Sustained action of multi-particulate system of telithromycin

Table of contents

1. Introduction………………………….…………..1

1.1. Single Unit Dosage Forms……………………3

1.2. Multiple Unit Dosage Forms…………………3

1.3. Why MUPS Technology?.................................5

1.4. Multiparticulates…………………………….11

1.5. Pelletization Techniques…….………………13

1.6. Coating of Pellets…………………………….19

2. Objectives………………………………………..24

3. Review of Literature……………………………..27

4. Methodology…………………………………….35

5. Results……………………………….…………...69

6. Discussions………………………………………84

7. Summary………………………………………….88

8. Conclusion………………………………………..92

9. Bibliography………………………………………93

10.Annexure………………………………………….99

Telithromycin Pellets

V. Mridula, Dept. of Pharmaceutics Page 1

1. INTRODUCTION

From many decades, conventional dosage forms, which are of prompt releasing nature

are used for treatment of acute and chronic diseases.

The conventional dosage forms provide no control over release of drug

To maintain the drug1 concentration within the therapeutically effective range it is often

necessary to take these types of conventional dosage forms several times a day. This

results in significant fluctations in drug levels.

The term “sustained action”2 is known to have existed in the medical and pharmaceutical

literature for many decades. It has been constantly used to describe a pharmaceutical

dosage form formulated to retard the release of a therapeutic agent such that its

appearance in the systemic circulation is delayed and / or prolonged and its plasma

profile is sustained in duration. The onset of its pharmacological action is often delayed

and the duration of its therapeutic effect is sustained.

1.The concept of sustained action is prolonged release of biologically active agents has

been well-appreciated and rationalized for decades.

In the field of pharmaceuticals, sustained release systems have been widely used in oral

medication, since early 1950s. Perhaps the earliest examples are enteric-coated orally

ingested tablets. Other slow release systems include encapsulated pellets or beads,

sparingly soluble salts, complex system, drug embedded in matrix, ion exchange resins,

and swelling hydro gels. Most of the early products can be classified under sustained

delivery systems, which means the release of active agent is slower than any conventional

formulation, but it is significant effected by external environment. The therapeutic range

and duration of action of drugs are important for consideration in drug therapy.

Therefore, sustained release products have received substantial attention in recent years.



2. A multiple unit dosage form could readily separate into sustained release units

throughout the gastrointestinal (GI) tract after ingestion.

One of the multiple unit dosage forms is the pellet, which reduces variation in gastric

emptying time and transit time, is less susceptible to dose dumping, and provides less

irritation from high local concentration of drugs.

3. Oral sustained action dosage forms are widely used for delivery of medicament. The

dosage forms can be categorized based on number of unit per dosage into single and

multiple unit dosage forms. The multiple unit dosage forms are preparations that consist

of several mini reservoirs.

Pellets3 or microencapsulated crystals filled in capsules or compressed into fast

disintegrating tablets are multiple unit dosage forms, which offer several advantages over

single unit dosage forms, such as independence of gastric emptying rate, increase in

Bioavailability 4, reduction in side effects, and possibility of combining incompatible

drugs in a single unit.

4. Pellets offer a high degree of flexibility in the design and development of oral dosage

forms. They can be divided into desired dose strengths without formulation or process

changes and also can be blended to deliver incompatible bioactive agents simultaneously

and/or to provide different release profiles at the same or different sites in the

gastrointestinal tract. In addition, pellets, taken orally, disperse freely in the GI tract

maximize drug absorption, minimize local irritation of the mucosa by certain irritant

drugs, and reduce inter and intra patient variability.

5. Pellets are spherical agglomerated powders and can be prepared by various processes

thus mechanism of pellets formations and not alike.

Pelletization techniques widely used in pharmaceutical industries are direct pelletization



extrusionspheronization 5 and layering. Direct pelletization technique using fluidized

bed equipment has many advantages such as one-unit process no starting material

required and short processing time.

6. The layering technique is the process in which drug in powder solution, or suspension

form is layered onto seed materials. Layering can be carried out in either conventional or

fluidized bed equipment. The latter offers much advantage such as one unit process,

higher yields, higher reproducibility, and good control over process parameters.

Therefore, the fluidized bed process is of interest and gains popularity in pellet

manufacturer.

1.1. Single Unit Dosage Forms:

The single-unit dosage forms usually refer to diffusion controlled systems which

include monolithic systems 6, where the diffusion of a drug through a matrix is the rate-

limiting step , reservoir or multilayered matrix systems, where the diffusion of the drug

through the polymer coating or layer of the system is the rate-limiting step. However,

generally, release of drugs will occur by a mixture of these two mechanisms .

Capsules can also be used as single-unit delayed-release delivery systems .

1.2. Multiple Unit Dosage Forms:

Multiparticulates as dosage forms have been known since the 1950s when the first

product was introduced to the market. Since then, these dosage forms have gained

considerable popularity because of their distinct advantages such as ease of capsule

filling, better flow properties of the spherical beads, ease of coating, sustained, controlled

or site-specific delivery of the drug from coated beads, uniform packing, even

distribution in the GI tract, and less GI irritation. In addition, beads are less susceptible to

dose dumping, which results in reduced peak plasma fluctuations, thus minimizing the



potential side effects without appreciably lowering drug bioavailability.

Types of multiple unit dosage forms comprise

• Pellets

• Granules

1.2.1. Mechanism of drug release:

The mechanism of drug release from multiparticulates can be occurring in the following

ways:

• Diffusion: On contact with aqueous fluids in the gastrointestinal tract (GIT), water

diffuses into the interior of the particle. Drug dissolution occurs and the drug solutions

diffuse across the release coat to the exterior.

• Erosion: Some coatings can be designed to erode gradually with time, thereby releasing

the drug contained within the particle

• Osmosis: In allowing water to enter under the right circumstances, an osmotic pressure

can be built up within the interior of the particle. The drug is forced out of the particle

into the exterior through the coating

Multiparticulate dosage forms can be prepared by a number of techniques such as drug

layering on non-pareil sugar or microcrystalline cellulose beads,7 spray-drying, spray

congealing, rotogranulation, hot-melt extrusion8 and spheronization of low melting

materials or extrusion-spheronization of a wet mass. Beads can also be either coated with

rate-limiting polymers or compressed into tablets to obtain slow-release, target-release or

controlled-release profiles.



1.3. WHY MUPS TECHNOLOGY?

Multi-particulate drug delivery systems are mainly oral dosage forms consisting of

multiplicity of small discrete units, each exhibiting some desired characteristics. In these

systems, the dosage of the drug substances is divided on a plurality of subunit, typically

consisting of thousands of spherical particles with diameter of 0.05-2.00 mm. Thus

multiparticulate dosage forms are pharmaceutical formulations in which the active

substance is present as a number of small independent subunits. To deliver the

recommended total dose, these subunits are filled into a sachet and encapsulated or

compressed into a tablet.

Multiparticulates are discrete particles that make up a multiple-unit system.

They provide many advantages over single-unit systems because of their small size.

Multiparticulates are less dependent on gastric emptying, resulting in less inter and intra-

subject variability in gastrointestinal transit time. They are also better distributed and less

likely to cause local irritation. Recently much emphasis is being laid on the development

of multiparticulate dosage forms in preference to single unit systems because of their

potential benefits such as increased bioavailability, reduced risk of systemic toxicity,

reduced risk of local irritation and predictable gastric emptying. There are many reasons

for formulating drug as a multiparticulate system for example, to facilitate disintegration

in the stomach, or to provide a convenient, fast disintegrating tablet that dissolves in

water before swallowing which can aid compliance in older patients and children

Multiparticulate systems show better reproducible pharmacokinetic9 behavior than

conventional (monolithic) formulations. After disintegration10 which occurs within a few

minutes often even within seconds, the individual subunit particles pass rapidly through

the GI tract. If these subunits have diameters of less than 2mm, they are able to leave the

stomach continuously, even if the pylorus is closed. These results in lower intra and inter

individual variability in plasma levels and bioavailability. Drug safety may also be

increased by using multiparticulate dosage forms, particularly for a modified release

systems. For example, if the film coat of a single-unit (monolithic) enteric coated tablet is



damaged, the complete dose will be released into the stomach where it may cause pain or

ulceration or reduced efficacy, depending on the reason for choosing the protection of the

enteric coating. Equally, if there is damage to the film coating of a monolithic tablet with

a sustained release formulation, this can lead to “dose dumping” and result in dramatic

side effects. By contrast, in multiparticulate formulation, the release characteristics are

incorporated into every single subunit and any damage only affects the release behavior

of the subunit involved, which represents a small part of the total dose, reducing the

likelihood of safety problems.

1.3.1 Approaches to MUPS:

Multiparticulates approaches tried for colonic delivery includes formulations

in the form of pellets, granules, microparticles and Nanoparticles. Because of their

smaller particle size compared to single unit dosage forms these systems are capable of

passing through the GI tract easily, leading to low inter and -intra subject variability.

Moreover, multiparticulate systems are to be more uniformly dispersed in the GI tract and

also ensure more uniform drug absorption11.

Multiparticulates may be prepared by several methods. Different methods

require different processing conditions and produce multiparticulates of distinct qualities.

Some of these methods may be broadly classified as pelletization12, granulation, spray

drying, and spray congealing. Drug particles may be entrapped within the

multiparticulates or layered around them. Subsequently, these multiparticulates may be

modified in many ways to achieve the desired drug release profile. One approach to the

modification of drug release profile in multiparticulates is to coat them. Reasons for the

application of coating onto multiparticulates are to obtain functional coats, provide

chemical stability, improve physical characteristics and enhance patient acceptance.

Coats are formed from various polymeric coating materials broadly classified as aqueous

polymer dispersions, polymer solutions, molten polymers and dry powders. Depending

on the type of coating material used, functions such as sustained release (SR), targeted



release, delayed release, and pulsatile release can be achieved. The most common method

used for the application of coating onto multiparticulates is air suspension coating. Other

methods include compression coating, solvent evaporation13, coacervation, and interfacial

complexation. It is also possible to form coated multiparticulates by spray drying and

spray congealing. A multiparticulate composition may allow controlled release of the

drug over a wide range of release rates, and permit the release rate to be set at a

predetermined rate, such a formulation may be formed using a melt-congeal process

which maintains the crystallinity of the drug during the melt-congeal process. A

multiparticulate delayed release system based on coated pellets containing an osmotic

active ingredient has been prepared. Following ingestion water penetrates into the core

and forms a saturated solution of the soluble components. The osmotic pressure gradient

induces a water influx resulting in a rapid expansion of the membrane leading to the

formation of pores. The osmotic ingredient and the drug are released through these pores

according to zero order kinetics. In comparison with the sodium chloride free formulation

the inclusion of the osmotically active ingredient results in a completely different

dissolution behavior. Lag time and dissolution14 rate were dependent on the coating level

and the osmotic properties of the dissolution medium.

Multiparticulate15 drug delivery systems are mainly dosage forms consisting of large

number of small discrete units each exhibiting desirable characteristics. Multiparticulates

may be prepared by different methods like pelletization, granulation, spray drying and

spray congealing. Drug particles may be entrapped within the multiparticulates (matrix

systems) or layered around them (Reservoir systems). They can be modified in many

ways to achieve desired drug release profile. Depending on the type of coating material

used, sustained release, delayed release, targeted release and pulsatile release can be

obtained in addition to improvement of chemical stability, physical characteristics and

patient acceptance. The purpose of designing multi particulate drug delivery system is to

develop a formulation with all the advantages of single unit formulations. Various

techniques like spheroidal oral drug absorption systems (SODAS), programmable oral



drug absorption systems, pelletized delivery system, and pelletized tablet systems were

developed. In spheroidal oral drug absorption system, the beads are coated with different

types of product specific polymers and encapsulated into a hard gelatin capsule. By

combining different beads, varying degrees of controlled release profiles can be obtained.

In pelletized delivery system, sustained release beads are manufactured by different

techniques like spheronization and coated with release modulating polymers. Later, the

coated beads are filled into hard gelatin capsules.. Pellets offer various advantages over

other systems like less patient compliance, high dose strength administration, and high

production rate and no taste compliance over tablets.. The other major advantages are

reduced risk of local irritation and toxicity, predictable bioavailability, minimized

fluctuations in plasma concentration of drug caused by food effects.

Ideal characters for coating of pellets:

Nature of Polymer16: The polymer used in preparation of pellet plays an important role

in drug release. It must have sufficient elastic properties to prevent rupture of coating

polymer and plastic properties to accommodate the changes in shape and deformation.

Ethyl cellulose possesses weak mechanical properties and hence the pellets compacted

with ethyl cellulose showed loss of sustained properties. Use of pseudo latexes

plasticized ethyl cellulose showed minimal effect on mechanical properties of ethyl

cellulose making it brittle with low values of puncture strength and elongation.

The coatings prepared from organic solvents of ethyl cellulose were more

resistant to compaction compared to that of aqueous solutions. The films formed byusing

organic solvents showed better mechanical properties. To reduce the damage to coating,

compressed pellets can be kept in hot air oven above the glass transition temperature

which resulted in covering of ruptures due to compression. Brittle character of ethyl

cellulose can be overcome by using multilayered beads consisting of alternating layers of

ethyl cellulose, drug or cushioning agent.



Crystals, granules or pellets coated with aqueous acrylic polymer dispersions (Eudragit NE 30D, Eudragit RS/RL 30D) were more flexible than ethyl cellulose films

and they can be compressed with little damage to the coating

Thickness of polymer coating17: - In general, a thicker coating can prevent damage due

to compression than the thinner coating. The deformation characteristics changed with

the increased coating. Ability of pellets to undergo plastic deformation as well as elastic

deformation increased with increasing coating level. However, an increased coating level

caused decrease in tensile strength, yield pressure and increased elastic recovery on

ejection. Increasing the punch velocity resulted in decrease in tensile strength of the

compacts and increase in both yield pressure and elastic recovery values. The punch

velocity dependence increased with increased coating levels.

Pellet Core18: - Not only the film but also the core of pellet should also have sufficient

flexibility. It must possess some degree of elasticity, which can accommodate changes in

shape and deformation. It should deform and recover after compression without damage

to the coating. . Compactability of lactose rich pellets was better than that of micro

crystalline cellulose pellets. The poor compactability of micro crystalline cellulose

pellets is due to loss of plasticity during wet granulation process. Lactose/micro

crystalline cellulose beads were more compressible and exhibited more fracture than

micro crystalline cellulose beads..

Porosity19: -Increased pellet porosity increased the degree of deformation of pellets

during compression and tensile strength of tablets because of formation of stronger inter-

granular bonds. The effect of intragranular porosity on drug release is also high.

Compacted pellets of high porosity were densely packed and deformed. So the drug

release was unaffected. The drug release was markedly increased when low porosity

pellets were compacted due to slight densification and deformation. So the use of highly

porous pellets was advantageous, in terms of preserving the drug release profile.



Size: - The size of the pellets also affects compaction properties and drug release from

the compacted pellets. At the same coating level, smaller pellets were more fragile than

larger pellets. This is due to the reason that increased surface area resulted in reduced film thickness . It was also found that increase in particle size resulted in more damage

to the coating, as indicated by larger difference between the release profile of tablets and

uncompressed pellets

Shape: - shape of the pellets was found to affect the compression behavior and tablet

forming ability of granular materials. More irregular shape induced more complex

compression behavior of granules i.e., more attrition of the granules was induced and

increased deformation was resulted. Isometric shaped pellets offer less contact points and

uniform drug release when compared with anisometric shaped particles.

Density: - Density of pellet is required to achieve prolonged gastric residence. The

critical density to achieve prolonged gastric residence may lie between 2.4 to 2.8g/cm3

Density and size of the pellets play an important role for achieving content and weight

uniformity. Segregation may occur when pellets are compressed using excipients with

smaller particle size and density.

Use of pellets with a narrow size distribution along with excipients of similar size,

shape and density can prevent seggregation.

Hardness of Pellets: - Harder pellets coated with Eudragit L30 D-55 were able to

resist the compression forces better when compared with softer, more porous pellets, which deform easier and therefore resulted in a higher degree of film rupture.



1.4. MULTIPARTICULATES

Multiple unit dosage forms are essential where drug-excipients or drug-drug

physicochemical interaction is possible in a single-unit formulation. They are also known

to have less variance in transit time through the gastrointestinal tract than single-unit

dosage forms. They are usually delivered in hard gelatin capsules or made into tablets

that disintegrate instantly.

1.4.1. PELLETS

Pharmaceutical pellets are agglomerates of fine powder particles or bulk drugs and

excipients, small, free-flowing, spherical or semi-spherical solid units, size ranges from

about 0.5mm to 1.5mm (ideal size for oral administration) , obtained from diverse

starting materials utilizing different processing techniques and conditions

1.4.1.1. Desirable properties of pellets:

Uncoated pellets:

• Uniform spherical shape and smooth surface

• Optimum size, between 600 and 1000μm

• Improved flow characteristics

• High physical strength and integrity

• Good hardness and low friability

• High bulk density20

• Ease and superior properties for coating

Coated pellets:

• Maintain all of the above properties.

• Contain as much as possible of the active ingredient to keep the size of the final

dosage form within reasonable limits

• Have desired drug release characteristics.



Figure 1: (a) Pellets, (b) Perfect pellet, (c) Coated pellet

1.4.1.2. Advantages of pellets

• The smooth surface and the uniform size of the pellets allow uniform coating not only

for each pellet but also from batch to batch. Coating of pellets can be done with

different drugs to enable a controlled release rate.

• In case of immediate release products, larger surface area of pellets enables better

distribution.

• Chemically incompatible products can be formed into pellets and delivered in a

single dose by encapsulating them.

• The beads or granules of different thickness of coatings are blended in the desired

proportions to give the desired effect.

• The thickness of the coat on the pellets dictates the rate at which the drug or contents

are released from the coated particles.

• By selecting the proper formulation, processing conditions and processing equipment,

it is possible to attain smooth surfaced and uniform pellets.

Improved appearance of the product and the core is pharmaceutically elegant

• Pellets can be divided into desired dosage strength without process or formulation

changes and also allows the combined delivery of two or more bioactive agents that

may or may not be chemically compatible, at the same site or at different sites within

the gastrointestinal tract.



• They offer high degree of flexibility in the design and development of oral dosage

form like suspension, tablet and capsule.

Recently, coated pellets are compressed to rapidly disintegrating tablets. For this purpose

small pellets with the mean diameters below 0.5 mm are most suitable. Such pellets can

be produced by direct pelletization methods

1.4.1.3. Disadvantages of pellets:

• The manufacturing of multiple unit dosage forms is more complicated and more

expensive.

• The filling into gelatin capsules is difficult to accomplish, especially in the case where

different subunits are involved.

1.5. PELLETIZATION TECHNIQUES21

Pelletization is an agglomeration process that converts fine powders or granules of

bulk drugs and excipients into small, free-flowing, spherical or semi-spherical units,

referred to as pellets. The type of coating technique strongly affects the film

microstructure and thus affects the release mechanism and rate from pellets coated with

polymer blends. There are several manufacturing techniques for production of spherical

pellets.

1.5.1. AGITATION22

1.5.1.1. Balling: Finely divided particles are converted upon the addition of appropriate

quantities of liquid, to spherical particles by a continuous rolling or tumbling motion.

Pans, discs, drums, or mixers may be used to produce pellets by the balling.

1.5.2. COMPACTION

1.5.2.1. Compression: Mixtures or blends of active ingredients and excipients are

compacted under pressure to generate pellets of defined shape and size.



1.5.2.2. Extrusion – Spheronization: It is a multistep process invented by Nakahara, in

1964, involves dry mixing of the active compound with excipients, granulation of wetted

mass, extrusion of the mass, transfer of the mass to spheronizer to produce spherical

shape, drying of the wetted mass in a dryer, and at the end screening to obtain required

particle size.

Figure 2: Principle of Extrusion – Spheronization process

1.5.3. LAYERING23

In this process, drug is layered onto seed materials (generally, a coarse material or

nonpareil) in powder, solution or suspension form and leads to heterogeneous pellets,

which consist of an inner core region and an outer shell region of a different composition.

This process is classified into three categories namely direct pelletization, solution or

suspension layering and powder layering.

1.5.3.1. Direct pelletization:

A process that leads to formation of homogeneous pellets which have

microscopically uniform structure and no core can be detected. Direct pelletization is

mainly performed in high shear mixers and fluidized bed equipment .



Figure-3 Direct pelletization

1.5.3.2. Powder Layering24

Powder layering involves the deposition of successive layers of dry powder of

drug or excipients or both, on preformed nuclei or cores with the help of a binding liquid.

Equipment used is tangential spray/centrifugal/rotary fluidized bed granulator .

Some of the disadvantages are:

• Low amount of drug loading which is not suitable for high-dose drugs

• Final composition of pellets can vary if spray loss occurs.

Figure 4: Principle of Powder layering process\

1.5.3.3 Solution/Suspension layering25

In the case of Solution/Suspension layering, growth of pellets involve deposition

of successive layers of solution and/or suspension of drug substance and binders on

existing nuclei, which may be inert seed, crystal or granule. The drug particles are

dissolved or suspended in the binding liquid, with or without the binder. Droplets of the

binding liquid spread on the surface of the nuclei. During drying, liquid evaporates and

the dissolved substances crystallize out and capillary forces which are formed draw the

particles towards each other and towards the inert seed, forming solid bridges. In

suspension layering, particles have low solubility and are bonded by solid bridges formed

from the hardening binder i.e., that higher concentration of binder might be necessary.In



this process fines are produced as a result of attrition or spray drying especially when the

process is not optimized .

The efficiency of the process and the quality of pellets produced are in part related

to the type of the equipment used.

As a starter seeds usually sugar spheres consisting of a sugar-starch mixture or

recently microcrystalline cellulose pellets and the pure drug crystals are used.

The most common configuration used is Wurster26, bottom spray coater.

This technology is applied to produce enteric coated multiple unit pellets for

improving the stability in acidic media, due to the enhancement of the polymer film

formation on the surface of the pellet. On the other hand enteric coating assures.

Immediate release of alkali media at the time of the release.

Figure 5: Principle of Solution and Suspension layering process



Mechanism involved in coating of pellets by Wruster process

The Wurster process is a coating technique that is well

suited to uniformly coat or encapsulate individual

particulate materials. This technology is characterized by

the location of a spray nozzle at the bottom of a fluidized

bed of solid particles. The particles are suspended in the

fluidizing air stream that is designed to induce a cyclic

flow of the particles past the spray nozzle. The nozzle

sprays an atomized flow of coating solution, suspension, or

other coating vehicle.

The atomized coating material collides with the particles as

they are carried away from the nozzle. The temperature of

the fluidizing air is set to appropriately evaporate solution

or suspension solvent or solidify the coating material

shortly after colliding with the particles.

All coating solids are left on the particles as a part of the

developing film or coating. This process is continued until

each particle is coated uniformly to the desired film

thickness.

The Wurster process is an industry recognized coating

technique for precision application of film coat to particulate materials such as

powders, crystals, or granules. The technology can be used to encapsulate solid

materials with diameters ranging from near 50µm to several centimeters. The process

has a greater drying capacity than other coating systems due to a relatively high

fluidizing air velocity. Since the particles actually separate as they are carried away

Fig:6 schematic

representation of

wruster process



from the nozzle, it is possible to coat small particles without agglomeration. Coating

possibilities are relatively unlimited including the ability to place a hydrophilic coat on

a hydrophobic core, or a water-based coat on a water-soluble core. Coating properties

can be optimized with coat formulation parameters, processing conditions, and

layering.

Fig: 7 Process principle of fluid bed coating

1.5.4. GLOBULATION27:

Globulation or droplet includes spray drying and spray congealing

1.5.4.1. Spray drying28:

Drug entities in solution or in suspension form are sprayed, with or without excipients,

into a hot air stream to generate dry and highly spherical particles. It is generally

employed to improve the dissolution rates and hence, bioavailability of poorly soluble

drugs



1.5.4.2. Spray congealing29:

A process in which a drug is allowed to melt, disperse, or dissolve in hot melts of gums,

waxes, fatty acids, etc., and is sprayed into an air chamber where the temperature is

below the melting points of the formulation components, to provide spherical congealed

pellets under appropriate processing conditions.

1.6. COATING OF PELLETS

The application of coating is usually based on one or more of the following:

• To mask the taste, odor or color of the drug.

• To provide physical and chemical protection to the drug.

• To control the release of the drug.

• To protect the drug from the gastric environment of the stomach with an acid resistant

coating.

• To incorporate another drug or formula adjuvant in the coating to avoid chemical

incompatibility or to provide sequential drug release.

• To provide pharmaceutical elegance by use of special color.

Types of Coating

1. Drug coating

2. Sub coating

3. Enteric coating

4. Cushion coating

5. Film coating

Film coating30

V. Mridula, Dept. of Pharmaceu

There are numerous

formulations; for example,sus

aim of this paper was to stud

coatings in a fluid-bed proces

thickness formed. Eight pellet

and the other batches can b

cylinders. The average coa

measurements did not appear

fluid-bed process, however, h

ratio greater than 1.5. The ch

monitored effectively employi

shape occurred at the beginni

min, after which the shape rem

DRUG PROFILE

TELITHROMYCIN

IUPAC1S,2R,5R,7R,8R,9S,11R,13R,14-dimethylamino-3-hydroxy-62-ethyl-9-methoxy-1,5,7,9,11,[4-(4-pyridin-3-ylimidazol-1-yazabicyclo[12.3.0]heptadecane

STRUCTURE

Molecular formula -C43H65N

Telithrom

utics

reasons for which film coatings are ap

stained action taste masking, and improve

dy the influence of pellet shape on the dep

ss by monitoring the pellet shape as a func

t batches were used, of which four were sph

be described as ovoids, dumbbells, long

at thickness of the pellets assessed by

r to be influenced by the initial shape of t

ad an impact especially for those pellets tha

ange in the pellet shape during film coating

ing a three-dimensional shape factor. Signifi

ing of the coating process up to approximat

mained constant.

4R)-8-[(2S,3R,4S,6R)-6-methyl-oxan-2-yl]oxy-13-hexamethyl-15-yl)butyl]-3,17-dioxa-15-e-4,6,12,16-tetrone

TELITHROMYCINN5010

mycin Pellets

Page 20

pplied to pellet

d stability. The

position of film

tion of the film

herical visually,

dumbbells, and

y cross-section

the pellets. The

at had an aspect

g could only be

icant changes in

tely the first 15



Molecular mass -812.004G/MOLMolecular weight -1178.8412

PHYSICOCHEMICAL CHARACTERISTICS

Description-white colour

Odor-odorless

Solubility-good water solubility.it is soluble in ethanol,methanol

Melting point-176-188c

Boiling point-966.2c at 760 mmhgFlash point-538.2c

Half life-10 hours

Mechanism of action31

Telithromycin prevents bacteria from growing, by interfering with their protein synthesis.

Telithromycin binds to the subunit 50s of the bacterialribosome, and blocks the progression of the growing polypeptide chain. Telithromycin has over 10 times higher

affinity to the subunit 50S than erythromycin. In addition, telithromycin strongly bind

simultaneously to two domains of 23S RNA of the 50 S ribosomal subunit, where older

macrolides bind strongly only to one domain and weakly to the second domain.

Telithromycin can also inhibit the formation of ribosomal subunits 50S and 30s



TELITHROMYCIN PATHWAY

Pharmacokinetics

ABSORPTION

Drug is mainly absorbed through tissues.

Its bioavailability is 57%

DISTRIBUTION32

Protein binding takes place 60-70%bound primarily to human serum albumin

Volume of distribution -2.91/kg

METABOLISM33

Telithromycin is mainly metabolized in liver

EXCRETION

It is through biliary and renal route.

ADVERSE EFFECTS

Gastrointestinal, including diarrhea, nausea, abdominal pain and vomiting. Headache and

disturbances in taste also occur. Less common side-effects include palpitations, blurred

vision, and rashes. Prolonged QTc intervals may also be caused by Telithromycin.

Drug interactions34

1..Telithromycin may increase the anticoagulant effect of acenocoumarol.

2. Telithromycin may reduce clearance of Alfentanil. Consider alternate therapy or

monitor for changes in the therapeutic/adverse effects of Alfentanil if Telithromycin is

initiated, discontinued or dose changed.

3. Telithromycin may reduce clearance of Alfuzosin. Consider alternate therapy.



4. Telithromycin may increase the effect and toxicity of the benzodiazepine, alprazolam.

5.Telithromycin may reduce clearance of Ambrisentan. Consider alternate therapy or

monitor for changes in the therapeutic/adverse effects of Ambrisentan if Telithromycin is


6. Aminoglutethimide may decrease the plasma concentration of Telithromycin. Consider alternate therapy.

7. Telithromycin may reduce clearance of Amiodarone. Consider alternate therapy or

monitor for changes in the therapeutic/adverse effects of Amiodarone if Telithromycin is


APPLICATIONS

1. Telithromycin is used to treat certain types of pneumonia (an infection of the lungs)

2. that is caused by bacteria.

3. Telithromycin is in a class of medications called ketolide antibiotics.

4. It works by killing bacteria. Antibiotics will not kill viruses that can cause colds, flu, or other infections.

5. It is a novel drug which shows high potency.



2 OBJECTIVES

Researchers to modulate and release the drug over an sustained period of time have

devised many drug delivery systems. The majority of these systems are and their

principal drug release mechanism is based on the drug diffusion through the matrix

system. The diffusion is altered by the pH35 of the medium, the presence of food, and the

body’s physiological factors, all of which cause difficulty in controlling the drug release

rate. Another delivery method used is the ‘pellet’. Selected dosage forms use the

principles of diffusion, erosion, and surface desorption, and combination of

diffusion,erosion36 and dissolution.

The objectives of the present investigations are:

1 .Preparation of Telithromycin sustained release pellets using different polymers

different techniques.

2. Characterization of telithromycin pellets.

3. In vitro37 evaluation of telithromycin pellets for the release characteristics.

4. To study the physic-chemical parameters of drug release from multiparticulate system.

5. To study the predetermined rate of drug release38.

6. To study the preformulation39 characteristics.

A survey of the literature indicates that extensive work was conducted in the

development of sustained release dosage forms. The drugs studied are Erythromycin

Theophylline,Zyban, Metformin hydrochloride, Terbutaline sulphate, Aceclofenac etc.

Many attempts were made to develop sustained release dosage forms to release the drugs

for an extended period of time.The drug release mechanism from such a system may

explained by the following dissolution ,erosion, surface desorption, combination of

diffusion and erosion. Hence, in the present proposed work, sustained release pellets of



telithromycin were planned on the principles of sustained release dosage forms. Further,

an attempt was made to develop sustained release dosage form with zero order release

TELITHROMYCIN

Telithromycin is the novel ketolide antibiotic.

Telithromycin prevents bacteria from growing by interfering with their protein synthesis

.It binds to 50 s of the bacterial ribosome and blocks the progression of the growing

polypeptide chain.

• The telithromycin conventional tablets can be obtained as

300mg,400mg.Telithromycin can be easily absorbed and elimination is through

biliary, and renal route.Its half life40 is 10 hours.It is white in colour,odorless,it is

having good water solubility.its bioavalability is 57%.protein binding41 takes place

60-70% bound primarily to human serum albumin.These biopharmaceutical42 and

physicochemical properties reveal that telithromycin is the ideal candidate to develop

in to sustained action pellets.

Rationale for Drug Selection

1. Telithromycin is a highly water-soluble drug. It is Soluble in ethanol, methanol, DMF

or DMSO. Good water solubility.

2. The marketed sustained release formulations of Telithromycin are available in tablet

form. dosage of 300mg,400mg.In order to get sustained release pellets for easy drug

release.

3. Telithromycin has a biological half life 10 hours



4. Adverse events associated with Telithromycin use are often gastrointestinal, including

diarrhea, nausea, abdominal pain and vomiting. Headache and disturbances in taste also

occur. Less common side-effects include palpitations, blurred vision, and rashes.

Prolonged QTc intervals may also be caused by Telithromycin.These adverse effects may

be partially avoided during sustained release dosage form.



3. REVIEW OF LITERATURE

DRUSANO.G43 et al

Telithromycin is a novel ketolide which is a semisynthetic derivative of erythromycin

A,having a 3-keto function instead of a 3-l-cladinose on the erythronolide A ring

.Telithromycin, a new ketolide antimicrobial agent, has sufficient potency, with an

antibacterial spectrum that covers all major respiratory tract pathogens, against isolates

from respiratory tract infections (RTIs) and exhibits potent antibacterial activity against

gram-positive aerobes, including Streptococcus pneumoniae, Streptococcus pyogenes,

fastidious gram-negative bacilli, including Heomophilus influenza and Moraxella

catarrhalis, intracellular pathogens, including Chlamydia pneumoniae, Legionella

pneumophila,and a typical mycophila as Mycoplasma .pneumonia.

CHOURASIA M.K JAIN44 et al

The purpose of designing multiparticulate dosage form is to develop a reliable

formulation that has all the advantages of a single unit formulations and yet devoid of the

danger of alteration in drug release profile and formulation behaviour due to unit to unit

variation ,change in gastro-luminal ph and enzyme population.

THANOO.B.C.SUNNY.45 et al

Pharmaceutical and research are increasingly focusing on delivery systems which

enhance desirable therapeutic objectives while minimizing side effects. Recent trends

indicate that multiparticulate drug delivery systems are especially suitable for achieving

sustained or delayed release oral formulations with low risk of dose dumping,flexibility

of blending to attain different release patterns as well as reproducible and short gastric

residence time.



VANDEN MOOTER46 et al

For decades an acute disease or chronic illness is being clinically treated through delivery

of drugs to the patients in the form of some pharmaceutical dosage forms like tablets,

capsules, pills, creams, liquids, ointments, aerosols, injectables and suppositories.

Presently, these conventional dosage forms are primarily prescribed pharmaceutical

products and available over-the-counter. To achieve and maintain the concentration of an

administered drug within therapeutically effective range, it is often necessary to take drug

levels in plasma.

SINHA V.R KUMARIA47 et al

The goal of any drug delivery system is to provide a therapeutic amount of drug to the

proper site in the body to achieve promptly, and then maintain, the desired drug

concentration. That is, the drug delivery system should deliver drug at a rate dictated by

the needs of the body over the period of treatment. This idealized objective points to the

two aspects most important to drug delivery, namely, spatial placement and temporal

delivery of the drug. Spatial placement relates to targeting a drug to a specific organ or a

tissue, while temporal delivery refers to controlling the rate of drug delivery to the target

tissue. An appropriately designed sustained release drug delivery system can be a major

advance towards solving these two problems. It is for this reason that the science and

technology responsible for development of sustained release pharmaceuticals have been

and continue to be the focus of a great deal of attention in both industrial and academic

laboratories.

DEVEREUX J.E NEWTON48 et al

Sustained release systems include any drug delivery system that achieves slow release of

drug over an extended period of time. If the systems can provide some control,weather



this be of a temporal or spatial nature, or both, of drug release in the body or in the other

words, the system is successful at maintaining constant drug levels in the target tissue or

cells,it is considered a controlled release system.

LIU ,L .FISHMAN49 et al

The design of sustained release delivery systems is subject to several variables of

considerable importance. Among these are the route of drug delivery, the type of delivery

system, the disease being treated, the patient, the length of therapy and the properties of

drug. Each of these variables is interrelated and this imposes certain constraints upon for

the route of delivery, the design of the delivery system and the length of therapy. Of

particular interest to the scientists designing the systems are the constraints imposed by

the properties of the drug. It is these properties, which have the greatest effect on the

behavior of the drug in the delivery system and in the body.

JOSEPH,N.J LAXMI50 et al

Drug stability : Of importance for oral dosage form is the loss of drug through acid

hydrolysis and / or metabolism in the GI tract. Most sustained release systems currently

in use release their contents over the entire length of GT tract. Thus, drugs with

significant stability problems in any particular area of the GT tract are less suitable for

formulation into sustained release systems that releases its contents throughout the GI

tract.

WADHWA .S51 et al

Given enormous advantages of multiparticulate systems over single-unit oral dosage

forms, extensive research has focused recently on refining and optimizing existing



pelletization techniques as well as on the development of novel manufacturing

approaches that use innovative formulations and processing equipment.

SELLESIA.I.G52 et al

As sustained release systems, floating dosage forms offer various potential advantages

evident from several recent publications.Drugs that have poor bio availability because

their absorption is restricted to upper GI tract can be delivered efficiently thereby

maximizing their absorption and improving their absolute biavailabilities.

NS Dey, 53 et al

Pharmaceutical invention and research are increasingly focusing on delivery systems

which enhance desirable therapeutic objectives while minimising side effects. Recent

trends indicate that multiparticulate drug delivery systems are especially suitable for

achieving controlled or sustained release oral formulations with low risk of dose

dumping, flexibility of blending to attain different release patterns as well as reproducible

and short gastric residence time. The release of drug from microparticles depends on a

variety of factors including the carrier used to form the multiparticles and the amount of

drug contained in them. Consequently, multiparticulate drug delivery systems provide

tremendous opportunities for designing sustained release oral formulations, thus

extending the frontier of future pharmaceutical development.

CHIN J.E54 et al

The aim of this study was to examine the transport mechanism of telithromycin in

comparison with erythromycin, azithromycin, clarithromycin and roxithromycin.: These

antibiotics were examined in Caco-2 cell monolayers in order to demonstrate the

potential involvement of P-GP in the absorption process, using verapamil as a P-GP

competitor. A model using concentration equilibrium conditions was developed to

delineate passive and active permeability components of telithromycin and roxithromycin



transport in order to predict absorption in humans. Comparison of telithromycin Papp

(AB)/Papp (BA) ratios with those of the other antibiotics indicated that an efflux pump

was involved which limited the transport of the macrolides to a greater extent than that of

telithromycin. Modulation of Caco-2 transport of these antibiotics by verapamil and their

reciprocal effect upon verapamil transport confirmed the involvement of P-GP and

demonstrated that two substrates of P-GP may increase the transport of each other.

Under concentration equilibrium conditions, both roxithromycin and telithromycin

exhibited high mean Papp values for passive diffusion which extrapolated to 88% and

77% predicted human absorption respectively, if the involvement of P-GP was

ignored.Both Km and Vm values suggested that saturation of P-GP by telithromycin may

occur at a lower dose level in humans than with roxithromycin (Km= 9.8µM, Vm= 0.3

µM and Km= 45 µM, Vm= 1.1 µM, respectively). At 4.10-5 M of either telithromycin or

roxithromycin the passive flux was respectively 48% and 16% greater than the active

efflux. The high absorption potential of telithromycin combined with the low Km and

Vm values and the high dose level suggest that in humans the efflux pump may not limit

ketolide absorption and that the interaction with other P-GP substrates may not

significantly increase its oral absorption.

RONINSON T.B55 et al

Telithromycin (HMR 3647) is a novel ketolide antimicrobial with good activity against

both common and atypical respiratory pathogens, including many resistant strains. This

randomized, three-period crossover study determined the dose proportionality of

telithromycin pharmacokinetics after single and multiple dosing in healthy subjects. In

each treatment period, subjects received a single oral dose of 400, 800 or 1,600 mg of

telithromycin followed 4 days later by the same dose once daily for 7 days. Blood and

urine samples were taken throughout the study for determination of pharmacokinetic

parameters for telithromycin and RU 76363, its main metabolite.



INGUNN THO ET.AL 56 et al

It is studied low-soluble pectin derivative PA (degree of methoxylation,10%) as an

extrusion aiding excipient in pellet preparation by spheronisation /extrusion. The

substance has a high drug loading capacity and produces disintegrating pellets that are

well suited for fast delivery of drugs with a low water solubility. The pellets are also

mechanically stable, compared to MCC.

MARCEL DEKKER INC 57 et al

The concept of sustained release formulations was developed to eliminate the need for

multiple dosage regimens, particularly for those drugs requiring reasonably constant

blood levels over a long period of time. In addition, it also has been adopted for those

drugs that need to be administered in high doses, but where too rapid a release is likely to

cause undesirable side effects.

NEWTON JM 58 et alThe design of sustained release delivery systems is subject to several variables of

considerable importance. Among these are the route of drug delivery, the type of delivery

system, the disease being treated, the patient, the length of therapy and the properties of

drug. Each of these variables is interrelated and this imposes certain constraints upo

choices for the route of delivery, the design of the delivery system and the length of

therapy. Of particular interest to the scientists designing the systems are the constraints

imposed by the properties of the drug. It is these properties, which have the greatest

effect on the behavior of the drug in the delivery system and in the body.

AMIT KRISHNA RATNAKAR59 et al

The present invention provides a multiple unit compositions comprising of film coated

pellets and, wherein each pellet comprises: i) a core comprising active ingredient(s); ii)



optionally a separating layer coated on the core; iii) at least two film layers comprising of

film polymers and plasticizer either coated on the core or on the separating layer to obtain

film coated pellets, such that the last film layer is formed from a solution comprising of

film polymer and plasticizer in organic solvent(s), resulting in no appreciable change in

release profile of active ingredient.

T Karunakar Reddy60 et al

The objective of the present study is to focus on formulation of Telithromycin film

coated pellets by Wurster coating technique with fluid bed processor, in the form of

capsules,). In this formulation film formers like Povidone and HPMC are used in drug

loading stage and Talc is used in film coated stage in the formulation of telithromycin

coated pellets.

S.THIERRY61 et al

The drug loaded core pellets were produced by aqueous extrusion

spheronization technique using microcrystalline cellulose as a spheronizing aid and PVP

K 30 as a binder. Different coat weights of Eudragit S-100 were applied to the drug

loaded pellets in an automatic coating machine to produce the pH sensitive coated pellets.

In vitro dissolution studies of the coated pellets performed following pH progression

method showed that the drug release from the coated pellets depended on the coat

weights applied and pH of the dissolution media.

D.Kumaraswamy62 et al

A new simple, rapid and reliable UV Spectrophotometry method was developed and

validated for the estimation of Telithromycinin blend & Capsules formulations. The

method was based on simple UV estimation in cost effective manner for regular

laboratory analysis. The instrument used was Perkin Elmer, UV Spectrophotometer

(Lambda 25) and using 0.1 N NaoH as solvent system. Sample were analysed using UV



Win Lab 5.2.0 Software and matched quartz cells 1 cm and was monitored at 302 nm.

Linearity was obtained in the concentration range of 2 - 10 mg mL–1 for telithromycin

The validation parameters, tested in accordance with the requirements of ICH guidelines,

prove the suitability of this method.



4. METHODOLOGY

LIST OF EXCIPIENTS AND MATERIALS.

Name of Excipient Manufacturer/supplier.

Telithromycin HEFEI TNJ CHEMICAL INDUSTRY

Sugar: Dynamix dairy industries Sodium CMC : Hercules aqualon Maize starch : Maize products Potato starch : Avebe

Pregelatinised starch : Avebe Colloidal anhydrous silica: Intas Pharma Titanium dioxide : Kronos international Magnesium stearate : Amshi drugs Non pareil seeds: Homedicines

Talc : Ashok minerals

crasmellose : Triveni inter chem.pvt.ltd

Hypermellose: shaanxi top pharm chemical co ltd



LIST OF EQUIPMENTS USED

Name of the equipment Make

Extruder and spheronizer Modern plastic and equipments

Hplc Agilent Technologies

Fluidized bed dryer Neelam industries

Tap density testor Electro lab

Uv visible spectrometer Shimadzu

Friability tester Electro lab

Dissolution testor Electro lab

Bulk density Electronics India

Stability chamber Thermo lab

Mechanical stirrers Remi motors

Weighing balance 5kg Mettler toledo

Weighing balance 10 kg Mettler toledo

Digital balance Mettler toledo

Ph meter Mettler toledo



Marketed MUPS sustained release pellets formulation

Company Drug Therapeutic Category formulation type

Elilily Erythromycin Antibiotic sustained release

Triveni chemicals diclofenac NSAID sustained release

Ssamex overseas ketorolac NSAID sustained release

Hainan coltd fenofibrate statin sustained release

Shanghai pharma theophyllone asthma sustained release

IDEAL CHARACTERISTICS OF EXCIPIENTS

1.Drug should be water soluble to perform the formulations.

2.Polymer should have compatibility with drug and other excipients.

3.It should have good coating agent.

4.Filler should have good capacity to fill and compatible with other excipients.

5.Binding agent should also have good binding agent to bind the substances very well.



6.Disintegrant agent should soluble in other excipients and should compatible with other

excipients.

DRUG-EXCIPIENT COMPATIBILITY

1.We have selected some excipients based on above characteristics

They are

A –Chemical nature

B- Impurity profile

C- Physical form

D- Moisture content

E-Surface area

F-Particle size

G-Morphology.



• EXCIPIENTS DETAILS

• Details of Non-Pareil Seeds

Non proprietary names Sugar spheres

Synonyms Non-pareil; Non-pareil 103;Nonpareilseeds; Nu-core; Nu-pareil;sugar seeds

Functional category Tablet and capsule diluents

Applications Used as inert cores in capsules andtablets formulations particularlyfor sustained release dosage forms

Description Spherical granules of a labelednominal –size range with uniformdiameter and containing not lessthan 62.5 % and not more than91.5 % sucrose

Typical properties Solubility in water variesaccording to the sucrose to starchratio. The sucrose component isfreely soluble in water whereas thestarch component in soluble incold water.

Stability and storage Stable when stored in cool anddried place in a well closedcontainer



Method of manufacture Made up from crystalline sucrose, which is coated using sugar syrupand a starch – dusting powder.

Details of sugar

Non proprietary names Compressible Sugar

Synonyms Direct compacting sucrose: Nu TAB

Emperical formula Contains, not less than 95.0 % and

not more than 98.0 % of sucrose

Functional category Tablet and capsule diluents, sweetening agent

Applications Dry binder in tablet formulationFiller in chewable tabletsSweetener in chewable tablets

Description Sweet – tasting, white crystallinepowder.

Typical properties Bulk density: 0. 492 g/cm3Tap density: 0.6 g/cm3Moisture content: 0.57%



Stability and storage : Stable in air under normalconditions of room temperature. Should be stored in well-closedcontainer in a cool, dry place.

Method of manufacture It is prepared by cocrystalization ofsucrose

Details of talc

Non proprietary names Purified talc, talc, talcum

Synonyms 553b;magsil osmanthus; magsil

star; powdered talc

Empirical formula It is purified, hydrated,magnesium

silicate

Functional category Anti sticking agent; glidant; tablet

and capsule diluent and lubricant

Applications Dusting powder preparationTablet and capsule glidant and

lubricant

Description Fine, white to grayish-whitecolored, odour less , impalpable,

unctuous, crystalline powder

Method of manufacture It is naturally occurring

hydropolysilicate mineral



Details of titanium dioxide

Non proprietary names Titanium dioxide; titanium oxide;titanii dioxidum.

Synonyms Anatase titanium dioxide; kowett;kronos

Empirical formula Tio2

Functional category Coating agent and pigment

Applications It is widely used in confectionery, cosmetics, foods and topicalpreparations

Description White, amorphous, odorless, andtasteless non-hygroscopic powder.

Typical properties Bulk density: 0.4-0.62 g/cm3Tap density: 0.625-0.830 g/cm3

Stability and storage Stable material at high temp.itshould be stored in well-closedcontainer in a cool and dried place.

Method of manufacture It is naturally occurring mineralrutile, Anatase and brookite.



Details of magnesium stearate

Non proprietary names Magnesium stearate, magnesiistearas.

Synonyms Magnesium octadecanoate

Empirical formula C36H70MgO4

Structural formula (CH3 (CH2) COO) 2Mg

Functional category Tablet and capsule lubricant

Applications It is widely used in cosmetics, foods and topical preparations

Description Fine, white, precipitated or milled, impalpable powder of low bulkdensity.

Typical properties Bulk density: 0.159 g/cm3Tap density: 0.286 g/cm3Flash point: 250º C

Stability and storage

conditions

It is stable and should be stored ina well-closed container in a cool, dry place



DETAILS OF SODIUM CMC

Non proprietary names Carmellose

Synonyms Akucell; aquasorb; blanose; cekol

Empirical formula It is sodium salt of apolycarboxymethyl ether ofcellulose.

Functional category Coating agent, binder,disintigrantApplications It is used in oral and topical

formulations as emulsifying agent,gel-forming agent.

Description White to almost white colored, odorless, granular powder.

Typical properties Bulk density: 0.520 g/cm3Tap density: 0.783 g/cm3melting point: 227º C

Stability and storageconditions

It is stable though hygroscopicmaterial. Under high humidityconditions it can absorb largequantity of water. It should bestored in a well-closed container ina cool, dry place.

Method of manufacture It is prepared by steeping cellulose.



Details of starch

Non proprietary names Maize starch, potato starch

Synonyms Amido; amidon; amilo

Empirical formula (C6H10O5)n

Functional category : Glidant, binder in both tablets andcapsules.

Applications It is used in oral solid dosageforms, topical dosage forms

Description White colored, odorless, tastelesspowder.

Typical properties Bulk density: 0.462 g/cm3Tap density: 0.658 g/cm3

Stability and storage Dry, unheated starch is stable ifprotected from high humidity. It should be stored in an airtightcontained in a cool, dry, place.

Method ofManufacturing

It is extracted from plant sourcesthrough a sequence of processingsteps involving coarse milling, repeated water washing, wetsieving, and centrifugal separation



Details of pregelatinized starch

Non proprietary names starch, pregelatinised starch

Synonyms Instastarch; lycatb PGS

Empirical formula (C6H10O5)n

Functional category Glidant, binder in both tablets andcapsules.

Applications It is used in oral solid dosageforms, topical dosage forms

Description : White colored, odorless, tastelesspowder.

Typical properties Bulk density: 0.586 g/cm3Tap density: 0.879 g/cm3

Stability and storage Dry, unheated starch is stable ifprotected from high humidity. It should be stored in an airtightcontained in a cool, dry, place


It is prepared by heating aqueousslurry containing up to 42 % w/wof starch at 62-72 º C 32.



Details of hypermellose

Non proprietary names Hydroxypropyl methylcellulose;hydroxypropyl methyl cellulose;HPMC; E464

Synonyms E1440 ,hydroxylpropyl starch

Empirical formula OCH2CHOHCH3binding agent; disintegrant;emulsifying agent; thickeningagent;viscosity-increasing agent.Itis used in antiseptics and is usedwidely in cosmetics. It is also usedanalytically as a bioseperationaqueous phase forming polymerfree-flowing white to off-whitecoarse powder.Acidity/alkanity ph4.5-5.7(10%w/v aqueous dispersionsolubility practically insoluble inwater and ethanol 95%ether. Hydroxypropyl starch is stable athigh humidity and is consideredtobe inert under normal conditions. Itis stable in emulsion system. Hydroxypropyl starch is producedindustrially from naturalstarch,using propylene oxide asthe modifying reagent in thepresence of alkali addinghydroxyl propyl groups at theOH positions by an etherlinkage

Functional categoryApplications

Description

Typical properties

Stability and storage




1 PREFORMULATION STUDIES

Preformulation involves the application of biopharmaceutical principles to the

physicochemical parameters of drug substance are characterized with the goal of

designing optimum drug delivery system.

Before beginning the formal preformulation the following factors to be

considered,

The amount of drug available.

The physicochemical properties of the drug already known.

Therapeutic category and anticipated dose of compound.

Pre formulation may be described as a phase of the research and development process

where the formulation scientist characterizes the physical, chemical and mechanical

properties of a new drug substance, in order to develop stable, safe and effective dosage

forms. Ideally, the Pre formulation phase begins early in the discovery process such that

appropriate physical, chemical data is available to aid in the selection of new chemical

entities that enter the development process. During this evaluation possible interaction

with various inert ingredients intended for use in final dosage form are also considered

2 Drug-Excipient compatibility studies:

Drug excipient compatibility studies were carried out by mixing the drug with various

excipients in different proportions (in 1:1, 1:0.5 ratio were prepared to have maximum

likelihood interaction between them) was placed in a vial, and rubber stopper was placed

on the vial and sealed properly. Studies were carried out in glass vials at Accelerated

conditions, 40ºC ± 2°C / 75%RH ± 5 % RH and a storage period of 4 weeks. After

storage, the sample was compared with control at 2-8°C and observed physically for



liquefaction, caking, and, discoloration. The compatibility study was also carried out by

differential scanning calorimetric (DSC) analysis

SNO Excipient Ratio code

1 PURE API 1 A

2 PURE API+HPMC 1:1 B

3 PURE API+SODIUM

CMC

1:2 C

4 PURE API +TALC 1:3 D

5 PURE API+SODIUM

CMC

1:1 E

6 PURE

API+HYPERMELLOSE

1:0.5 F

7 PURE API+MAGNESIUM

STEARATE

0.5:1 G

8 PURE API+COLLOIDAL

SILICATE

1:2 H

9 PURE

API+TRIETHYLCITRATE

1:1 I



Experimental MethodsPreparation of Buffers and Reagents

Sodium hydroxide solution, 0.2 M: 8.0 g of sodium hydroxide was dissolved in

distilled water and diluted to1000 ml with distilled water.

Potassium dihydrogen phosphate solution, 0.2 M: 27.218 g of potassium dihydrogen

phosphate was dissolved in distilled water and diluted to 1000 ml.

Hydrochloric acid solution, 0.1 N: 8.5 ml of concentrated hydrochloric acid was diluted

with distilled water and volume was made up to 1000 ml with distilled water. pH (1.2)

was adjusted with dilute hydrochloric acid.

Phosphate buffer solution, pH 6.8: 250 ml of 0.2 M potassium dihydrogen phosphate

was placed in a 1000 ml volumetric flask, 112 ml of 0.2 M sodium hydroxide was added

and then volume was adjusted with distilled water up to 1000 ml. pH was adjusted to 6.8

with dilute sodium hydroxide.

Analytical Methods

Preparation of Telithromycin standard Stock solution in phosphate buffer

solution, pH7.5: A standard stock solution of Telithromycin was prepared by dissolving

accurately weighed 100 mg of Telithromycin with little quantity of phosphate buffer

solution, pH 7.5in a 100 ml volumetric flask .The volume was made up to 100 ml with

phosphate buffer solution, ph 7.5to obtain a stock solution of 1000μg/ml.

Determination of analytical wavelength: From the standard stock solution, 1 ml was

pippeted into 100 ml volumetric flask. The volume was made up to 100 ml with

phosphate buffer solution, pH 7.5The resulting solution containing 10 μg/ml was scanned



between 200 and 400 nm. The λmax was found to be 263 nm. It is represented in the

below

Calibration curve of Telithromycin in phosphate buffer pH7.5:

Accurately weighed quantity of Telithromycin (100 mg) was dissolved in little quantity

of phosphate buffer solution, pH7.5, and volume was made up to 100 ml. From this, 1 ml

of solution was pippeted out in to a volumetric flask and volume was made up to 100 ml.

Appropriate aliquots were taken into different volumetric flasks and volume was made up

to 10 ml with phosphate buffer solution, pH7.5, so as to get drug concentrations of 4 to

24 g/ml. The absorbencies of these drug solutions were estimated at max 263 nm.

This procedure was performed in triplicate to validate the calibration curve. The data

were given in Table 11. A calibration curve was constructed as shown in the figure.



Data for Standard Plot of Telithromycin in Phosphate Buffer Solution, pH 7.5

1.2

1.0

0.8

0.6

0.4

0.2

0 4 8 12 14 16 20 22 24

SR. No.Concentration( g/ ml)

Absorbance at263nmnmAM + SD

1 0 0.00 + 0.000

2 4 0.16 + 0.001

3 8 0.33 + 0.003

4 12 0.48 + 0.002

5 16 0.58 + 0.002



Concentration in mcg/ml

Calibration curve of Telithromycin in phosphate buffer solution, pH7.5, at 263nm.

Interference of additives: Each additive weighing 10 mg was placed separately in a

series of 50 ml volumetric flasks containing 10 g/ml drug solutions in phosphate buffer

solution pH, 6.8. The flasks were kept aside for 45 minutes with occasional shaking. The

solutions were filtered and the absorbances of these solutions were measured at 226 nm

against blank reference. The absorbances of these solutions wer compared with the

absorbance of drug solutions without any additive.

Absorbances of Solution Containing Excipients With Drug And Without Drug At

263 Nm In Phosphate Buffer Solution, pH.7.5

DOSAGE FORM ANALYSIS BY HPLC METHOD

Solution Drug ProductPlacebo

Range

Interference

Yes / no

Absorbance 0.449 0.443 0.001-

0.004

No



Chromatographic condition

Stationary phase hypersil

Mobile phase buffer

Sph 7.4with koh solution

Flow rate 1ml/min

Control temperature ambient

Detector 280nm

Injection volume 20 microlitres.

Preparation of buffer

Dissolve 2.72g of kH2P04&0.525g of k2HPO4 and volume

makeup up to 1000 ml of purified water

PREPARATION OF STANDARD

1.40.4 mg of drug dissolved in 20 ml of methanol from this 2ml of solution dilute

2. And volume makes up to 50 ml with mobile phase.preparation of sample 40mg of

drug equivalent to 20ml of volumetric flask then add 15ml methanol and Sonicate it

passed through micrometer filter take 2ml of filtrate add volume up to 50 ml.



HPLC



Angle of repose: The angle of repose of Telithromycin pellets was determined by the

funnel method (Reposogram). The accurately weighed quantity of pellets was taken in a

funnel. The height of the funnel was adjusted in such a way that the tip of the funnel just

touches the apex of the heap of the pellets. The pellets were allowed to flow through the

funnel freely onto the surface. The diameter of the powder cone was measured and angle

of repose was calculated using the following equation.

tan = h/r (16)

Where h and r are the height and radius of the pellets cone, respectively. Flow

properties for different values of angle of repose were given below

Comparison Between Angle of Repose and Flow Property of Pellets or Drug

Angle of Repose Flow property

<25 Very bad

25-30 average

30-40 excellent

Bulk density: Loose bulk density (LBD) and tapped bulk density (TBD) were

determined. Telithromycin was passed through a #18 sieve to break the clumps, if any.

Accurately weighed 50 g of the drug was placed in a 100 ml graduated measuring



cylinder. Initial volume was observed. The cylinder was tapped initially 500 times from a

distance of 14 + 2 mm. The tapped volume (Va) was measured to the nearest graduated

unit. The tapping was repeated additional 750 times. Again the tapped volume was

measured to the nearest graduated unit. The LBD and TBD were calculate in g per ml

using following formulae

LBD = weight of the powder/volume of the packing (17)

TBD = weight of the powder/tapped volume of the packing

Particle size distribution: This practice was done for the pellets obtained after drug

coating to check average size of the pellets. 100 gms of the pellets were shifted in to sieve

shaker, the machine was run for 5 minutes, all the sieves were taken out and collected

the retained pellets by respective sieve and the % retention of pellets by that sieve was

calculated.

FORMULATION DEVELOPMENT

Telithromycin Sustained action Pellets: In this work, the method used for

preparing telithromycin sustained action pellets was extrusion-spheronising

technique

Extrusion-spheronising technique

The three main steps followed in Extrusion-spheronising technique to prepare sustained

release pellets of Telithromycin

1.GRANULATION:

2. COATING

3. PREPARATION OF PELLETS



1. At first granulation is done and later coating takes place finally pellets are prepared

2. At first it should pass through mesh size of 30# and it should passed through

Extruder 40rpm.

3. Later by subcoating with wurster intial with opadry clear 4%build up)

4. Later it is sifted material to rapid mixer granulater and spheronization is done at

800 rpm and polymer coating takes place

5.And allowed it for dry mixing for 10 minutes and rpm speed is 150 rpm .1800rpm

For 30 sec 1300rpm for 60 sec.

6 .Water is added for 3minutes till the formation of granules

7 .The chopper runs for 3 minutes for 1000rpm to complete granulation process

The size is 16/30 mesh

8. Finally pellets are formed

9. Allow these pellets for fluidized bed dryer for few minutes

10. By maintaining the temperature

11. After preparation of pellets we have to study the pellets by using different

excipients to get sustained action.

12. By this we can able to know which excipient is suitable for sustained action

Prototype Formulation

After studying the patents on telithromycin sustained release pellets, a list of binders,

which can be used, was prepared which included various binders like sugar,sodium

CMC, maize starch, potato starch, and Pregelatinised starch. Feasibility trial was



performed in order to bind the drug on to the non-pareil seeds using these binders. The

first binder selected was sugar and in total four trials were taken using sugar as binder.

For all the trials the coating solution was prepared by the following method:

Preparation of Coating Solution for batches 1 to 4.

Steps:1. Sugar was dissolved in water.

2. Telithromycin was dissolved in sugar solution

3. Talc was added to the above solution.

4. A white milky solution was obtained, which was then passed through # 30sieve

Formulation of Telithromycin For 100 Capsules.

Ingredients no Formulation Ingredients No.

1 2 3 4

Non pareil seeds 21.3 21.4 21.4 21.4

Telithromycin 4.1 4.1 4.1 4.1

Sugar 1.06 1.62 1.62 1.62

Talc 1.22 1.23 1.22 1.22

Purified water 10 10 10 10



Composition of Telithromycin pellets

Ingredient F

1

F

2

F

3

F

4

F

5

F

6

F

7

F

8

F

9

F

10

F

11

Core spheroids

Telithromy

cin)

. 1

69.7

1

69.7

1

69.7

1

69.7

1

69.7

. 1

69.7

1

69.7

1.

69.7

. 1

69.7

1

69.7

1

69.7

.

MCC (PH

101)

1

65.3

1

34.3

1

34.3

1

34.3

1

34.3

1

34.3

1

65.3

1

65.3

1

34.3

1

65.3

1

65.3

Lactose(Gran

ular 200)

1

00

5

5

5

5

5

5

7

5

1

00

1

00

7

5

5

5

5

0

7

5

HPC(Klucel

EXF)

1

0

6 1

0

6 1

0

1

0

6 1 6 6 1

0

Water QS

Total core

spheroids

4

45

3

65

3

69

3

65

3

89

4

14

4

41

3

91

3

65

3

91

4

20

Sub coat

HPMC 6 cps 1

4

1

0.5

1

0.5

1

0.5

1

0.5

1

0.5

1

4

1

0.5

1

0.5

1

4.5

1

5.5



Talc 6 4

.5

4

.5

4

.5

4

.5

4

.5

4

.5

6 4

.5

6 6

Total sub

coat spheroids

4

65

3

80

3

84

3

80.0

4

04

4

29

4

59.5

4

07.5

3

80

4

11.5

4

41.5

EC coating

Ethyl

cellulose 20 cps

5

6

4

5

4

5

6

6.6

5

6

6

6.6

7

5

7

5

5

6.2

7

5

7

5

CHARACTERIZATION OF THE FORMULATION

Precompression parameters

A) Characterization pellets, extra granular blend

1. Bulk density:

Bulk density of a compound varies substantially with the method of crystallization,

milling or formulation. Bulk density is determined by pouring pre sieved granules into a

graduated cylinder via a large funnel and measure the volume and weight.

Bulk density = weight of granules

2. Tapped density



Tapped density is determined by placing a graduated cylinder containing a

known mass of granules and mechanical tapper apparatus, which is operated for a fixed

number of taps until the powder bed volume has reached a minimum volume. using the

weight of the drug in the cylinder and this minimum volume, the tapped density may be

computed.

Tapped density = weight of granules

Tapped volume of granules

Determination of Bulk & tap Density: An accurately weighed quantity of the powder

(W), was carefully poured into the graduated cylinder and the volume (Vo) was

measured, then the graduated cylinder was closed with lid, set into the density

determination apparatus.

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 = bulk volume

Vf = tapped volume

3. Compressibility Index:

Carr’s Index is measured using the values of bulk density and tapped density. The

following equation is used to find the Carr’s index.

CI = (TD-BD) x100

Tapped density

Where TD = Tapped density



BD = Bulk density

4. Hausner’s Ratio:

It indicates the flow properties of the powder and ratio of Tapped density to the

Bulk density of the powder or granules. (Values are given in Table No:5)

Hausner’s Ratio = Tapped density/Bulk density

Scale of Flowability

Compressibility

Index

Flow Character Hausner Ratio

10 Excellent 1.00-1.11

11-15 good 1.13-1.18

16-20 Fair 1.19-1.25

21-25 passable 1.20-1.25

26-31 poor 1.35-1.45



Post compression parameters

1. Physical appearance:

The general appearance of tablets, its visual identity and overall elegance is

essential for consumer acceptance. The control of general appearance of tablet involves

measurement of number of attributes such as tablet size, shape, color, presence or

absence of odor, taste, surface texture and consistency of any identification marks.

2. Hardness:

The resistance of tablets to breakage, under conditions of storage, transportation or

handling before usage depends on its hardness. The hardness of tablet of each

formulation was checked by using Dr.Schleuniger Hardness tester in terms of Kilo ponds

(KP).

3. Thickness:

Thickness of tablet is important for uniformity of tablet size. Thickness was measured

using Vernier caliper. It was determined by checking ten tablets from each formulation.

4. Friability:

This test is performed to evaluate the ability of tablets to withstand abrasion in packing,

handling and transporting. Initial weight of 20 tablets is taken and these are placed in the

friabilator, rotating at 25rpm for 4min. The difference in the weight is noted and

expressed as percentage. It should be preferably between 0.5 to 1.0%.

%friability = (W1-W2)/W1 X 100

31-34 Very poor 1.47-1.59

> 38 Very very poor > 1.60



Where, W1= weight o f tablets before test

W2 = weight of tablets after test

5. Estimation of drug content:

Ten pellets from each formulation were powdered. The powdered sample equivalent to

56 mg of drug was transferred to a volumetric flask. Required amount of 0.1 M NaoH

was added, mixed and filtered, the filtrate was suitably diluted with 0.1 M NaoH and

analyzed against blank by UV spectrophotometer at 305nm (shiatsu UV-1700)

6. Acid resistance by physical observation:

Preparation of 0.1N HCl:

Dilute 85.6 ml of concentrated HCl in 10 liters of water and mix well.

Procedure: Transfer 900 ml of dissolution medium into dissolution vessel. Transfer one

tablet into each of vessel and fix the paddle, lift down the instrument and run

immediately. The temperature should be 37+0.5. After 2 hr time interval observe the

color change in media (yellowish green) and the color change in pellets (brownish color),

withdraw pellets from each vessel. The samples were analyzed by assay procedure at

305nm using double beam UV-Visible spectrophotometer. The content of drug (%

release in acid) was calculated using equation generated from standard calibration curve.

7. Dissolution (By UV):

Dissolution is a process by which the disintegrated solid solute enters the solution. The

test determines the time required for a definite percentage of the drug in a tablet to

dissolve under specified conditions.



Dissolution Parameters

Medium : 7.5 phosphate buffer

Apparatus : paddle (USP-1I)

RPM : 100

Temperature : 37o C

Time Points : 5, 10, 15, 30, 45, 60 min.

Buffer stage by UV:

For the oral dosage forms the in vitro dissolution study must be conducted in the

dissolution medium which simulate the in-vivo conditions (actual physiological

conditions).. The in vitro drug release studies from the prepared formulation were

conducted for a period of 1 hr using an Electro lab model dissolution tester USP Type-2

apparatus (rotating paddle) set at 100 rpm and a temperature of 37± 0.5°C.formulation

was placed in the 900ml of the medium. At specified intervals 5ml samples were

withdrawn from the dissolution medium and replaced with fresh medium to keep the

volume constant. Further dilutions of the sample was done(5ml to 10ml)with the

dissolution media of 7.5 buffer

The sample solution was analyzed at 305 nm for the presence of Model Drug, Using a

UV-visible spectrophotometer. It was justified that none of the ingredients used in the

formulation interfered with the assay method.

In vitro drug release kinetic studies

Kinetic model had described drug dissolution from solid dosage form where the dissolved

amount of drug is a function of test time. In order to study the exact mechanism of drug

release from the pellets, drug release data was analyzed according to zero order, first



order, Higuchi square root, Korsmeyer- Pappas model. The criteria for selecting the most

appropriate model were chosen on the basis of goodness of fit test.

The order and mechanism of Drug release from the dosage form were determined

by fitting the release rate studies data into Equations 1, 2, and 3. The values of K, KH, Ko,

n,t50% (time required for 50% of drug release), and r (correlation coefficient) were

determined. based on the value of n obtained by fitting the data into Equation 3, we

can describe the mechanism of drug release from the formulation.

Mt/M =Kot………….(1)

Mt/M =KHt1/2………….. (2)

Mt/M =Ktn……………… (3)

Where Mt/M is the fraction of drug released at any time t; and Ko, KH, and K are release

rate constants for Equations1, 2, and 3, respectively. In Equation 1, n is the diffusional

exponent indicative of mechanism of drug release. Nature of release of the drug from the

designed DR reservoir pellets and matrix pellets was inferred based on the correlation

coefficients obtained from the plots of the kinetic models. The data were processed for

regression analysis using MS EXCEL

Accelerated Stability study of the optimized batch

In order to determine the change in evaluation parameters and in vitro release profile on

storage, stability study of optimized batch was carried out at accelerated storage

condition at temperature 40 ± 20 C and 75% ± 5% RH in a humidity chamber for 1

month. Sample were withdrawn after 30 days interval and evaluated for change in in-

vitro drug release pattern, physical appearance.

Differential scanning calorimetric (DSC) analysis:

The physicochemical compatibilities of the Optimized formulations were tested by

differential scanning calorimetric (DSC) analysis. DSC thermograms of the powdered



tablets were derived from a DSC with a thermal analysis data station system, computer,

and plotter interface. The instrument was calibrated with an indium standard. The

samples (2-4 mg) were heated (50°C-300°C).

X-Ray Diffraction studies:

Crystallinity of the drug and the samples was determined using the Philips Analytical

XRD (Model: PW 3710, Holland) with copper target. The conditions were: 40 kV

voltages; 30 mA current; at room temperature. The samples were loaded on to the diffract

meter and scanned over a range of 2_Theta values form 30 to 600 at a scan rate of 0.05 0

/min



5. RESULTS

Sustained release pellets were developed for Telithromycin with a view to deliver the

drug in

a sustained manner. The details of results and discussion were given in the following

sections.

PREFORMULATION STUDIES

Description White colour

solubility

solubility-soluble in Ethanol,Methanol

it is good water solubility

Flow properties of API

Test Result

Bulk density 0.545

Tapped density 0.675

Cars index 19.26



Hausner’s ratio 1.23

Particle size distribution:

SieveNo.

Nominal meshaperture size,

m

Aperturesize(passed/Retained),

m

Meansizeopeningd, m

Weightofpowderundersize

%weightretainedonsmallersieve n,

m

Weightsizen x d

pan - - - - - -

16 1000 1000/pan 1000 0 0 0

20 710 710/1000 855 1 1 855

25 600 600/710 655 7 7 4585

30500 500/600

55089.5 89.5

49225

(n) =

100

(nd) =

54665



Drug-Excipient compatibility study at 40°C/75% RH

After 4 Weeks of study physical appearance of these compositions were compared with

the initial observations. The observations were recorded in the following.

Visual observation for Drug- Excipient Compatibility Study

Composition

Code

Initial I Week

40°C/75%

RH

II Weeks,

40°C/75%

RH

III Weeks,

40°C/75%

RH

IV Weeks,

40°C/75%

RH

AWhite

color fine

powder

White color

fine powder

White color

fine powder

White

color fine

powder

White

color fine

powder

B greyWhite

colored

powder

greyWhite

colored

powder

greyWhite

colored

powder

greyWhite

colored

powder

greyWhite

colored

powder

CWhite

colored

powder

White

colored

powder

White

colored

powder

White

colored

powder

White

colored

powder

D Blackcolored

solid

Blackcolored

solid

Black coloredSolid

Blackcolored

solid

Blackcolored

solid



EBlack

coloredsolid

Blackcolored

solid Black coloredsolid

Black

colored

solid

Black

colored

solid

FYellow

coloured

semi solid

Yellow

coloured

semi solid

Yellow

coloured semi

solid

Yellow

coloured

semi solid

Yellow

coloured

semi solid

G White

colored

powder

White

colored

powder

White colored

powder

White

colored

powder

White

colored

powder

H Pinkish

white

colored

Pinkish

white

colored

Pinkish white

colored

Pinkish

white

colored

Pinkish

white

colored

I Yellowish

colored

semisolid

Yellowish

colored

semisolid

Yellowish

colored

semisolid

Yellowish

colored

semisolid

Yellowish

colored

semisolid

J White

colored

powder

White

colored

powder

White colored

powder

White

colored

powder

White

colored

powder

k White colored powder

White colored powder

White colored

powder





After the storage, the samples were observed physically for discoloration. Physical

mixture of drug with pellets excipients after storage period of 4 weeks at 40°C / 75% RH

showed no physical changes. Hence the selected excipients were likely to be suitable for

the preparation of the pellets

Differential scanning calorimetric (DSC) analysis

The DSC thermo grams of Pure drug and other physical mixtures of various excipients

were as shown in figures. Various parameters like peak onset, peak and peak end set were

summarized in Table.

Diffrential scanning calorimetric studies

A-PELLETS

B-Telithromycin +HPMC


C-Telithromycin +sodium cmc

D-PURE DRUG TELITHROM

Telithrom

utics

c

MYCIN

mycin Pellets

Page 74



Evaluation of Pellets

Bulk

density

Tapped

density

carrs index hausners ratio

0.63 0.66 14.24 1.16

0.68 0.69 12.89 1.13

0.64 0.59 11.21 1.15

0.59 0.64 10.23 1.14

0.66 0.63 9.08 1.23



IN VITRO RELEASE PROFILE OF TELITHROMYCIN

% Drug release in 7.5PH phosphate buffer

A

F1

B

F2

C

F3

D

F4

F

F5

GF6

10.41.2 37.13

69.1239.5

48.6

20 42.87 44.12 76.9 49.5 56.9

30 52.12 56.289.12

58.4 67.9

0

10

20

30

40

50

60

70

80

90

100

0 10 20 30 40 50 60 70

Time(min)

%Drugrelease B1

F1

F2

0

10

20

30

40

50

60

70

80

90

100

0 10 20 30 40 50 60 70

Time(min)

%Drugrelease

F1

F2



45 60.06 60.4 90.59 64.2 78.6

60 73.09 65.3 92.8 70.54 87.3

70 80.3 64.3 80.3 70.3 60.3

x-ray diffraction

X-ray Diffraction studies were performed for proton pump inhibitor and optimized

formulations at various storage conditions (Initial, Accelerated stability-40 ± 2˚C/75 ±

5% RH).


Standard calibration curve o

Sr.No)*Conc.(

0

1

1

Telithrom

utics

of Telithromycin in 0.1 HCL

(mg/ml) Absorbance (nm)*

0 0

100.145±0.056

mycin Pellets

Page 78



2

20

0.280±0.075

3

30

0.427±0.064

4 40 0.576±0.062

5 50 5 50 0.695± 0.045

Each value represents mean ± S.D. (n = 3)

Cali ration curve of Telithromycin in 0.1 N HCl

y = 0 . 0 1 4 x + 0 . 0 0 2 8

R 2 = 0 . 9 9 9 2



absorbance

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

0 10 conc 20 30 40 50 60



I n - V i t r o D i s s o l u t i o n s t u d y

80

70

60

50

40

30

20

10

0

Time

0 10 20 30 40 50



Scanning electron microscope

Scanning Electron Photographs of different batches.



E1 E2 E3 E4 FL1 FL2 FL3 FL4 FD1 FD2 FD3

Circularity

S.D

0.832

0.06

7

0.790

0.04

5

0.800

0.05

2

0.800±0.05

2

0.821

0.05

3

0.821

0.05

3

0.804

0.07

2

0.794

0.07

8

0.891

0.04

1

0.923

0.03

5

0.936

0.06

3

Elongation

S.D

1.250

0.09

1

1.391

0.09

7

1.341

0.08

9

1.406

0.09

8

1.259

0.09

8

1.293

0.08

3

1.316

0.09

6

1.346

0.08

9

1.161

0.09

4

1.110

0.06

8

1.056

0.08

9

Rectang

S.D

0.830

0.05

7

0.836

0.06

8

0.831

0.06

5

0.837

0.06

3

0.833

0.07

1

0.836

0.05

9

0.836

0.05

9

0.841

0.07

2

0.799

0.06

3

0.789

0.05

8

0.791

0.06

4



6. DISCUSSIONS

Telithromycin , is a practically more soluble in water . Telithromycin prevents

bacteria from growing, by interfering with their protein synthesis. Telithromycin binds to

the subunit 50S of the bacterial ribosome, and blocks the progression of the growing

polypeptide chain. Telithromycin has over 10 times higher affinity to the subunit 50S

than erythromycin. In addition, telithromycin strongly bind simultaneously to two

domains of 23S RNA of the 50 S ribosomal subunit, where older macrolides bind

strongly only to one domain and weakly to the second domain. Telithromycin can also

inhibit the formation of ribosomal subunits 50S and 30S.

Telithromycin can metabolize through liver.Its half life is 10 hrs.Telithromycin

sustained action pellets can be performed by various techniques.

Among them extrusion spheronizer technique is new technique now a days.and

shows results accurately.we have to use many binders and coating agents to show the

sustained action

We had performed many evaluation parameters.

Bulk density

Tapped density

Porosity

Carrs index

Angle of repose.

Telithromycin pellets can be also studied by using analytical methods

They are

U-V SPECTROSCOPY



HPLC

UV-SPECTROSCOPY

Calibration curve of Telithromycin in phosphate buffer Ph 7.5:

Accurately weighed quantity of Telithromycin (100 mg) was dissolved in little quantity

of phosphate buffer solution, pH7.5, and volume was made up to 100 ml.From this, 1 ml

of solution was pippeted out in to a volumetric flask and volume was made up to 100 ml.

Appropriate aliquots were taken into different volumetric flasks and volume was made up

to 10 ml with phosphate buffer solution, pH7.5, so as to get drug concentrations of 4 to

24 g/ml. The absorbencies of these drug solutions were estimated at max 263 nm.

This procedure was performed in triplicate to validate the calibration curve. The data

were given in Table 11. A calibration curve was constructed as shown in the figure

DOSAGE FORM ANALYSIS BY HPLC METHOD

Chromatography condition

Stationaryphase-hypersil

Mobile phase-buffer – acetonitrile(40:60) ,Sph7.4 with koh solution

Flowrate-1ml/min

Controltemperature-ambient

Detector-280nm

Injectionvolume-20microlitres



Preparation of buffer:

Dissolve 2.72g of kH2P04 &0.525 g of k2HPO4 and volume

makeup up to 1000 ml of purified water.

PREPARATION OF STANDARD:

1.40.4 mg of drug dissolved in 20 ml of methanol from this 2ml of solution

dilute.And volume makes up to 50 ml by using mobile phase.

2.Preparation of sample-40 mg of drug equivalent to

20 ml of volumetric flask then add 15 ml of methanol and Sonicate it passed through

micrometer filter take 2ml of filtrate add volume up to 50 ml.

Dissolution studies also takes placed.disintegration also studied.

Comparision of in vitro release profiles were studied.

Preformulation studies also done.

Differential scanning calorimetry and x-ray diffraction studies takes place.

Suitable graphs are obtained.

Suitable excipients are chosen to get sustained action of multiparticulate system of

telithromycin.

We have compared conventional tablet of telithromycin with sustained action pellets

of telithromycin.

In vitro characterisation is also studied.

Its solubility ,stability is also studied.



The present study indicates dicrease in dissolution by decreasing its solubility

therefore it shows sustained action.

Telithromycin is anovel drug which shows several advantages than other drugs.

Finally we had used suitable excipients by using suitable equipment and suitable

temperature conditions to get sustained action of multiparticulate system of telithromycin

Finally embedded in hard gelatin capsule.



7 SUMMARY

The summary of the M. Pharm. dissertation work entitled “SUSTAINED ACTION OFMULTIPARTICULATE SYSTEM OF TELITHROMYCIN EMBEDDED IN HARDGELATIN CAPSULE is given below

Conventional dosage forms, which are prompt release in nature, have been used from

decades for treatment of acute and chronic diseases. To maintain drug concentration in

within the therapeutically effective range it is necessary to take these types of dosage

forms several times a day and which results in the fluctuations in drug levels. Recently,

several technical advancements have been made which results in new techniques for drug

delivery. These techniques are capable of controlling the rate of drug delivery, sustaining

the duration of therapeutic activity and/or targeting the delivery of drug to a tissue.

Controlled release pharmaceutical dosage forms may offer one or more advantages over

conventional (immediate release) dosage forms of the same drug.

The term “sustained release” is known to have existed in the medical and pharmaceutical

literature for many decades. It has been constantly used to describe a pharmaceutical

dosage from formulated to retard the release of a therapeutic agent such that its

appearance in the systematic circulation is delayed and / or prolonged and its plasma

profile is sustained in duration. The onset of its pharmacological action is often delayed

and the duration of its therapeutic effect is sustained.

A multiple unit dosage form could readily separate into sustained release units throughout

the gastrointestinal (GI) tract after ingestion. One of the multiple unit dosage forms is the

pellet, which reduces variation in gastric emptying time and transit time, is less

susceptible to dose dumping, and provides less irritation from high local concentration of

drugs.

Pellets offer a high degree of flexibility in the design and development of oral dosage

forms. They can be divided into desired dose strengths without formulation or process



changes and also can be blended to deliver incompatible bioactive agents simultaneously

and/or to provide different release profiles at the same or different release profiles at the

same or different sites in the gastrointestinal tract. In addition, pelletstaken orally,

disperse freely in the GI tract, maximize drug absorption, minimize local irritation of the

mucosae by certain irritant drugs, and reduce inter and intra patient variability.

The objectives of the present investigations are:

1) Preparation of Telithromycin sustained release pellets using different polymers

2) and different techniques

3) Characterization of Telithromycin pellets.

4) In vitro evaluation of telithromycin pellets for the release characteristics

In the present investigation, efforts were made to develop sustained release pellets of

telithromycin for treatment of respiratory disorders .

The drug chosen for the present investigation was telithromycin and which is an

antibiotic . The dose of telithromycin is 300mg and 400mg administered .It is available

in tablet forms .it can taken along with food also. Telithromycin is well absorbed and

extensively metabolized in the liver. On the basis of mass balance studies, at least 92% of

a single dose is absorbed. The plasma elimination half-life is 5 ± 2 hours. Telithromycin

is a white to off- white crystalline solid with a solubility of 572 mg/ml in 0.2 M sodium

chloride solution. These biopharmaceutical and physicochemical properties reveal that

Telithromycin is an ideal candidate to develop into sustained release pellets.



The chapter of “Literature Review” contained general concepts and requirements for

sustained release drug delivery system. Advantages and disadvantages of sustained

release drug delivery systems were also discussed. Description about drug selection for

oral sustained release drug delivery systems. General criteria for selection of drug for

sustained release dosage forms were also discussed.

A detailed discussion was done about the pelletization techniques. Each technique was

discussed in detail. A detailed discussion about the drug Telithromycin and other

excipients was also included in the literature review. The discussion on the marketed

products was also included in the literature review.

In order to solve the objectives of this dissertation, suitable analytical method (UV

Spectroscopy)and hplc was established and validated in phosphate buffer solution pH,

6.8.In addition, interference of additives in the estimation was determined. Physical

properties of Telithromycin were also determined.Various binders were tried out for drug

coating on to the non-pareil seeds.

Pregelatinised starch was finalized as the binder and its concentration and the fluid bed

processor parameters were optimized. Seal coating was also performed using the same

binder. The functional coating was done using Eudragit NE30D. The concentration of the

Eudragit was optimized.

A reproducible batch was prepared; evaluation of the pellets was done. Friability,bulk

density, Tap density, drug assay, sieve analysis were performed. Dissolution of the pellets

was done in pH 6.8, phosphate buffer solution. The dissolution was carried on for 24

hours. Accelerated stability studies was also done for 1 month, 40 C and 75 % RH.The

effect of curing of the dissolution of pellets was also studied.



The results and discussion of different methods of this thesis are described under

different headings using graphs and tables. No interference due to additives in the

estimation of Telithromycin was observed. Various binders were used and finally

pregelatinised starch was finalized as the binder. Dissolution datas of the conventional

tablet is compared with sustained release pellets and the prepared batches was compared.

F1 and F2 were calculated. On the bases of it the concentration of pregelatinised starch

and the polymer Eudragit was optimized.

The formulation was found to be reproducible. The stability studies of the prepared

pellets were done at 400 C and 75 % RH. The dissolution of the stability samples after

month was preformed and the dissolution datas were compared with the conventional

tablet. The F1 and F2 were calculated and the product was found to be stable. The pellets

were cured in hot air oven for 16 hours at 550C and the dissolution was done and the

increase in the rate of dissolution was observed.



8. Conclusion

1.Multiparticulate system is very important technique to deliver the recommended dose.

2.It also reduces patience complaince.

3.Telithromycin is a novel antibiotic which acts against bacterial infections.

4.It shows more potent than other antibiotics.

5. Suitable analytical method based on UV-Visible spectrophotometer was developed for

telithromycin . max is 226 nm in phosphate buffer solution, pH 6.8.

6.Eudragit NE 30D in a concentration of 8.6 % w/v was optimized as coating polymer for

150 mg sustained release pellets of Telithromycin.

7.. The effect of agitational intensity of dissolution medium on drug release rate of batch

17 pellets was studied at 50, 100, and 125 rpm.. The release study indicated that rpm 100

is ideal for the studies.



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10. ANNEXURE

ACCEPTED PAPER

S.NO TOPIC JOURNAL AUTHORS

1 Sustained action of

Multiparticulate system of

Telithromycin embeded in

hard gelatin capsule.

International

journal of pharma

world research.

V.Mridula

Dr.K.V.Subramanyam

Ramakhanth

Srujana

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