reverse osmosis

Distillation
Water is first heated to boiling. Then the water vapour passes
through a condenser where cooling water lowers the temperature
so the vapour is condensed, collected and stored.
Most contaminants stay behind in the liquid phase vessel.

Deionization:
Refer to water lacks ions present in tap water.
Tap water is usually full of ions from the soil (Na+, Ca2+), from the
pipes (Fe2+, Cu2+), and other sources.
Why de-ionize water? Because ions can interfere with chemical
processes.

Deionization:
Water is usually deionized by using an ion exchange process.
The ion-exchange equipment involves the passage of water
through a column of cation/anion exchangers, consisting of waterinsoluble, synthetic (resin).

Deionization:
These resins are mainly of two types;
The cation, or acid exchangers: permit the exchange

of the cations in solution (in the tap water) with
hydrogen ion from the resin
The anions or base exchangers: permit the removal of
anions.

Deionization:
These resins are mainly of two types;
The processes are indicated as follows, with M+ indicating the metal
or cation (as Na+) and the X-indicating the anion (as Cl-).
Cation Exchange
H-Resin + [M+ + X- + H2 O] M-Resin + H+ + X- + H2O
Anion Exchange
Resin-NH2 + [H+ + X- + H2 O] Resin-NH2.HX + H2O (pure)

Deionization:
N.B. Water purified in this manner is referred to as demineralized or
de-ionized water and may be used in any pharmaceutical preparation
or prescription required distilled water.
Advantages of ion exchange resins over distillation:

No need for heat and hence, less cost and troublesome of
maintenance.

The process of reverse osmosis:
Reverse osmosis is a filtration procedure typically used for water.
Removes many types of large molecules and ions.
It works by using pressure to force a solution through a membrane
retaining the solute on a side and allowing the solvent to pass
through the other side.

This is the opposite of nature osmosis process where solvent
moved from the region of low solute concentration to solute with
high concentration without applying an external pressure.
This process is commonly used in desalination of sea water to
produce fresh water. It is also used to purify fresh water for
industrial applications.

The pore size of semi permeable membranes can remove particles
defined in the range of
Microfiltration (0.1 to 2 microns, e.g., bacteria)
Ultrafiltration (0.01 to 0.1 microns, e.g., virus)
Nano filtration (0.001 to 0.01 microns, e.g., organic compounds in
the Molecular weight range of 300 to 1000).
Reverse osmosis removes particles smaller than 0.001 microns;
virtually all virus, bacteria, organic molecules, and 90-99% of all
ions should be removed.

Water for injection:
Used for parenteral solutions
As water for injection it should be sterile, pyrogen free and doesnt
contain antimicrobial agent or other added substances.
Obtained by autoclave sterilisation of pyrogen free distilled water
immediately after its collection.
Usually available in 1 L bottle. It is worth noting that this bottle is
not isotonic. Therefore, cant be administrated intravenously.

This water is used as a solvent, vehicle, diluent for already sterilised
and packaged injectable medications.
Water for injection free from CO2 used for phenobarbitone sodium
or aminophylline which are sensitive to presence of CO2.
Water of injection free from O2 used for apomorphine and
ergotamine maleate that are sensitive to oxidation.

Both water of injection free from CO2 and O2 are prepared in a
similar manner to water for injection except they are boiled for 10
minutes then cooled and sealed in their containers while excluding
air and then sterilised by autoclaving.

Bacteriostatic water for injection:
It is sterile water for injection contains one or more of a suitable
antimicrobial agent. The container label must state the name and
% of antimicrobial agent.
The presence of antimicrobial agent allows flexibility of multiple
dose vials. i.e. if the first person to withdraw the first dose
contaminates the vial contents, the antimicrobial agents will
destroy the micro-organism.

Bacteriostatic water for injection:
Packed in prefilled syringe or as a 30 ml vial
Used for small volume injectable preparations.
Restricted use for large volume parenteral administration due to
excessive and perhaps toxic amounts of antimicrobial agents.
If vehicle volume is greater than 5 ml, sterile water for injection is
preferable to be used rather than bacteriostatic water for injection.

Sodium Chloride injection USP
It is a sterile isotonic solution of sodium chloride in water for
injection where Na+ and Cl- contents are around 15 mEq/ L.
It contains no antimicrobial agents.
Used for preparation of suspension and solutions for parenteral
administration.
Is frequently used as a catheter or IV line flush to maintain patency.

Non-aqueous solutions:
Advantage of Non-aqueous solutions:
It is alternative to aqueous one in case the drug is unstable in
aqueous solution or it is difficult to ensure complete solution of the
ingredients at all storage temperatures.
Useful for Depot therapy. For example, Intramuscular injection of
drugs in oil. In some cases more hydrophobic drugs are synthesized
to achieve depot therapy such as propionate and benzoate esters
of Testosterone and Estradiol respectively.

Advantage of Non-aqueous solutions:
Oily solution remains as a discrete entity within muscle tissues and
release the drug slowly into the surrounding tissue. Contrary to
aueous solution that is miscible and diffuse readily with tissue
fluids releasing the drug quicker.
It is essential to choose a solvent for non-aqueous solution that
have the following properties; non-toxic, non-irritant, reasonable
cost, stable and compatible with other ingredients
This is commonly used for external applications rather than
internally or parenterally.

Examples of solvent used for non-aqueous solutions
(2) Alcohols
Ethyl alc is the most widely used solvent particularly for external
application. Where it is rapidly evaporated after external
application and imparting a cooling effect e.g. salicylic acid lotions.
It has antimicrobial effect at a concentration 15%.
It is more selective than water for extraction of crude drugs.

(2) Alcohols
Ethyl alc is either (1) Diluted Alc: prepared by mixing equal volumes of alc USP and
purified water USP and used as a hydro-alcoholic solvent in pharmaceutical
preparation or
(2) Rubbing Alc: contains 70% alc by volume and the rest is water, denaturants,
might contain coloe or perfume oils and stabilizer. It is employed as a rubefacient
externally and as a soothing rub for bedridden patients (to improve blood
circulation and avoid bed sores). Also could be used as a skin cleaner prior injection
and a vehicle for topical preparations.

(2) Alcohols
Due to its toxicity, it is used only for parenteral and oral application at low
concentration.
According to FDA, Alc contents in OTC oral drug products should follow;
Children age < 6 Yr .. Alc content limit is 0.5%
Children age 6- 12 Yr.. Alc content limit is 5%
Children >12Yr and adults Alc limit is 10%
Isopropyl alcohol has similar properties to ethyl alc and it is used as a solvent for
diclophane. Isopropyl alc is less abused than ethyl alc.

(3) Polyhydric alcohol:
Alcohols contain 2 OH groups per a molecule are known as glycols.
Due to their toxicity, they are rarely used internally except
polypropylene glycol (PG). That is used in conjunction with water
as a co-solvent.

(3) Polyhydric alcohol:
PG used in formulation of phenobarbital injections, digoxin
injection, Co-trimoxazole intravenous infusions and as a diluent for
chloramphenicol Ear drops and in hydrocortisone Ear drops and in
some oral preparation
PG is available in a wide range of viscosity grades that allow it to be
used as a solvent for Clotrimazole topical solution or as a cosolvent with water or alcohol.
Glycerol is an alc with 3 OH groups and is widely used as a cosolvent with water for oral use.

(4) Dimethylsulphoxide:
It is a highly polar compound and is thought to aid penetration of
drugs through the skin.
It is used as a carrier for external application of idoxuridine, an
antiviral agent.

(5) Ethyl ether:
It is widely used for the extraction of crude drugs. Due to its own
therapeutic activity, it is not used for internal use but used as a cosolvent with alcohol in some collodions.

(6) Liquid paraffin:
Its oily nature, make it unpleasant to be used externally. However,
it is used as a solvent for emulsion topical preparations.
Was used in one time as a solvent for nasal drops but currently it is
not used for this purpose due to the possibility of developing
lipoidal pneumonia if it is inhaled into the lungs.

(7) Miscellaneous solvents:
Isopropyl myristate and isopropyl palmitate are used for external
use in cosmotics due to low viscosity and lack of greasiness.
Dimethylformamide and Dimethylacetamide used as solvent in
veterinary formulations. Their toxicity renders them unsuitable for
human use.

Other formulations additives to solution:
Buffers
Density modifiers
Iso-tonicity modifiers
Viscosity enhancer
Preservatives
Reducing agents and Antioxidants
Sweeting agents
Flavours and Perfumes
Colors

Buffers
Buffers are employed to control the pH of the formulated product
and so optimise the physicochemical performance of the product.
Typically pH control is performed to maintain the solubility of the
therapeutic agent in the formulated product. The solubility of the
vast number of currently available drugs (they are either weak
acids or weak bases) is pH-dependent and, therefore, the solubility
of the therapeutic agent in the formulation may be compromised
by small changes in pH.

Buffers
Also they enhance the stability of final products where the
chemical stability of the active agent is pH-dependent.
The concentration (and hence buffer capacity) of buffer salts
employed in the formulation of oral solutions should be selected to
offer sufficient control of the pH of the formulation but yet should
be overcome by biological fluids following administration. This
latter
property
is
particularly
appropriate
for
parenteral
formulations to ensure absence of irritation or biological damage

following injection.

Examples of buffer salts used in pharmaceutical solutions include:
Acetates (acetic acid and sodium acetate): 12%
Citrates (citric acid and sodium citrate): 15%
Phosphates (sodium phosphate and disodium phosphate): 0.82%.
N.B. It must be remembered that the buffer system used in
solution formulations should not adversely affect the solubility of
the therapeutic agent, e.g. the solubility of drugs may be affected
in the presence of phosphate salts.

Density modifiers:
It is not common to control the density of solutions except for
those preparations for spinal anaesthesia.
Solutions of lower density than cerebrospinal fluid tends to rise
after injection and those with higher density tend to fall.
Careful control of these solutions density and position of injection
is highly important to control the area to be anaesthetized.

Density modifiers:
Isobaric, hypobaric and hyperbaric are terms used to describe the
density of solutions relative to spinal fluid and they means equal,
lower and higher density respectively.
Dextrose is the most commonly used density modifier

Iso-tonicity modifiers:
Solutions for injection as well as large volume solutions for
ophthalmic use must be isotonic to avoid pain and irritation.
Dextrose and sodium chloride are the most commonly used isotonicity modifiers.
Iso-tonicity is adjusted after addition of all of others ingredients in
the preparation as these ingredients will contribute in the overall
osmotic pressure of a solution.

Viscosity enhancers:
The administration of oral solutions to patients is usually performed using a
syringe, a small-metered cup or a traditional 5-ml spoon.
The viscosity of the formulation must be sufficiently controlled in order to
ensure the accurate measurement of the volume to be dispensed.
Accordingly there is a viscosity range that the formulation should exhibit to
facilitate this operation. In addition, aqueous based topical solutions are difficult
to remain at the site of application (skin) due to low viscosity. Therefore addition
of viscosity enhancer is a requirement.

Viscosity enhancers:
Certain liquid formulations do not require the specific addition of
viscosity-enhancing agents, e.g. syrups, due to their inherent
viscosity.
The viscosity of pharmaceutical solutions may be easily increased
(and controlled) by the addition of non-ionic or ionic hydrophilic
polymers.
Non-ionic (neutral) polymers
Cellulose derivatives, e.g.:
methylcellulose
hydroxyethylcellulose
hydroxypropylcellulose
polyvinylpyrrolidone
Ionic polymers
Sodium carboxymethylcellulose (anionic)
Sodium alginate (anionic).

Preservatives:
Preservatives are included in pharmaceutical solutions to control the microbial
bio-burden of the formulation. Ideally, preservatives should exhibit the
following properties:
Possess a broad spectrum of antimicrobial activity encompassing Grampositive and Gram-negative bacteria and fungi
Be chemically and physically stable over the shelf-life of the product
Have low toxicity.

Preservatives:
A wide range of preservatives is available for use in pharmaceutical solutions for
oral use, including the following (values in parentheses relate to the typical
concentration range used in oral solutions);
Benzoic acid and its salts (0.10.3%)
Sorbic acid and its salts (0.050.2%)
Alkyl esters of parahydroxybenzoic acid, known as parabens (0.0010.2%).
N.B. usually a combination of two members of this series is employed in
pharmaceutical solutions, typically methyl and propyl parahydroxybenzoates (in a
ratio of 9:1). The combination of these two preservatives enhances the
antimicrobial spectrum.

Preservatives:
Factors that directly affect the efficacy of preservatives in oral
solutions include:
(1) the pH of the formulation;
(2) the presence of micelles; and
(3) the presence of hydrophilic polymers.

Preservatives:
solutions include:
In some aqueous formulations the use of acidic preservatives, e.g. benzoic acid,
sorbic acid, may be problematic.
Organic acids, e.g. benzoic acid, sorbic acid, have pKa values around 4.2 and
therefore, in solution formulations whose pH is neutral, a high concentration of
preservative will be required to ensure that the required concentration of the
unionised species is obtained (will be explained later on)

Preservatives:
solutions include:
The antimicrobial properties are due to the unionised form of the preservative;
the degree of ionisation being a function of the pH of the formulation.

The activity of the unionised form is due to the ability of this form to diffuse across
the outer membrane of the microorganism and eventually into the cytoplasm. The neutral
conditions within the cytoplasm enable the preservative to dissociate, leading to
acidification of the cytoplasm and inhibition of growth.

Preservatives:
solutions include:
The fraction of acidic preservative at a particular pH may be calculated using a
derived form of the HendersonHasselbalch equation, as follows:
Fraction =
The importance of this equation will be illustrated as follows;

Preservatives:
solutions include:
Problem 1: Assuming that the MIC for the unionised form of an acidic preservative (pKa 4.2)
is 0.0185 mg/ml, calculate the required concentration to preserve an oral solution that has
been buffered to pH 4.7. The HendersonHasselbalch equation may be employed, as
described above, to determine the fraction of unionised acid within the formulation.
Fraction =
..
and therefore, the fraction = 0.24

Preservatives:
solutions include:
The required concentration is then calculated by dividing the MIC for the
unionised form of the preservative by the fraction of unionised preservative
present, i.e. 0.0185/0.24 = 0.07 mg/ml. In practice an excess is added and
therefore the actual concentration of preservative required would be 0.10.15
mg/ml.

Preservatives:
solutions include:
As you can observe, the pKa of the preservative is a vital determinant within the
above calculations. Organic acids, e.g. benzoic acid, sorbic acid, have pKa values
that are around 4.2 and therefore, in solution formulations whose pH is neutral, a
high concentration of preservative will be required to ensure that the required
concentration of the unionised species is obtained. If the above calculation is
repeated for an oral solution at pH 7.2, the following result is obtained:

Preservatives:
solutions include:
Fraction = 0.00001, Therefore, the required preservative concentration is 1850
mg/ml. the latter could explains why use of benzoic acid/sorbic acid is problematic
in certain formulations with neutral pH.
N.B. Alky esters of parahydroxybenozoic acid) and the phenolics are generally not
affected by formulation pH (within a pH range between 4.0 and 8.0) due to the high
pKa of the organic hydroxyl group.

Preservatives:
Factors that directly affect the efficacy of
preservatives in oral solutions include:
(2) The presence of micelles:

micelles are used for the solubilisation of lipophilic therapeutic
agents. If the preservative exhibits lipophilic properties (e.g. the
unionised form of acidic preservatives, phenolics, parabens), then
partition of these species into the micelle may occur, thereby
decreasing the available (effective) concentration of preservative in
solution. An equilibrium is established as follows; To correct this
problem, the preservative concentration must be increased to
ensure that the free concentration (those not associated with
micelles) in the formulation is MIC.

Preservatives:
Factors that directly affect the efficacy of preservatives in oral solutions include:
The presence of hydrophilic polymers:
The free concentration of preservative in oral solution formulations was
shown to be reduced in the presence of hydrophilic polymers, e.g.
polyvinylpyrrolidone, methylcellulose.
This is due to the ability of the preservative to interact chemically with the
dissolved polymer. This problem is addressed by increasing the concentration
of preservative in the formulation. In certain circumstances the preservative
may be incompatible with hydrophilic polymers in the formulation due to an
electrostatic interaction. Therefore, cationic hydrophilic polymers should not
be used in conjunction with acidic preservatives in oral solution formulations.

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Chapter I: Pharmaceutical solutions

Pharmaceutical solutions defined as:

Chapter I: Pharmaceutical solutions

Chapter I: Pharmaceutical solutions

Chapter I: Pharmaceutical solutions

Chapter I: Pharmaceutical solutions

Chapter I: Pharmaceutical solutions

Chapter I: Pharmaceutical solutions

Chapter I: Pharmaceutical solutions

Chapter I: Pharmaceutical solutions

Chapter I: Pharmaceutical solutions

Chapter I: Pharmaceutical solutions

Chapter I: Pharmaceutical solutions

Chapter I: Pharmaceutical solutions

Chapter I: Pharmaceutical solutions

Chapter I: Pharmaceutical solutions

Chapter I: Pharmaceutical solutions

Chapter I: Pharmaceutical solutions

The cation, or acid exchangers: permit the exchange

Chapter I: Pharmaceutical solutions

Chapter I: Pharmaceutical solutions

Advantages of ion exchange resins over distillation:

Chapter I: Pharmaceutical solutions

Chapter I: Pharmaceutical solutions

Chapter I: Pharmaceutical solutions

Chapter I: Pharmaceutical solutions

Chapter I: Pharmaceutical solutions

Chapter I: Pharmaceutical solutions

Chapter I: Pharmaceutical solutions

Chapter I: Pharmaceutical solutions

Chapter I: Pharmaceutical solutions

Chapter I: Pharmaceutical solutions

Chapter I: Pharmaceutical solutions

Chapter I: Pharmaceutical solutions

Chapter I: Pharmaceutical solutions

Chapter I: Pharmaceutical solutions

Chapter I: Pharmaceutical solutions

Chapter I: Pharmaceutical solutions

Chapter I: Pharmaceutical solutions

Chapter I: Pharmaceutical solutions

Chapter I: Pharmaceutical solutions

Chapter I: Pharmaceutical solutions

Chapter I: Pharmaceutical solutions

Chapter I: Pharmaceutical solutions

Chapter I: Pharmaceutical solutions

formulations to ensure absence of irritation or biological damage

Chapter I: Pharmaceutical solutions

Chapter I: Pharmaceutical solutions

Chapter I: Pharmaceutical solutions

Chapter I: Pharmaceutical solutions

Chapter I: Pharmaceutical solutions

Chapter I: Pharmaceutical solutions

Chapter I: Pharmaceutical solutions

Chapter I: Pharmaceutical solutions

Chapter I: Pharmaceutical solutions

Chapter I: Pharmaceutical solutions

Chapter I: Pharmaceutical solutions

the degree of ionisation being a function of the pH of the formulation.

Chapter I: Pharmaceutical solutions

Chapter I: Pharmaceutical solutions

and therefore, the fraction = 0.24

Chapter I: Pharmaceutical solutions

Chapter I: Pharmaceutical solutions