MONOPHASIC LIQUID DOSAGE FORM

Rikesh Lal ShresthaM.Pharm, 1st SemesterKathmandu University

Contents• Introduction• Classification of Monophasic liquid• Formulation Consideration• Manufacturing Consideration• Recent advance in monophasic liquid• Recent approach in monophasic liquid formulation• Conclusion• Recommendation

Introduction• Monophasic dosage form refers to liquid preparation containing two

or more components in one phase system, it is represent by true solution.

• A true solution is a clear homogenous mixture that is prepared by dissolving solute in a suitable solvent.

• The component of the solution which is present in a large quantity is known as “SOLVENT” where as the component present in small quantity is termed as “SOLUTE”.

Advantage • It is easier to swallow, therefore easier for children and old age people.

• Facilitate absorption of drug faster than solid dosage form as drug is

already in solution form.

• It is homogenous therefore give uniform dose than suspension or

emulsion which need shaking.

• Simple and fast to formulate

• It can be administered by various routes :

Oral, Parenteral (injection),enema for rectal use, otic(ear), nasal and

ophthalmic preparation.

Disadvantage• They are bulky, so difficult to transport and store.

• Water is commonly use vehicle, which is prone to microbial growth.

So addition of preservative is needed.

• When expose to direct sunlight it may undergo hydrolysis, so need to

store in cool and dark place.

• Drug stability reduce by hydrolysis or oxidation. So, they have shorter

expire date than solid dosage form.

• Other major sign of drug instability are color change, Precipitation,

microbial growth etc.

Classification

Liquids meant for internal administrations

• Syrup : Aqueous preparations of 60% to 85% sucrose with or without

flavoring agents and medicinal substances. e.g. Chlorpheniramine

maleate syrup, Chloral hydrate .

• Elixirs : Clear, aromatic, sweetened hydro alcoholic solutions with or

without medicinal substances, intended for oral use. Eg:

Dexamethasone elixir .

• Linctuses : Viscous, liquid and oral preparations that are generally

prescribed for the relief of cough. Eg: Codeine Linctus.

Market available Syrup/Elixir/ Linctus

Liquids meant for external administration Liquids used in the mouth

• Gargles :Aqueous solutions containing antiseptics or antibiotics used to

treat throat infections. Available in concentrated form with direction for

dilution with warm water before use. eg: Povidone Iodine gargle.

• 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.

• Throat paints : Viscous liquid preparation used for mouth and throat

infections. Eg: Phenol glycerine, Compound Iodine.

Market available Gargle, Mouthwash and Throat paints

Liquids meant for external administrationLiquids instill into body cavity

• Eye drops: Sterile, aqueous/oily solutions intended for instillation in

eye. Eg: Timolol maleate eye drops.

• Nasal drops Administered through the nose to obtain local effect. Used

during nasal congestion and upper-respiratory tract problem. Eg:

Oxymetazolin Hydrochloride nasal drops.

• Enemas: Aqueous or oily solution that is introduced into the rectum and

colon via the anus for cleansing, therapeutic or diagnostic purposes.

Market available Eye drop, Nasal drop and Enemas

Liquids meant for external administrationLiquid meant for skin

• Liniments : Oily liquid preparations, intended for external application

with rubbing action to the affected area. Use to relief pain and stiffness,

such as from muscles spasm and arthritis.

• Lotions : Topical preparation with a low to medium viscosity. Use to

moisturize dry skin. Eg: Calamine Lotion, baby lotion

• Paints : Solutions used to sterilize the skin. Eg. Betadine antiseptic

paint, Magenta paint

Market available Liniment, Lotion and Paint

ConsiderationFormulation Consideration

• Solubility

• Stability

• Preservatives

• Pharmaceutical elegance Viscosity modifiers

Sweetening agents

Flavouring agents

Colouring agents

Manufacturing Consideration

• Raw Materials

• Equipments

• Manufacturing Procedure

Approaches to increase the solubility of the drug pH adjustment : By addition of buffer to the formulation . Co-solvency: By addition of water miscible solvent in which drug

has good solubility. The solvent known as co-solvent.Micelle solubilization : At high concentration surfactant s are forced into water to form colloidal aggregate known as micelle. Drugs get adsorbed into micelle that increase drug solubility. Micelle form only at critical micelle concentration.

Complexation: Drug-complexing agent complexation formed when complexing agent is added to solution. It increase solubility of drug on the basis of Le Chatelier’s principle or “ The equilibrium law”.

Micronization: The process involve size reduction of drug particle 1 to 10microns

either by spray drying or fluid energy mill.

Hydrotrophy : Drug dissolve in the cluster of hydrotropic agent. Also there is drug- hydrotrophy agent complexation formation to increase drug solubility.

Preservative

Preservatives must have following criteria:• 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.

Types of Preservatives• Acidic : phenol, benzoic acid, sorbic acid• Neutral preservatives : chlorobutanol, benzyl alcohol• Quarternary ammonium compounds : Benzalkonium chloride

Stability

Chemical Stability Physical Stability Chemical stability of a formulation

is affected by: pH Temperature Ionic Strength Solvent effects Light Oxygen

Instability can be prevented byuse of:o Buffering agentso Antioxidantso Proper packaging(eg: use of amber bottle for light sensitive products)

A stable formulation retains its viscosity, color, clarity, taste, and odour throughout its shelf life

Objective evaluation Subjective evaluation

Colour can be measured spectrophotometrically.

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 EleganceViscosity modifiers

Sweetening agents

Flavouring agents

Colouring agents

Enhance viscosity. Eg: Povidone, hydroxyethylcellulose

To enhance palatability and mask the taste of the drugs. Eg : Sucrose, saccharin, aspartame

Taste Sensation Recommended flavour

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

Bitter Wild cherry, walnut, chocolate, mint.

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 .Eg: green with mint, brown with chocolate flavor etc.

Manufacturing Consideration Raw Materials : Incoming raw materials should be tested as per specifications

that is identity, purity, uniformity and microbial contamination .

Equipments : 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 Liquid

Recent Advance in Monophasic Liquid

• Recently developed method for the enhancement of solubility of drugs.– Nanocrystal– Nanomorph– Sonocrystallization– Supercritical Fluid Process

• Recent advances for the delivery of liquid dosage form– Novel Parenteral drug delivery– Novel ophthalmic drug delivery

Nanocrystal• A nanocrystal is a crystalline material whose

dimension is in nanometers. • It reduce drug particles size in range of 1-1000 nm. • Two methods used for producing nanocrystals;

‘bottom-up’ and ‘top-down’ development. • The top-down methods (i.e. Milling and High

pressure homogenization) start milling down from macroscopic level.

• In bottom-up methods (i.e. Precipitation and Cryo-vacuum method) nanoscale materials are chemically composed from atomic and molecular components.

NanoMorph• The NanoMorph technology convert drug

having low water-solubility from a coarse crystalline state into amorphous nanoparticles.

• A suspension of drug substance in solvent is fed into a chamber, where it is rapidly mixed with another solvent which converted it into a true solution.

• The polymer keeps the drug substance particles in their nanoparticulate state and prevents them from Aggregation or growth.

Sonocrystallization • Recrystallization of poorly soluble materials

using liquid solvents and antisolvents has also been employed successfully to reduce particle size.

• The novel approach for particle size reduction based on crystallization by using ultrasound.

• It utilizes ultrasound power characterized by a frequency range of 20–100 kHz for inducing crystallization.

• It reduce the drug particle size to micro level.

Supercritical Fluid Process• 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 of liquid-like density, gas-like compressibility and viscosity and higher diffusivity .

• 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 etc.

Novel Parenteral Drug Delivery• It use dendromers as drug carriers to achieve

administration of poorly water-soluble drugs. • Dendromers are hyperbranched polymers with

well-defined structure and molecular weight.• They have a globular shape, and large void

internal spaces that can be used for the encapsulation and delivery of drugs.

• Like cyclodextrins, dendomers have ability to deliver poorly soluble drugs.

Novel ophthalmic drug delivery• Small colloidal carrier particles such as liposomes,

microcapsules, nanoparticles are used to deliver precorneal short half life drugs.

• Drugs can be incorporated into the core of the carrier by dissolved in the polymer matrix.

• Colloidal carrier systems have the advantage that they may be applied in liquid form, just like eye drop solutions, because of their low viscosity.

• Nanoparticles have a particle size range from 10 to 1000 nm.

Novel ophthalmic drug delivery• Drug release from polymer either by degradation of

the polymer or through diffusion from polymeric matrix.

• Various synthetic and natural biocompatible polymers have been used to prepare nanoparticles.

• Example of biodegradable polymer : Polylactic acid Examples of nonbiodegradable polymers : Poly cyano acrylate derivatives.

Recent AdvancementRecent Approach in formulation of SyrupPreparing palatable tasting cough syrup of Noscapine Present invention involves formulation of Noscapine to

obtain a cough syrup.Method:Preparing an aqueous liquid syrup type carrier solution & buffer

to maintain the pH of 7 at all times.Aqueous liquid carrier comprises of sucrose, sorbitol,

presevatives and glycerin.Mixing noscapine alkaloid with liquid carrier.

Conclusion• Liquid dosage forms are easy to administer for children and

elderly as well as patient who find difficult in swallowing solid dosage form.

• During the formulation of monophasic liquid dosage forms, solubility of the active pharmaceutical ingredients should be considered hence appropriate solvent must be used in the formulation.

• The solubility and stability are major problem for liquid dosage form. But with the use of solubility enhancement technique ,poorly soluble drug can be formulated in solution is remarkable.

Recommendation• Solutions may act as a good media for microbial growth. So preservative

is necessary to add in formulation.

• To prevent hydrolysis, oxidation of drug, antioxidant is added in solution. The antioxidant use must be chemically inert and compatible with the API.

• Requiring patients to take more than two tea spoon full at a time may not be advisable because of lower patient compliance.

• Besides being suitable for elderly patient, there may risk of plasma level raising rapidly which may be harmful.

• Inappropriate excipient selection exerts negative influence on stability and toxicity of dosage form. So, effective use of excipients allows formulators overcome challenges.

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