Download 01-Yogi Agrawat

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:
Mr.R.P.Patel
(M.Pharm)
Department of Pharmaceutics
S. k. Patel college of
Pharmaceutical Edu. & Res.
Ganpat vidyanagar, Kherva.
Date:
Place: Ganpat vidyanagar,Kherva.
Principal I/C:
Dr. N. J. Patel
(M. Pharm., Ph. D.)
S. k. Patel college of
Pharmaceutical Edu. & Res
Ganpat vidyanagar, Kherva.
ACKNOWLEDGEMENT
This project report has been prepared to give a brief introduction of
“EFFERVESCENT FORMULATIONS” 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.
Agravat yogi mansukhlal
(FINAL B. PHARM)
DEDICATED
TO
MY FAMILY
&
FRIENDS
INDEX
Sr.no.
1
2
3
4
5
6
7
8
9
10
11
12
Name of chapter
Introduction
Composition of formulation
Types of effervescent formulation
Manufacturing techniques
Packaging
Market products available
Research
Analytical parameters
Advantages
Limitations
Summary
References
Page no.
1
5
15
27
33
36
39
50
53
56
58
60
Effervescent formulations
Chapter-1
INTRODUCTION
1
Effervescent formulations
2
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.
Effervescent formulations
3
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 40 oC. 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
Effervescent formulations
4
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 Ldopa/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.
Effervescent formulations
5
Chapter-2
COMPOSITION OF EFFERVESCENT
FORMULATION
Effervescent formulations
6
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
CO2 ↑------ (i)
-------à
Citric acid
Sodium bicarbonate
Carbon dioxide
H2C4H4O6 +
↑------ (ii)
Tartaric acid
dioxide
2 NaHCO3
-------à
Sodium bicarbonate
Na3C6H5O7 + 4 H2O +
Sodium citrate
Na2C4H4O6 + 2 H2O +
3
Water
2 CO2
Sodium tartrate Water Carbon
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
Effervescent formulations
7
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.
Effervescent formulations
8
Such plasticizers can also be ethylene glycol, 1,2-butylene glycol, 2,3butylene 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 30 oC. 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
Effervescent formulations
9
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. ClO 2 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.
Effervescent formulations
10
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
Effervescent formulations
11
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
Effervescent formulations
12
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, polyoxyethylenepolypropylene 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 150 oC 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
Effervescent formulations
13
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
Effervescent formulations
14
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.
Effervescent formulations
15
Chapter-3
TYPES OF EFFERVESCENT
FORMULATIONS
Effervescent formulations
16
(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-
Effervescent formulations
17
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.
Effervescent formulations
18
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.
Effervescent formulations
19
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
PLANT EXTRACT (B11)
FORMULATION
CONTAINING
The effervescent formulation elation in the form of granules or of a
tablet contains, in addition to the effervescent base, at least one watersoluble 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--
Effervescent formulations
20
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 60 oC; 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,
Effervescent formulations
21
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.
Effervescent formulations
22
(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 thermohygrometric 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
Effervescent formulations
23
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
Effervescent formulations
24
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.
Effervescent formulations
25
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, noneffervescent 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, antiinflammatories, 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,
Effervescent formulations
26
antiarthritics,
antiasthmatics,
anticoagulants,
anticonvulsants,
antidepressants,
antidiabetics,
antineoplastics,
antipsychotics,
antihypertensives, phenanthrene derivatives, antidiarrheal agents, diuretics,
and muscle relaxants.
Effervescent formulations
27
Chapter-4
MANUFACTURING TECHNIQUES
Effervescent formulations
28
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.
Effervescent formulations
29
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,
Effervescent formulations
30
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
Effervescent formulations
31
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.
Effervescent formulations
32
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 150oC. 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.
Effervescent formulations
33
Chapter-5
PACKAGING OF EFFERVESCENT
FORMULATION
Effervescent formulations
34
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, strippackaging 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
Effervescent formulations
35
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.
Effervescent formulations
36
Chapter-6
MARKET PRODUCTS AVAILABLE
Effervescent formulations
37
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..
B18
co.
10
Glucosamine
effervescent Glucosamine
tablets
11
Sulphate
Potassium
Airborn
B18
labs,Essex
Chloride Pottasium
Effervescent
12
Tower
Airborn
B4
Airborn
B4
Airborn
B4
Chloride
effervescent Vit-B(complex)
Dietory supplement tablets
13
Aliborange
Vit-C Vit-C,
Effervescent tablets
14
Revitalvit Calcium Tablet
Vit-D&K
Airborn
B4
15
Osteomax tablet
Mg&Vit-D
Airborn
B4
16
Solpadol
Paracetamol
& Sanofi-
B3
Effervescent formulations
17
Redoxone
38
Codeine
Synthelabo
Vit-C&Zinc
Sanofi-
B3
Synthelabo
18
LiFizz Multivitamin tab
Multivitamins
Sipharm
B4
19
Remedeine
Paracetamol&Di
Sanofi-
B3
hydrocodeine
Synthelabo
tartrate
20
Thymes blossom Efferbath
- - - - - -
Auravita
B21
Yerbamate&
Auravita
B21
tablets
21
Zotrime tab
Guarana
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
Chlorphenirami
Alka-seltzer
B1
effervescent tablets
ne
27
Nardil®
Penelzine
Vitar
B20
28
Parnate
Isocarboxide
Vitar
B20
29
Carbex
Selegiline
Vitar
B20
30
Instachlor
Chlorine
Vitar
B20
Effervescent formulations
39
Chapter-7
RESEARCH
Effervescent formulations
40
(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 m3/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
Effervescent formulations
41
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
Effervescent formulations
42
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
Effervescent formulations
43
(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
Effervescent formulations
44
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 60 oC. 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.
Effervescent formulations
45
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.
Effervescent formulations
46
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 watersoluble 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
Effervescent formulations
47
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 watersoluble 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
Effervescent formulations
48
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 85 oC. 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.
Effervescent formulations
49
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 postmenopausal 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
Effervescent formulations
Chapter-8
ANALYTICAL PARAMETERS
50
Effervescent formulations
51
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.
Effervescent formulations
52
 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.
Effervescent formulations
53
Chapter-9
ADVANTAGES
Effervescent formulations
54
(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
Effervescent formulations
55
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.
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Chapter-10
LIMITATIONS
Effervescent formulations
Limitations of effervescent formulations
57
(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.
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Chapter-11
SUMMARY
Effervescent formulations
59
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.
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Chapter-12
REFERENCE
Effervescent formulations
61
(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
Volume 187, Issue 2 , 5 October 1999, Pages 175-184
Pharmaceutics
(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)
Effervescent formulations
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(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
Effervescent formulations
(B20) http://www.vitar.cz/eng/calcm.phtml
(b21) www.allnaturalvitamins.net/
(b22)www.qfac.comac
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