Mr..MAHIBUB. MAHAMADSA . K.

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

Differentiate

various

liquid

dosage

forms

and

their

advantages/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 a suspension of one or more medicaments in a suitable vehicle.

Two main types: 1.Monophasic liquids: Solutions Elixirs Syrup Liquid drops Linctuses Mouth Wash 2. Biphasic liquids: Suspensions Emulsions

Covered in separate lecture

INTERNAL Mixture Syrup Elixir Linctus

EXTERNAL
Used on the Skin Ex: Lotion/Liniment Used in the mouth Ex: Gargles / Mouth wash
Instilled into the body cavities Ex: 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 other form Some drugs are inconvenient to administer in any 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 be formulated in drops form. infant patients oral cavity is very small, liquids are most suitable dosage form for them. Various flavors and colors attract certain patients like children and psychotic 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

Manufacturing of Monophasic liquids:

Manufacturing of Biphasic liquids:

WATER SURFACTANTS

OTHER HELPING AGENTS

PRESERVATIVES
CONTINUOUS PHASE

DISPERSE PHASE

FOR SUSPENSION MIXING GRINDING OF DRUG & OTHER SOLIDS AQUEOUS SOLUTION MILLED DRUG

FOR EMULSION

DISSOLVED DRUG IN OIL

DRUG SOLUTION IN OIL

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Continuous phase Disperse phase

PRE MIX OR CRUDE DISPERSION OTHER ADDITIVES (FLAVOURS, COLOURING AGENT) VOLUME ADJUSTMENT HOMOGENIZE

pH ADJUSTMENT

FINE DISPERSE DELIVERY SYSTEM

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Process

Equipment

Process variables

Properties affected by variables Appearance of liquid, Viscosity of liquid.

Monitoring output Potency, Appearance, pH, Viscosity, Specific gravity.

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.

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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 Particle size of solids, Viscosity of liquid.

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.

Potency, Particle size Distribution, 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 morphology Microbial count Rheology 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 on the final product .

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Continue.

Rheology of solvent- It will determine how well liquid will suspend the insoluble particles. Viscosity of the External phase is generated by one or more of following 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 the solvent or vehicle can be markedly influenced by the pH of the solvent. pH of the solvent is important because large number of chemotherapeutic agents are either weak acids or weak bases so their solubility markedly affected by the pH of the solvent.

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Monitoring outputs
Some outputs to be monitored are as under,
:

Appearance pH Viscosity Specific gravity Microbial count Content uniformity Dissolution testing
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Test parameters for liquid dosage forms.

Test parameter Appearance Specific gravity Viscosity PH Content uniformity Sedimentation Resuspendabili ty Particle size Release rate Suspension yes yes yes yes yes yes yes yes yes Emulsion yes yes yes yes yes No No yes yes

Mixture/Solution yes Yes yes yes yes No No No yes

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Appearance:

Appearance of the final product is checked and validated because it indicates the signs of instability and degradation. For e.g. settling of solid particles in case of suspension and turbidity in case of emulsion. Time for mixing or agitation and temperature of process can effect the appearance greatly.

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PH value

PH

of aqueous oral formulations should be taken at a given temperature and only after equilibrium has been reached in order to minimize the PH drift.

Electrolytes , such as potassium chloride , may be added to the aqueous external phase to stabilize their PH drift.

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Viscosity:

Viscosity is defined as the study of fluid flow. or It is a measurement of the applied stress per unit area to maintain a certain flow rate. The viscometer used for the measurement of viscosity should be properly calibrated at equilibrium at a given temperature to establish system reproducibility.

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Continue.

Viscosity of the liquid oral dosage form is important because it affects the settling rate of suspended particles in suspension and of globules of internal phase in emulsions and also in case of oral solutions it affects the overall appearance of the final product so it must be measured and validated properly.

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Specific gravity:

Specific gravity is the weight of the product per unit volume. For most of the liquid oral products it is 1gm/cube centimeter. A decrease in specific gravity of the product like suspensions indicates the presence of air within the structure of the formulation. Hydrometer is used to measure the specific gravity of liquid orals at a given temperature using well mixed uniform solution.
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Microbial count

Microbial count for the final product is essential to validate because by performing microbial count we can select the preservative for the final product storage. There are specifications for each liquid oral product for the bioburden content.

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Continue.

Preservative system used in the formulationThe use of small amounts of propylene glycol(515%) or disodium edetate(about 0.1%) or decrease in the PH of the disperse system have often been use to increase the efficiency of the preservative system.

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Dissolution testing:

There is not any official method for dissolution testing of dispersed system , but the best way to perform dissolution of suspension like system is to place a small amount of formulation inside a secure Durapore (polyvinylidene fluoride) membrane pouch of suitable viscosity and suspend it in a suitable dissolution medium using a USP method 1 paddle apparatus.

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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 and packaging 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 closure system
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 Internal Solutions

Oral solutions Oral drops Draughts Linctuses Elixirs Tinctures

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Oral solutions/Mixtures:
Formulation component: stabilizer, colouring & Preservative.

Is a liquid preparation meant for oral administration in which drug/drugs are dissolved. Vehicle, Chemical flavouring agent,

Solid drug + 3/4th of vehicle Examine for foreighn particles- Add any liquid ingredients Add more vehicle to produce final volume Trtansfer the mixture into the suitable bottle and cork it polish the bottle and remove finger prints, Attach label, wrap the bottle and dispense.
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Container: plan glass bottles,uniform diameter. Storage: In cool and dry place.

internal

Advantages of Oral solutions:

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
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 Oral drops

Oral drops are same as oral solution. Maine difference are total volume and drug concentration is small compare to normal solutions for adult use. Formulation component: same as solutions These are specially packed in small volume bottles with dropper fitted with cap or enclosed separately into the box. Drops are designed mainly for infants (children below 2 years) purpose.
Small volume is needed for infant patients by oral route 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 the medicine using dropper Small dose are easily can be formulated in drops 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 to describe a liquid preparation formulated as single dose, in a volume which is larger than generally utilized in traditional mixture formulations. Each draught was usually supplied in 50 mL unit dose container

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Linctuses are viscous, liquid and oral preparations that are generally used for relief of cough. Should be consume in small doses without diluting with water. Usually contain: sedative, expectorant drug Formulation components: Vehicles + Chemical stabilizer, colouring & flavouring agent, Preservative. Container: Well filled/closed air tight glass bottles having screw cap Storage: In cool place, protected from light. Advantages / disadvantages: Same as oral solutions.
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Linctuses

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 as antibiotics, antihistamines or sedatives. Container: Well filled/closed air tight glass bottles having 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 low volatility substance. To qualify as an alcoholic tincture, the extract should have an ethanol percentage of at least 40-60%. In herbal medicine, alcoholic tinctures are made with various concentrations of ethanol, 25% being the most common. Advantages: Ethanol is able to dissolve substances which are less soluble in water, same time the water content can dissolve the substances less soluble 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 reducing sugars 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 Coloring flavoring agent Chemical stabilizers, Preservative. Container: Glass bottle (Clolourless/ambered) fitted with white propylene moulded or black thermosetting plastic screw closures, Storage: In well dried, cool, dark place. Store below 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 process validation; Third edition The theory and practice of industrial pharmacy by Leon Lachman, Herbert A. Liberman, Joseph L. Kanig; Third edition. Remington's Pharmaceutical Sciences (Any edition)

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THANK YOU
ANY QUESTIONS ?
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