Liquid Dosage Forms

LIQUID DOSAGE FORMS

Prepared By : Mr. Naresh Rajgor, Assistant Professor, M.P. Patel College of Pharmacy, Kapadwanj LIQUID DOSAGE FORMS RAJGOR

PREPARED BY: MR. NARESH

INTRODUCTION Definition: “A solution is a liquid-prep liquid-preparati aration on that contains one or more soluble soluble chemical chemical substances dissolved in a specified solvent.” Liquid dosage form mainly divided into 1.

Solution

2. Syrup

3. Suspension

4. Emulsion

Advantages

•

Immediately available for absorption.

•

Administration convenient, particularly for infants, psychotic patients.

•

Easy to color, flavor & sweeten.

•

Liquids are easier to swallow than solids and are therefore particularly acceptable for pediatric patient.

•

A solu soluti tion on is an homo homoge geneo neous us syst system em and ther theref efor oree the the drug drug will will be unifo uniform rmly ly distributed throughout the preparation.

•

Some drugs like aspirin, KCl can irritate gastric mucosa if used orally as a solid dosage forms. But this effect can be reduce by solution system.

Disadvantages

•

Bulky than tablets or capsule, so difficult to carry transport.

•

Less stable in aqueous system. Incompatibility is faster in solution than solid dosage form.

•

Patients have no accurate measuring device.

•

Accident breakage of container results in complete loss.

•

Solution often provide suitable media for the growth o f micro organisms.

•

The taste of a drug, which is often unpleasant, is always more pronounced when in solution than in a solid form.

LIQUID DOSAGE FORMS RAJGOR


CLASSIFICATION

ADDITIVES USED IN LIQUID DOSAGE FORMS 1. Vehicles 2. Buffers 3. Dens Densit ity y modi modifi fier erss 4. Stabilizer zer 5. Isot Isoton onic icit ity y modi modifi fier erss 6. Visc Viscos osit ity y enha enhance nceme ment nt 7. Prese reserrvat vatives ves 8. Swee Sweete teni ning ng agen agents ts 9. Reduci Reducing ng agent agentss and and anti antioxi oxidant dantss 10. Flavors Flavors and perfumes perfumes 11. Colo Colors rs



1. VEHICLES:

Two types of vehicles; a. Aqueous vehicles b. Non- aqueous vehicles.

a. Aqueous vehicles

•

Water is the solvent solvent most widely widely used as a vehicle vehicle for pharmaceutical pharmaceutical products because of its physiological compatibility and lack of toxicity.

•

It possesses a high dielectric constant, which is essential for ensuring the dissolution of a wide range of ionizable materials.

Types of pharmaceutical water. Sr ..

Name

Properties

Remarks

Water

-Cheap -High Dielectric Constant -Miscible with alcohol, glycerol and other polar solvents -Non flammable -Inert

-Impurities

Purified Water

-Prepared by Distillation or ion exchange resin

-used for Parenterals Preparation

Water for injection

-Sterile -Pyrogen free

-Parenterals Preparation

Ster terile ile wate waterr for injec njecttion Steril eriliz izes es and and sui suittabl ably pack packed ed

-No -No ant antimi imicrob crobiial adde added d -Parenterals Preparation

Bacteriostatic water for injection

-Parenterals Preparation

Sterile water contain one or more suitable anti microbial

•

Approaches to improve aqueous solubility

•

Co-solvency

•

pH control



•

Solubilization (macrogol ethers, polyoxyethylated sorbitan, sucrose monoesters, lanolin esters)

•

Complexation

•

Chemical modification

•

Particle size control

b. Non-aqueous vehicles

1. Fixed Fixed oils oils of vegeta vegetable ble origin origin 2. Alcohols 3. Poly Polyhy hydr dric ic alco alcohol holss 4. Dime Dimeth thyl ylsu sulf lfox oxid idee 5. Ethyl et ether 6. Liqu Liquid id para paraff ffin in 7. Misc Miscel ella lane neous ous solv solven ents ts

1. Fixed Fixed oils oils of vege vegeta table ble orig origin in

•

These are non-volatile oils that consist mainly of fatty acid esters of glycol.

•

Almond oil, consist of glycerides mainly of oleic acid is used as a solvent for oilyphenol injections

•

Arachis oil is used as the solvent in dimercaprol injection.



•

Olive oil, sesame oil, maize oil, cottonseed oil, soya oil and caster oil are all suitable for parenteral and eye, ear drop formulation.

•

Ethyl oleate is useful solvent for both ergocalciferol injection and testosterone propionate injection.

•

Vegetable oils are also used for veterinary formulations.

Sr . No.

Name

Properties

Remarks

1

Corn oil

-Clear -Light yellow oily liquid

-Solvent and vehicle for injection

2.

Cotton seed oil

-Pale yellow oily liquid -Odourless

-Solvent and vehicle for injection

3.

Peanut oil

-Colourless to Pale yellow

-Solvent and vehicle for injection -- Liniments

4.

Sesame Oil

-Pale Yellow -Odourless

- Solvent and vehicle for injection - Cosmetics, liniments and ointments.

5.

Ethyl Oleate

-Pale yellow oily liquid Low viscosity

Vehicle for I.M,

6.

Silicons

Different Grade

Dermatological Preparations

2. Alcohols

•

Ethyl alcohol is the most widely used solvent in this class, particularly for external preparation, where it evaporates and produce a cooling effect

•

Ex: salicylic acid lotion

•

At concentrations greater than 15%, ethanol exhibits anti microbial activity but because of its toxicity, it is used orally or parenterally only at low concentrations, usually as a co solvent with water.

•

In some case isopropyl alcohol is also used externally as a solvent.



3. Poly Polyhy hydr dric ic alc alcoh ohol olss

•

Alcohols containing two hydroxyl groups per molecule are known as glycols but because of their toxicity, they are rarely used internally.

•

Propylene glycol is only the exception.

•

It is often used in conjunction with water or glycerol as a cosolvent.

•

It is used n formulation of digoxin inj, phenobarbital phen obarbital inj etc preparation.

•

They are used with various range like PEG 400, PEG 600 etc.

•

Glycerols an alcohol possessing three hydroxyl groups per molecule, is also used as a cosolvents with water for oral use.

Sr.No. Name

Properties

Remarks

1

Ethan hanol

-Miscible wit hwater -Antimicrobial Property

-Costly due to high excise duty

2.

Prop Propyl ylen enee Glyc Glycol ol

-sol -solve vent nt as well well as preservatives - miscible with water

-Oral Preparation -Hydrophilic ointments - injection of barbiturates,iodine

3.

Glycerol

-Colorless -Syrupy -Sweet taste -Hygroscopic

Use as -solvent -Preservative -Humectant -Use in throat paints, linctuses, syrups, Elixirs

4.

1,3 1,3 but butylen ylenee glyc glycol ol -Col Colour ourless less -Viscous -Miscible with water

- solvent for morphine injection

5.

Polyethylene glycol -colourless

-Used in lotion

6.

Sorbitol

-70% w/w used as vehicle

-white -miscible with water -sweet taste

4. Dimethylsulfoxide



•

This is highly polar compound and is thought to aid the penetration of drugs through the skin, used as a solvent for veterinary drugs, and as a permeation enhances for transdermal system.

5. Ethyl ether:

•

Widely used for the extraction of crude drugs.

• Not used internally •

Used as a cosolvent with alcohol in some collodion.

6. Liquid paraffin:

•

The oily nature makes its unplease so used externally.

•

It is used as a solvent fot the topical application of drugs in emulsion formulations.

•

It was widely used as the base for nasal drops.

7. Miscellaneous solvents:

•

Isopropyl myristate, isopropyl palmitate used in co smetics.

•

Dimethylformamide, dimethylacetamide use as solvent in veterinary preparation.

•

Xylene is present in some ear drops for human use to dissolve ear wax.

2. BUFFERS

•

These are materials which which when dissolved in a solvent will enable the solution to resist any changes in pH.

•

The choice of buffer depends on the pH and buffering capacity required.

•

It must be compatible with other excmipient and have a low toxicity.

•

Pharma Pharmaceu ceutic tical al buffer bufferss are carbona carbonates tes,, citrat citrates, es, glucon gluconate ates, s, lactat lactates, es, phosphat phosphates es or tartrates.

•

As the pH of body fluid is 7.4, products such as injections, eye drops and nasal drops should be buffered at this value to avoid irritation.

3. DENS DENSIT ITY Y MOD MODIF IFIE IERS RS



•

It is rarely necessary to control the density if solutions except when formulating spinal anesthetics.

•

Fluid present in cerebrospinal is isobaric in nature.

•

So, solution of lower density than cerebrospinal cause problem is hypobaric and with high density called hyperbaric..

•

So, the solution should be made isobaric with particular density.

4. ISOTO ISOTONI NICIT CITY Y MODIF MODIFIE IERS RS

•

Solution Solution for injection, injection, for applicatio application n to mucous membranes membranes are large volume solutions solutions for ophthalmic use should be made isotonic with tissue fluid to avoid pain and irritation.

•

Dextrose and sodium chloride are largely use to adjust the tonicity.

5. VISCO VISCOSIT SITY Y ENHA ENHANC NCEM EMEN ENT T

•

It may be difficult for aqueous based topical solutions to remain in place on the skin or in eyes for any significant time because of their low viscosity.

•

To counteract this effect, low concentrations of gelling agents can be used to increase the apparent viscosity of the product.

•

Ex: povidone, HPMC, HEC and carbomer.

6. REDUCI REDUCING NG AGEN AGENTS TS AND AND ANTI-O ANTI-OXIDA XIDANTS NTS

•

The decomposition of pharmaceutical products by oxidation can be controlled by the additio addition n of reduci reducing ng agents agents such such as sodium sodium metabi metabisul sulphit phitee or antiox antioxida idants nts such such as butylated butylated hydroxyani hydroxyanisole sole or butylated butylated hydroxytol hydroxytoluene, uene, butyrated butyrated hydroxyacet hydroxyacetate ate or pthalate.

7. PRES PRESER ERVA VATI TIVE VES S



•

In recent years, adequate preservation of liquid products has increased in importance.

•

Source of contaminations are raw materials, processing containers and equipments, the manufacturing environment, operators, packaging material etc.

•

An ideal preservative can be qualitatively meet the following criteria

•

1. It must be effective against a broad spectrum of microorganisms.

•

2. It must be nontoxic, nonsensitizing, adequately soluble, compatible and acceptable with respect to taste and odor.

Sr . No

Class

Usual concentration (%)

1

ACIDIC Phenol Chlorocresol O-phenyl phenol Alkyl esters of parahydroxybenzoic acid Benzoic acid and its salts Boric acid and its salts Sorbic acid and its salts

0.2-0.5 0.05-0.1 0.005-0.01 0.001-0.2 0.1-0.3 0.5-1.0 0.05-0.2

2

NEUTRAL Chlorobutanol Benzyk alcohol B- phenylethyl alcohol

0.5 1.0 0.2-1.0

3

MERCURIAL Thimerosal Phenylmercuric acetate and nitrate Nitromersol

0.001-0.1 0.002-0.005 0.001-0.02

4

QUARTERN ARY COMPOUNDS Benzalkonium chloride Cetylpyridinium chloride

0.004-0.02 0.01-0.02

AMMONIUM

8. SWEE SWEETE TENI NING NG AGE AGENT NTS: S: 1. Sucrose



2. Sorbit Sorbitol ol (Hal (Halff Sweet Sweet than than Sucr Sucrose ose)) 3. Glycerin 4. Honey 5. Saccha Saccharin rin Sodium Sodium (300-5 (300-550 50 time times) s) 6. Cyclam Cyclametae etaess (30 times times sweet sweeter er than than sucrose sucrose)) 7. Aspartame

•

Low molecul molecular ar weight weight carbohy carbohydra drates tes like like sucros sucrosee are tradit tradition ionall ally y used used sweeti sweetinin ning g agents.

•

Sucrose has advantage of being colourless, very soluble in water, stable over a pH range of about 4-8 and increases the viscosity of fluids.

•

Only six artificial flavours are permitted for oral use within the European union are sodium or calcium salt of saccharin, aspartame comounds like L- aspartic acid and L phenylalanine, acesulfame potassium, thaumatin, sodium cyclamide and neohesperidine.

8. FLAV FLAVOU OURI RING NG AGE AGENT NTS: S: 

The use of flavour is actually a composite sensation of taste, touch, smell, sound and heat.



All above mensioned factors involve a combination of physiochemical and psychological action influence the sensitivity of substances.



There are simply four types of tastes

•

- Sweet

•

- Sour

•

- Salty

•

-Bitter



And some others are a combination of the above.



Similarly there are seven basic odours like



•

- Ethereal

•

- Floral

- camphoraceous

- Musky

-Pepperminty

-Pungent

-Putrid

Classification of flavouring agents: Two Types: 1. Natural and 2. Synthetic 1. Natural a. Fruits (Sweet, Sur and Astringent) -Citrus Fruits (Orange, Lemon) -Rasberry and Strawberries b. Seeds (Vanilla, Anise, Nutmeg) c. Buds/Flawers -Orange flower water - clove blossoms

d. Leaves -Camomile -Thyme e. Roots - Glycyrrhiza f. Barks/Stems - White pine -Cinnamon -Wild Cherry Bark g. Woods - Quassia h. Gums - Gum arabic - Gum Tragacanth

- Rosemary

2. Synthetics SR . NO. SYNTHETICS

NATURE OF FLAVOUR

1.

Benzaldehyde

Bitter Almond, Cherry pits

2.

Decyl Aldehyde

Citrus Flavours (Orange, Lemon)

3.

Cinnamic aldehyde Cinnamon type



4. 5. 6. 7.

Ionones Ethy Ethyll acet aceto o acet acetat atee Terpene Alcohols Ethylmalonate

Berry type flavours Cher Cherry ry flavo flavor r Rasberry, strawberry and pineapple Wine like flavour

Sr No Taste of product

Suitable masking flavour

1

Sour

Citrus flavour

2

Salty

Butterscotch, apple and citrus

3

Bitter

Chocolate, mint, raberry

4

Sweet

Fruit, Berry, Vanilla

10. Coloring agents

1. Natural Colouring Agents (A) Plants: 

Many plants contain colouring agents which may be extracted. And used as colorant.



Some Examples are:

•

a. Chlorophyll-green

• b. Annatto seeds-yellow to orange •

c. Carots-yellows



•

d. Madder Plant-Reddish Yellow

•

e. Indigo-Blue

•

f. Saffron-Yellow

•

g. Caramel- Burnt Sugar (B) Animal:

a. Cochineal: 



It is an alkali alkaline ne soluti solution on of the solubl solublee Colour Colouring ing princi principle pless carami caraminic nic acid acid of chochineal insects preserved by the addition of glyccerin. It is very dark purplish red liquid.

• b. Carmine:  

It is the aluminium lack of the colouring principle obtained from cochineal. It gives red colour to aqueous solution.

(C) Minerals: 

Mineral colours are termed pigments.



They are used to colour lotions, cosmetics co smetics and other preparation for external application.



As they are toxic, their use for internal preparation is forbidden.



Ex: Red ferric oxide



Yellow Ferric Dioxide



Titanium dioxide



Carbon Black.

2. Synthetic colouring agents 

The synthe synthetic tic colours colours are coaltar coaltar dyes, dyes, because because many many of them them are produc produced ed from from substance obtained from coal-tar.



The certified colours are classified into three groups:





Group I- F.D. and C. Colours used in foods, drugs and cosmetics.



Groups II- The D. and C. Colour used in drug and Cosmetics.



Group III- The External D. and C. Colour.



Any color found in any of these lists is spoken as permitted color like



Blue- Brilliant Blue, Indigo Carmine



Green- Fast green, Guinea Green



Violet- Wood Violet



Red- Amaranth, Erythrosin Scarlet red



Yellow- Tartrazine, Sunset Yellow

MANUFACTURING OF LIQUID DOSAGE FORMS:

WASHING STO

R 1. Raw material • •

The raw material used for the manufacturing of pharmaceutical are as per the standard specification. These These specif specifica icati tions ons should should assure assure identi identity, ty, purity purity,, unifor uniformit mity y and freedom freedom from from excessive microbial contamination.



• • • • •

Inco Incomi ming ng raw raw mate materi rial al shoul should d be thor thorou ough ghly ly test tested ed befo before re they they are are rele releas ased ed for for manufacturing. Additional processing may be necessary to obtained a desirable property, such as particle size or microbial contamination. Aside from the active ingredient, water is usually the most important constituent in a liquid products. It should meet the USP requirement for purified water and obtained by ion exchange or distillation. To prevent prevent microb microbial ial growth growth,, variou variouss techni techniques ques employ employed ed includ includee revers reversee osmosi osmosiss purification, U.V. sterilization, membrane filtration and constant circulation in piping systems that have no dead ends where microorganism grow.

2. Equipment •

•

• • • • •

The type of equipment used in the manufacture of oral solutions consists of mixing tanks equipped with a means of agitation, measuring devices for large and small amounts of solids and liquids, and a filtration system for the final polishing and or sterilization of the solution. All equipment must be thoroughly cleaned and sanitized before use. Appropr Appropriat iatee disinf disinfect ectant ants, s, includ includee dilute dilute soluti solutions ons of hydrog hydrogen en peroxi peroxide, de, phenol phenol derivatives and peracetic acid. Equipm Equipment ent and lines lines can be steril sterilize ized d by such such method methodss as alcoho alcohol, l, boili boiling ng water, water, autoclaving, steam or dry heat. Tanks are usually constructed of polished stainless steel and are usually jacketed to allow for heating or cooling of the contents. They can be obtained in a number of different sizes. If tanks are use for the compounding of the bulk liquid, they have a built in agitation system. Water condensate that forms on the lid of mixing tanks and during heating and chilling steps may provide a source of microbial contamination co ntamination that is often overlloked.

•

The liquid is ten clarified by cycling through a filtration system and the polished solution is stored in an adjacent tank until released by the Q.C. dept. • The liquid may then be transported to the filling line, either manually by filling into portable transport tanks or by pumping through suitable liquid delivery system. • The distance should be less to prevent microbial growth. • A major source of microbial contamination is often the processing operators.



•

Head covering should be worn all times while gloves and face mask should be worn as necessary.

3. Compounding procedure • • • • • •

Dilute Dilute solutions solutions prepared from rapidly rapidly dissolving dissolving materials, materials, are simply simply prepared prepared by charging the solute to the solvent and agitating until the solution is homogeneous. When When more more conce concent ntrat rated ed solu soluti tion onss are are being being made, made, or when when the the solu solute te is slow slowly ly dissolving, it may be advantageous to employ heat. Ex: Syrup. During compounding the less dissolved substance should be preheated and than use. All the Excipient should be added step by step in the preparation. Dyes and flavours should be also predissolved. The active medicaments should be dissolved at last.

4. Filling and Packaging •

• • • • • • • •

The specific method used for filling a pharmaceutical liquid varies greatly depending on the characteristics of liquid, the type of package into which the liquid is placed and the required production output. Three basic filling methods methods like gravimetric, volumetric volumetric and constant level are used for most liquid filling operations. Gravimetric filling works on the principle of gravitational force but rarely used. Volumetric filling is usually accomplished by positive displacement piston action. Each filling station is is equipped with a measuring piston and cylinder The fill accuracy is controlled by the close tolerances to which the pistons and cylinders are manufactured. The fill amount is measured by the stoke of piston, which on all machine can be varied to a limited degree. This type of device is capable of accuracy to within fraction of milliliter. Volumetric filling encountered a problem when the product is viscous or less dense.

BOTTLE FILLING MACHINE



PACKING CONVEYOR BELT • • • • • • • •

Constant level filling uses the container as the means for controlling the fill of each unit. The fill amount is varied by adjusting the height to which the container is filled. The latest filling machine used is called vacu um filling. To fill by vacuum, a seal must be made between the filling head and the container, which causes the liquid to flow from the bulk liquid tank to the container. A vacuum is then developed within the container which causes the liquid to flow from the bulk liquid tank to the container. Generally glass or plastic materials are used as a packaging material for the liquid dosage forms. Before using glass or plastic materials, They should not react with the excipient or drug. Packaging material should be compatible with w ith the solution.

EVALUATION PARAMETERS • Appearance • pH • Viscosity • Specific gravity • Microbial count • Leakage test for filled bottle (By using plastic vacuum dessicator) • Check the cap sealing • Fill volume determination • Particulate matter testing • Water vapour permeability test • Stress test



SUSPENSION • •

Pharmaceutical suspensions may be defined as coarse dispersions in which insoluble solids are suspended in a liquid medium. Stokes relation describe the settling rate of particle in suspension, V= D2(ρ2 –ρ1) g 18η



Properties of an Ideal Suspension are: •Uniform dispersion •Palatable •Pleasing odor and color •No grittiness •Easy to pour yet not watery •No cap-lock •Temperature insensitive •Particles should settle slowly •Formulation should allow the easy redispersionof sedimentedparticles •A flocculated suspension is desirable than a deflloculatedsuspension •A suspension should not be too viscous to reduce the sedimentation rate



⇔

SUSPENSION FORMULATION

1. Aggregated systems 2. dispersed systems 3.Rheologic considerations 4.Formulation Adjuvant 5.Preparative techniques · Components

Function

API

Active drug substances

Wetting agents

They are added to disperse solids in continuous liquid phase.

Flocculating agents

They are added to floc the drug particles

Thickeners

They are added to increase the viscosity of suspension.



Buffers They are added to stabilize the suspension to a desired pH range. and pH adjusting agents Osmotic agents They are added to adjust osmotic pressure comparable to biological fluid. Colori Coloring ng agents agents Preservatives

They They are added added to impart impart desire desired d color color to suspens suspension ion and improv improvee elegance. They are added to prevent microbial growth.

External liquid vehicle They are added to construct structure structure of the final suspension.

Packaging and Storage of Suspensions: 1)Should be packaged in wide mouth containers having adequate air space above the liquid. 2) Should be stored in tight containers protected from: •freezing. •excessive heat & light. 3) Label: "Shake Before Use" to ensure uniform distribution of solid particles and thereby uniform and proper dosage.

Eval Evalua uati tion on of susp suspen ensi sion on

• • • • • • • • •

(Rea (Read d from from Lach Lachma mann nn for for de deta tail il))

Sedimentation volume Particle size change Electrokinetic method/Zeta Potential measurement Appearance Color, odor and taste Redispersibility and Centrifugation tests Rheological measurement Stress test pH Freeze-Thaw temperature cycling



1. Sedimentation volume

Examples of Pharmaceutical Suspensions:

1. Antacid oral suspensions 2. Antibacterial oral suspension 3. Dry powders for oral suspension (antibiotic) 4. Analgesic oral suspension 5. Anthelmenticoral suspension 6. Anticonvulsant oral suspension 7. Antifungal oral suspension



EMULSION Definition: • • • •

“Emulsion is the biphasic liquid dosage forms in which two immiscible liquids are made miscible by using emulsifying agents. It contain one disperse phase and other is continuous phase. OR It is thermodynamically unstable system consisting of at least two immiscible liquid phases one of which is dispersed as globules (the dispersed phase) in the other liquid phase (the continuous phase) stabilized by presence p resence of emulsifying agent. Ex: Milk

• • Types of emulsion: 1. Oil in water water (O/W): (O/W): (Oral (Oral use) use) 2. Water Water in in Oil Oil (W/O) (W/O):: (Exte (Externa rnall use) use) 3. Micro Micro emulsi emulsion on (tran (transpa sparen rentt emulsio emulsion): n):  The property of transparency is due to the small particle size of the dispersed phase (0.05 microns). 4. Double Double Emuls Emulsion ion (Mul (Multip tiple le emulsi emulsion) on)::  O/W/O  W/O/W It can be prepared prepared by proper selection selection of H.L.B. values.  5. Nano Emulsion

Determination of emulsion type Test

Observation

Comments

1. Dilu Diluti tion on Te Test st Emulsion can be diluted with only Useful for (Miscibility) external phase emulsions only


liquid


o/w emulsion can be diluted with water.

Test 2. Dye Te Test (Staining)

w/o emulsion can be diluted with oil.

Observation

Comments

Water soluble solid dye (amaranth) shows color only with O/W emulsion, while sudan-III or Scarlet red Dyes readily tint a W/O emulsion.

May fail if ionic emulgents are present.

CoCl2 Filter Filter paper impregnated with CoCl 2 dried (Blue) changed to pink when O/W emulsion is added. Paper 3.

4. Fluorescence Test

Many oils when exposed to U.V. light fluorescence.

Not always applicable

O/W exhibit dot patter. W/O entire field fluoresces. 5. Direction of creaming test

A. If emulsi emulsion on creams creams are are upwar upward d the emulsion is O/W type. B. If the emul emulsion sion cream creamss are downw downward ard it is W/O type emulsion.

6. Conductivity Test

Water conduct conduct an electric current current wile oils do not. Fails in non ionic O/W emulsion



PREPRATION OF EMULSION 1. Dry Gum Method Method (Contine (Continental ntal Method) Method)

• • •

This method is also called as 1:2:4 or 4,2,1, these figure represents the proportion of oils, water and gum. Oil Water Gu m 4 2 1 This ratio is used for the preparation of primary emulsion.

Emul LIQUID DOSAGE FORMS RAJGOR


2. Wet Gum Method: (English or American Method) • • • • • •

In this this method, method, the the proporti proportion on of gum, water water and and oil remains remains same same as that of dry gum, but but the procedure is differ. A mucilage mucilage is first first form form by triturati triturating ng the gum gum with with water.(1p water.(1parts arts gum and 2 parts parts water). water). Trit Tritur urat atee unti untill ll a musi musila lage ge is is for forme med. d. The oil oil is then then added added in small small propor proportio tions ns with with continu continuous ous trit tritura uratio tion. n. After the primary primary emulsion emulsion has has been formed, formed, the triturati trituration on should should be continu continuous ous for for five five minutes before it is diluted with water. This This method method is is slowe slowerr and and not reliab reliable le as dry gum method. method.

3. Bottle Method: •

It is modif modifica icatio tion n of dry gum mthod. mthod.1 1 parts parts of acacia acacia is mixed mixed with with 2 parts of volat volatile ile oil oil by shaking in a bottle. • Two parts parts of water are added added all at once and shaking shaking contin continued, ued, until until emulsi emulsion on is formed. formed. • The rema remaini ining ng water water is is then then added added in in small small port portion ionss with with shakin shaking. g. • This This method method is suitab suitable le for vola volatil tilee oils and and non-vi non-visco scous us oils. oils.

Types of oils Examples

Qty for pr primary em emulsion Oil

Water

Gum

1. Fixed oi oils

Almond oi oil Arachis oil Castor oil Cod liver oil

4

2

1

2. Mineral oil

Liquid paraffin

3

2

1

3. Vola Volati tile le oil oil

Turp Turpen enti tine ne oil oil Cinnamon Peppermint

2

2

1

4. Oleo-resin

Male fern Extract

1

2

1

FORMULATION OF EMULSION/ MANUFACTURING OF EMULSION LIQUID DOSAGE FORMS RAJGOR


• For the formulation of emulsion, both the physical and chemical parameters to be consider. • Physical Parameters. • 1. Heat • 2.Timing

Chemical parameters parameters (Read lachmann lachmann for detail) detail)

• Chemical stability LIQUID DOSAGE FORMS RAJGOR


• • • • • •

Safety Choice of lipid phase Choice of emulsifying agents Choice of surfactants Choice of antimicrobial preservatives choice of antioxidants EMULSIFYING AGENTS and SURFACTANT

ANTIMICROBIAL PRESERVATIVES Sr. No

Class


Usual concentration (%) PREPARED BY: MR. NARESH

1

ACIDIC Phenol Chlorocresol O-phenyl phenol Alkyl esters of parahydroxybenzoic acid Benzoic acid and its salts Boric acid and its salts Sorbic acid and its salts

0.2-0.5 0.05-0.1 0.005-0.01 0.001-0.2 0.1-0.3 0.5-1.0 0.05-0.2

2

NEUTRAL Chlorobutanol Benzyk alcohol B- phenylethyl alcohol

0.5 1.0 0.2-1.0

3

MERCURIAL Thimerosal Phenylmercuric acetate and nitrate Nitromersol

0.001-0.1 0.002-0.005 0.001-0.02

4

QUARTERN ARY AMMONIUM COMPOUNDS Benzalkonium chloride Cetylpyridinium chloride

0.004-0.02 0.01-0.02

LIST OF ANTIOXIDENTS

• • • • • • • •

Gallic acid Propyl gallate Ascorbic acid Ascorbyl palmitate Sulfites L- Tocopherol BHA BHT

⇔

EVALUATION/STABILITY OF EMULSION Creaming

•



•

Flocculation

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Coalescence

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Pha Phase separation

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Viscosity

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Elec Electr trop opho hore reti ticc prope propert rtie iess

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Part Partic icle le siz sizee numb number er ana analy lysi siss

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Stress Stress condit condition ion like like aging aging and and temper temperatu ature, re, Centr Centrifu ifugat gation ion







MICROEMULSIONS ”Microemulsions are thermodynamically stable , optically transparent , isotropic dispersions of aqueous and hydrocarbon liquids stabilized by an inter facial film of surfactant molecules.” Microemulsion sare monodispersed spherical droplets (diameter <100nm) of water in oil or oil in water, depending on the nature of the surfactant.



Microemulsions are formed because ... • The penalty for the apparent increase in free energy is compensated by the lowering of IFT to ultra low levels (10-2 – 10-3mN/m)



• The work done in lowering IFT is achieved through a gain in system entropy ΔS due to the creation of a large number of sub-micron sized droplets • All this occurs when at molecular levels, surfactants form the most condensed interfacial film between oil and water.

MULTIPLE EMULSION •These are known as double emulsion •These are more complex systems, as the drops of the dispersed phase contain even smaller dispersed droplets, in most vases identical with the continuous phase, but separated physically from from the the cont contin inuo uous us phas phase. e. Thes Thesee are are know known n as “Emu “Emuls lsio ion n of Emul Emulsi sion on mean meansm smul ulti tipl plee emulsion”. •Based on nature of the dispersed medium multiple emulsion classified as follows 1.O/W/O emulsion 2.W/O/W emulsion

1. O/W/O emulsion:

In O/W/O system , an aqueous phase separates internal and external phase. It is a system in which water droplets are surrounded in oil phase ,which in true encloses one or more oil droplets.



2. W/O/W emulsion:

In W/O/W sytem, an organic phase separates internal and external phase. it is a system in which oil droplets may be surrounded by aqueous phase, which in turn one or several water droplets. Advantages

•Remarkable degree of biocompatibility •Complete biodegradability •Hydrophilic and hydrophobic drugs can be entrapped •Protection from inactivation by the endogenous factors •Increase in drug dosing interval •Taste masking of bitter drugs

Disadvantages

•Short life •packed in a plastic or glass container so, care should be taken during handling and storage.

Preparation Methods of preparations:-

Sonication



Agitation

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Phase inversion



•Great care must be taken during preparation of final system. •However, because vigroustreatments employed for preparations of primary emulsions will often break the primary emulsion, this result in loss of phase identity. •Two different surfactants of different nature are used. •One surfactant stabilizes the lipophilicemulsion, while other stabilizes the hydrophilic emulsion. •Emulsifiers get absorbed at the surface of droplets during formation of emulsion and prevent them from drawing close enough to aggregate. Multiple emulsions are preapered by various methods

1)Two step emulsification



2)Modified two step emulsification 3)Phase inversion 4)Membrane emusificationmethod 5)Micro channel emulsification Evaluation of multiple emulsion

1)Characterization 2)Average globule size and size distribution 3)Number of globules 4)Percentage of drug entrapment 5)Rheological evaluation 6)Zeta potential 7)In-vitro stability studies 8)In-vitro drug release Application of multiple emulsions 1)Controlled and sustained drug delivery

2)Drug targeting 3)Vaccine adjuvant 4)Enzyme immobilizatoin BRIEF INTRODUCTION OF EXTRACT, TINCTURE AND INFUSION EXTRACT •

An extract is a substance made by extracting a part of a raw material, often by using a solvent such as ethanol or water.

•

Extracts are similar products that are then concentrated b y evaporations.

•

Extraction involves the separation of active portion of plant or animal tissues from the

inactive components through the use of selective solvent which are known as Galenica.

•

A medici medicinal nal prepar preparati ation on compos composed ed mainly mainly herbal herbal or vegetab vegetable le matter matter prepar prepared ed by extraction of crude vegetable drugs with suitablesolvents.

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Menstum:Solvent used for extraction( eg, water alcohol, ether)

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Marc:The innertfibrous and other insoluble materials remaining after extraction.

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Extracts are preparation of liquid( liquid extractaand tinctures), semisolid(soft extracts)

or solid consistancyobtain from herbal drugs or animal matter.

•

Liquid extracts:



•

They They are are liqu liquid id prep prepar arat atio ions ns of which which,, in gener general al,, one part part by mass mass or volum volumee is equivalent to 1 part by mass of the dry herbaldrug or animal.

•

Liquid extracts are prepared by using ethanol of a suitable concentration or water to extract herbal drug or animal matter, or by dissolving a soft or dry extract of herbal drug or animal matter in either ethanol of a suitable concentration or water.

• • • •

Soft extract: They are semisolid preparation obtained by evaporation of the solvent use for extraction. Dry extract: They They are are soli solid d prepa prepara rati tion onss obtai obtained ned by evapo evapora rati tion on of the the solv solvent ent use use for for thei their r

production and have lod or water content of not more than 5%m/m.

INFUSION

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They are dilute solutions containing readily soluble constituents of crude drugs.

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It involves pouring water over the drugs and then allowing it to keep in contact with water.(15 min) with stirring and finally filtering of the liquid.

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Fresh infusion is prepared by macerating the drug for a shorperiod of time with cold or hot water.

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Concentrated infusions are prepared by modified percolation and maceration process.

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Infusion pot

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Cons Consis istt of cover covered ed jar( jar( made made up of eart earthe henw nwar aree stai stainl nles esss-st stil ill, l, cera cerami mic, c, glas glass, s, porcelain)which is fitted at certain height a perforated tray upon which the crude may be allowed to rest in water being pour over it.

•

The drug may be enclosed loosely in a small muslin bag and suspended in the jar at a height were it will be just covered by the liquid.

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The perforated tray or muslin bag confers to advantages.

•

1.Comp 1.Complet letee extrac extractio tion n becaus becausee when when the menstr menstrums umsurr urroun oundin ding g the drug drug becomes becomes saturated it will sinks to the bottoms due to it’s increased density and another amount of fresh menstrumdisplaced it leading to circulatory diffusion.

•

2.At the end of infusion time, the drug can be lifted out, leaving clear liquid which can be strained quickly.

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Fresh (Dilute) Infusion



•

A fresh fresh infusi infusion on is an aqueous aqueous soluti solution on of active active consti constitue tuents nts of a vegeta vegetable ble drug drug prepared by the process of infusion.

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Water is used as menstrum.

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Fresh infusion should be used within 12 hours after it’s preparation because it gets spoiled due to bacterial and fungal growth.

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E.g. Fresh infusion of quassia

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Concentrated (stock) infusion

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Prepared by double or triple maceration.

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Eight times stronger than fresh infusion.

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Alcohol in the concentration of 20-25% is used

• • • • •

DECOCTION In this process, the crude drug is boiled in a specified volumof water for a defined time(10 min); it is then cooled and strained or filtered. This procedure is suitable for extracting water soluble, heat stable constituents and drugs of hard and woody nature. This This proces processs is typica typically lly used used in prepar preparati ation on of ayurve ayurvedic dicext extract ractss called called “quath “quath”” or “kawath”. The starting ratio of crude drug to water is fixed, e.g. 1:4 or 1:16, the volume is then brought down to ¼ it’s original volume by boiling b oiling during the extraction procedure. Then the concentrated extract it filtered and use as such for processed further. Infusion

1-Plant 2-Menstrum 3-Procedure 4-time 5-adjustment of final volume 6-appartus 7-storage

Decoction

Soft structure Cold or hot water Infusing the drug with menstrum Calculated as soon as water is added to drug No adjustment Earthenware pot Use within 12 hrs

Hard woody structure Hot water Boiling the drug with menstrum Calculated as soon as water begin to boil Adjustment required Ant covered apparatus Use fresh

TINCTURES •

A tincture is an alcoholic extract (e.g. of leaves or other plant material) or solution of a non-volatile substance (e.g. of iodine, mercurochrome). To qualify as a tincture, the alcoholic extract is to have an ethanol percentage of at least 40-60%.

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Tinctures are alcoholic extracts of drugs but are relatively weak compared with extracts.

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General method of preparation



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Herbs are put in a jar and a spirit of 40% pure ethanol is added.

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The jar is left to stand for 2–3 weeks, shaken occasionally, in order to maximize the concentration of the solution.

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To make a more precise tincture, more extensive measuring can be done by combining 1 part herbs with a water-ethanol mixture of 2-10 parts, depending on the herb itself. With most tinctures, however, 1 part water at 5 parts ethanol is used.

Examples that were formerly common in medicine include:

•

Tincture of Cannabis sativa

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Tincture of Benzoin

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Tincture of cantharides

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Tincture of ferric citrochloride (a chelate of citric acid an d Iron(III) chloride)

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Tincture of green soap

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Tincture of iodine

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Tincture of opium



Liquid Dosage Forms

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