DOSAGE FORMS

LIQUID DOSAGE FORMS

Definition: A mixture is a liquid preparation intended for oral administration in which drug(s) is (are) dissolved, suspended or dispersed in a suitable vehicle and generally several dose are contained in a bottle.

Characteristics

(i)          Liquid preparation

(ii)        Oral administration

(iii)       May be monophasic (solution)

Biphasic (suspension)

(iv)      Multiple dose preparation

N.B.

Mixture	Draught
Multiple dose preparation.	Single dose liquid.
Mixture	Solution
·         May be monophasic or biphasic. ·         For internal (oral) purpose ony.	·         Monophasic ·         For internal or external use.

Classification:

Mixtures may be classified as follows:

1.       Simple mixture-containing soluble solids.

2.       Mixture containing diffusible solids.

3.       Mixture containing indiffusible solids.

4.       Mixture containing precipitate forming liquids.

5.       Mixture containing colloidal particles.

1.       Simple mixtures

Definition A simple mixture is one which contains only soluble ingredients.

Examples: (i)         Ferric ammonium citrate mixture

                                Ferric ammonium citrate

                                Chloroform water

                     (ii)      Ferrous sulphate

                                Ascorbic acid

                                Orange syrup

                                Chloroform water

Method of dispensing

(a)     All the solids (soluble in water) are dissolved in 3/4^th volume of the vehicle.

(b)     The solution is passed through cotton wool to filter out any foreign particle. The cotton wool is washed with small volume of vehicle.

(c)     Any liquid ingredients are added.

(d)     Volatile oils (if any) are added.

(e)     More vehicle is added to make up the volume.

(f)      The mixture is transferred to a bottle, surface is polished (to remove finger print). Label is attached and the bottle is wrapped and dispensed.

2.       Mixtures containing diffusible solids

Diffusible solids are those substances which do not dissolve in water, but on shaking they can be mixed with it and remain evenly distributed throughout the liquid for sufficiently long time allowing uniform distribution of the drug in each dose. However, on standing the insoluble solids settle at the bottom of he bottle which require shaking of the bottle each time whenever a dose is to be measured.

Example

Preparation containing the following diffusible solids:

Bismuth carbonate             Magensium carbonate

Light kaolin                          Magnesium trisilicate

Magnesium oxide                Rhubarb powder

Method of dispensing

(a)     Diffusible solids are finely powdered with a mortar and pestle. They are mixed thoroughly.

(b)     3/4^th volume os vehicle is separated. From that portion small amount of vehicle is mixed and triturated to form a smooth paste. Remainder of the vehicle is added to that paste.

(c)     The mixture is passed through a muslin cloth to remove any foreign particles.

(d)     Liquid ingredients are added.

(e)     Volume is made up with the vehicle.

(f)      Mixture is transferred to a bottle, polished, labeled and dispensed. Label must contain “Shake the bottle before use”.

3.       Mixtures containing indiffusible solids

Indiffusible solids are those substances which do not dissolve in water and they do not remain evenly distributed throughout the vehicle, even after shaking they immediately settle at the bottom – therefore, it becomes difficult to measure the dose.

Example

Preparations containing:    Aspirin                                   Aromatic chalk powder

                                                Chalk powder                       Phenobarbitone

                                                Succinylsulphathiazole      Sulfadimidine

Principle

To reduce the settling of particles the viscosity of the mixture is increased by adding some thickening agents like gum acacia, tragacanth or compound targacanth powder or their mucilage.

Method of dispensing

(a)     The indiffusible powders are triturated with a mortar and pestle to make them fine powder.

(b)     Any diffusible or soluble powder substances are mixed with suspending agent (power). This powder mixture is triturated with a small amount of vehicle to form a smooth paste; then the remaining amount (3/4^th of the vehicle) is added and mixed.

(c)     Strained through a muslin cloth to remove any foreign particle.

(d)     Requied volume is made up with the rest amount of vehicle.

(e)     The mixture is transferred to bottle, labeled and polished. The label must contain “Shake well before use”.

4.       Mixture containing precipitate forming liquid

Some liquid preparations contain resinous matter that is precipitated on addition to water.

Examples

Preparations containing any of the following preparations:

Compound Benzoin Tincture

Benzoin Tincture

Lobelia Ethereal Tincture

Myrrh Tincture

Tolu Tincture

Principle

This preparations when mixed with water, resins precipitate out and adheres to the side of the container and forms non-dispersible clots in the liquid. To prevent this a protective colloid is dispersed in the vehicle before the tincture is added.

Tragacanth mucilage or compound tragacanth powder are suitable.

As the resin particles are precipitated the hydrocolloids (acacia, tragacanth and starch) are adsorbed over their surface conferring hydrophilic properties and preventing aggregation into clots.

Method using compound tragacanth powder

This method is chosen when the vehicle is not water or chloroform water. [N.B to avoid displacement of part of medicinally active vehicle by the mucilage]

(a)     Any insoluble solid is powdered and mixed thoroughly with the gum (powder).

(b)     The powder mixture is triturated withi small amount of vehicle to form a smooth cream and diluted gradually to about ½ the final volume.

(c)     The precipitate forming liquid is measured in a dry measuring cylinder and pour in a slow stream into the center of the suspension, stirred rapidly.

(d)     If electrolytes are present they can be added only after the resin has been protected (otherwise heavy clot will occur).

(i)       The electrolyte are diluted with about ½ of the remaining vehicle.

(ii)     The electrolyte is added slowly with constant stirring to reduce local concentration.

(e)     Volume is made up with the rest of the vehicle.

Method using tragacanth mucilage

This method is chosen when the vehicle is water or chloroform water.

(i)    To mucilage is mixed with an equal volume of vehicle in a beaker.

(ii)  The precipitate forming liquid is measured in a dry cylinder and poured slowly into the center of the mucilage with constant stirring.

(iii) Electrolyte is dissolved in ½ of the remaining vehicle and added slowly in the mixture with constant stirring.

 Example

Rx          

                Lobelia ethereal tincture                    – precipitate forming liquid

                Tragacanth mucilage                          – mucilage, viscosity building agents

                Potassium iodide                 – electrolyte

                Stramonium tincture

                Chloroform water D.S.                       Vehicle

                Water                                                    

Method

(i)                   Chloroform water D.S. + equal volume of water ® Chloroform Water (Vehicle)

(ii)                 Tragacanth mucilage + equal volume of vehicle ® Mixture 1

(iii)                Lobelia ethereal tincture + Stramonium tincture are poured slowly in mixture –1

(iv)               Potassium iodide + ½ of the remaining vehicle ® Solution-1

(v)                 Solution-1 is poured slowly in Mixture-1 with constant stirring.

(vi)               Vehicle is added to make up to the volume. The mixture is transferred in a bottle, labeled, polished.

5. Mixture containing colloidal particle

The particles are insoluble, but are in colloidal range hence, remain stable in suspension.

Example

Magnesium hydroxide mixture (Milk of magnesia)

(a)     Method: By precipitation

A solution of NaOH is added to a solution of magnesium sulfate. Precipitate of magnesium hydroxide is washed, and the allowed to stand. The clear supernatant liquid is decanted to remove SO₄^2–.

MgSO₄  +  2NaOH   =  Mg(OH)₂ ¯  +  Na₂SO₄.

This suspension sediments quickly but can be easily redispersed by shaking.

(b)     Method: By hydration of MgO

In presence of water magnesium oxide becomes hydrated to produce magnesium hydroxide.

MgO  +  2H₂O  =  Mg(OH)2¯ 

This method produces a viscous and unpourable suspension on keeping.

c) Method : Precipitation and hydration

(i)       A solution of NaOH is triturated with light magnesium oxide to form a smooth cream.

(ii)     The cream is diluted and added slowly to a stirred solution of magnesium sulphate.

(iii)    After the Mg(OH)₂ has settled the supernatant liauid is decanted and the precipitation washed with purified water unless if is virtually free from SO₄^2–.

(iv)   The precipitation is then mixed with purified water, chlroform water is added to give a final concentration of 0.25% v/w. The preparation is adjusted to final volume.

EYE DROP

Definition

Eye drops are sterile aqueous or oily solutions or suspensions for instillation in the eye. They are applied into the cul-de-sac (i.e. the space between the eye ball and eye lid).

Essential characteristics

(i)                   They should be sterile.

(ii)                 They should be iso-osmotic with lachrymal secretions; i.e. the eye drops are iso-osmotic with 0.9%w/v sodium chloride solution.

(iii)                They should have almost neutral pH (pH 7.4).

(iv)               They should be free from foreign particles, fibres and filaments.

(v)                 They should be preserved with a suitable bactericide.

(vi)               They should remain stable during its storage.

Ingredients

(i) Vehicle:                             Purified water

(ii) Antimicrobial agents or preservatives:     

(a)     Phenylmercuric acetate (PMA)                 –              0.002%w/v

(b)     Phenylmercuric nitrate (PMN) –              0.002%w/v

(c)     Benzalkonium chloride (BAC) –              0.01%w/v

(d)     Chlorhexidine acetate                                –              0.01%w/v

(e)     Chlorbutol                                                     –              0.5%w/v

(f)      Thiomersal                                                    –              0.1%w/v

(iii) Active ingredients:

                Water soluble drugs:           – Chloramphenicol, Ciprofloxacin, Gentamicin, Pilocarpine, Atropine

                Water insoluble drugs         – Hydrocortisone acetate

(iv) Viscosity building agents

                They are used in some special eye-drops for prolonged action of the drug;

                e.g.          Hydroxy propyl methyl cellulose (HPMC or Hypermellose)

                                Polyvinyl alcohol (PVA)

 

Procedure

Preparation of eye-drops consists of 4 – stages:

(i)       Preparation of bactericidal and fungicidal vehicles.

(ii)     Solution of the medicament(s) *(i.e. active ingredients) and if appropriate the adjuncts.

(iii)    Clarification

(iv)   Sterilization

Step-I: Preparation of vehicle

The preservative of choice is dissolved in purified water in the prescribed concentration.

Step-II: Solution of medicament(s) and adjuvants

All the medicaments and adjuvants are dissolved in the antimicrobial solutions to form a stabel mixture.

Step-III: Clarification

To remove any particulate matter the solution is clarified by passing through membrane filter having pore size of 0.8mm. The clarified solution is immediately transferred into final containers and sealed.

Step-IV: Sterilization

The eye-drops are sterilized by any one of the following sterilization methods:

(a)     Autoclaving

(b)     Heated at 98 to 100⁰C for 30 minutes.

(c)     Filtration through membrane filter (pore size 0.22mm)

Containers:

Eye drops are dispersed in neutral glass container. Either glass dropper or plastic cap-nozzle is used.

Labeling:

Eye drops should be labeled for external use only along with storage conditions to maintain full activity.

BIPHASIC LIQUID DOSAGE FORMS

Additives used in suspension dosage forms

1. Wetting agents: Some substances (e.g. sulfur, hydrocortisone etc.) are both insoluble in water and are poorly wetted by it. During preparation it is difficult to disperse the clumps and the foam produced on shaking. So wetting agents are used to reduce the interfacial tension between the solid particle and the vehicle and increase wetting of the particle.

e.g.    alcohol,  glycerin, propylene glycols, saponins of quillaia extract etc.

2. Flocculating agents: On standing for a long period the suspension may become difficult to redisperse on shaking. That time, controlled flocculation is required to prevent compact sediment, which is difficult to redisperse. Controlled flocculation can be produced either by,
(i) electrolytes (e.g. potassium citrate, phosphate salts), (ii) surfactants, and (iii) polymers.

3. Suspending agents / Thickening agents: Suspending agents are the substances, which are added to a suspension to increase the viscosity of the continuous phase so that the particles remain suspended for a sufficiently long time and it becomes easy to measure an accurate dose.

                                Due to increase in viscosity of the vehicle, the particles sediment at a much slower rate.

                                e.g. methylcellulose, hydroxy propyl methyl cellulose, sodium carboxymethylcellulose, bentonite, veegum etc.

4. Preservative: The aqueous vehicle may be liable for bacterial growth, so a preservative should be used. e.g. benzoic acid, sodium benzoate, methylparaben, proptlparaben etc. may be used.

5. Organoleptic additives: Colors, sweeteners and flavoring agents may be used to make the oral suspensions more palatable.

                                      Colors:             e.g. Amaranth, Tartrazine, Caramel, and other approved colors

                                      Sweeteners:     e.g. Sucrose

                                      Flavors:           e.g. Peppermint oil, Chocolate flavor, Raspberry syrup etc.

Additives used in emulsion dosage forms

A. Emulsifying agent: The emulsifying agents stabilize an emulsion by various mechanisms. They are also known as emulgents or emulsifiers.

Classification of emulsifiers:

Type	Examples	Mode of action
Hydrophilic colloids	Vegetable source Gum acacia Tragacanth Starch Animal source Wool fat Egg yolk Gelatin Synthetic Methyl cellulose, Hydroxyethyl cellulose,	(i)       They do not reduce the surface tension but forms a rigid film on the oil droplets and form a stable o/w emulsion - thus inhibits coalescence of droplets. (ii)     As an auxiliary emulsifier they increase the viscosity of the continuous phase so that movement of dispersed phase is reduced.
Finely divided solid particles	Colloidal clays: bentonite (aluminium silicate) veegum (magnesium aluminium silicate).	(i)       They tend to absorb at the oil-water-interface and form thick impenetrable films. (ii)     Sometimes increases the viscosity of water (as continuous phase).
Synthetic Surface Active Agents	Anionic Potassium stearate Sodium lauryl sulphate Cationic Cetyl trimethyl ammonium bromide (or cetrimide) Ampholytic N-dodecyl alanine Non-ionic Sorbitan mono-oleate (TWEEN) Polyoxyethylene sorbitan mono-oleate (Polysorbate)	(i)       They form a flexible film on the oil-water interface. (ii)     They lower interfacial tension markedly and this contribute to the stability of emulsion. (iii)    In case of ionic surfactants surface charge is developed, increasing the zeta-potential, which will cause repulsion between two adjacent globules.

Difference between emulsion and suspension

Emulsions	Suspensions
1.       They contain two immiscible liquids, one of which is dispensed as minute globules into the other. 2.       Emulsifying agents are required to make a stable emulsion. 3.       Emulsions are mainly of two types: o/w and w/o. 4.       During storage, freezing should be avoided as it may lead to cracking of emulsion.	1.       They contain finely divided solid particles dispersed in a liquid or semisolid vehicle. 2.       Suspending agents are required to make a stable suspension. 3.       Suspensions are mainly of two types: (i) Flocculated and (ii) De-flocculated. 4.       During storage, freezing should be avoided as it may lead to aggregation of suspended particles.