MONOPHASIC LIQUID DOSAGE FORM
Syllabus
Definition and account of
oral solutions, syrups and elixirs.
Their importance in the
Medical field.
Components of the
formulations with examples: Solvents, buffers, sweeteners, acidifiers, flavors,
and preservatives.
Development of the formula.
Preparation , equipment in
industrial scale.
Question s
1. Short note on preservatives
in pharmaceutical dosage forms. (98) 4
2. Short note on syrups. (98) 4
3. Give the importance of
colorants, sweeteners, solvents, stabilizers, flavoring agents in
pharmaceutical dosage forms. (98) 4 x 4
4. Discuss the preformulatory
and informulatory aspect of designing a multivitamin syrup. 16
5. What are syrups? Write about
the preparation, properties and uses of at least two medicated syrups. (93) 10
6. Differentiate between
solution and elixirs. (95) 8
7. Classify organoleptic
compounds with examples. (93) 10
Solution
In
pharmaceutical terms, solutions are liquid preparations that contains one or
more chemical substances dissolved in a suitable solvent or mixture of mutually
miscible solvents.
Classification of
solution
(i) According to the route
of administration
a) Oral solutions—through oral route.
b) Otic solutions—instilled in the ears.
c) Ophthalmic solution—instilled in the eyes.
d) Topical solutions—applied over the skin surface.
(ii) According to
composition and uses
a) Syrup—aqueous
solution containing sugar.
b) Elixir—sweetened
hydroalcoholic (combination of water and ethanol) solution.
c) Spirit—Solution
of aromatic materials in alcohol.
d) Aromatic Water—Solution of aromatic material in water.
e) Tincture / Fluid extract—Solution prepared by extracting active constituents
from crude drugs. e.g. Compound cardamom tincture. They may also be solutions
of chemical substances dissolved in alcohol or in hydroalcoholic solvent. e.g.
Tincture of Iodine.
f) Injection—Certain solution prepared to be sterile and pyrogen-free and intended
for parenteral administration.
Formulation
Consideration
|
1) Solubility
a)
pH
b)
Cosolvency
c)
Solubilization
d)
Complexation
e)
Hydrotrophy
f)
Chemical modification of the drug molecule
2) Preservation
a)
Preservatives
b)
Antioxidants
c)
Reducing agents
d)
Synergists
|
3) Organoleptic
consideration
a)
Sweetening agents
b)
Flavoring agents
c)
Coloring agents
d)
Viscosity control
e)
Overall appearance
4) Stability
a)
Chemical stability
b)
Physical stability
|
SOLUBILITY
When a solid solute is dissolved in a liquid solvent
two types of interactions are evident—one is the intra-molecular force between
the solute molecules and the other is the intermolecular force between the
solute and solvent molecules. When a solute dissolves, the substance’s
intra-molecular forces (cohesive force) must be overcome by the force of
attraction between the solute and solvent molecules (adhesive force).This
involves breaking the solute-solute forces and the solvent-solvent forces to
achieve the solute-solvent forces attraction.
Expression of solubility
According to Indian
Pharmacopoeia
|
Descriptive Phrase
|
Approximate quantities(ml) of solvent by volume for 1 part
(1 gm) of solute by weight
|
|
Very soluble
Freely soluble
Soluble
Sparingly soluble
Slightly soluble
Very slightly soluble
Practically insoluble
|
less than 1 part
from 1 to 10 parts
from 10 to 30 parts
from 30 to 100 parts
from 100 to 1000 parts
from 1000 to 10,000 parts
more than 10,000 parts
|
Solubility
The
solubility of an agent in a
particular solvent indicates the maximum
concentration to which a solution may be prepared with that agent and that
solvent.
Determination of
Equilibrium Solubility of a Drug
An excess of the drug ( finely
powdered to minimize the time required to attain the equilibrium) is placed in
a vial along with a specific amount of the solvent. The tightly closed vial is
then agitated at constant temperatures (preferably at temperature somewhat
higher than room temperature e.g. 300C so that constant conditions
can be maintained regardless of normal laboratory temperature variations), and
the amount of drug in solution is determined periodically by assay (by some
chemical method) of a filtered sample of the supernate. Equilibrium is not
achieved until at least two successive samplings give the same result.
The solubility is generally expressed in mg of solute per ml of solvent
at 250 C or per 100 ml etc.
Solubility of a drug depends on
temperature, solvent, pH and the chemical nature of the molecule itself. By
modifying these parameters the solubility of a drug can be manipulated
according to the requirement of designing the dosage form.
pH
A large number of drugs are either weak acids or
weak bases. The solubility of these agents can be markedly influenced by the pH
of the environment. When a weakly acidic drug is dissolved in water it can
remain in three states, namely undissolved, dissolved and ionized which can be
expressed in the following reaction format:
The
relationship between equilibrium solubility of a weakly acidic drug and the pH
of the environment can be expressed by Henderson-Hasselbach equation:
where pKa = Dissociation constant of the acid
[D-] = Molar
concentration of ionized drug
[DH] = Molar concentration of unionized drug
The
same equation can be written in the following forms:
where
DH
= Acid
D- =
Corresponding base of the acid (DH)
|
Weak Acid
|
Weak Base
|
 
DH =
acid
D
- = corresponding base of
DH
|
 
DOH =
base
D+ =
corresponding acid of the base DOH
|
To maintain the drug in soluble
state the solution of a drug must be done in a suitable buffer solution. The
buffer must have the following properties:
1. The buffer must have
adequate capacity in the desired pH range.
2. The buffer must be
biologically safe for the intended use.
3. The buffer (or its pH range)
must have minimum interference on the stability of the final product.
4. The buffer should permit
acceptable flavoring and coloring of the product.
e.g.
Some commonly used buffer systems are ammonium chloride, diethanol amine,
triethanolamine, boric acid, carbonic acid, phosphate buffer, glutamic acid,
tartaric acid, citric acid buffer, acetic acid buffer etc.
COSOLVENCY
Weak
electrolytes and nonpolar molecules frequently have poor water
solubility. These types of solutes are more soluble in a mixture of solvents
than in one solvent alone. This phenomenon is known as cosolvency; and
the solvents that, in combination increases the solubility of the solute are
called cosolvents.
To
increase the water solubility of a drug another water miscible solvent in which
the drug has good solubility is mixed.
Mechanism of
action
It
has been proposed that a cosolvent system works by reducing the interfacial
tension between the predominantly aqueous solutions and the hydrophobic solute.
Examples of
commonly used cosolvents
Ethanol,
sorbitol, glycerin, propylene glycol and several members of the polyethylene
glycol polymer (PEG200) series are the limited number of cosolvents (of water)
those are used and are acceptable in oral preparation.
Use of
cosolvents
Cosolvents
are used to increase the solubility of weak electrolytes, non-polar molecules
and volatile constituents used to impart a desirable flavor and odour to the
product.
DIELECTRIC CONSTANT
One
property of a solvent system is its dielectric constant. The dielectric
constant of a solvent can be defined as the ratio of the capacitances of a
capacitor filled with the solvent and air respectively.
 |
C
solvent
Dielectric constant (e ) =
C air
where, C is the capacitance of the condenser filled
with respective medium (solvent or air)
e.g dielectric water is 78.5
Every
solute shows a maximum solubility in any given solvent system, at one or more
specific dielectric constants.
To
determine the relationship between solubility of a solute with dielectric
constant(s) at which maximum solubility is attained is noted.
Pharmaceutical
formulations of comparable dielectric constant can thus be prepared, and the
most appropriate solvent system can be selected on the basis of solubility,
stability and organoleptic characteristics requirements.
SOLUBILIZATION
spontaneous
increase of solubility of a poorly water-soluble solute molecules into an
aqueous solution of surface active agents (or surfactants) in which a
thermodynamically stable solution is formed.
Mechanism
When
surfactants are added to water at low concentrations, they tend to orient at
the air-liquid interface.
As
additional surfactant is added, the interface becomes fully occupied, and the
excess molecules are faced into the bulk of the liquid.
At
still higher concentrations, the molecules of surfactant in the bulk of the
liquid begin to form oriented aggregates or micelles, this change in
orientation occurs abruptly (suddenly).
The
concentration of surface active agent at which micelles occurs is called critical
micelle concentration .
Solubilization
is thought to occur by virtue of the solute dissolving in or being adsorbed
onto the micelle. The water solubility of the solute increases with the
concentration of the micelles.
Examples of some solubilizing agents:
Other examples are Sucrose monoesters, Lanolin
esters etc.
It has generally been found that
surface-active-agents having HLB (Hydrophilic Lipophilic Balance) values higher
than 15 acts better as solubilizing agents.
COMPLEXATION
|
Solubility
of a compound may be increased by complexing with a complexing agent. e.g.
solubility of para amino benzoic acid (PABA) may be increased by complexing
with caffeine.
When
an insoluble compound forms a complex which is more soluble in the solvent -
the total solubility is equal to the inherent solubility of the uncomplexed
drug plus the concentration of drug-complex in solution.
When
a certain amount of drug is mixed in water some amount will get dissolved (A)
and some amount will remain undissolved. If a complexing agent is added to it
some drug will be complexed and become soluble in water. So the total
solubility will be will be increased.
When
more complexing agent is added total solubility will increase; at a certain
concentration of complexing agent the solution will become saturated with
respect to free drug and the complex (B). After this point if still complexing
agent is used then remaining drug (undissolved) will form complex and the
excess complex will be precipitated (C). When no drug is left for complexation,
complexes of higher order may be formed.
e.g. I2 is sparingly
soluble in water. To dissolve it KI (potassium iodide) is added which makes a complex KI.I2
(i.e. KI3). After point C it forms KI. 2I2, KI.3I2
etc.
HYDROTROPHY
The
term hydrotrophy has been used to designate the increase in solubility in water
of various substances due to the presence of large amounts of additives.
Mechanism of
action
Not
clear yet. Some workers have speculated that this phenomenon is more closely
related to complexation involving a weak interaction between the hydrotrophic
agent and the solute.
Another
view is that the phenomenon must be due
to change in solvent character because of the large amount of additive needed
to bring about the increase in solubility.
Examples
Since a large concentration of
hydrotrophic agent is required (in the range of 20 to 50%) to produce a modest
increase in solubility, hence its pharmaceutical applications are very less in
number.
Drug
|
Hydrotrophic agent
|
|
1. Benzoic acid
2. Theophylline
3. Iodine
4. Adrenochrome mono
semicarbazone
|
Sodium benzoate
Sodium acetate and sodium glycinate
Polyvinyl pyrrolidone (PVP)
Sodium salicylate
|
SOLVENTS FOR ORAL PREPARATIONS
The
solvents those are usually used in the oral liquid preparations are purified
water, alcohol, glycerin and propylene glycol.
PURIFIED WATER (H2O)
Naturally
occurring water exerts its solvent effect on most substances. In oral
preparations the water used is potable water or Purified Water USP.
Specifications
of Purified Water USP
Method of preparations : By distillation or
by ion-exchange.
Total solid : Less than 10 parts per million (ppm)
pH : Between 5 and 7.
ALCOHOL (ETHANOL)
Next to water, alcohol is the most useful solvent in
pharmacy.
·
It is used as a primary solvent for many organic compounds.
·
With water it acts as a cosolvent and increases the solubility of
drugs. Alcohol is often preferred because of its miscibility with water and its
ability to dissolve many water-insoluble ingredients, including drug
substances, flavorants, and antimicrobial preservatives.
·
Alcohol is frequently used with other solvents, as glycols and
glycerin, to reduce the amount of alcohol required.
·
It also is used in liquid products as an antimicrobial preservative
alone or as a co-preservative with parabens, benzoates, sorbates and other
agents.
Disadvantages
It produces pharmacologic and potential toxic
effects of alcohol when ingested in pharmaceutical products particularly by
children. Hence, it should not be given to children below 6 years. For OTC
(over the counter) oral product for children the recommended alcohol-content
limit is 0.5 %.
|
Age of the patient
|
Permitted alcohol content
|
|
For children below 6 years
For children between 6-12 years
Children over 12 years and adults
|
0.5 %
5.0 %
10.0%
|
 |
GLYCERIN (Glycerol)
·
Glycerin is a clear syrupy liquid with a sweet taste.
·
It is miscible both with water an alcohol.
·
Glycerin has preservative qualities.
Disadvantages
 |
As
a solvent, it is comparable to alcohol, but because of its viscosity, solutes
are slowly soluble in it unless it is rendered less viscous by heating.
PROPYLENE GLYCOL
It
is a viscous liquid, is miscible with water and alcohol. It is useful solvent
with a wide range of application and is frequently substituted for glycerin in
pharmaceutical formulation.
BUFFERS
A
buffer is a compound or mixture of compounds that, by its presence in solution,
resists changes in pH upon addition of small quantities of acid or base.
Buffering
agents are necessary to resist the change of pH upon dilution or addition of
acid or alkali in the liquid preparation.
The
usual buffering agents used in oral liquid preparations are acetate buffer and phosphate buffer.
|
Buffer
|
Mixture of
|
Buffering
Range
|
|
Acetate buffer
Phosphate buffer
|
Glacial acetic acid
Potassium, sodium, ammonium salt of acetic acid
Potassium dihydrogen phosphate
Di-sodium hydrogen phosphate
|
pH 2.8 to 6.0
pH 2.0 to 8.0
|
Buffering is required to:
1. Keeping weakly acidic or
basic drug in solution
2. Increase the stability of
the drug
3. Resist the change of pH upon
dilution or addition of acid or alkali (e.g. leaching or alkali from glass
container).
SWEETENERS
Solutions
come in immediate contact with the taste buds (on the tongue). Drugs and other
adjuvants are generally not good to taste (i.e. not palatable). To enhance
palatability and to mask the taste of the drugs etc. sweeteners are used.
Example: Sucrose (sugar),
saccharin, aspartame, liquid glucose.
Sucrose
Source Commercially sucrose is obtained from sugarcane, beet
root and shorgum.
Advantages
1. It is soluble in aqueous
medium.
2. It is available in highly
purified form at reasonable price.
3. It is chemically and physically
stable in the pH range of 4.0 to 8.0.
4. It is frequently used in
conjunction with sorbitol, glycerin and other polyols.
5. Above 66.7 % mold growth
will not take place.
Disadvantages
Concentration
of sucrose solution above 66.7% (w/w) the sucrose crystallize making the
solution hazy (i.e. reducing the gloss of the solution).
Caps of the containers are generally found to be
locked due to this crystallization. Sorbitol, glycerin or other polyols are
used to reduce the crystallization.
Liquid Glucose
Liquid
glucose is an extremely viscid substance that imparts both body (i.e highly
viscous) and sweetness to liquid formulations.
Preparation Partial hydrolysis of starch with strong acid produce liquid
glucose. Its main component is dextrose and maltose.
 |
Saccharin (Sodium and Calcium salts
are soluble)
Advantages
1. Saccharin is used to
supplement sugars and polyols as sweeteners.
2. It is approximately 250 to
500 times as sweet as sugar.
3. It has no calorie value,
hence can be given to obese patients and diabetic patients.
Disadvantages
It
has a bitter after taste.
Aspartame
 |
Aspartame is the methyl ester of aspartic acid and
phenylalanine.
Advantages
1. It is approximately 200
times sweeter than sugar.
2. No bitter after taste.
3. Solubility in water is
adequate for formulation purpose.
Disadvantage
Although it is very stable as dry powder, its
stability in aqueous solutions is pH and temperature dependent. it is stable at
pH between 3.4 and 5.0 and at refrigerated temperature.
COLORANTS
To
enhance the appeal of the vehicle, a coloring agent is generally used which
matches well with the flavour employed in the preparation e.g. green with mint,
brown with chocolate flavor etc. The colorant used is generally water soluble,
non-reactive with other components, and color-stable at the pH range and under
the intensity of light that the liquid preparation is likely to be exposed
during its shelf-life.
N.B. From the psychological point of view the scheme
may be as follows:
Color Red Orange Yellow Green Blue Violet
Psychological
reactions Exciting Cheerful Tranquilizing Subduing
Desirable
properties of a coloring agent
1. Must be harmless, should
have no physiological activity
2. It should be a definite
compound because then its coloring power will be reliable, its assay
practicable.
3. Its tinctorial (coloring )
power should be high so that only small quantities are required.
4. It should be unaffected by
light, temperature, micro-organisms, pH changes.
5. It should not interfere with
other adjuvants.
6. I must be free from
objectionable odour and taste.
7. it must by inexpensive.
Example
·
Coal tar colors e.g.
Amaranth
·
The permitted colors do not always give satisfactory shades when used
alone but most popular tints and shades can be obtained by blending
e.g.
Green S and Tartrazine Solution B.P.C. contains GreenS (greenish blue) and
Tartrazine (Yellow green)
PRESERVATION
Specific
organisms generally recognized as undesirable in oral liquids include Salmonella species, Escherichia coli, Enterobacter
species, Pseudomonas species
(commonly Pseudomonas aeruginosa), Clostridium and Candida albicans.
Source of
contamination:
Raw
materials, processing containers and equipment, the manufacturing environment,
operators, packaging materials and the user.
Characteristics
of an ideal preservative
1. It must be effective against
a broad spectrum of microorganisms.
2. It must be physically,
chemically and microbiologically stable for the life-time of the product.
3. It must be nontoxic,
non-sensitizing, adequately soluble, compatible with other formulation
components, and acceptable with respect to taste and odour at the
concentrations used.
Some
pharmaceutically useful preservative
|
Class
|
Preservative
|
Usual
concentration (%)
|
|
Acidic
|
Phenol
Chlorocresol
o-Phenyl phenol
Alkyl esters of parahydroxy benzoic acid
(e.g. Methyl and Propyl Paraben)
Benzoic acid and its salts
Boric acid and its salts
Sorbic acid and its salts
|
0.2 - 0.5
0.05 - 0.1
0.005 - 0.01
0.001 - 0.2
0.1 - .0.3
0.5 - 1.0
0.05 - 0.2
|
|
Neutral
|
Chlorbutanol
Benzyl alcohol
b-Phenyl ethyl alcohol
|
0.5
1.0
0.2 - 1.0
|
|
Mercurial
|
Thiomersal
Phenyl mercuric acetate and nitrate (PMA &
PMN)
Nitromersol
|
0.001 - 0.1
0.002 - 0.005
0.001 - 0.1
|
|
Quarternary ammonium compounds
|
Benzalkonium chloride
Cetylpyridinium chloride
|
0.004 - 0.02
0.01 - 0.02
|
|
Preservatives
|
Uses
|
|
Acidic
Phenol
Alkyl esters of
parahydroxy benzoic acid
(e.g. Methyl and Propyl
Paraben)
Sodium salt of benzoic
acid
Sodium salt of sorbic acid
Neutral
Chlorbutanol
Benzyl alcohol
b-phenyl ethyl alcohol
Mercurials
Quartenary
ammonium compounds
|
Have
characteristic odor and unstable when exposed to oxygen, hence used rarely.
Mostly
used
Adequately
soluble in water
Have
both antifungal and antibacterial activity
Methyl
& Propyl ester at a ratio of 10 to 1 produce a synergistic effect.
Mostly used
Have antibacterial action and antifungal action
Water soluble
The are volatile alcohols, hence, have odor and
loss of preservative action on aging.
Not used in oral liquid preparations.
Used in ophthalmic, nasal and parenteral products.
Not used in oral liquid preparations
Used in ophthalmic, nasal and parenteral products.
Disadvantage: Mercurials readily
reduced to free mercury.
Not used in oral preparations
Used in ophthalmic, nasal and parenteral
solutions.
Disadvantages: They are inactivated by
variety of anionic substances.
|
SYRUPS
Syrups
containing approximately 85% sucrose resist bacterial growth by virtue of their
exosmotic effect on micro-organisms. Syrups that contain less than 85% sucrose,
a sufficient concentration of polyol (e.g. sorbitol, glycerin, propylene glycol
or polyethylene glycol) should be added to have the required osmotic pressure.
It
is possible, however, for surface dilution to take place in a closed container
as a result of solvent evaporation followed by condensation, with the
condensate flowing back onto the liquid surface. The resulting diluted medium
for bacterial and fungal growth. A sufficient concentration of preservative or
5 to 10% ethanol should be added to arrest the growth of microorganisms.
FLAVORS
An
objectionable taste may lead to nausea, vomiting and refusal to take the
preparation regularly or at all. On the other hand, an attractive flavour will
encourage continuation of treatment.
The
four basic taste sensations are salty, bitter, sweet and sour. A combination of
flavoring agents is usually required to mask these taste sensations
effectively.
Flavor
selection
|
Taste sensation
|
Recommended
flavor
|
|
Salty
Bitter
Sweet
Sour
|
Butterscotch, maple, apricot, peach, vanilla,
wintergreen mint.
Wild cherry, walnut, chocolate, mint combinations,
anise etc.
Fruit and berry, vanilla
Citrus flavors, liquorice, root beer, raspberry
|
Flavor
adjuncts
Menthol,
chloroform and various salts frequently are used as flavor adjuncts.
Menthol and chloroform are sometimes referred to as desensitizing agents. They impart a
flavor and odor of their own to the product and have a mild anaesthetic effect
on the sensory receptor organs associated with taste.
MANUFACTURING CONSIDERATION
Raw materials
1. Incoming raw materials
should be tested against some specifications
regarding identity, purity, uniformity and freedom from excessive microbial
contamination.
2. Additional processing may be required e.g. size-reduction or
sterilization before manufacturing. It is usually much easier to begin with low
microbial counts in the raw materials than to try to reduce these counts
substantially during processing.
3. In oral liquid preparations water is the main vehicle. It should
meet the USP requirements for Purified
water. It may be obtained by distillation or ion-exchange treatment. To
reduce the microbial burden water is passed through UV-rays and constant
circulation in piping systems that have “dead ends” where micro-organisms can
thrive.
EQUIPMENTS
The following types of equipments may be used in the
manufacture of oral liquid solutions:-
1. Mixing tanks (SS 316 Stainless Steel) equipped with an agitator.
2. Measuring devices for large
and small amount of solids and liquids.
3. A filtration system for the
final polishing - e.g. Sparkler filter.
Cleaning of
equipments
All equipments must be thoroughly cleaned and
sanitized before use.
Disinfectants
used: Dilute solutions of H2O2,
phenol derivatives and paracetic acid.
Sterilized by: Alcohol, boiling water, autoclaving, steam or dry
heat.
Material of
construction
·
Tanks are usually constructed of
polished stainless steel and are usually jacketed to allow for heating or
cooling of the contents.
·
Tanks are covered and equipped with see-through charging ports and
illumination for easy observation of the contents. If the tanks are used for
compounding of the bulk liquid, they have a built in agitation system.
·
The compounded liquid may then be transported to the filling line,
either manually by filling into portable transport tanks (fitted with wheels)
or by pumping (or gravity flow) through a liquid delivery conduit.
·
All the equipments and pipe lines should be easy to disassemble, clean
and sanitise.
COMPOUNDING PROCEDURE
Objective Complete
solution should usually be confirmed at every stage in the manufacture of a
homogeneous liquid.
Formula
1. Active constituent / Drug
2. Vehicle (Water / Alcohol /
Glycerol)
Sweetening
agents (viscosity building agents) Syrup,
Sorbitol, Glycerol
3. Preservatives
4. Flavors
5. Colors (Dyes)
Steps of
preparation
1. Purified water is heated to
approximately 500C to facilitate the dissolution of the solid
solutes. Solid solutes are added to the warm water and stirred to dissolve
(e.g. sugar, drug).
2. If any additive is required
in small amount then it should be dissolved separately and then mixed with the
bulk mixture.
3. Any large volume liquids
(e.g. glycerol, sorbitol solution) are added and mixed until homogeneous.
4. Before adding flavors the
temperature should be reduced to 300C (since most of the flavors are
volatile). The flavor should be dissolved in small amount of alcohol (since
flavors are generally insoluble in aqueous medium) and then it is mixed with
the bulk mixture.
5. Dye should be dissolved n
small amount of water. Then transferred to the bulk mixture.
6. Finally volume is made up to
the required volume. The total mixture is agitated thoroughly until homogeneity
is obtained.
7. Finally the batch is
filtered to obtain a polished, clear solution.
ORAL SOLUTIONS
Liquid
system where all the solutes remain in dissolved state is known as solution. Solutions intended to be taken
orally is called oral solutions.
Advantages
1. Absorption is instant from
the gastro-intestinal tract.
2. Uniform dosage is certain.
3. They provide a safe means of
administering substances like potassium iodide that cause gastric pain if taken
dry, e.g. as powders or tablets.
4. The attractive appearance of
a solution in a well polished bottle has a beneficial psychological effect.
PREFORMULATION
Oral solutions contain
1. Active constituents (Water
soluble)
2. Preservative
3. Flavorant
4. Colorant
5. Chemical stabilizers
(Antioxidant, reducing agent, synergists)
Dose
Liquid
pharmaceuticals for oral administration are usually formulated such that the
patient receives the usual dose of the medication in a conveniently
administered volume, as 5 ml (one teaspoonful), 10 ml or 15 ml (one
table-spoonful).
On
the other hand many solutions used in paediatric patients are given by drop,
utilizing a calibrated dropper usually furnished by the manufacturer in the
product package.
Calculation
The strengths of pharmaceutical preparations are
usually expressed in terms of % strength (w/w, w/v, v/v).
Formulation
Some chemical agents may be slowly soluble. In this
case rate of dissolution may be enhanced by
1. application of heat: the
temperature should not destroy other ingredients.
2. decrease the particle size
to increase the specific surface area.
3. by agitation: but
dissolution is delayed compared to heat application.
Chemical
interaction
Chemical
interactions which may occur between the various components of a solution which
may result in a alteration in the preparation’s stability and / or potency. For
example, it has been demonstrated that esters of p-hydroxy benzoic acid
(methyl-, ethyl-, propyl- and butyl- parabens) frequently used preservatives in
oral preparations, have a tendency to partition into certain flavoring oils.
SYRUPS
·
Syrups are concentrated, aqueous
preparations of a sugar or sugar-substitute with or without added flavoring
agents and medicinal substances.
·
Syrups containing flavoring agents but not medicinal substances are
called flavored vehicles (syrups).e..g Cherry Syrup, Cocoa Syrup, Orange syrup,
Raspberry Syrup.
·
Syrups containing medicinal agents are called medicated syrups. e.g. Chlorpheniramine maleate syrup, Ipecac
syrup, Chloral hydrate syrup etc.
Components of
syrups
Most
syrups contain the following components in addition to the purified water and
any medicinal agents present:
1. the sugar, usually sucrose,
or sugar substitutes used to provide sweetness and viscosity,
2. antimicrobial preservatives,
3. flavorants, and
4. colorants.
Sucrose and
non-sucrose based syrup
Sucrose
is most frequently employed in syrups. In special circumstances it may be
replaced by sugars, such as, dextrose,
or non-sugars as sorbitol, glycerin
and propylene glycol.
Methyl
cellulose or hydroxyethyl cellulose -these two materials are not
hydrolyzed and absorbed into the blood stream, and their use results in an
excellent syrup-like vehicle.
Taste masking
by syrup
The
syrup imparts a characteristics “body” (viscosity) and together with the
sweetness and the flavorants results in a type of pharmaceutical preparation
that is quite effective in making the taste of added medicinal agents. When the
syrup is swallowed, only a portion of dissolved drug actually makes contact
with the taste buds, the remainder of the drug being carried past them and down
the throat in the containment of the viscous syrup.
In
the case of antitussive syrups (e.g. linctus) the thick sweet syrup has a
soothing effect on the irritated tissues of the throat as it passes over them.
Preservative
action of syrup
Simple
syrup NF contains 85% w/v sucrose. At this concentration the syrup is resistant
to microbial growth, due to unavailability of the water required for the growth
of micro-organisms.
85% w/v syrup has a specific gravity of 1.313
i.e. 100 ml syrup contains 85 gm
sucrose
Weight of 100 ml syrup = 100 x 1.313 = 131.3 gm
\ Weight of water present
in 100 ml syrup = (131.3 - 85)
gm
=
46.3 gm
Volume of water present in 100 ml
syrup =46.3 ml
\ Volume of sucrose present
in 100 ml syrup = (100 -
46.3) ml
=
53.7 ml
\ 100 ml 85% syrup contains
|
|
Weight
|
Volume
|
|
Sugar
Water
|
85.0 g
46.3 g
|
53.7 ml
46.3 ml
|
|
Syrup (total)
|
131.3 g
|
100.0 ml
|
The solubility of sucrose in
water is 1 g in 0.5 ml
\ to dissolve 85 g sugar
required will be = 85 x
0.5 ml
=
42.5 ml
Thus,
only a very slight excess of water (46.3 - 42.5 = 3.8 ml per 100 ml
of syrup) is employed in the preparation of syrup. The sight excess of water
permits the syrup to remain physically stable under conditions of varying
temperature.
If
the syrup were completely saturated with sucrose, under cool storage conditions
some sucrose might crystallize from solution and, by acting as nuclei, initiate
a type of chain reaction that would
result in the separation of an amount of sucrose disproportionate to its
solubility at the storage temperature. The syrup would then be very much
unsaturated and probably suitable for microbial growth. However, the syrup NF
is stable and resistant to crystallization as well as to microbial growth.
Preparation of
Syrups
Syrups
are frequently prepared by one of four general methods; depending upon the
physical and chemical characteristics of the ingredients.
1. Solution of the ingredients
with the aid of heat
2. Solution of the ingredients
by agitation without the use of heat
3. Addition of sucrose to a
prepared medicated liquid or to a flavored liquid and
4. by percolation of either the
source of the medicating substance or of the sucrose.
Solution with
the aid of heat
The
sugar is generally added to the purified water, and heat is applied until
solution is effected. Then other required heat-stable components are added to
the hot syrup, the mixture is allowed to cool, and its volume is adjusted to
the proper level by the addition of Purified Water.
The
use of heat facilitates the rapid solution of the sugar as well as certain
other components of syrups.
If excessive heating occurs then sucrose may be
hydrolyzed into dextrose (D-glucose), and fructose (levulose). This hydrolytic
reaction is referred to as inversion,
and the combination of the two monosaccharides is invert sugar. When heat is applied in the preparation of a sucrose
syrup, some inversion of the sucrose is almost certain. The speed of inversion
is greatly increased by the presence of acids, the hydrogen ion acting as a
catalyst to reaction.
Invert sugar is more sweeter than sucrose, and normally
colorless. Syrup darkens due to the effect of heat on the fructose. When the
syrup is greatly overheated, it becomes amber colored due to the caramelization
of the sucrose. Syrups so decomposed are more susceptible to fermentation and
microbial growth.
Because of the prospect of decomposition by heat, syrups cannot
be sterilized by autoclaving.
Solution by
agitation without heat
Sucrose
and other formulation agents may be dissolved in purified water by placing the
ingredients in a vessel of greater capacity than the volume of syrup to be
prepared, thus permitting the thorough agitation of the mixture.
Addition of
sucrose to a medicated liquid or to a flavored liquid
Medicated
liquid such as tincture or fluid extract is employed as the active ingredient
in the preparation of syrup.
If
the extract contains alcohol soluble ingredients and the alcohol amount is high
then sucrose is added directly and stirred.
If
alcohol content is low and all the ingredients are water soluble then the
liquid extract is directly mixed with a prepared syrup.
Preparation of
syrup by percolation
In this method purified water or an aqueous
solutionis passed slowly through a bed of crystalline sucrose, thus dissolving
it and forming the syrup. If required a poriton of the percolate is recycled.
Preparation of a multivitamin syrup
Formula: Each 15 ml contains
Active ingredients Vitamin B1 4.5 mg
Vitamin
B2 2.5 mg
Vitamin
B6 1.5 mg
Niacinamide 30 mg
D-Pantothenol 5 mg
Sweeteners Sorbitol 1
gm
Glycerin 0.5 gm
Sugar 7 gm
Preservative Sodium benzoate 0.016
% (w/v)
Methyl
paraben sodium 0.015 % (w/v)
Propyl
paraben sodium 0.0015%(w/v)
Stabilizer Disodium edetate 0.008%
Taste enhancer Citric acid 0.008%
(w/v)
Flavours q.s.
Colours Caramel q.s.
Vehicle Purified
water 15 ml
Procedure
1. Primary Syrup is prepared as
usual, filtered and cooled to room temperature. The material is transferred to
the mixing tank and stirring is started.
2. Vitamin B1 is dissolved in
small volume of water and added to the syrup.
3. Vitamin B2 is slightly
soluble in water, hence, it is dissolved with the aid of 10% sodium hydroxide.
Vitamin B6 is also added to dissolve. The mixture is transferred to the mixing
tank.
4. Niacinamide is dissolved in
small amount of water and added to the mixing tank.
5. D-pantothenol is dissolved
in hot water, cooled and transferred to the syrup.
6. Sorbitol and glycerin are
added.
7. All the preservatives are
dissolved in small volume of water and added to the syrup.
8. Citric acid and disodium
edetate is dissolved separately in water and then mixed to the syrup.
9. Flavors and color are added
and the final volume is made up with water.
10. Mixed for 2 hours and
filtered.