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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


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


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


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


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


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


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


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


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,


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].


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


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


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.


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


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.


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.


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


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.


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.



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;


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)



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



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



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.


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.


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.



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.


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


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.



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 physicochemical 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.



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.


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


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.


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


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


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



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



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.



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.



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.



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.




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.


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.


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.


Plan of work Page 47

9. Comparison of the test formulation with the marketed product.

10. Stability studies of optimized formulation following ICH guidelines.


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



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.



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



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



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



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



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



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



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



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


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.



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)


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.


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.



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


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.



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


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.



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)


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.


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



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.


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.


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


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


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.


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 - - - - - - -


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


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


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


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 - - - - - - -


Methodology Page 7115 strawberry flavor - - - - - - -

16 Menthol - - - - - - -

17 TOTAL 4000 4000 4000 4000 4000 4000 4000


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


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.


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)


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



E) BLENDING:


Methodology Page 76

Transfer the sifted Blend to the blending area.


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:







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)


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:


Xanthan Gum, Povidone (PVP K30),Tutti Frutti ,Neotame and Acesulfame



Resift the above co sifted materials along with Sucrose (#60 mesh) through #40 mesh

and collect in separate triple polybag

E) BLENDING:



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:








Methodology Page 79

BLENDING:

Transfer the sifted Blend to the blending area.


SOLID DISPERSION (METHOD – 6)


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:


Xanthan Gum, Povidone (PVP K30),Tutti Frutti ,Neotame and Acesulfame




mesh and collect in separate triple polybag


Methodology Page 80

E) BLENDING:



.

DRY GRANULATION (METHOD – 7)


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


Methodology Page 81

BLENDING:




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)


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.


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.


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


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


(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.


Octagonal blender

Fig - 04


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.



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



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.



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%.



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.



f) DISSOLUTION (By U.V Method)

WEIGHT PER ML CALCULATION


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)




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



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%



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 %



Wt/ml = Weight per ml of the Test Sample in mg/ml.

LC = Label claim of Cefuroxime per 5ml of reconstitute suspension



g) RELATED SUBSTANCES (By HPLC Method)

WEIGHT PER ML CALCULATION:


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)




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



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



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



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 =



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



RRT’s of Impurities calculated with respective to Model drug A peak RT



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


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














Observations


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


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%)


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


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


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


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


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


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


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


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


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


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.


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


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


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


Stability studies


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


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


Impurity name

% o

f im

puri

ty


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


Stability studies

On the 11 th day of reconstitution(RT)

0

0.2

0.4

0.6

0.8

1

1.2

1.4


Imputity name

% o

f im

pu

rity


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


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


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


ND0.1700.2820.2290.0470.631

ND0.1860.2950.2460.0540.804


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


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


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


00.10.20.30.40.50.60.7


Impurity name

% o

f im

pu

rity

Initial 3 rd month


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


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


Impurity name

% o

f im

pu

rity

Initial 3 rd month


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.



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



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:



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.



IR Spectrum of API

Fig- 4

IR Spectrum of API + Polyethylene Oxide

Fig- 5

Fig: 6



Fig- 6: IR Spectrum of API + Povidone K90

IR Spectrum of API + Povidone K90

Fig- 6



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



IR Spectrum of Placebo

Fig- 9

IR Spectrum of API + Placebo

Fig- 10





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



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



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.



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



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.


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,



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.



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.


References Page 143

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