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Introduction Page 1
1.0 INTRODUCTION
Oral drug delivery known for decades is the most widely utilized route for
administration among all routes that have been explored for systemic delivery of
different dosage forms. Popularity may be ease of administration as well as traditional
belief that by oral administration the drug is well absorbed like food stuff ingested
daily.
Suspensions occupy a central role in drug development. Because Drug in
suspension exhibits higher rate of bioavailability than other solid dosage forms.
Bioavailability is in following order,
Solution > Suspension > Capsule > Compressed Tablet > Coated tablet
Oral suspensions are solid-liquid dispersions whose drug delivery attributes
stand apart from those of solid and solution dosage forms. Among other positive
features, they are readily swallowed and thus particularly useful in paediatric and
geriatric medicines, and they allow the delivery of flexible and large doses of
insoluble or marginally soluble drugs that can't be easily accommodated in a single
capsule or tablet.
However, several challenges attend with formulating orally administered
suspensions. First, because of the substantial amount of interface between particles
and liquid, an oral suspension is thermodynamically unstable even though its active
and inactive ingredients may be chemically stable.
The inherent properties of a solid-liquid dispersion system affect not only its
physical stability but also its oral absorption. These properties include
(1) The interfacial area associated with the suspended particles;
(2) The polymorphic forms of the solids; and
(3) The growth of large crystals at the expense of small ones due to Ostwald ripening.
Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension
Introduction Page 2
As particle sizes decrease and interfacial free energy increases, the dispersion
systems naturally become increasingly unstable, resulting in aggregation, and particle
sedimentation with or without caking. If a compound is polymorphous, the solid form
of the drug may revert from a high energy state to a low one during the manufacture
and storage of suspensions. For these reasons, the most stable crystal form is
Preferable for preparing suspension dosage forms, but higher energy crystal forms
may have bioavailability advantages1.
We have evidence that stable oral suspensions can be developed using various
higher energy polymorphs to gain their bioavailability advantages. Another concern is
that orally administrated suspensions require acceptable organoleptic properties.
Many existing therapeutic agents have repugnant tastes that lessen patient
compliance, particularly in pediatric patients. Therefore, effective taste-masking
technologies are highly desirable. The third concern is the preparation of placebo
suspensions which are sometimes required for double-blind clinical trials. However,
developing a placebo suspension that looks and tastes like the active suspension is
more challenging than Preparing a placebo tablet or capsule.
The manufacture of generic drug products must make provision for market
competition and lower prices for the consumer, thereby making medicines more
affordable and more accessible to the wider population. Generic drug product
availability almost certainly influences the innovator drug product manufacturer to
develop new drug products that have improved efficacy and/or safety features.
Generic drug product development uses a different approach and strategy
compared to that used to develop a brand name drug product containing a new
chemical entity. Generic drug product manufacturers must formulate a drug product
that will have the same therapeutic efficacy, safety, and performance characteristics as
its brand name counterpart. In order to gain market approval, a generic drug product
cannot be ‘‘superior’’ or ‘‘better’’ than the brand name drug product.
TASTE MASKING
Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension
Introduction Page 3
The Unpleasant taste was the biggest barrier for completing treatment in
pediatrics. The field of taste masking of active pharmaceutical ingredients (API) has
been continuously evolving with varied technologies and new excipients. The flavor
of a substance is attributed to its taste, sight, odor and qualities such as mouth feel.
Taste refers to a perception arising from the stimulation of taste buds present on the
surface of the tongue. Humans can distinguish among five components of taste:
sourness, saltiness, sweetness, bitterness, and umami (savory). The sweet and the
sour-taste receptors are concentrated on the tip and both edges of the tongue
respectively, bitter taste is perceived by the receptors at the back of the tongue and
umami taste receptors are located all over the tongue. Taste masking becomes a pre-
requisite for bitter drugs to improve the patient compliance especially in the pediatric
and geriatric population
TASTE MASKING TECHNOLOGIES
Different taste masking technologies have been used to address the problem of
patient compliance. Taste masking technologies are increasingly focussed on
aggressively bitter tasting drugs like the macrolide antibiotics, non-steroidal anti-
inflammatory drugs and penicillins. Taste masking of water soluble bitter drugs,
especially those with a high dose, is difficult to achieve by using sweeteners alone. As
a consequence, more efficient techniques such as coating, microencapsulation and
granulation have been used in combination with the sweeteners. The different types of
technologies are as follows
Coating
Granulation
Sweeteners
Microencapsulation
Taste Suppressants and Potentiators
Solid Dispersions
Ion Exchange Resins
Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension
Introduction Page 4
Viscosity Enhancers
Complex Formation
pH Modifiers
Adsorbates
A. Coating
Coating is one of the most efficient and commonly used taste masking
technologies. Here, it is classified based on the type of coating material, coating
solvent system, and the number of coating layers. Hydrophobic polymers, lipids,
sweeteners and hydrophilic polymers can be used as coating materials, either
alone or in combination, as a single or multi-layer coat, to achieve the taste
masking by aqueous or organic based coating process.Taste masked famotidine
was formulated by using a combination of water soluble polymers like
polyvinylpyrrolidone and insoluble polymers like cellulose acetate as the coating
material. This polymeric solution gave a balance between taste masking and the
desired in-vitro release. The application of reverse enteric coating by using a
polymer synthesized from a hydrophobic monomer(cyclohexyl acrylate), a basic
monomer(dimethyl aminoethyl methacrylate) and a hydrophilic monomer to mask
the unpleasant taste of erythromycin. Hydrophobic polymers have been popularly
used for coating bitter medicaments to achieve taste masking. However,
hydrophilic polymers may also provide taste masking. For example, rotogranules
containing ibuprofen, polyvinylpyrrolidone, sodium starch glycolate and
sodiumlauryl sulfate were coated with hydrophilic polymers such as hydroxyethyl
cellulose or a mixture of hydroxyethyl cellulose and hydroxypropyl
methylcellulose to achieve taste masking. Sweeteners can be included in the
coating solution for a better taste masking performance. Kokubo and
Nishiyama(2006) described a similar approach to prepare the taste masked
etoricoxib [6]. Kokubo et al.(2001) prepared aqueous based film
coating(containing 2% w/wmethylcellulose of viscosity 2.0-8.0 mm2/s and a
sugar alcohol) to formulate taste masked coated particles . Taste masked pivoxil
Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension
Introduction Page 5
sulbactam formulation for syrup was prepared by melt granulating blend of
pivoxil sulbactam and glyceryl palmitostearate at temperature 45 to 47oC
followed by coating with colloidal silicon dioxide in a highspeed rotary mixer.
B. Granulation
Mixture of bitter medicaments and sweeteners, hydrophobic polymers, lipids
or waxes can be processed by dry, wet and melt granulation techniques to prepare
taste masked oral solid or liquid dosage forms. The melt granulation to achieve the
taste masking of calcium-containing compounds like calcium carbonate. Melt
granulation of a calcium-containing compound with a sugar alcohol as a binding
agent resulted in granules with an acceptable taste and mouth feel. Dabre et al.
(2007) developed taste masked pharmaceutical granules, which can be formulated
as dry syrup, suspension, conventional chewable or dispersible tablet. Granulation
of erythromycin with alginic acid was shown to enhance the mouth feel and
acceptance of the bitter medicament.
Granulation is a less expensive, rapid operation and an easily scalable taste
masking technology. Polymers, flavors and waxes have been used as granulating
agents to achieve the taste masking of bitter medicaments. Liquid and low melting
point waxes such as glycerol palmitostearate, glyceryl behenate and hydrogenated
castor oil are commonly used ingredients during the granulation to achieve taste
masking. Sugar alcohols and flavors are also added in the blend to increase the
efficiency of taste masking. Both pH dependent and independent water insoluble
polymers, especially the swelling polymers such as MCC and polycarbophil have
been employed. During granulation, particle coating may remain incomplete.
However, a swelling matrix phenomenon can reduce the overall diffusion of the
bitter active. Thus, swellable polymers can give a better taste masking in
granulation compared to non swellable polymers. Cation exchange resins, like
polacrillin potassium, have been used as a granulating agent to achieve taste
masking.
C. Sweeteners
Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension
Introduction Page 6
Sweeteners are commonly used in combination with other taste masking
technologies. They can be mixed with bitter taste medicaments to improve the taste of
the core material which is prepared for further coating or may be added to the coating
liquid. Taste masked lamivudine (antiretroviral drug) was prepared by using lemon,
orange and coffee flavors . Synthetic sweeteners such as sucralose are commonly used
in most taste masked products. Newer sweeteners derived from plant parts have been
evaluated for taste masking efficiency. For example, stevia was used to prepare the
taste masked ibuprofen. Enlists the examples of sweetening agents, the amounts
added and the benefits delivered by these taste masked formulations.
Sweeteners have been commonly used for the taste masking of
pharmaceuticals. Artificial sweeteners such as Sucralose, aspartame and saccharin
have been used in combination with sugar alcohols such as lactitol, maltitol and
sorbitol to decrease the after-taste perception of artificial sweeteners. Sucralose can be
used with physiologically acceptable acids (e.g. citric acid) to increase the taste
masking efficiency of the sweetener. Recently, sweeteners of plant sources such as
stevia and glycyrrhizin have emerged as a viable alternative to the artificial
sweeteners. Glycyrrhizin is extracted from glycyrrhiza root and is 50-60 times sweeter
than sucrose.. Non sucrose component of sugar beet extract was used as an edible
flavor improving agent.
D. Microencapsulation
Microencapsulation is a valuable technique applicable to protect materials
from volatilizing, oxidation as well as to mask their unpleasant taste.
Microencapsulation processes are commonly based on the principle of solvent
extraction or evaporation. However, modifications of other techniques such as phase
separation (coacervation) and spray drying are also utilized for microencapsulation.
Spray congealing is another method of microencapsulation. Menjoge and Kulkarni
(2006) described spray congealing of molten dispersion of clarithromycin, reverse
enteric polymers and lipids to prepare taste masked microcapsules .Coating by enteric
polymers in combination with water insoluble and gastrosoluble polymers or
Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension
Introduction Page 7inorganic or organic pore formers have been used for masking the unpleasant taste of
medicaments.
Combination of water soluble polymer like gelatin, and water insoluble
coating polymer like ethyl cellulose was used to prepare taste masked microcapsules
by the phase separation method. Enlists examples of taste masking excipients used for
microencapsulation of drug particles and advantages of the taste masked formulations.
Coating materials used in particulate coating are also commonly used for
microencapsulation. pH independent water insoluble polymers have been used with
enteric polymers, inorganic or organic pore formers to achieve taste masking by
microencapsulation. Buffering agents are also included in suspending medium to
increase taste masking efficiency of microcapsules in oral suspensions.
Microencapsulation can be an advantageous taste masking strategy for suspensions
due to the low particle size distribution of microcapsules that can remain suspended
for a longer time. The technique can be efficiently used for applying higher coating
levels.
E. Taste Suppressants and Potentiators
Most of the Linguagen’s bitter blockers (e.g. adenosine monophosphate)
compete with bitter substances to bind with the G-protein coupled(GPCR) receptor
sites . In general, the hydrophobic nature of these bitter substances contributes greatly
to their binding and inter-action with the receptor sites. Lipoproteins are universal
bitter taste blockers. Study on animal model showed that lipoproteins composed of
phosphatidic acid and lactoglobulin inhibit the taste nerve responses to the bitter
substances without affecting those due to the sugars, amino acids, salts or acids.
Venkatesh and Palepu(2002) described the application of taste suppressants like
phospholipid(BMI-60) in taste making of bitter medicaments. Neohesperidine
phospholipids have bitter taste suppression characteristics by interacting chemically
with the taste receptors. Cooling and warming agents suppress unpleasant taste of
medicament by subjecting taste receptors to extreme sensations to overpower the
bitter taste and confuse the brain. Mixture of cooling(e.g. eucalyptol) and warming
agents(e.g. methyl salicylate) was used for taste masking of thymol. Potentiators
Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension
Introduction Page 8increase the perception of the taste of sweeteners and mask the unpleasant after taste.
Potentiators such as thaumatine, neohesperidine dihydrochalcone(NHDC) and
glycyrrhizin can increase the perception of sodium or calcium saccharinates,
saccharin, aspartyl-pheny-lalanine, cesulfame, cyclamates, and stevioside.
Thaumatine was used with sugar alcohols to achieve the taste masking of bromhexine.
Describes examples of bitter taste blockers, suppressants and potentiators, their
amounts used and the problems overcome. The recent trend of use of bitter taste
blockers such as hydroxyflavanones, adenosine monophosphate and
gammaaminobutanoic acid were found to be effective to achieve the taste masking of
bitter drugs. Potentiators such as thaumatine and aldehydes can be used in
combination with the sweeteners to potentiate the palatable taste and to avoid an
unacceptable after-taste of sweeteners. A combination of cooling and warming agents
was an effective alternative to achieve taste masking.
F. Solid Dispersions
Specific interactions between poorly soluble drugs and hydrophilic polymers
can increase the solubility of the drug; likewise specific interactions between the drug
and the hydrophobic polymers might decrease the solubility of a drug . Recently solid
dispersions were introduced as a taste masking technology. Tsau and Damani(1994)
disclosed a drug-polymer matrix composition to achieve the taste masking of
dimenhydrinate. Amine or amido group of dimenhydrinate can have a physical and
chemical interaction with the carboxylic acid and esters groups of copolymers such as
shellac, zein and cellulose acetate phthalate. Cabrera (2005) developed the solid
dispersion of quinolone and naphthyridonecarboxylic acids in an insoluble matrix to
mask the taste of the active ingredient. Solid dispersion was prepared from the
solution of quinolone and the natural hydrophobic polymer shellac by solvent
evaporation. Solid dispersion of cephalosporins and cellulosic or methacrylic polymer
was formulated to mask the unpleasant taste of the medicament. Additional excipients
such as meglumine and magnesium silicate were added to increase the efficiency of
taste masking. Enlists taste masked examples of polymer-drug combi-nation using
solid dispersions. Hydrophobic polymers and long chain fatty acids have been used to
achieve the taste masking by solid dispersion. This approach usually requires a higher
Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension
Introduction Page 9concentration of excipients compared to other taste masking techniques. Natural
polymers such as shellac and zein, and enteric polymers like derivatives of acrylic
acid polymers and phthalate are good choices to develop the taste masked solid
dispersions.
G. Ion Exchange Resins
Ion exchange resins are high molecular weight polymers with cationic and
anionic functional groups. Resins form insoluble resinates through weak ionic
bonding with oppositely charged drugs and maintain low concentration of the free
drug in a suspension. After ingestion, the resinate exchange the drug with the counter
ion in gastrointestinal tract and the drug is eluted to be absorbed. Ion exchange resin
like Amberlite was used to formulate taste masked fast dissolving orally consumable
films of dextromethorphan. Describes examples of cation and anion exchange resins
and the amount of excipients added to achieve taste masking of bitter drugs, which
were selected based on the ionic characteristics of the drug.
H. Viscosity Enhancers
Suspending coated particles or microcapsules may not be efficient enough to
achieve taste masking of highly bitter medicaments in liquid oral suspensions. Usage
of viscosity enhancers in these cases would retard the migration of dissolved
medicament from the surface of the solid particle to the suspending medium.
Additionally, they can also decrease the contact between the bitter medicament and
the taste receptors, thus improving the overall taste masking efficiency. Hypromellose
was used as a viscosity modifier in taste masked azelastine suspension consisting of
sucralose as the sweetening agent. Fredrickson and Reo(2004) developed taste
masked multi-dose suspension of coated linezolid particles. Viscosity enhancers such
as xanthan gum, microcrystalline cellulose, and sodium carboxymethylcellulose have
been included in suspending vehicle to improve the taste masking efficiency.
I. Complex Formation
Complexing agents have been utilized to mask the objectionable taste of
drugs. The mechanism of taste masking by complex formation has two theoretical
possibilities. Either the cyclodextrins wraps the bad tasting molecule to inhibit its
Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension
Introduction Page 10interaction with the taste buds, or it interacts with the gatekeeper proteins of the taste
buds. Cyclodextrin was used to achieve taste masking of levosulpiride by complex
formation. Sweeteners such as acesulfame can form complex with medicaments to
achieve taste masking. Andreas (2003) described complex of xanthine and acesulfame
to achieve taste masking of the bitter medicament.
J. pH Modifiers
pH Modifying agents are capable of generating a specific pH
microenvironment in aqueous media that can facilitate in situ precipitation of the
bitter drug substance in saliva thereby reducing the overall taste sensation for liquid
dosage forms like suspension. Wyley (2004) described an application of pH
modifying agent such as L-arginine for taste masking of bitter medicament. L-
arginine maintains alkaline pH of the suspending vehicle to promote in situ
precipitation of des-quinolone in saliva. Redondo and Abanades (2003) developed
taste masked liquid formulation of ibuprofen by using sodium saccharin and pH
regulating agents.
K. Adsorbates
Adsorbates are commonly used with other taste masking technologies. The drug may
be adsorbed or/and entrapped in the matrix of the porous component, which may
result in a delayed release of the bitter active during the transit through the oral cavity
thereby achieving taste masking. Kashid et al.(2007) developed a taste masked
loperamide formulation with magnesium aluminum silicate by blending the drug and
the adsorbate, and further granulating with hydrophobic polymers to achieve taste
masking
FACTORS AFFECTING SELECTION OF TASTE MASKING TECHNOLOGY
A. Extent of Bitter Taste
With aggressively bad tasting medicaments even a little exposure is sufficient to
perceive the bad taste. For example, sweeteners could not achieve taste masking of
oral formulation of ibuprofen due to its dominating taste [10].Coating is more
efficient technology for aggressively bitter drugs even though coating imperfections,
Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension
Introduction Page 11if present, reduce the efficiency of the technique [103]. Similarly, microencapsulation
of potent bitter active agents such as azithromycin is insufficient to provide taste
masking of liquid oral suspensions [104]. Viscosity enhancers can complement the
taste masking efficiency. Oral suspension containing viscosity enhancers can
masquerade the objectionable taste, which arises from the leakage of drug from the
coated medicaments or microcapsules. This approach was also used for the
microencapsulated oxazolidinone particles to limit the transport of drug from the
polymer coated drug particles to the vehicle [105]. Conventional taste masking
techniques such as the use of sweeteners, amino acids and flavoring agents alone are
often inadequate in masking the taste of highly bitter drugs such as quinine, celecoxib,
etoricoxib, antibiotics like levofloxacin, ofloxacin, sparfloxacin, ciprofloxacin,
cefuroxime axetil, erythromycin and clarithromycin [106].
B. Dose of Active Pharmaceuticals
Dose of a drug may dictate whether a particular formulation strategy would be
suitable to achieve taste masking. In pediatric formulations, the dose is small enough
so as to allow the usage of flavoring agents to mask the taste of the medicine. For
example, low dose palatable pediatric aspirin oral formulation was developed by
adding sweeteners, but the same approach failed to address the problem of drugs like
acetaminophen because of its high dose. In such cases, coating is preferred to achieve
taste masking along with sweeteners to attain an acceptable final dosage form size
[107].
C. Drug Particle Shape and Size Distribution
Particle characteristics of the drug would affect the taste masking process efficiency.
Core materials with irregular shapes and small particle size lead to poor taste masking
efficiency and varying dissolution of coated particles [108]. Fines, abrasion and
variable coating thickness can lead to situations wherein the taste mask coating is
compromised. Multilayer coating using inner spacing layer to sequester the drug from
taste masking layer helps to reduce or eliminate such coating imperfections. Taste
masked granules of gatifloxacin and dextromethorphan were formulated by multilayer
coating consisting of inner spacing layer followed by outer taste masking layer [10].
Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension
Introduction Page 12D. Dosage Forms
It is estimated that 50% of the population have problem of swallowing tablets,
especially the pediatric and geriatric population. Chewable tablets and liquid oral
dosage forms have been used to address these problems. However, it is difficult to
formulate some drugs in these dosage forms due. to their poor palatability [17]. For
formulations which are swallowed unchewed capsules, coated tablets and slowly
disintegrating hard tablets have been used as preferred taste masking technologies.
Chewable tablets and liquid oral formulations are preferable in case of large dose
drugs for an ease of intake. Taste masking technologies such as sweeteners,
particulate coating, microencapsulation and granulation can be employed for
chewable tablets and supported with technologies such as viscosity enhancers and pH
modifiers to achieve taste masking in liquid oral formulations
[19].Microencapsulation of the unpleasant tasting active agent with ethyl cellulose or
a mixture of ethyl cellulose and hydroxypropyl cellulose or other cellulose derivatives
has been used to provide chewable taste-masked dosage forms. However, this
approach suffers from the disadvantage that the polymer coating releases the active
agent in an inconsistent fashion and may not provide an immediate release. Moreover,
coating is more suitable when the formulation is stored in a dry form. Viscosity
enhancers or pH modifiers can be used in the suspending medium to achieve taste
masking of suspended coated particles, especially for extremely bitter drugs like
erythromycin and its derivatives during the shelf life of a reconstituted suspension.
E. Drug Solubility
Physicochemical properties of the drug play an important role in the selection of taste
masking technology. For example, ondansetron has a relatively lower water solubility
at higher pH, based on which a rapidly disintegrating taste masked composition of
ondansetron was formulated by adding an alkalizing agent(sodium bicarbonate) to
reduce the water solubility and the consequent taste perception [110]. Douglas and
Evans(1994) described different approaches to achieve the taste masking of ranitidine
base and its salts having different solubility profiles. The bitter taste associated with a
poorly soluble form of ranitidine may be satisfactorily masked by lipid coating of the
Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension
Introduction Page 13drug substance. However, for water soluble forms of ranitidine(e.g. ranitidine
hydrochloride), the degree of taste masking achieved by simple lipid coating of the
drug substance may not be entirely satisfactory, particularly if the product is to be
formulated in an aqueous medium. Thus ranitidine hydrochloride was first
incorporated into the inner core of a polymeric binder, or a lipid or wax having a
melting point higher than that of the outer lipid coating to achieve an efficient taste
masking [9].
F. Ionic Characteristics of the Drug
Ionic characteristics of drugs govern the selection of ion exchange resin polymers and
the suitability of the drug candidate for this technology. For example, anionic
polymers (e.g. alginic acid) are good candidates for cationic drugs like donepezil
hydrochloride, and the cationic polymers are choice of excipients for anionic drugs
like sildenafil [53, 94].
CURRENT & FUTURE DEVELOPMENTS
The word ‘medicine’ for a child is synonymous with bad taste. Oral pharmaceuticals
have been continually adapted for making their “bitter taste better”, especially to the
pediatric and the geriatric consumers. Taste masking is a viable strategy to improve
the patient compliance, especially for bitter drugs, whereby, a gamut of
methodologies may be adopted to deliver a palatable formulation. Taste masked
products developed from innovative pharmaceutical technologies not only increase
the commercial profits, but also create brand value for a company. Some of the
branded products from patented taste masking technologies are Zantac® and
Pepcid®. Such intellectual wealth acts as an impetus for emergence of the innovative
low cost commercially viable taste masking technologies. Use of sweeteners is an age
old and most popular tool for disguising bitterness, the present trend has been towards
exploring intense sweeteners of natural origin that can hasten commercialization.
Also, the combination of sweeteners with other taste masking technologies including
microencapsulation, particulate coating, bitterness blockers, ion exchange resins and
potentiators is found to be a more efficient strategy. Improvement in coating
technology by use of multiple or spacer layers and a shift to aqueous based coating of
Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension
Introduction Page 14hydrophobic polymers are the newer trends. However, the technique requires
specialized skills for optimization and scale up of the process. Granulation, a simpler
technology finds more use of swelling polymers for efficient taste masking. Amongst
the strategies employed, bitter taste blockers which specifically block the bitter taste
but not the pleasant taste of any additive are being explored as universal taste masking
alternatives. Presently, they are limited in number, and most of them not being GRAS
(Generally Regarded As Safe) listed. With ongoing advancements,vusing a
combination of various taste masking technologies, future looks promising for taste
masking of bitter drugs.
Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension
Introduction Page 15
SUSPENSION
A Pharmaceutical suspension is a coarse dispersion in which internal phase is
dispersed uniformly throughout the external phase.
The internal phase consisting of insoluble solid particles having a specific
range of size which is maintained uniformly through out the suspending vehicle with
aid of single or combination of suspending agent.
The external phase (suspending medium) is generally aqueous in some
instance, may be an organic or oily liquid for non oral use.
CLASSIFICATION
Based On General Classes
Oral suspension
Externally applied suspension
Parenteral suspension
Based On Proportion of Solid Particles
Dilute suspension (2 to10%w/v solid)
Concentrated suspension (50%w/v solid)
Based On Electro kinetic Nature of Solid Particles
Flocculated suspension
Deflocculated suspension
Based On Size of Solid Particles
Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension
Introduction Page 16Colloïdal suspension (< 1 micron)
Coarse suspension (>1 micron)
Nano suspension (10 ng)
Features Desired In Pharmaceutical Suspensions
The suspended particles should not settle rapidly and sediment produced, must be
easily re-suspended by the use of moderate amount of shaking.
It should be easy to pour yet not watery and no grittiness.
It should have pleasing odour, colour and palatability.
Good syringe ability.
It should be physically, chemically and microbiologically stable.
Parenteral/Ophthalmic suspension should be sterilizable.
Advantages
Suspension can improve chemical stability of certain drug.
E.g. Procaine penicillin G
Drug in suspension exhibits higher rate of bioavailability than other dosage forms.
Bioavailability is in following order,
Solution > Suspension > Capsule > Compressed Tablet > Coated tablet
Duration and onset of action can be controlled.
E.g.Protamine Zinc-Insulin suspension
Suspension can mask the unpleasant/ bitter taste of drug.
Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension
Introduction Page 17 E.g. Chloramphenicol
INNOVATIONS IN SUSPENSIONS
Taste Masked Pharmaceutical Suspensions
Un-palatability due to bad taste is a major concern in most of the dosage forms
containing bitter drugs. In case of suspensions also taste masking is being applied to
mask bitterness of drugs formulated.
The taste masking approaches for suspensions can be summarized as
Polymer Coating of Drugs
The polymer coat allows the time for all of the particles to be swallowed before the
threshold concentration is reached in the mouth and the taste is perceived. The
polymers used for coating are
Ethyl cellulose
Eudragit RS 100
Eudragit RL 100
Eudragit RS 30 D
Eudragit RL 30 D
Polymer coated drug powders are also used for preparation of reconstitutable powders
that means dry powder drug products that are reconstituted as suspension in a liquid
vehicle such as water before usage. These reconstitutable polymer coated powders are
long shelf-life and once reconstituted have adequate taste masking.
Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension
Introduction Page 18Some examples of taste masked suspensions are as follows
Table -03
S.No Name of the drug Taste masking approach
1LEVOFLOXACIN
Polymer coating (Eudragit 100 : cellulose
acetate, 60:40 or 70:30)
2 ROXITHROMYCIN-I AND
ROXITHROMYCIN-IIPolymer coating with Eudragit RS 100
3 DICLOFENAC Polymer coating with Eudragit RS 100
Theory of Suspensions
Sedimentation Behavior
Introduction
Sedimentation means settling of particle or floccules occur under gravitational force
in liquid dosage form.
Theory of Sedimentation
Velocity of sedimentation expressed by Stoke’s equation
Vsed = d2 (ρs – ρo) g
18 ηo
= 2r 2 (ρs-ρo)
9 ηo
Where,
Vsed = sedimentation velocity in cm / sec
Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension
Introduction Page 19 d = Diameter of particle
r = radius of particle
ρs = density of disperse phase
ρ o = density of disperse media
g = acceleration due to gravity
η o = viscosity of disperse medium in poise
Stoke’s Equation Written in Other Form
V ' = V sed. εn
V ' = the rate of fall at the interface in cm/sec.
Vsed. = velocity of sedimentation according to Stoke’s low
ε = represent the initial porosity of the system that is the initial volume fraction
of the uniformly mixed suspension which varied to unity.
n = measure of the “hindering” of the system & constant for each system
Limitation of Stoke’s Equation 2, 7
Stoke’s equation applies only to:
Spherical particles in a very dilute suspension (0.5 to 2 gm per 100 ml).
Particles which freely settle without interference with one another (without
collision).
Particles with no physical or chemical attraction or affinity with the dispersion
medium.
But most of pharmaceutical suspension formulation has conc. 5%, 10%, or higher
percentage, so there occurs hindrance in particle settling.
Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension
Introduction Page 20Factors Affecting Sedimentation
Particle size diameter (d)
V α d 2
Sedimentation velocity (v) is directly proportional to the square of diameter of
particle.
Density difference between dispersed phase and dispersion media (ρs - ρo)
V α (ρ s - ρo)
Generally, particle density is greater than dispersion medium but, in certain
cases particle density is less than dispersed phase, so suspended particle floats & is
difficult to distribute uniformly in the vehicle. If density of the dispersed phase and
dispersion medium are equal, the rate of settling becomes zero.
Viscosity of dispersion medium (η)
V α 1/ ηo
Sedimentation velocity is inversely proportional to viscosity of dispersion
medium. So increase in viscosity of medium, decreases settling, so the particles
achieve good dispersion system but greater increase in viscosity gives rise to
problems like pouring, syringibility and redispersibility of suspenoid.
Advantages and Disadvantages due to viscosity of medium
Advantages
High viscosity inhibits the crystal growth.
High viscosity prevents the transformation of metastable crystal to stable crystal.
High viscosity enhances the physical stability.
Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension
Introduction Page 21
Disadvantages
High viscosity hinders the re-dispersibility of the sediments.
High viscosity retards the absorption of the drug.
High viscosity creates problems in handling of the material during manufacturing.
Sedimentation Parameters
Three important parameters are considered:
Sedimentation volume (F) or height (H) for flocculated suspensions
F = V u / VO -------------- (A)
Where, Vu = final or ultimate volume of sediment
VO = original volume of suspension before settling.
Sedimentation volume is a ratio of the final or ultimate volume of sediment
(Vu) to the original volume of sediment (VO) before settling. Some time ‘F’ is
represented as ‘Vs’ and as expressed as percentage. Similarly when a measuring
cylinder is used to measure the volume
F= H u/ HO
Where,
Hu = Final or ultimate height of sediment
H O = Original height of suspension before settling
Sedimentation volume can have values ranging from less than 1 to greater than1;
Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension
Introduction Page 22F is normally less than 1.
F=1, such product is said to be in flocculation equilibrium. And show no clear
Supernatant on standing Sedimentation volume (F¥) for deflocculated suspension
F ¥ = V¥/ VO
Where,
F¥=sedimentation volume of deflocculated suspension
V ¥ = sediment volume of completely deflocculated suspension. (Sediment volume
ultimate relatively small)
VO= original volume of suspension.
The sedimentation volume gives only a qualitative account of flocculation.
Fig -01
flocculated suspension
initial state (F=1)
State of suspension on storage of
some time (F=0.4)
Deflocculated suspension
Suspensions quantified by sedimentation volume (f)
Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension
Introduction Page 23
Degree of flocculation (β)
It is a very useful parameter for flocculation
Β = F/F∞
= Vu/Vo
V∞/Vo
= Vu/V∞
= ultimate sediment volume of flocculated suspension
Ultimate sediment volume of de flocculated suspension
Sedimentation velocity
The velocity dx / dt of a particle in a unit centrifugal force can be expressed in terms
of the Swedberg co-efficient ‘S’
Under centrifugal force, particle passes from position x 1at time t1 to position x2at time
t2.
The Sedimentation Behaviour of Flocculated and Deflocculated
Suspensions:
Flocculated Suspensions
Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension
Introduction Page 24
In flocculated suspension, formed flocs (loose aggregates) will cause increase
in sedimentation rate due to increase in size of sedimenting particles. Hence,
flocculated suspensions sediment more rapidly.
Here, the sedimentation depends not only on the size of the flocs but also on
the porosity of flocs. In flocculated suspension the loose structure of the rapidly
sedimenting flocs tends to preserve in the sediment, which contains an appreciable
amount of entrapped liquid. The volume of final sediment is thus relatively large and
is easily redispersed by agitation.
Deflocculated suspensions
In deflocculated suspension, individual particles are settling, so rate of
sedimentation is slow which prevents entrapping of liquid medium which makes it
difficult to re-disperse by agitation. This phenomenon also called ‘cracking’ or
‘claying’. In deflocculated suspension larger particles settle fast and smaller remain in
supernatant liquid so supernatant appears cloudy whereby in flocculated suspension,
even the smallest particles are involved in flocs, so the supernatant does not appear
cloudy.
Sedimentation behavior of flocculated and deflocculated suspensions
Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension
Introduction Page 25
Fig -02
Brownian movement (Drunken walk)
Brownian movement of particle prevents sedimentation by keeping the dispersed
material in random motion.
Brownian movement depends on the density of dispersed phase and the density
and viscosity of the disperse medium.
The kinetic bombardment of the particles by the molecules of the suspending
medium will keep the particles suspending, provided that their size is below
critical radius (r).
Brownian movement can be observed, if particle size is about 2 to 5 mm, when
the density of particle & viscosity of medium are favorable.
Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension
Introduction Page 26 If the particles (up to about 2 micron in diameter) are observed under a
microscope or the light scattered by colloidal particle is viewed using an ultra
microscope, the erratic motion seen is referred to as Brownian motion.
This typical motion viz., Brownian motion of the smallest particles in
pharmaceutical suspension is usually eliminated by dispersing the sample in 50%
glycerin solution having viscosity of about 5 cps.
The displacement or distance moved (Di) due to Brownian motion is given by
equation:
Where, R = Gas constant
T = Temp. In degree Kelvin
N = Avogadro’s number
η = Viscosity of medium
t = Time
r = Radius of the particle
The radius of suspended particle which is increased Brownian motions become
less & sedimentation becomes more important
In this context, NSD i.e. ‘No Sedimentation Diameter’ can be defined. It refers to
the diameter of the particle, where no sedimentation occurs in the suspensions
systems.
Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension
Introduction Page 27 The values of NSD depend on the density and viscosity values of any given
system.
Flocculating Agents
Flocculating agents decreases zeta potential of the suspended charged particle
and thus cause aggregation (floc formation) of the particles.
Examples of flocculating agents are:
Neutral electrolytes such as KCl, NaCl.
Calcium salts
Alum
Sulfate, citrates, phosphates salts
Neutral electrolytes e.g. NaCl, KCl besides acting as flocculating agents, also
decreases interfacial tension of the surfactant solution. If the particles are having less
surface charge then monovalent ions are sufficient to cause flocculation e.g. steroidal
drugs.
For highly charged particles e.g. insoluble polymers and poly-electrolytes
species, di or trivalent flocculating agents are used.
There are two important steps to formulate flocculated suspension
The wetting of particles
Controlled flocculation
The primary step in formulation is that adequate wetting of particles is
ensured. Suitable amount of wetting agents solve this problem which is described
under wetting agents.
Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension
Introduction Page 28
Careful control of flocculation is required to ensure that the product is easy to
administer. Such control is usually is achieved by using optimum concentration of
electrolytes, surface-active agents or polymers. Change in these concentrations may
change suspension from flocculated to deflocculated state.
Important Characteristics of Flocculated Suspensions
Particles in the suspension are in form of loose agglomerates.
Flocs are collection of particles, so rate of sedimentation is high.
The sediment is formed rapidly.
The sediment is loosely packed. Particles are not bounded tightly to each other.
Hard cake is not formed.
The sediment is easily redispersed by small amount of agitation.
The flocculated suspensions exhibit plastic or pseudo plastic behavior.
The suspension is somewhat unsightly, due to rapid sedimentation and presence of
an obvious clear supernatant region.
The pressure distribution in this type of suspension is uniform at all places, i.e. the
pressure at the top and bottom of the suspension is same.
In this type of suspension, the viscosity is nearly same at different depth level.
The purpose of uniform dose distribution is fulfilled by flocculated suspension.
Important Characteristics of Deflocculated Suspensions
In this suspension particles exhibit as separate entities.
Particle size is less as compared to flocculated particles. Particles settle separately
and hence, rate of settling is very low.
Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension
Introduction Page 29 The sediment after some period of time becomes very closely packed, due to
weight of upper layers of sedimenting materials.
After sediment becomes closely packed, the repulsive forces between particles are
overcome resulting in a non-dispersible cake.
More concentrated deflocculated systems may exhibit dilatant behavior.
This type of suspension has a pleasing appearance, since the particles are
suspended relatively longer period of time.
The supernatant liquid is cloudy even though majority of particles have been
settled.
As the formation of compact cake in deflocculated suspension, Brookfield
viscometer shows increase in viscosity when the spindle moves to the bottom of
the suspension.
There is no clear-cut boundary between sediment and supernatant.
Flocculation is necessary for stability of suspension, but however flocculation
affects bioavailability of the suspension. In an experiment by Ramubhau D et al.,
sulfathiazole suspensions of both flocculated and deflocculated type were
administered to healthy human volunteers. Determination of bioavailability was done
by urinary free drug excretion. From flocculated suspensions, bioavailability was
significantly lowered than deflocculated suspension. This study indicates the necessity
of studying bioavailability for all flocculated drug suspensions.
Rheological Behaviour
Introduction
Rheology is defined as the study of flow and deformation of matter. The
deformation of any pharmaceutical system can be arbitrarily divided into two types:
1) The spontaneous reversible deformation, called elasticity; and
Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension
Introduction Page 302) Irreversible deformation, called flow.
The second one is of great importance in any liquid dosage forms like suspensions,
solutions, emulsions etc.
Generally viscosity is measured as a part of rheological studies because it is easy to
measure practically.
Viscosity is the proportionality constant between the shear rate and shear stress, it is
denoted by η.
η = S/D
Where, S = Shear stress & D = Shear rate
Viscosity has units dynes-sec/cm 2 or g/cm-sec or poise in CGS system.
SI unit of Viscosity is N-sec/m2
1 N-sec/m2 = 10 poise
1 poise is defined as the shearing stress required producing a velocity difference of
1cm/sec between two
parallel layers of liquids of 1cm 2 area each and separated by 1 cm distance.
Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension
Introduction Page 31
Fig -03
Figure-03 showing the difference in velocity of layers
As shown in the above figure, the velocity of the medium decreases as the
medium comes closer to the boundary wall of the vessel through which it is flowing.
There is one layer which is stationary, attached to the wall. The reason for this is the
cohesive force between the wall and the flowing layers and inter-molecular cohesive
forces. This inter-molecular force is known as viscosity of that medium.
In simple words the viscosity is the opposing force to flow, it is characteristic of the
medium.
Formulation of Pharmaceutical Suspensions
Introduction
Suspension formulation requires many points to be discussed. A perfect
suspension is one, which provides content uniformity. The formulator must encounter
important problems regarding particle size distribution, specific surface area,
inhibition of crystal growth and changes in the polymorphic form. The formulator
must ensure that these and other properties should not change after long term storage
and do not adversely affect the performance of suspension. Choice of pH, particle
size, viscosity, flocculation, taste, color and odor are some of the most important
factors that must be controlled at the time of formulation.
The drug release from suspensions is mainly through dissolution .Suspension share
many physico- chemical characteristic of tablet & capsules with respect to the process
of dissolution.
As tablets and capsules disintegrate into powders and form suspension in the
biological fluids, it can be said that they share the dissolution process as a rate
limiting step for absorption and bio-availability.
Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension
Introduction Page 32
Wt1/3 = Wo1/3- K1/3 t
Where
Wt= particle weight at time t
Wo = initial particle weight
K1/3 = dissolution rate constant
And under sink condition (Cs >>>>> Cb)
K1/3 = (4Л/3δ2)1/3 *DCs/h
δ = solid density
Above equation mostly useful for dissolution of macroscopic solid spheres in which
the diffusion layer is considered constant and small compared with the size of the
sphere.
For multiparticulate system the square root relationship derived by Niebergall &
Goyan
Wt1/2 = Wo1/2- K1/2* t
Under sink condition,
K1/2 = (3Л/2δ)1/2 *DCs/k
K = proportionality constant between diffusion layer thickness and particle size.
Square root relationship is based on the observation that a square root dependency on
wt gave a steady dissolution rate constant for different particle size fractions of a
particular solid.
Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension
Introduction Page 33Higuchi & Hiestand explain the particulate dissolution system in which the size was
much smaller than the diffusion layer thickness.
Wt2/3 = Wo2/3- K2/3* t
Under sink condition
K2/3= (2*21/2/3δ1/2)2/3 *DCs
Formulation Factors Governing Drug Release
Wetting
Wetting of suspended particles by vehicle is must for proper dispersion.
Air entrapment on the particle promotes particles that rise to the top of the
dispersion medium, particle de-aggregation or other cause of instability. Poor
wetting on drug particle leads poor dissolution of particles and so retard release of
drug.
Viscosity
The total viscosity of the dispersion is the summation of the intrinsic viscosity of
the dispersion medium and interaction of the particles of disperse phase.
As per Stokes-Einstein equation,
D= KT/6лηr
Intrinsic viscosity of medium affects the dissolution rate of particles because of
the diffusion effect. On enhancement of viscosity the diffusion coefficient
decreases, which gives rise to a proportionate decreases in rate of dissolution
Effect of Suspending Agent
Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension
Introduction Page 34 Different suspending agents act by different way to suspend the drug for example
suspension with the highest viscosity those made by xanthan gum and tragacanth
powder shows inhibitory effects on the dissolution rate.
The suspension of salicylic acid in 1 % w/v dispersion of sodium
carboxymethycellulose and xanthan gum indicating effect of viscosity on
hydrolysis of aspirin in GIT is not significant from a bioavailability point of view.
EVALUATION OF SUSPENSIONS
Appearance of Phases
This test is done for the dispersed phase and dispersion medium. For
preparation of dispersion phase for suspension usually purified water and syrup are
used. The particle size distribution, clarity of syrup, the viscosity of gum dispersion,
quality control of water is monitored to keep an eye on the product quality.
Viscosity of Phases
Stability of a suspension is solely dependent on the sedimentation rate of
dispersed phase, which is dependent on the viscosity of the dispersion medium. So
this test is carried out to ensure optimum viscosity of the medium so a stable, re
dispersible suspension can be formed. The viscosity of the dispersion medium is
measured before mixing with dispersed phase and also viscosity after mixing is
determined using Brooke field viscometer. The calculated values are compared with
the standard values and if any difference is found necessary corrective action are
taken to get optimized viscosity.
Particle Size of Dispersed Phase
Optimum size of drug particle in the dispersed phase plays a vital role in
stability of final suspension. So this test is carried out to microscopically analyze and
find out particle size range of drug then it is compared with optimum particle size
required. If any difference is found, stricter monitoring of micronisation step is
ensured.
Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension
Introduction Page 35PH Test
PH of the phases of suspension also contributes to stability and characteristics
of formulations. So pH of the different vehicles, phases of suspension ,before mixing
and after mixing are monitored and recorded time to time to ensure optimum pH
environment being maintained.
Pourability
This test is carried out on the phases of suspension after mixing to ensure that
the final preparation is pourable and will not cause any problem during filling and
during handling by patient.
Final Product Assay
For proper dosing of the dosage form it is necessary that the active ingredient
is uniformly distributed throughout the dosage form. So samples are withdrawn from
the dispersed phase after micronisation and after mixing with dispersion medium,
assayed to find out degree of homogeneity. if any discrepancy is found out it is
suitably corrected by monitoring the mixing step to ensure a reliable dosage
formulation.
Sedimentation volume:
It is given by
Ultimate volume of’ sediment
F= Vu/Vo Original volume
Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension
Introduction Page 36If F >1, it is understood that the particles form a loose f1uff’ network in the vehicle,
causing the final volume of sediment to swell which can be greater than original
volume
When F = 1, the product is said to be in a state of ‘flocculation equilibrium’, which is
quite acceptable from a pharmaceutical standpoint.
Degree of flocculation - is given by
Ultimate sediment volume of flocculated suspension
β = V/V∞ Ultimate sediment volume of deflocculated suspension
Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension
Literature Review Page 37
2.0 LITERATURE REVIEW
Y.S.R. Krishnaiah, R.S. Karthikeyan, V. GouriSankar and V.Satyanarayana.,12
formulated “Three-layer guar gum matrix tablet formulations for oral controlled delivery
of highly soluble class III drug” using guar gum as a carrier. Matrix tablet granules
containing 30%, 40% or 50% of guar gum were prepared by the wet granulation
technique using starch paste as a binder. The three-layer guar gum matrix tablet estimated
using a HPLC method, provided the required release rate compare with the theoretical
release rate for guar gum formulations meant for twice daily administration. The results
indicated that guar gum, in the form of three-layer matrix tablets, is a potential carrier in
the design of oral controlled drug delivery systems for highly water-soluble drugs.
Gidwani, Suresh Kumar, Purushottam S., Tewari, Prashant Kumar.,13 designed
sustained release matrix pharmaceutical compositions containing 60mg of class III drug
constituting 8 to 50% by weight of the composition and hydrophobic polymers as a
retardant by hot melt granulation at a temperature of 40°C to 120°C, which release drug
in a sustained and reproducible manner over 24 hour. The Diluent comprises 10 to 70%
by weight of the composition such as calcium carbonate. Binder comprises 2 to 10%
consisting of gelatin and gum acacia. Glidant comprises 0.5 to 1.5% by weight of the
composition consisting of colloidal silicone dioxide. Lubricant comprises 0.5 to 1.0% by
weight of the composition selected from magnesium stearate. The tablets were film
coated with 0.5 to 4.0% by weight of the tablet using cellulose derivatives. The
dissolution was carried out in gastric simulated fluid pH 1.2 for the first hour and then in
phosphate buffer pH 6.8 USP.
Sweta et al.,14 developed “Controlled release monolithic matrix pharmaceutical
dosage form containing therapeutically effective amount of Class III drug, with rate
controlling water swellable polymer such as Xanthan gum comprises 7% to 60% by
weight of dosage form. And one hydrophobic material such as carnauba wax and stearic
acid comprises 20% to 60% by weight of dosage form. Further comprising
Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension
Literature Review Page 38
pharmaceutically acceptable excipients selected from fillers, binders, lubricants, glidants,
colouring agent, and flavoring agent. The in vitro release of drug is measured by a drug
release test which utilizes the USP Apparatus I at 100 rpm with 500 ml of phosphate
buffer at pH 6.8 and 37° C. Release rate is not less than about 75% after 16 hours.
Tulsidutt et al., 15 designed sustained release matrix pharmaceutical compositions
characterized by the absence of cellulose and/or their derivatives as release modifying
agent containing, class III drug constituting 8 to 50% by weight of total composition
formulated either water soluble material such as Polyethylene oxide, Sodium alginate,
Calcium alginate and Xanthan Gum and water insoluble material such as stearic acid and
polyvinyl acetate, or water swellable material such as guar gum, alginic acid.
Purushottam s et al.,16 developed sustained release matrix compositions
containing 60mg of Class III drug and hydrocolloid forming materials such as HPMC,
HPC, Povidone, SCMC, Sodium alginate, Polyvinyl alcohol, Xanthan gum. Hydrophobic
polymers as a retardant which release drug in a sustained and reproducible manner over a
prolonged period of time to achieve the sustained effect of drug over a 24 hour period
after oral administration.
Alan E. Royce 17 reported Polyethylene oxide polymer is employed as a directly
compressible binder matrix for therapeutically active dosage forms. Advantageously, the
polyethylene oxide has adjustable rate control effect on the release of medicament from
the dosage form, enabling in particular the preparation of sustained release dosage form.
Saleh M. Al-Saidan et al., 18 reported “In Vitro and In Vivo Evaluation of Guar
Gum Matrix Tablets for Oral Controlled Release of Water-soluble Diltiazem
Hydrochloride”, using various viscosity grades of guar gum prepared by wet granulation
method and subjected to in vitro drug release studies. The drug release from all guar gum
matrix tablets followed first-order kinetics. Guar gum matrix tablets showed no change in
physical appearance, drug content, or in dissolution pattern after storage at 40oC/ 75% RH
Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension
Literature Review Page 39
for 6 months. When subjected to invivo pharmacokinetic evaluation in healthy volunteers,
the tablets provided a slow and prolonged drug release. Based on the results of in vitro
and in vivo studies it was concluded that that guar gum matrix tablets provided oral
controlled release of water-soluble diltiazem hydrochloride.
Shashank Bababhai Patel et al., 19 developed “Once a day modified release oral
dosage form using co-polymer of polyvinyl acetate”. As the release-controlling agent
containing highly water soluble active ingredient.
D. Parekh et al., 20 designed oral controlled drug delivery for highly water-soluble
drug, using various hydrophilic polymer (HPMC), waxy substances (Compritol ATO 888
and Precirol ATO 5) and a natural gum (Xanthan Gum) were used.
Sung-Up Choi et al., 21 designed and evaluate a directly compressible hydrophilic
poly(ethylene oxide) (PEO) matrix for the oral sustained delivery of dihydrocodeine
bitartrate (DHCT). A direct compression method was used to prepare PEO matrices, and
the amount of PEO in the matrices was varied to optimize in vitro DHCT release profiles.
From the data obtained in this research, hydrophilic PEO matrices were found to be a
novel sustained-release carrier for the oral delivery.
Kewal K. Jain, MD., 22 Drug Delivery Systems-Extended-Release Oral Drug
Delivery Technologies: Monolithic Matrix Systems, pg no: 223-224.
Saptarshi Dutta et al., 23 developed modified release dosage form by replacing
conventional administration of drugs by delivery system which would release effective
quantities from a protected supply at a controlled rate over a long period of time. Ideally a
drug to provide desired therapeutic action should arrive rapidly at the site of the action
(receptor) in optimum concentration, remaining there for desired time, spare other site
and get removed from the site, one of the most recent and interesting result of
pharmaceutical research is the fact that absorption rate of release from the dosage form.
Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension
Literature Review Page 40
The product so formulated are designed as sustained action, sustained release, prolonged
action, depot, retard action, delayed action, that products in most case are similar in
appearance.
Ian J. Hardy et al., 24 studied the mechanism and kinetics of drug release on the
solubility of the active moiety and the swelling and erosion properties of the polymer,
with a water soluble compound released predominantly by diffusion. A simple, cost
effective and elegant solution for achieving a range of predictable release profiles from
linear to bi-modal for a water soluble drug from HPMC matrices, through the inclusion of
polyvinyl pyrrolidone (PVP).
Mohammad Mahiuddin Talukdar et al., 25 investigated the performance of
Xanthan gum (XG) and hydroxypropylmethyl cellulose (HPMC) as hydrophilic matrix-
forming agents in respect of compaction characteristics with its invitro drug release
behaviour. The overall compaction characteristics were found to be quite similar to each
other and were typical of polymer behaviour. But the flow characteristics were different,
i.e., XG was more readily flowable than HPMC. The observed difference in drug release
profiles between these two potential excipients were explored and explained by the
difference in their hydrophilicity and subsequent hydration properties.
Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension
Literature Review Page 41
2.1 GENERAL LITERATURE REVIEW
Samuel Levy, MD et al., 26 evaluate the potential benefit of oral highly soluble
drug (20 mg 3 times daily), an antianginal agent with a direct effect on ischemic
myocardium, in combination with oral diltiazem (60 mg three times daily) beta blockers.
David A. Fairman et al., 27 reported the class III drug acts as an effective
antianginal clinical agent by modulating cardiac energy metabolism. It selectively inhibits
long-chain 3-ketoacyl CoA thiolase (LC 3-KAT), there by reducing fatty acid oxidation
resulting in clinical benefit.
Evaristo Castedo et al., 28 analyzed the ischemia-reperfusion injury due to free
radicals that occurs during heart transplantation and to determine the potential
cytoprotective effect of highly soluble drug.
Gabriele Fragasso et al., 29 reported that the long-term addition of Class III drug
improves functional class and left ventricular function in patients with heart failure (HF).
Gilbert Regnier et al., 30 reported that the Class III drug is useful for the treatment
of ischeamic pathologies and peripheral vascular pathology.
Onay-Besikci A et al., 31 reported that the highly soluble drug is an effective and
well-tolerated antianginal drug that possesses protective properties against ischemia-
induced heart injury. It consists of two major sections: (1) comprehensive and critical
information about the pharmacological effects, mechanism of action, pharmacokinetics,
side effects, and current usage of Class III drug, and (2) developments in analytical
techniques for the determination of the drug in raw material, pharmaceutical dosage
forms, and biological samples.
Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension
Literature Review Page 42
Krishnamoorthy G’ Ganesh M 32, developed Spectrophotometric determination of
class III drug in bulk and solid dosage forms. Showing a maximum absorbance at 270nm.
Beer's law was obeyed in the concentration range of 400- 700 µg/ml.
Thoppil SO et al., 33 developed a simple, selective, precise and stability-indicating
high-performance thin-layer chromatographic method of analysis of highly soluble drug
both as a bulk drug and in formulations. This method was utilized to analyze class III
drug from conventional tablets and modified release tablets in the presence if commonly
used excipients.
M. Ganesh et al., 34 developed a new validated spectrophotometric method for
determination of class III drug in Formulation and comparison with UV method.
M.A. Naushad et al., 35 developed and validated the HPLC method for the analysis
of class III drug in bulk drug and pharmaceutical dosage forms.
Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension
Literature Review Page 43
Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension
Aim and Objective of the study Page 44
3.0 AIM AND OBJECTIVE OF THE STUDY
The Highly soluble drug selected for the study is a 3-ketoacyl-coenzyme, a
thiolase inhibitor with a cytoprotective effect, which by preserving the energy
metabolisms of the cell exposed to the hypoxia or ischemic, avoids the collapse of the
intracellular rate of adenosine triphosphate (ATP). Thus it ensures the functioning of the
ion pumps and the sodium-potassium transmembrane flux and maintains the cellular
homeostasis.
Highly soluble drug is used therapeutically in the long term treatment of angina
pectoris. It is freely soluble in water and has two pKa values of 4.32 and 8.95. This drug
is administered orally in doses of 40 to 60mg daily in divided doses as an immediate
release preparation. It is quickly absorbed and eliminated by the organism with plasma
half life of around 6.0 ± 1.4 hours and Tmax of around 1.8 ± 0.7 hours. Since it has a
shorter plasma half life, in practice 20mg preparation is given twice or thrice a day in
order to ensure relatively constant plasma levels but due to the fact that it is absorbed
quickly, these immediate release forms lead to maximum plasma levels immediately after
administration and to a very low plasma level at the time of the next dose, resulting in
great differences in peak and trough plasma levels at steady state. This drug is regarded as
a safe drug in the long term treatment of chronic ischemic disorders. This compels the
necessity of fabricating the immediate release dosage form into a modified release
preparation for achieving regular and constant plasma levels, which is also favourable for
compliance of the patient to his treatment.
OBJECTIVES OF STUDY
To provide a composition comprising a free flowing directly compressible vehicle
which can be blended with a medicament and directly compressed to prepare a
dosage form.
Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension
Aim and Objective of the study Page 45
To provide a compositions which is characterized by the absence of cellulose
and/or their derivatives as release modifying agents.
To provide a process for preparation of modified release compositions.
To provide a compositions which releases drug in a sustained and reproducible
manner over a prolonged period of time achieving a sustaining effect of drug over
8-12 hours period after oral administration
To provide composition of class III drug that demonstrate reliable release rate and
facilitated in-vivo absorption for desired period of time.
To provide MR composition which are useful for the treatment of angina pectoris
and has better patient compliance.
Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension
Plan of work Page 46
4.0 PLAN OF WORK
The present work was carried out to design and evaluate Modified release tablet of
highly soluble drug, a cellular acting anti-ischemic agent.
The Modified release tablets were prepared by direct compression technique using
Polyethylene oxide, Xanthan Gum, Povidone K90, as drug retardant polymers, which
control the release of drug, aimed to meet out the therapy for angina pectoris.
The scheme of the entire work is listed as follows
1. Literature review
2. Preformulation studies for highly soluble drug.
3. Compatibility studies using IR spectral studies and forced degradation
studies.
4. Preparation of a modified release tablet containing polymers, by direct
compression method.
5. Evaluation of Blend
Angle of repose
Bulk density and tapped density
Compressibility index
Hausner’s Ratio
Drug content uniformity
6. Evaluation of tablets
Weight Variation
Hardness
Friability
Thickness
7. Evaluation of in vitro release characteristics of all formulations using USP
dissolution apparatus 2 (paddle).
8. Checking the effect of pH (Multimedia dissolution) on the release pattern of a
modified release tablet using USP dissolution apparatus.
Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension
Plan of work Page 47
9. Comparison of the test formulation with the marketed product.
10. Stability studies of optimized formulation following ICH guidelines.
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Drug profile Page 48
DRUG PROFILE
Category: Antibiotic
Empirical Formula: C20H22N4O10S
Molecular Weight: 510.48 g/mol
Structure Formula:
Chemical Name: (1RS)-1-(acetyloxy)ethyl (6R,7R)-3-[ (carbamoyloxy)methyl]-7-[[(Z)-2-
(furan-2-yl)-2-(methoxyimino)acetyl]amino]-8-oxo-5- thia-1-azabicyclo[4.2.0]oct-2-ene-
2-carboxylate.
Physiochemical Properties
Appearance, odor and Color: A white or almost white powder.
Melting Point: Cefuroxime axetil (CA) shows polymorphism of three forms: Crystalline
form having a melting point of about 180° C., a substantially amorphous form having a
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Drug profile Page 49
melting point of about 135° C. and a substantially amorphous form having a lower
melting point in the range of about 70 to 95° C.
Solubility:
The amorphous Form is insoluble in water and in ether; slightly soluble in
Dehydrated alcohol; freely soluble in acetone; soluble in chloroform, in ethyl acetate, and
in methyl alcohol. The crystalline form is insoluble in water and in ether; slightly soluble
in dehydrated alcohol; freely soluble in acetone; sparingly soluble in Chloroform, in ethyl
acetate, and in methyl alcohol.
PHARMACODYNAMICS
The model drug has in vitro activity against a broad range of gram-positive and
gram-negative bacteria. The bactericidal action of Cefuroxime Axetil results from
inhibition of cell wall synthesis. Cefuroxime Axetil kills bacteria by binding to the target
sites in the bacterial cell membrane, the penicillin – binding proteins (PBPs). This effects
a change in the peptidoglycan by reducing the efficiency of cross-linking hence inducing
cell-wall weakness; as a result the bacterial cell wall swells and ruptures.
MECHANISM OF ACTION
Model drug is a second-generation cephalosporin that contains the classic β-
lactam ring structure. Bactericidal activity in vivo is resultant of its binding to essential
target proteins, termed the penicillin-binding proteins, which are located in, the bacterial
cell wall. Inhibition of these proteins leads to bacterial cell wall elongation and leakage,
thus the bacteria are unable to divide and mature.
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ACTIONS AND SPECTRUM
•Based on spectrum of activity, classified as a second generation cephalosporin.a
Generally no more active in vitro against susceptible gram-positive cocci than first
generation cephalosporins, but has an expanded spectrum of activity against gram-
negative bacteria compared with first generation drugs.
•Usually bactericidal.
•Like other β-lactam antibiotics, antibacterial activity results from inhibition of bacterial
cell wall synthesis.
•Spectrum of activity includes many gram-positive aerobic bacteria, some gram-negative
aerobic bacteria, and some anaerobic bacteria; inactive against Chlamydia, fungi, and
viruses.
•Gram-positive aerobes: Active in vitro and in clinical infections against Staphylococcus
aureus, S. epidermidis, Streptococcus pneumoniae, S. pyogenes (group A β-hemolytic
streptococci), and other streptococci. Oxacillin-resistant (methicillin-resistant)
staphylococci, Listeria monocytogenes, and most enterococci (e.g., Enterococcus
faecalis) are resistant.
•Strains of staphylococci resistant to penicillinase-resistant penicillins (oxacillin-resistant
staphylococci) should be considered resistant to cefuroxime and cefuroxime axetil,
although results of in vitro susceptibility tests may indicate that the organisms are
susceptible to the drug.63 In addition, β-lactamase-negative, ampicillin-resistant
(BLNAR) strains of H. influenzae should be considered resistant to cefuroxime and
cefuroxime axetil despite the fact that results of in vitro susceptibility tests may indicate
that the organisms are susceptible to the drug.
•Gram-negative aerobes: Active in vitro and in clinical infections against Citrobacter,
Enterobacter, Escherichia coli, Haemophilus influenzae (including ampicillin-resistant
strains), H. parainfluenzae, Klebsiella (including K. pneumoniae), Moraxella catarrhalis
(including ampicillin-resistant strains), Morganella morganii, Neisseria gonorrhoeae, N.
meningitidis, Proteus mirabilis, Providencia rettgeri, Salmonella, and Shigella.a Some
strains of Citrobacter, E. cloacae, and M. morganii are resistant.1 Acinetobacter
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Drug profile Page 51
calcoaceticus, Legionella, Campylobacter, Pseudomonas, P. vulgaris, Serratia usually are
resistant.
•Anaerobes: Active in vitro against Bacteroides (except B. fragilis), Clostridium (except
C. difficile), Fusobacterium, Peptococcus, and Peptostreptococcus
Biological Properties
cLogP : 0.653999984264
logP : -1.44000005722
pKa : 2.5
Cmax : 750 mg
T max : 45 minutes
Half-life (Mean) : 70 minutes
Pharmacokinetics
Absorption
After oral administration, Model drug is absorbed from the gastrointestinal tract
and almost complete, 95% of the dose gets absorbed upon oral administration.
The administration of food with model drug substantially increases its absorption 31, 35,
and 34. The bioavailability was shown to increase from 36% to 52% when a 500 mg dose
was taken in a fasting state
Compared to being administered after food.35 the mechanism for this increased
bioavailability is not completely understood. It has been proposed that food-induced
cholecystokinin release which causes the gall bladder to contract and release bile may be
responsible for improving absorption.36
Distribution
Model drug, as cefuroxime, is approximately 30% protein bound and has a
volume of distribution of about 15-20 per lit37. Distribution of this antibiotic into body
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fluids and tissues is variable, however, it does penetrate well (35-90%) into the tonsil
tissue, sinus tissue, and bronchial mucosa.38
Metabolism
Rapidly hydrolyzed by nonspecific esterase in the intestinal mucosa and blood to
cefuroxime. Cefuroxime is subsequently distributed throughout the extra cellular fluids.
The axetil moiety is metabolized to acetaldehyde and acetic acid
Due to the rapid conversion it is not possible to detect model drug in the systemic
Circulation31. Peak serum concentration achieved after a single 250 mg dose in the fed
state is 4.7 mcg/ml and is reached after 2.1 h post-ingestion.
Excretion
Once de-esterified and released into systemic circulation, cefuroxime is not
metabolized further, but is eliminated unchanged in the urine. In patients with normal
renal function, the plasma elimination half-life after a dose of 500 mg of cefuroxime is
1.4. h. The elimination half-life increases as the renal function declines. In patients with
creatinine Clearances <10 ml/min the elimination half-life extends to approximately 16.8
h.39 Based on these results, it is recommended that the dosing interval be extended in
patients with renal dysfunction
Dosage guide line for renal dysfunction
Estimated creatinine clearance recommended dosage
30 – 49 ml/min/1.73 m2 standard individual dose given Every 12 hr
10 – 29 ml/min/1.73 m2 standard individual dose given Every 24 hr
< 10 ml/min/1.73 m2 standard individual dose given Every 48 hr
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Contraindications
• Hypersensitivity to cephalosporin’s or penicillins
• Carnitine deficiency
THERAPEUTIC INDICATION OF CEFUROXIME AXETIL
Acute Otitis Media (AOM)
Treatment of AOM caused by Streptococcus pneumoniae, Haemophilus
influenzae (including β-lactamase-producing strains), Moraxella catarrhalis (including β-
lactamase-producing strains), or S. pyogenes.Not a drug of first choice; considered a
preferred alternative to amoxicillin or amoxicillin and clavulanate when these drugs are
ineffective or cannot be used (e.g., in patients with a history of non-type 1
hypersensitivity reactions to penicillin).
Bone and Joint Infections
Parenteral treatment of bone and joint infections caused by susceptible
Staphylococcus aureus (including penicillinase-producing strains).
Meningitis
Parenteral treatment of meningitis caused by susceptible S. pneumoniae, H.
influenzae (including ampicillin-resistant strains), Neisseria meningitidis, or S. aureus
(including penicillinase-producing strains).Not a drug of choice for meningitis; treatment
failures have been reported, especially in meningitis caused by H. influenzae. In addition,
bacteriologic response to cefuroxime appears to be slower than that reported with
ceftriaxone, which may increase the risk for hearing loss and neurologic sequelae. When
a cephalosporin is indicated for the treatment of bacterial meningitis, a parenteral third
generation cephalosporin (usually ceftriaxone or cefotaxime) generally recommended.
Pharyngitis and Tonsillitis
Treatment of pharyngitis and tonsillitis caused by S. pyogenes (group A β-
hemolytic streptococci).Generally effective in eradicating S. pyogenes from the
nasopharynx, but efficacy in prevention of subsequent rheumatic fever has not been
established.CDC, AAP, IDSA, AHA, and others recommend oral penicillin V or IM
penicillin G benzathine as treatments of choice; oral cephalosporins and oral macrolides
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Drug profile Page 54
considered alternatives.Amoxicillin sometimes used instead of penicillin V, especially for
young children.
Respiratory Tract Infections
Treatment of acute maxillary sinusitis caused by susceptible S. pneumoniae or H.
influenzae (non-β-lactamase-producing strains only).Data insufficient to date to establish
efficacy for treatment of acute maxillary sinusitis known or suspected to be caused by β-
lactamase-producing strains of H. influenzae or M. catarrhalis. Treatment of secondary
bacterial infections of acute bronchitis caused by susceptible S. pneumoniae, H.
influenzae (non-β-lactamase-producing strains only), or H. parainfluenzae (non-β-
lactamase-producing strains only).
Treatment of acute exacerbations of chronic bronchitis caused by susceptible S.
pneumoniae, H. influenzae (non-β-lactamase-producing strains only), or H.
parainfluenzae (non-β-lactamase-producing strains only).
Parenteral treatment of lower respiratory tract infections (including pneumonia)
caused by susceptible S. pneumoniae, S. aureus (including penicillinase-producing
strains), S. pyogenes (group A β-hemolytic streptococci), H. influenzae (including
ampicillin-resistant strains), Escherichia coli, or Klebsiella.1
Treatment of community-acquired pneumonia (CAP).Recommended by ATS and
IDSA as an alternative for treatment of CAP caused by penicillin-susceptible S.
pneumoniae.Also recommended as an alternative in certain combination regimens used
for empiric treatment of CAP.Select regimen for empiric treatment of CAP based on most
likely pathogens and local susceptibility patterns; after pathogen is identified, modify to
provide more specific therapy (pathogen-directed therapy).
For empiric outpatient treatment of CAP when risk factors for drug-resistant S.
pneumoniae are present (e.g., comorbidities such as chronic heart, lung, liver, or renal
disease, diabetes, alcoholism, malignancies, asplenia, immunosuppression; use of anti-
infectives within the last 3 months), ATS and IDSA recommend monotherapy with a
fluoroquinolone active against S. pneumoniae (moxifloxacin, gemifloxacin, levofloxacin)
or, alternatively, a combination regimen that includes a β-lactam active against S.
pneumoniae (high-dose amoxicillin or fixed combination of amoxicillin and clavulanic
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acid or, alternatively, ceftriaxone, cefpodoxime, or cefuroxime) given in conjunction with
a macrolide (azithromycin, clarithromycin, erythromycin) or doxycycline.Cefuroxime and
cefpodoxime may be less active against S. pneumoniae than amoxicillin or ceftriaxone.
If a parenteral cephalosporin is used as an alternative to penicillin G or
amoxicillin for treatment of CAP caused by penicillin-susceptible S. pneumoniae, ATS
and IDSA recommend ceftriaxone, cefotaxime or cefuroxime; if an oral cephalosporin is
used for treatment of these infections, ATS and IDSA recommend cefpodoxime,
cefprozil, cefuroxime, cefdinir, or cefditoren.
Septicemia
Parenteral treatment of septicemia caused by susceptible S. aureus (including
penicillinase-producing strains), S. pneumoniae, E. coli, H. influenzae (including
ampicillin-resistant strains), or Klebsiella.
In the treatment of known or suspected sepsis or the treatment of other serious
infections when the causative organism is unknown, concomitant therapy with an amino
glycoside may be indicated pending results of in vitro susceptibility tests.
Skin and Skin Structure Infections
Oral treatment of uncomplicated skin and skin structure infections caused by
susceptible S. aureus (including β-lactamase-producing strains) or S. pyogenes.Parenteral
treatment of skin and skin structure infections caused by susceptible S. aureus (including
β-lactamase-producing strains), S. pyogenes, E. coli, Klebsiella, or Enterobacter.
Urinary Tract Infections (UTIs)
Oral treatment of uncomplicated UTIs caused by susceptible E. coli or K.
pneumoniae.Parenteral treatment of UTIs caused by susceptible E. coli or K. pneumoniae.
Gonorrhea and Associated Infections
Oral or parenteral treatment of uncomplicated gonorrhea caused by susceptible N.
gonorrhoeae.May be effective in urethral, endocervical, and rectal gonorrhea;not
recommended for pharyngeal infections.Not a drug of choice for treatment of
uncomplicated gonococcal infections;oral cefuroxime may be an alternative for
uncomplicated urogenital and anorectal infections when IM ceftriaxone or oral cefixime
cannot be used.Parenteral treatment of disseminated gonococcal infections caused by
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susceptible N. gonorrhoeae. Not included in current CDC recommendations for
disseminated gonococcal infections.
Lyme Disease
Treatment of early Lyme disease manifested as erythema migrans.IDSA, AAP,
and other clinicians recommend oral doxycycline, oral amoxicillin, or oral cefuroxime
axetil as first-line therapy for treatment of early localized or early disseminated Lyme
disease associated with erythema migrans, in the absence of specific neurologic
involvement or advanced atrioventricular (AV) heart block.Treatment of early neurologic
Lyme disease† in patients with cranial nerve palsy alone without evidence of meningitis
(i.e., those with normal CSF examinations or those for whom CSF examination is deemed
unnecessary because there are no clinical signs of meningitis).Parenteral anti-infectives
(IV ceftriaxone, IV penicillin G sodium, or IV cefotaxime) recommended for treatment of
early Lyme disease when there are acute neurologic manifestations such as meningitis or
radiculopathy.
Treatment of Lyme carditis.IDSA and others state that patients with AV heart
block and/or myopericarditis associated with early Lyme disease may be treated with an
oral regimen (doxycycline, amoxicillin, or cefuroxime axetil) or a parenteral regimen (IV
ceftriaxone or, alternatively, IV cefotaxime or IV penicillin G sodium).A parenteral
regimen usually recommended for initial treatment of hospitalized patients; an oral
regimen can be used to complete therapy and for the treatment of outpatients.Treatment
of borrelial lymphocytoma.Although experience is limited, IDSA states that available
data indicate that borrelial lymphocytoma may be treated with an oral regimen
(doxycycline, amoxicillin, or cefuroxime axetil).
Treatment of uncomplicated Lyme arthritis† without clinical evidence of
neurologic disease.An oral regimen (doxycycline, amoxicillin, or cefuroxime axetil) can
be used,but a parenteral regimen (IV ceftriaxone or, alternatively, IV cefotaxime or IV
penicillin G sodium) should be used in those with Lyme arthritis and concomitant
neurologic disease. Patients with persistent or recurrent joint swelling after a
recommended oral regimen should receive retreatment with the oral regimen or a switch
to a parenteral regimen.Some clinicians prefer retreatment with an oral regimen for those
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Drug profile Page 57
whose arthritis substantively improved but did not completely resolve; these clinicians
reserve parenteral regimens for those patients whose arthritis failed to improve or
worsened.Allow several months for joint inflammation to resolve after initial treatment
before an additional course of anti-infectives is given.
Perioperative Prophylaxis
Perioperative prophylaxis in patients undergoing noncardiac thoracic or
orthopedic surgery. A preferred agent. Has been used for perioperative prophylaxis in
patients undergoing cardiac surgery, GI surgery,or gynecologic or obstetric surgery (e.g.,
vaginal hysterectomy). Other drugs usually preferred.
AVAILABILITY
Oral suspension: 125 mg/5 ml
Powder for injection: 750 mg, 1.5 g, 7.5 g
Premixed containers: 750 mg/50 ml, 1.5 g/50 ml
Tablets: 125 mg, 250 mg, 500 mg
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Excipient Profile Page 58
EXCIPIENTS PROFILE
Stearic acid
SynonymsAcidum stearicum; cetylacetic acid; Crodacid; Cristal G; Cristal S;
Dervacid
DescriptionStearic acid is a hard, white or faintly yellow-colored, somewhat
glossy, crystalline solid or a white or yellowish white powder.
Empirical Formula C18H36O2
Solubility
Freely soluble in benzene, carbon tetrachloride, chloroform,
and ether; soluble in ethanol (95%), hexane, and propylene glycol;
practically insoluble in water.
Functional
categoriesEmulsifying agent; solubilizing agent; tablet and capsule lubricant.
Density (bulk) 0.537 g/cm3
Melting point 69–70 C
Applications
Stearic acid is widely used in oral and topical pharmaceutical
formulations. It is mainly used in oral formulations as a tablet and
capsule lubricant; although it may also be used as a binder or in
combination with shellac as a tablet coating. It has also been
suggested that stearic acid may be used in enteric tablet coatings
and as a sustained-release drug carrier.
IncompatibilitiesStearic acid is incompatible with most metal hydroxides and may
be incompatible with bases, reducing agents, and oxidizing agents.
Stability and storage
conditions
Stearic acid is a stable material; an antioxidant may also be added
to it; The bulk material should be stored in a well closed container
in a cool, dry place.
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Excipient Profile Page 59
sucrose
SynonymsBeet sugar; cane sugar; a-D-glucopyranosyl-b-D-fructofuranoside;
refined sugar; saccharose; saccharum; sugar
Description white crystalline powder; it is odorless and has a sweet taste.
Empirical Formula C12H22O11
SolubilityPractically insoluble in water, soluble in ethanol (96%) and in light
petroleum (50-70°C).
Functional
categories
Confectionery base; coating agent; granulation aid; suspending
agent; sweetening agent; tablet binder; tablet and capsule diluent;
tablet filler; therapeutic agent; viscosity-increasing agent
Density (bulk) 0.93 g/cm3 (crystalline sucrose); 0.60 g/cm3 (powdered sucrose)
Melting point 160–186 C
Applications
Sucrose is widely used in oral pharmaceutical formulations.
Sucrose syrup, containing 50–67% w/w sucrose, is used in
tableting as a binding agent for wet granulation. In the powdered
form, sucrose serves as a dry binder (2–20% w/w) or as a bulking
agent and sweetener in chewable tablets and lozenges.
Incompatibilities
Powdered sucrose may be contaminated with traces of heavy
metals, which can lead to incompatibility with active ingredients,
e.g. ascorbic acid.
Stability and storage
conditions
Sucrose has good stability at room temperature and at moderate
relative humidity. It absorbs up to 1% moisture, which is released
upon heating at 90 C. The bulk material should be stored in a well-
closed container in a cool, dry place.
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Excipient Profile Page 60
Xanthan Gum
SynonymCorn sugar gum; polysaccharide B-1459; Rhodigel;
Vanzan NF; Xantural.
DescriptionXanthan gum occurs as a cream- or white-colored,
odorless, free-flowing, fine powder.
Molecular Formula (C35H49O29)n
SolubilityPractically insoluble in ethanol and ether; soluble in
cold or warm water
Viscosity1200–1600 mPa s (1200–1600 cP) for a 1% w/v
aqueous solution at 258°C.
Functional categoryGelling agent; stabilizing agent; suspending agent;
sustained-release agent; viscosity-increasing agent.
Grade Keltrol CG, Grindsted Xanthan 80, Vanzan NF
Stability and storage
condition
Aqueous solutions are stable over a wide pH range
(pH 3–12), although they demonstrate maximum
stability at pH 4–10 and temperatures of 10–608°C.
Incompatibilities
Xanthan gum is an anionic material and is not
usually compatible with cationic surfactants,
polymers, or preservatives, as precipitation occurs.
Application
Xanthan gum is used to prepare sustained-release
matrix. Xanthan gum has also been used to produce
directly compressed matrices that display a high
degree of swelling due to water uptake, and a small
amount of erosion due to polymer relaxation.
Safety
The estimated acceptable daily intake for Xanthan
gum has been set by the WHO at up to 10 mg/kg
body-weight.
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Excipient Profile Page 61
Povidone
Synonym
Kollidon; Plasdone; poly [1-(2-oxo-1-pyrrolidinyl) ethylene];
polyvidone; polyvinylpyrrolidone; PVP; 1-vinyl-2-
pyrrolidinone polymer.
DescriptionPovidone occurs as a fine, white to creamy-white colored,
odorless or almost odorless, hygroscopic powder.
Molecular Formula (C6H9NO)n
Functional Category Disintegrant; dissolution aid; suspending agent; tablet binder.
Solubility
Freely soluble in acids, chloroform, ethanol (95%), ketones,
methanol, and water; practically insoluble in ether,
hydrocarbons, and mineral oil.
Melting point Softens at 150 0C.
Density (bulk)
Density (tapped)
0.29–0.39 g/cm3
0.39–0.54 g/cm3
Stability and storage
conditions
Povidone may be stored under ordinary conditions without
undergoing decomposition or degradation. However, since
the powder is hygroscopic, it should be stored in an airtight
container in a cool, dry place.
Incompatibilities
It forms molecular adducts in solution with sulfathiazole,
sodium salicylate, salicylic acid, phenobarbital, tannin, and
other compounds;
Safety
When consumed orally, povidone may be regarded as
essentially nontoxic since it is not absorbed from the
gastrointestinal tract or mucous membranes. Povidone
additionally has no irritant effect on the skin and causes no
sensitization.
ApplicationIn tableting, povidone solutions are used as binders in wet
granulation processes.
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Excipient Profile Page 62
neotame
Synonyms
3-(3,3-Dimethylbutylamino)-N-(a-carboxyphenethyl)succinamic
acid methyl ester; N-[N-(3,3-dimethylbutyl)-L-a-aspartyl]-L-
phenylalanine 1-methyl ester; L-phenylalanine, N-[N-(3,3-
dimethylbutyl)- L-a-aspartyl]-1-methyl ester.
Description
Neotame occurs as an odorless, white to off-white powder. It has
an intense sweet taste 7000–13 000 times sweeter than sucrose
depending on the matrix.
Empirical Formula C20H30N2O5
Functional
categoriesFlavor enhancer; sweetening agent
pH 5.0–7.0
Density (bulk)
Melting point 80–83 C
Applications
Neotame is a water-soluble, nonnutritive, intense sweetening agent
used in beverages and foods. Neotame may be used in sub-
sweetening quantities as a flavor enhancer, e.g. with mint or
strawberry flavor.
Stability and storage
conditions
Neotame stability is affected by moisture, pH, and temperature.
The bulk material should be stored in a well-closed container, in
a cool, dry place; it is stable for up to 5 years at room temperature
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Excipient Profile Page 63
Acesulfame Potassium
Synonyms
Acesulfame K; ace K; acesulfamum kalicum; E950; 6-methyl-3,4-
dihydro-1,2,3-oxathiazin-4(3H)-one-2,2-dioxide potassium salt;
potassium 6-methyl-2,2-dioxo-oxathiazin-4-olate; Sunett; Sweet
One.
DescriptionAcesulfame potassium occurs as a colorless to white-colored,
odorless, crystalline powder with an intensely sweet taste.
Empirical Formula C4H4KNO4S
SolubilitySoluble in water, very slightly soluble in acetone and in ethanol
(96%).
Functional
categoriesSweetening agent.
Density (bulk) 1.04 g/cm3
Melting point 250 C
Applications
Acesulfame potassium is used as an intense sweetening agent in
cosmetics, foods, beverage products, table-top sweeteners, vitamin
and pharmaceutical preparations, including powder mixes, tablets,
and liquid products.It enhances flavor systems and can be used to
mask some unpleasant taste characteristics.
Stability and storage
conditions
In the bulk form it shows no sign of decomposition at ambient
temperature over many years. In aqueous solutions (pH 3.0–3.5 at
208C) no reduction in sweetness was observed over a period of
approximately 2 years. Stability at elevated temperatures is good,
although some decomposition was noted following storage at
408C for several months. The bulk material should be stored in a
well-closed container in a cool, dry place and protected from light.
Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension
Materials and Instruments Page 64
8.0 MATERIALS AND INSTRUMENTS
Table- 07: Material used
S.No Ingredients Manufacturer
1 Highly bitter drug BP/Ph.Eur Aurobindo
2 Stearic acid Ph.Eur Taurus chemicals limited
3 Xanthan gum FF Ph.Eur C.P Kelco U.S Ink
4 Povidone K30 Ph.Eur ISP Technologies
5 Acesulfame potassium sunset Ph.Eur Nutrinova
6 Neotame Ph.Eur
7 Tutti-frutti IH Firmenich
8 Orange flavor IH Firmenich
9 Strawberry flavor IH Firmenich
10 Sucrose Ph.Eur M.B. Sugars & Pharmaceuticals
Table- 08: Instruments used
S.No. Name of Instrument Manufacturer
1 Digital Weighing balance Essae digi
2 Vibratory Sifter Ganson / Anchor
3 Octagonal Blender Ganson / Bectochem
4 Tablet Compression machine Cadmach Machinery pvt. Ltd
5 Vernier calipers Mitatoyo
6 Friability apparatus Electrolab
7 Hardness tester Varian
8 Moisture balance Essae Teroka
9 GPCJ 1.1 Pam Glatt
10 Six station dissolution test apparatus Electro Lab
11 UV-Visible Spectrophotometer Shimadzu
12 pH meter Mettler Toledo
Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension
Preformulation studies Page 65
9.0 PREFORMULATION STUDIES
Before formulation of drug substances into a dosage form, it is essential that drug
polymer should be chemically and physically characterized. Preformulation studies gives
the information needed to define the nature of the drug substance and provide a
framework for the drug combination with pharmaceutical excipients in the fabrication of
a dosage form.
Compatibility studies by IR
One of the requirements for the selection of suitable excipients or carrier for
pharmaceutical formulation is its compatibility. Therefore in the present work a study was
carried out by using infrared spectrophotometer to find out if there is any possible
chemical interaction of highly bitter drug with Stearic acid, Xanthan gum ,Povidone
K30 ,Acesulfame potassium ,Neotame ,Tutti-frutti ,Orange flavor ,Strawberry
flavor ,Sucrose
and used for the study.
Procedure
Weighed amount of drug (3mg) was mixed with 100mg of potassium bromide
(dried at 40-50oC). The mixture was taken and compressed under 10-ton pressure in a
hydraulic press to form a transparent pellet. The pellet was scanned in IR
spectrophotometer.
Compatibility studies by force degradation studies
The Binary mixtures of drug and excipients (1:1) were prepared, and packed in
both closed vials and kept in accelerated environmental conditions (400/75% RH) for 1
month. At the end of 1 month period all the samples were observed for Physical
observation, Assay and Impurity levels.
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Preformulation studies Page 66
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Methodology Page 67
10.0 METHODOLOGY
10.1 Dry powder formulation methodology and Compositions
Taste masking becomes a pre-requisite for bitter drugs to improve the patient compliance
especially in the pediatric and geriatric population. Different taste masking technologies
have been used to address the problem of patient compliance.
Taste masking technologies are increasingly focused on aggressively bitter tasting drugs
like the macrolide antibiotics, Cephalosporin’s, non-steroidal anti-inflammatory drugs
and penicillins.
Taste masking of water insoluble bitter drugs, especially those with a high dose, is
difficult to achieve by using sweeteners alone. As a consequence, more efficient
techniques such as coating, microencapsulation and granulation have also been used in
combination with the sweeteners.
In order to mask the taste of this highly bitter drug different technologies have been used
and the details are as given below:
Dry mixing
Granulation (Non-Aqueous)
Hot-Melt Granulation
Spray drying
Complexation
Solid dispersion
Dry granulation
Dry granulation with combination of sweeteners and flavors
The dry powder was filled in amber colored with a fill weight of 40g per bottle
which is equivalent to 10 doses.
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Methodology Page 68S.N
oIngredients DRY MIXING GRANULATION (NON AQUEOUS)
F001 F002 F003 F004 F005 F006 F007
1 Model Drug 153.48* 153.48* 153.48* 153.48* 153.48* 153.48* 153.48*
2 Stearic acid 600 800 1200 150 150 150 1503 Xanthan gum 1 10 1 2 2 2 2
4 Povidone k-30 13 10 13 13 13 13 13
5 Acesulfame potassium 15 15 15 21 21 21 21
6 Neotame 15 15 15 2.1 2.1 2.1 2.17 Tutti-frutti 30 30 30 100 100 100 1008 Sucrose 3175.64
22969.642 2583.642 3561.54 3561.54 3561.54 3561.5
49 IPA - - - qs - - Qs10 Acetone - - - - - qs -
11 Methylene chloride - - - - qs(120) - Qs
12 Glyceryl behinate - - - - - - -
13 Hydrogenated castor oil - - - - - - -
14 Eudragit - - - - - - -
15 Carbapol 934 - - - - - - -
16 KYRON T-114 - - - - - - -
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Methodology Page 69 17 TOTAL 4000 4000 4000 4000 4000 4000 4000
10.2 Composition of formulation of modified release tablets of highly soluble drug
S.No
Ingredients HOT MELT GRANULATION SPARY DRYING
COMPLEXATION
SOLID DISPERSION
F008 F009 F010 F011 F012 F013 F14
1 Model Drug 153.48* 153.48* 153.48* 153.48* 153.48* 153.48* 153.48*
2 Stearic acid 150 - - 150 - - -3 Xanthan gum 2 2 2 2 2 2 2
4 Povidone k-30 13 13 13 13 13 13 13
5 Acesulfame potassium 21 21 21 21 21 21 21
6 Neotame 2.1 2.1 2.1 2.1 2.7 2.1 2.77 Tutti-frutti 100 100 100 100 100 100 1008 Sucrose 3561.54 3561.54 3561.54 3561.54 3331.92 3683.42 3357.82
9 IPA - - - - - qs -10 Acetone - - - - 60% - -
11 Methylene chloride - - - qs(220) - - Qs
12 Glyceryl behinate - 150 - - - - -
13 Hydrogenated castor oil - - 150 - - - -
14 Eudragit - - - - - - 50
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Methodology Page 7015 Carbapol 934 - - - - - 25 -
16 KYRON T-114 - - - - 375.90 - -
17 TOTAL 4000 4000 4000 4000 4000 4000 4000
S.No
Ingredients DRY GRANULATIONSingle slug Double slug Single slug (flavor)
F015 F016 F017 F018 F019 F020 F021
1 Model Drug 153.48* 153.48* 153.48* 153.48* 153.48* 153.48* 153.48*
2 Stearic acid 150 300 150 300 150 150 1503 Xanthan gum 2 2 2 2 2 2 2
4 Povidone k-30 13 13 13 13 13 13 13
5 Acesulfame potassium 21 21 21 21 21 21 21
6 Neotame 2.1 2.1 2.1 2.1 2.7 2.1 2.77 Tutti-frutti 100 100 100 100 100 100 1008 Sucrose 3561.54 3311.54 3561.54 3311.54
9 Aerosil - - - - - - -10 Acetone - - - - - - -
11 Methylene chloride - - - - - - -
12 Glyceryl behinate - - - - - - -
13 Hydrogenated castor oil - - - - - - -
14 orange flavor - - - - - - -
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Methodology Page 7115 strawberry flavor - - - - - - -
16 Menthol - - - - - - -
17 TOTAL 4000 4000 4000 4000 4000 4000 4000
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Methodology Page 72
Table- 10: Application of ingredients in formulated tablet with its concentration
used
Inactive Ingredient* Used as*Used Concentration
per tablet*
Core Ingredients
Stearic acid Ph.Eur Taste masking agent
Xanthan gum FF Ph.EurSuspending & viscosity-
increasing agent
Povidone K30 Ph.Eur Suspending agent.
Acesulfame potassium
sunset Ph.EurSweetener
Neotame Ph.Eur Sweetener
Tutti-frutti IH Flavoring agent
Orange flavor IH Flavoring agent
Strawberry flavor IH Flavoring agent
Sucrose Ph.Eur Bulk sweetener
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Methodology Page 73
10.3 Preparation of a dry powder
DRY MIXING (METHOD: 1)
Sifting:
Sift all the materials using Vibratory sifter.
Divide the total quantity of stearic acid into 3 parts
Cosift Model drug and Stearic acid through #60 mesh as follows,
Cosift the part I of Stearic acid with total dispensed quantity of model drug
through #60 mesh.
Cosift the part II of Stearic acid with the above blend through #60 mesh.
Cosift the PART III of Stearic acid with the above blend through #60 mesh.
Co sift Xanthan Gum, Povidone (PVP K30), Tutti Frutti Aspartame and
Acesulfame potassium with the above co sifted model drug and Stearic acid
through #40 mesh in geometrical fashion and collect in separate triple polybag.
Resift the above co sifted materials along with Sucrose (#60 mesh) through #40
mesh and collect in separate triple polybag.
BLENDING:
Transfer the Co sifted Blend to the blending area.
Load the Co sifted Blend into the Octagonal blender and blend for 20 minutes.
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Methodology Page 74
Parameters of blend are as follows
Parameter Specification
Description White to off-white, flavored powder
Average fill mass (net content)
40.00 g + 2%(39.2 g to 40.8 g)
Uniformity of fill Mass 40.00 g + 5%(38 g to 42 g)
Water Content (By KF)
Not More Than 3.0%
FILLING & SEALING
After proper blending fill the blend in bottles (100ml amber glass Bottle) and
seal the bottle with white CRC 28mm cap and rubber stopper (bromobutyl
26mm grey).
Parameters for Filling and Sealing
Bottle 100ml amber glass Bottle
CR Screw Cap Poly propylene white CRC 28 mm cap
Rubber stopper Rubber stopper Bromobutyl 26mm grey
Fill weight / Bottle 40g ± 2% (39.2 g to 40.8 g)
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Methodology Page 75
Cap Sealing Leak test (water should not penetrate into
the filled and sealed bottle)
Granulation (non aqueous) (Method – 2)
a) Weighing and Sieving:
All the raw materials were passed through sieve no. 60 and weighed accurately as per the
formulae.
b) Granulation:
The thoroughly mixed model drug and Stearic acid was kneaded for 10 mins with solvent
till it forms dough mass. This mass was then passed through sieve no. 14 to form
granules.
C) Drying:
The granules were spread on the tray and kept for drying at 400c for 30 min using hot air
oven which inturn are passed through the sieve no. 60 to get uniform granules
D ) Sifting:
Sift above the materials through 60# using Vibratory sifter.
Xanthan Gum, Povidone (PVP K30), Tutti Frutti ,Neotame and Acesulfame
potassium with the above through #40 mesh in geometrical fashion and collect in
separate triple polybag
Resift the above co sifted materials along with Sucrose (#60 mesh) through #40
mesh and collect in separate triple polybag.
E) BLENDING:
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Methodology Page 76
Transfer the sifted Blend to the blending area.
Load the Co sifted Blend into the Octagonal blender and blend for 20 minutes.
HOT MELT GRANULATION (METHOD – 3)
A ) Weighing and Sieving:
Model drug weighed accurately as per the formulae and were passed through sieve no. 60
B) Granulation:
Preparation of solution: Accurately weighed quantity of Stearic acid was taken and
melted at 60°c a clear solution is obtained.
Preparation of granules: The thoroughly mixed drug powder was kneaded for 10
mins with solution till it forms dough mass. This mass was then passed through sieve
no. 14 to form granules.
C) Drying:
The granules were spread on the tray and kept for drying at 400c for 30 min using hot
air oven which in turn are passed through the sieve no. 60 to get uniform granules
D) Sifting:
Sift above the materials through 60# using Vibratory sifter.
Xanthan Gum, Povidone (PVP K30), Tutti Frutti ,Neotame and Acesulfame
potassium with the above through #40 mesh in geometrical fashion and collect in
separate triple polybag
Resift the above co sifted materials along with Sucrose (#60 mesh) through #40
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Methodology Page 77
mesh and collect in separate triple polybag
E) BLENDING:
Transfer the sifted Blend to the blending area
Load the Co sifted Blend into the Octagonal blender and blend for 20 mins.
SPARY DRYING (METHOD – 4)
A ) Weighing and Sieving:
Model drug and Stearic acid weighed accurately as per the formulae and were passed
through sieve no. 60
B) Spray drying
Drug and Stearic acid (1:1) were dissolved in methylene chloride (qs) The dispersion was
subjected to spray drying using a spray dryer set at an inlet temperature of 45° C. and
outlet temperature of 37° C.
C) Drying:
The powder was further dried at 30 to 40° C. for about 3 hours to remove residual
solvent.
D) Sifting:
Sift above the materials through 60# using Vibratory sifter.
Xanthan Gum, Povidone (PVP K30),Tutti Frutti ,Neotame and Acesulfame
potassium with the above through #40 mesh in geometrical fashion and collect in
separate triple polybag
Resift the above co sifted materials along with Sucrose (#60 mesh) through #40 mesh
and collect in separate triple polybag
E) BLENDING:
Transfer the sifted Blend to the blending area
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Methodology Page 78
Load the Co sifted Blend into the Octagonal blender and blend for 20 mins
COMPLEXATION (METHOD – 5)
Mixing
Take 129 ml of purified water and 190 ml of acetone in a vessel
Add 97.8gm of kyron T114 and 39.12 gm of drug which is sift through 60#
Add the material to above solution of step1 continues stirring and stir this solution
for another 15 minutes
Observe the ph 5.0-5.5 if required adjust the ph by 20% KOH solution and stir for
3 hour
Drying
Load the complex into ss tray and keep them tray dryer
Adjust the temperature of tray dryer and continues drying
Check the moisture content of complex it should show below 5.0%w/w.
Sifting:
Sift above the materials through 60# using Vibratory sifter.
Xanthan Gum, Povidone (PVP K30), Tutti Frutti ,Neotame and Acesulfame
potassium with the above through #40 mesh in geometrical fashion and collect in
separate triple polybag
Resift the above co sifted materials along with Sucrose (#60 mesh) through #40
mesh and collect in separate triple polybag.
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Methodology Page 79
BLENDING:
Transfer the sifted Blend to the blending area.
Load the Co sifted Blend into the Octagonal blender and blend for 20 minutes.
SOLID DISPERSION (METHOD – 6)
A ) Weighing and Sieving:
Drug and polymer weighed accurately as per the formulae and were passed through
sieve no. 60
B) Dispersion
Drug and polymer were dissolved in solvent (qs). The dispersion was allowed to dry
at room temperature and fine powder was obtained.
C) Drying:
The powder was further dried at 30 to 40° C. for about 3 hours to remove residual
solvent.
D) Sifting:
Sift above the materials through 60# using Vibratory sifter.
Xanthan Gum, Povidone (PVP K30),Tutti Frutti ,Neotame and Acesulfame
potassium with the above through #40 mesh in geometrical fashion and collect in
separate triple polybag
Resift the above co sifted materials along with Sucrose (#60 mesh) through #40
mesh and collect in separate triple polybag
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Methodology Page 80
E) BLENDING:
Transfer the sifted Blend to the blending area
Load the Co sifted Blend into the Octagonal blender and blend for 20 mins
.
DRY GRANULATION (METHOD – 7)
A ) Weighing and Sieving:
Drug, Stearic acid and aerosil weighed accurately as per the formulae and were
passed through sieve no. 60
B) Mixing
Drug, Stearic acid and aerosil mixed thoroughly by RMG to get uniform mix.
c) Slug and Deslug
The tablets were prepared using 16 mm round flat punch. The tablets were compressed by
maintaining a constant hardness 4±0.5 kg/cm2.
D) Milling And Sifting:
The tablet were passed through 1.5 screen and passed through 60#.
Xanthan Gum, Povidone (PVP K30),Tutti Frutti ,Neotame and Acesulfame potassium
with the above through #40 mesh in geometrical fashion and collect in separate triple
polybag
Resift the above co sifted materials along with Sucrose (#60 mesh) through #40 mesh
and collect in separate triple polybag
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Methodology Page 81
BLENDING:
Transfer the sifted Blend to the blending area
Load the Co sifted Blend into the Octagonal blender and blend for 20 mins
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
7.0 EVALUATION OF SUSPENSION
Evaluation of suspension includes
7.1 Evaluation of dry powder
7.2 Evaluation of reconstituted suspension
7.1 EVALUATION OF DRY POWDER Evaluation of dry powder for oral suspension was done by determination of
a) BULK DENSITY & TAPPED DENSITY
A quantity of 5g of the powder (W) from each formula was introduced into a 25
ml measuring cylinder. After the initial volume was observed, the cylinder was allowed
to fall under its own weight onto a hard surface from the height of 2.5 cm at 2 sec
intervals. The tapping was continued until no further change in volume was noted.
The bulk density, and tapped density were calculated using the following
formulas
Bulk density = W / VO
Tapped density = W / Vf
Where, W = weight of the powder,
VO = initial volume,
Vf = final volume.
b) COMPRESSIBILITY INDEX
Compressibility index is an important measure that can be obtained from the bulk
and tapped densities. In theory, the less compressible a material the more flowable it is. A
material having values of less than 12% is defined as the free flowing material.
Compressibility index = 100 (VO – Vf)
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
V0
Table – 24
% Comp. Index Properties
1-10 Excellent
11-15 Good
16-20 Fair
21-25 Passable
26-31 Poor
32-37 Very poor
>38 Very very poor
c) ANGLE OF REPOSE
In order to determine the flow property, the Angle of repose was determined. It is
the maximum angle that can be obtained between the free standing surface of the powder
heap and the horizontal plane.
Ө = tan -1 (h/r)
Where,
h = height
r = radius
Ө = angle of repose
Procedure:
An accurately weighed sample was taken.
A funnel was fixed in the stand in such a way that the tip of the funnel was at the
height of 6 cm from the surface.
The sample was passed through the funnel slowly to form a heap.
The height and the circumference of the powder heap formed were measured.
The radius was measured and the angle of repose was determined using the above
formula. This was repeated five times for a sample.
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Table – 25
Flow Property Angle Of Repose(Degrees)
Excellent 25-30
Good 31-35
Fair(aid not needed) 36-40
Passable(may hang up) 41-45
Poor(must agitate, vibrate) 46-55
Very poor 56-65
Very, very poor >66
d) AVERAGE FILL MASS:
Procedure:
Take 10 containers and individually weigh each container and its contents.
Empty the container completely as possible and weigh. The difference between the
mass represents the mass of the contents.
Mass of 10 containers net Content Averages fill mass, in gm ------------------------------------- 10
e) WATER CONTENT (By KF):
Procedure:
Transfer 35 to 45 mL methanol into the titration vessel, and titrate with Karl-
Fischer reagent to the electrometric end point to consume any moisture that may be
present. Transfer immediately about 100mg of dry powder accurately weighed, mixed,
and again titrate with the reagent to the electrometric end point. Calculate the water
content of the sample using KF factor. Perform ion duplicate and report the mean value.
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Calculation:
Titre value x KF FactorWater Content (%): = ------------------------------- Wt. of the sample, in mg
f) BLEND UNIFORMITY
Blend uniformity test was carried out on the final formulation this test was carried out
by determining the uniformity of blend at different time intervals based on average blend
uniformity and % RSD the time interval for proper blending was determined
OBSERVATIONS
a) COMPRESSIBILITY INDEX
Table – 26
S.No
Formulation
CodeVo V
BulkDensit
y
Tapped
Density
Compressibility
index
1 F001 28 24 0.714 0.833 14.3
2 F002 32 27 0.625 0.741 15.6
3 F003 31 27 0.645 0.741 12.9
4 F004 31 26 0.645 0.769 16.1
5 F005 28 24 0.714 0.833 14.3
6 F006 29 25 0.690 0.800 13.8
7 F007 30 26 0.667 0.769 13.3
Vo – volume before tapping
V - Volume after tapping
c) Angle of repose
Table – 27
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
S.No.Formulation
Code
Height (h)
(Cms)
Radius (r)
(Cms)h/r = tan –1 h/r
1 F001 2.5 3.7 0.68 34
2 F002 2.4 3.7 0.65 33
3 F003 2.6 4.1 0.63 32
4 F004 2.3 3.2 0.72 36
5 F005 2.7 4 0.68 34
6 F006 2.3 3.5 0.66 33
7 F007 2.7 4.2 0.64 33
d) AVERAGE FILL MASSTable – 28
S.NO Formulation codeAverages fill mass
(42.5 g +/-2%)
1 F001 42.05
2 F002 43.10
3 F003 42.40
4 F004 41.90
5 F005 42.18
6 F006 42.70
7 F008 42.60
e) WATER CONTENTTable – 29
S.NO Formulation code Water content
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
(NMT 3.0%)
1 F001 0.20
2 F002 0.18
3 F003 0.16
4 F004 0.13
5 F005 0.17
6 F006 0.16
7 F007 0.15
f) Blend uniformity at different time intervals for final formulation (F007)
Table – 30
Location limits Results in (%)
At 10 min At 15 min At 20 min
U 1
Model drug
equivalent to
112.5 mg-137.5
mg of
cefuroxime
(90% to 110%)
99.2 101.9 102.8
U2 100.2 99.9 101.3
U3 98.1 98.1 100.2
M1 100.8 98.5 101.4
M2 99.9 102.8 99.2
M3 106.2 99.2 100.6
L1 98.3 96.8 99.5
L2 100.6 99.5 98.9
L3 97.4 100.6 99.1
B0 105.5 98 98.9
AVG 100.6 99.5 100.2
S.D 3.0 1.8 1.3
R.S.D
(NMT 5.0%)3.0 1.9 1.3
Different sampling locations of octagonal blender are as follows.
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Octagonal blender
Fig - 04
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Evaluation of reconstituted suspension
7.2 EVALUATION OF RE CONSTITUTED SUSPENSION:
After re constitution of suspension it was stored at refrigerator (2-80C) and room
temperature (3720C) and evaluates the critical parameters of the suspension
a) RECONSTITUTION TIME:
Procedure for reconstitution of suspension:
Take the dry powder bottle and add small quantity of water (around10 mL)
then shake well followed by make up to the mark with water and mix well. (For
reconstitution around 16 mL will take for getting up the mark)
Tap the bottle note down the initial time (t1) then shake gently to loosen the dry
powder. Add half the required amount of water and shake vigorously. Slowly add the
water up to the mark on the bottle. Again note down time (t2).
Reconstitution time (T) = t2- t1
b) DESCRIPTION:
Transfer 10 to 25ml of the sample to a dry Nessler’s cylinder. Observe the color and
clarity against white background.
c) DELIVERABLE VOLUME:
Take 10 reconstituted suspension bottles and gently pour the contents of each
container into a separate dry calibrated 100 mL graduated measuring cylinder. Allow
each container to drain for a period not to exceed 30 minutes. Measure the volume of
each mixture when free from air bubbles.
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Evaluation of reconstituted suspension
d) PH:
Reconstitute the sample with water up to label mark. Wash the electrode with
distilled water and wipe it with tissue paper. Transfer the sample solution into a beaker.
Dip the electrode in sample solution and wait for 10 minutes then, measure the pH.
Record the stabilized reading.
e) ASSAY (By HPLC Method):
WEIGHT PER ML CALCULATION
Weight Per ml: Determine at 25°C using specific gravity bottle
Procedure:
Take a clean dried empty specific gravity bottle with stopper and note down the
weight (W1), fill the specific gravity bottle with distilled water, close the stopper note
down the weight (W2). Then completely, empty and dry the specific gravity bottle, fill
with suspension sample & note down the weight (W3).
Calculation: (W3- W1) Wt/mL = ---------------- x 0.99602 = ___________ mg/mL (W2- W1)
Weight of the Empty specific gravity = W1 mg
Specific gravity bottle + water = W2 mg
Specific gravity bottle + sample = W3 mg
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Evaluation of reconstituted suspension
Procedure:
Chromatographic system:
Column : Betasil C1: 250 mm×4.6 mm; 5um
Column temperature : 25°C± 2°C
Flow rate : 1.0 mL / minute
Injection volume : 5 l.
Detector Wave length : 278 nm
Run Time : About 45 minutes
Diluent-1: Methanol (100%)
Diluent-2: Mix 900ml of methanol and 100ml of water.
Buffer Solution: (0.2 M monobasic ammonium phosphate)
Dissolve about 23g of monobasic ammonium phosphate in 1000ml of distilled
water and mix well.
Mobile phase:
Mix 625ml of buffer and 375ml of methanol v/v then filter through 0.45µm
membrane filter and degassed.
Standard Preparation:
Weigh accurately about 60 mg of Model drug (equivalent to 50mg of
Cefuroxime) working standard and transfer into a 50ml volumetric flask, then add 30ml
of diluent-1, sonicate to dissolve then make up the volume with diluent-1, and mix well.
Pipette out 5ml of the above solution into a 20ml volumetric flask and make up to mark
with diluent-2, and mix well.
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Evaluation of reconstituted suspension
Test Preparation:
Weigh accurately about 11800 mg of reconstitute suspension (equivalent to
250mg of Cefuroxime) in to a 100 mL volumetric flask, add 70mL of diluent-1, sonicate
for 30minutes and make up to mark with diluent-1. Centrifuge the solution at 2000rpm.
About 5 minutes. Pipette out 5ml of the above solution into 50ml with diluent-2.
Procedure:
Separately inject equal volumes of about 5 µl of diluent-2 as blank, five replicate
injections of Standard preparation and two preparation of injections of test preparation
into the chromatograph, record the chromatograms, and measure the responses for the
peaks of Model drug diastereoisomers A and B.
System Suitability:
(a) Tailing factor for the Model drug A peak from standard chromatogram should not be
more than 2.0
(b) Tailing factor for the Model drug B peak from standard chromatogram should not be
more than 2.0.
(c) Resolution for Model drug diastereoisomers A and B Not Less Than 1.5
(d) Sum of theoretical plate count for Model drug diastereoisomers A and B not less than
4000
(e) The relative standard deviation of sum of the Model drug diastereo isomers A and B
from replicate five injections of standard preparation should not be more than 2.0%.
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Evaluation of reconstituted suspension
Calculation:
Calculate the quantity, in mg of Cefuroxime in 5 ml of the oral suspension sample taken
by using the formula:
AT WS 5 100 50 P 424.38 ---------x-------x------x--------x ---------x----------x------- ---- x 5 x Wt/ml AS 50 20 WT 5 100 510.48
Where,
AT = the sum of the Model drug diastereoisomers A and B peak area obtained from
the Test preparation of Cefuroxime.
AS = the sum of the Model drug diastereoisomers A and B peak areas obtained from
the Standard preparation Cefuroxime.
WS = Weight of Model drug working standard taken in mg for standard Preparation.
WT = Weight of test sample taken in mg for test preparation of Model drug.
P = Purity of Model drug working standard as such basis in %
Molecular weight of Cefuroxime = 424.38.
Molecular weight of Model drug = 510.48.
Wt/ml = Weight per ml of the Test Sample in mg/ml.
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Evaluation of reconstituted suspension
f) DISSOLUTION (By U.V Method)
WEIGHT PER ML CALCULATION
Weight Per ml: Determine at 25°C using specific gravity bottle
Procedure:
Take a clean dried empty specific gravity bottle with stopper and note down the weight
(W1),
Fill the specific gravity bottle with distilled water; close the stopper note down the weight
(W2).
Then completely, empty and dry the specific gravity bottle, fill with suspension sample &
note down the weight (W3).
Calculation:
(W3- W1)
Wt/mL= ---------------- x 0.99602 = ___________ mg/mL
(W2- W1)
Weight of the Empty specific gravity = W1 mg
Specific gravity bottle + water = W2 mg
Specific gravity bottle + sample = W3 mg
Dissolution Parameters:
Medium : 0.07M pH 7.0 Phosphate Buffer
Volume : 900mL
Apparatus : USP Type-II (Paddle)
RPM : 50
Time : 30 minutes.
Temperature : 37.0 ± 0.5°C
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Evaluation of reconstituted suspension
Dissolution Medium (0.07 M pH 7.0 phosphate buffer):
Dissolve 3.7g of monobasic sodium phosphate and 5.7g of anhydrous dibasic
sodium phosphate in 1000 mL of water, ensure that final pH of medium should maintain
pH 7.0.
Standard Preparation:
Weigh accurately about 33.5 mg of Model drug (equivalent to 27.8mg of
Cefuroxime) working standard and transfer into a 100ml volumetric flask, then add 30ml
of methanol dissolve then make up the volume with methanol Pipette out 1ml of the
above solution into a 200ml volumetric flask and make up to mark with dissolution media
Test Preparation:
Reconstitute the 6 samples; determine the weight per ml of these suspensions. Set
the parameters of dissolution apparatus as mentioned above. Weigh and transfer the 5.0
mL constituted Model drug for oral suspension equivalent to 125 mg of cefuroxime
(about 6.0 g of the Sample) from each bottle of six dissolution vessels and start the
dissolution test. At the end of the specified time interval, withdraw about 10 ml of sample
solution from each dissolution vessel, by using auto sampler 10µ free flow filter.
Procedure
Measure the standard solution absorption for five times at 280 nm using
dissolution media as blank. Measure the time point of test preparation against dissolution
media as a blank.
System suitability
The relative standard deviation of absorbance of paracetamol from five replicate
scanning of standard solution should not be more than 2.0%
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Evaluation of reconstituted suspension
Calculation: Calculate the amount of Cefuroxime dissolved in dissolution medium
% Labelled Amount =
AT WS 1 900 200 P 424.38 ---------x----- ------x ---------x---------x ------ x ---------- x ---------- x Wt per ml x 5 AS 100 200 Wt 2 LC 510.48
Where,
AT = absorbance obtained for Model drug from sample preparation
AS = absorbance obtained for Model drug from standard preparation
WS = Weight of Model drug working standard taken in mg for standard Preparation.
Wt = Weight of test sample taken in mg for each dissolution bowel as
CefuroximeAxetil.
P = Purity of Model drug working standard as such basis in %
Molecular weight of Cefuroxime = 424.38.
Molecular weight of Model drug = 510.48.
Wt/ml = Weight per ml of the Test Sample in mg/ml.
LC = Label claim of Cefuroxime per 5ml of reconstitute suspension
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Evaluation of reconstituted suspension
g) RELATED SUBSTANCES (By HPLC Method)
WEIGHT PER ML CALCULATION:
Weight Per ml: Determine at 25°C using specific gravity bottle
Procedure:
Take a clean dried empty specific gravity bottle with stopper and note down the
weight (W1), fill the specific gravity bottle with distilled water, close the stopper note
down the weight (W2). Then completely, empty and dry the specific gravity bottle, fill
with suspension sample & note down the weight (W3).
Calculation:
(W3- W1)
Wt/mL = ---------------- x 0.99602 = __________ mg/mL
(W2- W1)
Weight of the Empty specific gravity = W1 mg
Specific gravity bottle + water = W2 mg
Specific gravity bottle + sample = W3 mg
Chromatographic system:
Column : Betasil C1: 250 mm×4.6 mm; 5um
Column temperature : 25 °C± 2°C
Flow rate : 1.0 mL / minute
Injection volume : 100 l.
Detector Wave length : 278 nm
Diluted standard Run Time : About 60 minutes.
Test sample Run Time : About 110 minutes
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Evaluation of reconstituted suspension
Diluent-1: Methanol (100%)
Diluent-2: Mix 900 ml of methanol and 100 ml of Buffer.
Diluent-3: Buffer (100%)
Buffer Solution: (0.2 M monobasic ammonium phosphate) Dissolve about 23g of
monobasic ammonium phosphate in 1000ml of distilled water and mix well.
Mobile phase:
Mix 700ml of buffer and 300ml of methanol v/v then filter through 0.45µm membrane
filter and degassed.
Diluted Standard Preparation:
Weigh accurately about 75mg of Model drug (equivalent to 62.5mg of
Cefuroxime) working standard and transfer into a 50 ml volumetric flask, then add 30ml
of Diluent-1, sonicate to dissolve then make up the volume with Diluent-1. Pipette out 5
ml of the above solution into a 100 ml volumetric flask and make up the volume with
diluent-2. Pipette out 2 ml of the above solution into a 100ml volumetric flask and make
up the volume with Diluent-3.
Test Preparation:
Weigh accurately about 11800 mg of reconstituted suspension (equivalent to
250mg of Cefuroxime) in to a 100 mL volumetric flask, add 50mL of diluent-1, sonicate
for 30minutes and make up to mark with diluent-1. Centrifuge the solution at 2000 rpm
about 5 minutes. Pipette out 5ml of the above solution into 50 ml with diluent-2. Pipette
out 10ml of the above solution into 20ml with diluent-3. Filter the solution through
hydrophilic PVDF 0.45 m membrane filter.
Note:
While sonicating the test sample need to maintain the temperature of the sonicator
bath should be between 20 to 25°C
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Evaluation of reconstituted suspension
Reference solution:
Weigh accurately about 300 mg of Model drug (equivalent to 250mg of
Cefuroxime) in to a 100 mL volumetric flask, add 70mL of diluent-1, sonicate for
30minutes and make up to mark with diluent-1. Centrifuge the solution at 2000 rpm
about 5 minutes. Pipette out 5ml of the above solution into 50 ml with diluent-2. Pipette
out 5 ml of the above solution into 20ml with diluent-3. Filter the solution through using
0.45m membrane filter (millex).
Expose 5 ml of reference solution, in to ultraviolet light at 254 nm for 24 Hours to
generate Delta3-isomers and Anti Isomer peaks.
Identification of Impurities:
Use the chromatogram obtained with reference solution to identify the pair of
peaks due to Delta-3 and Anti Isomer impurities peaks.
Procedure:
Separately inject equal volumes of about 100 µl of diluent-3 as blank, two
replicate injections of Standard preparation and one injections of test preparation into the
chromatograph, record the chromatograms, and measure the responses for the peaks.
System Suitability Parameters for Model drug Limit
Sum of theoretical Plate Count for Model drug
diastereoisomers A and B. ≥ 4000
Tailing factor for Model drug diastereoisomers A NMT 2.0
Tailing factor for Model drug diastereoisomers B NMT 2.0
Ratio of two peaks obtained from diluted standard for
diastereomers A and B.
Should be between
0.9 to 1.1
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Evaluation of reconstituted suspension
Resolution for Model drug diastereoisomers A and B. NLT 1.5
Resolution between Model drug diastereoisomers A and
Delta-3 Isomer. NLT 1.5
Calculation:
The percentage content of Cefuroxime impurities
E-Isomer =
AIET x WS1 x 5 x 2 x 100 x 50 x 20 x P x 5 x Wt /ml x 424.38x100
ADS 50 100 100 WT 5 10 100 LC 510.48
Delta-3-Isomer =
AIDT x WS1 x 5 x 2 x 100 x 50 x 20 x P x 5 x Wt /ml x 424.38 x100
ADS 50 100 100 WT 5 10 100 LC 510.48
Cefuroxime Acid Impurity =
AIDT1 x WS1 x 5 x 2 x 100 x 50 x 20 x P x 5 x Wt /ml x 424.38 x100
ADS 50 100 100 WT 5 10 100 LC 510.48
Cefuroxime Lactone Impurity =
AIDT2 x WS1 x 5 x 2 x 100 x 50 x 20 x P x 5 x Wt /ml x 424.38 x100
ADS 50 100 100 WT 5 10 100 LC 510.48
Maximum individual unknown impurity =
AIUIT x WS1 x 5 x 2 x 100 x 50 x 20 x P x 5 x Wt /ml x 424.38 x100
ADS 50 100 100 WT 5 10 100 LC 510.48
Total impurities =
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Evaluation of reconstituted suspension
ATIT x WS1 x 5 x 2 x 100 x 50 x 20 x P x 5 x Wt /ml x 424.38 x 100
ADS 50 100 100 WT 5 10 100 LC 510.48
Where,
AIET = Sum of Area of E-Isomer impurity peaks in test solution.
AIDT = Area of Delta-3 Isomer impurity in test solution
AIDT1 = Area of Cefuroxime Acid impurity in test solution
AIDT2 = Area of Cefuroxime Lactone impurity in test solution
AIUIT = Area of maximum individual unknown impurity in test solution.
ATIT = Total area of all impurities after subtracting blank, Model drug
diastereoisomers A and B and Placebo peaks.
ADS = Sum of the Area of diluted standard diastereoisomers Model drug A and B.
WS1 = Weight of working standard in mg.
WT = Weight of test sample in mg.
P = Purity of Model drug working standard as such basis in %.
LC = Label claim cefuroxime 125mg
Wt/ml= Weigh per ml of the Test Sample in mg
Molecular weight of Cefuroxime = 424.38.
Molecular weight of Model drug = 510.48.
RRT’s of Impurities calculated with respective to Model drug A peak RT
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Evaluation of reconstituted suspension
Table – 31
Name of the impurities RT RRT
Cefuroxime Lactone
Impurity
4.46 0.12
Cefuroxime Acid
Impurity
5.84 0.15
Delta-3 Isomer 43.84 1.13
E1 Isomer 62.20 1.61
E2 Isomer 75.02 1.94
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
ObservationsOBSERVATIONS
b) DESCRIPTIONTable – 32
S.No Batch noDescription
On the day of reconstitution On 11 th day of reconstitutionAt 2-8°c At 25±2°c
1 Innovator white coloured flavoured suspensionwhite coloured flavoured suspension
white coloured flavoured suspension
2 F001 Off white coloured flavoured suspensionOff white coloured flavoured suspension
Off white coloured flavoured suspension
3 F002 Off white coloured flavoured suspensionOff white coloured flavoured suspension
Off white coloured flavoured suspension
4 F003 Off white coloured flavoured suspensionOff white coloured flavoured suspension
Off white coloured flavoured suspension
5 F004 Off white coloured flavoured suspensionOff white coloured flavoured suspension
Off white coloured flavoured suspension
6 F005 Off white coloured flavoured suspensionOff white coloured flavoured suspension
Off white coloured flavoured suspension
7 F006 Off white coloured flavoured suspensionOff white coloured flavoured suspension
Off white coloured flavoured suspension
8 F007 Off white coloured flavoured suspensionOff white coloured flavoured suspension
Off white coloured flavoured suspension
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Observations
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Observations
a) RECONSTITUTION TIMETable – 33
S.No Batch no Re constitution time
1 Innovator About 5 min
2 F001 About 4min
3 F002 About 5min
4 F003 About 5min
5 F004 About 4min
6 F005 About 4min
7 F006 About 5min
8 F007 About 5min
c) DELIVERABLE VOLUMETable – 34
S.No Batch no Deliverable volume(min)
1 F001 48
2 F002 49
3 F003 50
4 F004 50
5 F005 50
6 F006 50
7 F007 50
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Observations
d) PHTable – 35
S.No Batch no
PH
On the day of re
constitution
On the 11 th day of
reconstitution
At 2-8°c At 25 ± 2°c
1 innovator 5.2 5.0 4.9
2 F001 5.0 4.8 4.5
3 F002 5.2 5.1 5.0
4 F003 4.8 4.5 4.1
5 F004 5.2 5.1 4.6
6 F005 5.3 5.1 5.0
7 F006 5.3 5.0 4.7
8 F007 5.8 5.2 5.0
ASSAY
Table – 36
S.No Batch no
Assay (92.5%- 107.5%)
On the day of re
constitution
On the 11 th day of reconstitution
At 2-8°c At 25 ± 2°c
1 innovator 125.38 mg (100.3%) 125.13mg (100.1%)124.75mg
(99.80%)
2 F001 125.50 mg (100.4%) 125.38mg (100.3%) 124.63mg (99.7%)
3 F002 125.63 mg (100.5%) 125.25mg (100.2%) 124.88mg (99.9%)
4 F003 126.25 mg (101.0%) 125.88mg (100.7%)125.25mg
(100.2%)
5 F004 126.13 mg (100.9%) 125.75mg (100.6%)125.13mg
(100.1%)
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Observations
6 F005 126.38 mg (101.1%) 126.00mg (100.8%)125.38mg
(100.3%)
7 F006 125.88 mg (100.7%) 125.63 mg (100.5%) 124.75mg (99.8%)
8 F007 126.00 mg (100.8%) 125.50 mg (100.4%) 124.75mg (99.8%)
f) DISSOLUTION
Dissolution Profile for formulated suspensions
Table – 37
formulation% of labeled amount f2 value
15 min 30 min 45 min
Innovator 79 82 92
F001 71 82 89 68
F002 70 79 86 62
F003 68 73 84 54
F004 85 88 94 67
F005 74 80 91 77
F006 73 81 90 74
F007 76 82 93 86
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Observations
0
20
40
60
80
100
120
0 10 20 30 40 50
time (in min)
% o
f d
rug
rele
ase
F001 F002 F003 F004 F005 F006 F007
Comparison of innovator with final formulation
Table – 38
formulation% of labeled amount
15 min 30 min 45 min
Innovator 79 82 92
F007 76 82 93
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Observations
0
20
40
60
80
100
0 10 20 30 40 50
time(in min)
% o
f dr
ug r
elea
se
Innovator F007
Similarity factor calculation
f1 = { [ å t=1 n½Rt – Tt ½ ] / [ å t=1
n Rt ] } . 100
f2 = 50. log { 1 + ( 1/n) å t=1 n (Rt - Tt ) 2 ] –0.5 . 100
Table – 39
Time in min Cumulative percentage (R-T) (R-T)2
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Observations
RLD values TEST values
0 0 0 0.0 0.0
15 79 76 3.0 9.0
30 82 82 0.0 0.0
45 92 93 1.0 1.0
F1 2 (NMT 15)
F2 86 (NLT 50)
Comparison of dissolution Based on stearic acid concentration
Table – 40
Formulation % of labeled amount f2 value15 min 30 min 45 min
F003(stearic acid 1200mg)68 73 84 54
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Observations
F004(stearic acid 600mg)85 88 94 67
F008(stearic acid 850mg)76 82 93 86
0
20
40
60
80
100
120
0 10 20 30 40 50
time (in min)
% o
f d
rug
rele
ase
F003 F004 F007
Dissolution of final formulation at different time intervals of blending
Table – 41
BLENDING TIME
% of labeled amount f2 value
15min 30 min 45 min
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Observations
10min 70 76 82 56
15 min 72 78 84 62
20 min 76 80 91 80
0
20
40
60
80
100
0 10 20 30 40 50
time (in min)
% o
fdru
g re
leas
e
innovator At 10 min At 15 min At 20 min
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Observations
g) RELATED SUBSTANCES
Table – 42
Name of the
impurities
Impurity level in %
Innovator Reconstituted suspension (F007)
On the day of re
constitution
On the 11th day of re constitution On the day of re
constitution
On the 11th day of re constitution
Stored at 2- 8oc Stored at (RT) Stored at 2- 8oc Stored at (RT)
acid Impurity 0.135 0.140 0.160 0.041 0.170 0.172
lactone Impurity ND ND ND ND ND ND
Delta-3 Isomer 0.192 0.281 0.302 0.106 0.229 0.267
E- Isomers 0.114 0.124 0.224 0.182 0.282 0.311
Maximum single
un known impurity
0.047 0.205 0.312 0.035 0.047 0.053
Total impurities 0.721 0.799 0.816 0.413 0.631 0.726
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Observations
On the day of reconstitution
Innovator
Innovator
F007
InnovatorInnovator
F007
F007
F007
0
0.05
0.1
0.15
0.2
0.25
Acid Delta 3 E-isomer Max sing
Impurity name
% o
f im
puri
ty
Innovator F007
On the 11 th day of reconstitution(2-8°c)
Innovator
Innovator
Innovator
F007
F007
Innovator
F007
F007
0
0.05
0.1
0.15
0.2
0.25
0.3
Acid Delta 3 E-isomer Max sing
Impurity name
% o
f im
pu
rity
Innovator F007
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Observations
Total impurities
Innovator
F007
Innovator
F007
InnovatorF007
0
0.2
0.4
0.6
0.8
1
Total
% o
f im
puri
ty
Innovator F007 Innovator F007
Innovator F007
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Stability studies
Stability studies of the formulations
Stability is an important parameter evaluated for the formulations to assess the
stability of the drug in the formulation at the probable storage conditions.
a blend of 100 bottles was prepared using final optimized formula (F7).blend
was filled in 100ml amber glass bottle having poly propylene white CRC 28 mm cap
with rubber stopper bromobutyl 26 mm grey and kept in stability chambers maintained
at 25◦c /60% RH (3 month) 40◦c /75%RH (1, 2, 3 month) for evaluation with respect to
assay and dissolution studies.
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Stability studies
Stability data at 40°C ± 2°C/75% RH ± 5% RHTable – 43
Tests specification Initial 1st month 2nd months 3rd monthFor dry powderDescription White to off white flavored
powderComplies Complies Complies Complies
Water content Not more than 6.0% 0.16 0.15 0.18 0.16B) For Reconstituted Suspension — On Day Of ReconstitutionDescription Off white to yellow colored
flavored suspensionComplies Complies Complies Complies
PH Between 3.5-7.0 5.88 5.72 5.59 5.20Assay (By HPLC) % Labeled amount
between 90-110% 100.8 100.6 100.3 99.8
Dissolution (in %) f2 value in between 50-100 86 82 82 77Related Substances (in %)Cefuroxime LactoneCefuroxime AcidE – isomersΔ3 isomersMax. Single unknown Imp.Total Impurities
Not more than 1.0%Not more than 1.0%Not more than 1.5%Not more than 2.0%Not more than 1.0%Not more than 7.0%
ND0.0410.1820.1060.0350.413
ND0.0490.2670.2120.0360.611
ND0.1450.2770.2670.0520.691
ND0.1760.3240.3190.0650.934
For re constituted suspension on the 11 th day of reconstitution(at 2-8°c)Description Off white to yellow colored
flavored suspensionPH For information only 5.19 5.15 5.07 5.05Assay (By HPLC) % Labeled amount
between 90-110% 100.4 100.3 100.3 99.8
Related Substances (in %)Cefuroxime LactoneCefuroxime Acid
Not more than 1.0%Not more than 1.0%
ND0.170
ND0.179
ND0.192
ND0.225
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Stability studies
E – isomersΔ3 isomersMax. Single unknown Imp.Total Impurities
Not more than 1.5%Not more than 2.0%Not more than 1.0%Not more than 7.0%
0.2820.2290.0470.631
0.2870.2560.0550.726
0.2950.2860.0570.738
0.3050.2890.0821.076
Dissolution (in %) f2 value in between 50-100 82 NP 80 76For re constituted suspension on the 11 th day of reconstitution(at RT)Assay (By HPLC) % Labeled amount
between 90-110% 99.8 99.7 99.6 99.5
PH For information only 5.0 4.9 4.9 4.8Related Substances (in %)Cefuroxime LactoneCefuroxime AcidE – isomersΔ3 isomersMax. Single unknown Imp.Total Impurities
Not more than 1.0%Not more than 1.0%Not more than 1.5%Not more than 2.0%Not more than 1.0%Not more than 7.0%
ND0.1580.3110.2670.0530.726
ND0.2630.3560.2140.0661.099
ND0.2670.3760.2910.0681.162
ND0.4130.3860.2970.0781.186
Dissolution (in %) f2 value in between 50-100 82 77 75 71
IMPURITY PROFILE DISSOLUTION PROFILE
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Stability studies
On the day of reconstitution
0
0.2
0.4
0.6
0.8
1
Acid E- isomer Delta3 Max sing Total
Impurity name
% O
f im
puri
ty
Initial 1 st month 2 nd month 3 rd month
on the day of re constitution
0204060
80100120
0 10 20 30 40 50
time ( in min)
% o
f dr
ug r
elea
se
initial 1st month
2 nd month 3 rd month
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Stability studies
On the 11 th day of reconstitution at (2-8°c)
0
0.2
0.4
0.6
0.8
1
1.2
Acid E- isomer Delta3 Max sing Total
Impurity name
% o
f im
puri
ty
Initial 1 st month 2 nd month 3 rd month
on the 11 th day of re constitution(at 2-8°c)
0
20
40
60
80
100
0 10 20 30 40 50
time (in min)
% o
f dr
ug r
elea
se
initial 2 nd month 3 rd month
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Stability studies
On the 11 th day of reconstitution(RT)
0
0.2
0.4
0.6
0.8
1
1.2
1.4
Acid E- isomer Delta3 Max sing Total
Imputity name
% o
f im
pu
rity
Initial 1 st month 2 nd month 3 rd month
on the 11 th day of re constitution(RT)
0
20
40
60
80
100
0 10 20 30 40 50
time (in min)
% o
f d
rug
rele
ase
initial 1st month
2 nd month 3 rd month
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Stability studies
Stability data at 25°C ± 2°C/60% RH ± 5% RHTable – 44
Tests specification Initial 3rd monthDescription White to off white flavored powder Complies Complies Water content Not more than 6.0% 0.16 0.16B) For Reconstituted Suspension — On Day Of ReconstitutionDescription Off white to yellow colored flavored
suspensionComplies Complies
PH Between 3.5-7.0 5.88 5.43Assay (By HPLC) % Labeled amount between 90-110% 100.8 100.6Dissolution (in %) f2 value in between 50-100 86 81Related Substances (in %)Cefuroxime LactoneCefuroxime AcidE – isomersΔ3 isomersMax. Single unknown Imp.Total Impurities
Not more than 1.0%Not more than 1.0%Not more than 1.5%Not more than 2.0%Not more than 1.0%Not more than 7.0%
ND0.0410.1820.1060.0350.413
ND0.0460.2860.1940.0440.586
For re constituted suspension on the 11 th day of reconstitution(at 2-8°c)Description Off white to yellow colored flavored
suspensionComplies Complies
PH For information only 5.19 5.16Assay (By HPLC) % Labeled amount between 90-110% 100.4 100.1Related Substances (in %)Cefuroxime LactoneCefuroxime AcidE – isomersΔ3 isomersMax. Single unknown Imp.Total Impurities
Not more than 1.0%Not more than 1.0%Not more than 1.5%Not more than 2.0%Not more than 1.0%Not more than 7.0%
ND0.1700.2820.2290.0470.631
ND0.1860.2950.2460.0540.804
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Stability studies
Dissolution (in %) f2 value in between 50-100 82 78For re constituted suspension on the 11 th day of reconstitution(at RT)Assay (By HPLC) % Labeled amount between 90-110% 99.8 99.6PH For information only 5.0 4.9Related Substances (in %)Cefuroxime LactoneCefuroxime AcidE – isomersΔ3 isomersMax. Single unknown Imp.Total Impurities
Not more than 1.0%Not more than 1.0%Not more than 1.5%Not more than 2.0%Not more than 1.0%Not more than 7.0%
ND0.1580.3110.2670.0530.726
ND0.2580.3630.2790.0681.102
Dissolution (in %) f2 value in between 50-100 81 76
DISSOLUTION PROFILE IMPURITY PROFILE
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Stability studies
on the day of re constitution
0
20
40
60
80
100
0 10 20 30 40 50
time (in min)
% o
f dru
g re
leas
e
intial 3 rd month
On the day of reconstitution
00.10.20.30.40.50.60.7
Acid E- isomer Delta3 Max sing Total
Impurity name
% o
f im
pu
rity
Initial 3 rd month
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Stability studies
on the 11 th day of re constitution(at 2-8°c)
0
20
40
60
80
100
0 10 20 30 40 50
time (in min)
% o
f d
rug
rele
ase
initial 3 rd month
On the 11 th day of reconstitution at(2-8°c)
0
0.2
0.4
0.6
0.8
1
Acid E- isomer Delta3 Max sing Total
Impurity name
% o
f im
puri
ty
Initial 3 rd month
on the 11 th day of re constitution (RT)
0
20
40
60
80
100
0 10 20 30 40 50
time (in min)
% o
fdru
g r
ele
ase
initial 3 rd month
On the 11 th day of reconstitution(RT)
0
0.2
0.4
0.6
0.8
1
1.2
Acid E- isomer Delta3 Max sing Total
Impurity name
% o
f im
pu
rity
Initial 3 rd month
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Result and Discussion Page 126
11.0 RESULT AND DISCUSSION
Most of the conventional drug delivery system for treating the anginal was not
much effective, as the drug do not reach the site of action in appropriate concentration.
Thus an effective and safe therapy of this anginal disorder using specific drug delivery
system was a challenging task to the pharmaceutical technologists.
Modified release delivery systems was a technology by which we can achieve predictable
and reproducible release rates, extended duration of activity for short half-life drugs,
decreased toxicity, reduction of required dose, optimized therapy, and better patient
compliance. Considerable attention was focused on hydrophilic polymers in the design of
oral drug delivery systems because of their flexibility to obtain a desirable drug release
profile, cost effectiveness and broad regulatory acceptance.
The drug has been administered by oral route at doses of from 40 to 60 mg/day, in the
form of tablets containing 20 mg of active ingredient in an immediate release form.
Since the drug is rapidly absorbed and eliminated by the body, its plasma half-life being
less than 6 hours, leading to administration of the active ingredient into 2 or 3
administration per day in order to ensure sufficient plasma levels. The dosage regimen
most frequently required during the treatment is three tablets per day. Multiple daily
administration bear the risk of being forgotten both by the patients leading to active life
and by elderly patients already taking a number of medications
Because of the rapid absorption and the 6 hour half life, such immediate release forms
results in low levels in the blood by the time of the next administration. It is known to be
important to maintain the effective myocardial protection throughout the 24 hours period
and especially in the early morning when the consequences of ischemia are more serious,
because complete coverage of the day is not achieved with the immediate release form.
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Result and Discussion Page 127
This led to the development of modified release form enabling perfect 24 hour coverage,
ensuring a sufficient level in the blood between two administrations whilst retaining a
large plasma peak after each administration so as to maintain the efficacy of the drug,
maintaining the energy metabolism of a cell exposed to hypoxia or ischemia and avoiding
the lowering of the intracellular level of ATP. It also allows peripheral vasodilator effects
to be avoided, while stabilizing blood flow rates and tensional effects
This led to the formulation of a matrix tablet which enables the modified release of drug
by oral route which composes of a hydrophilic matrix characterized in that the modified
release is controlled by the use of a non-cellulosic derivative polymer
This matrix tablet, administrable preferably twice a day, enables prolonged active
ingredient release to be obtained whilst retaining a large plasma peak on each
administration. It allows plasma levels greater than 70 µg/l to be obtained in humans after
each administration and a plasma level greater than or equal to 40 µg/l to be maintained
until the next administration, which was not the case with the immediate release tablet
when administered 3 times per day.
Among the hydrophilic polymers, cellulose derivatives such as methyl cellulose, hydroxyl
propyl methyl cellulose and sodium carboxymethyl cellulose are generally considered to
be stable and safe as release retardant excipients in the development of modified release
dosage forms. But this present invention deals with the fabrication of matrices with non-
cellulosic polymer including water soluble/ swellable polysaccharides such as Xanthan
gum and Polyethylene oxide for retarding the drug release to get the desired release
profile matching with the innovator. Since semi synthetic polymers are quite expensive
when compared with natural polymers such as Guar gum and Xanthan gum, the use of
natural polymers were considered, as they are nontoxic and easily available.
Poly (ethylene oxide) is also a non-ionic water-soluble resin, available
in a variety of molecular weight grades ranging from 100,000 to
7,000,000 Daltons. The common grades of PEO which are used for
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Result and Discussion Page 128
extended-release applications include POLYOX WSR-205 NF, WSR-1105
NF, WSR N-12K NF, WSR N-60K NF, WSR-301 NF, WSR-303 NF and WSR
Coagulant NF. They are the fastest hydrating water-soluble polymers
amongst the hydrophilic polymers, which makes PEO products a
suitable choice for applications where slower initial drug release is
required
The present study was to develop a modified release formulation of a class III highly
soluble drug with hydrophilic polymers such as Xanthan gum & Polyethylene oxide
which can retard the drug release up to 8-12 hrs. The formulation of modified release
matrix tablet was prepared by direct compression technology using a combination of
polymer with different concentration in order to match with the innovator release profile.
Six formulations were designed with different combination of polymer to drug ratio to
prepare the modified release matrix tablets. It was observed that the amount of polymer
influences the drug release. In vitro release study results revealed that the release of drug
was retarded with the proportional increase of the polymer concentration.
Compatibility Studies
By IR Spectra
Drug excipient compatibility studies were carried out to check whether any
compatibility related problems are associated between drug and excipients used in the
formulations.
The IR Spectrum of pure drug was compared with the IR spectrum of the drug with mixer
of excipients. The IR spectrum of the formulation was matching with the IR spectrum of
pure drug, which reveals that there is no interaction between the drug, excipients and
polymer used in the tablets as there was no appearance or disappearance of any
characteristics peaks. (Fig.08-14)
By forced degradation studies:
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Result and Discussion Page 129
The Binary mixtures of drug and excipients were prepared and packed in closed
vials and kept in accelerated environmental conditions of 400/75% RH for 1 month. At
the end of 1 month period all the samples were observed for physical observation and
Impurity levels
Table- 40
Compatibility data for Drug: Excipients
S. No Composition DetailsRati
o
Related Substances
Highest
unknownTotal
1 Drug - 0.009 0.03
2 Drug + Xanthan gum 1:10 0.014 0.102
3Drug + Anhydrous dicalcium
phosphate 1:10 0.011 0.076
4 Drug + Povidone K 90 1:5 0.012 0.052
5 Drug + Lactose monohydrate 1:10 0.052 0.285
6 Drug + Polyethylene oxide 1:10 0.017 0.072
7 Drug + Colloidal anhydrous silica 0.023 0.064
8 Drug + Magnesium stearate 1:1 0.019 0.057
9 Drug + Opadry II Pink 85G44092 1:1 0.043 0.192
10 Drug + Glycerine 1:1 0.022 0.031
Overall, no noticeable change was observed in physical attributes (color, texture, etc) of
the binary mixtures. Further, the total impurities in blends are compared to drug alone,
corroborating the chemical compatibility between active substance and excipients
attempted during the formulation development.
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Result and Discussion Page 130
IR Spectrum of API
Fig- 4
IR Spectrum of API + Polyethylene Oxide
Fig- 5
Fig: 6
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Result and Discussion Page 131
Fig- 6: IR Spectrum of API + Povidone K90
IR Spectrum of API + Povidone K90
Fig- 6
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Result and Discussion Page 132
IR Spectrum of API + Xanthan Gum
Fig- 7
IR Spectrum of API + Polyethylene Oxide + Povidone K90 + Xanthan Gum
IR Spectrum of API+ PEO+ Povidone K90+ Xanthan Gum
Fig- 8
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Result and Discussion Page 133
IR Spectrum of Placebo
Fig- 9
IR Spectrum of API + Placebo
Fig- 10
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Result and Discussion Page 134
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Result and Discussion Page 135
Evaluation of Blend
Based on Preformulation data, Xanthan Gum, Povidone K90, and Polyethylene oxide was
taken as drug release retardants for formulation of matrix MR tablets of a highly water
soluble drug. The tablets were formulated by direct compression technology using the
above mentioned polymers to match the drug release with that of Innovator.
The blended powders of different formulation were evaluated for angle of repose, loose
bulk density (LBD), tapped bulk density (TBD), compressibility index, Hausner’s Ratio
and drug content uniformity (Table- 20). The result of angle of repose in formulations F1,
F4, F5 & F6 (35, 28°, 33°& 30°) indicate good flow properties of the granules. In F2 &
F3 (40° & 47°) found to be poor flow.
Compressibility Index indirectly measures the flowability of powder mass (Fiese and
Hagen, 1986), the Compressibility Index value of all formulation was measured and
found to be 17%, 19%, 23%, 17%, 26% & 22% for formulations F1, F2, F3, F4, F5 & F6
respectively. This result is an indication that the transport of blend from the hopper into
the feed frame and for subsequent die filling could be better for the formulations F1, F2,
F4 & F6 than F3 & F5 because it is known that the CI value below 15% indicates good to
Excellent flowability of a material. The Hauser ratio, LBD and TBD ranged from 1.21 ±
0.007 to 1.34 ± 0.005, 0.4168 ± 0.002 to 0.4546 ± 0.004 and 0.5346 ± 0.003 to 0.5963 ±
0.005 respectively (Table- 20). The drug content in a weighed amount of powder blend of
all MR formulations ranged from 98.27 ± 0.88 to 98.57 ± 0.84 (Table- 20).
Formulation of modified release core tablets
The modified release tablet was formulated to release the drug from 8hrs-12hrs by
varying polymers and its concentration.
In formulation F1, F2 & F3, Xanthan Gum was used in the ratio of 14%w/w, 24%w/w
and 38%w/w of the total weight of the tablets (i.e.) 30mg, 50mg, & 80mg / tab
respectively. The release of the drug from the formulation F1 was not satisfactory since
the total drug was released within 2hrs. In F2 & F3, the concentration of Xanthan Gum
was increased to prolong the drug release. But the drug release was prolonged for a period
of 3hrs & 4hrs respectively. Since F1, F2 & F3 release profile was not matching with the
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Result and Discussion Page 136
innovator product and further increasing the Xanthan gum concentration in the
formulation may lead to reduction of flow property of blend and also possibility of
microbial contamination, the polymer ‘Xanthan gum’ was replaced with ‘Polyethylene
oxide’, in order to retard the rate of release of drug..
In formulation F4, the Polyethylene oxide was used with a maximum amount of 73mg/tab
based on IIG limit and was observed that the drug release was retarded to a extend of 6hrs
only, which not matching with that of innovator. Moreover the tablets formulated only
with PEO were found to have slight rough surface which may affect the appearance of
tablets after coating.
Hence Formulation F5 was designed with the combination of 2 polymers namely Xanthan
gum & Polyethylene oxide in the ratio of 24% w/w & 34% w/w respectively to prolong
the drug release. But the drug release was retarded for a period of more than 12hrs and
was not matching with the proposed specification. Moreover since the quantity of
Xanthan gum was more in the formulation, the impurity in the tablet formulated was
found to exceed the limit as per ICH guidelines when kept at stability for a period of 1
month at 40oC/75% RH.
Next trial F6 was formulated by decreasing the concentration of Xanthan gum from 24%
to 14%w/w (i.e.) from 50mg/tab to 30mg/tab to match the dissolution profile with that of
innovator and also to have a stable product, where the amount of Polyethylene oxide was
kept constant with 73mg/tab. The physical parameters were found to be satisfactory &
dissolution profile was found to be matching with innovator having f2 value of 71.
Evaluation of modified release core tablets
The matrix tablets of various batches formulated were evaluated for test such as
uniformity of weight, hardness, thickness, friability and drug content. The weight
variation tests were performed according to as per procedure given in British
pharmacopoeia. The average percentage deviation of all tablet formulation was found to
be (F1: -1.5 to +2.0; F2: -1.7 to +1.4; F3: -1.8 to +1.2; F4: -1.6 to +1.5; F5: -2.0 to +2.0;
F6: -1.9 to +1.6 ) which was found to be within the pharmacopoeial limit of ± 7.5 %
hence all formulation passed the test for uniformity of weight. The thickness of the matrix
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Result and Discussion Page 137
tablet was found to be in the range of 4.1 to 4.4 mm. The hardness of all batches ranged
from 9.4-12.2 Kp. Another measure of tablet strength is friability. The friability of all
formulation ranged from (0.06 % to 0.34%) which was below 1% limit as per the British
pharmacopoeia indicating that the friability is within the specification limit. All the tablet
formulations showed acceptable pharmacotechnical properties and complied with the in-
house/BP specifications for weight variation, drug content, hardness and friability.
Evaluation of Film coated Tablets
After compression, the matrix tablets were film coated with a non-cellulosic
polymer, namely Opadry II Pink 85G44092, containing PVA, for good appearance and to
protect the tablet from environment. The film coated matrix tablets were evaluated for test
such as uniformity of weight, hardness, thickness, friability and drug content. The average
percentage deviation of all tablet formulation was found to be (F1: -1.5 to +1.5; F2: -1.4
to +1.1; F3: -1.3 to +1.5; F4: -0.9 to +1.5; F5: -1.3 to +2.5; F6: -1.8 to +1.4) within the
pharmacopoeial limit. The thickness of the matrix tablet was found to be in the range of
4.2 to 4.5 mm. The hardness of all batches ranged from 10.5-15.3 Kp.
Invitro evaluation of modified release film coated tablet
The performance of modified release formulation has been reported to be greatly
affected by physicochemical properties of polymer. The amount of polymer may
influence the release of drug from the formulation.
In vitro release study performed in 0.1N HCl with 900 ml, paddle, 50 rpm, reveals
that the release of drug was retarded with the proportional increase of the polymer
concentration. When the hydrophilic matrix tablets of Class III drug come into contact
with the dissolution medium, they take up water and swell, forming a gel layer around the
matrix. Then the dissolved drug diffuses out of the swollen hydrophilic matrix at a rate
determined by the amount and viscosity of Xanthan gum and Polyethylene oxide in the
tablet formulation. The hydrophilic polymer swells quickly & completely providing a
stronger gel to prevent the immediate tablet disintegration and controlling the diffusion of
the drug.
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Result and Discussion Page 138
In vitro release study data indicate that duration of release of drug is dependent on the
percentage of selected polymer used in the formulations. An increase in the polymer
concentration not only causes increase in the viscosity of the gel but also leads to
formation of gel layer with a longer diffusional path. This leads to a decrease in the
diffusion of the drug and therefore a reduction in the drug release rate.
Initially tablets prepared with drug to polymer ratio of 1:0.8 with Xanthan gum in
formulation F1 released 100% of drug within 2 hrs. Hence the polymer concentration was
increased in the further trials of F2 and F3 with drug to polymer ratio of 1: 1.4 and 1: 2
respectively, which released 100% drug at 3 & 4 hrs respectively, which states that the
amount of polymer incorporated was not adequate to control the release of drug from the
formulation.
Hence in Formulation F4, the polymer Xanthan gum was replaced with another non
cellulosic polymer namely Polyethylene oxide with drug to polymer ratio of 1: 2. But the
rate of drug release was not matching with that of innovator, releasing (100 %) at the end
of 6 hrs. Hence formulations F5 and F6 were designed with the combination of two
polymers namely Xanthan gum & Polyethylene oxide in the ratio of 1.4: 2 & 1.08: 2
respectively. Formulation F5 was found to release the drug more than 12hrs which was
not matching with the innovator as the release of drug was more retarded than the
innovator release profile. Hence next trial F6 formulated showed a comparable release
profile releasing the drug of 100% at 8hrs matching with innovator.
Accelerated Stability study
Reproducible batch with same qualitative and quantitative composition of F6, namely F7,
F8 and F9 was charged for stability at 40˚C/75% RH for 3 months in PVC/PE/PVDC –
Alu clear blister of 1 x 10’s. Sample were collected at an interval of 1 month, 2 month
and 3 months and evaluated for impurity profile and dissolution in 0.1N HCl, USP- II
paddle apparatus, 50rpm. The dissolution profile of F7, F8 and F9 charged at
40°C/75%RH in 1M, 2M and 3M was found to be similar with that of dissolution profile
of initial samples releasing not more than 45% at 1st hour and 45 to 65% at 2nd hour, 65 to
85% at 4th hour and not less than 85% at 8th hour respectively. Moreover the impurity
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Result and Discussion Page 139
profile was observed to be well within the specification limit of less than 0.2% for known
impurity and 0.2% for unknown maximum single impurity and 1.5% for total impurity.
Hence the modified release tablets were found to be stable at the above condition for a
period of 3 months.
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Summary and Conclusion Page 140
12.0 SUMMARY AND CONCLUSION
The ultimate goal of Modified release drug delivery is to get optimal treatment
with maximal safety. Compared with immediate release formulation Modified release
formulation allow a longer dosing interval, which has the advantage of greater
convenience and potentially improved compliance. This can be reasonably accomplished
by development of models that is constructed from a non-immunogenic and
biodegradable polymer backbone attached with exact functional group.
The present work was carried out to design and evaluate Modified release tablet of
highly soluble drug, a cellular acting anti-ischemic agent. The Modified release tablets
were prepared by direct compression technique using Polyethylene oxide, Xanthan Gum,
Povidone K90, as drug retardant polymers, which control the release of drug, aimed to
meet out the therapy for angina pectoris. The types of excipient influenced the rate and
extend of drug release from direct compression based matrix tablets.
In formulation F1, F2 & F3, Xanthan gum was used as the only polymer to retard the
drug release by gradually increasing the concentration in each trial. In these formulation
the drug was retarded upto 2hr, 3hr & 4hr respectively, which was not matching with the
innovator. Further increasing the Xanthan gum concentration leads to reduction of flow
property of blend with the possibility of microbial contamination and increase in the
impurity profile of the product. Hence the polymer, Xanthan gum was replaced with PEO,
in order to retard the rate of release of drug to match the dissolution profile.
In formulation F4, the PEO was used with a maximum amount of 7.3mg/tab
based on IIG limit and was observed that the drug release was retarded to a extend of 6hrs
only, which not matching with that of innovator. The tablets formulated only with PEO
were found to have slight rough surface which may affect the appearance of tablets after
coating.
Hence Formulation F5 was designed with the combination of 2 polymers namely Xanthan
gum & PEO in the ratio of 24% w/w & 34% w/w respectively to prolong the drug release.
But the drug release was more retarded and was not matching with the proposed
specification. Moreover since the quantity of Xanthan gum was more in the formulation,
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Summary and Conclusion Page 141
the impurity in the tablet formulated was found to exceed the limit as per ICH guideline
when kept at stability for a period of 1 month at 40oC/75%RH condition.
Hence formulation F6 was formulated by decreasing the concentration of Xanthan gum
from 24% to 14%w/w (i.e.) from 50mg/tab to 30mg/tab to match the dissolution profile
with that of innovator and also to have a stable product. The amount of PEO was kept
constant at 73mg/tab. The physical parameters were found to be satisfactory &
dissolution profile was found to be matching with innovator having f2 value of 70. The
product was also found to be stable at 40oC/75%RH for a period of 3 months.
Powder blends were evaluated for tests such as bulk density, tapped density,
compressibility index, Hausner’s Ratio and content uniformity before being punched as
tablets, which ultimately showed that it was suitable for direct compression. Tablets were
tested for weight variation, thickness, hardness and friability and were found to be
satisfactory meeting the proposed specification. In vitro dissolution tests were performed
and f2 values were calculated for optimized batches. Dissolution profile matched with
innovator and f2 value was satisfactory.
Dissolution study was conducted in 0.1N HCl and also in pH 4.5 acetate buffer,
pH 6.8 phosphate buffer and in water to check the effect of pH on the dissolution profile
of the product. The results have revealed that the rate of drug release was independent of
pH. It was observed that the amount of polymer influences the drug release. In vitro
release study results revealed that the release of drug was retarded with the proportional
increase of the polymer concentration. When Xanthan gum was increased in the
formulation the drug release was retarded but the tablets became soft when kept in
stability leading to increase in the impurity level and also with a drop in the dissolution
(faster dissolution). The use of polymer PEO alone in the formulation was not able to
control the release of the drug with the IIG limits specified by the USFDA. Hence a
combination of hydrophilic polymer namely Xanthan gum and PEO when used in an
appropriate concentration controls the rate of drug release maintaining the impurity limit
within the proposed specification. Moreover the stability result has also revealed that the
product was stable upto 3 months in 40°C/75%RH.
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
Summary and Conclusion Page 142
In conclusion, the present study indicated that the using a hydrophilic non-
cellulosic polymer in an appropriate combination in tablet could control the rate of drug
release matching with that of the innovator. Success of the In vitro drug release studies
recommends the product for further in vivo studies, which may improve patient
compliance.
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
References Page 143
REFERENCES
1. S.J. Daharwal Gastro-Retentive Drugs: A Novel Approach towards Floating Therapy,
“Pharmainfo” Vol. 5 Issue 1 2007.
2. British Pharmacopoeia 2009, 6th edition.
3. Sunil Kamboj et al., Matrix Tablets: An Important Tool for Oral Controlled-Release
Dosage Forms, Pharmainfo, 2009 Vol. 7 Issue 6.
4. R.K.Khar, S.P.Vyas (2002) “controlled drug delivered”. Pg. no .1-50.
5. Brahmanker D.M. and Jaiswal S.B. in "Biopharmaceutics and Pharmacokinetics", "A
Treatise," Vallabh Prakashan, 1st edn, 1995, pg.no.347-352.
6. Manish Shivadas Wani, Controlled Released System - A Review, “Pharmainfo” Vol. 6
Issue 1 2008.
7. Chien Y.W., “Novel Drug Delivery Sysem” (IInd Edn), Revised and expanded 1982,
pg.no.139-140.
8. Chien Y.W., “Novel Drug Delivery System” (IInd Edn), Revised and expanded, 1992,
pg.no.1-2.
9. Jain N.K., “Controlled and Novel Drug Delivery” CBS 1-2, 2002, pg.no.676-698.
10. Lee V.H., Robinson J.R, in, “Sustained and Controlled Release Drug Delivery
System,” Marcel Dekker, New York, pg.no.71-121, 138-171.
11. Gilbert .s. banker “Modern pharmaceutics” 4rth edition pg. no.501-513.3.R.K.Khar,
S.P.Vyas (2002) “controlled drug delivered”. Pg. no .1-50.
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
References Page 144
12. Y. S. R. Krishnaiah, R. S. Karthikeyan, V. Gouri Sankar and V. Satyanarayana Three-
layer guar gum matrix tablet formulations for oral controlled delivery of highly soluble
drug “Journal of Controlled Release” Volume 81, Issues 1-2, 17 May 2002, Pages 45-56.
13. Gidwani, Suresh Kumar, Singnurkar, Purushottam S., Tewari, Prashant Kumar
Sustained release highly soluble drug pharmaceutical compositions and a method of their
preparation “European Pharmacopoeia” EP 1 195 160 B1, 10 APR 2002
14. Sweta et al., Controlled release pharmaceutical dosage forms of highly soluble drug,
world “Intellectual Property Organization” 19 MAR 2003. Publication Number WO
2009/03451 A2.
15. Tulsidutt et al., sustained release composition of highly soluble drug and process for
preparation thereof “world Intellectual Property Organization” 28 MAY 2009.
16. Purushottam s et al., sustained release highly soluble drug pharmaceutical
compositions and a method of their preparation, “European Pharmacopoeia” 1195160 A1,
10 APR 2002.
17. Alan E. Royce Directly compressible polyethylene oxide vehicle for preparing
therapeutic dosage forms, “United States Patent” 5,273,758. 28 Dec 1993.
18. Saleh M. Al-Saidan et al., In Vitro and In Vivo Evaluation of Guar Gum Matrix
Tablets for Oral Controlled Release of Water-soluble Diltiazem Hydrochloride, “AAPS
PharmSci- Tech” (1) Article 5, 30 June 2005.
19. Shashank Bababhai Patel et al., Modified release oral dosage form using co-polymer
of polyvinyl acetate, “United States Patent” 7,427,414 B2. 23 Sep 2008.
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
References Page 145
20. D. Parekh et al formulation and evaluation of sustained release tablets of highly
soluble drug using various polymers, Padm. Dr. D.Y.Patil Institute of Pharmaceutical
Sciences and Research, Pune.
21. Sung-Up Choi et al., Development of a Directly Compressible Poly (Ethylene Oxide)
Matrix for the Sustained-Release of Dihydrocodeine Bitartrate “Drug Development and
Industrial Pharmacy” 2003, Vol. 29, No. 10, Pages 1045-1052.
22. Kewal K. Jain, MD., Drug Delivery Systems Extended-Release Oral Drug Delivery
Technologies: Monolithic Matrix Systems Edition 2008, pg no: 223-224.
23. Saptarshi Dutta et al Modified release dosage form and drug delivery, “Journal of
Pharmacy Research 2009” 2(11), 1728-1729.
24. Ian J. Hardy et al., Modulation of drug release kinetics from hydroxypropyl methyl
cellulose matrix tablets using polyvinyl pyrrolidone “International Journal of
Pharmaceutics” 337 (2007) 246–53.
25. Mohammad Mahiuddin Talukdar et al., Comparative study on xanthan gum and
hydroxypropyl methylcellulose as matrices for controlled-release drug delivery I.
Compaction and in vitro drug release behaviour “International Journal of
Pharmaceutics” 129 (1996) 233-241.
26. Samuel Levy, Combination Therapy of highly soluble drug with Diltiazem in Patients
with Coronary Artery Disease “Am J Cardiol” l995; 76:128-l 68.
27. David A. Fairman et al., The Antianginal Agent Class III drug Does Not Exert Its
Functional Benefit via Inhibition of Mitochondrial Long-Chain 3-Ketoacyl Coenzyme A
Thiolase “Circ Res”. 2003; 93:e26-e32. Jul 17, 2003.
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
References Page 146
28. Evaristo Castedo et al., Ischemia-Reperfusion Injury during Experimental Heart
Transplantation. Evaluation of highly soluble drug Cytoprotective Effect, “Rev Esp.
Cardiol” 2005; 58(8):941-50.
29. Gabriele Fragasso et al., A Randomized Clinical Trial of Class III drug, a Partial
Free Fatty Acid Oxidation Inhibitor, in Patients with Heart Failure “Journal of American
College of Cardiology Foundation” 2006; 48:992– 8.
30. Gilbert Regnier et al., highly soluble drug Compounds, “United States Patent” 5,
283-246. 1 Feb 1994.
31. Onay-Besikci A et al., A Comprehensive Review of the Pharmacological Effects and
Analytical Techniques for the Determination of highly soluble drug, “Cardiovascular
Therapeutics” 26 (2008) 147–165.
32. Krishnamoorthy G; Ganesh M Spectrophotometric determination of Class III drug in
bulk and solid dosage forms “Indian Journal of Pharmaceutical Sciences” 2001 Sep-Oct;
63(5): 436-7.
33. Thoppil SO, Cardoza RM, Amin PD Stability indicating HPTLC determination of
highly soluble bulk drug and in pharmaceutical formulations “Journal of Pharmaceutical
and Biomedical Analysis” Volume 25, Issue 1, April 2001, Pages 15-20.
34. M.Ganesh et al., A new validated spectrophotometric method for determination of
Class III drug in Formulation and comparison with UV method, “Der Pharma Chemica”
2009, 1(2): 97-104.
35. M. A. Naushad et al., Development and validation of the HPLC method for the
analysis of highly soluble bulk drug and pharmaceutical dosage forms “Journal of
Analytical Chemistry” Volume 63, Number 10 / October, 2008.
Design and Characterization of Modified release Matrix tablet of Highly soluble drug
References Page 147
36. Vinod P. Shah et al., Dissolution Profile Comparison Using Similarity Factor, f2
37. Raymond C Rowe, Handbook of pharmaceutical excipients, Sixth edition
Design and Characterization of Modified release Matrix tablet of Highly soluble drug