Liquid Prep - Merged
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Transcript of Liquid Prep - Merged
LIQUID PREPARATIONS
Marilyn A. Ngo,
M.S. Pharmacy
Liquid Preparations may be dispensed in one of 3 ways
In its original container
Repacking a bulk product at the time a
prescription is presented by the patient
Compounding the solution, suspension or
emulsion in the dispensary
Classification of Liquid Preparation
Solutions (single phase system)
Mixtures (two phase system)
Galenicals (extractives)
Sterile Products
Oral Solutions
Homogenous mixtures of one or more solutes
dissolved in suitable solvent or mixture of
mutually miscible solvents
Solutions are classified on the basis of physical
properties, method of preparation, use and
type of ingredients
Syrup, Elixir, Spirit, Aromatic water, tincture,
fluidextract
ADVANTAGES OF SOLUTIONS AS AN ORAL DOSAGE FORM
Liquids are easier to swallow than solids and
are therefore particularly acceptable for
pediatric and geriatric use
A drug must usually be in solution before it can
be absorbed
Solution is a homogenous system and
therefore the drug will e uniformly distributed
throughout the preparation
DISADVANTAGES OF SOLUTIONS AS AN ORAL DOSAGE FORM
Liquids are bulky and therefore inconvenient to transport and store
Stability of ingredients in aqueous solution is often poorer than if
formulated as a tablet or capsule
Solutions often provide suitable media for the growth of
microorganisms and may therefore require the incorporation of a
preservative
Many liquid preparations are designed so that the normal dosage
of the drug is present in 5mL, or a multiple of 5 mL, of the product
The taste of a drug, which is usually unpleasant, is always more
pronounced when in solution than in solid form
Design & Formulation
Involves the combination of ingredients with medicinal agents to enhance the acceptability of effectiveness of the product
Several considerations- concentration of the drug, solubility of the drug, selection of the liquid vehicle, physical and chemical stability, preservation of the preparation, appropriate excipients such as buffers, solubilizers, sweetening agents, viscosity controlling agents, color and flavors
Successful design and formulation of liquids, as well as other dosage forms, requires both scientific and pharmaceutical acuity
Solubility
Solubility of a substance at given temperature is defined as quantitatively as the concentration of the dissolved solute in a saturated solution (I.e. the dissolved-solute phase)
Generally, the drugs are present in solution at unsaturated concentrations, otherwise, the drug may crystallize as a result of changes in temperature or by “seeding” from other ingredients or particulate matter present
Effects of pH, effect of molecular structure, effect of temperature
Solubilization Techniques
Solubilization – process by which the apparent
solubility of a poorly water soluble substances
is increased
Any material can be solubilized in any solvent
by proper choice of solubilzing agent
Techniques include addition of cosolvent, salt
formation, prodrug method, micellization
Stability
Drug substances in general are less stable in liquid media than in the solid dosage form.
It is necessary to consider the effects upon stability caused by excipients such as colorants, flavors, preservatives, solubilizers, thickening agents, sweetening agents
Chemical Stability – consider both the pH solubility profile and stability profile in order to select the optimum pH for formulating the liquid oral dosage form
Physical Stability – involves the formation of precipitate, less soluble polymorph, adsorption of the drug substances onto container surfaces, microbial and product appearance
The acceptability of the product is a subjective evaluation and includes properties such as color, odor, taste and clarity
CHOICE OF SOLVENT
Aqueous solutions
Non-aqueous solutions
Miscellaneous solutions
Aqueous Solutions
Purified Water
Water for Injections
Although water is very widely used for inclusion
in pharmaceutical preparations, it may not be
possible to ensure complete solution of all
ingredients at all normal storage temperatures.
Cosolvency, pH, solubilization, complexation,
chemical modification, particle size control
Water
Purified water is obtained by deionization,
distillation, ion exchange, reverse osmosis,
filtration or other suitable procedures
Water for Injections, Bacteriostatic Water for
Injections, or Sterile Water for Injections – for
parenteral administration
Major impurities in water are calcium, iron,
magnesium, silica and sodium
Non-Aqueous solutions
Fixed oils of vegetable origin
Alcohols
Polyhydric alcohols
Dimethylsulphoxide
Ethyl ether
Liquid paraffin
Alcohols
Second most commonly used solvent in
pharmaceutical industry for many organic compounds
When mixed with water, a hydroalcoholic mixture is
formed capable of dissolving both alcohol-soluble and
water-soluble substances, a feature especially useful
for extraction and purification of active constituents
from crude drugs and synthetic procedures
Alcohol, diluted alcohol, rubbing alcohol, isopropyl
rubbing alcohol
Recommended Alcohol content OTC oral drugs
Children under 6 years of age – 0.5%
Children 6 to 12 years of age – 5%
Children over 12 years of age and adults –
10%
Glycerin
Clear, syrupy liquid with a sweet taste and is miscible with water and alcohol
Used in wide variety of pharmaceutical formulations include oral, otic, ophthalmic, topical and parenteral preparations
In topical preparations, glycerin is used for its humectant and emollient properties
In oral preparations, glycerin is used as solvent, sweetening agents, antimicrobial preservatives and viscosity increasing agent
Propylene Glycol
Widely used as solvent, extractant, preservative in a variety of liquid pharmaceutical formulations including parenteral
Viscous liquid and miscible with water and alcohol
Often used in place of glycerin
As an antiseptic it is similar to ethanol, and against molds it is similar to glycerin and only slightly less effective than ethanol
Used as carrier for emulsifiers and as vehicle for flavors, as opposed to ethanol, due to its lack of volatility
Miscellaneous Solvents
Isopropyl myristate and isopropyl palmitate
Dimethylformamide and dimethylacetamide
Kerosene
Xylene
Glycofurol
Other Formulation Additives
Buffers
Density modifiers
Isotonicity modifiers
Viscosity enhancement
Preservatives
Reducing agents and antioxidant
Sweetening agents
Flavors and perfumes
Colors
Buffers
These are materials which, when dissolved in a solvent, will enable the solution to resist any change in pH should an acid or alkali be added
Carbonates, citrates, gluconates, lactates, phosphates, tartrates
Most body fluids has a pH of 7.4
Although buffers ensure pH stability, the buffer system can effect other properties such as solubility and kinetics
Can act as general-acid or general-base catalysts and cause degradation of the drug substance. Ionic strength contribution of the buffer systems can also effect stability. Therefore, the effect of buffer species should be studies before selecting any buffer system
Buffers Commonly Used in Liquid Pharmaceutical Products
Buffer pH Usual conc (%)
Acetic acid and a
salt
3.5-5.7 1-2
Citric acid and a
salt
2.5-6 1-3
Glutamic acid 8.2-10.2 1-2
Phosphoric acid
salts
6-8.2 0.8-2
Density Modifiers
It is rarely necessary to control the density of
solutions EXCEPT when formulating spinal
anesthetics
Solutions of lower density than cerebrospinal
fluid will tend to rise after injection and those of
higher density will fall
Most widely used material for density
modification is DEXTROSE
Isotonicity Modifiers
Compounds contributing to the isotonicity of a
product reduce the pain of injection in areas
with nerve ending
Buffers may serve as tonicity contributors as
well as stabilizers for pH
Dextrose and NaCl
Viscosity Enhancement
It may be difficult for aqueous based topical
solutions to remain in place on the skin or in
the eyes for any significant time because of
their low viscosities
To counteract this effect, low concentrations of
gelling agents can be used to increase the
apparent viscosity of the product
Povidone, hydroxyethylcellulose, carbomer
Preservatives
When choosing a suitable preservative it must be ensured that: adsorption of the preservative onto the container from the product does not occur; and its efficiency is not impaired by the pH of the solution or by the interactions with other ingredients
Must fulfill certain criteria for acceptability – safety and lack of toxicity after oral intake; must be soluble, stable and microbiologically active; compatible with the active ingredients as well as other components of the formulation
In general, alcohol content of 15% by weight in acid solutions and 18% by weight, in alkaline solutions is sufficient to prevent microbial growth
Most alcohol containing preparations such as elixirs, spirits, tinctures are self preserving and will not require preservation
Alcohols
Ethanol is useful as preservatives when it is used as solvent, however, it does need a relatively high concentration, somewhat greater than 15% to be effective
Too high concentration may result in incompatibilities in suspension and emulsion system
Propylene glycol is used as solvent in oral solution and topical preparations, and it can function as a preservatives in the range of 15 to 30%
Chlorobutanol and phenylethyl alcohol, used in lower concentrations (about 1%) as preservatives
Acids
Benzoic acids, sorbic acid
Benzoic acid has low solubility in water,
inhibitory action varies from 0.1-0.5%, activity
depends on the pH of the medium because
only the undissociated acid has antimicrobial
properties. Optimum activity occurs at pH
values below 4.5 and pH values above pH 5,
benzoic acid is almost inactive
Esters
Parabens are esters of p-hydroxybenzoic acid and include methyl, ethyl, propyl, butyl derivatives
Water solubility of the parabens decreases as the molecular weight increases, from 0.25% for the methyl ester to 0.02% for the butyl ester
Stable over a pH range 4-8
Broad spectrum of antimicrobial activity,and most effective against molds and yeasts
Antimicrobial activity increases as the chain length of the alkyl moiety is increased but aqueous solubility decreases, therefore a mixture of parabens is frequently used to provide effective preservations
Quarternary Ammonium Compounds
Benzalkonium Chloride – mixture consisting principally
of homologs C12H25 and C14H29. This preservative is
used at relatively low concentrations (0.002-0.02%)
Optimal activity over the pH 4-10. Stable at room
temperature
Because of its cationic nature – it is incompatible with
many anionic compounds such as surfactants and can
bind to nonionic surfactants
Used as external preservatives
Antimicrobial Preservatives
Benzalkonium chloride, benzathonium chloride, benzyl alcohol, bronopol
Centrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorcresol, cresol
Ethanol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylmercuric nitrate
Propylene glycol, thimerosal
Antifungal Preservatives
Butyl parabens, methyl paraben, ethyl
paraben, propyl paraben
Benzoic acid, potassium sorbate
Sodium benzoate, sodium propionate
Sorbic acid
Common Preservatives Used in Pharmaceutical System
Acidic – Phenol (0.1-0.5%), alkyl esters of p-hydroxybenzoic acid (0.001-0.2%), benzoic acid and its salt (0.1-0.3%), boric acid and its salt (0.5-1%)
Neutral – chlorobutanol (0.5%), benzyl alcohol (3%)
Mercurial – thiomersal (0.001-0.1%), nitromersol (0.001-0.1%)
Quarternary ammonium compounds – benzalkonium chloride (0.002-0.02%), cetylpyridinium chloride (0.0005-0.0007%)
Esters – butyl paraben (0.1-0.4%), methyl paraben (0.1-0.25%), propyl paraben (0.1-0.25%)
Reducing Agents and Antioxidants
The decomposition of pharmaceutical products by the oxidation can be controlled by the addition of reducing agents such as sodium metabisulfite, or antioxidants such as butylated hydroxyanisole or butylated hydroxytoluene
For unit dose parenteral products, such as injections of nicotinamide and ascorbic acid, it is possible to use Water for Injections free from dissolved air and to replace the air in the headspace by nitrogen or another inert gases
Sweetening Agents
Low molecular weight carbohydrates, such as sucrose,
are traditionally the most widely used sweetening
agents
Sucrose has the advantage of being colorless, very
soluble in water, stable over a pH range of about 4 – 8,
and by increasing the viscosity of fluid preparations,
will impart to them a pleasant texture in the mouth. It
will mask the bitter and salty drugs and has soothing
effect on the membranes of the throat
Sweetening Agents
Polyhydric alcohols such as sorbitol, mannitol
and to a lesser extent glycerol, also possess
sweetening power and can be included in the
preparations for diabetic use. Maltilol, lactilol,
isomalt, fructose, xylitol
Artificial sweeteners. E954, E951, E950, E957,
E952, E959
Sweetening agents
Sweetener Sweetening
power
Comments
Sucrose 1 Most commonly
used
Saccharin =500 Unpleasant
aftertaste
Sodium
cyclamate
=30 Banned
aspartame =200 Not very stable in
solution
Flavors and Perfumes
The simple use of sweetening agents may not be sufficient to render palatable a product containing a drug with a particularly unpleasant taste. In many cases, therefore, a flavoring agent can be included
Particularly useful in pediatric formulation to ensure patient compliance
The inclusion of flavors has the additional advantage of enabling the easy identification of liquid products
Can be obtained from either natural or synthetic sources
Suitable Masking Flavors for Various Product Tastes
Salty – Apricot, butterscotch, liquorice, peach,
vanilla, maple, wintergreen
Bitter – Anise, chocolate, mint, passion fruit,
wild cherry
Sweet – Vanilla, fruits, berries
Sour – Citrus fruits, liquorice, raspberry
Colors
Once a suitable flavor has been chosen, it is
often useful to include a color associated with
that flavor in order to improve the
attractiveness of the product
Another reason for the inclusion of colors is to
enable easy product identification
Colors
Includes lakes and dyes
Lakes are pigments that are insoluble in water and which impart color by dispersing and reflecting light, they are not used for aqueous solutions
Dyes are water soluble and exhibit color by transmitting light, should be used at the lowest possible concentration required to produce the desired color, higher concentration result in a dull color
Most liquid drug products have dye concentrations of less than 0.001%, because dyes are present in trace amounts, they should be dissolved prior to mixing with the bulk of the formulations. This ensures complete dissolution before further processing
Factors influencing the shade and stability of dyes in liquid systems: pH, microbiological activity, exposure to light in the final package and compatibility of the dye with other ingredients
Manufacturing Consideration
Raw Materials
Equipments
Methods of preparation
Filling and Sealing
Raw Materials
All raw materials should conform to well thought out specification. These specifications should assure identity, purity, uniformity and freedom from excessive microbial contamination
Although purified water (USP) is required in all operations, it is particularly important in liquid manufacturing, if deionized and other water treatment equipment is used, special attention must be given to routine microbiological and chemical testing
Storage tanks for glycerin and propylene glycol should be constructed to facilitate examination as well as cleaning
Raw Materials
Aside from active ingredients, water is usually the most
important constituent in a liquid product. It should meet
the USP requirements for purified water
Techniques employed to upgrade the microbial purity
of water supply in oral liquid – reverse osmosis
purification, UV sterilization, membrane filtration,
constant circulation in piping system that have no
“dead ends” where microorganism can thrive
Equipments
Simple solutions are most straightforward to scale up, but require tanks of adequate size and suitable mixing capacity
Most equipment should have heating and cooling capabilities for rapid dissolution of formulation components
Adequate transfer systems and filtration equipments are required, but they must be monitored to ensure that they can clarify the product without removing active or adjuvant ingredients
All equipments must be made of suitable, non-reactive, sanitary materials and be designed and constructed to facilitate easy cleaning
Equipments
Liquid pharmaceutical processing includes tanks, kettles, pipes, mills, filter, housing are most frequently fabricated from stainless steel
Stainless steel is virtually non-reactive but may react with some acidic pharmaceutical liquids. This problems can be minimized by treating the stainless steel with an acetic acid or nitric acid solution to remove surface alkalinity. This process known as passivation, may be needed at periodic intervals
Interaction with metallic surfaces can be minimized by using polytetrafluoroethylene (teflon) liners. Although teflon is inert, these liners have the potential disadvantages of cracking, breaking, flaking and peeling with resulting product contamination
Equipments
Type of equipment used in the manufacture of oral solution consist of mixing tanks, measuring devices for large and small amounts of solids and liquids, filtration system for the final polishing and/or sterilization of the solution
All equipments must be thoroughly cleaned, sanitized –sterilized if possible before use
Equipment and lines can be sterilized by such methods as alcohol, boiling water, autoclaving, steam or dry heat
Methods of Preparation
Dilute solutions of rapidly dissolving materials are prepared by adding the solute to the solvent and agitating until the solution is homogenous
Heat maybe required for more concentrated solutions or when the solute is slow to dissolve
Excipients are usually added in a specified order to increase the rate of dissolution and facilitate a rapid approach to equilibrium
Methods of Preparation
If the solutes were charged directly to the bulk mixing tank, it would be difficult to detect small amounts of undissolved material at the bottom of the tank
As a rule, complete solution should be confirmed at every stage in the manufacture of homogenous liquid. In the laboratory, liquids are usually measured by volume. However, in large scale production, gravimetric means of measurements are used
Solutions must be filtered and clarified – this stage of process is termed Polishing
Methods of Preparation
Highly polished solution requires the removal of particulate matter down to at least 3 um in size
Filters used in the manufacture, processing liquid drug products intended for human use should not release fibers
Filter aids are commonly used to improve clarity and increase the flow rate, thus decreasing filtration time
Amount and type of filter aid must be determined during the development of the product, the amount usually does not exceed 0.5 g/L. examples of filter aids are diatomaceous earth, carbon, expanded perlite and cellulose
Filling and Sealing
Upon approval by QC – liquid may be transported to the filling line, either manually by filling into portable transport tanks or by pumping (gravity flow) through a suitable liquid delivery conduit
Method of filling a pharmaceutical liquid depend on the characteristic of the liquid – viscosity, surface tension, foam producing, compatibility of the material with the construction of filling machine, type of package (bottle)
Small volumes of liquids (usually for pediatric use) are delivered by the stroke of the plunger of a syringe, which forces the liquid through a 2 way valve that provides for alternative filling of the syringe from a reservoir and delivery to a container. For heavy, viscous liquids, sliding piston valve provides more positive action
Filling and Sealing
Large volume filling does not normally require the precision required for small volumes. Therefore, bottles of solution are usually filled by gravity, pressure or vacuum devices
Methods of filling – gravity filling, pressure pump filling, vacuum filling
High viscous solution require specially designed equipment. To obtain a reasonable flow rate, high pressure must be applied or containers with large openings must be used to permit the entry of large delivery tubes. Sometimes, jacketed reservoir tanks can be employed to raise the temperature of the product and thereby lower its viscosity
Filling and Sealing
Excessive foaming is a problem common to all types of machines that fill containers with liquid but is particularly bothersome in high speed automatic equipment. Foaming during the filling operation can be reduced by employing filling equipment that minimizes product turbulence, closed system filling to limit the introduction of air or other gases that cause foaming, mechanical defoaming devices, or reduction in the speed of the filling line
Microbial survey should be performed on all packaging materials that come in contact with the product to ensure the absence of microbial contamination
Gravity Filling
Slow but simple process
Liquid reservoir is positioned above the filling
line, with a hose connection from the reservoir
to a shutt off device at the filling line which is
usually hand operated, the bottles are filled to
a graduation mark
Pressure Pump Filler
Often operated semi-automatically and differs
from the gravity filler principally in that the
liquid is under pressure
It is usually equipped with an overflow tube
connected to a receiver to prevent excess
filling
Vacuum Filling
Commonly used for large liquid volumes because it is easier adapted to automation
Vacuum is produced in a bottle when a nozzle gasket makes seal against the lip of the bottle to be filled
Vacuum draws the liquid from reservoir through the delivery tube into the bottle. When the liquid level reaches the level of an adjustable overflow tube, the seal is mechanically loosened and the vacuum is released
Any liquid that has been drawn into the vacuum line is collected in a receiver and returned to the reservoir
Procedure for most solutions are classified into the following categories
Simple solutions
Solutions of chemical reactions
Solution by distillation
Solution by extraction (maceration, percolation,
digestion, infusion, decoction)
Complex solution
Classification of Solutions
Aqueous solutions
Non-aqueous solutions
Aqueous solutions
Aromatic waters
Aqueous acids
Douches
Enemas
Gargles
Washes
Juices
Sprays
Aromatic waters
Clear, saturated aqueous solutions of volatile
oils or other aromatic or volatile substances
Do not contain preservatives
Prepared by distillation, direct solutions or
alternated solutions
Aqueous Acids
Hydracids – do not contain oxygen
Oxygen containing acid
It should be borne in mind that acids are
always added to water
Douches
Aqueous solutions used as a cleansing or
antiseptic agent directed against a part or into
a cavity of the body
Most frequently dispensed in the form of
powder with directions for dissolving in a
specified quantity of water, usually warm
Enemas
Rectal injections employed to evacuate the
bowel, to influence the general system by
absorption, or to affect locally the seat of
disease
Possess anthelminthic, nutritive, sedative or
stimulating properties, or they may contain
radiopaque substances for roentgenographic
examination of the lower bowel
Gargles
Aqueous solution used for treating the pharynx
and nasopharynx by forcing air from the lungs
through the gargle which is held in the throat
Must be diluted with water before use
Washes
Aqueous solutions most often used for its
deodorant, refreshing or antiseptic effect.
May contain alcohol, local anti-infective agents
such as hexetidine and cetylpyridinium
chloride, glycerin,synthetic sweetners and
surface-active, flavoring, coloring agents
Listerine, astring-osol and bactidol
Juices
Prepared from fresh ripe fruit, aqueous in character
and are used in making syrups which are employed as
vehicles
Freshly expressed juice is preserved by benzoic acid
and is allowed to stand at room temperature for several
days, until the pectins which are naturally present are
destroyed by enzymatic action of pectinase as
indicated by the filtered juice yielding a clear solution
with alcohol
Sprays
Solutions of various drugs in aqueous vehicles
and are applied to the mucus membranes of
the nose and throat by means of nebulizer or
atomizer
Isotonic with nasal secretions
May contain antibiotic, antihistamins,
vasoconstritors, alcohol and suitable
solubilizing and wetting agents
Sweet or other Viscid Aqueous solutions
Syrups
Honeys
Mucilages
Jellies
Syrups
Concentrated solutions of sugar or sugar-
substitute and intended for oral administration
Simple syrup, Medicated Syrup & Flavored
Syrup
Basic methods – solution with heat, agitation
without heat, addition of medicating liquids,
percolation
Important points to be considered in the manufacture of syrup
Manufacture of syrup must be conducted with care to avoid
contamination
To prevent bacterial and mold growth, preservatives may be
added. Combination of alkyl esters of p-hydroxybenzoic acid are
effective inhibitors of yeast
Store in tight, light resistance container and in a cool place
Cannot be sterilized in an autoclave without some caramelization
Glycerin or sorbitol may be added to retard crystallization of
sucrose or increase the solubility of added ingredients
When heat is employed, invert sugars are produced
Invert Sugars
Dextrose + levulose
More readily fermentable than sucrose
Tends to darken in color due to levulose
Its two reducing sugars are of value in retarding the oxidation of other substances
1.23 times as sweet as sucrose. The relative sweetness of levulose, sucrose and dextrose is 173:100:74
Honeys
Thick liquid preparations somewhat allied to
the syrups, differing in the use of honey,
instead of syrup, as a base
Oxymel and Squill Oxymel BPC
Mucilages
Thick, viscid, adhesive liquids by dispersing gums in
water or extracting with water the mucilaginous
principles from vegetable substances
All prone to decomposition, showing appreciable
decrease in viscosity on storage, they should never be
made in larger quantities than can be used
immediately, unless a preservative is added
Primarily used as aid in suspending insoluble
substances in liquid
Jellies
Class of gels in which the structural coherent
matrix contains a high portion of liquid, usually
water
Non-Aqueous Solutions
Alcohol or hydroalcoholic solutions (Elixirs, Spirits)
Ethereal Solutions (Collodions)
Glycerin Solutions (Glycerites)
Oleaginous Solutions (Liniments, Oleovitamins, toothache drops
Medicated Solutions for Vaporizations (Inhalations, Insufflations, Inhalants)
Elixirs
Clear, pleasantly flavored, sweetened
hydroalcoholic liquids intended for oral use
Ethanol, water but glycerin, sorbitol, propylene
glycol, flavoring agents, preservatives and
syrups
Prepared by simple solution or admixture of
several ingredients
Spirits
Essences
Alcoholic solutions of volatile substances prepared
usually by simple solutions, admixture of the
ingredients, solution with maceration, chemical
reaction and distillation
Store in a tight, light resistant containers to prevent
loss by evaporation and to limit oxidative changes
Flavoring agents while others used for therapeutic
effect of the medicinal substances they contain
Collodions
Liquid preparation containing pyroxylin in a
mixture of ethyl ether and ethanol
Applied to the skin by means of soft brush or
other suitable applicator and, when ether and
ethanol have evaporated, leave a film of
pyroxylin on the surface
Made flexible by the addition of castor oil
Glycerites
Solutions or mixtures of medicinal substances
in not less than 50% glycerin
Hydroscopic and should be stored in tightly
closed container
Most of them are extremely viscous and some
of them are of jelly-like consistency
Liniments
Solutions of various substances in oil, alcoholic
solutions of soap or emulsion
Usually applied with friction and rubbing of the
skin, the oil or soap base providing for case of
application and massage
Alcoholic liniments are used generally for their
rubefacient, counter-irritant, mildly astringent
and penetrating effects
Oleovitamins
Fish liver oils diluted with edible vegetable oil
of solutions of the indicated vitamins or
vitamins concentrates (usually vitamin A and
D) in the fish liver oils
Popular commercial dosage form is the SOFT
Gelatin capsule
Toothache Drops
Preparations used for temporary relief of
toothache by application of a small pledget of
cotton saturated with the product into the tooth
cavity
Clove oil and mixtures of phenol with camphor
or creosote
Inhalations
Drugs or solutions of drugs administered by the nasal or respiratory route for local or systemic effect
Nebulizers are suitable for the administration of inhalation solutions only if they give droplets sufficiently fine and uniform in size so that the mist reach the bronchioles
Solutions may be nebulized by the use of inert gas
Insufflations
Consist of finely powdered or liquid drugs that
are carried into the respiratory passage by the
use of special delivery systems such as
pharmaceutical aerosol
Inhalants
Drugs or combination of drugs which by virtue
of their high vapor pressure, can be carried by
an air current into the nasal passage where
they exert their effect
Inhaler
LIQUID PREPARATIONS – part 2 Marilyn A. Ngo
M.S. Pharmacy
Dispersion
Dispersed phase/ internal phase
Dispersing phase/dispersion medium/ external
phase
Types: colloidal dispersion (1 nm to 0.5 um);
coarse dispersion (10-50 um); fine dispersion
(0.5-10 um)
MIXTURE (2-phase systems)
Suspensions
Emulsions
Suspension
2-phase system which consists of a finely divided solid (dispersed phase) dispersed in a solid, liquid or gas (dispersing medium)
Dispersed phase with mean particle diameter of up to 1 micrometer is usually termed as colloidal dispersion
A solid in liquid dispersion, in which the particles are above colloidal size, is termed coarse suspension
Emulsion
2-phase system in which one liquid is dispersed in the form of small droplets throughout another liquid
Stabilized by the presence of an emulsifying agent
The dispersed liquid or internal phase usually consists of globules of diameters down to 0.1 micrometer which are distributed within the external or continuous phase
Physical Properties of Well-Formulated Suspensions and Emulsions
Must remain sufficiently homogenous for at least the period
between shaking the container and removing the required amount
Sediment or creaming produced on storage, if any, must be easily
resuspended by moderate agitation of the container
The product may be required to be thickened in order to reduce
the rate of settling of the particles or the rate of creaming of oil
globules
Any suspended particles should be small and uniformly sized in
order to give a smooth, elegant product, free from gritty texture
Pharmaceutical Applications of Suspensions
Suspensions can be used as oral dosage
forms, applied topically to the skin or mucus
membranes surfaces, or given parenterally by
injection
Formulations of Suspensions
Particle size control
Use of wetting agents
Flocculated and deflocculated system
Viscosity Modifiers
Particle Size Control
To ensure that the drug to be suspended it of a fine particle size prior to formulation
To ensure a slow rate of sedimentation of the suspended particles
Large particles, if greater than about 5 um diameter, will also impart a gritty texture to the product, and may cause irritation if injected or instilled into the eyes.
If there is a temperature fluctuations, degree of crystal growth can occurs on storage. Solubility of the drug may increase as the temperature rises, but on cooling, the drug will crystallize out. This particular problem with slightly soluble drugs such as paracetamol
If the drug is polydispersed, then the very small crystals of less than 1 um diameter will exhibit greater solubility than the larger ones. Over a period of time, the small crystals will become even smaller, whereas the diameter of the larger particles will increase
Particle Size Control
Advantageous to use a suspended drug of a narrow size range
Inclusion of surface active agents or polymeric colloids, which adsorb on to the surface of each particle, may also help to prevent crystal growth
Different polymorphic forms of a drug may exhibit different solubilities, the metastable state being the most soluble
Conversion of the metastable form, in solution, to the less soluble stable state, and its subsequent precipitation, will lead to changes in particle size
Use of Wetting Agents
Some insoluble solids may be easily wetted by water and will disperse readily throughout the aqueous phase with only minimal agitation
Most, however, will exhibit varying degrees of hydrophobicity and will not be easily wetted
Some particles will form large porous clumps within the liquid, whereas others remain on the surface and become attached to the upper part of the container.
The foam produced on shaking will be slow to subside because of the stabilizing effect of the small particles at the liquid/air interface
Use of Wetting Agents
To ensure adequate wetting, the interfacial tension between the solid and the liquid must be reduced so that the adsorbed air is displaced from the solid surfaces by the liquid
The particles will then disperse readily throughout the liquid, particularly if an intense shearing action is used during mixing
Most widely used: surface active agents, hydrophilic colloids, solvents
Surface Active Agents
HLB value between about 7 and 9
Hydrocarbon chains would be adsorbed by the hydrophobic particle surfaces, whereas the polar groups project into the aqueous medium and become hydrated
Wetting of the solid occurs as a result of a fall both in interfacial tension between the solid and the liquid and, to a lesser extent, between the liquid and air
Concentrations of up to about 0.1%, for oral use, the polysorbates (Tweens) and sorbitan esters (Spans). For external application, sodium lauryl sulfate, sodium dioctylsulphosuccinate and quillaia extract can also be used. For parenteral administration, polysorbates, some of the poloxamers (polyoxyethylene/polyoxy-propylene copolymers) and lecithin
Disadvantages in the use of this type of wetting agent include excessive foaming and the possible formation of a deflocculated system, which may not be required
Hydrophilic Colloids
Acacia, bentonite, tragacanth, alginates, xanthan gum
and cellulose derivates
Will behave as protective colloids by coating the solid
hydrophobic particles with the multimolecular layer
Will impart a hydrophilic character to the solid and so
promote wettings
Used as suspending agent, and may, like surfactants,
produce a deflocculated system, particularly if used at
low concentrations
Solvents
Alcohol, glycerol and glycols, which are water
miscible will reduce the liquid/air interfacial
tension
Solvents will penetrate the loose agglomerates
of powder displacing the air from the pores of
the individual particles, so enabling wetting to
occur by the dispersion medium
Relative Properties of Flocculated and Deflocculated Particles in Suspension
Deflocculated Flocculated
Particles exist in suspension as
separate entities
Particles form loose aggregates
Rate of sedimentation is slow Rate of sedimentation is high
Sediment is formed slowly Sediment is formed rapidly
Sediment eventually becomes
very closely packed
Sediment is loosely packed and
possesses a scaffold like
structure
Suspension has a pleasing
appearance
Suspension is somewhat
unsightly
Controlled Flocculation
Achieved by combination of particle size control, use of electrolytes to control zeta potential, and the addition of polymers to enable crosslinking to occur between particles
Underflocculation will give those undesirable properties that are associated with deflocculated systems
Overflocculated product will look inelegant and, to minimize settling, the viscosity of the product may have to be so high that any necessary redispersion would be difficult
Flocculating Agents
In many cases, after the incorporation of a non-ionic wetting agent a suspension will be found to be deflocculated, either because of the reduction in solid/liquid interfacial tension, or because of the hydrated hydrophilic layer around each particle forming a mechanical barrier to aggregation
Use of an ionic surfactant to wet the solid could produce either a flocculated or a deflocculated system, depending on any charge already present on the particles
If particles are of opposite charge to that of the surfactant then neutralization will occur
High charge density is imparted to the suspended particles then deflocculation will be the result
Convert deflocculated to a partially flocculated state, this may be achieved by the addition of electrolytes, surfactants and/or hydrophilic polymers
Electrolytes
Addition of an inorganic electrolyte to an aqueous suspension will alter the zeta potential of the dispersed particles and, if this value is lowered sufficiently, flocculation may occur
Scultz- Hardy rule shows that the ability of an electrolyte to flocculate hydrophobic particles depends on the valency of its counter ion. Trivalent ions are less widely used than mono- or divalent electrolytes because they are generally more toxic.
If hydrophilic polymers, which are usually negatively charged, are included in the formulation they may be precipitated by the presence of trivalent ions
Most widely used: sodium salts of acetates, phosphates and citrates, and the concentration chosen will be that which produces the desired degree of flocculation
Care must be taken not to add excessive electrolyte or charge reversal may, occur on each particle, so forming, once again, a deflocculated system
Surfactants
Ionic surface active agents may also cause flocculation by neutralizing the charge on each particle, thus resulting in a deflocculated system
Non-ionic surfactants will have a negligible effect on the charge density of a particle but may, because of their linear configurations, adsorb on to more than one particle, thereby forming a loose flocculated structure
Polymers Flocculating Agents
Starch, alginates, cellulose derivates, tragacanth, carbomers and silicates
Their linear branched chain molecules form a gel-like network within the system and become adsorbed on to the surfaces of the dispersed particles, thus holding them in a flocculated state
Care must be taken to ensure that, during manufacture, blending is not excessive as this may exhibit the crosslinking between adjacent particles and result in the adsorption of each molecule of polymer on to one particle only. If this should occur then a deflocculated system may result, because the formation of the hydrophilic barrier around each particle will inhibit aggregation
High concentration of polymer may have similar effect if the whole surface of each particle is coated. It is essential that areas on each suspended particle remain free from adsorbate, so that crosslinking can recur after the product is sheared
Viscosity Modifiers
Polysaccharides – acacia, tragacanth, alginates, starch, xanthan gum
Water soluble celluloses – methylcellulose, hydroxyethylcellulose, carmellose sodium, microcrystalline cellulose
Hydrated silicates – bentonite, magnesium, aluminum silicate (Veegum), hectorite
Carbomers (carboxypolymethylene) – synthetic copolymer of acrylic acid and allyl sucrose. Concentration used up to 0.5%, mainly for external application
Colloidal silicon dioxide (Aerosil) – finely divided product, that is dispersed in water, will aggregate, forming a 3 dimensional network. Concentration used of up to 4%, for external use
Several Preparations which may be classified as Suspensions
Gels
Magmas and Milks
Lotions
Mixtures
Gels
Semisolid systems of either suspensions made up of small inorganic particles or large organic molecules interpenetrated by a liquid
Thixotropic, forming semisolid on standing and becoming liquid on agitation
To ensure homogeneity, they should be shaken before use
Aluminum Hydroxide Gel
Magmas and Milks
Aqueous suspensions of insoluble, inorganic drugs and differ from gels mainly in that the suspended particles are larger
Thick and viscous, no need to ass a suspending agents
Shaken well before use
Freezing must be avoided
Prepared by simple hydration (bentonite magma) or by chemical reaction (milk of magnesia and milk of bismuth)
Lotions
Liquid suspensions intended for external application to the body
Prepared by triturating the ingredients to a smooth paste and then cautiously adding the remaining liquid phase
Usually applied with friction
Wide variety of ingredients may be added to the preparation to produce better dispersions or to accentuate the cooling, soothing, drying, moisturizing, or protective properties of lotion
Cosmetic aspect is of great importance
Tend to separate at long standing, it requires a shake well label. Should be labeled “for external use only”
Care should be taken to avoid contamination during manufacturing, even if preservatives are present
Mixtures
Aqueous liquid preparations which contain suspended, insoluble, solid substances and are intended for internal use
Insoluble substance does not make the mixture very viscous and the particles may be suspended by the use of suitable suspending or thickening agents
Shake well label affixed to the container
Subject to microbial contamination, a preservative should be added to the formulation
Kaolin Mixture with Pectin, Brown Mixture
Emulsion
2-phase system in which one liquid is dispersed in the
form of small droplets throughout another liquid
Dispersed phase is also known as internal or
discontinuous phase. Dispersed medium is also known
as external or continuous phase
If the dispersed globules are of colloidal dimensions (1
nm to 1 micrometer) the preparation, which is quite
often transparent or translucent is called
MICROEMULSION
Types of Emulsion
Oil in water
Water in oil
Water in oil in water
Emulsifying agent
3rd basic component of an emulsion
Prevent the separation of two phases
Classified into: Natural emulsifying agent,
Finely divided solids and synthetic emulsifying
agent
Natural Emulsifying Agent
Derived from either animal (gelatin, egg yolk, casein, wool fat and cholesterol) and vegetable origin (acacia, tragacanth, choldrus and pectin)
2 disadvantages: they show considerable batch to batch variation in composition and hence in emulsifying properties; and many are susceptible to bacterial or mold growth. For these reasons, they are not widely used in manufactured products requiring a long shelf life, but rather for extemporaneously prepared emulsions designed for use within a few days of manufacture
Natural Emulsifying Agent
Polysaccharides – acacia, stabilizes o/w emulsions by forming a strong multimolecular film round each oil globule, and so coalescence is retarded by the presence of a hydrophilic barrier between the oil and water phases. Because of its low viscosity, creaming will occur readily, therefore a suspending agent such as tragacanth or sodium alginate can also be included. Because of its sticky nature, it is limited to products for internal use
Semisynthetic polysaccharides – several grades of methylcellulose and carmellose sodium. Exert their action similar to acacia
Natural Emulsifying Agent
Sterol-containing substances – beeswax, wool fat and wool
alcohols. Beeswax is used mainly in cosmetic creams of both o/w
and w/o type in conjunction with borax. Because of the systemic
toxicity of boric acid and its salts, however, beeswax is used as
stabilizer for w/o creams. Wool fat will form w/o emulsions of low
dispersed phase concentration, it has characteristic odor and
need to incorporate antioxidants, it is not widely used, however, it
is found in low concentration in many ointments. The principal
emulsifying agent in wool fat is wool alcohols. Wool alcohols does
not have the same strong odor as wool fat but does require the
presence of antioxidant. It is effective as w/o emulgent
Finely divided solids
Montmorillonite clays (Bentonite and aluminum
magnesium silicate) and colloidal silicon
dioxide are used mainly for external use
Aluminum and magnesium hdroxides are also
used internally
Can be adsorbed at the o/w interface, forming
a coherent film that physically prevents
coalescence of the dispersed globules.
Synthetic emulsifying agent
Anionic – sodium lauryl sulfate
Cationic – benzalkonium chloride
Nonionic – polyethylene glycol 400
monostearate
Anionic Surfactants
Cheap, toxic and used externally
Alkali metal and ammonium soaps – sodium stearate. These emulgents are incompatible with polyvalent cations, often causing phase reversal, and it is therefore essential that deionized water is used in their preparation
Soaps of divalent and trivalent metals – will only produce w/o emulsion
Amine soaps – triethanolamine. It forms stable o/w emulsions. Neutral pH. Restricted to external used. Incompatible with acids and high concentrations of electrolytes
Sulphated and sulphonated compounds – sodium lauryl sulfate. Widely used to produce o/w emulsions. Because of its high water solubility and its inability to form condensed films
Cationic Surfactants
Quarternary ammonium compounds
Widely used for their disinfectant and preservatives
Useful in o/w emulsifiers
Because of the toxicity, they tend to be used only for the formulation of antiseptic creams
Incompatible with anionic surfactants and polyvalent anions, and are unstable at high pH
Cetrimide – most useful of these cationic emulgents. Used at a concentration of 0.5%
Non-ionic Surfactants
Low toxicity and irritancy, some can therefore be used for orally and parenterally administered preparations
Greater degree of compatibility with other materials than do anionic or cationic emulgents, and less sensitive to changes in pH or to the addition of electrolytes
Expensive
Most non-ionic surfactants are based on: fatty acid or alcohol (usually 12-18 carbons), the hydrocarbon chain of which provides the hydrophobic moiety; an alcohol and/or ethylene oxide grouping, which provide the hydrophilic part of the molecule
Best type of non-ionic surfactant to use is one with an equal balance of hydrophilic and hydrophobic groupings. An alternative would be to use two emulgents, one hydrophilic and one hydrophobic.
Glycol and glycerol esters – glyceryl monostearate; sorbitan esters – sorbitan monostearate; polysorbates (Tween); fatty alcohol polyglycol ethers –macrogol cetostearyl ether; fatty acid polyglycol estes; poloxalkols; higher fatty alcohols; amphoteric surfactants – lecithin (used to stabilize IV fat emulsions)
Methods of preparation (emulsion)
Emulsifier in water method
Emulsifier in oil method – Continental method
Soap method
Alternate addition method – English Method
Tests for identification of emulsion type
Miscibility tests
Conductivity tests
Staining test
Equipments for breaking up the internal phase into droplets can be divided into 4 board categories
Agitator or mechanical stirrers
Homogenizers
Ultrasonifiers
Colloid mills
Formulation of Emulsions
Choice of emulsion type
- o/w or w/o emulsion
- Fats or oils for oral administration, either as medicaments in their own right or as vehicles for oil soluble drugs, are invariably formulated as oil in water emulsions
- Emulsions for IV administration must be of o/w type, IM administration injections can also formulated as w/o type
Choice of oil phase
- liquid paraffin, castor oil, cod liver oil, arachis oil are for oral administration
- Cottonseed oil, soya bean oil, safflower oil are used for their high calorific value in emulsions for IV feeding
- Turpentine oil and benzyl benzoate are for external application
Formulation of Emulsion
Emulsion consistency
- w/o type will have a greasy texture and often exhibit a higher apparent viscosity than o/w emulsion, often used to convey a feeling of richness to many cosmetic formulations
- O/w emulsion will feel less greasy or sticky on application to the skin, and will be absorbed more readily because of their lower oil content, and can be more easily washed from the skin surface
- Ideally emulsions should exhibit rheological properties of plasticity or pseudoplasticity and thixotrophy
Choice of of emulsifying agent
- toxicity and irritancy considerations
- Cationic surfactants in general are toxic even at lower concentration. Limited to externally used preparations
- Anionic alkali soaps, often have high pH and are thus unsuitable for application to broken skin. Even on normal intact skin, it can cause irritation
- Parenteral administration – non-ionic surfactants such as lecithin, polysorbate 80, methylcellulose, gelatin and serum albumin
Formulation of HLB method
Calculating the relative quantities of these
emulgents necessary to produce the most
physically stable emulsion for a particular
oil/water combination
Other Formulation Additives
Buffers
Density modifiers
Humectants
Antioxidants
Flavors, colors and perfumes
Sweetening agents
Preservation of Suspensions
Prevent the growth of microorganisms that
maybe present in the raw material and/or
introduced into the product during use
Bentonite, may contain Clostridium tetani, but
can be sterilized by heating the dry powder at
160 C for 1 hour or by autoclaving aqueous
dispersion
Preservation of Emulsions
Benzoic acid and sorbic acid and their salts, p-hydroxybenzoic acid esters, chlorocresol, phenoxyethanol, bronopol, quarternary ammonium compounds
It must be realized that no single preservative exhibits all of the desirable properties outlined. In many cases, a combination of methyl and propyl p-hydroxybenzoates at a ratio usually of 10:1
Desirable Features of a Preservative
Suitable for Use in an Emulsion
Wide spectrum of activity against all bacteria, yeasts and molds
Bactericidal rather than bacteriostatic activity
Freedom from toxic, irritant or sensitizing activity
High water solubility
Compatibility with the other ingredients and with container
Stability and effectiveness over a wide range of pH and temperature
Freedom from color and odor
Retention of activity in the presence of large numbers of microorganisms
Physical stability of suspensions
Assessed by the measurement of its rate of
sedimentation, the final volume or height of the
sediment, and ease of redispersion of the
product
Physical Stability of Emulsions
Avoidance of Creaming
Prevention of flocculation
Coalescence (breaking, cracking)
Creaming and its avoidance
Creaming is the separation of an emulsion into two regions, one of which is richer in the disperse phase than the other. Inelegant. If the emulsion is not shaken adequately, there is a risk of the patient obtaining an incorrect dosage
Consideration of the qualitative application of Stoke’s law will show that the rate of creaming can be reduced by the following methods:
- production of an emulsion of small droplet size
- Increase in the viscosity of the continuous phase
- Reduction in the density difference between the two phases
- Control of disperse phase concentration
Flocculation Prevention
Flocculation involves the aggregation of the dispersed globules into loose clusters within the emulsion. The individual droplets retain their identities but each cluster behaves physically as a single unit. Increase the rate of creaming
Redispersion can easily be achieved by shaking
The presence of a high charge density on the dispersed droplets will ensure the presence of a high energy barrier, and thus reduce the incidence of flocculation in the primary minimum
Important in formulating emulsions for parenteral nutrition which contain high levels of electrolytes
Coalescence
Resisted by the presence of a mechanically strong adsorbed layer of emulsifier around each globule. This is achieved by the presence of either a condensed mixed monolayer of lipophilic and hydrophilic emulgents or multimolecular film of a hydrophilic material
Hydration of either of these types of film will hinder the drainage of water from between adjacent globules which is necessary prior to coalescence.
As 2 globules, approach each other their close proximity causes their adjacent surfaces to flatten
As a change from a sphere to any other shape results in an increase in surface area and hence in total surface free energy, this globule distortion will be resisted and drainage of the film of continuous phase from between the 2 globules will be delayed
The presence of long, cohesive hydrocarbon chains projecting into the oil phase will prevent coalescence in a w/o emulsion
Chemical Instability of Emulsions
Anionic and cationic emulgents are incompatible
Presence of electrolyte can influence the stability of emulsion
either by reducing the energy of interaction between adjacent
globules, or salting out effect, by which high concentrations of
electrolytes can strip emulsifying agents of their hydrated layers
and so cause their precipitation
To precipitate hydrophilic colloids by the addition of alcohol
Changes in pH may lead to the breaking of emulsion
Oxidation , Microbiological contamination, adverse storage
conditions
Oxidation
Resulting rancidity is manifested by the formation of
degradation products of unpleasant odor and taste
These problems can also occur with certain
emulsifying agents, such as wool fat or wool alcohols
Oxidation of microbiological origin is controlled by the
use of microbial preservatives and atmospheric
oxidation by the use of reducing agents or anti-
oxidants
Microbiological Contamination
Contamination of emulsions by microorganisms can adversely affect the physicochemical properties of the product, causing such problems as gas production, color and odor changes, hydrolysis of fats and oils, pH changes in the aqueous phase and breaking of the emulsion
Most fungi and many bacteria will multiply readily in the aqueous phase of an emulsion at room temperature and many molds will also tolerate a wide pH range
Some hyrophilic colloids, may provide a suitable nutritive medium of use by bacteria and molds
Pseudomonas species can utilize polysorbates, aliphatic hydrocarbons and compounds
Some fixed oils, including arachis oil, can be used by some Aspergillus and Rhizopus species, and liquid paraffin by some species of Penicillium
Adverse Storage Conditions
Increase temperature will cause an increase in the rate of creaming, owing to a fall in apparent viscosity of the continuous phase
Temperature increase will also cause an increased kinetic motion, both of the dispersed droplets and of the emulsifying agent at the o.w interface
Increase motion of the emulgent will result in a more expanded monolayer and so coalescence is more likely
Freezing of the aqueous phase will produce ice crystals that may exert unusual pressures on the dispersed layer of emulgent. In addition, dissolved electrolyte may concentrate in the unfrozen water, thus affecting the charge density on the globules
Stability Testing of Emulsions
Methods of assessing stability – macroscopic
examination, globule size analysis, viscosity
changes
Accelerated Stability tests – storage at adverse
temperatures, centrifugation, rheological
assessment
Manufacture of Suspensions
Manufacture of Emulsions
LIQUID PREPARATIONS – part 3
Marilyn A. Ngo
M.S. Pharmacy
Galenicals (Extractives)
Galen, 2nd Century Greek physician
Involves the separation of medicinally active portions of plant or animal tissues from the inactive or inert components by the use of selective solvents in standard extraction procedures
Relatively impure liquids, semisolids or powders which may be used per se or may be processed further for oral or external use
Classes of Preparation (Galenicals)
Decoctions
Infusions
Tinctures
Fluidextracts (liquid extracts)
Extracts
Decoctions
Preparations containing water-soluble and heat
stable constituents extracted from crude drugs
by boiling the latter in water
Infusions
Dilute solutions of readily soluble constituents
of crude drugs prepared by short maceration of
the drugs with either cold or boiling water
Tinctures
Alcoholic or hydroalcoholic solutions prepared
from vegetable materials or from chemical
substances (eg Iodine Tincture)
10%, 20%
Prepared from vegetable drugs are made by 2
processes: Process P & Process M
Fluidextracts (Liquid Extracts)
Liquid preparations of vegetable drugs,
containing alcohol as a solvent or as a
preservatives, or both, so made that each mL
contains the therapeutic constituents of 1 g of
the standard drug that is represents
Made by percolation with the following
variations: Process A, Process E & Process D
Extracts
Concentrated preparations of vegetable or animal drugs obtained by removal of the active constituents of the respective drugs with suitable menstrua, evaporation of all or nearly all of the solvent, and adjustment of the residual masses or powders to the prescribed standards
Most extracts are prepared by percolation
Forms of extracts are recognized: semiliquids or liquids or syrupy consistency; plastic masses known as pilular or solid extracts; dry powders known as powdered extracts
Compounding Procedure
Rationale for most of the steps in compounding liquid preparations lies in the knowledge of equilibrium solubility
Rate at which solution is achieved is influenced by the compounding procedure
As an additional aid in formulators, the official compendia provides approximate solubilities of USP/NF articles as indicated by the descriptive terms
Relative Solubilities of USP and NF articles
Descriptive term Parts of solvent required for
one part of solute
Very soluble
Freely soluble
Soluble
Sparingly Soluble
Slightly Soluble
Very Slightly Soluble
Practically insoluble
Less than 1
From 1 to 10
From 10 to 30
From 30 to 100
From 100 to 1000
From 1000 to 10,000
10,000 and over
Compounding Procedure
As the proportion of solvent required increases or when more
concentrated solutions are being made, it may be advantageous
to employ heat, taking into consideration the thermal stability of
the components
Solutes present in small concentrations should be pre-dissolved
prior to mixing to the main portion of the batch to ensure complete
solution of the substance before the batch is further processed
To produce a clear liquid preparation, the final bulk product is
clarified through a filtration system with or without prior addition of
a filter aid. Polished solution is then stored in a holding tank until
released by Quality Control
Sterile Preparations
Distinct class of products introduced into
internal body compartments. Because all
components and processes are selected and
designed to eliminate contamination of all
types (physical, chemical and microbiological),
maximum compliance to cGMP is mandatory
Classification of Sterile Products based on Route of Administration
Parenteral preparations – those intended for injection
under or through one or more layers of the skin or
mucous membranes. IV, IM, SC, Intradermal,
intraspinal
Ophthalmic preparations – for the eye
Otics – for the ears
Nasal preparations – for the nose and throat
Irrigating solutions – for washing wounds or abraded
mucous membranes
Components
Highest quality
General characteristics: therapeutically effective,
provide maximum safety, function efficiently, free from
contamination, physically and chemically stable even
after thermal sterilization, produce little or no tissue
irritation at site of administration
On the basis of their functions, components are
classified into the therapeutic or active ingredient,
vehicle and additives
Pyrogens
Lipid substances associated with a carrier molecule,
which is usually a polysaccharide but may be a protein
Product of metabolism of microorganisms such as
most bacteria, many molds and viruses
Febrile reactions about an hour after injection into man.
This is accompanied by chills, body aches, cutaneous
vasoconstriction and rise in arterial blood pressure
Antipyretics eliminate the fever, but not the systemic
effects of pyrogens
Official test for detecting and measuring pyrogens
Bacterial endotoxins test
Pyrogen test
Bacterial Endotoxins Test
Test for estimating the concentration of bacterial endotoxins that
may be present in sample using Limulus Amebocyte Lysate (LAL)
which has been obtained from the aqueous extracts if the
circulating amebocytes of the horseshoe crab, Limulus
polyphenus, and which has been prepared and characterized for
use as an LAL reagent for gel-clot formation
Endotoxin units
Procedures include incubation for preselected time of reacting
endotoxin and control solutions with LAL reagent and reading of
the spectrophotometric light absorbance at suitable wavelength
Pyrogen Test
Designed to limit to an acceptable level the risks of febrile reaction
in the patient to the administration, by injection, of the product
concerned.
Involves measuring the rise in temperature of rabbits following the
IV injection of a test solution and is designed for products that can
be tolerated by the test rabbit in a dose not to exceed 10 mL/kg
injected IV within a period of not more than 10 minutes
If no rabbit shows an individual rise in temperature 0.6 oC or more
above its respective control temperature, and if the sum of the 3
individual maximum temperature rises does not exceed 1.4 oC, the
product meets the requirements for the absence of pyrogens
Pyrogen tests
May be destroyed or eliminated through
physical, chemical or combination of both
means
Depyrogenation Method
Adequate washing with detergent treatment followed by dry heat sterilization is recommended for glasswares and equipment. Optimum temperature is 250 oC for 45 minutes or 180 oC for 3 to 4 hours. Autoclaving temperatures will not destroy pyrogens during normal cycle
Distillation is the most reliable method of eliminating pyrogens from water. Pyrogenic substances are not volatile and thus will remain in the distilland
Removal of pyrogens by select adsorbents has limited use because of the concurrent phenomenon of adsorption of solute ions of molecules
Vehicles
Water for injections
Prepared by distillation or by reverse osmosis
Non-aqueous solvents (polyethylene glycol, propylene glycol and fixed oils) – solubility factors or hydrolytic reactions
Must not be toxic, irritating or sensitizing and must not exert an adverse effect on the ingredients of the formulation
Additives
Essential for almost every product to enhance its stability
Must exhibit the following characteristics: – Perform its function throughout the useful life of the product
– Must be non-toxic and non-irritating
– Must not exert any adverse effect on the product
– Must not interfere with therapeutic efficacy or assay of the active therapeutic compound
Includes solubilizers, antioxidants, chelating agents, buffers, antimicrobial agents, tonicity contributors, hydrolysis inhibitors, antifoaming agents and numerous other substances for specialized purposes
Additivies – Antibacterial/Antifungal Agents
USP states that antimicrobial agents in bacteriostatic or fungistatic concentrations must be added to preparations contained in multiple dose containers
Must be present in adequate concentration at the time of use to prevent the multiplication of microorganisms inadvertently introduced into the preparation while withdrawing a portion of the contents with a hypodermic needle and syringe
Two mercurials, phenylmercuric nitrate and thimerosal, the four homologous esters of p=hydroxybenzoic acid, phenol, benzyl alcohol, and chlorobutanol
Additives- Antioxidant
Oxidation is one of the pathways of degradation which can be accelerated during thermal sterilization
To protect a therapeutic agent susceptible to this reaction, antioxidants are required.
Antioxidants used in sterile products are classified into: reducing agents, blocking agents, synergists, chelating agents, inert gases
Reducing agents
Antioxidants which function by being
preferentially oxidized
Ascorbic acid, sodium bisulfite and
metabisulfite, sodium formaldehyde
sulfoxylate, thiourea
Blocking agents
Antioxidants which block an oxidative chain
reaction in which they are nor usually
consumed
Ascorbic acid esters, butyl hydroxytoluene
(BHT), and tocopherols
Synergists
Compounds increase the effectiveness of anti-
oxidants, particularly those blocking oxidative
reactions
Ascorbic acid, citric acid, citraconic acid,
phosphoric acid and tartaric acid
Chelating agents
Those that complex with catalysts which
otherwise would accelerate the oxidative
reaction
Ethylenediaminetetraacetic acid salts
Inert gases
Nitrogen and carbon dioxide have been used
to displace oxygen from a solution and reduce
the possibility of oxidative changes in the
formulation
Additives - Buffers
Added to maintain the required pH for many products
A change in pH may cause significant alterations in the rate of degradation reactions.
Changes in pH may occur during storage as a result of : 1. Dissolving of glass constituents in the product; 2. Release of constituents from rubber closures or plastic components in contact with the products; 3. Dissolving of gases and vapors from the air space in the container or by diffusion through the rubber or plastic component; 4. Reactions within the products
Acetates, citrates and phosphates
Additivies – Tonicity Contributors
Compounds contributing to the isotonicity of a
product reduce the pain of injection in areas
with nerve endings
Buffers may serve as tonicity contributors as
well as stabilizers for the pH
Containers
Containers for sterile products are made of glass or
plastic
Glass is still preferred for injectable products, and
composed principally of silicon dioxide tetrahedron,
modified physiochemically by such oxides as those of
sodium, potassium, calcium, magnesium, aluminum,
boron and iron
2 general types of glass are soda lime and
borosilicates
Based on its chemical resistance, glass compounds are classified into 4 types
Type I – highly resistant borosilicate glass
Type II – treated soda lime glass
Type III – soda lime glass
Type NP – general purpose soda lime glass
Containers
Glass containers like ampule cartridges and vials may be manufactured from glass tubings or by blow molding
Rubber closures are used to seal the openings of cartridges, vials and bottles, providing a material soft and elastic enough to permit entry and withdrawal of a hypodermic needle without loss of the integrity of the sealed containers
Accessories used in conjunction with closures are aluminum caps with or without flif-off seals
Production of a sterile preparation consists of the following steps
Compounding
Filtration
Filling
Sealing
Sterilization
Compounding
Processing of sterile preparations follow normal
manufacturing procedures which must be done in
aseptic condition based on the cGMP
All conditions must be carefully designed and
controlled to prevent the entrance of microorganisms to
a product.
Good environmental control. Good hygiene. All
equipments and materials used whenever possible
must be sterile
Filtration
Membrane filters, with a porosity ratings of 0.22 or 0.45 microns are usually specified for sterile filtration
Larger size has a faster flow rate (8 times) but would require the use of a prefilter to remove some colloidal matter which cause rapid clogging and thus reduce the filtration cycle
The process removes particulate matter down to at least 3 microns in size
The efficiency of membrane filters is tested by Bubble test
Filling
Bulk preparations are subdivided into unit dose containers during filling
Process forces a measured volume of the preparation through the orifice of a delivery tube designed to enter the constricted opening of a container by means of Gravity, Vacuum or with the aid of Pressure Pump
Method selected for filling sterile preparations should provide the degree of accuracy and precision required by the nature of the product
Slight excess is required in each container provide loss that will occur at the time of administration by adherence to the wall of the container and retention in the syringe and hypodermic needle lumen
Sealing
Will retain the contents of a sterile product and will assure a
tamper proof presentation
Containers should be sealed in an aseptic area adjacent to the
filling machine
Ampuls are sealed by heating with a high temperature gas-oxygen
flame to form: Tip seals & Pull seals
Sometimes, it is necessary to displace the air in the space within
the ampul above the product to prevent decomposition. Stream of
inert gas, such as nitrogen or carbon dioxide is introduced during
or after filling with the product and the ampul is sealed
immediately before the gas can diffuse to the outside
Sealing
Dye leakers test is useful method for evaluating the efficiency of sealing process of ampuls. Methylene blue is used. Vials and bottles are NOT subjected to a dye-leakers test
Bottles, cartridge and vials are stoppered by rubber closures held in place by aluminum caps
Bottom edge of these caps are bent (crimped) around and under the tip of the glass container. It offers a tamper-evident presentations since the cap cannot be removed without destroying the cap. Perforations permit tearing away the portions of the cap to be discarded preparatory to use
Sterilization
Complete destruction or elimination of
microbial life
Choice of most effective sterilization procedure
is dependent on: 1. Compatibility of the
process with the preparation; 2. Successful
validation of the process
2 main divisions of sterilization procedures are
physical processes and chemical processes
Physical Processes of Sterilization
Thermal methods
Non-thermal methods
Thermal Methods
Microorganisms are killed by heat by what is thought to
be coagulation of the protein of a living cell
Lethal effectiveness of heat is dependent on: degree of
heat, exposure period and moisture present
Within the range of sterilizing temperatures, the time
required to produce a lethal effect is inversely related
to the moisture present. For these reasons dry heat or
moist heat are used as the conditions require
Non-thermal Methods
Ultraviolet light
Ionizing Radiations
Filtration
Aseptic Processing
Non-Thermal Methods – UV light
Commonly employed to aid in the reduction of airborne
contamination and to attempt to sterilize surfaces
within the processing environment
Germicidal light produced by mercury vapor lamps is
emitted at a wavelength of 2537 Angstrom units (253.7
millimicrons). Function of the intensity of radiation and
time of exposure. It also varies with the susceptibility of
the organisms
Organisms dies or is unable to reproduce
Non-Thermal Methods- Ionizing Radiations
High energy radiations emitted from radioactive
isotopes such as Cobalt 60 (gamma rays) or
produced by mechanical acceleration of
electrons to very high velocities and energies
(cathode rays, beta rays)
Destroy microorganisms by stopping
reproduction as a result of lethal mutations
Non-Thermal Methods - Filtration
Non-thermal method for the sterilization of
select solutions by removing microorganisms
fro the solution while permitting the passage of
all the desired components of the solution and
imparting no undesirable components from the
filter
Non-Thermal Methods – Aseptic Processing
Closely involved with sterilization although it is
technically not a sterilization process
Condition and manipulations followed gives the
assurance that microorganisms do not enter a
product
Used for products that cannot terminally
sterilized after they have been sealed in the
final container
Chemical Processes of Sterilization
Gas sterilization
Surface Disinfection
Chemical Processes – Gas Sterilization
Ethylene oxide is believed to exert its lethal
effect upon microorganisms by alkylating
essential metabolites, affecting particularly the
reproductive process
Ethylene dioxide sterilization is the acceptable
practical method for sterilizing plastic.
Other gases used are beta propiolactone,
formaldehyde, sulfur dioxide
Chemical Processes – Surface Disinfection
Disinfectants do not sterilize a surface,
however, as adjuncts to thorough cleaning of
surfaces, disinfectants properly used may be
expected to provide an aseptic condition of the
surfaces involved
Sterility test
Performed on products and materials subjected to
previously validated sterilization procedures
USP provides 2 basic methods for sterility testing: 1.
Direct inoculation of test samples on culture media; 2.
Membrane filtration technique which involves filtering
test samples through membrane filters, washing the
filters with fluids to remove inhibitory properties and
transferring the membrane aseptically to appropriate
culture media
Air Control
HEPA (high efficiency particulate air) filter composed of
glass and asbestos or electrostatic precipitators.
Effectiveness of HEPA filters is tested by DOP (dioctyl-
phthalate) test method
Laminar Airflow Devices in the form of rooms, cabinets
or benches are based on the procedure discovered by
Whitfield in 1961. Horizontal air flow appears to be the
most superior of the other flow hoods.
Production Facilities
Clean up area
Preparation area
Aseptic area
Quarantine area
Finishing or packaging area
Personnel
Good health and free from dermatological conditions that might
increase the microbial load
Neat, orderly and reliable
Uniforms used in the aseptic areas should be Sterile. Uniforms
usually consists of coverall for both men and women, hoods to
completely cover the hair, face masks, and cloth or plastic hoods.
Sterile rubber gloves are also required for most aseptic
operations, preceded by thorough scrubbing of the hands with a
disinfectant soap. The uniform is designed to confine the
contaminants discharged from the body of the operator, thereby
preventing their ingress into the product