INVESTIGATION ON THE TYPE AND AMO UNT OF DRY …shodhganga.inflibnet.ac.in/bitstream/10603/72502/10... · Investigation on the type and amount of dry powdered cushioning agents Various

INVESTIGATION ON THE TYPE AND AMO UNT OF DRY POWDERED CUSHIONING AGENTS

4 Investigation on the type and amount of dry powdered cushioning agents

INVESTIGATIONS ON THE TYPE AND AMOUNT OF DRY POWDERED CUSHIONING AGENTS

4.1. Introduction The development of Multiple-Unit dosage formulations in the form of

compressed tablets rather than hard gelatin capsules is becoming increasingly important.

An ideal Multiple-Unit disintegrating tablet dosage form is the one, which on oral

administration or in-vitro, disperse or disintegrate rapidly in the gastric medium or

dispersion medium, to release a large number of particles, that have maintain integrity of

both core and their release- retarding properties such that their drug release kinetics are

unaltered. The compression of coated Multiple-Unit (pellets) is a delicate process, since

it changes the structure of the coating film by causing fissures to appear or by rupture,

which leads to partial or total loss of properties of the film. Fissuration of the pellets

irreversibly changes the release profile of the active principle they contain. In order to

conserve the characteristics of the film coating of the pellets, before and after

compression, these pellets have to be diluted with auxiliary substances such as

"Cushioning Agents" that absorb the physical stress, separate the coated particles during

compaction and allow disintegration of the tablet in liquid medium with useful drug

release pattern along with aesthetic value ^ . This is of significant value for the many

geriatric and pediatric patients who have difficulty in swallowing. At the same time

certain tensile strength should be generated to the compact that will be helpful to

maintain its integrity during packaging, handling and transporting ^ . To protect the

pellets from damage during tableting, cushioning agents require certain derived

properties so that they should also perform its role for the preparation of desired tablet as

filler-binder and disintegrant. For the preparation of Multiple-Unit tablet with high dose

drugs the size of dosage form is very important for designing, packaging and handling

too. The desired size of tablet should be small, which largely depend on the size of

subunits and the ratio of pellets to cushioning agent.

The effect of compression on pellets and tablet character can be highly

influenced by appropriate selection of the excipients mainly the amount of and type of

cushioning agent ^ .

40

Investigation on the type and amount of dry powdered cushioning agents

Various properties required for the tablet containing SR Multiple-Unit

(pellets) and plain drug are:

• Pellet properties

1. Release of drug from SR coated pellets after compression should be similar as

that of uncompacted pellets

2. The size and shape of pellets should not change to a great extent due to

compressional pressure

3. Tableting should not bring any changes in the coating polymers of pellets.

• Tablet properties

1. Tablet prepared should have optimum tensile strength

2. Tablet should disintegrate rapidly to release the SR pellets

3. Tablet should be able to release the drugs in desired rates (i.e. fast release for

uncoated drug and SR for coated Multiple-Unit drug pellets).

The desired mechanical properties of the pellets are that they are strong,

not brittle and have a low elastic resilience. They should deform under load application

and load recovery without fracture. Pellet core should exhibit some degree of plasticity

so that it can accommodate a possible change in shape when the coated pellets are

subjected to tableting ^ .

For satisfying the pellet's properties the use of auxiliary agent such as

highly compressible fillers that can minimize the damage by providing the cushioning

effect to the coated pellets and prevents any change in polymer film. Cushioning effect

can be provided either by self-fragmentation or deformation during compaction and

preventing the compressional forces to cause damage to the coated pellets. Various

materials were studied to evaluate the behavior of compression on them. On compaction

at tableting pressure MCC and Cornstarch are most prone to plastic deformation with

only small elastic recovery, whereas PEG 4000 is a material that primarily deform

plastically. While DCP fragments in to pieces and lactose holds an intermediate

position .

41


There is a need for a fast disintegrating Multiple-Unit tablets that can be

produced on industrial scale with a simple manufacturing process based on a direct

compression method. It was observed that the deformation and probably breaking of

coating increased with increasing cushioning agent particle size. Hence to minimize the

degree of deformation and probably breaking of coating, excipient particles of small size

and high porosity should be incorporated in the tablet formulation . Incorporating

certain fine auxiliary agents that can provide the required tensile strength to the tablet

and disintegrate rapidly when placed in aqueous vehicle can satisfy tablet properties.

Directly compressible agents as hydrophilic-soluble and hydrophobic-swelling as

Lactose, PEG, MCC, DCP and cornstarch respectively individually and in combination

can provide the desired tablet.

When drug containing coated pellets is compressed with cushioning

agents as MCC or glyceryl palmitostearate plus MCC beads showed results that the

inclusion of cushioning agents is an effective method of formulation modification that

permits their compaction without fracture & yet provides satisfactory tablets having the

same dissolution profile characteristics as uncompacted beads ^ . Thus, the literature

indicated that the properties of cushioning materials could affect the tableting properties

of the pellets.

The process by which a particulate solid is transformed by the application

of pressure to form a coherent compact or tablet is called as "compaction" that can

further be defined as "the compression and consolidation of two phases (particulate solid

- gas) system due to the applied force." Compression is a reduction in the bulk volume of

the material as a result of the gaseous phase. This clearly indicates requirement of pores

in the material to be used for tableting (e.g. MCC, starch etc). Consolidation is an

increase in the mechanical strength of the material resulting from particle-particle

interactions. This clearly indicates requirement of fine material having the tendency to

increase the surface area after compression by fragmentation to result in high particle-

particle interactions (e.g. lactose, DCP etc).

Prior to penetration of upper punch in to the die, the particles undergo

rearrangement by flow with respect to each other, with the fine particles entering the

voids between the larger ones, resulting in a "closer packing" arrangement required for

preparing tablet with acceptable characters.

_ _


As pressure is applied, the porosity of the bed of particles is reduced.

Initially this is achieved by particle rearrangement, for which only a low pressure is

required. Subsequently when rearrangement is effectively complete, further

consolidation is achieved by particles undergoing fragmentation or deformation, or most

probably both fragmentation and deformation in varying degrees, depending on the solid.

Thus for example MCC, PEG and starch are primarily a deforming material, DCP

dihydrate fragments and lactose holds an intermediate position.

As the upper punch penetrates the die containing the powder bed, initially,

there are essentially only points of contact between the particles. Utilizing the punches,

application of an external force to the bead results in force being transmitted through

these interparticulate points of contact, where the stress is developed and local

deformation of the material occurs. The deformation will feature either one or a

combination of the following: elastic, plastic, and / or fragmentation. The type of

deformation mainly depends on the physical properties of the material.

After releasing the applied force, if the particles regain their original form,

and return to the closely packed arrangement state then such deformation is called as

elastic deformation. Polymer coated pellets preferentially undergo elastic deformation,

due to packed and nonporous arrangement of the core pellets and elastic nature of the

film coating materials. As the volume of the powder bed is reduced progressively with

further load application, either plastic deformation or fragmentation becomes the

dominant mechanism of compaction. Plastic deformation usually occurs with powders in

which the shear strength is less than the tensile strength. MCC, PEG and cornstarch are

the plastically deformable materials due to the porous structure that can be beneficial for

cushioning of pellets and thereafter also increases compression nature of the tablet ^^.

Whereas fragmentation is dominant with hard, brittle materials in which the shear

strength is greater than the tensile strength. DCP undergo deformafion by fragmentafion

and thereby increases interparticle forces of the tablet ^^ While Lactose monohydrate

undergo both fragmentation and deformation resulting in tablet with high tensile

strength.

Particles, by whatever mechanism, have been brought into sufficient close

proximity with each other; a coherent compact cannot be formed unless some form of

bonding occurs between particles. Further concluded that three types of bond are

43


applicable: solid bridges, intermolecular forces and mechanical interlocking. In the tablet

dosage form mechanical interlocking is dominating; and as smooth spherical particles

(pellets) will have little tendency to interlock, and so tablets containing high

concentration of pellets will always have low hardness as that of simple tablet . To

tackle this phenomenon the cushioning blend apart from protecting the pellets have to

contribute in the hardness of tablet, that occurs by selecting excipients with high

mechanical interlocking and plastic deformation.

Increasing the amount of cushioning agent helped to minimize the

damage to the pellets by cushioning action, keeping pellets away from each other, and

distributing the force of compression amongst them. The increased amount of cushioning

agents provides large surface for disintegrating activity and results in tablet that produce

instantaneous disintegration of the tablet.

It has been found that coated pellets can be compressed into tablets whilst

retaining SR of the drug, provided that the effect of excipients and the compression force

is considered and determined. The protective effect of an excipient is dependent on the

particle size and the compaction characteristics of the material, i.e. whether

fragmentation or plastic or elastic deformation is the predominant volume reduction

mechanism. In general, materials that deform plastically, such as microcrystalline

cellulose and polyethylene glycol, give the best protective effect.

Now day's symptoms of bronchial asthma are becoming more common in

old age patients. Theophylline is the most prescribed xanthine derivative in the

bronchodilator segment. In 1990. CR dosage form accounted 90 % of the entire

Theophylline market in France. Germany, Italy, UK, Japan and in USA '. A marked,

significant improvement of 24 h lung function data was observed after adding

Theophylline to a modern drug therapy including P2- agonist in a substantial proportion

to treat asthma. Combination of SR theophylline along with Salbutamol in capsulated

form is available in market, but capsule dosage form of high dose like Theophylline

suffers patient incompliance problem due to larger size of capsule. While SR product

should be independent as possible of pH, G.I. motility and so the use of multiparticulate

drug deliver system in disintegrating tablet formulation with quick release Salbutamol is

rational. While, Chronopharmacology provide rational for designing of SR Theophylline

for the treatment of bronchal asthma, as circadian rhythmicity of bronchal asthma is well

44


known and Dyspnoea attacks are much more common in night in between 4 and 5 a.m.

and so it is customary to use Theophylline in SR form .

Gastro-intestinal bleeding is a major drawback of theophylline, especially

in old age persons. So, localized concentration of drug is not desired as resulted with

conventional and monolithic dosage form. Multiple-Units i.e. pellets distribute more

uniformly in the GIT and releases the drug at a predetermined rate and thereby

minimizes the localized concentration of drug. Theophylline shows a comparable extent

of absorption in all regions of the intestine ^ .

Oesophageal erosion and ulceration have been reported in patients taking

theophylline. Whereas capsules are prone for esophageal transit and so the effect is likely

to be preciphated. For this reason the use of theophylline in tableted form is

recommended. Peak serum-theophylline concentrations occur within I to 2 h, and

generally about 4 h after ingestion of SR preparations. So, combination with quick

release Pi blocker e.g. Salbutamol is recommended.

4.2. Aims of the Work

• Designing Multiple-Unit dispersible tablet for symptomatic relief and

prevention of bronchial asthma in elderly patients, commonly complaining

about swallowing problem of high dose drug like Theophylline.

• Investigation of various powdered excipients capable of providing cushioning

effect to the Theophylline Anhydrous pellets (300 mg / tablet) on

compression in a tablet form, having plain Salbutamol Sulphate (04mg /

tablet)

• Evaluating the ratio of cushioning agent to drug pellets that can maintain the

integrity of the film coat and release character of pellets even after

compression of pellets in a tablet form.

45


4.3. Plan of Work

The study included

1. Designing the core pellets of Theophylline anhydrous by Extrusion

Spheronization technique

2. Preparation of pellet formulation batches by spray coating technique using

Eudragit® RSPO elucidating SR as well as suitable mechanical characteristics

3. Evaluation of coated pellets for various properties

• Mean pellet diameter

• Density

• Strength

• Drug content

• Assessment of release of drug from coated pellets

• Surface characterization

4. Simultaneous estimation of Metformin HCl and Gliclazide

5. Designing and preparation of formulation batches for Multiple-Unit tablets of

SR Theophylline and immediate release Salbutamol sulphate containing

various type and amount of cushioning agent(s)

6. Evaluation of compressed tablets containing SR coated pellets for various

properties

Weight variation test

Tablet hardness

Friability

Disintegration time

Content uniformity

Dissolution testing

7. Stability studies of selected pellet and tablet batches

46


4.4. Drug Profiles

4.4.1. Anhydrous Theophylline ^ '

Structural formula

CH,

Chemical Name

Mechanism of action

Molecular formula

Molecular weight

Indications

Dose

Description

Solubility

Adverse effects:

: 3.7-Dihydro-l, 3-dimethylpurine-2, 6(lH)-dione; 1,3-

Dimethylxanthine

: Directly relaxes bronchal smooth muscles and pulmonary

blood vessel also act by prostaglandin antagonist.

C7H8N4O2

180.2

Symptomatic relief or prevention of bronchal asthma, as a

bronchodilator and has bronchoprotective activity.

: 13mg/kg.

: A white odorless crystalline powder.

: Slightly soluble in water and in chloroform; sparingly

soluble in dehydrated alcohol; very slightly soluble in ether

Gastro-intestinal irritation, stimulation of the CNS, nausea, vomiting,

abdominal pain, diarrhoea. Urinary retention and hypotension. Overdosage may also lead

to diuresis and repeated vomiting, cardiac arrhythmia, convulsions, and death. Plasma

concentration of greater than 20 meg per ml is considered to be toxic.

Pharmacokinetics:

Theophylline is rapidly and completely absorbed from GIT. SR

preparations of theophylline can provide adequate plasma concentrations usually when

administered every 12 h. Peak serum-Theophylline concentrations occur within 1 to 2 h,

and generally about 4 h after ingestion of sustained-release preparations. It is

47


approximately 40% bound to plasma proteins. It is metabolized in liver that is excreted in

urine; about 10% of a dose is excreted unchanged in the urine. The serum half-life in

adult is 7 to 9 h and in children 3 to 5 h. It crosses the placenta and enters in breast milk.

The most widely accepted explanation for circadian variation in its pharmacokinetics is

slower absorption at night.

Pharmacology:

Theophylline directly relaxes bronchial smooth muscle, relieves

bronchospasm, and has a stimulant effect on respiration. It stimulates the myocardium

and central nervous system. Theophylline is used as a bronchodilator in the management

of asthma. Although selective p2 adrenoreceptor stimulants such as Salbutamol are

generally the preferred bronchodilators for initial treatment, theophylline is commonly

used as an adjunct to (32 agonist and corticosteroid therapy in patients requiring an

additional bronchodilating effect. Theophylline causes smooth muscle bronchodilation

and improves lung emptying during tidal breathing. This latter change increases

inspiratory capacity.

Uses and administration:

It acts as a bronchodilator and has bronchoprotective activity in

obstructive airway disease. In the long-term management of chronic bronchospasm, it

may be given by mouth in doses ranging from 350 to 1000 mg daily in divided doses as

conventional tablets, capsules, liquid preparations, or sustained-release preparations. A

usual dose of sustained-release theophylline is 175 to 500 mg 12-hourly. SR

Theophylline is an important add-on-therapy in the management and control of nocturnal

asthma. According to British Thoracic Society guidelines on the management of asthma,

the combination of SR Theophylline and P2 agonist (Salbutamol) is recommended.

48


^A.l. Salbutamol Sulphate ' '

Structural formula:

Chemical Name

Action

Molecular formula

Molecular weight

Indications

Dose

Description

Solubility

Adverse effects:

1/2H:S0,

2-tert-Butylamino-l- (4-hydroxy-3- hydroxymethylphenyl)

ethanol Sulphate

Stimulates P2 adrenergic receptor to stimulate

sympathomimetic activity in smooth muscles

(C,3H2,N03)2, H2SO4

576.7

Relief and prevention of bronchospasm in patients with

reversible obstructive airway disease and prevention of

exercise induced bronchospasm

2-4 mg three times in a day

A white or almost white crystalline powder. Salbutamol

sulphate 1.2 mg is equivalent to 1 mg of Salbutamol.

Freely soluble in water; slightly soluble in alcohol,

chloroform, and ether; very slightly soluble in

dichloromethane.

Salbutamol may cause fine tremor of skeletal muscle, palpitations, and

muscle cramps. Slight tachycardia, tenseness, headaches, and peripheral vasodilatation

have been reported after large doses.

Pharmacokinetics:

Salbutamol is readily absorbed from the gastro-intestinal tract. It is

subjected to first-pass metabolism in the liver and possibly in the gut wall; the main

metabolite is an inactive sulphate conjugate. It is rapidly excreted in the urine as

49


metabolites and unchanged drug. The onset of action is within 30 min when taken orally.

The plasma half-life has been estimated to range from about 2 to as much as 7 h.

Pharmacology:

Salbutamol is a direct-acting sympathomimetic agent with predominantly

P-adrenergic activity and a selective action on P2 receptors (p2 agonist). This preference

for (32 receptor stimulation results in its bronchodilating action being relatively more

prominent than its effect on the heart.

Uses and administration:

P2 agonists such as Salbutamol form the initial therapy of chronic as well

as acute asthma. Bronchodilators such as Salbutamol form the first-line treatment of

chronic obstructive pulmonary disease. It is used as bronchodilator in the management of

disorders involving reversible airways obstruction such as asthma. Salbutamol may be

given by mouth in a dose of 2 to 4 mg three or four times daily as the sulphate salt. It can

also be given in combination with other bronchodilators.

4.5. Profile of Formulation Excipients

4.5.1. Corn Starch'"'''

Empirical formula : (CeHioOs)^

Where « = 300-1000

Molecular weight : 50,000-1,60,000

Functional category : Tablet and capsule filler, binder and excipient in dusting

powder.

Description : Starch occurs as an odorless, and tasteless fine whit colored

powder and some times slight yellowish in colour

comprising very small spherical or ovoid granules.

Properties : Density (bulk): 0.462 g/cm^

Density (tap) : 0.658 g/cm^

Particle size : 2- 32 fam

Solubility : Pracfically insoluble in cold ethanol (95 %) and in cold

water. Starch swells instantaneously in water by about 5 -

10 % at 37° C.

50


It consists of amylose, amylopectin and two polysaccharide based on

alpha glucose. Cornstarch is also known as maize starch.

Starch is used as an excipient primarily in oral solid dosage formulation

where it is utilized as a binder, diluent and disintegrant. It has poor flow characteristics

due to its cohesive nature. At 25 kN it gives tablet of tensile strength approximately 06

kg/cm that indicates good compactability character to cornstarch. Cornstarch contains

about 27 % amylose. Dry unhealed starch is stable if protected from high humidity.

Starch is considered to be inert under normal storage conditions.

4.5.2. Microcrystalline Cellulose (PH 101) ' ' ' ' '

Empirical formula : (CeHioOj)/?

Where n s 220

Molecular weight : =36000

Functional category : Pharmaceutical aid (suspending agent, tablet and capsule

Adjuvant, tablet disintegrant)

Description : Fine, white, odorless, tasteless, crystalline powder composed

of coarse particles.

Properties : Density (bulk): 0.32g/ cm^

Density (tap) : 0.45 g/ cm''

Particle size : Typical mean particle size is 20-200 fj.m.

Solubility : Practically Insoluble in water but swells; producing a white

opaque dispersion or gel, slightly soluble in dilute sodium

hydroxide solution. It is insoluble in dilute acids and most

organic solvents.

Microcrystalline cellulose is partially depolymerised cellulose prepared

from a-cellulose.

When compressed, MCC particles deform plastically due to the presence

of slip planes & dislocation. A strong compact is formed due to the extremely large

number of clean surfaces brought in contact during plastic deformation & the strength of

hydrogen bonds formed. The bonding mechanism is interlocking with the adjacent

molecules. The particle size of Avicel 101 is small (20-200 |am) and so increases binding

strength and decreases disintegration time.

At 10-25% MCC is found to act as filler, binder and disintegrant.

MCC is commonly used for the preparation of tablet in direct compression technique.

' ' 51


4.5.3. Polyethylene Glycol 4000

Empirical formula

97

: HOCH2 (CH20CH2);„ CH2OH

Where m = 69.0 - 84.0

: 3000 - 4800

: Tablet and capsule lubricant, ointment base, plasticizer,

solvent, and suppository base.

: PEG 4000 is white or off-white colored, hard wax like

solid, powder or flakes. They have faint, sweet odor.

: Density : 1.080 g/cm^

Melting point: 55-63 °C

: PEG is soluble in water, alcohols, acetone, and chloroform

and are miscible with other glycols; they are practically

insoluble in ether

PEG 4000 is stable, hydrophilic not hygroscopic substance. In solid

dosage form PEG 4000 can enhance the effectiveness of tablet binders and impart

plasticity to granules. However they have limited binding action when used alone and

can prolong the disintegration if present in concentration greater than 5 % w/w. PEG

4000 is not significantly absorbed from the gastro-intestinal tract. It also acts as

plasticizers with film forming materials and as a lubricants for water-soluble tablets.

Molecular weight

Functional category

Description

Properties

Solubility

4.5.4. Lactose Monohydrate 95,98

Empirical formula

Molecular weight

Functional category

Description

Properties

Solubility

C12H22O11. H2O

360.31

Diluent for dry powder inhalers; tablet and capsule diluent

Lactose occurs as white to off white crystalline particles

or powder. Lactose is odorless and slightly sweet tasting;

ot-lactose monohydrate is approximately 15 % as sweet as

sucrose.

Density (bulk) : 0.62 g/cm^

Density (tapped): 0.94 g/cm^

Av. particle size : 12 |am

Freely but slowly soluble in water; practically insoluble in alcohol.

52


Lactose monohydrate is widely used as filler or diluent in tablets and

capsules. Direct compression grades of lactose are more fluid and more compressible

than crystalline or powdered lactose and generally contain specially prepared pure a-

lactose monohydrate. Direct compression grades of lactose may also be combined with

MCC or starch, and usually require a tablet lubricant such as 0.5% Mg. Stearate. The use

of direct compression lactose results in tablet of high breaking strength. Lactose

monohydrate is stable in air and is unaffected by humidity at room temp. It contains

approximately 05 % w/w water of crystallization. Under compression it deforms by

permanent deformation.

4.5.5. Anhydrous Dibasic Calcium Phosphate 95,99

Empirical formula

Molecular weight

Functional category

Description

CaHP04

136.06

Tablet and capsule diluent-filler.

It is a white, odorless, tasteless powder or crystalline solid

material

Properties : Density (bulk) : 0.78 g/cm

Density (tapped): 0.82 g/cm^

Particle size : Average particle diameter is 180 \im

Solubility : Practically insoluble in cold water, ether, ethanol and

water.

Anhydrous dibasic calcium phosphate (DC?) is used as excipients and

source of calcium in nutritional supplement. It is also used because of its compaction

properties. The predominant deformation mechanism of DC? is brittle fracture and this

educes the strain-rate sensitivity of material. However, unlike the DC? dihydrate when

compacted at higher pressure can exhibit lamination and capping. The unmilled or coarse

grade is typically used in direct compression tablet formulations. DC? is non

hygroscopic and stable in room temperature. Each gof calcium hydrogen phosphate

(dihydrate) represents approximately 5.8 mmol of calcium and of phosphate.

53

Invest igalion on the type and amount of dry powdered cushioning agents

4.5.6. Eudragit® RSPO

Chemical name :

Functional category

Description :

Properties

Solvents

Characteristics of the film

100, 101

Poly (ethyl acrylate, methyl methacrylate,

trimethylammonioethyl methacrylate chloride) 1:2:0.1

It acts as a SR coating material that is pH independent

It is a solid, Colorless-clear to white-opaque powder with

weakly amine-like odor. It contains at least 97 % of dry

substance.

The true density is 0.816 - 0.836 mg/cm"'

Preferably acetone, methyl alcohol and methylene

chloride, as well as solvent mixtures of approximately

equal parts of acetone/isopropyl alcohol and isopropyl

alcohol/methylene chloride.

Eudragit® RSPO lacquer films are colorless, transparent

and somewhat brittle. Although insoluble, they swell in

water; in natural and artificial digestive juices and in

suitable buffer solution and are permeable to these liquids.

Eudragit* RSPO is a copolymer of acrylic and methacrylic acid esters

with a low content of quaternary ammonium groups. It is having 5 % of functional

quaternary ammonium groups. They produce low water permeability SR film. The

ammonium groups are present as salts and give rise to the permeability of the lacquer

films. They afford water-insoluble, but permeable, film coatings.

It is recommended that plasficizers (polyethylene glycols, dibutyl phtha-

late, citric acid esters, triacetin, castor oil) be added to enhance the elasficity of the

Eudragit® RSPO films. The addition of 10 % of plasticizer, calculated on the dry

polymer substance content is generally adequate.

Eudragit® RSPO films are only slightly permeable to the drug release.

The diffusion rate is of course, dependent upon the solubility and molecular size of the

active substance and upon the layer thickness of the film.

54


4.6. Experimental

4.6.1. Materials

Following materials were

Chemicals

Anhydrous Theophylline

Salbutamol sulphate -

Cornstarch -

Microcrystalline cellulose PH 101 -

Polyethylene glycol 4000

Lactose monohydrate

Dibasic calcium phosphate -

Polyvinyl pyrolidon K30 -

Aerosil" -

Eudragit® RSPO

Sodium starch glycolate

Magnesium stearate -

Pineapple flavor -

Potassium dihydrogen phosphate -

Concentrated hydrochloric acid -

used for the experimental work.

Suppliers

Bakul Aromatics and Chemicals Ltd., Mumbai.

Cipla Laboratories, Daund

Dipa Chemical Industries, Aurangabad

Chemfields Ltd., Nagpur


Research-Lab Fine Chem Industries, Mumbai

S.D. Fine Chemicals, Mumbai

ISP Technologies, New Jersy

Degussa India Ltd., Mumbai

Degussa India Ltd., Mumbai

J. Rettenmaier & Sohne, Germany


Zim Laboratories, Nagpur

Research-labs fine chemicals, Mumbai


Equipments / Instruments

Electronic Balance

Extruder-spheronizer

Coating pan

pH meter

USP Dissolution apparatus

Brookfield viscometer

Hardness tester (Monsanto type)

Hardness tester (Pfizer type)

UV double beam spectrophotometer

Hot air oven

Make

Afcoset, Mumbai and Scaltach, Mumbai

Umang Pharmatech Pvt. Ltd., Mumbai

Mixofil India, New Delhi

Hanna Instruments, Germany and Elico India Pvt. Ltd., Mumbai Veego Scientific, Mumbai

Brookfield Engg. Laboratories Inc., Mumbai

Indian Equipment Corporation, Mumbai

Dolphin, Mumbai

Milton Roy, Mumbai and Shimadzu, Japan

Spectrum, Mumbai and Kumar Industries, Mumbai

55

hwestigation on the type and amount of dry powdered cushioning agents

Single punch tableting machine

Friabilator

Disintegrating test apparatus

Scanning electron microscope

Spray Gun and Pilot type pen gun

Photomicrograph

_ Cadmach machine Ltd., Ahmedabad and Magumps Ltd., Mumbai

- Veego Scientific, Mumbai

- Veego Scientific, Mumbai

- JXA 840-A, Japan

- Pilot, Mumbai

- Intel, China

4.6.2. Preparation of Core Pellets

Pellets were prepared by wet granulation followed by extrusion and

spheronization. Water along with PVP 4% was used as aqueous agglomeration liquid.

Procedure:

a. Microcrystalline cellulose and Theophylline anhydrous were passed

through sieve No. 80 and weighed accurately. A mixture of MCC and

anhydrous Theophylline (40:60) were blended in plastic bag.

b. Aqueous 4 % PVP-K30 agglomeration liquid was added to powder blend

gradually, and after each addition it was kneaded thoroughly in mortar by

ieve a wet mass that would readily form pellets.

c. ;s was immediately extruded through roller type

oiler of 1 mm pore diameter at a constant speed of 15

d.

e.

f

led were spheronized in an spheronizer attached with

attern friction plate. The spheronization was carried

00 rpm.

;re dried at 40-45°C overnight.

- 24 mesh was used for further processing.

56


4.6.3. Sustained Release Coating of Drug Pellets

The pellets obtained were coated with Eudragit® RSPO polymer to confer

upon them slow release properties. The coating was carried out in a coating pan with hot

air supply. The cores were warmed to a bed temperature of about 37 C. The drug cores

were then coated with the polymer solutions by using pilot type spray gun at pressure of

about 2 bars. To prevent the agglomeration; talc was applied whenever necessary. After

application of desired coat weight gain (7.5 and 10%), the pellets were allowed to roll

with warm air at 40-45* C for 10 min.

Drug loaded pellets were coated with 10 % solution of Eudragit

RSPO in acetone and IP A (1:1) mixture. Dibutyl phthalate was used as plasticizer at

10% concentration by weight of polymer. Two coated pellet formulations

containing 7.5% (T-I) and 10% (T-II) coat weight gain were collected and preceded

for further studies. Coated pellets of Sieve fraction 16-18 was used for further

processing.

The process conditions maintained while coating the drug pellets in the

coating pan are given in Table 4.3.

Process parameters

Equipment speed

Tilt angle pan

Spray gun location

Air pressure

Bed to gun distance

Spray rate

Hot air system

Talc application

Setting for coating pan

~36RPM

- 4 5 "

Top spray perpendicular to pellets

2bar

~ 8 cm

2-4 ml/min

Occasional

As required

Table 4.1: Process Conditions for Coating of Drug Loaded Pellets.

All the prepared pellets were dried in hot air oven till they achieve

constant weight and were stored in air and light resistant containers. The complete

process of coating is depicted in Figure 4.1.

57


Preparation of coating solution

Spray application of solution on pellet:

Drying of coated pellets

Sifting of coated drug pellets

Figure 4.1: Flow Chart of Coating Process of Pellets in Coating Pan.

4.6.4. Preparation of SR Multiple-Unit Tablets

Tablet formulations TT-1 to TT-20 were prepared by using direct

compression technique for evaluating the selection of cushioning agent. This technique

was used due to the enormous advantages provided by this method and due to the

suitability of the method for such type of studies. Before compaction of each batch, the

punches and die were lubricated with a suspension of 1 % of magnesium stearate in

ethanol. The formulations prepared are given in Table 4.2.

In the formulations various agents such as MCC, Lactose, Cornstarch,

PEG 4000 and DCP were evaluated for providing cushioning effect to the pellets.

Furthermore the ratio of pellets to cushioning agent was also evaluated by taking 70:30,

60:40, 50:50 and 40:60 compositions of pellets to cushioning agent.

All the auxiliary ingredients were sieved through sieve No.80 and were

bended by hand in plastic bag for few min. This blend was then thoroughly mixed with

respective pellets. The final mix was then compacted in an instrumented single punch

tablet press fitted with captap type of punch.

58

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For evaluating the effect of blend of excipients as cushioning agent in

Multiple-Unit tablets, formulation ML-1, 2, 3 and MS-1, 2, 3 were prepared as shown in

Table 4.3. Tablet formulations that disintegrate rapidly were prepared by direct

compression technique.

Ingredients (mg) Pellets T-II* Salbutamol sulphate MCC-PH-101 Lactose

Cornstarch

SSG

Aspartame

Aerosil

Talc

Flavour

MCC: lactose/ Cornstarch Total Weight

ML-1

561

4.8

392.7

168.3

-

45

23.5

4.7

4.7

23.5

70:20

1228.2

ML-2

561

4.8

280.5

280.5

-

45

23.5

4.7

4.7

23.5

50:50

1228.2

ML-3

561

4.8

168.3

392.7

-

45

23.5

4.7

4.7

23.5

30:70

1228.2

MS-1

561

4.8

392.7

-

168.3

45

23.5

4.7

4.7

23.5

70:20

1228.2

MS-2

561

4.8

280.5

-

280.5

45

23.5

4.7

4.7

23.5

50:50

1228.2

MS-3

561

4.8

168.3

-

392.7

45

23.5

4.7

4.7

23.5

20:70

1228.2

Table 4.3: Formulations of Disintegrating Tablet for Selection of Cushioning Agent and Its Composition.

Tablet formulations MC-1, 2 and 3 (Table 4.4) were prepared for

evaluating the ratio of pellets to cushioning agent i.e. MCC-lactose blend (1:1) that

produces tablet which disintegrate immediately and releases pellets with drug release as

that of uncompacted pellets.

60


Ingredients (mg)

Pellets T-II*

Salbutamol sulphate

Cushioning agent (MCC& Lactose 1:1) SSG

Aspartame

Aerosil

Talc

Flavour

CA: Pellets

Total Weight

MC-1

561

4.8

240

32.2

16.8

3.2

3.2

16.8

30:70

878

MC-2

561

4.8

374

37.56

19.6

3.75

3.75

19.6

40:60

1024.06

MC-3

561

4.8

561

45

23.5

4.7

4.7

23.5

50:50

1226.08

Table 4.4: Formulations of Disintegrating Tablet for Optimization of Cushioning Agent Ratio to Pellets.

4.6.5. Characterization of Coated Pellets

Physical testing of polymer coated pellets included

1. Mean pellet diameter

Mean diameter of pellets was determined by screw gauge. 25 pellets were

randomly selected and average diameter of pellets was calculated in micron (|a).

2. Density'o^-'"^

The pour density of the coated pellets was assessed using 25 ml graduated

measuring cylinder. The pellets were poured into the measuring cylinder, which was

tapped 50 times. The poured and tapped densities were determined from the weight and

volume of the pellet bed. It was expressed as (g/ml). The ratio of the tapped to poured

bulk density, i.e. the Hausner ratio, was also calculated to evaluate the flow properties of

pellet formulations.

3. Strength '"^

This property is related to the fundamental bonding forces arising from

the pelletization process. Pellets (10) from each formulation batch were evaluated for

breaking strength using Monsanto type hardness tester and average was calculated. It

was expressed in Kg/ cm .

__


4. Drug content:

Weighed 2 g pellets were mechanically busted. Accurately weighed

crushed sample equivalent to 300 mg of Theophylline was transferred to 100 ml

volumetric flask and diluted to 100 ml with 1.2 pH buffer solution and stirred

magnetically for 1 h for complete dissolution of drug. The drug solution was then filleted

through Whatmann filter paper 44. One ml of this solution was taken and it was diluted

to 100 ml with the same buffer solution and absorbance was noted at 271 nm against

blank. Total drug content present was determined using calibration curve.

5. Dissolution studies

The coated pellets were evaluated for in vitro release profile using type I

USP dissolution test apparatus as per given in USP 24 for Theophylline extended-release

capsule '"^ Constant 900 ml of dissolufion medium; buffer pH 1.2 for first h and pH 6.0

for the rest of period was used. The medium was maintained at 37 + 0.5° C and the Speed

of Basket was operated at 50 rpm. 5ml aliquots were withdrawn after every h and fresh

dissolution medium was replaced. The filtrate was analyzed for absorbance of sample

solution at 271 nm. The amount of drug present in sample solution was calculated from

the calibration curve.

> Optimization of pellets

From the pellet batches, a batch that gave the better SR of drug and

strength required for minimizing the damage during tableting was optimized. This

optimized formulation was subjected to the further studies of surface characterization

and stability studies.

• Surface Characterization

The Surface topography studies of the pellets were invesfigated using

images obtained by Scanning Electron Microscopy. The pellets were scanned using

scanning electron microscope (JXA 840- A-Japan). For the SEM, the pellets were

mounted directly on to the SEM sample stub using double sided sticking tape, and coated

with gold in Quick Auto Coater (JEOL Japan), with a thickness of 300 mm under

reduced pressure of 0.001 torr. The shape and surface characteristic of the pellets was

observed in electron micro analyzer and photographs were taken using SM 45041

camera.

' 62


• Stability Studies

Stability studies on optimized formulation were carried out to determine

effect of formulation additives on stability of drug and also to determine physical

stability of formulation under accelerated storage conditions of temperature.

Adequate samples of batch T-II were wrapped in aluminum foil and were

stored in hot air oven maintained at 45° C. Samples were withdrawn after 30 days and

were analyzed for drug content, strength and in-vitro drug release.

4.6.6. Estimation of Theophylline and Salbutamol Sulphate ' ^

Experimental studies revealed that by activation of drugs the maximum

absorbance of drug solution changes. In case of Theophylline in acidic pH maximum

absorbance was observed, at 27Inm.Whereas Salbutamol sulphate was analyzed in the

visible range by spectrophotometer by activating the drug with the addition of sodium

nitrite solution and hydrochloric acid, which in alkaline pH shows maximum absorbance

at 425 nm.

• Preparation of calibration curve for Anhydrous TheophvUine:

Accurately weighed 60 mg of Theophylline anhydrous was taken in a 100

ml volumetric flask; to it 5 ml of 1 N hydrochloric acid and 25 ml distilled water was

added. The solution was shaked for 15 min and diluted up to the mark with distilled

water. Resultant solution was diluted in a volumetric flask with water to get the solutions

of 2-14 (ig/ml. The absorbances of the resultant solutions were measured at 271 nm

against blank.

Concentration (^g/ml)

0 2 4 6 8 10 12 14

Absorbance at 271 nm

0 0.145 0.284 0.436 0.577 0.705 0.824 0.959

Table 4.5: Absorbance of Serial Dilutions for anhydrous Theophylline.

63


1 .

0.8

§0.6

o 5 0.4^ <

0.2-

n ±.

Calibration Curve of Theophylline

y = 0.0685X + 0.0116 ^//^ R = 0.9988 ^Z''

0 2 4 6 8 10 12 14 16 Concentration (mcg/ml)

Figure 4.2: Calibration Curve of Drug anhydrous Theophylline.

• Preparation of calibration curve for Salbutamol Sulphate:

Accurately weighed amount of pure Salbutamol sulphate was allowed to

stand for 5 min with 3%w/v solution of sodium nitrite and IN hydrochloric acid in 2:1

proportion. The solution was rendered alkaline by the addition of 3 parts of 1 N sodium

hydroxide and again allowed to stand for 5 min. The absorbances of the resultant

solutions were measured at 425 nm against reagent blank. The drug solutions of 2-16

Jig/ml were prepared and absorbances were noted.

Concentration (Hg/ml)

0 2 4 6 8 10 12 14 16

Absorbance at 425 nm

0 0.127 0.246 0.382 0.511 0.629 0.763 0.847 0.982

Table 4.6: Absorbance of Serial Dilutions for Salbutamol sulphate.

64

Investigation on the type atid amount of dry powdered cushioning agents

1.2 n

1

80.8-c (0 €0.6 -o CO

<0.4

0.2

fl i_

Calibration Curve of SalbutamI Sulpliate

y = 0.0614X + 0.0073 ^ R = 0.9987 ^^-^"^

0 2 4 6 8 10 12 14 16 18 Concentration (mcg/ml)

Figure 4.3: Calibration Curve of Drug Salbutamol sulphate.

4.6.7. Characterization of Multiple-Unit Tablets ' '""

The tablet formulations MT, ML, MS and MC were evaluated for

following tests

1. Weight variation test

Weight variation test was carried out by accurately weighing 20 tablets

individually; calculated the average weight and compared the individual tablet weight to

the average.

2. Tablet hardness

Although hardness test is not official, tablet should have sufficient

hardness to withstand handling during packaging and transportation. Hardness of the

tablet was measured with Pfizer type tablet hardness tester.

3. Friability

Preweighed 10 tablets were placed in the friabilator, which was then

operated for 4 min. Tablets were dedusted, reweighed, and calculated in % weight loss.

4. Disintegration time

The disintegration time was tested in a disintegration apparatus. Water

was used as the disintegration medium mid the temperature was set at 37°C. The time

taken until no material from any of the tablets was left on the mesh (#10) was recorded.

65


5. Content uniformity

Two tablets were randomly selected and individually grinded into fine

powder and the powder was dissolved in 100 ml of pH 1.2 buffer and filtered through

Whatmann filter paper 44. 1ml of this solution was diluted to 100 ml with buffer. The

absorbance of the sample solutions was recorded at 271 for Theophylline. Whereas

Salbutamol sulphate was analyzed at 425 nm by activating the drug in alkaline medium;

using reagents blank. The amount of drugs present in sample solution was calculated

from respective calibration curves.

6. Dissolution test:

The disintegrating Multiple-Unit tablet was evaluated for in vitro release

profile as per given in USP 24 for Theophylline extended-release capsule; using type II

dissolution test apparatus. Constant 900 ml of dissolution medium was used; buffer pH

1.2 for first h and pH 6.0 for the rest of period. The medium was maintained at 37+0.5°

C and the Speed of paddle was operated at 50 rpm. Initially 5ml aliquots were withdrawn

after every 10 min for an h followed by withdrawal of dissolution media at hourly

intervals and replaced by fresh dissolution medium. The filtrate was analyzed for

absorbance of sample solution at 271 nm for Theophylline and 425 nm for Salbutamol

sulphate with 2:1 proportion of 3%w/v solution of sodium nitrite, IN hydrochloric acid

and the solution was rendered alkaline by the addition of 1 N sodium hydroxide. The

amount of drugs present in sample solution was calculated from the respective

calibration curves.

• Stability Study of Tablet:

The optimized formulation of tablets were kept in aluminum foil and

placed in oven at 45°C for 30 days. After 30 days the tablets were analyzed for the

content uniformity by the method as described earlier.

66


4.7. Results and Discussion

4.7.1. Pellet Properties

In this study the term pellets refers to the spherical agglomerates prepared

by extrusion-spheronization which were then coated to prolong the release time of drug

with Eudragit® RSPO. Visual examination of the coated pellets showed a smooth surface

without visible flaws in the coating.

It was reported that occurrence of shrinking of pellets during freeze

drying is minimal when compared to oven dried pellets and so in the present study hot

air ovens were used for the drying of every pellet batches. Evaporation of water in an

oven is accompanied by shrinking process. The resultant pellets are smaller than the wet

ones and are considerably more dense '' .

The properties of pellets determined are given below:

1. Mean pellet diameter:

Coated pellets of Sieve fraction 16-18 were used for the preparation

of tablets so as to minimize the effect of size of pellets during the compression. So

the particle size was calculated from the selected fraction only. The average particle

size of pellets T-I and T-II was found to be 857 + 12.63 and 878 + 13.68 ^m. The

difference in average Particle size resuhs due to the use of 7.5 % and 10 % coat weight

gain of pellet formulations.

2. Density:

Density is indicative of packaging character, size, flow property and

strength of pellets. Both poured and tapped density along with the Hausner ratio is given

in Table 4.7. Hausner ratio is tapped density / poured density, which could be used to

predict flow properties. As the Hausner ratio values for both the formulations were less

than 1.25; it indicates that the pellets were free flowing in nature.

Table 4

Pellet formulation No.

T-I

T-II

.7: Density and

Poured density (g/ml) 0.74

0.75

Hausner Ratio Va

Tapped density (g/ml) 0.77

0.79

ues.

Hausner ratio

1.04

1.05

67


3. Strength:

The strength of pellet is very important when the pellets are to be

compressed in to a tablet. The average breaking strength of pellet formulation T-I and T-

II was found to be 2.9 + 0.1 and 3.1 + 0.11 kg/cm^ respectively. This indicates that MCC

along with drug had provided effective binding with 4% aqueous PVP solution and

significantly contributed to the strength of coated pellets. The results are clearly

indicative of increasing tendency for the pellet strength due to increase in coating.

4. Drug content:

Drug containing coated pellets were evaluated to determine drug content

and found to contain 53.27 % and 53.48 % Theophylline anhydrous in pellet formulation

T-I and T-II respectively.

5. Dissolution studies:

In the present investigations, the use of dissolution study on pellets

dispersion is performed. The in vitro drug release ultimately aims to assess the

Pharmaceutical bioavailability of drug from the ultimate dosage form, which is a tablet,

not a single pellet. Whereas In vivo, the drug that can be absorbed will be a function of

the Multiple-Unit pellet release, i.e., it is the average dissolution process that needs to be

evaluated and described. Hence, the measurement of individual pellet release profiles

was not performed.

The pellet formulation T-I coated with Eudragit® RSPO at 7.5 % coat

weight gain resulted in drug release at faster rate as compared to pellet formulation T-II.

The formulation T-II gave considerable prolongation of release and was able to show

nearly 90 % drug release at 08" h of study, and resulted in almost linear drug release

curve. The results indicated that pellet formulation T-II could satisfy the limits of

theophylline extend release capsule for release property as per USP. It was, therefore,

concluded that for these coated pellets, the drug transport across the polymer coating was

the rate-controlling step of the drug release process.

The drug release profile of coated pellets at different coating weight gains

is given in Figure 4.4.

68


Drug Release Profile of Pellet Formulation T-l and T-ll

100 n

9

1 80

# 60J

« 40 -3 E 1 20 O

n

^^X^ / y^ Xy^

y O *

J^ -»-Pellet T-l -•-Pel let T-ll

0 2 4 6 8 10 Time (h)

Figure 4.4; Drug Release Profile for Pellets Formulation T-I (7.5 % Weight Gain) and T-II (10% Weight Gain).

Time (h)

1 2 3 4 5 6 7 8

Cumulative % release

T-I n.66

33 50.3 69.8 77.1 86.84 92.52 95.14

T-n 7.2

24.95 41.00 53.42 68.15 76.52 84.57 89.2

Table 4.8: Cumulative % Release of Theophylline From Formulations of Coated Pellets T-I and T-II.

To overcome the doses related side effect and also to increase patient

compliance. Theophylline is required to be administered in a SR dosage form. For the

study, the methacrylate polymer Eudragit* RSPO was used in varying concentration.

From the results, it can be concluded that increasing the amount of polymer, increases

the duration of drug release.

> Optimization of Pellets: From the prepared batches of the pellets T-I and T-II, batch T-II showed

better- release of drug that can be correlated with the limits of theophylline extend

release capsule as per USP. Furthermore pellets for tableting should have essential

strength to resist the compression forces and so the other deciding factor for optimization

of pellet batch T-II was the high strength of pellet. This optimized pellet formulation T-II

was subjected to the further studies of surface characterization and stability studies.

69


• Surface Characterization

Surface topography studies of the pellet formulation T-II were

investigated using Scanning Electron Microscopy (SEM), it can be concluded that Pellets

coated with Eudragit® RSPO grade was found to have smooth surface. SEM studies of

the coated pellets were carried out using Joel Micro analyzer. The photomicrographs of

an optimize pellet batch T-II is shown in figure 4.5.

[A] [B] Figure 4.5: SEM Photographs of Pellet Formulation T-II at 65 x [A] and 1,000 x [B]

Magnifications.

From the SEM photographs at 65 and 1000 x magnification it can be

concluded that the pellets were coated uniformly and the higher magnification showed

the continuous and smooth coating of pellets, which resulted in SR of drug through the

pellets. The shape of the pellet was spherical, which indicates the success of Extrusion

Spheronization process by using water with 4% PVP as agglomeration liquid.


No substantial changes in drug content and crushing strength were

observed after storage of optimized pellet formulation batch T-II at 45°C for one month.

The drug content of pellets before and after stability studies was 53.48 and 53.39 %

respectively while the strength of 3.00 kg remains as such.

The release profile of drug after end of 30 days at 45° + 1° C is shown in

Figure 4.6. The result showed no significant change on the drug release characteristics

from the pellet formulation T-II. The stability study indicates that Eudragit® RSPO

coated pellets by 10 % weight gain resulted in stable formulation.

70

Investigation on the type and amount of dry powdered aishioning agents

100 n

8 80-• e # 60-

£ 40 1

E i 20 -

n

Stability Study of T-ll batch

^ ^ ^ ^ • ^

Jr jT

jT

/

*

-•-Odays - • - 3 0 days

0 2 4 6 8 10

Time (h)

rO , , 0 Figure 4.6: Effect of Temperature (45 +1 C) on in-vitro Drug Release of Batch T-II

4.7.2. Multiple-Unit Tablet Properties

Compaction of Multiple-Units, such as pellets, can produce disintegrating

tablets or matrix tablets, depending on the compaction process and the materials used.

Generally it is desired that the reservoir pellets present in disintegrating tablets should

not get damaged during compaction and the pellets should also retain its drug release

characteristics. The required properties of these tablets are in general terms the same as

those of conventional tablets, i.e. they should have a certain strength, disintegration time,

and weight uniformity. The drug release is of particular importance here, since damage

to the coating can fundamentally change the drug release when compacted without using

cushioning agent.

Disintegrating tablets containing coated particles need to be compressed

with certain type and amount of exipients, otherwise the blend will not form stable SR

tablet and fissure may occur in the film coating of pellets. Addition of exipients makes it

possible to form solid compacts, which upon addition of a disintegrant, disintegrate

rapidly and allow intact, unaltered particles to disperse in the media.

To evaluate the effect of type and amount of cushioning agents various

tablet formulations were prepared and evaluated for the weight variation, content

uniformity, hardness, friability, disintegration time and the drug release.

71


4.7.2.1. Selection of Individual Cushioning Agent:

The physical characters of tablet formulations MT-1 to MT-20 prepared

from Pellet formulation T-II (hereafter termed as tablet formulation -1) is shown in Table

4.9. In this study five commonly used excipients were tried for cushioning as well as

tableting agents viz. MCC 101, Lactose Monohydrate obtained from sieve No. 100

(hereafter termed as lactose), Cornstarch, Polyethylene Glycol 4000 (PEG 4000) and

anhydrous Dibasic Calcium Phosphate (hereafter termed as DCP).

Parameters

Formulations | MT-1 MT-2 MT-3 MT-4 MT-5 MT-6 MT-7 MT-8 MT-9 MT-10 MT-11 MT-12 MT-13 MT-14 MT-15 MT-16 MT-17 MT-18 MT-19 MT-20

Visual inspection

#

#

#

#

#

V #

V V #

V V V V V V #

V V V

Disintegration time (Sec)

(n=6) -

-

-

-

-

73 ±2.76 -

33 + 2.07 ND

-

97 ±3.9 53 ±2.23 127 + 3.69

ND 247 ±5.06 104 ±4.63

-

134±4.13 ND ND

Weight variation

-

-

-

-

-

Pass -

Pass -

-

Pass Pass Pass

-

-

Pass -

Pass -

-

Hardness (kg.) (n=3)

-

-

-

-

-

3.2 + 0.15 -

2.2 + 0 -

-

3.8 + 0.15 3.7 + 0.17 3.8 + 0.17

-

-

4.7 + 0.11 -

4.6 + 0.21 -

-

Friability (%)

(n=10) -

-

-

-

-

1.13 -

3.41 -

-

0.76 1.40 0.83

-

-

0.51 -

0.86 -

-# = Very weak tablet or When visually inspected by breaking the tablets, SR coated pellets were found to be broken. V = intact tablet and no breakage of pellets when viewed visually. ND = Tablet failed to disintegrate even after 09 min.

Table 4.9: Comparative Physical Characteristics of Disintegrating Tablet Formulation-1.

Physical Characterization

As anticipated due to the material characteristics and the proportion of

cushioning agent, tablet formulations MT-1, 2, 3, 4, 5, 7, 10 and 17 were unable to

protect the pellets and fragmentation of coated pellets was visually observed. So, further

studies of these formulations were not carried out.

72


Pellets in tablet formulation MT-1 to MT-5 were unable to resist the

compressional forces due to the less proportion of cushioning agent. It clearly indicates

that no cushioning agents at a proportion of 30:70 to pellets can resist the breakage of

pellets during compaction. While formulation MT-7 & 10 (40% lactose and DCP

respectively) were also fail to impart cushioning effect on the pellets, due to the material

characteristics. Formulation MT-7 formed very weak tablet; due to the poor binding

property of lactose that were imparted only by weak distance forces ^ . If although tablet

formulation MT-10 was able to retain its shape, as after compaction bonding by

mechanical interlocking has been suggested as the possible bonding mechanism for

DCP. But, the pellets were broken completely due to the hard and less deformable nature

of DCP that failed to show cushioning effect on pellets ^ . Formulation MT-17

containing lactose 60 parts to pellets was unable to produce the tablet with required

strength, as the tablet of lactose was formed due to weak forces which were unable to

hold its shape.

Tablet formulation MT- 9, 14 and 19 contains PEG 4000 at 40, 50 and 60

parts to pellets, due to which, visually the pellets seem to retain the pressure, but the

tablets failed to disintegrate even after 09 min. Whereas same results were obtained for

formulation MT-20 containing 60 parts of DCP to pellets. Such resuft was observed due

to the formation of hard tablet because of mechanical interlocking of DCP. Formulation

MT-15 showed the DT of 247 sec, which was due to the non-swelling and non-

dissolving nature of DCP. So these formulations were also omitted form further studies.

Despite of average DT and visual inspection tablet formulation MT-8

failed to proceed for further testing due to the brittle nature of the tablet. This tablet

failed the standards of hardness and friability.

From the physical parameters it was clear that PEG 4000 and DCP was

unable to show characters required for disintegrating tablet and cushioning effect to the

pellets. The tablet formed by PEG resembles like that of matrix tablet and did not get

disintegrated even after 09 min. The tablets prepared by DCP were either fail to

disintegrate in the stipulated time or unable to provide cushioning effect to the pellets

due to its hard, non-swelling and non-dissolving nature. Another reason for not selecting

DCP as a filler binder was the introduction of unfavorable changes in the physical

properties of the tablets on aging, such as, hardness, disintegration time and drug

dissolution time "''.

73


In rest of the tablet formulations no significant difference was observed in

the weight of individual tablets from average weight and were found to be within the

range of pharmacopoeial standards. All other physical tests were under limits as

prescribed. The dissolution profile of tablet formulations MT6, MT-11, MT-12, MT-13,

MT-16, and MT-18 is given in Figure 4.7.

100 n

18 80-

a. ^ 6 0 -o > tS 40 3 E 1 20 O

n -

Drug Release Profile of Tablet Formulation-1

y <^^^^ JK ^^''^J^^^'^^

//A^ j^^

J^ w

- • - T T - I I

- • - M T - 6

-i^-MT-11

MT12

-«-MT-13

- • - M T - 1 6

MT18

U 1 1 r 1

0 2 4 6 8 Time(h)

Figure 4.7: Drug Release Profile of Tablet Formulation-1.

Time

1 2 3 4 5 6 7 8

Cumulative % Drug Re Pellet formulation

TT-JI 7.2

24.95 41

53.42 68.15 76.52 84.57 89.2

MT-6

10.7 29.12 43.5 57.63 72.14 80.81 87.61 92.4

MT-n

7.9 25.51 42.58 53.28

69 77.19 83.12 89.51

MT-12

27 55.42 73.81 91.69

-

-

-

-

eased

MT-13

14.62 39.15 72.01 88.1

-

-

-

-

MT-16

6.8 24.3

41.76 54.11 67.92 77.2 84.61 89.7

MT-18

10.24 31.54 49.73 69.62 78.21 86.42 89.25 96.29

Table 4.10: Release Profile of Tablet Formulation -1

It is clearly evident that tablet formulations containing MCC viz. MT-6,

MT-11 and MT-16 containing 40, 50 and 6Q parts to the pellets respectively, were

successfully able to withstand the degradative forces imparted during compaction of

pellets and resulted in negligible damage to the polymer coating membrane (figure 4.7).

This revealed that only MCC at more than 40% can provide cushioning to the pellets and

prevents the pellet coat from any damage. The rest of materials failed up to 60 parts to

the pellets.

74


Tablet formulation MT-18 containing cornstarch and pellets (60:40)

slightly resist the compression forces, but nearly 80% of the drug was released within 5

h. This might be due to the nature of cornstarch for undergoing plastic deformation under

pressure and good compression characteristics ^^ Whereas formulation MT-13

containing cornstarch and pellets (50:50) completely subside to show cushioning effect

to pellets.

Tablet formulation MT-12 contains 50 parts of lactose to the pellets and

was able to show slight or no cushioning effect. Dissolution results of formulations MT-

12 showed loss of SR properties upon compaction and more than 90% of drug releases

within 4 h. indicating that polymer layers of pellets were disrupted during compaction

and was unable to withstand the compressional forces exerted during tableting. The

hardness and friability of tablet formulation MT-12 was found to be near to the limits,

which might be due to the poor binding character of lactose. It was reported that on

compression lactose showed consolidation mainly by fragmentation first and then by

plastic deformation , this might be the reason for lactose to fail as cushioning agent.

The fragile nature and formation of fragments during compression might have damaged

the coating of pellets and failed to provide the desired cushioning activity.

While formulation MT-13 containing 50 parts of cornstarch to the pellets

was also unable to uphold the compressional pressure and released nearly 90 % drug

within 4 h, which was resultant due to the hard nature of cornstarch.

If although MCC at 40% and more concentration resulted in desired

cushioning effect, the DT of disintegrating tablets was high and so the combination of

MCC along with soluble or swellable type of ingredients viz. lactose and cornstarch were

tried (Tablet Formulation -2). The other reason for combination of excipients were the

high cost, poor flow properties, and low bulk density of MCC, which prevents its use as

primary filler-binder. These problems can be tackled by mixing it with inexpensive filler-

binder with good flowability such as lactose or starch ^^

Another reason for choosing MCC as integral part of tablet formulation

was that the formulations containing MCC as the diluent were found to be least affected

by the pressure effects on the release rate of drug from coated pellets ^ .

75

Investigation on the type and amount of dry powdered aishioning agents

4.1.2.2. Effect of Combination Materials

The results of combination of MCC with lactose ML-1 to ML-3 and

cornstarch MS-1 to MS-3 (hereafter termed as tablet formulation - 2) obtained are shown

in Table 4.11.

Table 4.11

Parameters Disintegration time (Sec) (n=6) Weight variation Hardness (kg.) (n=3) Friability (%) (n=10) : Comparative

ML-1

56 + 2.43

Pass

4.6 + 0.15

0.58

Physi

ML-2

44 + 2.4

Pass

4.4 + 0.12

0.60

ML-3

64 + 2.58

Pass

4.0 + 0.21

1.08

MS-1

68 + 2.64

Pass

3.6 + 0.15

0.83

cal Characteristics o

MS-2

59 + 2.16

Pass

3.6 + 0.21

0.76

' Disii

MS-3

72 + 2.88

Pass

3.2 + 0.1

0.84

itegratin Formulation -2.

From the disintegrating tablet formulation -2; formulations after physical

characteristics were selected (ML-1, ML-2 and MS2) and preceded for dissolution

studies. Formulation ML-3 failed to show comparable DT and friability, due to slow

intake of water in the tablet that delayed the swelling of MCC as well as SSG and due to

the fiagile nature of lactose. These results occurred because of less concentration of

MCC to pellets (30:70) in the tablet. In case of formulation MS-land MS-3 both the

ingredients MCC and cornstarch acts as a swelling material and so it delayed the DT of

tablet. The dissolution profile of tablet formulations ML-1, ML-2 and MS-2 is given in

Figure 4.8.


76


Time

1 2 3 4 5 6 7 8

Cumulative % Drug Released Pellet formulation

TT-II 7.2

24.95 41

53.42 68.15 76.52 84.57 89.2

ML-1

9.25 26.58 42.12 57.6

68.52 77.64 87.68 90.68

ML-2

8.6 23.94 42.5 52.91 66.77 76.59 85.21 91.59

MS-2

6.7 27.62 43.3 56.24 69.29 78.62 88.22 91.67

Table 4.12: Release Profile of Tablet Formulation -2.

From the dissolution profile of tablet formulation - 2 it can be suggested

that ML-1, 2 and MS-2 formulations were able to show the cushioning effect and so the

optimization amongst them was done only by their physical characters and except DT all

the characteristics were almost same. So, the tablet formulation ML-2 having DT only 44

sec was selected for the next study. Tablet formulation ML-2 contains 1:1 ratio of MCC

and lactose.

The resultant desired cushioning effect might be due to the soft nature of

MCC with certain sort of ductility in the basic cellulosic molecule along with relatively

high plastic deformability on compression '' .

After compaction bonding occurs by mechanical interlocking mechanism

for MCC and by distance forces for lactose resulted in desired hardness and friability in

formulation ML-1 and ML-2. The DT of 44 sec in formulation ML-2 resulted due to the

use of MCC along with lactose. On contact with aqueous fluid tablet wets easily due to

the presence of MCC that penetrates water in to hydrophilic tablet matrix by means of

capillary action. This water dissolves the soluble lactose due to its osmotic effect and

forms channels in the tablet, and the increased water flux into tablet resulted in fast

swelling of SSG and subsequent disruption of the hydrogen bonds of MCC ^^ Thus

combination of dissolution and swelling mechanism of lactose, MCC and SSG resulted

in complete and quick breakdown of tablet structure, which ultimately produce

disintegration of tablet.

Other rational for choosing MCC: lactose blend as cushioning agent was

the good flow and density property of blend along with economical advantages which are

very vital for industrial point of view.

77


Tablet formulation containing cornstarch MS-2 was able to produce the

cushioning effect to pellets, but failed to show desired physical characters as DT,

hardness and friability. As observed it was experienced that the mechanical strength of

the compacts decreased due to inclusion of starch as an external diluent, at the same time 55 Starch is highly lubricant sensitivity material and reduces the strength of compact . The

rational behind high DT was the use of only swelling type of disintegrants and so, it

forms hurdle for water penetration that resulted in increased DT.

4.7.2.3. Effect of Pellet Proportion

The results of tablet formulations with varying ratio of cushioning agent:

pellets MC-1 to MC-3 (hereafter termed as tablet formulation - 3) obtained are shown in

Table 4.13.

Parameters CA: pellets Visual inspection Disintegration time (Sec) (n=6) Weight variation

Hardness (kg.) (n=3)

Friability (%)(n= 10) Content uniformity (%)

Theophylline Salbutamol

MC-1 30:70

#

-

-

-

-

-

-

MC-2 40:60

V 51 + 3.03 Pass 3.9 + 0.15 1.2

94.28 96.71

MC-3 50:50

V 43 + 2.58 Pass 4.4 + 0.06 0.60

95.72 99.87

# = When visually inspected by breaking the tablets, SR coated pellets was found to be broken. V = No breakage of pellets when viewed visually. Table 4.13: Comparative Physical Characteristics of Disintegrating Tablet

Formulation-3.

Tablet formulation MC-1 resulted in tablet that when visually inspected

by breaking, showed complete breakdown of SR coated pellets. Low concentration of

cushioning agent lack the protective function during compaction, as expected. The rest of

studies were terminated for this particular formulation.

In tablet formulation MC-2 and MC-3 the content uniformity were well

within the range of 90 to 110% prescribed for Theophylline extend release capsule USP

^' and 90 to 110 % for Salbutamol sulphate tablet IP " ^

The physical parameters showed less DT for formulation MC-3 as

compared to MC-2 while the hardness and friability of formulation MC-2 were not under

limits prescribed for effective handling during processing and transportation. As tablet

hardness is based on the amount of mechanical interlocking in the substrate particles.

78

Investigation on the type and amount of dry powdered cushimting agents

formulation MC-2 showed less strength and friability as compared to formulation MC-3

due to limited sights for interlocking owing to high ratio of smooth surfaced pellets that

limits formation of mechanical interlocking. The dissolution profile of tablet formulation

-3 is given in Figure 4.9.

100 -

« S 80 o o OC ^ 60 o > « 40 3 E 1 20 -O

0 -(

Drug Release profile of Tablet Formulation-3

y^ /

-•-TT-II -•-MC-2 -A-MC-3

> 2 4Time{h)6 8 10


Table 4.14: Rel

Time

1 2 3 4 5 6 7 8

ease Pr

Cumulative % Drug Released Pellet formuladon

T-II 7.2

24.95 41

53.42 68.15 76.52 84.57 89.2

ofile of Tablet Formulation -

MC-2

10.38 23.94 40.5 51.25 66.3 74.62 83.29 87.17

-3.

MC-3

9.21 23.37 42.61 53.52 69.11 76.9 85.9 90.72

From the results of dissolution profile of tablet formulation- 3 it was

observed that in formulation MC-2 (40:60 ratio of cushioning agent: pellets) release was

slightiy retarded, which might be resulted due to densification of polymer layer due to

pressure imparted on the pellets during compression. The compression pressure was

unable to produce any fissure, which was the indication of effective cushioning activity

at 40:60 ratio of cushioning agent to pellets. Whereas in formulation MC-3 (50:50 ratio

of cushioning agent to pellets) no such densification was observed and the release profile

is comparable to that of uncompacted pellet formulation T-II.

79


From the dissolution results it was proved that the pellets in tablet

formulation MC-3 withholds its release characteristics and the physicochemical

properties of tablets stands for all necessary limits. So, the Multiple-Unit tablet

formulation MC-3 containing effective type and amount of cushioning agent was

selected as the optimized formulation for delivering SR Theophylline anhydrous in a

pelletized form and quick release Salbutamol sulphate.


No substantial changes in content uniformity of tablet were observed

when kept at 45^+ 1° C for 30 days. The content uniformity of tablet formulation MC-3

before and after 30 days was 95.72 and 95.38 % respectively for theophylline and for

Salbutamol sulphate it was 99.87 and 99.82 % respectively.

Stability study indicates that tablet containing Salbutamol sulphate and

Eudragit® RSPO coated pellets of theophylline along with other tableting materials

resulted in stable formulation.

The Multiple-Unit tablet formulation was meant for quick release of

Salbutamol sulphate for effective relief from asthmatic attack. The dissolution study was

carried out and it was observed that nearly 90% of drug was released within 30 min. The

dissolution rate of Salbutamol sulphate from the optimized tablet formulation MC-3 is

given in Figure 4.10.

Release of Salbutamol sulphate From Tablet

100 -

o S 80-•

1 # 60 ^ > « 40 3 E 1 20

0 -

Formulation MC-3

^ ^ ^ ^ *

y/'^ ^

0 10 20 30 40 50 Time (min)

1

60

Figure 4.10: Release of Salbutamol suljAate From Tablet Formulation- MC-3.

80


Time (Min)

10 20 30 40 50

Cumulative % Salbutamol Sulphate Released

49.25 72.51 87.26 95.24 97.35

Table 4.15: Release of Salbutamol sulphate From Tablet Formulation-MC-3.

> Digital Photomicrographs:

The evidence of successful cushioning of pellets in formulation MC-3 can

be observed from the digital Photomicrographic image of broken tablet as shown in

Figure 4.11.

Figure 4.11: Digital Photomicrograph of Fractured Surface of Tablet Formulation MC-3 at 60 X Magnification.

Above image of digital photomicrograph clearly indicate that upon

compaction; discrete pellets can still be clearly distinguished within the Tablet. The

pellets were able to retain its spherical shape even after compression. The maintenance of

shape by pellets showed that no stress was occurred on the polymer coating film and so

maintained its releasing character at 10 % Eudragit® RSPO coating.

81


4.8. Conclusion

This study showed that cushioning agent containing blend of MCC 101

and lactose monohydrate in 1:1 ratio was able to impart protective effect on the pellets

during compression. While the optimum ratio of cushioning agent to pellets was found to

be 50:50 so as to impart cushioning effect and required tablet characteristics. Such

results were observed due to the following reasons:

1. The effective cushioning was the result of behavior of the materials during

compression and this study showed that both plastic deformation and

fragmentation of cushioning material on compression is necessary to show

cushioning effect to the pellets.

II. The pressure applied to the pellets was transmitted from pellets and spread

out over larger contact area provided via the powdered cushioning agents.

Hence the stress at these contact areas levels out. Thus no further damage of

the coated pellets occurred, which results in no significant change in release

of drug from the coated pellets, even after compaction. Both deformation-

fragmentation and large contact area provides required tablet characteristics

either by mechanical interlocking or forces developed in the powder particles.

III. The protective effect of the cushioning agent increased with increasing

porosity and decreasing size. So MCC 101 a porous and fine material had

successfully provided cushioning effect along with fine lactose monohydrate.

IV. The more uniform particle size distribution of MCC 101 and lactose

monohydrate resulted in formation of uniform layer around the pellets and

protects them from the compression force.

In order to evaluate the extent of damage to the coating of pellets due to

compaction, drug release profile of uncompacted pellets and Multiple-Unit tablets was

compared, and it was concluded that no significant change in release profile of MC-3

tablet formulation was evident, which was owed to the presence of proper type and

amount of cushioning agent.

On dispersion of tablet formulation MC-3 in the aqueous vehicle S.R.

pellets disperses instantaneously, and facilitate swallowing due to the aesthetic values

imparted by MCC, lactose, aspartame and flavour. These compacts readily disintegrate

82


in dissolution media and can be crushed prior to swallowing; again, this is of significant

value for elderly and pediatric patients who have difficulty during swallowing.

The order of least damage to the coating followed: MCC < PEG 4000 <

cornstarch < lactose < DCP. Wherein PEG was unable to use as it interferes in the

release properties of pellets from the tablet. MCC in combination with lactose at 1:1

ration proved to act as cushioning agent and satisfies the tablet properties also.

From the results it can be concluded that, compression of coated pellets

into tablets resulted in different release characters that were dependent on the type and

amount of cushioning excipients used. On compression an excipient mixture consisting

of MCC and lactose (1:1) was found to be suitable for cushioning of coated pellets at 40:

60 ratio of cushioning agent to pellets. But, the resuhant tablet MC-2, lack in some

physical characteristics of tablet. While Multiple-Unit tablet MC-3 containing 50:50 ratio

of cushioning agent to pellets resulted in tablets that exhibited in-vitro drug release

profile which resembles closely to the constituent uncompressed pellets, and the tablet

had fast disintegrating time, reasonable hardness and low friability, satisfying the

prerequisites of a Multiple-Unit tablet formulation.

83

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