Post on 18-Jan-2018
description
Solutions are:
Solution Dosage forms are prepared by dissolving the active ingredient(s) in an
aqueous or non aqueous solvent.
Solutions can be formulated for different routes of administration
Orally: Syrups, elixirs, drops
In mouth and throat: Mouth washes, gargles, throat sprays.
In body cavities: Douches, enemas, ear drops, nasal sprays.
On body Surfaces: Collodions, lotions.
Advantages of SoIutions (1) Easier to swallow therefore easier for: children - old age - unconscious people.
(2) More quickly effective than tablets and capsules.
(3) Homogenous therefore give uniform dose than suspension or emulsion which need shaking.
(4) Dilute irritant action of some drugs (aspirin, Kl, KBr) minimize adverse effects in the GIT like KCl.
Disadvantages of SoIutions
(1) Bulky therefore difficult to transport and store.
(2) Unpleasant taste or odours are difficult to mask.
(3) Needs an accurate spoon to measure the dose.
(4) Less stable than solid dosage forms.
(5) Solutions often provide suitable media for microbial
growth.
Formuation of Solutions
(Aqueous Solutions):
√ H2O is the most widely used solvent for use as vehicle because its lack of toxicity, physiological compatibility and ability to dissolve a wide range of materials.
√ At least Purified water BP should be used in all sort of solutions.
√ Water for injections must be used in case of parenteral solutions and it must be pyrogen free.
√ For CO2 sensitive drugs (phenobarbitone-Na, or aminophylline) or oxidation sensitive drugs (apomorphine, ergotamine) CO2 or airfree water for injection must be used.
Approaches to Improve Aqueous Solubility
The following methods may be used in order to improve aqueous solubility.
(1) Cosolvency: Vehicles used in combination with water to improve
the solubity of of the drug are called cosolvents.
For example,
a blend of propylene glycol and water is used to improve
the solubility of cotrimoxazole.
Paracetamol elixir is formulated as an elixir by the use of propylence
glycol and syrup.
(2) pH control:
■ The solubility of a weak base can be increased by lowering the
pH of its solution whereas the solubility of a weak acid is
improved by a pH increase.
■ The chemical stability of a drug may also depend on pH.
So it must be carefully controlled.
■ The solutions for parenteral, opthalmic and mucous
membrane use must be carefully controlled to avoid pain and
irritiation.
■ The bioavailability of drugs may be influenced by the pH
of their solution.
(3) Solubilization
■ The solubility of insoluble or poorly soluble drugs in water can be
improved by the addition of surface active agents.
■ The hydrophillic surfectants possessing HLB values above 15
are usually used as solubilizing agent.
■ The surfectant chosen must be nontoxic, nonirritant, miscible
with solvent systems and compatible with other ingredients,
free from disagreable odour and taste.
■ For example, the solubilization of iodine to produce iodophores
is achieved by use of macrogel ethers.
(4) Complexation.
■ Poorly soluble drugs sometimes interact with a soluble material
to form a soluble intermolecular complex. This complex could
not cross lipid membrane. So a device must be developed to
release drug from the complex before contact with biological fluids.
■ Hydrotropy; the increase in aqueous solubility of material
by inclusion of additives. This method could also be used for
complexation.
■ For example, complexation of iodine with a 10-15% solution
of polyvinylpyrrolidone to improve the aqueous solubility
of the active agent.
(5) Chemical Modification:
■ Chemical modification of drug may be necessary in order to
produce a water soluble derivative.
■ For example, the synthesis of the sodium phosphate salts
of hydrocortisone, prednisolone and betamethasone.
(6) Particle Size Control:
■ As particle size decreases solubility will increases.
■ This phenomenon is very important for suspension
formulation rather than solution.
Formulation of SolutionNon-aqueous solutions
The use of alternative solvents : If complete solution of the active
ingredients is not possible at all storage temperatures or if the drug is
unstable in aqueous systems it may be necessary to use alternative
solvent.
For example, IM injection of solutions of drugs in oils is often used for
depot therapy and some drugs (propionate and benzoate esters of
testesterone and oestradiol) are specially synthesized to improve their
oil solubilities.
Fixed Oils & Vegetable Origin: These are nonvolatile oils which
consist of fatty acid esters of glycerol. Olive oil, sesame oil, maize oil,
cottonseed oil, soya oil and castor oil are suitable for parenteral use.
For example, almond oil consists of glycerides mainly of oleic acid
is used as solvent for oily phenol injection BP.
Some fixed oils are sufficiently tasteless and odourless to be suitable
for oral use as solvents of Vitamin A & D.
Alcohols: Ethyl alcohol is the most widely used solvent in this class
specially for external application. For example, Salicylate lotion BP.
At concentration above 15%, it exhibits antimicrobial activity. Usually
it is used as cosolvent with water.
If required for external use then industrial methylated spirit (IMS) is
usually included rather than the more expensive ethanol.
An alcohol possessing similar properties is isopropyl alcohol, is used
as a solvent for dicophane.
Polyhydric Alcohols: Alcohols having two hydroxyl groups are known
as glycols but due to their toxicity they are rarely used internally.
Propylene glycol is an exception often used in conjunction with water
or glycerol as a cosolvent
It is used in formulation of Digoxin Inj BP, Phenobarbitone Inj. BP,
Cotrimoxazole IV inj BP.
Dimethylsulfoxide (DMSO)
This is a highly polar compound and is thought to aid the penetration of drugs through the skin.
For example, DMSO is used as a carrier for idoxuridine (antiviral agent) for application to human skin.
Ethyl Ether: It is used as a cosolvent with alcohol in some collodions.
Liquid Paraffin: The oily nature of this material makes it unpleasent to use externally, although it is often used as a solvent for the tropical application of drugs in emulsion formulations.
Isopropyl myristate and isopropyl palmitate are oily materials, used as solvents for external use particularly in cosmetics.
Formulation Additives• Buffers
To resist any change in pH. It must be compatible with other excipients and
have low toxicity. Most pharmaceutically acceptable buffer systems are carbonates, citrate, gluconates, lactates, phosphates and tartarates.
• Isotonicity modifiers• Solutions for injection• Application to mucous membrane• Large-volume solutions for ophthalmic applicationmust be made isotonic to avoid pain and irritation.
Most widely used isotonicity modifiers are: dextrose and NaCl
• Viscosity enhancementIt is difficult for aqueous-based topical solutions to remain on the skinor in the eye; therefore low concentrations of jelling agents are added to increase the viscosity of the product.
• PreservativesSolution 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. 4. Consumer use may result in the introduction of microorganism. so a preservative should be added to the product
Preservative used 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 odour
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 ascorbic 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 .
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.
•AntioxidantsVitamins, essential oils & almost all fats and oils can be oxidized.
Oxidation reaction can be initiated by:
1. heat: maintain oxidizable drugs in a cool place
2. light: use of light- resistant container
3. heavy metals (e.g. Fe, Cu): effect of trace metals can be
minimized by using citric acid or ethylenediamine tetra acetic
acid (EDTA) i.e. sequestering agent .
Antioxidants as propyl & octyl esters of gallic acid, tocopherols or
vitamin E, sodium sulfite, ascorbic acid (vit. C) can be used.
•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.
• Flavours and perfumes
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.
Pharmaceutical Solutions
Aqueous
1.Douches2.Enemas3.Gargles4.Mouthwashes5.Nasal washes6.Juices7.Sprays8.Otic solutions9. Inhalations
Sweet &/Viscid1.Syrups2.Honeys3.Mucilages4.Jellies
Nonaqueous
1.Elixirs2.Spirits3.Collodions4.Glycerins5.Liniments6.Oleo Vitamin
Syrups:
Concentrated viscous liquid prepn containing
large amount of dissolved sugar (or sugar
substituent) with or without added flavouring
agents and medicinal substances.The concn
of sugar in syrup should be 66.7%.
Syrups are two types:
1)Non-medicated syrup: contain flavouring agents but not
medicinal substances.
For example, Cherry syrup. Cocoa syrup, orange syrup,
raspberry syrup etc.
2) Medicated syrup: contain therapeutic agents. Now these
syrups are used to extremporneous preparation of liquid
dosage forms of medicines.
Medicated syrup is formulated by the components ; sucrose,
purified water, flavouring agent & other excipients.
Components of Syrup
► Sucrose or sucrose substitutes: provide sweeting effects
and viscosity.
► Antimicrobial preservatives
► Flavourants
► Colourants.
Medicated syrups contain special solvents, solubilizing agents,
thickeners or stabilizers along with active ingredients.
Sugar used in Syrup: Sucrose is the most frequently used sugar
substance in syrups. Dextrose is also used as sugar substituent.
Non-sugar substance: Sorbitol, glycerin and propylene glycol (PEG).
Artificial sweeteners: Saccharin, Aspartame, Neotame etc.
Why most syrups contain sucrose of 60-80%?
Most syrups contain sucrose of 60-80%,
► not only because of the desirable sweetness and viscosity but also
to enhance stability in contrast to unstable character of dilute
sucrose solutions.
► Aqueous dilute sugar medium is an efficient nutrient medium for
microbial growth particularly yeasts and molds. But concentrated
sugar solutions are resistant to microbial growth.
Antimicrobial Preservatives:
Amount of preservative required to protect a syrup against microbial
growth varies with the proportion of water available, the nature and
inherent preservative activity of some formulative materials and the
capability of the preservative itself.
E.g. benzoic acid (0.1 to 0.2%), Na-benzoate(0.1 to 0.2%) and various
combinations of methyl, propyl and butylparabens.
Flavourant
Most syrups are flavoured with synthetic flavourants or with naturally
occuring materials as volatile oils (e.g. orange oil), vanillin and others
to render the syrup pleasant testing.
Colorants
To enhance the appeal of the syrup, a colouring agent is generally
used which correlates with flavourant (e.g. green with mint, brown
with chocolate etc).The colorant should be water soluble, nonreactive
and color stable at different pH range.
Advantages and Syrup
1.Syrups retard oxidation because it is partly hydrolysed into reducing sugar such as levulose and dextrose.
2. It prevents decomposition of many vegetable substances, syrups have high osmotic pressure which prevents microbial growth.
3. They are palatable due to presence of sugar, suitable vehicle for administration of bitter and bad odorous substances.
4. They are more quickly effective than solid dosages (e.g. tablet, capsule etc.) 5. They are homogenous formulation so the active ingredients are also homogenously distributed.
6. This is a suitable formulation for pediatric and geriatric patients.
Disadvantages of Syrup
1.It is possible in a closed container of syrup for surface dilution
due to solvent evaporation.
2. Solvent evaporation condenses upper internal surface of the
container and then flows back on to the surface of the product
which provide an ideal medium for the growth of certain
microorganism.
3. During storage and use of syrup involves crystallization of the
sugar within the screw cap. This problem is solved by addition of
polyhydric alcohols.
Elixirs
Elixirs are clear, sweetened, hydroalcholic solutions intended for
oral use and are usually flavoured to enhance their palatability.
Nonmedicated elixirs are employed as vehicles and medicated
elixirs for the therapeutic effect of the medicinal substances they
contain.
Difference between Syrup and elixirsSyrup Syrups are concn aq,
prepn of sugar or nonsugar substitute with or without added of flavouring agent and also the medicaments.
Usually more sweet than elixir.
More viscous than elexir. More effective than elixir.
Elixir Elixirs are clear, sweetened,
hydroalcoholic solutions intended for oral use, are usually flavoured to enhance their palatability.
Less sweet than syrup. Less viscous due to
containing lower proportion of sugar.
Less effective than syrup.
Difference between Syrup and elixirs
Syrup Syrups are unable to
maintain alcohol soluble components in solution.
From a manufacturing stand point, syrups are not preffered over elixir.
Syrup containing over 60-80% of sugar were usually self preserving.
Elixir Elixirs are better able to
maintain both water soluble acid, alcohol soluble components in solution
Elixirs are preffered over syrup.
Elixir containing over 10-20% of alcohol are usually self preserving.
Formulation of Elixir
(1)Vehicles:
■ The elixirs are usually prepared by using water, alcohol, syrup
glycerin, sorbitol, propylene glycol as vehicle. Among them water is
used to dissolve the majority of ingredients.
■ The flavouring agents containing essential oils are soluble in
alcohol. Certain ingredients of elixir are easily soluble in alcohol. In
this case concn of alcohol is 5-40% (to make a clear soln).
■ Glycerin, sorbitol and propylene glycol are used as a vehicle for
many ingredients which are not soluble in water and alcohol.
(2) Adjuvents:
■ Chemical Stabilizers: The various chemicals or solvents are used
to make stable elixirs. For example, in neomycin elixir, citric acid
is added to adjust the pH between 4 to 5 to prevent darkening of
elixir on storage.
■ Colourant:
The coalter dyes are commonly used in elixir. For example,
amaranth compound, tartrazine, green sulphur.
■ Flavourant:
The colourants used in elixirs are Raspberry syrup, lemon syrup,
orange syrup etc.
■ Preservatives:
The mould growth and fermentation in elixirs are inhibited by using
alcohol 20% or more, propylene glycol, glycerol as a vehicle. The high
osmotic pressure of elixir prevents the growth of microorganism.
Benzoic acid, methyl paraben, propyl paraben etc are also used
as preservatives in many elixirs.
(3) Container: Elixirs are dispensed in well closed, airtight glass bottles having screwcaps.
(4) Storage:Elixirs are required to be stored in a cool place protected from light.
Why preservatives are added in the syrup?
Although syrups have 66.7% sugar content, it require addition of
preservatives for following reasons;
(1)Solvent evaporation of syrup some times cause flow back of the
evaporated solvent to the upper layer of syrup producing a dilute
layer which provides an ideal media for microbial growth. This is
why preservative is essential in syrup.
(2) Syrups are usually formulated in a temperature controlled
environment. These may be transferred to other region of
uncontrolled temperature, it may cause the crystallization of the
sugar molecule and may remain as sediment to the solution. Thus
two layers are formed upper layer remain as solvent and the
lower layer remain as solute. Since the solvent layer is less
sugar content, it may be easily attacked by the microorganisms.
This is why preservatives are added to the syrup formulation.
Concentration of Sucrose controlling in Syrup Why is so important?
In dilute solutions sucrose provides an excellent nutrient for
molds, yeasts, and other microorganisms.
In concentration of 65 % by weight or more the solution will
retard the growth of such microorganisms.
A saturated solution may lead to crystallization of a part of
the sucrose under conditions of changing temperature.
How heat may cause the Deterioration of Syrup?When heat is used in the preparation of syrups, there is almost certain to be an inversion of a slight portion of the sucrose.
C12H22O11 2 C6H12O6
Sucrose heat & acid Invert sugar (dextrose and levulose)
The speed of inversion is greatly increased by acids; the hydrogen ion acts as a catalyst in this hydrolytic reaction.
Invert sugar♣ is more readily fermentable than sucrose♣ tend to darken in color♣ retard the oxidation of other substances.
The levulose formed during inversion is sweeter than sucrose; therefore the resulting syrup is sweeter than the original syrup.
When syrup is overheated it caramelizes.
Manufacturing of Solutions
■ Very simple equipments like mixing vessels, agitation system and
filtration system is necessary for formulation of syrup. Solutes are
simply added to the solvent in a mixing vessel and stirring is continued
until dissolution is complete.
■ Heat may be necessary in some cases for complete dissolution of materials. Care must be taken also for volatile and thermolabile materials.
■ Size reduction of solid materials may speed up the solution process.
■ Solutes needed in low concn are often predissolved in a small volume of the solvent and then added to the bulk.
■ Volatile materials such as flavours and perfumes are added at the end of a process and after cooling if necessary to reduce evaporation.
■ Finally the formulation is filtered for final clarification.
Stability of Solutions
Both the chemical and physical stability of solutions in their container
are important. A solution must retain its initial clarity, colour, odour,
taste and viscosity over its allocated shelf life.
Major signs of instability are
colour change,
precipitation
microbial growth
chemical gas formation
Clarity can be easily assessed by visual examination or optical
density measurement after agitation. Colour may be assessed by
visually or spectrophotometrically. The stability of flavours and
perfumes is difficult to assess but now a days chromatographic
methods are used.
Organoleptic powers are screened by a panel accessors. If a suitable
majority of the panel members are unable to detect a difference
between stored sample and freshly prepared reference material,
it may be assumed that the taste and odour of the sample has not
significantly changed.
Different Types of solutions
(a)Mixtures: Mixures are aqueous prepn either solution or suspension.
Most mixture prepn are manufactured on a small scale and allocated
shelf life of a few weeks before dispensing.
(b) Draughts: A draught is a mixture of only one or two large doses of
about 50 ml of solutions.
(c) Linctuses: A linctus is a viscous preparation usually prescribed for the
relief of cough. It is usually consists of a simple solution of the active
agent in a high concentration of sucrose often other sweetening
agents.
(d) Mouthwashes and Gargles: Aqueous solutions for the prevention
and treatment of mouth and throat infections can contain antiseptics,
analgesics and astringents. They should be diluted with warm water
before use.
(e) Nasal Products
Small volume solutions in an aqueous vehicle formulated at pH of
6.8 to avoid irritation in nasal mucous. Made isotonic with nasal
secretions using NaCl. Viscosity is controlled by cellulose derivatives
due to low buffering capacity of nasal mucous membrane.
Active ingredients include antibiotics, antiinflammatories and
decongestants.
(f) Ear Drops
These are simple solutions of drugs in either water, glycerol, propylene
glycol or alcohol/water mixtures for local use and include antibiotics,
antiseptics, cleansing solutions and wax softeners.
(g) Enemas
Aqueous or oily solutions, emulsions and suspensions available for
the rectal administration of medicaments for cleansing, diagnostic or
therapeutic purposes.
(h) Lotions:
A solution, designed to apply to the skin without friction. It may contain
humectants so moisture is retained on the skin after application or alcohol
which evaporates quickly imparting cooling effect on skin.
(i) Liniments:solutions or mixtures of various substances in oil, alcoholic solutions
of soaps, or emulsions.
They are intended for external application and should be so labeled.
They are applied with rubbing to the affected area, the oil or soap base
providing for ease of application and massage.
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.
(j) Paints:
Liquid prepn for application to the skin or mucous membrane, often
applied with a small brush. The solvents (e.g. alcohol, acetone)
evaporates quickly leaving a film on the skin containing active agents.
(k) 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.
The official medicated collodion, Salicylic Acid Collodion USP, contains 10 % w/v of Salicylic Acid in Flexible Collodion USP and is used as a keratolytic agent in the treatment of corns and warts.
(l) Aromatic Water:
Aromatic waters (medicated waters) are clear, saturated aqueous solution
of volatile oils or other aromatic or volatile substances. ■ They are used principally as flavored or perfumed vehicles.
■Volatile oils solutions represent an incompatibility problem of salting out.
This occurs after the incorporation of a very soluble salt in their solution.
■ Aromatic water will deteriorate with time therefore should be made in small quantities
- protected from intense light and excessive heat by storing in air
tight, light resistant containers.
■ If they become cloudy or otherwise deteriorate; they should be
discarded. Deterioration may be due to volatilization, decomposition or
mould growth.
There are 2 official methods of preparation:
(a)Distillation process (Stronger Rose Water NF) Adv.: most satisfactory method Dis.: slow and expensive
The drug should be coarsely ground and mixed with sufficient
quantity of purified water in the distillation unit.
After distillation any excess oil in the distillate is removed by
filtration.
Drug should not be exposed to the action of direct heat during
distillation; otherwise, the odour of the carbonized substance
will be noticeable in the distilled aromatic water.
If the volatile principle in the water are present in small quantities
the distillate is returned several times to the still with fresh portions of
drug.
(b) Solution process (Peppermint water)
Aromatic water may be prepared by shaking volatile substance
with purified water. The mixture is set aside for 12 hours &
filtered. Talc (inert) may be used to increase the surface of the
volatile substance, ensure more rapid saturation of the water
and act as a filter aid.
(m) Infusions
Infusions are concentrated solutions of active principles from animal
or vegetable sources. These are prepared by extracting the drug
using 25% alcohol but without application of heat. This is then
diluted 1 to 10 in the final product.
(n) Extracts: These similar product of infusions but concentrated by evaporation.
(p) Tinctures:
Alcoholic extracts of drugs but are relatively weak compared with
extracts.
(q) Spirits:
Alcoholic solutions but of volatile materials which are used as
flavoring agent.