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Mr..MAHIBUB. MAHAMADSA . K.MAHIBUB MAHAMADSALECTURER -FACULTY OF PHARMACY UiTM-BARTAM CAMPUS, KEPALA.BETAS, P.PENANG .mehboob@ppinang.uitm.edu.my

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Differentiate various liquid dosage forms and theiradvantages/disadvantages.

Understand the classification of liquid dosage forms Know the components used in the liquid preparations. Know the general manufacturing procedure for liquid dosage

forms Know the various general quality control test for liquid dosage

forms Know the various types of internal oral liquid preparations

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WHAT ARE ORAL LIQUIDS?

Oral Liquids are homogeneous liquid preparations,usually consisting of a solution, an emulsion or asuspension of one or more medicaments in asuitable vehicle.

Two main types:

1.Monophasic liquids: 2. Biphasic liquids:Solutions SuspensionsElixirs EmulsionsSyrupLiquid drops Covered in separate lectureLinctusesMouth Wash

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INTERNAL

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EXTERNAL

Mixture

Linctus

Syrup

Elixir

Used on the SkinEx: Lotion/Liniment

Used in the mouthEx: Gargles / Mouth

wash

Instilled into the bodycavitiesEx: Ear / Nasal drops

Easy to administer More quickly effective than solid dosage form. Young children and some adults have difficulty in

swallowing tablets can prefer oral mixture Some drugs are inconvenient to administer in any

other form Some medicament may cause irritation in

stomach in the powder or tablet form. Easy to divide the dose as per need.

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Continue….Small dose are easily can beformulated in drops form.

infant patients oral cavity is verysmall, liquids are most suitabledosage form for them.

Various flavors and colors attractcertain patients like children andpsychotic patients.

Local action can be achieved Example:mouth washes

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Not unit dosage form unlike tablet/capsule. Bulky in volume. Spillage may occur if packaging is not

effective. Need measuring device to administer- drug. Cost of production is not economical

compare to tablets. Easy to degrade the drug in presence of water

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Manufacturing of Monophasic liquids:

CONTINUOUSPHASE

WATERSURFACTANTS

OTHERHELPING AGENTS

PRESERVATIVES

MIXING

AQUEOUS SOLUTION

DISPERSE PHASE

FOR SUSPENSION FOR EMULSION

DRUG SOLUTIONIN OILMILLED DRUG

GRINDING OFDRUG &OTHER SOLIDS

DISSOLVED DRUG IN OIL

Manufacturing of Biphasic liquids:

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PRE – MIXOR

CRUDE DISPERSION

HOMOGENIZE

FINE DISPERSE DELIVERY SYSTEM

OTHER ADDITIVES(FLAVOURS, COLOURING AGENT)

VOLUME ADJUSTMENT

pH ADJUSTMENT

Dispersephase

Continuous phase

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Process Equipment Process variables Properties affected by variables

Monitoring output

Mixing of liquid

Kettle & Tank fitted with agitator

Capacity of unit,Shape & position of agitation system,Order of addition,Rate of addition,Fill volume,Mixing speed of agitator,Temperature of liquid,Mixing time.

Appearance of liquid, Viscosity of liquid.

Potency, Appearance, pH,Viscosity, Specific gravity.

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Process Equipment Process variables Properties affected by variables

Monitoring Output

Mixing & blending of solids

Blade mixers & tumblers.

Capacity of unit, Mixing speed of unit,Shape of unit, position of mixing element within unit,Product load.

Particle size of solids,Blending uniformity.

Potency,Particle size analysis,Content uniformity of active component.

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Process Equipment Process variables Properties affected by variables

Monitoring output

Dispersing Homogenizer, Colloid mill, ultrasonic device/

Bore opening/clearance of rotor & stator/power setting,Pressure/rotor speed/power consumption,Feed rate, Temperature, Dispersion time, Order of mixing.

Particle size of solids,Viscosity of liquid.

Potency,Particle sizeDistribution,Viscosity,Specific gravity.

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Preformulation Test:(Tests before preparation)

It includes mainly following tests Particle size and size distribution Particle shape or morphologyMicrobial countRheology of solvent or vehicle PH of the solvent or vehicle

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Continue…

Raw materials are checked and validated for, Particle size and size distribution- Particle size

distribution range is 0.2-2microns for suspensions. Particle shape(Morphology)-It is also important to

consider because it affects the product appearance,solubility, settling rates and drug stability.

Microbial content-To prevent microbial growth onthe final product .

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Continue….

Rheology of solvent- It will determine how wellliquid will suspend the insoluble particles. Viscosity ofthe External phase is generated by one or more offollowing components:

Suspended solids Blend of oils and waxes presence of polyols and polyoxyethylene derivatives High concentration of dispersed solids in water Dispersed clays, gums, cellulosic, and/or polymers

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Continue….

pH of the solvent-Solubility of the drug in thesolvent or vehicle can be markedly influenced bythe pH of the solvent. pH of the solvent isimportant because large number ofchemotherapeutic agents are either weak acids orweak bases so their solubility markedly affectedby the pH of the solvent.

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Monitoring outputs

Some outputs to be monitored are as under,:

AppearancepHViscositySpecific gravityMicrobial countContent uniformityDissolution testing

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Test parameter Suspension EmulsionAppearance yes yesSpecific gravity yes yes

Viscosity yes yes

PH yes yes

Content uniformity

yes yes

Sedimentation yes No

Resuspendability

yes No

Particle size yes yes

Release rate yes yes

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Test parameters for liquid dosage forms.Mixture/Solution

yesYes

yes

yes

yes

No

No

No

yes

Appearance:

Appearance of the final product is checked andvalidated because it indicates the signs of instabilityand degradation. For e.g. settling of solid particlesin case of suspension and turbidity in case ofemulsion.

Time for mixing or agitation and temperature ofprocess can effect the appearance greatly.

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PH value

PH of aqueous oral formulations should be taken at agiven temperature and only after equilibrium hasbeen reached in order to minimize the PH drift.

Electrolytes , such as potassium chloride , may beadded to the aqueous external phase to stabilize theirPH drift.

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Viscosity:

Viscosity is defined as the study of fluid flow. orIt is a measurement of the applied stress per unit areato maintain a certain flow rate.

The viscometer used for the measurement ofviscosity should be properly calibrated atequilibrium at a given temperature to establishsystem reproducibility.

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Continue….

Viscosity of the liquid oral dosage form isimportant because it affects the settling rate ofsuspended particles in suspension and ofglobules of internal phase in emulsions andalso in case of oral solutions it affects theoverall appearance of the final product so itmust be measured and validated properly.

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Specific gravity:

Specific gravity is the weight of the product per unitvolume.

For most of the liquid oral products it is 1gm/cubecentimeter.

A decrease in specific gravity of the product likesuspensions indicates the presence of air within thestructure of the formulation.

Hydrometer is used to measure the specific gravityof liquid orals at a given temperature using wellmixed uniform solution.

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Microbial count

Microbial count for the final product is essential tovalidate because by performing microbial count wecan select the preservative for the final productstorage.

There are specifications for each liquid oral productfor the bioburden content.

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Continue….

Preservative system used in the formulation-The use of small amounts of propylene glycol(5-15%) or disodium edetate(about 0.1%) ordecrease in the PH of the disperse system haveoften been use to increase the efficiency of thepreservative system.

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Dissolution testing:

There is not any official method for dissolutiontesting of dispersed system , but the best way toperform dissolution of suspension like system is toplace a small amount of formulation inside a secureDurapore (polyvinylidene fluoride) membrane pouchof suitable viscosity and suspend it in a suitabledissolution medium using a USP method 1 paddleapparatus.

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Filling and packaging operation validation

Following tests are performed mainly

Leakage test for filled bottle

Cape sealing test

Fill volume determination

Water vapour permeability test

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Continue….

Some precautions to be taken while filling andpackaging

Proper control of product temperature

Proper agitation in holding tanks and filling heads

Uniformity and homogeneity of active ingredient

Maintain stability in the primary container closuresystem

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◦ Internal Solutions

Oral solutionsOral dropsDraughtsLinctusesElixirsTinctures

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Oral solutions/Mixtures:Is a liquid preparation meant for oral administration

in which drug/drugs are dissolved.

Formulation component: Vehicle, Chemicalstabilizer, colouring & flavouring agent,Preservative.

Solid drug + 3/4th of vehicle Examine for foreighnparticles- Add any liquid ingredients Addmore vehicle to produce final volume Trtansferthe mixture into the suitable bottle and cork itpolish the bottle and remove finger prints, Attachlabel, wrap the bottle and dispense.

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Advantages of Oral solutions:

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Same as general advantages in slide number 5 Absorption is faster compare to solid dosage

forms Patient with swallowing problem can administer Disadvantages of Oral solutions:

Same as disadvantages mentioned in in slide number 7 Prone to microbial growth Need preservative as vehicles are usually contains water

Container: plan glass bottles,uniform internaldiameter.

Storage: In cool and dry place.

Oral drops Oral drops are same as oral solution. Maine difference are total volume and drug

concentration is small compare to normal solutions foradult use.

Formulation component: same as solutions These are specially packed in small volume bottles with

dropper fitted with cap or enclosed separately into thebox.

Drops are designed mainly for infants (children below2 years) purpose.

Small volume is needed for infant patients by oralroute as their oral cavity is small.

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Advantages of Oral drops:

Can administer to infants easily Avoid the loss of medicines due to infant

rejection during administration of themedicine using dropper

Small dose are easily can be formulated indrops form.

Small in volumes easy to carry. High concentrated preparation assures

complete dose in small volume.

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Draughts :

A draught is an older term used todescribe a liquid preparation formulatedas single dose, in a volume which islarger than generally utilized intraditional mixture formulations. Eachdraught was usually supplied in 50 mLunit dose container

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LinctusesLinctuses are viscous, liquid and oral preparations

that are generally used for relief of cough. Shouldbe consume in small doses without diluting withwater.

Usually contain: sedative, expectorant drugFormulation components: Vehicles + Chemical

stabilizer, colouring & flavouring agent,Preservative.

Container: Well filled/closed air tight glass bottleshaving screw cap

Storage: In cool place, protected from light.

Advantages / disadvantages: Same as oral solutions.37

Elixirs:Elixirs are clear, sweetened, aromatic, hydroalcoholic

liquids intended for oral use.Formulation components: Vehicles(ethyl alcohol,

water, glycerine or propylene glycol), flavoring /Chemical stabilizers/coloring agent, Preservative.

Elixirs are usually contains potent drug such asantibiotics, antihistamines or sedatives.

Container: Well filled/closed air tight glass bottleshaving screw cap

Storage: In cool place, protected from light.Advantages / disadvantages: Same as oral solutions.

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Tinctures:A tincture is typically an alcoholic extract of plant or

animal material or solution of such or of a lowvolatility substance.

To qualify as an alcoholic tincture, the extract shouldhave an ethanol percentage of at least 40-60%.

In herbal medicine, alcoholic tinctures are made withvarious concentrations of ethanol, 25% being themost common.

Advantages: Ethanol is able to dissolve substanceswhich are less soluble in water, same time thewater content can dissolve the substances lesssoluble in ethanol + same as slide 5

Disadvantages: Slide 7

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Syrups:Syrup is a concentrated or nearly saturated solution of sucrose in

purified water. The concentration of sugar is 66.7% w/w.Syrups are sweet viscous preparations.

Specific ADVANTAGES:

Retards oxidation because it is partly hydrolyzed into reducingsugars

Acts as preservative due to high osmotic pressure Acts as sweetener hence valuable vehicle for bitter drugs.

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Continue….

Formulation components: Vehicles Coloringflavoring agent Chemical stabilizers,Preservative.

Container: Glass bottle (Clolourless/ambered)fitted with white propylene moulded orblack thermosetting plastic screw closures,

Storage: In well dried, cool, dark place. Storebelow 250C

Advantages / disadvantages: Same as oral solutions

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References:

Lieberman H. A. , Rieger M. M. and Banker G. S. “Pharmaceutical Dosage Forms: Disperse System” ,vol.3; Second Edition,473-511

R. A. Nash and A. H. Wachter “Pharmaceutical processvalidation”; Third edition

The theory and practice of industrial pharmacy by LeonLachman, Herbert A. Liberman, Joseph L. Kanig; Thirdedition.

Remington's Pharmaceutical Sciences (Any edition)

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THANKYOU

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ANY QUESTIONS ?