Liquid Dosage form: Monophasic

Prepared and

Presented by:

Manisha

Shrestha

Introduction Monophasic dosage forms refers to liquid preparations in

which there is only one phase and is represented by a true solution.

A true solution is a clear homogenous mixture that is prepared by dissolving a solid, liquid or gas (solute) in a suitable solvent.

The solvent, or mixture of solvents, is the phase in which the dispersion occurs, and the solute is the component which is dispersed as molecules or ions in the solvent.

Advantages Easier to swallow therefore easier for:

children, old age, unconscious people

Fast Absorption No need of dissolution Faster action than solid dosage

forms Homogenous therefore give uniform dose than suspension

or emulsion which need shaking. Provide a safe means of administering substances like

potassium iodide and bromide which cause gastric pain if taken in dry form.

Use flavours and sweeteners make them palatable especially for children.

Simple and fast to formulate. Can be administered via a number of routes:

Oral, Parenteral preparations (injections), enemas for rectal use, topical (for use on the skin), otic (ear), nasal and ophthalmic preparations

Disadvantages Bulky therefore difficult to transport and store.

Water is commonly used vehicle, so prone to microbial growth. Incorporation of a preservative is necessary.

Less dosage accuracy. Needs an accurate spoon to measure the dose.

Solution can undergo hydrolysis when kept in direct sunlight. Thus there is a need of special storage condition and label of Keep away from direct sunlight.

Some drugs are poorly soluble. The solubility of a drug needs to be taken into consideration when preparing a solution.

Drug stability is often reduced by solvolysis, hydrolysis or oxidation. So solutions have shorter expiry date than equivalent solid dosage forms.

Major signs of instability:

Colour change

Precipitation

Microbial growth

Chemical gas formation

Formulation

Consideratio

n

Solubilit

y

Equipment

s

Manufacturin

g

Consideratio

nsManufacturin

g Procedure

Preservativ

esStabilit

y

Raw

Material

s

Pharmaceutical

elegance

Viscosity

modifiers

Sweetening

agents

Flavouring

agents

Colouring

agentsConsideratio

ns

Drug Solubility

The solubility is defined as the the maximum quantity of solute that can dissolve in a certain quantity of solvent at a specified temperature.How do substances dissolve?

Solvation There is an interaction between the

solute and the solvent.

solvent

solute

The solute particles are usually

surrounded by the solvent particles.

This process is called solvation.

Different substances have different solubilities.

A substance that cannot be dissolved in another (or does so to a very limited extent) is said

to be insoluble.

Approaches to increase the solubility of the drug1. pH adjustment

2. Cosolvency

3. Miceller

solubilization

4. Complexation

5. Chemical modification

6. Particle size reduction

7. Hydrotrophy

Choice of

solvents

Wate

r

Alcoh

ol

Glycer

ol

Propyle

ne

glycol

Advantage

has no

pharmacologic

activity

non-toxic, nonirritant,

tasteless, relatively

cheap, and many

drugs are water

soluble.

Disadvantages

Presence of

dissolved and

suspended

impurities.

Microbial bio-burden

high

Drug undergeso

Advantages:

Dissolve many

water-insoluble

ingredients

It is invariably

used as hydro-

alcoholic mixture

Disadvantages

produces

pharmacologic

and potential

toxic effects

when ingested,

particularly by

children.

soluble in all

proportions in

Water or Alcohol

used as vehicle

in Elixirs,

Solution and in

Syrups .

good vehicle for

application in

the skin and to

sores

as demulcent

and humectants

Used as

solvent in

oral liquid,

topical and

parenteral

preparation

s

Wetting

agent for

natural

gums

As

humectants,

preservative

and

stabilizer

PreservativesPreservatives used must be

Effective against

broad spectrum of

microorganisms

Physically, chemicaly

and microbiologically

stable for lifetime of

the product

Non toxic, non

sensitizing, soluble,

compatible and with

acceptable taste and

odour

Acidic types

phenol, chlorocresol,

alkyl esters of para-

hydroxybenzoic acid,

benzoic acid, boric

acid, and sorbic acid

Types of

Preservatives

Neutral preservatives

chlorobutanol, benzyl

alcohol

Quarternary ammonium

compounds

Benzalkonium chloride

Stability

Physical

Stability

Chemical

Stability

Techniques for predicting

Chemical Stability are well

defined through specific

chemical tests.

Generally chemical stability of a

formulation is affected by:

pH

Temperature

Ionic Strength

Solvent effects

Light

Oxygens

Instability can be prevented by

use of:

o Buffering agents

o Antioxidants

o Proper packaging

(eg: use of amber bottle for light

sensitive products)

A physically stable

formulation retains its

viscosity, colour, clarity,

taste, and odour throughout

its shelf life

Objective

evaluationSubjective

evaluation

Colour can be

measured

spectrophotometricall

y.

Clarity can be

determined by

measurement of its

turbidity or light

scattering equipment.

Viscosity can be

measured by use of

viscometers.

Taste and odour can be

determined either by

pharmaceutical

investigator or by a

panel of unbiased, taste

sensitive individuals.

Pharmaceutical elegance

Viscosity

modifiersSweetening

agents

Flavouring

agents

Colouring agents

Enhance

viscosity

Examples

Povidone,

hydroxyethylcellul

ose, carbomer,

etc.

To enhance

palatability and

mask the taste of

the drugs

Examples

Sucrose, saccharin,

aspartame, liquid

glucose, etcTaste Sensation Recommended flavour

Salt Butter scotch, maple, apricot, peach, vanilla,

wintergreen mint.

Bitter Wild cherry, walnut, chocolate, mint

combinations, passion fruit, mint spice, anise.

Sweet Fruit and berry, vanilla.

Sour Citrus flavours, liquorice, raspberry.

To enhance the

appearance of the

vehicle; which matches

well with the flavor

employed in the

preparation

Examples

green with mint, brown

with chocolate flavor etc.

Manufacturing

Considerations

Raw

Material

s

Equipmen

ts

Manufacturi

ng

Procedure

Incoming raw materials should

be tested against some

specifications regarding

identity, purity, uniformity and

freedom from excessive

microbial contamination

Additional processing done if

required

e.g: size-reduction or sterilization

before manufacturing.

In oral liquid preparations, water

is the main vehicle. So, it should

meet the requirements for

Purified water.

The following types of equipments

may be used in the manufacture of

liquid formulations:-

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 e.g. filter press

Cleaning of equipments

All equipments must be thoroughly

cleaned and sanitized before use

Disinfectants used: Dilute solutions

of H2O2, phenol derivatives

Sterilized by: Alcohol, boiling water,

autoclaving, steam or dry heat.

Manufacturing of Monophasic liquids

Process flow Control Variables Measured response

Addition of Raw

materials

(Active+ excipients

as per formula)

Mixing

Jacketted vessel

with variable speed

mixer

Filtration

Filter Press or

Cartridge Filter

Filling

Automatic Filling

Machine

Mixing time

RPM

Temperature

Final Volume

Pore size

Filter integrity

Filling Machine

Speed

Clarity

Viscosity

Assay

Clarity

Volume

Filling/ Packaging

Gravimetri

c

Volumetri

cConstant

level Containers are filled

with liquids to a

given weight.

Usually limited to

large container

filling or highly

viscous products.

Cannot be used in

high speed,

automatic

equipments.

Containers are filled with

liquid to a given volume.

Fill amount is measured

by the stroke of the piston

and cylinder assembly.

Problems may arise when

containers used are not

dimensionally uniform

Fill amount is

verified by adjusting

the height to which

the container is to be

filled.

Variations in

container dimension

may result in

variations in the net

fill per unit.

Techniques of filling

Vacuum filling Gravity Vacuum filling Pressure Vacuum filling

Vacuum developed

within the container

causes liquid to flow

from tank to container.

Bulk liquid tank is placed

above filling stem so that liquid

flows to the container due to

force of gravity

Pressure applied to bulk

liquid tank and vacuum

developed in the container

results in pressure difference

so that liquid flows to the

container

Monophasic Liquid Dosage Forms

Liquids meant for internal

administration

Liquids meant for external

administration

Liquids applied to

the skin

Liquids used in

mouth

Liquids instilled

into body cavities

Syrups

Mixtures

Elixirs

LinctusesLotions

Liniments

Gargles

Mouthwashes

Throat paints

Douches

Ear drops

Nasal drops

Eye drops

Collodions

Paints

Enemas

Liquids meant

for internal

administration

s

Syrup

Concentrated

aqueous

preparations of 60%

to 85% sucrose with

or without flavoring

agents and

medicinal

substances. e.g.

Chlorpheniramine

maleate syrup,

Chloral hydrate

syrup etc

Elixirs

Clear, aromatic,

sweetened

hydroalcoholic

solutions with or

without medicinal

substances, intended

for oral use.

eg:Dexamethasone

elixir (Medicated)

Compound

benzaldehyde elixir

(Non-medicated)

Mixture

Liquid preparation

meant for oral

administration in

which medicaments

are dissolved in a

suitable vehicle.

Eg: Orange peel

infusion

Linctuses

Viscous, liquid and

oral preparations that

are generally

prescribed for the

relief of cough.

Eg: Codeine Linctus.

Liquids meant for external administrationsGargles

Aqueous solutions

containing

antiseptics,

antibiotics or

anesthetics used to

prevent or treat

throat infections.

Available in

concentrated form

with direction for

dilution with warm

water before use.

eg:Phenol gargle

Throat sprays

sprayed into the

throat are intended

to medicate the

lungs

Throat paints

Viscous liquid

preparation used

for mouth and

throat infections.

Eg:Phenol

glycerine,

Compound Iodine

paint

Mouthwash

Aqueous solution with

a pleasant taste and

odor used to clean

and deodorize the

buccal cavity.

Have antiseptic and

astringent activity.

eg: Antiseptics-

phenol derivatives

Astringents-Zinc

Chloride

Liquids meant for external administrations

b) Liquids

instilled into

body cavities

Douches

Medicated solution

meant for rinsing a

body cavity as

eyes, ear or nasal

cavities for

cleaning or

removing the

foreign particles or

discharge from

them. Eg: isotonic

sodium chloride

solutionOtic preparations

Applied to or in the

ear to treat or

prevent dermatitis

of the ear,

cerumen build up

and ear infection.

Eg: soda glycerine

Eye drops

Sterile,

aqueous/oily

solutions

intended for

instillation in

eyeball. Eg:

Moxifloxacin eye

drops

Nasal drops

Administered through

the nose to obtain a

systemic or local

effect.

Used for symptoms

such as nasal

congestion caused

by an allergy, or a

related upper-

respiratory problem.

Eg:Beclomethasone

dipropionate nasal

drops

Enemas

Aqueous or oily

solution that is

introduced into the

rectum and colon

via the anus for

cleansing,

therapeutic or

diagnostic purposes

Liquids meant for external administrations

c) Liquids

meant for

external use

(Skin)

Collodions

Highly flammable syrupy

solution of pyroxylin

dissolved in ether and

alcohol, which dries to a

clear tenacious film

Used as a topical

protectant to close small

wounds, abrasions and

cuts

to hold surgical dressings

in placeLotions

Either liquid or semi-liquid

preparations that contain

one or more active

ingredients in an

appropriate vehicle.

Topical preparation with a

low to medium viscosity

Intended for application to

unbroken skin without

friction.

Eg: Calamine Lotion,

Liniments

Alcoholic and oily liquid

preparations

Intended for external

application with rubbing to

the affected area

Topically used to relieve

pain and stiffness, such

as from sore muscles or

from arthritis.

Paints

Solutions used to

sterilize the skin.

Eg. Crystal violet

, Magenta paint

Formulation

problems

Stability

Sterility

Organoleptic Qualities

Viscosity

Tonicity

Specific gravity

Recent AdvancesThe Recent Approach in formulation of Syrup

Preparing palatable tasting cough syrup containing Noscapine

Present invention involves formulation of noscapine to obtain a

liquid suspension

METHOD:

Preparing an aqueous liquid syrup type carrier solution &buffer to

maintain the PH of 7at all times.

Mixing alkaloid noscapine with the liquid carrier to form a fine

suspension

Aqueous liquid carrier comprises sucrose, sorbitol, a preservative,

CMC , glycerin and suspending agent

Reference: Process of making cough syrup with masked noscapine, by Virgil

D. Bianculli, Publication number US4029797 A.

(https://www.google.com/patents/US4029797)

The Recent Approach in formulation of flavoured mouthwash

This invention involves preparing visually clear, stable aqueous citrus flavoured

mouthwash which reduces flammability hazards associated with mixing volatile

alcohols and also reduces capital costs by requiring fewer mixing vessels.

Formulation

Citrus flavor oil - 0.01-0.5%

Emulsifier - 0.1-2.0%

Alcohol - 1-25%

Purified water - 60-95%

Steps:

(a) preparing a blend of the alcohol with the citrus flavor oil;

(b) preparing a second blend of water and the emulsifier;

(c) subsequently combining blends (a) and (b); and

(d) intimately mixing the resultant combination.

Reference: Blending citrus oils, alcohols, water, and emulsifiers, by Craig T.

Elton and Stephen Reynolds, Publication number US4420471 A.

(http://www.google.com/patents/US4420471)

The Recent Approach in formulation of Eye drops

Opthalmic formulation comprising a beta blocker and carbopol

The present invention relates the manufacturing of beta blocker

which improves its I.O.P lowering effect

Formulation:

Timolol - 0.5%

Timolol maleate - 0.72gm

Benzylconium chloride - 0.72gm

Carbopol - 2.0gm

Sodium hydroxide - pH 6.5-7.5

water for injection - 100ml

Reference: Ophthalmic formulation comprising a beta blocker and carbopol,

by Bakulesh Mafatlal Khamar, Publication number EP1137407 B1.

(http://www.google.com/patents/EP1137407B1?cl=en)

Recommendations Formulation considerations

Proper choice of drug solubilizing parameters and solvents.

Proper choice of stabilizers

Proper choice of all the required adjuvants

Manufacturing Considerations

Raw materials used in manufacturing liquid should be properly checked

for the specifications such as:

Identity

Purity

Uniformity

Freedom from excessive microbial contamination

Equipment considerations

Mixing tanks

Measuring devices

Filtration systems

Conclusion Although the stability and solubility are critical factor for the

monophasic liquid dosage forms, the popularity of the

formulation has not decreased due to the ease of administration

and palatability for pediatric, geriatric, intensive care and

psychiatric patient.

The possibility of simplifying complex process leading to new

formulation development or their optimisation will depend on:

availability of basic needs related to ingredient combination such

as solubility, compatibility, choice of solvents etc, which will be

gained by investigating ingredient properties.

Understanding the effect of ingredients on product stability.

Considering all the required parameters properly for theequipments used with their proper handling.

Recent advances Supercritical Fluid (SCF) Process

novel nanosizing and solubilisation technology.

Supercritical fluids : fluids whose temperature and pressure are greater than its critical temperature (Tc) and critical pressure (Tp), allowing it to assume the properties of both a liquid and a gas.

SCFs have properties useful to product processing because they are intermediate between those of pure liquid and gas (i.e., liquid-like density, gas-like compressibility and viscosity and higher diffusivity than liquids).

Once the drug particles are solubilized within SCF, they may be recrystallised at greatly reduced particle sizes. to sub-micron levels.

Commonly used supercritical solvents include carbon dioxide, nitrous oxide, ethylene, propylene, propane, n-pentane, and water.

Several methods of SCF processing have been developed such as solution enhanced dispersion by SCF (SEDS), supercritical antisolvents processes (SAS), Rapid Expansion of Supercritical Solutions (RESS), Gas Anti Solvent Recrystallization (GAS)

Solid Dispersion-Solubilization

method refers to a group of solid products consisting of at least two

different components, generally a hydrophilic matrix and a hydrophobic drug.

In this technique, a poorly soluble drug is dispersed in a highly soluble solid hydrophilic matrix, which enhances the dissolution of the drug.

Solid dispersion techniques can yield eutectic (non-molecular level mixing) or solid solution (molecular level mixing) products.

Advantage:

Presence of the drug in microcrystalline state, improved wettability and formation of high free energy amorphous forms of the drug during solid dispersion formation contribute towards enhancement of drug solubilization.

The most commonly used hydrophilic carriers for solid dispersions include polyvinylpyrrolidone, polyethylene glycols, Plasdone-S630. Surfactants like Tween-80, Docusate sodium, and Sodium Lauryl Sulphate can also be used in the formation of solid dispersion.

There are various techniques to prepare the solid dispersion of hydrophobic drugs to improve their aqueous solubility

CONCLUSION AND

RECOMMENDATION Even though the stability and solubility are critical factor for the

pharmaceutical liquid dosage forms, the popularity of the formulation do

not decrease due to the ease of administration and demand for pediatric,

geriatric, intensive care and psychiatric patient.

In order to enhance the stability, different factors must be considered

such as compatibility with the excipients and choice of appropriate

solvent and storage condition such as light and temperature, oxygen.

Therefore, uses of buffers, antioxidants, reducing agents are necessary.

Also, monophasic liquid must be packed in amber coloured bottle with

label of “Keep away from Sunlight”.

to improve the solubility solubilizing agents as surfactants and different

technique co-solvency complexation, particle size reduction, chemical

modifications etc. can be applied

Also, monophasic liquid dosage forms contain water as vehicle, sucrose

which makes them prone to microbial growth. So, use of suitable

preservative is necessary.

For those intended for oral route, appropriate flavors and sweetener with

identical colors are to be incorporated to make them palatable and

appealing to use.

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Churchill Livingstone, London, 2002, pp 309-322.

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Phillips E.M., Stella V.J. Rapid expansion from supercritical solutions: application to pharmaceutical processes.Int.J.Pharm.1993;94:1-10.

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