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LIQUID PREPARATIONS
Objectives:
•Discuss the advantages and disadvantages of solutions
•Identify the sources of instability.
•Discuss the pharmaceutical considerations of solutions
•Discuss different classifications of Solutions
•Solutions, Emulsions, Suspensions
Prepared by dissolving the active ingredients in an aq. solvent
Suspending the drug in an appropriate medium or by incorporating the agent into one phase or 2 phase of an o/w system
Advantages:
• Readily available for absorption
• Easier to swallow
• Homogenous
• Reduced gastric irritation caused by certain solid doses from drugs
• Formulated for different routes
• Can be easily adjusted by dilution
Disadvantages
• Less stable
• Susceptible to microbial contamination
• Unpleasant taste or odor are difficult to mask
• Bulky
• Less precise in dosage administration
• Suspension & emulsions have the added drawback thoroughly shaken to allow accurate dosing
Sources of Instability of Liquid Preparations
•pH
•Temperature
•Concentration of reactants
•Light or radiation
•Packaging components
Considerations in the Formulations of Liquids
1.SOLUBILITY
2.STABILITY
3.PRESERVATIVE
4. SWEETENING AGENTS
5.VISCOSITY
6.FLAVORS
7.COLORING AGENTS
8.APPEARANCE
SOLUBILITY
• Can be increased by pH control or by the addition of buffer – w/c will not affect the stability of the product & organoleptic characteristics
Co-solvents can be used
Alcohol
Sorbitol
Glycerin PG
STABILITY
• A solution must retain its clarity, color, odor, taste and viscosity over its shelf life.
Consider the package and the effect of
the package
Stability of the active ingredient in the final
product
PRESERVATIVESolution may become contaminated for a number of reasons:
1.Raw materials used in the manufacture of solutions are excellent growth media for bacterial substances such as gums, dispersing agents, sugars and flavors
2.Equipment, environment and personnel contribute to product contamination.
3. Consumer use may result in the
introduction of microorganism.
➔ a preservative should be added to
the product
PRESERVATIVE
Preservative should be:
1.Effective against a wide spectrum of microorganisms
2.Stable for its shelf life
3.Non toxic, non sensitizing
4.Compatible with the ingredients in the dosage form
5.Free of taste and odor
ACIDIC NEUTRAL MERCURIAL QUATERNARY AMMONIUM COMPOUNDS
PHENOL (0.2-0.5%)
CHLOROBUTANOL(0.5%)
THIOMEROSAL (0.001-0.1%)
BENZALKONIUM CHLORIDE (0.004-0.02%)
CHRLOROCRESOL(.05-0.1%)
BENZYL ALCOHOL (1.0%)
PHENYL MERCURIC ACETATE & NITRATE (0.002-0,005)
CETYLPYRIDINIUM CHLORIDE (0.01-0.02%
O-PHENYL-PHENOL (0.005-0.01%
A-PHENYL ETHYL ALCOHOL (0.2-1.0%)
NITROMERSOL (0.001-0.1%
ALKYL ESTERS OF PARAHYDROXYBENZOIC ACID (0.001-0.2%)
BENZOIC ACID and SALTS (0.1-0.3%)
BORIC ACID (0.5-1.0%)
SORBIC ACID (0.05-0.2%)
Preservatives may be used alone or in combination to
prevent the growth of microorganisms.
Alcohols
Ethanol is useful as a preservative when it is used as a solvent.
It needs a relatively high concentration (> 10%) to be effective.
Propylene glycol also used as a solvent in oral solutions and
topical preparations. It can function as a preservative in the
range of 15 to 30%. It is not volatile like ethanol.
Acids
Benzoic acid and sorbic acid have low
solubility in water.
They are used in a concentration range
from 0.1 % to 0.5%.
Only the non-ionized form is effective
and therefore its use is
restricted to preparations with a pH
below 4.5
Esters
Parabens are esters (methyl, ethyl, propyl and butyl) of p-
hydroxybenzoic acid.
They are used widely in pharmaceutical products and are
effective and stable over a pH range of 4 to 8.
They are employed at concentrations up to about 0.2%.
Frequently 2 esters are used in combination in the same
preparation WHY?
- To achieve a higher total concentration
- To be active against a wider range of microorganisms.
Quaternary Ammonium Compounds
Benzalkonium chloride is used at a relatively low
concentration 0.002 to 0.02%.
This class of compounds has an optimal activity over the
pH range of 4 to 10 and is quite stable at most
temperatures.
Because of the cationic nature of this type of preservative
it is incompatible with many anionic compounds.
SWEETENING AGENTS
•Sucrose is the most widely used sweetening agent.
Advantages: Colourless, highly water soluble, stable over a wide pH range (4-8), increase the viscosity, masks both salty and bitter taste, has soothing effect on throat.
•Polyhydric alcohols (sorbitol, mannitol and glycerol) possess sweetening power and can be
used for diabetic preparations.
•Saccharin. Used to supplement sugars and polyols as sweeteners• Approx 250 to 500 x as sweet as sugar• Have a bitter aftertaste if not properly used in the
formula.
•Aspartame. A synthetic sweetener that is 200
times sweeter than sucrose and no aftertaste
VISCOSITY-ENHANCING AGENTS
•Used to improve palatability and ease of pourability
•Can be achieved by increasing the sugar concentration or incorporating viscosity controlling agents • Polyvinylpyrrolidone (PVC)• Cellulosic derivatives (methyl cellulose, CMC)
FLAVORS
Mask unpleasant taste or odour
Enable the easy identification of the product.
Natural products: fruit juices, aromatic oil (peppermint, lemon)
Artificial perfumes are cheaper, more readily available and more stable than natural products.
FLAVORS
•Fruit flavors• Disguise acid or sour taste
•Butterscotch, liquorice, cinnamon• Effective w/ salty taste
•Salty taste, chocolate, anise and fruit flavor• Mask bitter taste
•Chloroform, menthol• Mild local anesthetic, and soothing effect
Flavors may be chemically unstable because of oxidation, reduction, or hydrolysis and stability may be affected
COLORING AGENTS
•To mask unpleasant appearance or increase the acceptability of the preparation to the patient
•Acceptability may be enhanced by inclusion of a color that is closely associated with the flavor.
Requirements for dyes:
• Non toxic
• Non irritant
• Compatible with the active and other ingredients of the preparation
• Solubility
• Stability and compatibility
3 categories:
1. Mineral pigments❑ Iron oxide – used in solid pharmaceutical dosage form
and preparation for external use❑ Low solubility in liquids
2. Natural colorants❑ Anthocyanins, carotenoids, chlorophylls, xantophylls,
riboflavin, saffron and caramel❑ Used for oily or fatty products
3. Synthetic organic dyes
3. Synthetic Organic dyes❑Commonly known as “coal tar” dyes❑Preferred to natural colorants because they
provide a wider range of bright and stable colors
APPEARANCE
• Overall – depends on the color and clarity
• Purification step is required to achieve maximum clarity
• “polishing” – removal of particulate matter may be accomplished by:1. Settling and subsequent decantation2. Centrifugation3. Filtration – practical method when large volume are
involved
MANUFACTURING CONSIDERATIONS
RAW MATERIALS
EQUIPMENT
COMPOUNDING PROCEDURE
PACKAGING
Raw Materials
• Should conform to specification which should assure identity, purity, uniformity and freedom from excessive microbial contamination.
• Incoming raw materials – should be impounded and thoroughly tested before they are release
• Water is most important constituent as a vehicle
WATER
Water is used both as vehicle and as a solvent for the desired
flavoring or medicinal ingredients.
Advantages: Tasteless, odourless, lack of pharmacological
activity, neutral and very cheap
Tap Water
It is not permitted to use tap water for the dispensing of
pharmaceutical dosage forms due to its possible bacterial
contamination and the presence of dissolved salts that destroy the
active ingredients or enhance their decomposition.
Freshly Boiled and Cooled Water
Boiling is seldom used to destroy
vegetative bacteria. But, on storage for
long time spores may yield vegetative
microorganism.
Purified Water
Must be used for most pharmaceutical operations
and in all the tests and assays.
Such water is prepared by distillation, deionization or
reverse osmosis.
"Hard" waters are those that contain the Ca and Mg
cations.
“Alkaline" waters are those that contain bicarbonates
as the major impurity.
Ultraviolet energy, heat or filtration (Millipore filtration)
can be used to remove or kill the microorganisms
present in the water.
Water for injection
Must be used for the formulation of
parental solutions.
It is obtained by sterilizing pyrogen-free
distilled water.
Techniques employed for purification of water
•Reverse osmosis
•Purification
•UV sterilization
•Membrane filtration
EQUIPMENT
•Mixing tanks equipped with a means of agitation, measuring devices and filtration system, sterilization
PACKAGING
• The specific method used for filling a pharmaceutical liquid varies greatly depending on the characteristic of a liquid (viscosity, surface tension, foam producing qualities and compatibility with the materials used in the construction of the filling machine.
Three basic filling methods
1. Gravimetric
2. Volumetric
3. Constant level
Gravimetric method
•Limited to large containers or to highly viscous products.
Volumetric method
•Accomplished by the pumping of a liquid at a constant pressure through an orifice of constant size
Constant level filling
•Uses the containers as the means of controlling the fill of each unit.
Common problem encountered in filling liquids
Excessive foam
Foaming during the filling operation
often can be decreased by filling
equipment that minimizes product
turbulence, closed system filling to limit
the introduction of air or gases
Addition of defoaming device
SOLUTIONS
•Homogenous mixture prepared by dissolving a solid, liquid, or gas in another liquid
Classification of Solutions According to Vehicle
(a) Aqueous solutions
(b) Non-aqueous solutions
Aqueous Solutions
Aqueous solutions are homogeneous mixtures that are
prepared by dissolving a solid, liquid or gas in an aqueous
medium (vehicle).
Vehicle: This may be water, aromatic water or extracts.
Pharmaceutical Solutions
Aqueous1. Douches
2. Enemas
3. Gargles
4. Mouthwashes
5. Nasal washes
6. Juices
7. Sprays
8. Otic solutions
9. Inhalations
Sweet &/or Viscid
1.Syrups
2.Honeys
3.Mucilages
4.Jellies
Nonaqueous
1.Elixirs
2.Spirits
3.Collodions
4.Glycerins
5.Liniments
6.Oleo Vitamin
Douches
Douche is an aqueous solution, which is directed against a part
or into a cavity of the body.
It functions as a cleansing or antiseptic agent.
Douches most frequently dispensed in the form of a powder
with directions for dissolving in a specified quantity of water.
Enemas
These preparations are rectal injections employed to:
▪ evacuate the bowel (evacuation enemas),
▪ influence the general system by absorption (retention
enemas) e.g. nutritive, sedative or stimulating properties
▪ affect locally the site of disease (e.g. anthelmintic property)
▪ they may contain radiopaque substances for
roentgenographic examination of the lower bowel.
Retention enemas are used in small quantities (about 30ml)
and are thus called retention microenema.
Gargles• Aq solutions frequently containing antiseptics,
antibiotics or anesthetics used for treating the pharynx and nasopharynx by forcing air from the lungs through the gargle that is held in the throat.
Mouthwashes
•Aq. solutions often in concentrated form containing one or more active ingredients and excipients.
•Used by swishing the liquid in the oral cavity. Used for 2 purpose: therapeutic & cosmetic
These include Syrups, Honeys, Mucilages, and
Jellies. All of these preparations are viscous
liquids or semisolids. The sweetness and viscid
appearance are given by sugars, polyols, or
polysaccharides (gums).
SYRUPS Syrups are concentrated solutions of sugar such as sucrose in
water or other aqueous liquid.
simple syrup: when water is used alone for making syrup.
medicated syrup: when the aqueous preparation contains
some added medicinal substance
flavored syrup: which contains aromatic or pleasantly
flavored substances and is intended to be
used as a vehicle or flavor for prescriptions
HONEYSAre thick liquid preparations. At one time, before sugar was available, honey
was used as a base, instead of syrup.
MUCILAGES
▪ The official mucilages are thick viscid, adhesive liquids, produced by
dispersing gum (acacia or tragacanth) in water.
▪Mucilages are used as suspending agents for insoluble substances in
liquids; their colloidal character and viscosity prevent immediate
sedimentation.
▪ Synthetic agents e.g. carboxymethylcellulose (CMC) or polyvinyl alcohol are
non-glycogenetic and may be used for diabetic patients.
Jellies
▪ A class of gels in which the structural coherent matrix
contain high portion of liquid, water.
▪ Preparations having a jelly-like consistency. They are
prepared also from gums.
▪ Are used as lubricants for surgical gloves and catheters
▪ Lidocaine HCl Jelly USP is used as a topical
anaesthetic.
Advantages
▪ If the drug is not completely soluble or unstable in
aqueous medium it may be necessary to use an
alternative non-aqueous solvent.
▪Oily solutions of drugs are often used for depot therapy
e.g. in muscles (Depo Provera and haloperidol
decanoate.)
▪Note: depot therapy is in Long-acting forms of
subcutaneous/intramuscular injections
This section is devoted to four groups of non-
aqueous solutions:
1. alcoholic or hydroalcoholic solutions, e.g. elixirs and
spirits,
2. ethereal solutions, e.g. the collodions
3. glycerin solutions, e.g. the glycerites,
4. oleaginous soIutions e.g. the liniments, medicated oils,
oleo-vitamins, sprays, and toothache drops.
ELIXIRS
▪ Are clear, pleasantly flavored, sweetened hydroalcoholic
liquids intended for oral use.
▪ They are used as flavors and vehicles e.g. Dexamethasone
Elixir USP and Phenobarbital Elixir USP.
▪The main ingredients in elixirs are ethanol
and water but glycerin, sorbitol, propylene
glycol, flavoring agents, preservatives, and
syrups are often used in the preparation of the
final product.
▪EIixirs contain ethyl alcohol, however, the
alcoholic content will vary greatly, from elixir
containing only a small quantity to those that
contain a considerable portion as a necessary
aid to solubility
SPIRITS
▪Alcoholic or hydroalcoholic solutions of volatile substances. The
active ingredient may be gas, liquid or solid.
▪Spirits may be used internally for their medicinal value, by
inhalation but is mostly used as flavouring agents.
▪Spirits should be stored in tight, light-resistant containers and in
a cool place,
▪Spirits are preparation of high alcoholic strength and when
diluted with aqueous solutions or liquids of low alcoholic content
turbidity may occur.
COLLODIONS
▪Are liquid preparations containing pyroxylin (a
nitrocellulose) in a mixture of ethyl ether and ethanol.
▪ They are applied to the skin by means of a soft brush or
other suitable applicator and, when the ether and
ethanol have evaporated, leave a film of pyroxylin on the
surface.
GLYCERINS
▪Glycerins or glycerites are solutions or mixtures of
medicinal substances in not less than 50% by weight of
glycerin.
▪Most of the glycerins are extremely viscous.
▪Glycerin is a valuable pharmaceutical solvent forming
permanent and concentrated solutions not otherwise
obtainable.
▪Glycerins are hygroscopic and should be: stored in
tightly closed containers.
LINIMENTS
▪ Are alcoholic or oil-based solutions or emulsion containing
therapeutic agents intended for external application
▪ They are applied with rubbing to the affected area,
embrocations
▪ Alcoholic liniments are used generally for their rubefaciant
and counterirritant effects. Such liniments penetrate the skin
more readily than do those with an oil base.
▪ Oily liniments, have milder action but are more useful when
massage is required.
Rubefacient
a substance for external application that
produces redness of the skin e.g. by causing
dilation of the capillaries and an increase in
blood circulation.
Counterirritant
a medicine applied locally to produce superficial
inflammation in order to reduce deeper
inflammation
OLEO VITAMINS
▪ Oleo vitamins are fish liver oils diluted with edible
vegetable oil or solutions of the indicated vitamins
(usually vitamins A and D).
▪ The indicated vitamins are unstable in the presence of
rancid oils and, therefore, those preparations, should
be stored in small, tight containers, preferably under
vacuum or under an atmosphere of an inert gas,
protected from light.