MULTIVITAMINSMULTIVITAMINS

Most popular dosage Most popular dosage formform

Liquid products for oral use, Liquid products for oral use, compressed tablets and capsulescompressed tablets and capsules

In developing the formula of any In developing the formula of any multivitamin we should want to multivitamin we should want to follow….follow….

The limits prescribed under drugs and The limits prescribed under drugs and cosmetics act and rulescosmetics act and rules

Stabilities of individual vitamin Stabilities of individual vitamin compounds and inter-vitamin compounds and inter-vitamin incompatibilitiesincompatibilities

Absorption profiles of vitaminsAbsorption profiles of vitamins Overage recommended by FIPOverage recommended by FIP

Limit prescribedLimit prescribed

STABILITIESSTABILITIES

VITAMIN-AVITAMIN-A It undergo addition reactions with It undergo addition reactions with

bisulphates and some solvents those bisulphates and some solvents those have double bond in its moleculehave double bond in its molecule

Exists in cis-trans isomersExists in cis-trans isomers When trans form changes to cis form When trans form changes to cis form

can reduce 65-70% of potency Without can reduce 65-70% of potency Without showing any change in chemical assayshowing any change in chemical assay

Oxidation is the most important Oxidation is the most important reasonreason

Air, peroxides and the presence Air, peroxides and the presence of catalysts etc…..of catalysts etc…..

Trace metal like Cu and Fe Trace metal like Cu and Fe promote oxidative degradationpromote oxidative degradation

Antioxidant agents like Antioxidant agents like nordihydroguaiaretic acid (NHGA) nordihydroguaiaretic acid (NHGA) and ascorbyl palmitate will and ascorbyl palmitate will prevent oxidationsprevent oxidations

Vitamin A stabilizers- N-N-Vitamin A stabilizers- N-N-diphenyl-p-phenylene diphenyl-p-phenylene diamine,malt extract,tocopherol diamine,malt extract,tocopherol and 2-6-di-tertiary butyl-4-methyl and 2-6-di-tertiary butyl-4-methyl phenol…phenol…

Readily degraded in aqueous Readily degraded in aqueous media than oily vehicles.media than oily vehicles.

Vit A alcohol has been reported to Vit A alcohol has been reported to be more stable than palmitate in be more stable than palmitate in aqueous dispersions containing aqueous dispersions containing polysorbate 80polysorbate 80

Vit A is thermostable.Vit A is thermostable. Uv radiations inactivate it.Uv radiations inactivate it. Most stable at pH 6.Most stable at pH 6. Decomposed in the presence of Decomposed in the presence of

vit-B in most vehiclesvit-B in most vehicles The best vehicle for combinations The best vehicle for combinations

of vit A,B1andC is of vit A,B1andC is SYRUP:GLYCERIN:WATERSYRUP:GLYCERIN:WATER

In 2:2:1 proportionsIn 2:2:1 proportions

Mixture of nordihydroguaiaretic Mixture of nordihydroguaiaretic acid and ascorbyl palmitate will acid and ascorbyl palmitate will be ideal antioxidant.be ideal antioxidant.

In oily solutions vit-A can be In oily solutions vit-A can be stabilized with0.05% of methyl or stabilized with0.05% of methyl or ethyl gallateethyl gallate

For combinations of A,E and C For combinations of A,E and C vitamins a mixture of NHGA and vitamins a mixture of NHGA and disodium EDTA may be better4disodium EDTA may be better4

VITAMIN –B1VITAMIN –B1

Sensitive to heat and oxidation in Sensitive to heat and oxidation in solutionsolution

In solid form, however, it is neither In solid form, however, it is neither thermostable nor liable oxidation. it thermostable nor liable oxidation. it is stable to light.is stable to light.

Optimum pH is 3.7-4Optimum pH is 3.7-4 At pH 2,100%stability for 6 months At pH 2,100%stability for 6 months

at 37at 37OOc has been reported.c has been reported.

Vit B1 is reported to interact with Vit B1 is reported to interact with panthothenic acid, panthothenic acid, cynocobalamine and riboflavincynocobalamine and riboflavin

In capsules and tablets calcium In capsules and tablets calcium panthothenate should be used.panthothenate should be used.

In solutions panthothenyl alcohol In solutions panthothenyl alcohol fares betterfares better

Ferric chloride helps to overcome Ferric chloride helps to overcome its incompatibility with vit B12 its incompatibility with vit B12 ratio which should not exceed ratio which should not exceed 120:1.120:1.

Riboflavin has been reported to Riboflavin has been reported to interact with thiamine in aqueous interact with thiamine in aqueous solutions producing precipitatessolutions producing precipitates

Riboflavin has been reported to Riboflavin has been reported to interact with thiamine in aqueous interact with thiamine in aqueous solutions producing precipitates solutions producing precipitates of thiochrome or chloroflavin in of thiochrome or chloroflavin in traces.traces.

This difficult can be entirely This difficult can be entirely eliminated by incorporation of eliminated by incorporation of ascorbic acid.ascorbic acid.

FOLIC ACIDFOLIC ACID

Folic acid dissolves in acids and Folic acid dissolves in acids and alkalies.alkalies.

Insoluble in water and alcohol.Insoluble in water and alcohol. Inactivated by heat and light.Inactivated by heat and light. It is also sensitive to oxidation It is also sensitive to oxidation

and reduction.and reduction.

It gets decomposed in the It gets decomposed in the presence of acids and alkalis.presence of acids and alkalis.

Folic stabilized in pH 6.5.Folic stabilized in pH 6.5. Inclusion of anti oxidants and Inclusion of anti oxidants and

storage in the absence of light storage in the absence of light and air.and air.

NICOTINIC ACIDNICOTINIC ACID

Appreciably soluble in water and Appreciably soluble in water and alcohol.alcohol.

It is stable to oxidation and heat It is stable to oxidation and heat and its solutions can be and its solutions can be autoclaved without loss of autoclaved without loss of activity.activity.

1% solution has a pH of about 3.1% solution has a pH of about 3.

PANTHOTHENIC ACIDPANTHOTHENIC ACID

It is a yellow viscous oil and is used only in It is a yellow viscous oil and is used only in the form of its calcium salts.the form of its calcium salts.

It is thermostable and destroyed by It is thermostable and destroyed by alkalies.alkalies.

Calcium salt is very stable and the Calcium salt is very stable and the stabilizing effect on calcium stabilizing effect on calcium panthothenate at pH 7-9.panthothenate at pH 7-9.

Panthothenyl alcohol is more preferred in Panthothenyl alcohol is more preferred in liquid preparations because of its liquid preparations because of its comparative insensitivity to hydrolysis.comparative insensitivity to hydrolysis.

BIOTINBIOTIN

Biotin is slightly soluble in water and Biotin is slightly soluble in water and alcoholalcohol

Readily soluble in alkalies.Readily soluble in alkalies. Stable in oxygen and heat in the pure Stable in oxygen and heat in the pure

crystalline form as well as in the form crystalline form as well as in the form of neutral or slightly acidic solution.of neutral or slightly acidic solution.

Solutions remain reasonably stable, Solutions remain reasonably stable, upto pH 9. upto pH 9.

Oxidizing agents decompose it.Oxidizing agents decompose it.

IONOSITOLIONOSITOL

Very stable, soluble in waterVery stable, soluble in water Slightly soluble in alcoholSlightly soluble in alcohol It is neutral.It is neutral.

RIBOFLAVINRIBOFLAVIN

Crystalline riboflavin is stable under Crystalline riboflavin is stable under normal conditions of storagenormal conditions of storage

Its solutions are subject to influence of Its solutions are subject to influence of light and alkaline substances.light and alkaline substances.

The degradation can be considerably The degradation can be considerably reduced by buffering water.reduced by buffering water.

Its solubility can be increased by Its solubility can be increased by solubilizing agents such as N-methyl- solubilizing agents such as N-methyl- acetamide, tryptophane, urethane, acetamide, tryptophane, urethane, Gallic acid-Gallic acid-

Propylene glycol etc….Propylene glycol etc…. Riboflavin phosphate is 100 times Riboflavin phosphate is 100 times

more soluble than riboflavinmore soluble than riboflavin It is more sensitive to ultra-violet It is more sensitive to ultra-violet

light.light.

PYRIDOXINE PYRIDOXINE HYDROCHLORIDEHYDROCHLORIDE Soluble in about 5 parts of water and Soluble in about 5 parts of water and

1% aqueous solution has a pH of 3.1% aqueous solution has a pH of 3. Solutions are stable to heat.Solutions are stable to heat. Stability decreases with rise in pH.Stability decreases with rise in pH. In solid state the vitamin is quite In solid state the vitamin is quite

stable to oxygen although light stable to oxygen although light destroys it at a slow rate.destroys it at a slow rate.

VITAMIN –B12VITAMIN –B12

Cynocobalamine is soluble in 80 parts Cynocobalamine is soluble in 80 parts of water but is freely soluble in alcohol.of water but is freely soluble in alcohol.

Aqueous solutions are neutral.Aqueous solutions are neutral. Stability is maximum b/w pH4 and 7 at Stability is maximum b/w pH4 and 7 at

room temperature.room temperature. Its crystals are hygroscopic and absorb Its crystals are hygroscopic and absorb

about 12% water on exposure to airabout 12% water on exposure to air sensitive to light and reducing sensitive to light and reducing

substances.substances.

Vitamin C causes rapid Vitamin C causes rapid decomposition in solution.decomposition in solution.

70% sorbitol as such or in 70% sorbitol as such or in combination with glycerol are combination with glycerol are suitable vehicles for vitamin B12 suitable vehicles for vitamin B12 and vitamin C combinations.and vitamin C combinations.

VITAMIN CVITAMIN C

Strong monobasic acid.Strong monobasic acid. Powerful reducing agent in neutral and Powerful reducing agent in neutral and

acidic solutions.acidic solutions. Degraded mainly due to oxidation.Degraded mainly due to oxidation. First oxidation product is First oxidation product is

dehydroascorbic acid which can be dehydroascorbic acid which can be reversed back to ascorbic acid on reversed back to ascorbic acid on reaction with hydrogen sulfide or reaction with hydrogen sulfide or hydrogen iodide.hydrogen iodide.

Further oxidation converts vitamin C Further oxidation converts vitamin C into oxalic acid and this reaction is into oxalic acid and this reaction is not reversible.not reversible.

Aqueous solution of ascorbic acid are Aqueous solution of ascorbic acid are rapidly decomposed by atmospheric rapidly decomposed by atmospheric oxygen particularly at high oxygen particularly at high temperatures.temperatures.

Light, alkalies, trace metals hasten Light, alkalies, trace metals hasten the decomposition.the decomposition.

Reducing agents like potassium Reducing agents like potassium iodide, however, retard the iodide, however, retard the degradation.degradation.

In the solid state vit. C is In the solid state vit. C is comparatively more stable.comparatively more stable.

Vitamin C has been reported to Vitamin C has been reported to be more stable in syrup and be more stable in syrup and polyhydroxy vehicles.polyhydroxy vehicles.

VITAMIN-DVITAMIN-D

It occurs in several forms like D2 It occurs in several forms like D2 (calciferol), D3 and D4.(calciferol), D3 and D4.

It is an oil soluble vitamin and is It is an oil soluble vitamin and is relatively stable to heat and oxidation.relatively stable to heat and oxidation.

Prolonged exposure to light , however, Prolonged exposure to light , however, reduces its potencyreduces its potency

Calciferol is liable to oxidation.Calciferol is liable to oxidation. Vitamin D3 is also oxidised and Vitamin D3 is also oxidised and

inactivated in moist airinactivated in moist air

VITAMIN-EVITAMIN-E

It occurs in the form of 3 homologues It occurs in the form of 3 homologues namely alpha, beta and gamma namely alpha, beta and gamma tocopherols,tocopherols,

Alpha tocopherols are most active.Alpha tocopherols are most active. It is practically insoluble in water. but It is practically insoluble in water. but

it is soluble in fats.it is soluble in fats. It undergoes slow oxidation in the air.It undergoes slow oxidation in the air. The acetate of alpha tocopherol is The acetate of alpha tocopherol is

stable to light and oxidation.stable to light and oxidation.

VITAMIN-KVITAMIN-K

Stable to oxidation and moisture Stable to oxidation and moisture but it is photosensitive.but it is photosensitive.

It is unaffected by dilute acids but It is unaffected by dilute acids but is susceptible to alkalies.is susceptible to alkalies.

Vitamin K oxide is more stable to Vitamin K oxide is more stable to light.light.

MULTIVITAMIN MULTIVITAMIN FORMULATIONSFORMULATIONS Stabilities of multivitamins is very Stabilities of multivitamins is very

big problem.big problem. Certain degree of pH one vit is Certain degree of pH one vit is

stable and deteriorate the other .. stable and deteriorate the other .. Same way for vehicle…..Same way for vehicle…..

One formulation for multivitamins One formulation for multivitamins in water,glycerin and propylene in water,glycerin and propylene glycol in the ratio of 20:40:40glycol in the ratio of 20:40:40

Another series in 20% water and Another series in 20% water and 80% propylene glycol.80% propylene glycol.

Some of these formulations had Some of these formulations had EDTA to mop up trace metals and EDTA to mop up trace metals and some included antioxidantssome included antioxidants

All the formulations were All the formulations were analyzed for vitamin contents at analyzed for vitamin contents at the start and after storage at 47the start and after storage at 47ooc c for 1 month.for 1 month.

From the observations some From the observations some generalizations were made,generalizations were made,

Thiamine and pyridoxine are Thiamine and pyridoxine are more stable in formulations more stable in formulations containing minimal amount of containing minimal amount of water.water.

Riboflavin stability varied from 65 Riboflavin stability varied from 65 to 92% in all formulationsto 92% in all formulations

Formulations containing either Formulations containing either sequestering agents or anti sequestering agents or anti oxidants increased stabilities of oxidants increased stabilities of vit C and vit A.vit C and vit A.

General conclusion - General conclusion - FORMULATION CONTAINING FORMULATION CONTAINING SMALL AMOUNT OF WATER WERE SMALL AMOUNT OF WATER WERE STABLE.STABLE.

The liquid products were based on a The liquid products were based on a number of vehicles such as sorbitol number of vehicles such as sorbitol 46%w/v,glycerin24%,propylene 46%w/v,glycerin24%,propylene glycol 24%v/v and sorbitol25%w/v, glycol 24%v/v and sorbitol25%w/v, glycerin10%v/v,propylene glycerin10%v/v,propylene glycol50%v/v and sorbitol glycol50%v/v and sorbitol 18.75%w/v.18.75%w/v.

The pH in all cases was adjusted at The pH in all cases was adjusted at 3.5,4 and 4.5 and chelating agents 3.5,4 and 4.5 and chelating agents and antioxidants were presents in and antioxidants were presents in each formulationseach formulations

Stored in amber coloured bottles Stored in amber coloured bottles at 37Oc for30.60and 90 days.at 37Oc for30.60and 90 days.

Number of Additives should be Number of Additives should be there in all multivitamin productsthere in all multivitamin products

The additives besides the ones The additives besides the ones needed for a particular dosage needed for a particular dosage form may be listed as:.form may be listed as:.

Vehicles such as water, alcohol, Vehicles such as water, alcohol, propylene glycol, glycerin, propylene glycol, glycerin, sorbitol liquid(70%), liquid sorbitol liquid(70%), liquid glucose etc…glucose etc…

Antioxidants such as sodium Antioxidants such as sodium metabisulphite,thiourea,BHA,BHT,metabisulphite,thiourea,BHA,BHT,propylgallate.propylgallate.

Sequestering agents such as Sequestering agents such as EDTA and its salts.EDTA and its salts.

Synergists like citric acid, tartaric acid, Synergists like citric acid, tartaric acid, phosphoric acid.phosphoric acid.

Viscosity builders such as acacia, Viscosity builders such as acacia, Tragacanth, gelatin, methyl cellulose, Tragacanth, gelatin, methyl cellulose, CMC etc..CMC etc..

Preservatives such as parabens, Preservatives such as parabens, benzoates, sorbates etcbenzoates, sorbates etc

Excipients such as sorbitol, mannitol, Excipients such as sorbitol, mannitol, sucrose, dextrose etc..sucrose, dextrose etc..

Typical formula Typical formula elixerelixer

Chewable tabletChewable tablet

Preparation of tabletsPreparation of tablets

For preparing the tablets the For preparing the tablets the ingredients can be mixed in a powder ingredients can be mixed in a powder blender except vitamins A and D.blender except vitamins A and D.

Then slugs can be made with flat faced Then slugs can be made with flat faced punches and ground to give granules punches and ground to give granules of 15 mesh.of 15 mesh.

To these granules vitamin A and D can To these granules vitamin A and D can be added as micro-capsules.be added as micro-capsules.

Then granules can be compressed.Then granules can be compressed.

Patient acceptabilityPatient acceptability

Any product depends on its Any product depends on its organoleptic properties, organoleptic properties, particularly flavor and taste.particularly flavor and taste.

As far as vitamins concerned the As far as vitamins concerned the following are the taste are listed following are the taste are listed in the literaturein the literature

VITAMINSVITAMINS TASTE SENSATIONTASTE SENSATION

VIT A , D2, EVIT A , D2, E No tasteNo taste

Thiamine HclThiamine Hcl Bitter & yeastyBitter & yeasty

Pyridoxine HclPyridoxine Hcl Slightly bitter & Slightly bitter & saltysalty

CyanocobalamineCyanocobalamine TastelessTasteless

NiacinamideNiacinamide Intensely bitterIntensely bitter

Calcium Calcium pantothenatepantothenate

BitterBitter

BiotinBiotin TastelessTasteless

Folic acid Folic acid Tasteless Tasteless

Ascorbic acidAscorbic acid SourSour

Sodium ascorbate Sodium ascorbate Salty & soapySalty & soapy

REFRENCESREFRENCES

A textbook of pharmaceutical A textbook of pharmaceutical formulations by B.M MITHAL…. formulations by B.M MITHAL…. Page no.325-332.Page no.325-332.