CONTENTS

Sl. No. Title Page

No.

1. INTRODUCTION 01 – 02

2. ADVANTAGES AND DISADVANTAGES 02

3. CLASSIFICATION 02 – 03

4. EXCIPENTS USED IN THE FORMULATION 03 – 07

5. MANUFACTURE 07 - 14

6. PACKAGING 14 – 15

7. DISCUSSION ABOUT SYRUP 15 – 22

8. REFERENCES 23 - 24
 : LIQUID DOSAGE FORM :
INTRODUCTION
Definition:
The liquid form of a drug dose for administration or consumption. Route of
administration may be oral, intravenous, intramuscular, cutaneous,
subcutaneous, etc.
Droughts:
Liquid oral formulations comprising single or several doses of medication
Elixirs:
Excipients and medicaments in a liquid d formulation for oral administration.
Emulsions:
Water-based suspension of oils and fats using an emulsifying agent. Emulsifying
agent coats oil particles so they do not coalesce when the interfacial tension
between oil and water decreases. As a result, an emulsion is created.
Suspensions:
One or more active components dispersed in a suitable medium are used in
biphasic liquid formulations for oral administration. When shaken, it disperses
into a uniform suspension that is stable enough to deliver the precise dosage.
Gargles:
Externally applied aqueous solutions that are concentrated for treating throat
infections.
Gels: Dispersions of medicaments in water used as antacids.
Lotions:
External liquid preparations are generally administered without friction.
Liniments:
The application of external liquid preparations is generally done via friction.
Mixtures:
One or more medications are included in liquid oral preparations.
Mouthwashes:
In a similar manner to gargles, these mouthwashes are used for oral cleanliness
and
to treat oral infections.
Nasal drops:
Dropper-instilled liquid solutions used to treat nose infections and blockages.
Solutions:
Liquid medicine that can be used for internal or exterior applications. .Syrups:
With or without sugar and medicaments, sweet, viscous, concentrated liquid
medicines are made.

CLASSIFICATION OF LIQUID DOSAGE FORM:

Basically, liquid dosage forms are divided into two parts according to phase.
Monophasic liquid dosage form:
Monophasic means only one phase is there. That is the liquid phase. Its 2 types,
> Internal Use- Syrup, mixture, linctuses, elixirs, parenteral preparations.

1
> External use-
MOUTH : Gargle, mouthwash
SKIN : Lotions
OTHERS : Nasal drops, eardrops.

Biphasic liquid dosage form:

Biphasic means two phases are there. That is a solid phase and a liquid phase.
> Internal Use- Suspension
> External Use- Emulsion

ADVANTAGES AND DISADVANTAGES OF LIQUID DOSAGE FORM:

Adavntages:
>Very useful for those patient who have trouble swallowing.
>The rate of absorption of the liquid dosage form is so faster than the solid dosage
form.
>Liquid dosage forms are flexible to take proper those than solid dose .
Disadvantages:
>It needs a lot of special storage conditions.
>Affected by micro-organisms: Due to the presence of sweetening and flavoring
agents.
TYPES OF ADDITIVES USED IN THE LIQUID DOSAGE FORMS:
For the preparation of a liquid dosage form, we need a lot of additives materials.
These materials are known as Active Pharmaceutical Ingredients (APIs).
Vehicles:
Vehicles are those materials that are chemically inert and don’t have any
therapeutic value. But these are used in the formulation of liquid dosage forms to
improve the stability, patient acceptability, function of the dosage form.

Examples Of aqueous vehicles: Water , Glycerin , Alcohol etc.

Examples Of oily vehicle: Vegetable, mineral oils.
Stabilizers:
Stabilizers are those materials used to increase the stability of material or
formulation by preventing degradation of the product.
According to the material, it varies.
Preservatives:
Preservatives are those ingredients used for the preservation or for the protection
of the formulation from the attack of mico-organisms.
Suspending Agents:
Suspending agents are those excipients, which are useful to help active
pharmaceutical ingredients to stay suspended into the formulation and prevent
the cake formation under the container of the formulation .
Suspending agents are using in the preparation of the suspension.

2
Emulsifying Agents:
Emulsifying agents are those surface active ingredients used in the formation of
the emulsion. It’s useful to absorb the water-oil droplet interface.
Example of emulsifying agents: Gun acacia, Tragacanth.

Solubilizers:
Solubilizers are those materials used to increase the solubility of a material to
improve bioavailability.

Example of solubilizers: Polysorbate.

Coloring Agents:
Colouring agents are used in the liquid dosage form to improve the acceptance of
consumers.

Examples of natural colors: Titanium dioxide, carotene, ferric oxide etc..

Examples of Synthetic colors: Erythrosine, Tetrazine etc..
Flavouring Agents:
Flavouring agents are used in the liquid dosage form to improve the acceptance of
consumers.

Examples of flavoring agents: Apple, Ginger, Clove, Rose etc..

Sweetening Agents:
Sweetening agents are used to overcoming the unpleasant smell of the
formulation.

Examples of sweetening agents: Sucrose, Fructose, Saccharine, Sorbitol etc

CLASSIFICATION OF LIQUID DOSAGE FORMS:

Liquid dosage forms are broadly classified into two group:
[Link] liquid dosage forms
[Link] liquid dosage forms

[Link] Liquid Dosage Forms

A. Monophasic liquid dosage forms for oral use
Mixture, Linctuses, Draughts, Elixirs, Syrups, Drops
B. Monophasic liquid dosage forms for external use
Lotions, Liniments, Collodions
C. Monophasic liquid dosage Forms for special use
Gargles, Mouth washes, Throat paints, Eye drops, Eye lotions, Ear Drops,
Douches
D. Parenteral Solutions (Injectictions)

This is the simplest form of presenting medication for rapid and high absorption of
medicinal product.
It is a one-phase system consisting of two components, solute and the solvent.
3
 A. Monophasic liquid dosage forms for oral use
This class of monophasic liquid dosage form comprises one phase pourable
pharmaceutical formulations intended for oral use. Examples include mixture,
linctuses, draughts, elixirs, syrups and drops.

a. Mixture –
Pharmaceutical mixtures are liquid oral preparation consisting of one or more
medicaments dissolved, suspended or diffused an aqueous vehicle.
They are usually freshly or recently prepared and are used fairly quickly, usually
within a month for short term therapy like cough, diarrhea, constipation etc.
Mixtures are further classified into five different groups:
i. Simple mixture containing soluble substances
ii. Mixtures containing diffusible solids; that is, solids which do not dissolve in
water, but may be mixed by shaking.
As a result, it is evenly distributed throughout the liquid for sufficient time.
iii. Mixtures containing indiffusible solids; that is, solids which are not dissolved in
water and do not remain uniformly distributed in the solvent for sufficiently long
time.
iv. Mixtures containing precipitate forming liquids and
v. Mixtures containing slightly soluble liquids

b. Linctuses –
Linctuses are viscous oral liquids containing one or more medicament dissolved in
a vehicle that usually contains high proportion of sucrose or other sugars. They
are chiefly used as demulcent, expectorant or sedative principally in the treatment
or relief of cough. As such, inctus is intended to be sipped slowly in small doses
and allowed to trickle down the throat in an undiluted form. This gives maximum
and prolonged effect of medicament in the throat.

c. Draughts –
A draught is an older term used to describe liquid oral preparations which contain
only one or two large doses. The volume of the formulation is usually larger than
that generally utilised in traditional mixture formulations and each dose is
supplied in separate bottles.

d. Elixirs –
Elixirs are clear, flavoured, sweetened, hydroalcoholic liquid oral preparations that
usually contain either potent or unpleasant-tasting drugs. They may be medicated
or nonmedicated. Compared to syrups, elixirs are usually less sweet and less
viscous because they contain a lesser amount of sugar. Because of their
hydroalcoholic character, elixirs are better able than are syrups to maintain both
water-soluble and alcohol-soluble components in solution.

e. Syrups-
Syrups are concentrated aqueous solutions containing one or more sugar
components, chiefly sucrose, or sugar substitute. The concentration of sugar in
4
syrup is 66.7 % W/W. Syrups may be medicated or nonmedicated. The
nonmedicated often referred to as simple syrups are used as vehicles for medicinal
substances to be added later, either in the extemporaneous compounding of
prescriptions or in the preparation

f. Drops (Paediatric drops)-

Drops are liquid preparations of potent drugs usually in solution that are intended
to be administered in small volumes with the aid of a suitable measuring device
(calibrated dropper) to pediatric patients.

B. Monophasic liquid dosage forms for external use

This class includes liquid preparation such as lotions, liniments and collodions
a. Lotions-
Lotions are solutions, but may also be suspensions or emulsions, intended for
external application to the skin. They are rubbed on the skin without friction with
the help of some absorbent material such as cotton, wool or gauze soaked in it. In
some cases, lotions are applied to the scalp, where the vehicle for the medication is
alcohol based, allowing for rapid drying of the hair and thus making the product
more acceptable to the patient (e.g. Salicylic Acid Lotion 2% BPC). In these cases,
problems of flammability are addressed by suitable labelling.
b. Liniments-
Liniments are liquid preparation intended to be rubbed with friction and massaged
onto unbroken skin to obtain analgesic, rubefacient or generally stimulating
effects. They are usually solutions of oils, alcohols or soaps, but may be
formulated as emulsions.
c. Collodions-
Collodions are principally solutions of pyroxylin in a vehicle of ether and alcohol
that are intended to be painted onto the skin using a brush or rod and left to dry.
When dry, the collodion leaves a protective film covering the site. Collodions are
highly volatile and highly flammable and care should be taken to label any
preparation appropriately.

C. Monophasic liquid dosage forms for special use

a. Gargles-
Gargles are aqueous solutions containing antiseptics, antibiotics, and/or
anaesthetics that are intended for prevention or treatment of throat infections.
They are generally formulated in a concentrated form.

b. Mouthwashes-
These are aqueous solutions with pleasant taste and odour intended for local
treatment of the membranous lining of the mouth and gums. They generally
contain antibacterial agents, alcohol, glycerine, sweetening agents, flavouring
agents and colouring agents.

c. Throat paints-
Throat paints are viscous liquid preparations that are applied with the help of a
brush to the mucosa of the mouth or throat. Glycerine is commonly used as a

5
based in throat paints because it possesses a sweet taste and it adheres to mucous
membrane for a long period.

d. Eye drops-
These are sterile solution or suspensions of drugs that are instilled into the eye
with a dropper. The eye drops are usually made in aqueous vehicle. It should be
isotonic with lachrymal secretions, buffered and free from foreign particles to avoid
irritation to the eye.

e. Eye lotions-
Eye lotions are sterile aqueous solutions used for washing the eye. They are
supplied in concentrated form and are required to be diluted with warm water
immediately before use. Eye lotions are generally used to remove foreign
substances from the eye.

f. Ear drops-
These are medicated solutions of drugs that are instilled in to the ear with a
dropper. These are generally used for cleaning the ear, softening the wax and for
treating the mild infections.

g. Nasal drops and sprays-

Nasal drops are solutions of drugs that are instilled into the nostrils with the help
of a dropper. Nasal sprays are the same preparations as nasal drops but instilled
into the nostrils in the form of a spray. Both formulations intended for
administration to the nasal cavities to obtain a systemic or local effect.

h. Douches-
Douches are liquid preparations used to cleanse deodorize, soothe or medicate
wounds, body orifices or cavities.

i. Enemas-
Enemas are liquid preparations often formulated as solutions (though they may be
presented as an emulsion or suspension) and are intended for rectal
administration. They are used for cleansing, therapeutic or diagnostic purposes.

j. Inhalations-
They are preparations containing volatile substances. They are used to relieve
congestion and inflammation of the respiratory tract. They are added to hot water
and the vapours are inhaled.

k. Aerosol-
Aerosols are liquid preparations dissolved in a solvent. The solvent is a gas. It is
delivered in the form of a spray. It is mainly used for treating asthma and also for
migraine.

6
 D. Parenteral Solutions (Injections)
Parenteral solutions are sterile drug solutions intended for administration by
needle or pressure syringe. Drugs may be injected into most any vessel or tissue of
the body, but the most common routes are intravenous (IV), intramuscular (IM),
and subcutaneous (SC).

Parenteral solutions may be small-volume injections, packaged in ampules for

single-dose administration, or vials for multiple-dose injections. Large-volume
parenterals containing 100 mL to 1 litre of fluid, are intended for the slow
intravenous administration (or infusion) of medications and/or nutrients in the
institutional or home care setting.

2. Biphasic Liquid Dosage Forms

Biphasic liquid dosage form is one which contains two phases. A good example of
such liquid dosage form is suspensions and emulsions.

A. Suspensions
Suspensions are biphasic liquid dosage forms containing essentially insoluble
finely divided solid particles or drug(s) suspended with the help of a suspending
agent(s) in a liquid medium. The solid particles act as disperse phase whereas
liquid acts as a continuous phase.

B. Emulsions
An emulsion is a biphasic liquid preparation containing two immiscible liquids
(usually oil and water) one of which is dispersed as minute globules into the other
and rendered homogeneous by the addition of an emulsifying agent. The liquid
which is converted into minute globules is called the disperse phase and the liquid
in which the globules are dispersed is called the continuous phase.

Emulsion are of 2 types :

a. Oil in water type (O/W): Emulsion in which oil is in the dispersed phase
whereas water is in the continuous phase.
b. Water in oil type (W/O): Emulsion in which water is in the dispersed phase
whereas oil is in continuous phase.

EXCIPIENTS USED IN THE FORMULATION OF LIQUID DOSAGE

FORMS:
Liquid dosage forms are prepared by combining drug substance(s) with different
excipients. These excipients serve a variety of function in the liquid formulation;
however, several excipients behave differently at different concentration and one
excipient can be used for multiple purposes depending upon the need of the
dosage form.

When formulating liquid medicines, it is essential to ensure that all the different
excipient used is physically and chemically compatible with the drug substance
and every other component of the formulation. Below is a list of common
excipients generally used in the formulation of liquid dosage forms.

7
1. Vehicles/ Solvents :

In liquid pharmaceutical formulations, vehicles are major components used as a

base in which drugs and other excipients are dissolved or dispersed. They function
by breaking of bond and reducing effective charge on ions thus, increasing solute-
solvent forces of attraction which are eventually greater than solute-solute and
solvent-solvent forces of attraction.
Vehicles used in the formulation of liquid dosage forms may be aqueous (e.g.,
water, polyhydric alcohols, hydro-alcoholic solutions and buffers) or oily (e.g.,
vegetable or mineral oils, organic oily bases, emulsified bases etc). The choice of
vehicle used depends on the nature and physicochemical properties of the active
pharmaceutical ingredient (API) and the intended use of the formulation.
a. Water as a solvent
Water is the most widely used solvent in pharmaceutical formulations. In routine
use, it lacks toxicity, is compatible with bodily fluids, and can dissolve most
compounds that are used as pharmacologic agents (due to its high dielectric
constant) but likely to cause instability of hydrolytically unstable drugs and
provides suitable media for microbial growth.

The compendial requirement for water used in the formulation of liquid dosage
forms is Purified Water, USP, except for those intended for parenteral
administration (injections) for which water for injection is used. Water used for
compounding oral solutions and the reconstitution of oral suspensions must meet
official standards.

It is worthy of note that drinking water, bottled or from the municipal tap, is not
covered by a compendial monograph and therefore cannot be used in the
formulation of liquid dosage form obviously due to the possible incompatibility of
formulation components with dissolved impurities in water.
b. Alcohol as a solvent
Alcohol frequently referred to as ethyl alcohol or ethanol is the most commonly
used solvent in liquid pharmaceutical formulation next to water. It is a clear,
colourless, mobile, and volatile liquid with a slight, characteristic odour and
burning taste.
Alcohol USP contains ethanol, C2H5OH, not less than 92.3% and not more than
93.8%, by weight, which corresponds to not less than 94.9% and not more than
96.0%, by volume. Ethanol is miscible with water, glycerine, propylene glycol, and
polyethylene glycol 400. It is used as a primary solvent for many organic
compounds. Water–alcohol mixtures can be very effective in solubilizing poorly
soluble drugs.
c. Glycerin, USP (Glycerol) as a solvent
This is a clear, colourless, odourless, viscous, hygroscopic liquid with sweet taste,
approximately 0.6 times as sweet as sucrose. It is a triol alcohol without the
central nervous system depressant activity of ethanol.
Glycerin is miscible with water, alcohol, propylene glycol, and polyethylene glycol
400. As a solvent, the solubilizing properties of glycerin are comparable to alcohol
but because of its viscosity, solutes are slowly soluble in it unless it is rendered
less viscous by heating.

8
Also, the increased viscosity imparted to the final product may be an undesired
outcome of the use of this solvent.
Glycerol is used in both internal and external preparations. It serves as an
excellent solvent for a range of substances such as alkalis, neutral salts, tannins
etc.
d. Propylene Glycol as a solvent
Propylene glycol USP is a clear, colourless, viscous, practically odourless liquid,
with a sweet, slightly acrid taste resembling that of glycerin. It is a diol and like
glycerin, it has no central nervous system activity.
Propylene glycol has become widely used as a solvent, extractant and preservative
in a variety of pharmaceutical formulations. It is used more often in modern
formulations, possibly replacing glycerin as it dissolves a wide variety of materials,
such as corticosteroids, phenols, sulpha drugs, barbiturates, vitamins (A and D),
most alkaloids, and many local anaesthetics.

e. Polyethylene Glycol 400 as a solvent

Polyethylene glycol 400 (PEG 400) is a low-molecular-weight grade of polyethylene
glycol. It is a clear, colourless, viscous liquid. PEG 400 is a liquid at room
temperature, and it is the most common polyethylene glycol used in drug product
formulations.
In concentrations up to approximately 30% v/v, PEG 400 has been used as the
vehicle for parenteral dosage forms. Like glycerin and propylene glycol, PEG 400 is
miscible with water and alcohol.

2. Co-solvents :

Co-solvents are primarily liquid components often used to increase the water
solubility of drugs which do not contain ionisable group(s) and whose solubility
can thus not be increased by pH adjustment. They work by reducing the interfacial
tension between predominantly aqueous solutions and hydrophobic solutes.
Co-solvents are partially polar due to the presence of hydrogen bond donors
and/or acceptors, thus ensuring miscibility with water. The selection of a co-
solvent depends on a number of factors, including the solubility and stability of
drug substance in the vehicle and toxicity of the vehicle. Most water-miscible
organic liquids are however toxic and only a few are used as co-solvents in
pharmaceutical solutions.
Each co-solvent is characterized by an acceptable concentration range, which
cannot be exceeded without incurring biological damage. The use of co-solvents in
parenteral formulations has been limited by the uncontrolled precipitation of the
drug substance upon dilution in aqueous/biological media which results in
embolism or necrosis at the injection site. In vitro and in vivo models are available
to evaluate the safety of co-solvent excipients.
Examples of excipients used as co-solvents include glycerol, propylene glycol,
ethanol, the low molecular weight PEGs etc.

9
3. Surfactants :

Surfactants or surface-active agents are molecules with well-defined polar

(hydrophilic) and non-polar (hydrophobic) regions that associate in aqueous media
to form dynamic aggregates, known as micelles. Non-polar drugs can partition into
these micelles and be solubilized.
Depending on the nature of the polar area, surfactants can be anionic (e.g.,
sodium dodecyl sulfate), cationic (e.g., trialkylammonium), zwitterionic (e.g.,
glycine and proteins) and nonionic (e.g., polyethylene glycol). Among these, the
most commonly used ones are the anionic and non-ionic surfactants.
Nonionic surfactants, rather than ionic surfactants, are generally considered to be
more suitable for pharmaceutical applications, not only because of their lower
toxicity but also because the surfactant’s shell can confer stealth properties to the
micelle, avoiding uptake by macrophages of the reticular endothelial system (RES),
thus, prolonging their lifetime in blood circulation.
Since the process of solubilization occurs due to the presence of micelles, generally
high concentrations of surfactants are needed to significantly improve drug
solubility. The concentration at which the micelles form in appreciable numbers is
called the critical micelle concentration (CMC). Depending on surfactant
concentration, normal micelles can be spherical, cylindrical, or lamellar in shape.
Examples of surfactants used in pharmaceutical liquid dosage forms are shown in
the table below.

4. Preservatives :

Preservatives are chemical compounds that are added to formulations to protect

them from microbial contamination. An ideal preservative should be

1. effective at low concentrations against all possible microorganisms

2. non-toxic, non-sensitizing, soluble and compatible with the API, other
excipients, and the container system
3. stable for the shelf-life of the product.

Microbial contamination presents a significant health hazard in aqueous-based

liquid dosage forms. Therefore, the use of preservatives becomes unavoidable in
such cases to prevent the growth of microorganisms during production and over
storage time. Although it may be most desirable to develop a “preservative-free”
formulation to address the increasing concerns about the biological activity or
unwanted effects of these excipients, most formulations require some kind of
preservative to ensure no microbial growth.
The majorities of preservatives are of both acid and non-acid types and are
bacteriostatic rather than bactericidal. Among the acidic types are phenol, benzoic
acid, boric acid, chloro-cresol, 9-phenyl phenol, alkyl esters of para-
hydroxybenzoic acid, sorbic acid, and their respective salts. Neutral preservatives
include chlorobutanol, benzyl alcohol, and beta-phenylethyl alcohol.
Under alkaline conditions, it is generally regarded that microbial growth is
insignificant and at these pH values, the need for a preservative is not generally
recommended.
Preservatives often contain reactive functional groups, which are responsible for
their antimicrobial activity but lead to unwanted reactions. Therefore, in addition
10
to the excipient’s antimicrobial activity, other parameters should be evaluated
during the formulation development for its compatibility with the API, other
excipients, and the container system. The table below shows common
preservatives used in liquid dosage forms and their typical concentration level.

5. Viscosity modifiers/ Suspending agents :

Viscosity modifiers also known as suspending agents are excipients that minimize
interparticle attraction and aggregation by functioning as energy barrier thus
retarding particle settling. The selection of an appropriate suspending agent is one
of the most crucial factors in formulating a pharmaceutical suspension. Other
factors considered in the selection of the appropriate suspending or viscosity
enhancing agents include desired rheological property, suspending ability in the
system, pH stability, chemical compatibility with drug substance and other
excipients, reproducibility, hydration time, and cost.
Common viscosity modifiers used in liquid pharmaceutical dosage forms include
cellulose derivatives (e.g., methylcellulose, microcrystalline cellulose,
carboxymethylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl
cellulose and hydroxypropyl methylcellulose etc), clays (e.g., hectorite, bentonite,
aluminium and/or magnesium silicate), natural gums (e.g., acacia, guar gum,
tragacanth, xanthan gum, alginates, carrageenan and locust bean gum), synthetic
polymers (e.g., carbomers, polyvinyl pyrrolidone, polyvinyl alcohol and poloxamer),
and miscellaneous compounds (e.g., colloidal silicon dioxide and silicates). In
many cases, these excipients are used in combination.

6. Buffers :

The terms buffer, buffered solution, and buffer solution when used with reference
to hydrogen-ion concentration or pH refer to the ability of a system, particularly an
aqueous solution, to resist a change of pH on adding acid or alkali, or on dilution
with a solvent. Control of the formulation pH, could prevent large changes during
storage and also ensure the physiological compatibility of the formulation with the
biological fluid. Therefore, most formulation scientists utilize buffer solution to
control potential changes in the pH of formulations.
The required amount of buffer capacity needed is generally between 0.01 and 0.1
M and a concentration between 0.05 and 0.5 M is usually sufficient. The selection
of a suitable buffer should be based on

1. Suitability of the buffer for the intended liquid formulation (for example, a
boric acid buffer may be used for optical and intravenous delivery but not in
oral liquids because of its toxicity),
2. Stability of the drug substance and excipients in the buffer, and
3. Compatibility between the buffer and container.

Buffer systems used in pharmaceutical dosage forms generally consist of either a

mixture of a weak acid and its corresponding salt with a strong base or a mixture
of a weak base and its corresponding salt with strong acid. Drug substance in
solution may itself act as a buffer. If the drug is a weak electrolyte such as salicylic
acid or ephedrine, the addition of base or acids, respectively will create systems in
which the drug can act as a buffer.

11
It is worth noting that dilution of a drug product’s solution that has been
formulated with a buffer system is likely to reduce the capacity (or the strength) of
the buffer system, and consequently the ability of the buffer to resist the change in
pH. Also, other factors such as amount and the type of co-solvents present,
temperature and ionic strength may contribute to affect the pH of the formulation.
For example, the pH of acetate buffers is known to increase with temperature,
whereas the pH of boric acid buffers decreases with temperature.

The buffer may negatively affect the solubility of drugs substance and excipients.
The effect depends on the polarity of the solute and salts when combined in the
formulation. Non-polar solutes are solubilized (salted in) by weakly polar organic
salts and are desolubilized (salted out) by polar salts. Conversely, polar solutes are
solubilized by polar salts and desolubilized by organic salts.

The stabilizing effect of buffers that have multiple charged species in solution
could also determine the potential reaction between drug substance and
excipients. For example, buffers that use carbonates, tartrate, citrate, and various
phosphate salts may precipitate with calcium ions by forming sparingly soluble
salts; the precipitation being dependent on the pH of the solution. The activity of
phosphate ions may be lowered due to interactions with other solution
components.

7. Antioxidants :

Antioxidants are added to some liquid dosage forms to delay or inhibit the
oxidation process of molecules. Antioxidants act by getting preferentially oxidized
or by blocking an oxidative chain reaction. Examples antioxidants used in liquid
dosage forms are shown in the table below.

8. Chelating agents :

Chelating agents, also known as sequestrants, are molecules that protect drugs
from catalysts that accelerate oxidative reaction. They function by forming stable
complexes with metal ions particularly di-valent and tri-valent metal ions
(including trace metals and heavy metals) thus inactivating their catalytic activity
in oxidation of drug substances. Typical examples of this excipients include
disodium edentate, calcium disodium edetate, edetic acid etc.

9. Sweeteners :

Sweeteners are employed in liquid pharmaceutical dosage forms intended for oral
administration specifically to increase the palatability of the therapeutic agent.
Examples include sucrose, sorbitol, mannitol, saccharin sodium, xylitol, high
fructose corn syrup etc.

10. Flavouring agents :

Flavours are used to mask the taste of drugs, many of which have a very
unpleasant taste. Flavours used in the formulation of pharmaceutical liquid
dosage forms must be nontoxic, soluble (if used for a clear product like syrup,
elixir), stable and compatible with the components of the formulation. Masking of
few flavours is very difficult due to their complexity. A good example of such

12
flavour is that of male fern extract which is initially sweet, then astringent and
finally bitter.

Flavouring agents such as vanilla, raspberry, orange oil, lemon oil are used for oral
solutions. Menthol is used in both oral and nasal solutions. Certain flavours
appeal to certain patient populations and certain parts of the world; this must be
borne in mind by the formulation scientist. For example, fruit and bubble gum
flavours are acceptable to children, whilst mint flavour is not.

11. Colourants :

Colourants (colouring agents) are largely incorporated into pharmaceutical

products to standardize or improve an existing drug colour, to mask a colour
change and improve appearance and/ or sometimes to complement a flavour or
match the colour of a medicine with its taste. Examples being the addition of red
colour with cherry flavour, yellow with lemon, green with mint, purple with
blackcurrant, etc.

Whilst colours are obtained both from natural sources (e.g. carotenoids) or
synthesized (e.g. amaranth), the majority used are synthetically produced. Like
flavouring agents, colour preference varies between cultures.

12. Antifoaming agents :

Antifoaming agents are excipients that prevent foam formation during

manufacturing processes or when reconstituting liquid dosage forms. They do so
by lowering surface tension and cohesive binding of the liquid phase.

Examples of excipients used as antifoaming agents include simethicone

(polymethylsiloxane), paraffin oils, organic phosphates, alcohols etc.

13. Humectants :

Humectants, such as propylene glycol, glycerol, polyethylene glycol and sorbitol

are hygroscopic excipients used at ~5% in liquid dosage forms (e.g., aqueous
suspensions and emulsions for external application) to retard the evaporation of
aqueous vehicle from dosage forms during storage and use. However, high
concentrations may also remove moisture from the skin, causing dryness.

14. Emulsifying agents :

Emulsifying agents adsorb at the interface or on the surface of the suspended

droplets, reducing the interfacial tension and preventing droplet coalescence.
Examples include sodium lauryl sulphate, cetrimide, macrogols etc.

15. Flocculating agents :

These are neutral electrolytes that are capable of preventing caking of suspended
solids. They act by reducing the zeta potential of suspended charged particles to
zero and thus cause aggregation or floc formation of the particles.

13
 In case of weakly charged, water-insoluble, organic non-electrolytes, monovalent
ions including sodium or potassium chloride in small concentration (0.01 – 1.00
%), are often adequate to induce flocculation while in case of insoluble, highly
charged, polyelectrolyte species, water-soluble divalent or trivalent ions such as
aluminium chloride, calcium salts, citrates, sulphates, and potassium
biphosphates at concentrations 0.01 – 1.00 % may be required for floc formation
depending on the particle charge.

MANUFACTURE OF LIQUID DOSAGE FORMS

Most liquid dosage forms are prepared:

1. by simply dissolving the solutes (active pharmaceutical ingredient and excipients)

in an aqueous or nonaqueous solvent or solvent mixture;
2. by suspending the solutes in appropriate medium;
3. by incorporating the solutes into an oil or water phase.

On an industrial scale, they are prepared in large mixing vessels with ports for
mechanical stirrers. The vessels are generally thermostatically controlled to
maintain a certain temperature if desired. The order of addition of components is
fixed through product development and scale-up exercises.

PACKAGING OF LIQUID DOSAGE FORMS

Liquid dosage forms vary widely both physically and chemically, and in the ways
they are distributed and used. Consequently, the materials from which the
containers and packaging components are made also vary considerably and these
containers are usually in direct contact with the formulation.

For stability concerns, the container must not physically or chemically interact
with the product so as to alter the strength, quality, or purity of the product
beyond the official requirements.

Liquid do3sage forms that contain light-sensitive active ingredients should be

supplied in containers that are light resistant. If the preparation contains volatile
ingredients, the liquid preparation should be kept in a tightly closed container.

Except where indicated in the individual monograph, containers used in packaging

liquid preparations for parenteral and oral use should be made from material that
is sufficiently transparent to permit the visual inspection of the contents.

Labelling of liquid dosage forms:

Every pharmaceutical preparation must comply with the labelling requirements
established under Good Manufacturing Practice. The label should include:

1. The name of the pharmaceutical product

2. The name(s) of the active ingredients; International Nonproprietary Names
(INNs) should be used wherever possible
3. The amount of active ingredient in a suitable dose-volume
4. The name and concentration of any antimicrobial preservative and the name of
any other excipient
5. The batch (lot) number assigned by the manufacturer;

14
6. The expiry date and, when required, the date of manufacture;
7. Any special storage conditions or handling precautions that may be necessary
8. Directions for use, warnings, and precautions that may be necessary
9. The name and address of the manufacturer or the person responsible for
placing the product on the market.

If the Liquid preparation is supplied as granules or powder to be constituted just before

issue for use, the label should include:
i. That the contents of the container are granules or powder for reconstitution
ii. The strength as the amount of the active ingredient in a suitable dose-volume of
the constituted preparation
iii. The directions for preparing the liquid including the nature and quantity of
liquid to be used
iv. The storage conditions and shelf-life of the constituted preparation.

> BRIEFLY DISCUSSION ABOUT SYRUP :

*Here ‘SYRUP’ is taken as an example of Liquid dosage form.
INTRODUCTION :
A concentrated solution of sugar in water to which specific medicinal substances
are usually added. Syrups usually do not represent a very high percentage of the
active drug.

HISTORY OF SYRUP :
Indigenous peoples living in northeastern North America were the first groups
known to have produced maple syrup and maple sugar.
According to Indigenous oral traditions, as well as archaeological evidence, maple
tree sap was being processed into syrup long before Europeans arrived in the
region.
Canada produces 85 percent of the world's maple syrup. With for- ests brimming
with majestic red, black and sugar maples, the country has just the right mix of
cold spring nights and warm daytime temperatures to produce an abundance of
the clear-coloured sap used to make maple syrup.
Europian Consists :
In the early stages of European colonization in northeastern North America, local
Indigenous peoples showed the arriving colonists how to tap the trunks of certain
types of maples during the spring thaw to harvest the sap.
The "Royal Cosmographer of France", wrote about Jacques Cartier drinking maple
sap during his Canadian voyages. By 1680, European settlers and fur traders were
involved in harvesting maple products. However, rather than making incisions in
the bark, the Europeans used the method of drilling tapholes in the trunks with
augers.

Prior to the 19th century, processed maple sap was used primarily as a source of
concentrated sugar, in both liquid and crystallized-solid form, as cane sugar had
to be imported from the West Indies.
Maple sugaring parties typically began to operate at the start of the spring thaw in
regions of woodland with sufficiently large numbers of maples.

15
Syrup makers first bored holes in the trunks, usually more than one hole per large
tree; they then inserted wooden spouts into the holes and hung a wooden bucket
from the protruding end of each spout to collect the sap. The buckets were
commonly made by cutting cylindrical segments from a large tree trunk and then
hollowing out each segment's core from one end of the cylinder, creating a
seamless, watertight container.

Sap filled the buckets, and was then either transferred to larger holding vessels
(barrels, large pots, or hollowed-out wooden logs), often mounted on sledges or
wagons pulled by draft animals, or carried in buckets or other convenient
containers.

The sap-collection buckets were returned to the spouts mounted on the trees, and
the process was repeated for as long as the flow of sap remained "sweet". The
specific weather conditions of the thaw period were, and still are, critical in
determining the length of the sugaring season.

As the weather continues to warm, a maple tree's normal early spring biological
process eventually alters the taste of the sap, making it unpalatable, perhaps due
to an increase in amino acids.
The boiling process was very time-consuming. The harvested sap was transported
back to the party's base camp, where it was then poured into large vessels (usually
made from metal) and boiled to achieve the desired consistency.
The sap was usually transported using large barrels pulled by horses or oxen to a
central collection point, where it was processed either over a fire built out in the
open or inside a shelter built for that purpose (the "sugar shack").

Processing :
Open pan evaporation methods have been streamlined since colonial days, but
remain basically unchanged. Sap must first be collected and boiled down to obtain
syrup. Maple syrup is made by boiling between 20 and 50 volumes of sap
(depending on its concentration) over an open fire until 1 volume of syrup is
obtained, usually at a temperature 4.1 °C (7.4 °F) over the boiling point of water.

As the boiling point of water varies with changes in air pressure the correct value
for pure water is determined at the place where the syrup is being produced, each
time evaporation is begun and periodically throughout the day.
Syrup can be boiled entirely over one heat source or can be drawn off into smaller
batches and boiled at a more controlled temperature.
Defoamers are often added during boiling.
Boiling the syrup is a tightly controlled process, which ensures appropriate sugar
content. Syrup boiled too long will eventually crystallize, whereas under-boiled
syrup will be watery, and will quickly spoil.
The finished syrup has a density of 66° on the Brix scale (a hydrometric scale
used to measure sugar solutions).
The syrup is then filtered to remove precipitated "sugar sand", crystals made up
largely of sugar and calcium malate.
These crystals are not toxic, but create a "gritty" texture in the syrup if not filtered
out.
In addition to open pan evaporation methods, many large producers use the more
fuel efficient reverse osmosis procedure to separate the water from the [Link]

16
producers can also use batchwise recirculating reverse osmosis, with the most
energy-efficient operation taking the sugar concentration to 25% prior to boiling.
The higher the sugar content of the sap, the smaller the volume of sap is needed to
obtain the same amount of syrup. To yield 1 unit of syrup, sap at 1.5 percent
sugar content will require 57 units, while sap at 3.5 percent sugar content only
needs 25 units of sap.
The sap's sugar content is highly variable and will fluctuate even within the same
tree.

Off-Flavours :
Off-flavours can sometimes develop during the production of maple syrup,
resulting from contaminants in the boiling apparatus (such as disinfectants),
microorganisms, fermentation products, metallic can flavours, and "buddy sap",
an off-flavour occurring late in the syrup season when tree budding has begun.
In some circumstances, it is possible to remove off-flavours through processing.

Production :

Syrups can be made by dissolving sugar in water or by reducing naturally sweet

juices such as cane juice, sorghum juice, or maple sap. Corn syrup is made
from corn starch using an enzymatic process that converts it to sugars.A must
weight-type refractometer is used to determine the sugar content in the solution.

For fermentation

Syrup is used to feed microbiological life. Syrup consists of carbohydrates and

water. Cold drinking water (from tap water (even without a faucet aerator), lakes,
etc.) can hold more dissolved oxygen than warm water.

Saccharomyces cerevisiae, is an important yeast in ethanol

fermentation and winemaking. S. cerevisiae is able to grow both in the presence
and absence of oxygen, but the fermentation rate increases during the stationary
phase in the presence of oxygen.

Examples of hydrolyzed sugars with high water ratio used in fermentation:

 Inverted sugar syrup

o Fermented water
o Kombucha is produced by fermenting sugared tea using
a symbiotic culture of bacteria and yeast (SCOBY).
o Winemaking kits: Cheap winemaking kits usually instruct that the
grape juice should be diluted sucrose (bought separately) should be
dissolved in water.

However, concentrated syrups contain little water and thus have little impact in
terms of oxygen. For example, glucose syrup containing over 90% glucose is used
in industrial fermentation.

Maple syrup production is centred in northeastern North America; however, given

the correct weather conditions, it can be made wherever suitable species of maple
trees grow, such as New Zealand, where there are efforts to establish commercial
production.
17
A maple syrup production farm is called a "sugarbush". Sap is often boiled in a
"sugar house" (also known as a "sugar shack", "sugar cabin", "sugar shanty", or
cabane à sucre), a building louvered at the top to vent the steam from the boiling
sap.
Maples are usually tapped beginning at 30 to 40 years of age. Each tree can
support between one and three taps, depending on its trunk diameter. The average
maple tree will produce 35 to 50 litres (9.2 to 13.2 US gal) of sap per season, up to
12 litres (3.2 US gal) per day.

This is roughly equal to seven percent of its total sap. Tap seasons typically
happen during late winter and spring and usually last for four to eight weeks,
though the exact dates depends on the weather, location, and climate.
The timing of the season and the region of maximum sap flow are both expected to
be significantly altered by climate change by 2100.
During the day, starch stored in the roots for the winter rises through the trunk as
sugary sap, allowing it to be tapped.

Sap is not tapped at night because the temperature drop inhibits sap flow,
although taps are typically left in place overnight.
Some producers also tap in autumn, though this practice is less common than
spring tapping. Maples can continue to be tapped for sap until they are over 100
years old.
Packing Regulation :
In Canada, the packing of maple syrup must follow the "Packing" conditions stated
in the Maple Products Regulations, or utilize the equivalent Canadian or imported
grading system.

As stated in the Maple Products Regulations, Canadian maple syrup can be

classified as "Canadian Grade A" and "Canadian Processing Grade". Any maple
syrup container under these classifications should be filled to at least 90% of the
bottle size while still containing the net quantity of syrup product as stated on the
label.

Every container of maple syrup must be new if it has a capacity of 5 litres or less
or is marked with a grade name. Every container of maple sugar must also be new
if it has a capacity of less than 5 kg or is either exported out of Canada or
conveyed from one province to another.
Each maple syrup product must be verified clean if it follows a grade name or if it
is exported out of the province in which it was originally manufactured.

PHARMACEUTICAL SYRUP :

The syrup is a saturated or concentrated, viscous aqueous solution of

sucrose/sugar substitute with or without flavor/medicinal substances purified
water.
Simple syrup contain 85% w/v (65% w/w); specific gravity 1.313 (USP) or 66.7%
w/w as per Indian Pharmacopeia/BP.

Composition of syrup :
Most syrups contain the following components in addition to the purified water
and drug(s):

18
(a) Sugar, usually sucrose or other sugar substitutes are used to provide
sweetness and viscosity, (Sugar-free alternative- Sorbitol, Saccharine, Aspartame)
(b) Antimicrobial preservatives,
(c) flavorants & colorants,
(d) Syrups may also contain solubilizing agents, thickeners, or stabilizers.

Syrup may contain preservatives. Glycerin, methylparaben, benzoic acid, and

sodium benzoate may be used to prevent bacterial and mold growth. Glycine,
benzoic acid (0.1%–0.2%), sodium benzoate (0.1%– 0.2%), and various
combinations of methylparaben, propylparaben, and butylparaben or alcohol are
commonly used as antimicrobial preservatives.

TYPES OF SYRUP :

[Link] SYRUP
When Purified Water alone is used in making the solution of sucrose, the
preparation is known as “syrup,” or “simple syrup”
or
Simple syrup contains only sucrose (sugar) & Purified water.
Example:
a. Simple syrup IP

Sucrose 66.7 gm
Purified warer q.s. 100 gm

b. Simple syrup USP

Sucrose 85 gm

Purified water q.s 100 mL

[Link] SYRUP
When Syrup contains medicinal substance is know as medicated syrup – cough
syrup, Ginger syrup
Ginger Syrup
Strong ginger texture 5 mL

Syrup q.s. 100 mL

[Link] SYRUP
Syrups containing flavoring agents but not medicinal substances are called
flavored vehicles; Containing Aromatic/ Flavoured – Flavoured syrup
Example: Cherry & Raspberry syrup

19
ADVANTAGES OF SYRUP :
[Link] as Antioxidant- Retard oxidation because sugar partly hydrolyzed into
dextrose & levulose (reducing sugary ) – So prevent decomposition of many
substances – No preservative needed.

[Link] as preservative- Exert high osmotic pressure – prevents the growth of MOs
(Bacteria, Fungi, molds etc)

[Link] as Palatable sweet – a vehicle for bitter / Nouseous substances.

[Link] decomposition of many vegetable drugs.

METHODS OF PREPARATION OF SYRUP :

Syrups are prepared using one of four techniques:

1. Solution with heat,

2. Solution by agitation,
3. The addition of sucrose to a liquid medication or flavored liquid, and
4. Percolation.

1. Solution with Heat/Hot process

 This method is a suitable preparation method, if the constituents are not

volatile or not degraded by heat.
 Purified water is heated to 80–85°C, and then removed from its heat source.
 Weight desired amount of Sucrose is added with vigorous agitation.
 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.
 In instances in which heat-labile agents or volatile substances, such as
flavors and alcohol, are added, they are incorporated into the syrup after
cooling to room temperature.
 Example: Syrup IP, Acacia Syrup NF, Cocoa syrup NF, Tolu Syrup IP

Invert sugar: When heat is used in the preparation of syrups, inversion of a slight
portion of the sucrose (a disaccharide) into monosaccharides, dextrose (glucose),
and fructose (levulose) by hydrolyzation process. This hydrolytic reaction is
referred to as “inversion,” and the combination of the two monosaccharide
products is “invert sugar.”

Sucrose solutions are dextrorotary, but, as hydrolysis proceeds, the optical

rotation decreases and becomes negative when the reaction is complete. The rate
of inversion is increased greatly by the presence of acids; the hydrogen ion acts as
a catalyst in this hydrolytic reaction.

Fructose is responsible for the darkening of syrup.

Invert sugar is more readily fermentable than sucrose and tends to be darker in
color. But, its two reducing sugars prevent the oxidation of other substances.

𝐶12𝐻24𝑂6 → 𝐶6𝐻12𝑂6(𝑔𝑙𝑢𝑐𝑜𝑠𝑒) + 𝐶6𝐻12𝑂6(𝑓𝑟𝑢𝑐𝑡𝑜𝑠𝑒)

20
2. Solution by Agitation (without Heat)

This method is used for substances that degradation on heating or volatilize

formulation constituents. i.e suitable for heat labile substances.

Sucrose & other ingredients are dissolved in purified water through agitation
(without heat).

Example– Sulphate syrup

3. Addition of Sucrose to a Liquid Medication or Flavored Liquid:-

 This method is often used with fluidextracts or tinctures.

 Fluid extract or tinctures are added to a syrup.
 Addition of these may cause precipitation of alcohol soluble materials due to
dilution.
 Example- Aromatic eridictyon syrup NF

4. Percolation (Cold process)

In the percolation method, either purified water or the medicinal component

(dissolve in purified water) is passed slowly through a bed of crystalline sucrose,
thus, dissolving it and forming a syrup.

 Sucrose is placed in suitable percolator.

 Purified water (with medicament) is allowed to slowly pass through sucrose
 Percolate may return back in necessary
 final volume is adjusted by purified water
Example: Ipecac syrup

FORMULATION OF SYRUP :

1. VEHICLE-
Purified water is used to prepare syrups.

2. ADDITIVES
a. Chemical Stabilizers
Glycerin, sorbitol & propylene glycol are addded in a small quantity to prevent
Crystallization of Sucrose.

b. Colouring agents
Coal tar dyes like Amaranth, tartrazine & green S are added to syrup.

c. Flavouring agents
Tincture- tincture, lemon & ginger
Fruit juice- rasbberry juice, wild cherry
Essence- Vanilla, orange

d. Preservatives
Benzoic acid & Its derivatives, Sod. benzoate, Methyl paraben etc

21
LIST OF SOME SYRUPS :

 Acetomel – a syrup made from honey and vinegar with a sweet and sour
taste
 Agave syrup – a sweetener commercially produced from several species of
agave
 Attar – a type of sweet syrup used in the preparation of Middle Eastern
desserts
 Cheong – a name for various sweetened foods in Korean cuisine in the form
of syrups, marmalades, and fruit preserves
 Cherry Smash – a fountain syrup made from cherry syrup along with a
blend of other fruit flavors which soda jerks mixed with carbonated water
and phosphate.
 Cider syrup – is also known as apple molasses, a kind of fruit syrup
 Corn syrup – made from the starch of corn (called maize in some countries)
and contains varying amounts of maltose and higher oligosaccharides,
depending on the grade
 Cough syrup – a form of cold medicine
 High-fructose corn syrup
 High-maltose corn syrup
 Date honey – a thick dark brown, very sweet, fruit syrup extracted
from dates.
 Grape syrup – a condiment made with concentrated grape juice
 Grenadine – a commonly used, non-alcoholic bar syrup, characterized by a
flavor that is both tart and sweet, and by a deep red color.
 Honey syrup – made by stirring a heated mixture of honey and water until
the honey dissolves.

STORAGE OF SYRUP :
Store in dried, well closed bottles in a coll dark place, below 25 0C.

 Syrup on Storage subject to Crystallisation which causes locking of Cap of

the container. Glycerine, Sorbital & Propylene glycol is added in small
quantity to the syrup to prevent crystallization of sucrose.
 Storage: completely filled & well-stoppered bottle and stored in a cool place
(not exceeding 25-degree centigrade)
 Syrup may be dark color due to the fermentation of sugar.

22
REFERENCES :
1. Aulton, M. and Taylor, K. (2013). Aulton's Pharmaceutics: The Design and
Manufacture of Medicines, (4th ed.). Edinburgh: Churchill Livingstone.

2. Chaudhari, S. and Patil, P. (2012). Pharmaceutical Excipients: A review.

International Journal of Advances in Pharmacy. Biology and Chemistry.

3. Durgin, J., and Hanan, Z. (2009). Durgin and Hanan's Pharmacy Practice for
Technicians, (4th), Canada Felton, L. (2012). Remington Essentials of
Pharmaceutics. UK: Pharmaceutical Press.

4. Sachan, A., Singh, D., Kumar, Y. and Kumar, M. (2017). A Review On Excipients
Used In Oral Liquid Dosage Forms International Journal of Pharmacy &
Technology.

5. Allen. Lyod. V, “Ansel’s Pharmaceutical Dosage Forms and DrugDelivery

System”, 9th edition, 2011, Lippincott Williams &Wilkins.

6. Aulton. M. E, “Pharmaceutics: The Science of Dosage From Design”, 1998,

Churchill Livingstone.

7. Lachman, L., Liebermann, H.A. & Konig, J.L. “The Theory and Practice
of Industrial Pharmacy, 3rd edition, 1986.

8. Ansel, H. (2010). Pharmaceutical Calculations, (13th ed.). London: Wolters

Kluwer Health and Lippincott Williams & Wilkins.

9. Chaudhari, S. and Patil, P. (2012). Pharmaceutical Excipients: A review.

International Journal of Advances in Pharmacy, Biology and Chemistry.

10. Dash, A., Singh, S. and Tolman, J. (2014). Pharmaceutics-Basic Principles and
Application to Pharmacy Practice, USA: Academic Press.

11. Denton, P. and Rostron, C (2013). Pharmaceutics: The Science of Medicine

Design. United Kingdom: Oxford University Press.

12. Gautami, J. (2016). Liquid Dosage Forms. Nano Science & Nano Technology.

13. Myimon Marriott, J., Wilson, K., Langley, C., and Belcher, D.(2010).
Pharmaceutical Compounding and Dispensing (2nd ed.). UK: Pharmaceutical
Press.

14. [Link]

15. [Link]

23
16. Peter ASA, Hymavathi TV, Yasoda DP. A Study on the Different Methods of
Preparation of Lutein from Supercritical Fluid Processed Lutein Esters. J Nutr
Food Sci. 2012.

17. Figueiras A, Cardoso O, Veiga F. Preparation and characterization of

Trimethoprim inclusion complex with Methyl-B-Cyclodextrin and determination of
its antimicrobial activity. Pharm Anal Acta. 2015.

18. Zhang L, Zhao H, Zhou G, Niu T, Yang J. Simulation Database System of the
Active Ingredients in Compound Decoction of Chinese Medicine. J Bioequiv
Availab.2010.

19. Naveed S, Sajid S. Degradation in Pharmaceutical Creams: Ascorbic Acid

Demonstrating Phenomenon: A Review. J Bioequiv Availab. 2016

20. Khokhlov AL, Shitov LN, Ryska M, et al. The Pharmacokinetic Properties and
Bioequivalence of Methyldopa Formulations:Results of an Open-label, Randomized,
Two-period, Crossover, Single- dose Study. J Bioequiv Availab. 2016.

21. Delsin SD, Mercurio DG, Fossa MM, Maia Campos PMBG. Clinical Efficacy of
Dermocosmetic Formulations Containing Spirulina Extract on Young and Mature
Skin: Effects on the Skin ([Link]
[Link]). Hydrolipidic Barrier Structural Properties. Clin Pharmacol Biopharm.
2015;4:144. and

22. Galicia-QC, Valle LCF, Soto MH, et al. Adverse Events Reactions Reported With
the Use of a Fixed- Dose Combination of Nor- Pseudoephedrine, Triiodothyronine,
Atropine, Aloin and Diazepam in Obese Mexican Patients. J Pharmacovigil. 2015.

23. Karwa M, Arora S, Agrawal SG. Recent Regulatory Amendment in Schedule Y:

Impact on Bioequivalence Studies Conducted In India. J Bioequiv Availab. 2013.

24. Xie PS, Sun S, Xu S, Guo L. Value the Unique Merit of HPTLC Image Analysis
and Extending its Performance by Digitalization for Herbal Medicines Quality
Control. J Chromatograph Separat Techniq. 2014.

24