Lectures1,2,3, 4 PDF

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:
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.

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.

Reducing agents and Antioxidants:
Antioxidants are included in pharmaceutical solutions to enhance the stability
of therapeutic agents that are susceptible to chemical degradation by
oxidation.
Typically antioxidants are molecules that are redox systems that exhibit higher
oxidative potential than the therapeutic agent or, alternatively, are compounds
that inhibit free radical-induced drug decomposition.
Typically in aqueous solution antioxidants are oxidised (and hence degraded) in
preference to the therapeutic agent, thereby protecting the drug from
decomposition.

Reducing agents and Antioxidants:
Typically antioxidants are employed in low concentrations (0.2% w/w) and it is
usual for the concentration of antioxidant in the finished product to be
markedly less than the initial concentration, due to oxidative degradation
during manufacture of the dosage form.
Antioxidants may also be employed in conjunction with chelating agents, e.g.
ethylenediamine tetraacetic acid, citric acid, that act to form complexes with
heavy-metal ions, ions that are normally involved in oxidative degradation of
therapeutic agents.

Sweeting agents:
Sweetening agents are employed in oral solutions specifically to increase the
palatability of the therapeutic agent, mask the unpleasant taste and increase
the viscosity of the preparation.
Sucrose (has the following advantage; colourless, very soluble in water and
stable over pH 4-8), liquid glucose, glycerol, sorbitol, saccharin sodium and
aspartame are mainly used in oral preparations.

Sweeting agents:
The use of artificial sweetening agents (has a higher sweetener power than
sucrose, 100 to 1000 times more sweetener and used in lower conc 0.2%) in
formulations is increasing and, in many formulations, saccharin sodium is used
either as the sole sweetening agent or in combination with sugars or sorbitol to
reduce the sugar concentration in the formulation.
N.B. the artificial sweetener drawback is imparting a bitter/metallic taste.
Therefore, they always used with sugars. The most widely used artificial
sweetener is sodium and calcium salts of saccharin and less widely used is
aspartame.

Sweeting agents:
The use of sugars in oral formulations for children and patients with diabetes
mellitus has to be avoided.
Formulations for diabetic patients will be prepared with sorbitol, mannitol, and
to a lesser extent with glycerol but not sucrose.

Flavours and Perfumes:
Unfortunately the vast majority of drugs in solution are unpalatable and
therefore, the addition of flavours is often required to mask the taste of the
drug substance.
Taste-masking using flavours is a difficult task; however, there are some
empirical approaches that may be taken to produce a palatable formulation.
The four basic taste sensations are salty, sweet, bitter and sour. It has been
proposed that certain flavours should be used to mask these specific taste
sensations in particular:

Flavours that may be used to mask a salty taste include:
Butterscotch
Apricot
Peach
Vanilla
Wintergreen mint.
Flavours that may be used to mask a bitter taste include:
Cherry
Mint
Anise

Flavours that may be used to mask a sweet taste include:
Vanilla
Fruit and berry.
Flavours that may be used to mask a sour taste include:
Citrus flavours
Raspberry.

Usually a combination of flavours is used to achieve the optimal taste-masking
property.
Certain excipients may added to oral solution formulations, referred to as
flavour adjuncts (e.g. menthol, chloroform) that add flavour to the formulation
but, in addition, act to desensitise the taste receptors. Therefore, these agents
augment the taste-masking properties of conventional flavours.

Colors:
Colours are pharmaceutical ingredients that impart the preferred colour to the
formulation.
When used in combination with flavours, the selected colour should match
the flavour of the formulation, e.g. green with mint-flavoured solutions, red for
strawberry-flavoured formulations. Although the inclusion of colours is not a
prerequisite for all pharmaceutical solutions, certain categories of solution
(e.g. mouthwashes/gargles) are normally coloured.
Use of colour allows easy identification of the product by the patient.

Colors:
Types of colours;
(1) natural colouring agents: caramel, chlorophyll and carotenoids, they show
variations in chemical composition and availability as most natural products.
(2) synthetic colouring agents: dyes tend to give bright colours and are more stable
than natural colours. E.g. sodium salts of sulphonic acids

Approaches to improve aqueous solubility of active ingredients:
For poorly soluble drugs, one or more of the following methods
should be used to improve aqueous solubility.
1- Co-solvency
2- Influence of pH of the medium
3- Solubilisation
4- Complexation
5- Chemical modification.
6- Particle size control

(1) Co-solvency
Defined as water-miscible organic solvents that are used in liquid drug
formulations to increase the solubility of poorly water- soluble substances.
Most commonly used blend is water/ethanol blend.
Other suitable solvents are water/sorbitol or glycerol or propylene glycol.
A common example is the elixir, which by definition is a sweetened, hydroalcoholic solution intended for oral use.

(1) Co-solvency
Propylene glycol and water blend: is used to improve the solubility of cotrimoxazole.
The choice of suitable co-solvents is somewhat limited for pharmaceutical use
because of possible toxicity and irritancy, particularly if required for oral or
parenteral use.

(2) Influence of pH of the medium:
Most of the drugs are weak electrolytes (weak acids and weak bases).
Weak acids and weak bases undergo ionization in solution.
Drugs are more soluble in water when they are in the ionized form, unionized drugs are
poorly water soluble.
Ionized drug is in the form of salt, or charged drug, the extent of ionization of drug in a
solution depends on the pH of the medium.

(2) Influence of pH of the medium:
For example:
Acidic drugs (phenobarbital) are more soluble in alkaline pH and begin to precipitate as
the pH decreases. (Increased pH leads to increased ionization leads to increased water
solubility).
Basic drugs (Procaine HCL) are more soluble in acidic pH and begin to precipitate at
alkaline pH due to decrease of drug ionization and formation of insoluble non-ionic form
of the drug.

(3) Solubilisation:
By the addition of a surface active agents (surfactants).
Surface active agents enhance the solubility of poorly water-soluble drugs due
to the formation of micelles. This phenomenon is known as micellar
solubilisation.
Surfactants have polar head and non-polar chain

(3) Solubilisation:
When surfactants are placed in water, at certain concentration (critical micelle
concentration) they will form a micelles by orienting themselves in a way where
the polar heads are exposed into the aqueous medium while the non-polar
chains are oriented towards each other forming the micelles. The poorly
soluble drug (hydrophobic drug) could be encapsulated inside the core of
micelles ended by increase drug solubility in the aqueous medium.

(3) Solubilisation:
The amount of surfactant must be carefully controlled:
A large excess of surfactant: is undesirable because of cost, toxicity, may also
reduce the bioavailability of a drug if it is strongly adsorbed into the micelles.
An insufficient amount of surfactant: may not fully solubilize the drug, or may
lead to precipitation either on storage or on dilution of the product.

Approaches to improve aqueous solubility of
active ingredients:
(3) Solubilisation:
Surfactant chosen must be miscible with the solvent
system, compatible with the other ingredients, free
from disagreeable odour and taste and be nonvolatile.
Examples for solubilization.
Solubilization of fat soluble vitamins such as
phytomenadione using polysorbates.

(3) Solubilisation:
Examples for solubilization.
Antifungal drug such as griseofulvin, which has been formulated with
cetomacrogol.
Use of macrogol ethers with iodine to form iodophores. This product has
several advantages including improved chemical stability, reduced loss of active
ingredients, less corrosion of surgical instruments and enhanced activity.

(4) Complexation:
Interaction of a poorly soluble drug with a soluble material to form a soluble
intermolecular complex.
Examples:
Complexation of iodine with a 10-15% solution of polyvinylpyrrolidone
(PVP), to improve the aqueous solubility of the active agent.
Beta-cyclodexterin and nicotinamide used to increase the solubility of
poorly water soluble drugs.

(5) Chemical modification.
The drug may be chemically modified to produce a water soluble
derivative (usually salt form). Modification of chemical structure
of the drug molecule, by addition of polar groups like carboxylic
acids, ketones and amines. This can increase solubility by
increasing hydrogen bonding and the interaction with water.
Examples: Synthesis of the sodium phosphate salts of
hydrocortisone.

(6) Particle size control:
Decrease the particle size causes an increase in the solubility due to increasing
the surface area of the solid particles. High surface area allows a greater
interaction with the solvent.
The increase in the solubility ceases when the particle size attains very small
radius. Where any further decrease in particle size causes a decrease in
solubility rather than an increase Why?
This is due to generation of
electrostatic charges on the particles that is predominant in small particles

leading to particle aggregations and clumps formation.

Types of pharmaceutical solutions:
1. Orally (Elixirs, Linctuses, Mixture and Draughts)
2. In mouth and throat (mouth washes, gargles, throat sprays)
3. External solutions (collodions, lotions, paints).
4. In body orifices (enemas, ear drops)
5. Intermediate solutions
6. Parenteral solutions
7. Rectal Solutions

1. Orally (Elixirs, Linctuses, Mixture and Draughts)
2. In mouth and throat (mouth washes, gargles, throat sprays)
3. External solutions (collodions, lotions, paints).
4. In body orifices (enemas, ear drops)
5. Intermediate solutions
6. Parenteral solutions
7. Rectal Solutions

Oral solution:
A- Elixirs:
An elixir is a liquid oral preparation that usually contains either potent or
unpleasant-tasting drugs.
The formulation is clear and generally contains a high proportion of sugar or
other sweetening agent, included to mask offensive or nauseating tastes.
Paediatric elixirs are usually formulated with fruity syrup as a base flavouring
agent.
In general, non-aqueous solvents (alcohol, glycerine or propylene glycol) form a
significant proportion of the vehicle used in elixirs, or alternatively solubilising
agents are included.

Oral solution:
A- Elixirs:
Examples of Elixir:
Non-medicated Elixir: such as aromatic Elixir, compound
benzaldehyde Elixir and iso-alcoholic Elixir. This may be useful for
extemporaneous filling of prescriptions involving the addition of
therapeutic agent to a pleasant taste vehicle and dilution of an
existing medicated elixir.

Oral solution:
A- Elixirs:
Examples of Elixir:
Medicated elixir:
Digoxin Elixir USP: Digoxin is a cardiotonic glycoside obtained from
the leaves of digitalis lanata. It is prepared to contain 0.25mg of
digoxin/ 5ml teaspoonful.
Phenobarbital Elixir USP: is a long acting barbiturates giving
sedation effect in treatment of children, infant and certain adult
patients it contains 20mh/ 5ml teaspoonful

Oral solution:
B- Mixtures and Draughts:

Mixtures: Simple liquid preparations intended for oral use
containing dissolved medicaments may be described as oral
solutions or mixtures.
Draughts: A draught is an older term used to describe a liquid
preparation formulated as a single dose, in a volume which is
larger than generally utilised in traditional mixture formulations.
Each draught was usually supplied in a 50mL unit dose container.

Oral solution:
(2) Mouthwashes and Gargles:

Gargles and mouthwashes are aqueous solutions that are
intended for treatment of the throat (gargles) and mouth
(mouthwashes) and are generally formulated in a concentrated
form.
Mouthwash contains 5 groups of excipients;
(1) Alcohols, (2) Humectants, (3) surfactants, (4) flavours, (5)
colouring agents.

Oral solution:

(1) Alcohols (10-20%): It enhances the flavour, provide sharpness of
taste, aids in masking unpleasant taste of active ingredients, act as a
solubilizing agent for some flavouring agents and may act as a
preservatives.
(2) Humectants: e.g. Glycerine and sorbitol. Forms 5 - 20% of the
mouthwash. They increase the viscosity of the preparation,
enhances the sweetness of the product. Along with alcohol, they
improve the preservatives qualities of the product.

Oral solution:

(3) Surfactants: non-ionic surfactant (0.1 0.5%) are used while
anionic surfactants such as sodium lauryl sulphate is occasionally
used. Surfactants are used because they aid in solubilisation of
flavours and in the removal of debris by providing foaming
(4) Flavours: used along with alcohol and humectants to overcome
the disagreeable taste. The main flavouring agents used are;
peppermint, cinnamon.

Oral solution:

Gargles
They are aqueous solution contains antiseptic, antibiotics and/or
anaesthetic used for treating pharynx and nasopharynx by forcing
air from the lungs through the gargle that is held in the throat,
then gargles is expectorated. Many gargles must be diluted with
water prior use. E.g 7.5% povidone-iodine and 35%alc is used as
gargles or mouthwash after dilution with water.

Oral solution:

Gargles
These preparations must be diluted before use and care should be
taken to ensure that appropriate instructions are included on the
label and that the container used will be easily distinguishable
from those containing preparations intended to be swallowed.

Oral solution:
(3) External solutions:

They are solutions developed for external application
Lotions:
Lotions are solutions, but may also be suspensions or emulsions,
that are intended to be applied to the skin without friction on a
carrier fabric such as lint and covered with a waterproof dressing. In
some cases lotions are applied to the scalp, where the vehicle for the
medication is alcohol based, allowing for rapid drying of the hair and
thus making the product more acceptable to the patient (e.g.
Salicylic Acid Lotion 2% BPC). In these cases, problems of
flammability are addressed by suitable labelling.

Oral solution:

Liniments: A liniment is a liquid preparation intended to be rubbed
with friction and massaged onto the skin to obtain analgesic,
rubefacient or generally stimulating effects. Liniments should not be
used on a broken skin to avoid irritation. They are usually solutions
of oils, alcohols or soaps, but may be formulated as emulsions.
Usually Oleaginous liniments are less irritant than alcoholic liniment.

Oral solution:
Collodions:
These
are
principally
solutions
of
pyroxylin
(nitrocellulose) in a vehicle of ether and alcohol that are intended to

be painted onto the skin and left to dry. When dry, the collodion
leaves a flexible film of cellulose on the skin which may be used to
seal minor injuries or retain a dissolved drug in contact with the skin
for an extended period. Collodions are highly volatile and highly
flammable and care should be taken to label any preparation
appropriately.

Oral solution:
Collodions:
E.g. Salicylic acid Collodion (10%): it is used for its keratolytic effect
to remove corns from toes. The product applied as a one drop at a
time onto the corn or wart allowing time to dry before the next drop
is added. Salicylic acid can be irritant to the normal skin. Therefore
the adjacent skin should be lined healthy with some white
petroleum prior product application.

Oral solution:
Paints:
Liquids for application to the skin or mucous membranes in small
amounts and are usually applied with a small brush. The solvent is
normally alcohol, acetone, ether that evaporates quickly leaving a
film on the skin that contains the active ingredient. A viscosity
modifier (Glycerol) is added to ensure prolonged contact with the
skin.

Oral solution:
(4) In body orifices:
A- Ear Preparations:
Known as Otic or aural products
Prepared for local use including antibiotics, antiseptics, cleansing
solutions and wax softners. Drugs are dissolved in a solvent that is
water, glycerol, propylene glycol or alcohol/water mixtures.
They applied to auditory canal as drops, sprays or washes.

Oral solution:
B- Eye Preparations:
These are small volume sterile liquids designed to be instilled on to
eyeball or within the conjunctival sac for local effect.
C- Irrigations:
They are sterile, large volume aqueous solutions for the cleansing of
the body cavities and wounds.
They should be made isotonic with tissue fluid.

Oral solution:
D- Nasal Products:
They are formulated as small volume solutions of an aqueous
vehicle. Oil are no longer used because the buffering capacity of
nasal mucus is low.
pH is necessary to be at 6.8.
Should be isotonic with nasal secretions. Isotonicity is adjusted by
sodium chloride.

Oral solution:
E- Nasal Products:
Viscosity could be modified with cellulose derivatives
Antibiotics,
Anti-inflammatory,
formulated as nasal products.
decongestants
are
drugs

Oral solution:
E- Douches:
They are an aqueous solution applied into a part or a cavity of the
body for cleansing or antiseptic purpose.
Eye douches: used to remove the foreign particles and discharges
from the eyes. It is directed gently at an oblique angle and
allowed to run from the inner to the outer corner of the eye.

Oral solution:
E- Douches:
Pharyngeal douches: used to prepare the interior of the throat
for an operation and cleanse it
Vaginal douches: the most common type of douches and used for
irrigative cleansing of the vagina and for hygiene purposes. Liquid
concentrate or powders may be diluted in a warm water prior use

Oral solution:
E- Douches:
Vaginal douches:
Ingredients of vaginal douches include the following:
Antiseptic: e.g boric acid or sodium borate

Astringents: zinc sulphate, ammonium alum
Quaternary ammonium compounds: as benzalkonium chloride
Detergents: sodium lauryl sulphate
Oxidizing agents: sodium perborate
Salts to alter pH such as sodium citrate, sodium bicarbonate
Anaestics or antipruritics: eg. Phenol / menthol
Aromatics as thymol/ menthol

Oral solution:
(5) Intermediate products:
A- Aromatic waters and Spirits:
They are pharmaceutical solutions that are used during manufacture
of other preparations.
(1) Aromatic waters: are aqueous solutions of volatile materials that
are used mainly for their flavouring properties.
Aromatic waters such as peppermint water and anise water
have carminative properties and chloroform water has a
preservative action.
They manufactured as concentrated waters and are then
diluted, traditionally 1:40 in the final preparation.
(2) Spirits: Alcoholic solutions of volatile materials that are used as a
flavouring agent.

Oral solution:
B- Extracts, Infusions and Tincture:
They are terms used for concentrated solutions of active principles

from animal or vegetables sources
Infusions: They are prepared by extracting the drug using 25%
alcohol but without the application of heat, traditionally they are
diluted 1:10 in the final product.
Extracts: They are similar products to Infusions but they are
concentrated by evaporation

Oral solution:
Tinctures: They are alcoholic extracts of the drug but they are
relatively weak compared to Extracts.
E.g. Iodine Tincture: prepared by dissolving 2% iodine crystals and
2.4% potassium iodide in an amount of alc equal to half the volume
of tincture to be prepared. Then dilution of the solution to the
required volume with water.

Oral solution:
Tinctures:
Iodine react with potassium iodide to form tri-iodide (improved
water solubility) that prevents formation of ethyliodide that will be
accompanied by loss of the antibacterial activity.

Oral solution:
C -Syrups:
Syrups are highly concentrated, aqueous solutions of one or more

sugar component or a sugar substitute that traditionally contain a
flavouring agent, e.g. cherry syrup, cocoa syrup, orange syrup,
raspberry syrup.
An unflavoured syrup is available that is composed of an aqueous
solution containing 85% sucrose.

Oral solution:
C -Syrups:
Therapeutic agents may either be directly incorporated into these

systems or may be added as the syrup is being prepared. If the
former method is employed, it is important to ensure that the
therapeutic agent is soluble within the syrup base It should also
be remembered that the choice of syrup vehicle must match the
physicochemical properties of the therapeutic agent.

Oral solution:
C -Syrups:
For example, cherry syrup and orange syrup are acidic and
therefore the solubility of acidic or some zwitterionic therapeutic
agents may be lowered and may result in precipitation of the drug
substance. Under these circumstances, the physical stability of the
preparation will have been compromised and the shelf-life of the
product will have been exceeded. The use of acidic syrups may
additionally result in reduced chemical stability for acid-labile
therapeutic agents.

Oral solution:
C -Syrups:
The major components of syrups are as follows:

Purified water
Sugar (sucrose) or sugar substitutes (artificial sweeteners).

Oral solution:
C -Syrups:
Traditionally syrups are composed of sucrose (usually between 60

and 80%) and purified water. Due to the inherent sweetness and
moderately high viscosity of these systems, the addition of other
sweetening agents and viscosity-modifying agents is not required.
In addition, the high concentration of sucrose and associated
unavailability of water (termed low water activity) ensures that
the addition of preservatives is not required.

Oral solution:
C -Syrups:
As the concentration of sucrose is reduced from the upper limit

(e.g. through dilution), the addition of preservatives may be
required.
In some formulations, other non-sucrose bases may replace
traditional syrup.

Oral solution:
C -Syrups:
One of the most popular is Sorbitol Solution USP, which contains
64% w/w sorbitol (a polyhydric alcohol), although other
alternatives are available that are based on mixtures of sorbitol
and glycerin. These non-sucrose bases may be mixed with
traditional syrups, if required, in the formulation of oral syrups
that possess a low concentration of sucrose in comparison to
traditional syrups.

Oral solution:
C -Syrups:
More recently, many products have been formulated as

medicated sugar-free syrups due to the glycogenetic and
cariogenic properties of sucrose.
For the afore-mentioned reasons, all medicinal products designed
for administration to children and to diabetic patients must be
sugar-free. Syrup substitutes must therefore provide an
equivalent sweetness, viscosity and preservation to the original
syrups.

Oral solution:
C -Syrups:
To achieve these properties artificial sweeteners (typically
saccharin
sodium,
modifiers
(e.g.
preservatives
aspartame),
methylcellulose,
(e.g.
sodium
non-glycogenetic
viscosity
hydroxyethylcellulose)
benzoate,
parahydroxybenzoate esters) are included.
benzoic
acid
and
and

Oral solution:
C -Syrups:
Classification of Syrup:
(1) Simple Syrup,
(2) Medicated Syrup,
(3) Flavoured Syrup,
(4) Invert Syrup.

Oral solution:
C -Syrups:
Simple Syrup: sucrose (65 85% w/w) in purified water with a
specific gravity 1.3.
Medicated syrup: Aqueous saturated solution of sugar contains
one or more medicinal agent.
Flavoured Syrup: contains aromatic or flavoured agents and has
no medicinal substance. Used as a vehicle or flavour for
prescription.

Oral solution:
C -Syrups:
Invert Syrup: According to BPC (British Pharmacopeia Codex), it is
formed by hydrolysis of sucrose by hydrochloric acid and
neutralization with sodium or calcium carbonate. Invert syrup
contains 66.7% w/w sucrose. Levulose formed due to hydrolysis
has more sweetener activity (1.23 times sucrose). Levuloase is
sensitive to heat and darken very fast. This explains why the
solution is darkened after hydrolysis of sucrose. The addition of
inverted syrup to the syrup, it prevents the sucrose crystal
decomposition during storage.

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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

(2) The presence of micelles:

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