a for elective subject on effervescent …gnu.inflibnet.ac.in/bitstream/123456789/2269/1/01-yogi...

A

PROJECT REPORT

FOR ELECTIVE SUBJECT

ON

“EFFERVESCENT FORMULATIONS”

SUBMITTED TO THE

HEMCHANDRACHARYA NORTH GUJARAT UNIVERSITY, PATAN

2004-2005

IN

PARTIAL FULFILLMENT

OF THE REQUIREMENT FOR THE

DEGREE OF

BACHELOR OF PHARMACY

SUBMITTED BY

YOGI AGRAVAT (FINAL B. PHARM)

S.K. PATEL COLLEGE OF PHARMACEUTICAL

EDUCATION AND RESEARCH,

GANPAT VIDYANAGAR, KHERVA

NORTH GUJARAT.

CERTIFICATE

This is to certify that the project work for elective subject entitled

”EFFERVESCENT FORMULATIONS” represents the bonafide work of

AGRAVAT YOGI M. carried out under my guidance and supervision at the

Pharmaceutics department of Shree S. K. Patel college of pharmaceutical

education and research, GANPAT VIDYANAGAR, (KHERVA) during the

academic year 2004-2005. He has collected the literature very sincerely and

methodically. This work is up to my satisfaction.

Guide: Principal I/C: Mr.R.P.Patel Dr. N. J. Patel (M.Pharm) (M. Pharm., Ph. D.) Department of Pharmaceutics S. k. Patel college of

S. k. Patel college of Pharmaceutical Edu. & Res Pharmaceutical Edu. & Res. Ganpat vidyanagar, Kherva. Ganpat vidyanagar, Kherva.

Date: Place: Ganpat vidyanagar,Kherva.

AACCKKNNOOWWLLEEDDGGEEMMEENNTT

This project report has been prepared to give a brief introduction of

“EEFFFFEERRVVEESSCCEENNTT FFOORRMMUULLAATTIIOONNSS” which was under taken for partial

fulfillment of degree course in pharmacy. The project work has to be

undertaken and completed as per the direction of the syllabus.

In this field with very limited acknowledgement need of mine was

fulfilled by my able guide Mr.R.P.Patel. He gave me direction on how to work

on this project & helped in each & every part of this project work. My

special words of thanks to him that he is a “Noble Man” in our department who is ready at all time to guide as well as to teach me and also all the

students. My heartly thanks to Mr.B.S.Dave who inspired me to do this

work.

I am thankful to our principal Dr. N. J. Patel who has been a

constant source of inspiration throughout my B. Pharm.

My sincere thanks to Asst.Prof.J.K.Patel and

Asst.Prof.P.D.Bharadia and Mr.V.M.Patel and Mrs.H.V.Patel for their

suggestions and moral support. I also thank entire staff members who

helped me a lot to complete this project work.

I am thankful to Librarian Mr. P. I. Patel and Computer Lab. Asst.

Chaula Ma’m who has also been helpful to me.

A special thanks reserved for my college friends and Dharati group

for their co-operation and giving constant support.

At this stage I thank with deep gratitude to my parents for their

moral support, constant encouragement and patience absolutely needed to

complete my entire graduation. I also thank to my class mates for

finalization of my thesis.

AAggrraavvaatt yyooggii mmaannssuukkhhllaall (FINAL B. PHARM)

DEDICATED

TO

MY FAMILY

&

FRIENDS

INDEX

Sr.no. Name of chapter Page no. 1 Introduction 1 2 Composition of formulation 5 3 Types of effervescent formulation 15 4 Manufacturing techniques 27 5 Packaging 33 6 Market products available 36 7 Research 39 8 Analytical parameters 50 9 Advantages 53 10 Limitations 56 11 Summary 58 12 References 60

Effervescent formulations 1

Chapter-1

INTRODUCTION


INTRODUCTION (a1,b2,b19)

Effervescent mixtures have been known and used medicinally for many

years. Effervescent powders used as saline cathartics were available in the

eighteenth century and were subsequently listed in the official compendia as

compound effervescent powders. These were more commonly known as

‘Seidlitz powders’. Effervescent mixtures have been moderately popular

over the years since along with the medicinal value of the particular

preparation. In addition, they provided a pleasant taste due to carbonation

which helped to mask the objectionable taste of the drugs.

Effervescent formulations are known in the prior art for various active

ingredients and vitamins. These effervescent formulations generally include

an agent which is capable of releasing CO2, and an agent which induces the

release of CO2. Suitable agents capable of releasing CO2 which are used

include alkali metal carbonates or alkali metal bicarbonates, such as sodium

carbonate and sodium bicarbonate. Alkaline earth metal carbonate

formulations are mainly contained in mineral preparations. Suitable agents

for inducing CO2 release include edible organic acids, or their acidic salts,

which are present in solid form and which can be formulated with the active

ingredient and the other auxiliaries to provide granules or tablets, without

premature evolution of CO2.

Suitable edible organic acids include, for example, tartaric acid, malic

acid, fumaric acid, adipic acid, succinic acid, ascorbic acid, maleic acid or

citric acid. Pharmaceutically acceptable acidic salts include, for example,

salts of polybasic acids which are present in solid form and in which at least

one acid function is present, such as sodium dihydrogen or disodium

hydrogen phosphate or the corresponding citrates.

The active ingredients are either present in the effervescent formulation

as readily soluble compounds, or they are solubilized by salt formation

during the dissolution process. However, it is also possible to disperse

poorly soluble active ingredients.

Selegiline hydrochloride is extremely sensitive to the customary

effervescent bases such as sodium bicarbonate, sodium carbonate or sodium

hydrogen citrate in combination with organic edible acids, such as citric acid

or tartaric acid.


In these customary effervescent formulations, the selegiline active

ingredient is degraded to amphetamine, methamphetamine and

demethylselegiline, and the active ingredient undergoes sublimation. It

should be noted that degradation to the above mentioned metabolites occurs

only partly. The main part of selegiline sublimes in the presence of alkali

metal compounds, particularly alkali metal carbonates, so that surprisingly,

loss of active ingredient occurs even in the case of only slight

metabolization. The required purity and quantity are no longer met after

storage of these effervescent selegiline formulations.

Surprisingly, effervescent formulations based on alkaline earth metals in

accordance with the present invention are very stable. Most suitably calcium

carbonate and citric acid are used as the effervescent base.

It can be advantageous to have some of the calcium carbonate react with

citric acid to give calcium citrate. Small amounts of sodium citrate do not

cause instabilities. However, these amounts may not be more than about

15% of the total weight of the effervescent formulation.

At room temperature and even in the stress test at 40oC. And 75%

relative atmospheric humidity, the effervescent selegiline formulations

according to the present invention show no relevant loss of quality. This is

of particular importance since effervescent formulations have to be well

protected against atmospheric humidity during production, filling and

storage. Therefore, their preparation is generally carried out only in areas

having low atmospheric humidity (Ritschel, Bio Tablette, Echtio Cauher KG

1966, p. 115 f). As discussed by Wells in Pharmaceutical Preformulation

(John Wiley publisher, 1988), basic catalysis is in a large number of

medicaments a decisive reason for instability.

Although calcium carbonate is known to be used in effervescent tablets

but only in cases where calcium therapy is required with calcium as an

active ingredient, but not as medicinal excipient for other active ingredients

where calcium does not contribute to the therapy. Calcium-containing

effervescent tablets are generally employed for treating mineral metabolism

problems.

A ready-to-drink solution or suspension with pleasant taste can be

prepared with the effervescent formulations of the present invention,

suitably in a volume of from 40 to 80 ml of water, which can be easily drunk

even in cases of tremor. This also applies to geriatric patients. Buccal or


sublingual effervescent preparations are administered directly at the mucosa

of the mouth.

The dose in the buccal preparation can be considerably lower, for

example 1-5 mg of e.g. selegiline. In the case of low-dosed active

ingredients, the effervescent formulations according to the present invention

can comprise up to about 90%, and in the case of high-dosed active

ingredients, from about 30% to about 70% of an effervescent base.

The effervescent formulations also permit combined taking together with

other active ingredients, as is frequently required in the case of selegiline in

Parkinson treatment. Thus, effervescent selegiline formulations can be

administered in combination with other soluble tablets, in particular L-

dopa/benzerazide combinations or soluble amantadine tablets.

Vacuum drying cabinets can be used, for example, to achieve rapid

drying. In another method of preparation the acid is partially reacted with the

basic components, followed by drying under reduced pressure. A soluble

lubricant is admixed to the dry granules before compression. However,

tableting can also be carried out by using external lubrication.


Chapter-2

COMPOSITION OF EFFERVESCENT

FORMULATION


COMPOSITION (A3,A4,A7,A8,B8)

Effervescent granules are usually prepared from a combination of citric

and tartaric acid rather than from a single acid because the use of either acid

alone causes difficulties. When tartaric acid is the sole acid, the resulting

granules readily crumble and lack mechanical strength. Citric acid alone

results in a sticky mixture which is difficult to granulate during the

manufacturing process.

The reaction between citric acid and sodium bicarbonate and tartaric acid

and sodium bicarbonate, which results in liberation of carbon dioxide, may

be shown as follows:

H3C6H5O7.H2O + 3 NaHCO3 -------à Na3C6H5O7 + 4 H2O + 3

CO2 ↑------ (i)

Citric acid Sodium bicarbonate Sodium citrate Water

Carbon dioxide

H2C4H4O6 + 2 NaHCO3 -------à Na2C4H4O6 + 2 H2O + 2 CO2

↑------ (ii)

Tartaric acid Sodium bicarbonate Sodium tartrate Water Carbon

dioxide

It should be noted that it requires 3 molecules of sodium bicarbonate to

neutralize 1 molecule of citric acid and 2 molecule of sodium bicarbonate to

neutralize 1 molecule of tartaric acid. The proportion of acids may be varied,

as long as the total acidity is maintained and the bicarbonate completely

neutralized. Usually it is desired that ratio of citric acid to tartaric acid

equals 1:2 so that the desired ratio of the ingredients can be calculated as

follows:

Citric acid: Tartaric acid: Sodium bicarbonate = 1:2:3.44 (by weight) (2)

The alkali-sensitive active ingredient, such as selegiline, is suitably

bound to neutral auxiliary ingredients to obtain good homogeneity. Suitable

neutral carrier substances for the effervescent formulations according to the

invention include lactose, sucrose, sorbitol, mannitol, starch, pectins or

cellulose. Other auxiliary ingredients, such as colorants, sugars or

sweeteners, can improve the appearance and/or the taste of the aqueous


solutions or suspensions obtainable by disintegration of the effervescent

tablet.

The criteria for the selection of dissolution media for buffered or

effervescent tablets are the same as for conventional tablets.It will be

advisable to verify if the buffering capacity and ionic strength of the media

are appropriate for the formulation under evaluation.

Effervescent tablets generally contain ingredients such as tartaric acid,

citric acid, and sodium bicarbonate. These powders would be appropriately

mixed and pressed into tablets using the same procedure as chewable tablets.

They will not require a disintegrant since they will effervesce when placed

in water. Compressed tablet mixtures generally contain the active drug, a

diluent (e.g., lactose), a disintegrant (e.g., starch), and a lubricant (e.g., 1%

magnesium stearate)

When higher melting temperature, higher molecular weight or high

softening temperature binders are employed, the hot-melt extrusion may

require higher processing temperature, pressure and/or torque than when

binders having a lower molecular weight, melting or softening temperature

are employed. By including a plasticizer, and, optionally, an antioxidant, in a

formulation, processing temperature, pressure and/or torque may be reduced.

Plasticizers are not required in order to practice the invention. Their addition

to the formulation is contemplated as being within the scope of the

invention. Plasticizers are advantageously included in the effervescent

granules when hot-melt extrudable binders having a melting or softening

point temperature greater than 150oC. are employed.

The plasticizer should be able to lower the melting temperature or glass

transition temperature (softening point temperature) of the hot-melt

extrudable binder. Plasticizers also generally reduce the viscosity of a

polymer melt thereby allowing for lower processing temperature and

extruder torque during hot-melt extrusion. It is possible the plasticizer will

impart some particularly advantageous physical properties to the

effervescent granules. Plasticizers include, low molecular weight polymers,

oligomers, copolymers, oils, small organic molecules, low molecular weight

polyols having aliphatic hydroxyls, ester-type plasticizers, glycol ethers,

poly(propylene glycol), multi-block polymers, single block polymers, low

molecular weight poly(ethylene glycol), citrate ester-type plasticizers,

triacetin, propylene glycol and glycerin.


Such plasticizers can also be ethylene glycol, 1,2-butylene glycol, 2,3-

butylene glycol, styrene glycol, diethylene glycol, triethylene glycol,

tetraethylene glycol and other poly(ethylene glycol) compounds,

monopropylene glycol monoisopropyl ether, propylene glycol monoethyl

ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether,

sorbitol lactate, ethyl lactate, butyl lactate, ethyl glycolate, dibutylsebacate,

acetyltributylcitrate, triethyl citrate, acetyl triethyl citrate, tributyl citrate and

allyl glycolate. All such plasticizers are commercially available from sources

such as Aldrich or Sigma Chemical Co.

The amount of plasticizer used in the effervescent granules will depend

upon its composition, physical properties, effect upon the effervescent

granules, interaction with other components of the granules and other such

reasons. Generally, the plasticizer content will not exceed about 40% wt. of

the formulation

The term "acidic agent" refers to any compound or material that can

serve as a proton source and can react with the alkaline agent of the

invention to form a gas causing a solution containing them to effervesce.

The acidic agent can have more than one acid dissociation constant, i.e.

more than one acid functional group. The acidic agent can be any organic or

inorganic acid in the free acid, acid anhydride and acid salt form. An acidic

agent which is in solid state at room temperatures and shows pH 4.5 or lower

when saturated into water at room temperatures or its acid alkali metal salts

(e.g. sodium salt, potassium salt, etc.) can be employed. As the acidic agent

for the effervescent granule, a compound which is not harmful to animals

including man is desirably employed. The acidic agent can be tartaric acid,

citric acid, maleic acid, fumaric acid, malic acid, adipic acid, succinic acid,

lactic acid, glycolic acid, alpha hydroxy acids, ascorbic acid, amino acids

and their alkali hydrogen acid salts. And, even in the case of an acid

substance such as phosphoric acid or pyrophosphoric acid or other inorganic

acids which is liquid or in liquid state at room temperature, when their acid

alkali metal salts are solid at room temperature, those acid alkali metal salts

can be employed as acidic agents. Among the above-mentioned acidic

agents, those having a relatively large acid dissociation constant (103 or

more) and a small hygroscopicity (critical humidity at 30oC. is 40% RH or

more) are preferably employed.

It is preferred if the acidic agent can form a eutectic mixture with a

binder. Because these acids are directly ingested, their overall solubility in


water is less important than it would be if the effervescent granules of the

present invention were intended to be dissolved in a glass of water.

The term "alkaline agent" means an alkaline compound that releases a

gas, or causes a solution to effervesce, when exposed to a proton source such

as an acidic agent or water. The alkaline agent can be a carbon dioxide gas

precursor, an oxygen gas precursor or a chlorine dioxide gas precursor.

When the alkaline agent is a carbon dioxide precursor, compounds such as

carbonate, sesquicarbonate and hydrogencarbonate salts (in this

specification, carbonate and hydrogencarbonate, or bicarbonate, are

generically referred to as carbonate) of potassium, lithium, sodium, calcium,

ammonium, or L-lysine carbonate, arginine carbonate, sodium glycine

carbonate, sodium amino acid carbonate can be used. When the alkaline

agent is an oxygen gas precursor, compounds such as anhydrous sodium

perborate, effervescent perborate, sodium perborate monohydrate, sodium

percarbonate and sodium dichloroisocyannurate can be used. When the

alkaline agent is a chlorine dioxide (ClO2) precursor, compounds such as

sodium hypochlorite and calcium hypochlorite can be used. ClO2 can be

used as a chemical sterilizer in cleansing operations.

Where the effervescent agent includes two mutually reactive

components, such as an acidic agent and an alkaline agent, it is preferred,

although not necessary, that both components react completely. Therefore, a

ratio of components which provides for equal amounts of reaction

equivalents is preferred. For example, if the acid used is diprotic, then either

twice the amount of a mono-reactive carbonate alkaline agent or an equal

amount of an all-reactive alkaline agent should be used for complete

neutralization to be realized. However, in other embodiments of the present

invention, the amount of either the acidic agent or the alkaline agent can

exceed the amount of the other component. This can be useful to enhance

taste and/or performance of a tablet containing an overage of either

component.

Having an excess of either the acidic agent or alkaline agent in the

effervescent granule will generally result in increased rate of effervescence

when compared to an effervescent granule having the same amounts, on an

equivalent basis, of both agents. Regardless of whether either agent is in

excess, the total amount of gas produced by an effervescent granule will not

exceed the theoretical amount of gas produced by the agent serving as the

limiting reagent.


It is possible that including a plasticizer in the present effervescent

granules will alter its rate of effervescence. Generally, increasing the amount

of plasticizer present will increase or prolong the time of effervescence.

The rate of effervescence can also be controlled by varying the

hydrophilicity or hydrophobicity of the hot-melt extrudable binder.

Generally, the more hydrophobic the binder, the slower the rate of

effervescence. The solubility and rate of dissolution of a hydrophobic binder

are important factors to consider as the level of binder in the effervescent

granule is increased. For example, one can prepare an effervescent granule

having a rapid rate of effervescence by a water soluble hot-melt extrudable

binder such as an electrolyte or nonelectrolyte such as xylitol, which can

form a eutectic mixture with an appropriate acidic agent during hot-melt

extrusion.

Non-effervescent disintegrants include starches such as corn starch,

potato starch, pregelatinized and modified starches thereof, sweeteners,

clays, such as bentonite, micro-crystalline cellulose, alginates, sodium starch

glycolate, gums such as agar, guar, locust bean, karaya, pecitin and

tragacanth. Disintegrants can comprise up to about 20 weight percent and

preferably between about 2 and about 10 percent of the total weight of the

composition.

Coloring agents can include titanium dioxide, and dyes suitable for food

such as those known as F.D. & C. dyes and natural coloring agents such as

grape skin extract, beet red powder, beta-carotene, annato, carmine,

turmeric, paprika, etc. The amount of coloring used can range from about

0.1 to about 3.5 weight percent of the total composition.

Flavors incorporated in the composition may be chosen from synthetic

flavor oils and flavoring aromatics and/or natural oils, extracts from plants,

leaves, flowers, fruits and so forth and combinations thereof These may

include cinnamon oil, oil of wintergreen, peppermint oils, clove oil, bay oil,

anise oil, eucalyptus, thyme oil, cedar leave oil, oil of nutmeg, oil of sage,

oil of bitter almonds and cassia oil. Also useful as flavors are vanilla, citrus

oil, including lemon, orange, grape, lime and grapefruit, and fruit essences,

including apple pear, peach, strawberry, raspberry, cherry, plum, pineapple,

apricot and so forth. Flavors which have been found to be particularly useful

include commercially available orange, grape, cherry and bubble gum

flavors and mixtures thereof. The amount of flavoring may depend on a


number of factors, including the organoleptic effect desired. Flavors may be

present in an amount ranging from about 0.5 to about 3.0 by weight based

upon the weight of the composition. Particularly preferred flavors are the

grape and cherry flavors and citrus flavors such as orange.

Lubricant means a material which can reduce the friction arising at the

interface of the tablet and the die wall during compression and ejection

thereof. Lubricants may also serve to prevent sticking to the punch and, to a

lesser extent, the die wall as well. The term "antiadherents" is sometimes

used to refer specifically to substances which function during ejection. As

used in the present disclosure, however, the term "lubricant" is used

generically and includes "antiadherents". Tablet sticking during formation

and/or ejection may pose serious production problems such as reduced

efficiency, irregularly formed tablets, and non-uniform distribution of

intended agents or ingredients to be delivered thereby. These problems are

particularly severe with high speed tableting approaches and methods.

Lubricants may be intrinsic or extrinsic. A lubricant which is directly

applied to the tableting tool surface in the form of a film, as by spraying onto

the die cavity and/or punch surfaces, is known as an extrinsic lubricant.

Although extrinsic lubricants can provide effective lubrication, their use

requires complex application equipment and methods which add cost and

reduce productivity.

Intrinsic lubricants are incorporated in the material to be tableted.

Magnesium, calcium and zinc salts of stearic acid have long been regarded

as the most efficient intrinsic lubricants in common use. Concentrations of

two percent or less are usually effective.

Lubricants can be used in an amount of up to 1.5 weight percent and

preferably between about 0.25 and about 1.0 weight percent of the total

composition.

Intrinsic lubricants pose certain serious difficulties when used in

conventional tablets. Many lubricants materially retard the disintegration of

non-effervescent tablets. However, the effervescent granules used in the

dosage form of the present invention overcome any such retardation. In

dissolution of conventional effervescent tablets, the lubricant may cause

"scumming" and/or agglomeration. Stearates, for example leave an

objectionable "scum" when an effervescent tablet is placed in a glass of


water. This "scum" reduces the aesthetic appeal of the solution made from

an effervescent dosage form. However, because the tablets of the present

invention dissolve in the mouth, the solution is never seen by the user.

Therefore, the propensity of a lubricant to "scum" is of less importance.

Thus, lubricants which can cause dissolution or scumming problems in other

dosage forms can be used in dosage forms according to the present invention

without material adverse effect.

The coating can also be used in conjunction with an effervescence to

cause the effervescence to occur at specific areas of the gastrointestinal tract.

Examples or coatings used include: cellulose derivatives including cellulose

acetate phthalate (CAP); shellac and certain materials sold under the

trademark Eudragit.TM. (various grades may be used in specific

combinations). Hydroxypropylmethyl cellulose phthallate in a grade that

dissolves at pH 5 is the preferred coating material.

Precoating materials may also be used. Examples include cellulose

derivatives such as methylcellulose, hydroxypropyl cellulose, hydroxypropyl

methylcellulose or combinations and certain materials sold under the

trademark Eudragit.TM. (Various grades which may be combined).

Hydroxypropylmethyl cellulose phthallate in a grade that dissolves at pH 5

is the preferred coating material.

Examples of hot-melt extrudable binders which can be used in the

effervescent granules include acacia, tragacanth, gelatin, starch, cellulose

materials such as methyl cellulose and sodium carboxy methyl cellulose,

alginic acids and salts thereof, polyethylene glycol, guar gum,

polysaccharide, bentonites, sugars, invert sugars, poloxamers (PLURONIC

F68, PLURONIC F127), collagen, albumin, gelatin, cellulosics in

nonaqueous solvents, and combinations of the above and the like. Other

binders include, for example, polypropylene glycol, polyoxyethylene-

polypropylene copolymer, polyethylene ester, polyethylene sorbitan ester,

polyethylene oxide and the like.

Binders may be used in an amount of up to about 60 weight percent and

preferably about 3 to about 8 weight percent of the total composition. All

binders used in this invention are hot-melt extrudable. Binders having

melting or softening point greater than about 150oC can be used. Hot-melt

extrudable binders having a melting or softening point temperature greater

than about 150oC. Will require use of a plasticizer during hot-melt extrusion


such that the binder melting or softening point temperature will be lowered

below 150oC. The binder can be used in any form such as powder, granules,

flakes or heat-molten liquid. While the amount of binder to be added can be

modified, it is usually present in an amount less than about 10% by weight

and preferably in the range of about 3-8% by weight of the granule.

Other materials may be used to aid in site specific delivery, and include,

for example, sugars, polysaccharides, starches, polymers, etc. These

compounds may be included as coatings or as matrix materials and aid in

releasing the drug in specific sections of the gastrointestinal tract, thus

promoting site-specific delivery.

As the therapeutic compound, use can be of synthetic antibacterial agents

of hardly water-soluble pyridone-carboxylic acid type such as benofloxacin,

nalidixic acid, enoxacin, ofloxacin, amifloxacin, flumequine, tosfloxacin,

piromidic acid, pipemidic acid, miloxacin, oxolinic acid, cinoxacin,

norfloxacin, ciprofloxacin, pefloxacin, lomefloxacin, enrofloxacin,

danofloxacin, binfloxacin, sarafloxacin, ibafloxacin, difloxacin and salts

thereof. Other therapeutic compounds which can be formulated along with

the effervescent granules into an effervescent solid dosage form include

penicillin, tetracycline, erythromycin, cephalosporins and other antibiotics.

Other ingredients or techniques may preferably be used with the present

dosage forms to enhance the absorption of the pharmaceutical ingredient, to

improve the disintegration profile, and/or to improve the organoleptic

properties of the material and the like. These include, but are not limited to,

the use of additional chemical penetration enhancers, which are referred to

herein as noneffervescent penetration enhancers; absorption of the drug onto

fine particles to promote absorption by specialized cells within the

gastrointestinal tract (such as the M cells of Peyer's patches); ion pairing or

complexation; and the use of lipid and/or surfactant drug carriers. The

selected enhancement technique is preferably related to the route of drug

absorption, i.e., paracellular or transcellular.

A bioadhesive polymer may preferably be included in the drug delivery

device to increase the contact time between the dosage form and the mucosa

of the most efficiently absorbing section of the gastrointestinal tract.

Examples of known bioadhesives used include: carbopol (various grades),

sodium carboxy methylcellulose, methylcellulose, polycarbophil (Noveon


AA-1), hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium

alginate, and sodium hyaluronate.

Disintegration agents may also be employed to aid in ispersion of the

drug in the gastrointestinal tract. Disintegration agents include any

pharmaceutically acceptable effervescent agent. In addition to the

effervescence-producing disintegration agents, a dosage form according to

the present invention may include suitable noneffervescent disintegration

agents. Nonlimiting examples of disintegration agents include:

microcrystalline cellulose, croscarmelose sodium, crospovidone, starches

and modified starches.

Propylglycol or glycerin as a binder is only needed in small amounts to

achieve the wanted mechanical characteristics of the effervescent tablets and

to keep the wanted dissolving attitude. Handling the binder propylglycol or

glycerin is also very simple. It can be mixed with the active substance or

with the combination of active substances and possibly with the carrier

without destroying their tipping ability and thus their simple ability to be

mixed with the sherbets. At the same time there is no danger that the binder

could cause a loss of carbon dioxide of the sherbets.


Chapter-3

TYPES OF EFFERVESCENT

FORMULATIONS


(1)Effervescent drug delivery system for oral administration(A5)

The pharmaceutical compositions of the orally administerable

medicaments in combination with an effervescent as a penetration enhancer

for influencing absorption of a drug in the gastrointestinal tract.

Effervescence leads to an increase in the rate and/or the extent of absorption

of the drugs that are known or suspected of having poor bioavailability. It is

believed that such increase can rise from one or all of the following

mechanisms:

1. reducing the thickness and/or the viscosity of the mucus layer which is

present adjacent to the gastrointestinal mucosa;

2. alteration of the tight junctions between cells, thus promoting absorption

through the paracellular route;

3. inducing a change in the cell membrane structure, thus promoting

transcellular absorption;

4. increasing the hydrophobic environment within the cellular membrane.

The present dosage forms include an amount of effervescent agent

effective to aid in penetration of the drug in the gastrointestinal tract, aid in

penetration of the drug across the gastrointestinal mucosa. The formulations

may be distinguished from other effervescent formulation that are enteric

coated on the basis of the amount of effervescent material that they contain.

Prior formulations contain approximately half to a quarter as much

bicarbonate as drug on a weight basis (together with a proportionate amount

of acid). In these cases, the small amount of effervescent couple serves only

to rapidly disintegrate the tablet.

Preferably, the effervescent is provided in an amount of between about

5% and about 95% by weight, based on the weight of the finished tablet, and

more preferably in an amount of between about 30 to about 60%. However,

the amount of effervescent agent must be optimized for each specific drug.

For drugs that are weekly acidic or weakly basic, the pH of the aqueous

environment can influence the relative concentrations of the ionized and the

unionized forms of the drug present in solution, according to the Henderson-


Hasselbach equation. The pH of solutions in which an effervescent couple

with equimolar amounts of base and acid has dissolved is slightly acidic due

to the evolution of CO2. While it is impractical and may not be desirable to

change the pH of the contents of the small intestine. Thus, the relative

proportions of the ionized and unionized forms of the drug may be

controlled.

The materials used to promote site-specific absorption may preferably be

included as coatings and/or as matrix materials. If a coating is used, it may

be applied to the entire dosage form or to the individual particles of which it

consists. Coating materials may be used to prevent the release of the active

agent before the dosage form reaches the site of more efficient absorption.

(2) Multi-Sensory Technologies for Today’s Effervescent Bath and Shower Products (A9)

The fizzing sound of the effervescent reaction, the burst of fragrance

delivered directly under the bather’s nose, the dispersion of color throughout the bath water, and the tactile sensations of emollients both in the water and

on the skin after the bath helps create high levels of consumer satisfaction.

a. Multi-Sensory Stimulation

One of the beauties of effervescent products is that they are able to

stimulate up to four senses — smell, sight, touch and sound — at one time.

Taste can certainly also be stimulated, but that sense is usually beyond the

scope of our industry.

b. Olfactory Stimuli

All product developers and marketers have learned that fragrance

selection can make or break a product. In the case of bath products, it can

make the bath water smell nice; it can scent the entire room; it can leave a

lingering scent on the skin; and, in the case of aromatherapy fragrances, it

can provide specific effects such as calming or invigorating benefits.

Granules act a lot like tablets in that they are dense and sink while they

are effervescing. At most, they will last on the bottom for 30 or 40 seconds.

This means that the fragrance release from granules will be very quick.

Another important point about fragrance release from granules is that this

form allows consumers to easily measure out the amount of product being

used.


As you see, the molded product has a density less than 1, so it will float.

It also has a high dissolution rate, greater than a gram per second.

c. Visual Stimuli

A solution to this is water-soluble glitter. This material is available in many

colors. The colored flecks tend to float on the foam’s surface, giving it a speckled appearance. As they dissolve, their color spreads out a bit giving a

“melting” look. It imparts a sparkly look to the product and does not cause a mess in the tub.

d. Tactile Stimuli

When it comes to bath products, the sense of touch focuses on two areas:

the feel of the water and the feel of the skin, both during and after product

use. As one can imagine, emollients, humectants and polymers are

frequently added to effervescent bathing products. Emollients include

vegetable oils such as sunflower oil, jojoba oil and almond oil and esters

such as IPM and the various benzoate esters. Humectant polymers such as

PEG and polyquaternium-10 have been used successfully.

Materials that cause skin tingling sensations are also interesting. Menthol

is the most common of these materials.

(3) Effervescent granules with delayed effervescent effect (A2)

The effervescent granules with delayed effervescent effect consist of at

least one acid component and one component evolving gas under the action

of acid, as well as of active substances, fragrances, plant extracts, vitamins,

minerals etc. admixed as needed, the particles of the acid component being

coated with--preferably 1 to 30% by weight of--at least one carbonate

compound--possibly including a partial reaction--and/or a hydrocolloid. The

gas-evolving component consists of alkali hydrogen carbonate, alkali

carbonate, and/or alkaline-earth carbonate particles which are coated with at

least one further substance, particularly with a melt of polyethylene glycol

6000. The particles preferably have a grain size above 0.2 mm.

It is described in a few examples that for the purposes of improved

stability, not only the acid component but also the carbonate component of

the effervescent mix be coated with very slight amounts of polyethylene

glycol and HPMC (hydroxypropylmethylcellulose). This again would lead to

a delay that is highly insufficient for the purposes of the present invention.


For active substances such as paracetamol, lactulose, N-Acetylcysteine,

ranitidine, plant extracts, multivitamins and/or trace elements, for instance,

an organic acid treated with 1 to 10% by weight of calcium carbonate can

serve as the acid component to which the alkali hydrogen carbonates, alkali

carbonates, and/or alkaline-earth carbonates that have been delayed in their

effervescent effect are then added as described above. This yields, on one

hand the desired, delayed effervescent effect and on the other hand the

intended stability.

The sachets are preferably made in a width of 10 to 30 mm and a length

of 7 to 20 cm. The amount of effervescent granules that is required depends

on the active substances that should be incorporated. The weight of a sachet

may for instance be 1 g if only small amounts of active substances are to be

dissolved. In the case of effervescent mineral mix sachets which should

contain a given amount, for instance, of calcium or magnesium, it will be

necessary to use the appropriate amount of citric acid in order to set the

desired pH value, so that the effervescent mineral mix sachets may weigh as

much as 4-5 g.

(4) EFFERVESCENT FORMULATION CONTAINING

PLANT EXTRACT (B11)

The effervescent formulation elation in the form of granules or of a

tablet contains, in addition to the effervescent base, at least one water-

soluble or at least suspendable plant extract whose particles are coated with

at least one oily, fatty or waxy substance. At least one emulsifier and/or at

least one antifoam may be present in the coating and/or as a further

component of the mixture, in particular applied as a further component of

the mixture to a pharmaceutically permissible filler as carrier. The individual

phases are prepared by a procedure in which the plant extract or the filler is

heated--preferably in a granulator, in particular in a vacuum granulator--and

wet or mixed with a melt or solution of the oily, fatty or waxy substance or

at least one emulsifier and/or at least one antifoam and then dried--

preferably in a vacuum--and sieved to the desired particle size.

By means of conventional measures, such as, for example, by the

addition of antifoams, such as, for example, simethicone or dimethicone, or

by the application of the antifoam to the dry plant extract itself it was

possible to achieve only a slight improvement by reducing the foaming and--


associated with this--also only a slight reduction in the dissolution time of

the effervescent tablet.

Granulation of the plant extracts with the object of increasing the size of

the particles and reducing their number within the effervescent tablet in

order thus to prevent the formation of a concentrated solution around the

plant extract particles and effervescent particles during dissolution of the

tablet in water also did not achieve the object since precisely these

granulated particles then agglomerated to an extreme extent and exhibited

undesired and by no means rapid dissolution properties.

In order, if required, to impart better flowability to the extracts treated

with fatty, oily or waxy substances, it is possible to add a fine filler which

adheres to the fatty surface and thus prevents the agglomeration of the active

ingredient phase. All conventional pharmaceutical tablet fillers suitable for

this purpose, such as sugar alcohols, mannitol, sorbitol and furthermore

maltodextrin, pulverized sucrose, pulverized lactose, fructose, glucose, etc.

These fillers can be introduced directly into the plant extract phase (cf.

Example 1), or the plant extract phase is homogeneously mixed with a filler

after the preparation and then mixed with the effervescent granules

containing the remaining ingredients, flavors, etc.

For example, mannitol or sorbitol takes up a part of the oily, fatty or

waxy substance and also the emulsifier and prevents the agglomeration of

the coated particles of the plant extract phase.

The preparation of the plant extract phase can be carried out as follows:

the freely soluble plant extracts are preheated to 45 to 60oC; a solution or

melt of the fatty, oily or waxy substances--preferably with one or more

emulsifiers--is applied. This solution is uniformly distributed while stirring,

and the solvent is then evaporated, preferably by means of a vacuum before

drying, it is also possible to add fillers to it.

All conventional effervescent components may be used for the

preparation of the effervescent base or of the effervescent granules, the acid

component preferably consisting of citric acid, tartaric acid, malic acid or of

the salts thereof, such as, for example, monosodium citrate or monosodium

tartrate. The base fraction of the effervescent base expediently consists of

CO2 -eliminating alkali metal bicarbonates or carbonates, such as sodium

and/or potassium bicarbonate or carbonate, and partly, but not exclusively,


of alkaline earth metal carbonates, such as calcium carbonate and/or

magnesium carbonate.

In particular, sweeteners, such as sugar, sodium cyclamate, saccharin

sodium, aspartame and acesulfame, and flavors or other galenical fillers,

such as sugar alcohols, e.g. mannitol and sorbitol, and also maltodextrin,

optionally sucrose, fructose, lactose, etc., may be used as additives and

excipients.

(5) Multiple unit effervescent dosage forms comprising proton

pump inhibitor (B9,B12,B16)

A new tableted multiple unit effervescent dosage form containing an

acid susceptible proton pump inhibitor in the form of the racemate, an

alkaline salt thereof or one of its single enantiomers or an alkaline salt

thereof, and effervescent tablet constituents. The proton pump inhibitor is

preferably omeprazole or an alkaline salt thereof, or S-omeprazole or an

alkaline salt thereof. The Applicant has now surprisingly found that

effervescent tablets according to the present invention comprising enteric

coated units of an acidic susceptible proton pump inhibitor can be

manufactured by compressing said units into tablets without significantly

affecting the properties of the enteric coating.

One object is to provide a tableted multiple unit effervescent dosage form

comprising an acid susceptible proton pump inhibitor, or an alkaline salt

thereof or one of its single enantiomers or an alkaline salt thereof, in which

the active substance is in the form of enteric coating layered units

compressed together with effervescent tablet excipients into such an

effervescent tablet. The enteric coating layer(s) covering the individual units

of active substance has properties such that the compression of the units into

a tablet does not significantly affect the acid resistance of the enteric coated

units.

The tabletted multiple unit effervescent dosage form is especially

suitable for patients with swallowing disorders and in pediatrics.


(6) Pharmaceutical compositions containing an effervescent

acid-base couple (B2,B14,B19)

A pharmaceutical composition in the form of effervescent tablets

comprising an active ingredient and an effervescent blend, wherein the

effervescent blend comprises an acidic component and sodium glycine

carbonate as alkaline components. Preferred acid components are fumaric

acid, maleic acid, and their salts. Tablets are prepared in normal thermo-

hygrometric conditions and with standard tabletting equipment.

The acid and the alkali are the essential components which provide the

effervescence and the disintegration of the tablet when is contacted with

water.

Sodium bicarbonate is one of the most used carbonate because it is very

soluble and of low cost. Alternatively, modified sodium bicarbonate can be

used, obtained by heating common sodium bicarbonate in order to convert

the surface of its particles to sodium carbonate so increasing its stability.

Other physiologically acceptable alkaline or alkaline earth metal

carbonates may be used, such as potassium or calcium (bi) carbonate,

sodium carbonate or sodium glycine carbonate.

Conventional excipients such as diluents, ligands, bufferings,

sweeteners, flavourings, colourings, solubilizers, disintegrants, wetting

agents and other excipients of common use may be added to the formulation.

The instability of effervescent tablets, their tendency to absorb moisture

and lose reactivity is generally known. Due to this instability in the presence

of water, conventional wet granulation and the subsequent granulate

compression are very hardly applicable.

Alternatively, techniques of anhydrous granulation, in the absence of

aqueous phases, have been applied using volatile organic solvents like

ethanol. However such techniques requires special manufacturing

environments with strictly controlled relative humidity conditions (normally

lower than 20%) and with explosion proof equipments.

The use of sodium glycine carbonate in effervescent formulations is

described in patent applications and scientific literature regarding


formulations containing hydrated amoxycillin (PCT WO 9115197),

isosorbide-5-mononitrate (DE 4416769) and enzymes (FR 2305194). The

acidic component in these formulations is constituted of citric, tartaric, malic

or adipic acid and the manufacturing process foresees steps of slugging,

milling slugs, blending and compressing or the use of anhydrous excipients

or, also, an external lubrication of the machine is performed.

One of the preferred acids is fumaric acid which may be present in the

form of salt such as mono sodium or potassium fumarate. Another preferred

acid is maleic acid eventually present as a salt. The choice of the acid is

made according to the characteristics of the active ingredient.

The formulation may comprise other excipients like:

a lubricant selected from PEG higher than 4000 and preferably PEG 6000

sodium benzoate, sodium and potassium fumarate, leucine, alanine;

Other advantages of the composition are the low content of sodium ions,

due to the employ of sodium glycine carbonate, with respect to other sodium

carbonates and the less fizzy effervescence, more pleasant to the patient.

Moreover the composition of the invention, because of its small size,

light effervescence and rapid disintegration, can also be prepared as fast

dissolving or sucking in the mouth. Infact, as introduced in the mouth, when

in contact with saliva, the tablet disintegrates and rapidly forms a solution or

an aqueous dispersion easily swallowable

(7) A solid pharmaceutical dosage form adapted for direct oral

administration. (A2)

Formulations incorporating the effervescent granules according to one

aspect of the present invention can further include one or more additional

adjuvants and/or active ingredients which can be chosen from those known

in the art including flavors, diluents, colors, binders, filler, surfactant,

disintegrant, stabilizer, compaction vehicles, and non-effervescent

disintegrants. The effervescent granules themselves do not generally include

therapeutic compounds or other active ingredients.

The formulation provides a thermal heat process for preparing an

effervescent granule comprising a pharmacologically active agent. In some

embodiments, the method comprises combining an acidic agent, a


pharmacologically active agent, a hot-melt extrudable binder which can

combine with said acidic agent, a pharmacologically active agent, and a

plasticizer. The inclusion of a plasticizer in the formulation is optional. The

acidic agent, alkaline agent, hot-melt extrudable binder and the optional

plasticizer may then be dry blended to form a mixture. The mixture may

then be hot-melt extruded to form a eutectic mixture. The effervescent

mixture is then hot-melt extruded to form effervescent granules having a

controllable rate of effervescence. The mixture is then screened and blended

after which said mixture is subjected to compression until tablet form is

achieved.

The effervescent granules of this formulation can be in the state of

powder or fine particles to increase the dissolution rate, and preferably a

particle size such that 90% or more passes a 16 mesh (1,000 mu.) screen,

and more preferably a particle size such that more than 90% passes a 18

mesh (850 mu m) screen. Generally, the larger the effervescent granule, the

longer it will take to completely disintegrate. This is particularly true when

there are low levels of effervescent couple present in the granules.

By controlling the relative ratio of acidic agent: alkaline agent, the

effervescent granules can be used to regulate the pH of their environment.

Thus, the present granules can be used to regulate the pH of body cavities

such as the mouth, rectum or vagina.

When the solubility of the active ingredient increases at the acid side, the

pH of the solution is lowered by adding the acidic agent in an amount more

than equivalent to the alkaline agent. When the solubility of the active

ingredient increases at the basic side, the pH of the solution is raised by

adding the alkaline agent in an amount more than equivalent to the acidic

agent. In either case, the pH near the acidic agent immediately after the

dissolution is low, while the pH near an alkaline agent is high. In a case

where the solubility of an active ingredient does not depend on pH, the ratio

of an acidic agent and an alkaline agent can be optionally selected.

An acidic agent and a carbon dioxide precursor are used respectively in a

powdery or granular state, usually 90% or more of them being capable of

passing through a 100 mesh (150 .mu.) screen. The particle size of the

binder used will usually be about 100 mesh (150 .mu.). In any case, it is

generally acceptable that the additional amount of either component can

remain unreacted.


Rate of effervescence of the effervescent granule can be controlled by:

(1) varying the relative amounts of the components; (2) optionally forming a

eutectic mixture between the acidic agent and hot-melt extrudable binder;

(3) varying acidic agent: alkaline agent ratio; (4) hydrophilicity vs.

hydrophobicity of hot-melt extrudable binder; (5) varying the effervescent

couple: hot-melt extrudable binder ratio; and (6) varying the amount of

plasticizer present.

It should also be noted that when the effervescent granules are included

in a tablet form, The hardness of the tablet can be controlled by the pressure

used on the punches to compress the effervescent granule-containing

formulation and by the amount of effervescent granules, concentration of

effervescent couple, and amounts of drug and other excipients present in the

tablet composition.

The effervescent granules of the formulation can be included in

formulations containing active ingredients and particularly

pharmacologically active agents. When the effervescent granules are

formulated into tablets, such tablets can also contain coloring agents, non-

effervescent disintegrants, lubricants and the like. The effervescent granules

of the invention can be formulated in a variety of forms such as a tablet,

capsule, suspension, reconstitutable powder and suppository.

The mass of each such pharmaceutical tablet generally should be less

than about 2.0 g and preferably less than about 0.5 g. The tablet may include

surface markings, cuttings, grooves, letters and or numerals for the purpose

of decoration and/or identification. Preferably, the tablet is a compressed

tablet. It includes effervescent granules, together with a therapeutic

compound and other components. The size of the tablet is also dependent

upon the amount of material used. Circular, disk-like tablets desirably have

diameters of about 11/16 inch or less, whereas elongated tablets desirably

have a long dimension of about 7/8 inch or less.

The therapeutic compounds which can be formulated in suitable dosage

forms along with the effervescent granules of the invention also include

antibacterial substances, antihistamines and decongestants, anti-

inflammatories, antiparasitics, antivirals, anxiolytic agents, morphine

derivatives, serotonin agonists, levorotatory isomers of thyroxine,

cholesterol lowering agents, alpha adrenergic blocking agents, local

anesthetics, antifungal, amoebicidal, or trichomonocidal agents, analgesics,


antiarthritics, antiasthmatics, anticoagulants, anticonvulsants,

antidepressants, antidiabetics, antineoplastics, antipsychotics,

antihypertensives, phenanthrene derivatives, antidiarrheal agents, diuretics,

and muscle relaxants.


Chapter-4

MANUFACTURING TECHNIQUES


General methods of preparing effervescent granules(A3,A5,B5,B6,B18)

There are three methods of preparation for the effervescent granules viz.

wet granulation, dry granulation and fusion. The fusion method is the

preferred method of preparation of effervescent granules although other two

methods can also be used.

1)Wet granulation

This is the oldest method of granule preparation, although it suffers from

problems of reproducibility. The individual steps in the wet granulation

process of tablet preparation include milling and sieving of the ingredients,

dry powder mixing, wet massing, granulation, drying and final grinding.

Wet massing is the most important step in the wet granulation process. In

this step, the granulating agent is added to the powder mixture. At the end of

wet massing, the damp powder will pack to the consistency of a dry snow

ball and crumble into fragments, not into powder, under the finger pressure.

The granulating agent can be water added to solvents such as alcohol,

propylene glycol or glycerin which act as moistening agents.

In the granulation step, the granules themselves are formed by forcing

the moistened powder through a screen in an oscillating granulator, hammer

mill or multi mill. The resulting granulated material is dried on trays in hot

air circulation oven or preferably in fluidized bed dryer.

Particles may agglomerate and form a lump during oven drying.

Therefore, dry screening is necessary. The screen used for sizing should

have slightly larger opening than that used to prepare the original granules if

excessive powder is not to be formed and granulation lost during sizing.

2) Dry granulation:

Typically, the process involves compressing a powder mixture into a

rough tablet or ‘slug’ on a heavy duty rotary tablet press. The slugs are then broken up into granular particles by a grinding operation, usually by passage

through an oscillating granulator the individual steps include mixing of the

powders, compression (slugging) and grinding.


3) Fusion method:

The most important method for preparing the effervescent granules is the

fusion method. In this method, the compressing step of dry granulation

process is eliminated. Instead, the powders are heated in an oven or using

other suitable source of heat. The particular advantage of this method is that

it uses the water of crystallization present in citric acid as binding agent. Just

before mixing the powders, the citric acid crystals are powdered and then

mixed with the other powders (previously passed through sieve #60) to

ensure uniformity of the mixture. The sieves and the mixing equipment

should be made of stainless steel or other material resistant to the effects of

acids. The mixing of the powders is carried out as rapidly as possible, in an

environment of low humidity to avoid the absorption of moisture from the

air by the chemicals and a premature chemical reaction. After mixing, the

blend is placed on a plate of glass or suitable dish in an oven previously

heated to 93-104o C. The blend is turned during the process.

The heat causes the release of the water of crystallization form the citric

acid. The released water then dissolves a portion of the powder mixture and

causes the chemical reaction to start, with the consequent release of some

carbon dioxide. This caused the softened mass of powder to become

somewhat spongy, and when of the proper consistency, similar to bread

dough, the mass is removed from the oven and rubbed through an acid

resistant sieve to produce granules of desired size. When all the mass has

passed through the sieve, the granules are immediately dried at a

temperature not exceeding 54o C and immediately transferred to containers

which are tightly sealed.

According to a method of producing effervescent tablets which consist

of at least one active substance or a combination of active substances, of at

least one binder, possibly of carriers as sweeteners, flavours, colourings,

scents, softeners and bleaches, and of sherbets, wherein propylglycol or

glycerin is used as a binder, wherein the active substance or the combination

of active substances and possibly the carriers are mixed with the binder,

wherein the sherbets are added to this mixture in an air-conditioned room

and wherein the mixture including the sherbets is formed into tablets.

Further, there is provided an effervescent tablet consisting of at least one

active substance or one combination of active substances, of at least one

binder, possibly of carriers as sweeteners, flavours, colourings, scents,


softeners and bleaches, and of sherbets, which comprise propylglycol or

glycerin as a binder.

The active substances to be used in the method and for the effervescent

tablet according to the invention are not limited at all. They include, for

example, calcium, magnesium, potassium, iron-II-gluconate, vitamin E,

vitamin C, paracetamol, cimetidine, piracetam, acetylsalicyl acid, ambroxol,

indomethacin and acetylcysteine or any other active substance.

The combination of substances to be used includes for example multi

vitamins, multi vitamins with minerals, beta carotin with vitamin E and/or

vitamin C, vitamin C with minerals, anionic and/or not-ionic tensides or

other washing active substances. Also all combinations of active substances

which can be orally taken in solving form can be used.

Those skilled in the art also know possible compositions of sherbets for

the effervescent tablets. These sherbets consist of a base component and an

acid component wherein especially the acid component also can be used as

an active substance. One known example thereof is ascorbic acid (vitamin

C). Usually, as base component sodium carbonate, sodium hydrogen

carbonate, potassium carbonate, potassium hydrogen carbonate and calcium

carbonate are used. As an acid component besides ascorbic acid mono

sodium citrate, wine acid and/or citric acid can be considered.

Advantageously, the method according to the invention includes

intensely mixing the active substance or the combination of active

substances and possibly carriers with the binder before adding the sherbets,

and directly forming a mixture including the sherbets into tablets.

Advantageously, in case of both the method and the effervescent tablet

according to the invention the amount of binder is in the range of 0.004 to

2.5% per weight of the whole effervescent tablets, especially in the range of

0.004 to 1.5% per weight of the whole effervescent tablets, and more

especially in the range of 0.01 to 1.0% per weight of the whole effervescent

tablets. Further, the amount of sherbets advantageously is in the range of 58

to 93% per weight of the whole effervescent tablets, and especially in the

range of 70 to 90% per weight of the whole effervescent tablets.

Processing, manufacturing, mixing and packaging of effervescent

product should be carried out under humidity controlled conditions. It is


important to note that complete segregation of a humidity-controlled area is

important. Moisture will move against air currents and temperature gradients

to achieve equilibrium with surrounding areas. The use of access rooms to

enter and exit main environmental areas is important to minimize transfer of

moisture from uncontrolled areas to controlled areas. Another area of

concern during the production of effervescent powders is the processing or

blending of the raw materials. Conventional blending equipment can be

utilized for effervescent powders provided the equipment could be operated

in very low humidity areas. All equipment should be well grounded, and

capable of being dried absolutely after washdown operations. Any traces of

moisture in the equipment will give erratic product results and most likely

result in lost batches of product. With the blending of an effervescent

product mixture comes the issue of the product stability. Controls must be

established to insure that the effervescent powder is consistent in regards to

particle size and moisture level. Once the effervescent powder is consistent,

storage studies should be done on the effervescent powder product prior to

placing it in its final protective package to ascertain the handling and storage

conditions, which are acceptable.

4) Hot Melt Extrusion

In one aspect of this hot-melt extrusion method is described herein. An

acidic agent and an alkaline agent, preferably a carbon dioxide precursor,

and a hot-melt extrudable binder, all in a dry state, are placed into a mixer or

hopper and agitated (blended) until thoroughly mixed to form an

effervescent mixture. The effervescent mixture is then hot-melt extruded at a

rate and temperature sufficient to melt or soften the binder, to minimize

degradation of the components and to form an extrudant which is

subsequently ground or chopped into effervescent granules.

An acidic agent and a hot-melt extrudable binder, capable of forming a

eutectic mixture with the acidic agent, are placed into a mixer and agitated

until thoroughly mixed to form a mixture which is hot-melt extruded and

ground to form a granular eutectic mixture. An alkaline agent, such as a

carbon dioxide precursor, is added to the granular eutectic mixture and

thoroughly blended to form an effervescent mixture. The effervescent

mixture is then hot-melt extruded at a rate and temperature sufficient to melt

or soften the eutectic mixture, to minimize degradation of the components,

e.g. degradation of NaHCO3 to Na2 CO3, and to form an extrudant which is

subsequently ground or chopped into effervescent granules.


The hot-melt extrusion process preferably employed is conducted at an

elevated temperature, i.e. the heating zone(s) of the extruder is above room

temperature (about 20oC.). It is important to select an operating temperature

range that will minimize the degradation or decomposition of the

effervescent composition during processing. The operating temperature

range is generally in the range of from about 50oC. to about 150

oC. as

determined by the setting for the extruder heating zone(s). The temperature

of the mixture being hot-melt extruded will not exceed 150oC. and

preferably will not exceed 120oC. The hot-melt extrusion is conducted

employing a dry granular or powdered feed.

Conversely, one can prepare an effervescent granule having a slow rate

of effervescence by employing a poorly water soluble hot-melt extrudable

binder such as hydrogenated castor oil, lipids, wax, cholesterol, fatty acids or

mono-, di- or triglycerides. Additionally, an effervescent granule having an

intermediate rate of effervescence can be prepared by employing a binder, or

combination of binders, such as those just discussed and optionally a surface

active agent or cosolvent that improves wetting or disintegration of the

effervescent granule.


Chapter-5

PACKAGING OF EFFERVESCENT

FORMULATION


PACKAGING (A6,B7)

Processing and environmental conditions all having to do with the

stability of effervescent products. Finally the most critical factor that has to

do with the stability of an effervescent product is the packaging. In the U.S.,

effervescent powders are most frequently strip wrapped in individual

pouches arranged in conveniently sized strips and stacked in a paperboard

box. Each dose of effervescent is hermetically sealed in its own container

and is not exposed to the atmosphere until the time of use. The most

commonly used materials for pouches are heat-sealable, aluminum foil

laminates. Aluminum foil laminates are comprised of three layers, a paper

outer layer, middle foil layer and a heat sealable inner polyethylene layer the

laminates create a flexible, absolute barrier to gases, water vapor, and light.

It is nontoxic and immune to microbiological attack. It has excellent heat

conductivity, thereby making it an excellent choice for heat-sealing, strip-

packaging operations.

Protection of an effervescent tablet:

NSI wanted new effervescent tablets to stand out from the crowd. A PP

tube with a metallized label and desiccant cap are just the ticket.

Effervescent tablets carry an active ingredient that is released when the

tablet is dissolved in water. The allure of this delivery system is two-fold.

First, some people don't like to or are physically unable to swallow a pill; if

the pill's contents can be incorporated in a dissolvable tablet, swallowing is

no more difficult than quaffing a glass of water. Second, active ingredients

dissolved in water enter the bloodstream almost immediately.

NSI will market its effervescent products under two labels: Vita

Fizz(TM) and Effer Power(TM). Each label comprises the same five items:

children's vitamin, multi-vitamin, calcium, vitamin C and Hangover

Relief(TM). While the Vita Fizz label is for distribution to U.S. health food

stores, Effer Power(TM) is aimed at mass merchandisers. Hangover Relief is

packaged in a 10-count and the other four products in 20-count tubes.

Advances in packaging

For the sake of improving safety in handling and use, special package

types have been designed for some formulations which have been used for

many years. These new package types include water-soluble bags and


squeeze bottles. Some of the new packaging, e.g. water-soluble films, are

somewhat more expensive than conventional packaging materials, but the

end users are encouraged to value their health.

Squeeze bottle: These are calibrated plastic packages which are used to

store liquid formulations. When the bottle is squeezed, a known volume of

the formulation is released. This technique improves the accuracy of dosing

the liquid and reduces the danger of accidental spillage, and hence reduces

the risk of environmental pollution. The technique also improves safety in

handling, particularly during measurements, since direct contact is avoided

as much as possible.

Water-soluble bags: This involves the packaging of wettable powders

in special bags made of polyvinyl alcohol and polyesters. Before application,

the bag together with the component powder are dissolved in water during

preparation of the spray solution.

Advantages:

- Since the bag dissolves completely and the remaining packaging material is

not a hazardous waste, this technique is environmentally acceptable.

- The technique maintains precise dosage without spills

- Since there is no direct contact with the pesticide, user exposure hazards

are minimized.

Conclusion:

As was pointed out, improved technology in the development of new

formulations makes it possible to avoid environmental contamination and to

improve safety in the handling and use of pesticides. Since some of these

formulations are still new, they have not fully penetrated the market in

developing countries. However, regulatory pressure from environmental

authorities and consumers, including stringent registration requirements, are

expected to play a major role in the adoption and registration of safer, more

revolutionary types of pesticide formulations. It is therefore advised that

conventional formulations be replaced by the newer and safer types of

formulations discussed above. This switch would have significant safety

advantages both for the user and for the environment.


Chapter-6

MARKET PRODUCTS AVAILABLE


Sr. No.

Name of product Active ingredient

Manufacturer Ref.

1 Aspro (GB-A-1287475) Aspirin Nicholus B13

2 Biompi(GB-A-1300998) Ampicilin Biochemie B14

3 Amorcent(EP-0281200-A1) Amoxicillin Gist-brocades B13

4 Citracal liqitab Ca-Citrate Revital B3

5 Suprum forte Vit-B (complex) Revital B3

6 Ferrotine Vit-C,Iron Revital B3

7 Citrapar Paracetamol Revital B3

8 Effervit Glucosamine Wampole’s B4

9 Gluceffer tab Glucosamine Bajamar chem..

co.

B18

10 Glucosamine effervescent

tablets

Glucosamine

Sulphate

Tower

labs,Essex

B18

11 Potassium Chloride

Effervescent

Pottasium

Chloride

Airborn B4

12 Airborn effervescent

Dietory supplement tablets

Vit-B(complex) Airborn B4

13 Aliborange Vit-C

Effervescent tablets

Vit-C, Airborn B4

14 Revitalvit Calcium Tablet Vit-D&K Airborn B4

15 Osteomax tablet Mg&Vit-D Airborn B4

16 Solpadol Paracetamol & Sanofi- B3


Codeine Synthelabo

17 Redoxone Vit-C&Zinc Sanofi-

Synthelabo

B3

18 LiFizz Multivitamin tab Multivitamins Sipharm B4

19 Remedeine Paracetamol&Di

hydrocodeine

tartrate

Sanofi-

Synthelabo

B3

20 Thymes blossom Efferbath

tablets

- - - - - - Auravita B21

21 Zotrime tab Yerbamate&

Guarana

Auravita B21

22 jan-e-vries powder Yerbamate Auravita B21

23 ZanFSI Clear Creatine Creatine ZanFSI B1

24 ProEndorphin tab Phenylalanine Alka-seltzer B1

25 Celltech Creatinine Creatinine Qfac.Comac B2

26 Chlorpheniramine

effervescent tablets

Chlorphenirami

ne

Alka-seltzer B1

27 Nardil® Penelzine Vitar B20

28 Parnate Isocarboxide Vitar B20

29 Carbex Selegiline Vitar B20

30 Instachlor Chlorine Vitar B20


Chapter-7

RESEARCH


(A)Floating or pulsatile drug delivery systems based on coated

effervescent cores (A8)

The objective of this study was to develop and evaluate floating and

pulsatile drug delivery systems based on a reservoir system consisting of a

drug-containing effervescent core and a polymeric coating. Preliminary

studies identified important core and coating properties for the two systems.

The mechanical properties (puncture strength and elongation) of acrylic

(Eudragit® RS, RL or NE) and cellulosic (cellulose acetate, ethyl cellulose)

polymers, which primarily determined the type of delivery system, were

characterized with a puncture test in the dry and wet state. For the floating

system, a polymer coating with a high elongation value and high water- and

low CO2 permeabilities was selected in order to initiate the effervescent

reaction and the floating process rapidly, while for the pulsatile DDS, a

weak, semipermeable film, which ruptured after a certain lag time was best

(ethyl cellulose/dibutyl sebacate 20%, w/w). With the floating system, the

polymeric coating did not retard the drug release.

A polymer (cellulose acetate or hydroxypropylmethylcellulose) was

added to the core to control the drug release. The time to flotation could be

controlled by the composition (type of filler, concentration of effervescent

agents) and hardness of the tablet core and the composition (type of

polymer and plasticizer) and thickness of the coating. For the pulsatile

system, a quick releasing core was formulated in order to obtain a rapid drug

release after the rupture of the polymer coating. Pulsatile drug delivery

systems are characterized by two release phases, a The cores for the

pulsatile system were coated with an ethanolic ethyl cellulose (10%, w/v)

solution, 20% (w/w) dibutyl sebacate based on the polymer weight) in a

Glatt lab-coater. The coating conditions were: air inlet temperature, 40–45°C; outlet temperature, 26–30°C; air flow, 110 m

3/h; pan speed, 10 rpm;

nozzle diameter, 1.2 mm; atomising air pressure, 1.1 bar; spray rate, 40

g/min).

Polymer films were prepared by casting the organic polymer solution

onto Teflon frames mounted on levelled glass plates (area of casting,

12.0×12.0 cm2; standard formulation, polymer, 6 g; plasticizer, 1.2 g (20%,

w/w, based on the polymer); solvent, 40 ml (ethanol for Eudragit® RS and

RL and ethyl cellulose and acetone for cellulose acetate and lyophilised

Eudragit® NE). The films were dried for 48 h at room temperature, then

peeled from the Teflon plate and stored at room temperature at 52% RH for


48 h and cut into pieces of 4×4 cm2. The exact film thickness was measured

at five points with a thickness gauge Minitest 600 (Erichsen, Hemer,

Germany). For the preparation of wet films, the dry films were put into bags

(7×7 cm2, made from a 40-mesh plastic screen with three sides sewn closed)

to avoid sticking and folding of the films in the medium. The bags with the

films were then placed in 0.1 N HCl and shaken in a horizontal shaker

(GFL® 3033, Gesellschaft für Labortechnik, Burgwedel, Germany; 37°C,

70 rpm, 24 h).

In another modification, HPMC was incorporated within the effervescent

drug core (single-layer system). The generated CO2 was not separated from

the HPMC layer as with the two-layer system, but was entrapped in the

HPMC matrix and could therefore not escape from the gelled matrix. The

time to flotation of these tablets was slightly higher than with the two-layer

system, which could be explained by a slower CO2 formation because of the

presence of the effervescent agents within the HPMC matrix. Without

HPMC, the drug was released completely within 30 min, while the inclusion

of 10 or 20% (w/w) HPMC significantly retarded the drug release. At a 10%

HPMC content in the one-layer tablet, the release was slightly faster without

effervescent agents in the formulation.

The generated gas within the gelled HPMC matrix probably formed an

additional diffusion barrier for the drug. As expected, even rupturing of the

coating had no influence on the drug release, because the polymeric coating

was not a release-controlling barrier. The polymeric film prevented the

disintegration of the HPMC tablet in the beginning and ensured gel

formation, which was a prerequisite for the retarding effect and for the

entrapment of the generated gas. Uncoated tablets rapidly disintegrated prior

to gel formation because of the disintegrating effect of the effervescent

agents. With increasing coating level, the floating started later due to the

delayed water penetration through the thicker coating.

(B) Disinfectant effervescent tablet formulation (A5) A water soluble effervescent tablet formulation for preparing a

disinfecting solution comprising a first tablet containing a bromide releasing

agent and a second tablet containing a hypochlorite releasing agent.

It is an object of the present invention to provide an effervescent tablet

formulation that can be used to prepare a disinfecting solution wherein the

formulation avoids the disadvantages and problems of prior art disinfectant


concentrates.

It is an object of the present invention to provide a product to be used for

preparing a solution for disinfecting dental and medical instruments and

equipment that dissolves fully and results in a solution which has

disinfecting power for a useful period of time over a wide pH range.

The present invention comprises a water soluble effervescent tablet

formulation that can be added directly to water to prepare a disinfecting

solution. The preferred disinfecting agent is a combination of a bromide

releasing agent and a hypochlorite releasing agent. Further, the formulation

includes a stabilizer for increasing the stability of the effective disinfecting

species in solution. In particular, a two tablet system has been developed

wherein the bromide releasing agent is in one effervescent tablet and the

hypochlorite releasing agent is in a second effervescent tablet.

Sodium bromide is useful as the bromide releasing agent. Sodium

dichloroisocyanurate is useful to provide both hypochlorite and to act as a

stabilizing agent to maintain desired levels of the active ingredients. Both

tablets contain effervescent agents such as are used in the art; for example,

sodium bicarbonate in combination with citric acid. Other ingredients may

optionally be included such as surfactants, deodorants, lubricants, and fillers.

The tablets prepared from the active agents and the effervescent agents

are of such a size and concentration to allow using whole tablets or multiple

tablets in a one quart volume or other typically used volume. The use of

tablets eliminates having to dilute and mix concentrates, and store diluted

liquids. The use of tablets further eliminates having to pour powder

concentrates which may produce undesirable and harmful dust. The

effervescence provides rapid solubility and mixing of the active ingredients.

The use of the two tablet system allows for formation of the preferred

hypobromous acid species

. An effervescent tablet formulation for preparing a disinfecting solution,

comprising:

A first tablet comprising an effervescing agent and a bromide releasing

agent; and

A second tablet comprising an effervescing agent and a hypochlorite

releasing agent


(C) Effervescent microspheres and Manufacturing (A6,B19)

The invention concerns multilayer microspheres containing an acid

substance, a basic substance, and a water-soluble isolating agent which,

when it dissolves in water, after almost instant effervescence, brings about a

homogeneous dispersion of active principal(s) which is present in the acid

and basic substances. The invention also concerns a method for preparing

such microspheres by rotational granulation on a fluid air bed associated

with a system of tangential spraying of the wetting liquid.

The present invention relates to multilayer effervescent microspheres

and to a process for preparing such microspheres.

The term "microsphere" will be intended to refer to microgranules

formed of a support material consisting of a matrix in which the active

principle(s), to which auxiliary substances are optionally added, is (are)

dispersed. In accordance with the European Pharmacopea monograph on

spheres, microspheres have an average diameter of less than 1.0 mm and

greater than or equal to 1.0 .mu.m. They are generally intended for oral or

parenteral administration and are used either as constituents of

pharmaceutical form, such as tablets, or in their natural form combined or

otherwise with other excipients, and distributed or otherwise in unit doses,

such as sachets, gel-capsules or powder for injectable preparation.

These effervescent forms are intended to be dispersed in water before

absorption. Their breakdown is ensured by a release of carbon dioxide

resulting from the action of an acid--generally an organic acid, citric acid

being the one most commonly used--on a base--generally a carbonate such

as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, calcium

carbonate, magnesium carbonate or lysine carbonate to avoid the

introduction of sodium.

The known effervescent forms also comprise diluent adjuvants

(generally sugars), binders, sweeteners and flavorings.

Most of the standard processes for preparing effervescent forms

comprise a step of granulating powder, either via a wet route or via a dry

route.

The effervescent mixture contains at least one crystalline solid organic


acid and at least one carbonate releasing CO2 in the reaction with the organic

acid and is characterized in that the acid crystals bear a coating containing

calcium carbonate which adheres to the surface of the acid crystals by means

of the bonding layer formed by partial react-on of the calcium carbonate of

the coating with a surface layer of each acid crystal. The mixture is prepared

by heating the organic acid in ethanol and water to about 60oC. in a mixer at

a pressure of about 0.1 bar or less and by introducing the calcium carbonate

which is left to react until the pressure has risen to about 0.9 bar.

The present invention relates to multilayer effervescent microspheres

containing an acidic substance, a basic substance and a water-soluble

isolating agent whose dissolution in water leads, after almost immediate

effervescence, to a solution or a homogeneous dispersion of active principle.

According to a first variant, the water-soluble isolating agent is dispersed

in the entire bulk of each microsphere, the latter having a two-layer

structure: a layer of acidic substance in which is dispersed the water-soluble

isolating agent and a layer of alkaline substance in which is dispersed the

water-soluble isolating agent.

According to a second variant, the water-soluble isolating agent is in the

form of a thin film separating the acidic and alkaline substances. In this case,

each microsphere has a three-layer structure: a layer of acidic substance and

a layer of alkaline substance separated by a layer of water-soluble isolating

agent.

Whether the microspheres have a two-layer or three-layer structure, the

water-soluble isolating agent serves two purposes; it acts as a binder and as

an isolating barrier intended to avoid an effervescence reaction between the

alkaline substance and the acidic substance during the preparation process

but also during storage of the microspheres, irrespective of the storage

conditions.

The water-soluble isolating agent is chosen from polyvinylpyrrolidone,

hydroxypropyl cellulose, methyl cellulose, lactose and sucrose.

The present invention also relates to a process for preparing the

effervescent microspheres described above using the method of rotary

granulation in a fluidized air bed.


The advantage of rotary granulation applied to these effervescent

compositions is the continuous linking of the operations in one and the same

chamber which, as a result of the components used and certain precautions

taken, induces no effervescence. Furthermore, this rotary granulation

technique allows the relative proportions of the various compounds to be

modified, in particular the relative molar proportions of the acidic and basic

fractions.

Specifically, the process according to the invention makes it possible

advantageously to obtain effervescent forms whose relative proportion of

alkaline and acidic fractions is less than the stoichiometric proportion

implemented in the prior art for effervescent tablets manufactured by the

granulation method, without the quality of the effervescence being adversely

affected.

In particular, the relative proportion of the alkaline and acidic fractions

implemented in the context of the process according to the invention is less

than 0.6, in particular less than 0.25.

All the steps of the process according to the invention are carried out

under atmospheric pressure, without any specific dehydration system or any

specific precautions.

The apparatus used to carry out the process for preparing the

effervescent microspheres is, for example, apparatus constructed by the

company Glatt, onto which a rotor tank is fitted.

Said process is performed by rotary granulation in a fluidized air bed

combined with a system for spraying powder and a system for the tangential

spraying of wetting liquid. The process comprises two continuous steps, a

first step of spheronization of microspheres using a powder A and a second

step of spheronization of a powder B on the microspheres of powder A, one

of the powders A and B being acidic and the other alkaline and it being

possible for each of them to contain or consist of one or more active

principles.

During the first spheronization, the powder A is placed in the moving

rotary granulation tank and suspended in the air bed. The components of the

powder A are mixed together for five minutes and the air inlet temperature is

stabilized to a temperature To.


The powder A thus blended is sprayed with a wetting liquid containing

the water-soluble isolating agent. The microspheres of powder an obtained

are dried by bringing the air inlet temperature to Ts and are then optionally

screened using a 1000 .mu.m screen. During the second spheronization, the

air inlet temperature is brought to. The powder B and the wetting liquid

containing the water-soluble isolating agent are then simultaneously sprayed

onto the dried powder A microspheres obtained previously. The powder B is

sprayed by means of the powder spraying system installed on the Glatt

apparatus. The two-layer microspheres obtained are dried by bringing the air

inlet temperature to Ts. After drying, the microspheres must be packaged

quickly, but a small amount of moisture uptake does not harm the storage.

During the two spheronizations, the wetting liquid containing the water-

soluble isolating agent is the same, for example polyvinylpyrrolidone (PVP)

dissolved in an alcohol or an aqueous-alcoholic mixture, in particular PVP

dissolved to 4% by weight in ethanol at 60% by volume.

The two-layer microspheres obtained according to the process of the

invention have an average particle size of between 20 and 500 .mu.m.

A subject of the present invention is also a process for preparing

effervescent microspheres which have a three-layer structure according to

the second variant described above.

Said process is performed according to the method of rotary granulation

in a fluidized air bed combined with a system for the tangential spraying of

wetting liquid.

The process comprises three continuous steps, a first step of

spheronization of microspheres using a powder A, a second step of

spheronization of a water-soluble isolating agent on the microspheres of

powder A, and then a third step of spheronization of a powder B on the

microspheres A protected with a film of water-soluble isolating agent, one of

the powders A and B being acidic and the other alkaline and it being

possible for each of them to contain or consist of one or more active

principles.

During the first spheronization, the powder A containing an added

binder, for example PVP, is placed in the moving tank and suspended in the

air bed. The components of the powder A are mixed together for five


minutes and the air inlet temperature is stabilized to to. The powder A thus

blended is sprayed with a wetting liquid. The microspheres of powder A

obtained are dried by bringing the air inlet temperature to Ts. During the

second spheronization, the air inlet temperature is brought to To. The water-

soluble isolating agent is added directly to the tank and the wetting liquid

sprayed until microspheres of powder A which are coated with a film of

water-soluble isolating agent are obtained, and are dried by bringing the air

inlet temperature to Ts. After drying, the coated microspheres are screened

and the powder B is then added directly to the rotary granulation tank when

the air inlet temperature has stabilized at To. The three-layer microspheres

are obtained by spraying the preceding microspheres with a wetting liquid.

The three-layer microspheres obtained are dried by bringing the air inlet

temperature to Ts. After drying, the microspheres must be packaged quickly,

but a small amount of moisture uptake does not harm the storage.

During the first two steps, the wetting liquid is, for example, an

aqueous-alcoholic solution, in particular ethanol at 60% by volume. During

the final step, the water-soluble isolating agent can be introduced by means

of the powder B, in which case the wetting liquid used will be the same as

during the first two steps, or alternatively the isolating agent is introduced by

means of the wetting liquid, which will be an alcoholic or aqueous-alcoholic

solution containing the isolating agent, for example PVP dissolved to 4% by

weight in ethanol at 60% by volume.

The three-layer microspheres obtained according to the process of the

invention have an average particle size of between 200 and 1000 .mu.m.

According to the process for manufacturing microspheres, whether they

are two-layer or three-layer microspheres, the powder of alkaline nature

contains a sodium bicarbonate or any other carbonate usually used in the

preparation of effervescent forms, such as lithium hydrogen carbonate,

monosodium carbonate, lithium glycine carbonate, monopotassium

carbonate, calcium carbonate, magnesium carbonate; one or more active

principles if the latter have alkaline properties; whereas the powder of acidic

nature contains an organic acid, for example citric acid or a compound used

as active principle, for example ascorbic acid, acetylleucine and/or one or

more active principles if the latter have acidic properties.

The acidic and alkaline powders can also contain a diluent, for example

lactose or Glucidex; flavorings and sweeteners, for example orange


flavoring, citric acid, sodium saccharinate; various excipients.

According to one embodiment of the invention, the powder A is of

alkaline nature and the powder B is of acidic nature.

According to another embodiment of the invention, the powder B is of

alkaline nature and the powder A of acidic nature.

The wetting liquid is sprayed by means of a nozzle 1.2 mm in diameter,

at an average flow rate of between 10 and 30 g/min. The air inlet

temperature of the fluidized bed is between 55 and 650C during the

spheronization steps (To) and between 75 and 85oC. during the drying

phases (Ts).

The microspheres obtained according to the process of the invention

contain 5 to 75% of alkaline substance, 10 to 75% of acidic substance, 3 to

15% of water-soluble isolating agent, 5 to 50% of diluent and 1 to 30% of

flavorings and sweeteners.

The relative humidity of the microspheres obtained according to the

process of the invention, measured for fifteen minutes by the infrared

balance method at 90oC., is between 1 and 2% at the rotary granulation tank

outlet.

The overall yield for the process is calculated from the fraction of

particles smaller than 2500 .mu.m in size, the working yield of the spheres

corresponds to the fraction of particles between 200 and 1000 .mu.m, for the

process for preparing three-layer microspheres, between 20 and 500 .mu.m

for the process for preparing two-layer microspheres.

The feasibility of the process according to the invention is evaluated

according to the ease with which the microspheres are obtained, the speed of

production of a batch and the yield for each step.

Analysis of the batches includes particle size analysis of a sample of 100

g of spheres by the superimposed screens method (sample obtained from the

total fraction of a batch), after which a morphological study of the

microspheres obtained, relating to the overall appearance, sphericity,

cohesion and uniformity of the particles, is carried out by examination with a

binocular magnifying glass.


According to one variant of the invention, the two-layer or three-layer

effervescent microspheres are manufactured by the mounting technique

combined with a system for the tangential spraying of wetting liquid. The

powder A and the powder B can be mounted successively on spheres of

active principle coated with water-soluble isolating agent, or on neutral

spheres

(D) Novel formula of an effervescent vaginal tablet (A2)

The use of a vaginal tablet containing progesterone has been reported in

dogs but has not been pharmacologically evaluated in humans. In the present

study we examined the pharmacokinetics

of natural progesterone

administered in the form of vaginal tablets to non-oestrogen-primed post-

menopausal women. Dosages of 50 and 100 mg were used to determine

single-dose pharmacokinetics. The effect of continuous use on hormonal,

chemical, and lipid profiles were evaluated Our study was conducted to

assess the pharmacokinetics of natural progesterone administered in the

novel formula of an effervescent vaginal tablet.

Our study was conducted to assess the pharmacokinetics of natural

progesterone administered in the novel formula of an effervescent vaginal

tablet advantages are related mostly to patient compliance. Vaginal tablets

are easily administered by the woman herself. There is no messy discharge

as is sometimes seen with vaginal suppositories or creams. Only three

women (6%) experienced minimal vaginitis during the treatment, and none

withdrew from the study due to local vulvovaginal irritation. The vaginal

tablet should be inserted only twice daily. This is a convenient schedule also

for working women who can insert the tablet in the morning before going to

work and in the evening when they return, compared to the vaginally used

oral progesterone gelatin capsule that needs to be inserted 3 or 4 times per

day. Advantages are related mostly to patient compliance. Vaginal tablets are

easily administered by the woman herself. There is no messy discharge as is

sometimes seen with vaginal suppositories or creams. Only three women

(6%) experienced minimal vaginitis during the treatment, and none withdrew

from the study due to local vulvovaginal irritation. The vaginal tablet should

be inserted only twice daily. This is a convenient schedule also

for working

women who can insert the tablet in the morning before going to work and in

the evening when they return, compared

to the vaginally used oral

progesterone gelatin capsule that needs to be inserted 3 or 4 times per day


Chapter-8

ANALYTICAL PARAMETERS


Evaluation parameters: Both physical &chemical properties should be considered when

evaluating effervescent formulation. Here only physical properties

will be discussed because chemical properties will be affected by it’s effervescent base.

Many tests for example titrimetric, gravimetric, colorimetric,

volumetric tests as well as loss of weight measurements have been

proposed to determine the carbon dioxide content. Method based on

carbon dioxide pressure generation and weight loss has been

recently applied.

The determination of water content by Karl fisher titration in

effervescent preparation was possible after extraction with dioxanes.

Sodium bicarbonate which reacts with Karl fisher reagent is

insoluble in dioxanes and does not interfere with determination.

For tablets:

The disintegration and dissolution time is very important

characteristics for effervescent products. It is expected that a well

formulated effervescent tablets will disintegrate and dissolve within

1 to 2 min to form a clear solution. Consequently the residue of

undissolved drug must be minimal. The temperature of the water

also influence the dissolution time. It is therefore important to

choose the temperature of water that is actually used by the

consumer.

Such factors such as the crushing strength and friability will

influence the possibility of packaging the tablets on packaging lines

as effervescent tablets chip easily at the edges during handling.

When the tablets are filled in the tubes, the tablet height is of utmost

importance since the looseness or tightness of the packaging

depends on the tablet height.

When small or fairly small amounts of drug form part of the

formulation it is essential that the content uniformity be carefully

supervised.

For powder and granules:

Disintegration and dissolution time are as much important as powder

weight variation.

As the mass of the powder is many times larger than that of the

tablet, larger amount of raw material will have to be handled when

packaging the same number of tablets. Therefore the production area

will be larger.


All the steps during production of effervescent formulation should

be in dehumidified conditions. (less than 20 %RH &20°c) or mixing,

drying , granulating , milling can be performed in the normal

humidity conditions and store the final mixture in dehumidified

areas provided that packaging should also be in dehumidified area.

In direct compression method, the mixing can be done at normal

humilities but in that case the mixture is dried to prevent a premature

effervescent reaction. By means of causing dehumidified air to flow

through the bed in a suitable container. Tabletting and packaging are

also done in dehumidified conditions. Thus the number of

manufacturing stages in the low humidity zones is reduced.


Chapter-9

ADVANTAGES


(1)ADVANTAGES (A1)

Effervescent products offer many advantages but only when manufactured

and packaged correctly. Advantages of effervescence include:

good tasting, sparkling drinks containing ingredients which do not

normally taste good in liquid form

high dose products where large conventional tablets would have to be

swallowed

better delivery for those persons who dislike or cannot swallow tablets

and capsules

quicker and more complete absorption of dosages

compounds normally not stable or soluble in liquid form

A properly prepared effervescent tablet or powder can allow a large dose

of ingredients to be taken in a single serving. The organic food acid

combines with the carbonate source to form potassium, sodium, calcium or

magnesium salts of the acid and buffers the solution to a normal pH, so it is

easy on the stomach. Clinical studies performed on a variety of effervescent

products demonstrate that the ingredients penetrate the blood stream within

as little as 15 minutes.

1. Better and quicker absorption

In water, soda and fruit juices, effervescent tablets produce a pleasant

tasting, slightly sour solution. This is due to organic fruit acids

contained in the tablets. In conventional solid tablets, the compounds

often dissolve slowly in the stomach, which frequently delays or

reduces absorption. With effervescent tablets dissolved in a liquid, the

ingredients are absorbed quickly, completely and uniformly.

2. Optimal compatibility

After swallowing, conventional solid tablets or capsules are

transported to the stomach where they dissolve gradually. The passage

takes variably long in different people, depending on anatomical and

physiological factors. In case of a longer passage time, solid dosage

forms can dissolve partially and this can cause irritation of mucous

membranes. With a dissolved effervescent tablet, the ingredients are

evenly distributed in the solution, so that high, localized

concentrations cannot occur. The solution of the effervescent tablet


contains a balanced ratio of acids and carbonates. This balance is

called a buffer.

3. Increase in liquid intake

Daily liquid consumption should be 1.5 - 2 liters in adults. With

increased intake required during excessive fluid loss caused by events

such as intensive physical activity, diarrhea, or high temperatures in

summer. The intake of dissolved effervescent tablets supports the

daily liquid supply.

4. Advantages in case of swallowing problems

Many people have problems swallowing solid tablets or capsules. For

these people, effervescent tablets are a good alternative.

5. Simple handling and measuring into exact doses

Effervescent tablets are simply dissolved in a glass of water, soda, or

fruit juice - and after a short period of time a palatable solution is

ready for drinking. This is a great advantage over having to dissolve

granules or powders. Granules and instant powders must be measured

first and then stirred in the glass several times to obtain a uniform

solution. With effervescent tablets, the dose is standardized and the

liquid quantity is variable allowing for the taste to be adjusted

according to individual preference.


Chapter-10

LIMITATIONS


Limitations of effervescent formulations (A1)

1. It cannot be given to the children because of possibility of gas

(CO2) toxicity.

2. If packaging is not done properly then there are chances of

degradation by environmental moisture.

3. It has shorter shelf life as compared to other solid dosage forms.

4. It requires special machinery requirements for manufacturing.

5. This dosage form is costly then tablets.


Chapter-11

SUMMARY


Summary Effervescent formulations are those which are capable of producing

CO2 on contact with water. When these agents are added in the

glassful of water they give effervescence.

This technique is generally employed for antacid preparations. In this

preparation alkali metal bicarbonates & alkali metal carbonates like

Sodium carbonate &Sodium bicarbonates are added which reacts with

citric acid or tartaric acid to give effervescence.

Other ingredients of this formulation are coloring agents, flavoring

agents, lubricants, binders etc..

Different types of effervescent formulation are effervescent

formulation for oral use, effervescent bath products, effervescent

formulation for delayed effect, effervescent formulations containing

plant extract, effervescent proton pump inhibitors etc..

Effervescent formulations can be prepared by one of the following

methods: wet granulation, dry granulation, fusion method, hot melt

extrusion etc..

The packaging of effervescent formulation should be such that it can

maintain stability of the product especially protect the product against

moisture. For this purpose squeezed bottles or water soluble bags are

used.

The future of effervescent preparation is very bright. There are many

advance in this technology that are: floating or pulsatile drug delivery

system based on coated effervescent cores, effervescent micro

spheres, effervescent vaginal preparation etc..

There ate many advantages of this dosage form which are patient

compliance, increased rate of absorption, large dose can be given etc..

There are certain limitations too. That are it can not be given to the

children because of risk of carbon dioxide toxicity; it’s shorter shelf life; chance of product deterioration if packaging is not done properly

and the cost of manufacturing is high, as compared to other tablets.

Anyway, the future of effervescent formulation is very bright.


Chapter-12 REFERENCE


(a)from books:

(a1). Mohrle,R.,Effervescent tablets,In.,Pharmaceutical dosage

forms,Vol;1,(H. A. Lieberman &L. Lachman,eds.),Marcel Dekker,Inc.,New

York,1980,pp.225-258.

(a2) Reviews of patents on effervescent granules by A.V. Gothoskar&S.J.

Kshirsagar

(a3). Saleh, A.I., Aboutaleb, A., Boymond, C., Stamm, A. An approach to

the direct compression of effervescent tablets: mechanical properties

of the ingredients. Expo. Congr. Int. Technol. Pharm. 3, 38-48 (1985)

(a4). scheisen, G., Schmidt, P.C. Preparation and optimazation of

lubricants for effervescent tablets. Eur. J. Pharm. Biopharm. 41

(a5). International Journal of Pharmaceutics

Volume 187, Issue 2 , 5 October 1999, Pages 175-184

(a6). Anderson, H.R., Banker, G.S. and Peck, G.E., 1982. Quantitative

evaluation of pharmaceutical effervescent systems I: Design of testing

apparatus. J. Pharm. Sci. 71, pp. 3–13.

(a7). Krögel, I. and Bodmeier, R., 1996. Evaluation of the floating

properties of coated drug delivery systems containing effervescent

excipients. Eur. J. Pharm. Biopharm. 42, p. 21.

(a8). Krögel, I. and Bodmeier, R., 1997. Development of floating or

pulsatile DDS based on effervescent cores. Proc. Int. Symp. Control. Release

Bioact. Mater. 24, pp. 237–238.

(a9). AH Rau and H Yorozu, Effervescent bath tablet formulation

technology, Cosmet Toil 107(12) 55-62 (1992)

http://www.sciencedirect.com/science?_ob=JournalURL&_cdi=5069&_auth=y&_acct=C000052102&_version=1&_urlVersion=0&_userid=2304338&md5=270532aa74ab6ad06dd4a156d8cacf87

http://www.sciencedirect.com/science?_ob=IssueURL&_tockey=%23TOC%235069%231999%23998129997%23130172%23FLA%23display%23Volume_187,_Issue_2,_Pages_143-278_\(5_October_1999\)%23tagged%23Volume%23first%3D187%23Issue%23first%3D2%23Pages%23first%3D143%23last%3D278%23date%23\(5_October_1999\)%23&_auth=y&view=c&_acct=C000052102&_version=1&_urlVersion=0&_userid=2304338&md5=db9af326f812ccfd1f93a530cf06f17b

http://www.sciencedirect.com/science?_ob=ArticleURL&_aset=B-WA-A-W-BC-MsSAYZW-UUW-AAUEWBWYBD-AAUZYABZBD-YDZBVZVCV-BC-U&_rdoc=14&_fmt=full&_udi=B6T7W-3XJKT41-4&_coverDate=10%2F05%2F1999&_cdi=5069&_orig=search&_st=13&_sort=d&view=c&_acct=C000052102&_version=1&_urlVersion=0&_userid=2304338&md5=a2ea579820dbb3928c473448ac690f91#bbib2




(b)from internet:

(b1)http://www.alka-seltzer.com/as/facts.htm

(b2)http://www.drugdeliverytechnology-articleindex.htm

(b3)www.effervescent-vitamins.com

(b4) http://www.myvitanet.com/

(b5) www.pharmaceutical-technology.com

(b6)URL: http://www.bmp-production.de/

(b7) http://www.pharmaquality.com/Cover%20Story8.htm

(b8) http://www.recip.se/faq.asp

(b9) http://www.ibismedical.com/

(b10)http://www.uni-pharma.gr/company1.htm

(b11) http://www.phcog.org/positions.html

(b12) http://www.blackwellpublishing.com/.

(b13) http://www.medshopexpress.com/

(b14) http://www.drugstore.com/

(b15) http://www.healthtouch.com/

(b16) http://www.blueprintforhealthmn.com/

(b17) http://www.healthsentinel.com/

(b18)http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a682878.ht

ml

(b19)http//www.mypharmacy.co.uk

http://www.effervescent-vitamins.com/

http://www.myvitanet.com/

http://www.bmp-production.de/

http://www.pharmaquality.com/Cover%20Story8.htm

http://www.recip.se/faq.asp

http://www.ibismedical.com/

http://www.uni-pharma.gr/company1.htm

http://www.phcog.org/positions.html

http://www.blackwellpublishing.com/

http://www.medshopexpress.com/

http://www.drugstore.com/

http://www.healthtouch.com/

http://www.blueprintforhealthmn.com/

http://www.healthsentinel.com/

http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a682878.html

http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a682878.html


(B20) http://www.vitar.cz/eng/calcm.phtml

(b21) www.allnaturalvitamins.net/

(b22)www.qfac.comac

http://www.vitar.cz/eng/calcm.phtml

http://www.allnaturalvitamins.net/

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