DDR SDRAM Controller IP Designed for Reuse

FORMULATION AND EVALUATION OF CAPECITABINE AND METACLOPRAMIDE BILAYER TABLETS

INTRODUCTION 1

Drug delivery systems (DDS) are a strategic tool for expanding markets/indications, extending

product life cycles and generating opportunities. Oral administration is the most popular route for

systemic effects due to its ease of ingestion, pain, avoidance,versatility and most importantly,

patient compliance. Also solid oral delivery systems do not require sterile conditions and are

therefore, less expensive to manufacture. Patient compliance, high-precision dosing, and

manufacturing efficiency make tablets the solid dosage form of choice. Excipients and

equipments choices will be significantly affected should solid dosage form technologies change

in response to the unprecedented shifts in the drug discovery such as genomics. Injections

generally are not favoured for use by patients unless facilitated by sophisticated auto injectors.

Inhalation is one good alternative system to deliver these drugs, but the increased research into

biopharmaceuticals so far has generate predominantly chemical entities with low molecular

weights.

The development of enhanced oral protein delivery technology by immediate release tablets

which may release the drugs at an enhanced rate are very promising for the delivery of poorly

soluble drugs high molecular weight protein and peptide. The oral route remains the perfect route

for the administration of therapeutic agents because the low cost of therapy, manufacturing and

ease of administration lead to high levels of patient compliance. Many patients require quick

onset of action in particular therapeutic condition and consequently immediate release of

medicament is required. It is estimated that50% of the population is affected by this problem,

which results in a high incidence of ineffective therapy

Oral solid dosage forms:

A solid dosage form is drug delivery system that includes tablets, capsules, sachets and pills as

well as a bulk or unit-dose powders and granules. Among the various dosage forms oral solid

dosage forms have greater importance and occupies a prime role in the pharmaceutical market.

Oral route of drug administration is widely acceptable and drugs administered orally as solid

dosage form represents the preferred class of products. Over 90% of drugs formulated to produce

systemic effects are produced as solid dosage forms. Because of these reason whenever New

chemical entity (NCE) has discovered, which shows a sufficient pharmacological action, first the

pharmaceutical company asks whether the drug is successfully administered by oral route or not.

DEPARTMENT OF PHARMACEUTICS, SRI PADMAVATHI SCHOOL OF PHARMACY PAGE 1


The oral route of administration still continues to be the most preferred route due to its manifold

advantages including:

Tablets and capsules represent unit dosage forms in which the accurate dose of drug to show

sufficient pharmacological action can be administered. In case of liquid oral dosage forms

such as Syrups, Suspensions, Emulsions, Solutions and Elixirs the patient is asked to

administer the medication of 5-30 ml. Such dosage measurements are typically error by

factor ranging from 20-50 %, when the drug is self administered by patient.

Solid dosage forms are less expensive to shipping and less prone for the degradation when

compared to liquid dosage forms.

Tablets:

“In 1843, the first patent for a hand operated device used to form a tablet was granted.” Tablets

are defined as solid preparations each containing a single dose of one or more active ingredients

and obtained by compressing uniform volumes of particles. They are intended for oral

administration, some are swallowed whole, some after being chewed. Some are dissolved or

dispersed in water before being administered and some are retained in the mouth, where the

active ingredient “liberated”. Tablets are used mainly for systemic drug delivery but also for

local drug action. For systemic use drug must be released from tablet that is dissolved in the

fluids of mouth, stomach and intestine and then absorbed into systemic circulation by which it

reaches its site of action. Tablets remain popular as a dosage form because of the advantages,

afforded both to the manufacturer [e.g. simplicity and economy of preparation, stability and

convenience in packing, shipping and dispensing] and the patient [e.g. accuracy of dosage,

compactness, portability, blandness of taste and ease of administration].

They may differ greatly in size and weight depending on the amount of drug substance present

and the intended method of administration. They may have lines or break-marks and may bear a

symbol or other markings. Tablets may be coated.



Advantages of Tablets

The primary potential advantages of tablets are,

They are the unit dosage forms, which offer the great capabilities of all oral dosage forms

for the greatest dose precision and the least content variability.

The cost is lower of all oral dosage forms.

They are the lightest and most compact of all.

They are in general the easiest and cheapest to packaging and shipment.

Product identification is potentially the simplest and cheapest, requiring no additional

processing steps when employing an embossed or monogrammed punch face.

They may provide the greatest case of swallowing with the least tendency for hang up

above the stomach, especially when coated, provided the tablet disintegration is not

excessively rapid.

They lend themselves to certain special profile products, such as enteric or delayed

release products.

They are better suited to large scale production than with other unit oral dosage forms.

They have the best combined properties of chemical, mechanical and microbiological

stability of all the oral forms.

Disadvantages

In spite of all these advantages, tablet also possesses some disadvantages. The disadvantages of

tablets include the following

Some drugs resist compression in to dense compacts, owing to their amorphous nature or

flocculent, low density character.

Drugs with poor wetting properties, slow dissolution properties, intermediate to large

dosages, optimum absorption high in the GIT or any combination of these features may

be difficult or impossible to formulate and manufacture as a tablet that will still provide

adequate or full drug bioavailability.

Bitter tasting drugs, drug with obnoxious odor or drugs that are sensitive to oxygen or

atmospheric moisture may require encapsulation / entrapment prior to compression /

coating.

Classification of tablets



I. Classification based on mode of administration

1) Tablets to be swallowed

2) Chewable tablets

3) Tablets used in oral cavity

Buccal tablets

Sublingual tablets

Troches and lozenges

Dental cones

4) Tablets administered other than oral route

Implants

Vaginal tablets / suppositories

II. Classification based on drug manufacturing process

1) Standard compressed tablets

2) Multiple compressed tablets

Compression-coated tablets

Layered tablets

3) Coated tablets

4) Molded tablets (Tablet triturates)

III. Classification based on drug release profile

1) Fast dissolving tablets

2) Immediate release tablets

3) Controlled Release tablets (Sustained Release Tablets)

4) Delayed Release tablets (Enteric coated tablets)

IV. Tablets used to prepare solutions

Effervescent tablets

Dispersible tablets

Sustained drug release



The goal of sustained –release dosage form is to maintain therapeutic blood or tissue

levels of the drug for an extended period. This is usually accomplished by attempting to obtain

zero order release from the dosage form. Zero order release constituents drug release from the

dosage form that is independent of the amount of drug in the delivery system (a constant release

rate). Sustained release system generally do not attain this type of release and usually try to

mimic Zero order release by providing drug in a slow first order fashion ( concentration

dependent).Systems that are designated as prolonged release can also be considered as attempts

at achieving sustained release delivery. Repeat – action tablets are an alternative method of

sustained release in which multiple doses of the drug are contained within a dosage form, and

each dose is released at a periodic interval. Delayed release system in contrast, may not be

sustaining, since often the function of these dosage forms is to maintain the drug within the

dosage form for sometime before release. Commonly, the release rate of drug is not altered and

does not result in sustained delivery once drug release has begun.

Advantages of sustained release products

Decreased local and systemic side effects

Reduced gastro intestinal irritation.

Better drug utilization

Reduction in the total amount of drug used.



Minimum drug accumulation on chronic dosing.

Optimized therapy.

Reduction in fluctuation in drug level and hence more uniform

pharmacological response.

More uniform blood concentration.

For drugs with very short elimination half –lives, sustained release products maintain

the efficacy over a long duration.

Improved patient compliance

Less frequent dosing.

Reduced night time dosing.

Reduced patient care time.

Economy result from a decrease in nursing time and hospitalization.

Disadvantages of sustained release products

1. Dose dumping may occur either as a release of more than the usual fraction of drug or as the

release of drug at a greater rate.

2. Removal of drug from the system is difficult in case of any toxicity, adverse drug reaction are

accidentally becomes intoxicated.

3. Orally administered sustained release products may yield erratic or variable drug absorption as

a result of various drug interactions with the content of GI tract and changes in GI motility.

4. Sustained release may not be practicable for drugs that are usually given in large doses in

conventional dosage forms.

5. Higher cost of medication has compared to conventional drug products.

IMMEDIATE RELEASE TABLETS

The need for new oral drug delivery system continues, due to poor patient acceptance for

invasive methods, need for exploration of new market for drugs and coupled with high cost of

disease management. Developing new drug delivery techniques and utilizing them in

product development is critical for pharma companies to survive this century.

An immediate release dosage form allows a manufacturer to extend market

exclusivity, while offering patients a convenient dosage form or dosage regimen. Immediate



Release Tablets are those tablets which are designed to disintegrate and release their

medication with no special rate controlling features, such as special coatings and other

techniques.

Recently immediate release tablets have started gaining popularity and acceptance as a drug

delivery system, mainly because they are easy to administer, has quick onset of action is

economical and lead to better patient compliance. They are also a tool for expanding markets,

extending product life cycles and generating opportunities.

Advantages of Immediate Release Tablets

Economical and cost effective.

Quick onset of action.

Suitable for industrial production.

Improved stability and bioavailability.

Provides some advantages of liquid dosage forms.

Adaptable and amendable to existing processing and packaging machinery.

Unique product differentiation

Disadvantages of Immediate Release Tablets

Rapid drug therapy intervention is not possible.

Sometimes may require more frequency of administration.

Dose dumping may occur.

Reduced potential for accurate dose adjustment.

Over 90% of the formulations manufactured today are ingested orally. This shows that this class

of formulation is the most popular worldwide and the major attention of the researcher is towards

this direction. The major aim of controlled drug delivery is to reduce the frequency of dosing.

The design of modified release drug product are to optimize a therapeutic regimen by providing

slow and continuous delivery of drug over the entire dosing interval providing greater patient

compliance and convenience. Bilayer tablet is the new era for the successful development of

controlled release formulation.

Bilayer tablet is better than the traditionally used dosage forms Bi-layer tablet is suitable

for sequential release of two drugs in combination it is also capable of separating two

incompatible substances and also for sustained release tablet in which one layer is immediate



release as initial dose and second layer is maintenance dose. In certain cases bilayered tablets

have 2 sustain release layers of different drugs. Bilayer tablet is an improved technology to

overcome the shortcoming of the single layered tablet. Bilayer tablets contain immediate and

sustained release layers. The immediate release layer delivers the initial dose, it contains super

disintegrants which promotes drug release rate and attains the onset of action quickly (loading

dose ) whereas sustained release(maintenance dose) layer releases drug in sustained manner for

prolonged time period. The biphasic system is used mostly when maximum relief needs to be

achieved quickly and it is followed by a sustained release phase. It also avoids repeated

administration of drug. Coronary vasodilators, anti hypertensives, anti histaminics, analgesics,

antipyretics and antiallergenic agents are mainly suitable for this type of drug delivery .Some

bilayer tablets have both the layers as the sustain release layers examples are certain anti diabetic

agents.

NECESSITY OF BILAYER TABLETS 2

1. For the administration of fixed dose combination of different APIs, prolong the drug

product shelf life

2. Controlling the delivery rate of either single or two different active pharmaceutical

ingredient(s).

3. To modify the total surface area available for API layer either by sandwiching with one

or two inactive layers in order to achieve or erodible barriers for modified release.

4.

ADVANTAGES OF BILAYERED TABLETS 3, 4

1. These types of incompatabiliteis are commonly used to avoid chemical incompatabilities

of formulation components by physical separation.

2. Cost is lesser as compared to other dosage forms.

3. Greater chemical and microbiological stability.

4. Objectionable odor and bitter taste can be masked by coating technique.

5. Flexible concept.

6. Easy to swallow with least tendency for hang up.

7. Suitable for large scale production.

8. They are unit dosage form and often the greatest dose precision and least contact

variability.



DISADVANTAGES OF BILAYERED TABLETS5

1. Some drugs resist compression into dense compacts owing to amorphous nature.

2. Bitter testing drugs, drugs with an objectionable odor or drugs that are sensitive to

oxygen may require encapsulation or coating.

3. Difficult to swallow in case of children and unconcisious patients.

4. Drugs with poor solubility, slow dissolution properties optimum absorption high in GIT

may be difficult to formulate that will still provide adequate or full drug bioavailability.

GENERAL PROPERTIES OF BI-LAYER TABLET DOSAGE FORMS: 6

1. A bi-layer tablet should have elegant product identity while free of defects like chips,

cracks, discoloration, and contamination.

2. Should have sufficient strength to withstand mechanical shock during its production

packaging, shipping and dispensing.

3. Should have the chemical and physical stability to maintain its physical attributes over

time.

4. The bi-layer tablet must be able to release the medicinal agents in a predictable and

reproducible manner.

5. Must have a chemical stability shelf-life, so as not to follow alteration of the medicinal agents.

TYPES OF BILAYER TABLETS7

The term bilayered tablets containing subunits that may be either the same (homogeneous) or

different (heterogeneous).

Homogenous type

Bilayer tablets are preferred when the release profiles of the drugs are different from one

another. Bilayer tablets allows for designing and modulating the dissolution and release

characteristics .Bilayer tablets are prepared with one layer of drug for immediate release while

second designed to release drug later either as second dose or in an extended release

manner.

Heterogeneous type

Bilayer tablet is suitable for sequential release of two drugs in combination separate two

In compatible substances.



ADVANTAGES OF BILAYER TABLET OVER THE OTHER CONVENTIONAL

TABLET

1. This formulation can be used to separate two incompatible substances.

2. When the two different layers of the tablet contain two different drug ,then the tablet can

be easily used in combination therapy.

3. It makes possible extended-release preparations with the immediate-release quantity in

one and the slow-release portion in the second layer.

4. In case of drugs having a low half-life, each of the two layers of the tablet respectively

content a loading dose and maintaince dose of the same and thus increase the

bioavailability of the drug.

5. Analytical work may be simplified by separating of the layer prior to assay.

6. Two-layer tablet require less material than compression coated tablets, weight less, and

may be thinner.

7. The weight of each layer can be accurately controlled, in the contrast to putting one drug

may be thinner

VARIOUS APPROACHES USED IN THE BILAYER TABLET 7

Floating Drug Delivery System

Floating Drug Delivery System designed to have a low density and thus float on gastric

Contents after administration until the system either disintegrate. The bilayer tablet is designed

in such a manner that one layer gives the immediate dosing of the drug which gives faster onset

of action while other layer is designed as a floating layer which floats in the stomach.

Polymeric Bio adhesive System

Polymeric Bio adhesive System designed to imbibe fluid following administration such

that the outer layer becomes a viscous, tacky material that adhere to the gastric mucosa/mucous

layer .This should encourage gastric retension until the adhesive force are weakened. These are

prepared as one layer with immediate dosing and other layer with bioadhesive property.

Swelling System

Swelling System designed to be small on administration so as not to make ingestion of

the dosage form difficult(e,g.,10-12 mm in diameter for round tablets, where as less than 23 mm

long and also less than 11mm wide for an oval or capsule-shaped tablet).



On ingestion they will rapidly swell or disintegrate or unfold to a size that precludes passage

through the pylorus until after release has progressed to a required degree. Gradual erosion of the

system or its break down into smaller particles enables it to leave stomach .The simple bilayer

tablet may contain an immediate release layer with the other layer as extended release or

conventional release.

LITERATURE REVIEW

1. Swati Aggarwalet et al, This work is mainly focused improved performance, patient

compliance and enhanced quality have emerged in the recent past. Multilayer is getting

increasing attention from a variety of industries for a variety of reasons: patent extension,



therapeutic, marketing to name a few. To reduce capital investment, quite often existing but

modified tablet presses are used to develop and produce such tablets .The present article

provides a on the oral drug delivery system, types of tablets, and challenges in bilayer tablet

manufacturing, various tablet presses used, quality and GMP requirements for their

production and recent developments in the field of bilayer technology, Bi-Layer Tablet

Technology - Opening New Ways in Drug Delivery Systems: An Overview, International

Journal of Research in Pharmaceutical and Biomedical Sciences ISSN: 2229-37012.

2. Kotta, kranthi kumar et al. were designed the concept of bilayered tablets containing

Pioglitazone hydrochloride for immediate release using crossPovidone as super disintegrant

and Metformin hydrochloride for sustained release using poly ethylene oxide (PEO-303) as

matrix forming polymer. The release kinetics of Metformin hydrochloride was evaluated

using the regression coefficient analysis.The polymer Polyethylene oxide (PEO- 303) had

significant effect on the release of Metformin HCl matrix tablets (F5).Formulation and

evaluation of bilayermatrix tablet of pioglitazone Hcl Metformin Hcl usp 15mg&500mg,

Asian Journal Of Pharmaceutical And Clinical Research, Vol 6, Suppl 3, 2013.

3. Anindita De et al, Bilayer tablets of Domperidone (IR) Rabeprazole (SR) were formulated

for the management of gastro esophageal disorder. Immediate layer of Domperidone

formulated using Tulsion T-339 as super disintegrant. For sustained release of Rabeprazole

HPMC as the rate controlling polymers was used. Preformulation studies were performed

prior to compression. The individual layers of the Bilayer tablets were evaluated for weight

variation, dimension, hardness, friability, drug content, and disintegration time and invitro

drug release using USP dissolution apparatus type II (paddle). It was found that the

optimized formulation showed 12.8%, 18.0%, 38.8%, 59.5%, 74.9%, 88.5% and

98.9%release for rabeprazole in 0.5,1,2, 4, 6, 8, 12 hours respectively. However,

domperidone released 98.28% at the end of 30 minutes. The IR spectrum studies revealed

that there is no disturbance in the principal peaks of pure drugs. This further confirms the

integrity of pure drugs and no incompatibility of them with excipients. The stability studies

were carried out for the optimized batch for three months and it showed acceptable results

design, development and in-vitro evaluation of floating bilayer tablet of domperidone and

rabeprazole for the treatment of gastro esophageal reflux disorder, international journal of

pharmaceutical and chemical sciences issn: 22775005 vol. 2



4. Metkar Vishal et al., developed bi-layer tablets of lornoxicam, a highly potent nonsteroidal

anti-inflammatory drug with short half-life. Immediate release layer prepared by using dry

granulation method in which ac-di sol used as a disintegrant for immediate release of drug,

roll compaction of drug with sodium citrate which act as buffering agent and create basic

microenvironmental pH inside the tablets favorable to drug release in acidic conditions.

Sustained release layer formulated by using HPMC as release retardant. They found that

Batch F8 formulate as bilayer tablet was selected as optimized batch of bilayer tablet

formulation.Formulation development and evaluation of Bilayer tablets of Lornoxicam,

International Journal of Drug Development & Research, Vol. 4 , Issue 2 , April-June 2012.

5. S. Jayaprakash et al., were formulated Bilayer tablets of Amlodipine besilate (IR)

Metoprolol succinate (SR) for the management of hypertension. Preformulation studies were

performed prior to compression. The compressed bilayer tablets were evaluated for weight

variation, dimension, hardness, friability, drug content, disintegration time and invitro drug

release using USP dissolution apparatus type 2 (paddle). It was found that the optimized

formulation showed 9.96%, 35.56%, 52.12%, 90.46% release for Metoprolol succinate.

Formulation and evaluation of bilayer tablets of amlodipine besilate and metprolol succinate,

Scholars Research Library Der Pharmacia Lettre,3 (4) ,2011,143-154

6. Hosna Banu et al., were designed acetaminophen extended release bi layer tablets containing

immediate release layer and extended release layer. Formulation ER-4(containing 10%

HPMC 100 cps and 1.5% sodium starch glycolate) and ER-6 (containing 1.5% Methocel

K4M CR and 0.5% sodium starch glycolate) were found to follow compendia specification

for drug release profile. Formulation development of bi-layer acetaminophen tablets for

extended drug release, Journal of Chemical and Pharmaceutical Research , 3(6), 2011, 348-

360.

7. Prabhakar Shirse was formulated and evaluated the bilayered tablets containing Diclofenac

Sodium in the sustained release (SR) portion and Ranitidine HCl in the immediate release

(IR) portion. The powders were evaluated for their flow properties and the finished tablets

were evaluated for their physical parameters. The release rate of ranitidine HCl from all the

formulations was more than 80% at 45 min. Formulation and Evaluation of Bilayer Tablets

of Diclofrenac Sodium with Ranitidine HCL for Sustained and Immediate Release Journal of

Applied Pharmaceutical Science 02 (05); 2012: 136-141.



8. Arti Mohan et al., were developed immediate release and sustained release in a single

bilayer tablet which would release 30% of the drug within 30 minutes and the balance 70%

would then release over a period of 12 to 24 hours They concluded that the percentage drug

release of the optimized batch was found to be 97.51% at 24th hour. Thus bilayer tablets

could be a potential dosage form for delivering Tramadol as immediate release and

controlled release manner. Formulation and Evaluation of Immediate Release and Sustained

Release Bilayer Tablets of Tramadol Hydrochloride, American Journal of Advanced Drug

Delivery,2013.

9. Kumara Swamy S et al., were aimed to formulate three drugs in the form of bilayered

tablets and the prepared tablets were evaluated for weight variation, thickness, disintegration

time, hardness, friability, drug content and dissolution studies. Based on dissolution test, it

was concluded that the release profile of the Formulation 5 (F5) had matched with that of the

innovator and showed the percent drug release at the end of 45 minutes as 100.0±0.05% of

EFV portion, 98.12±0.32% of FTC portion and 99.12±0.09% of TDF portion. Formulation

and Evaluation of Bilayer Tablets of Efavirenz, ,Emtricitabine and Tenofovir Disoproxil

Fumarate, Journal of Advanced Pharmaceutical Sciences, eISSN 2249-5797.

10. Swamy P.V et al ., were designed and evaluated bilayer buccal tablets of granisetron

hydrochloride (an anti-emetic drug), in order to overcome bioavailability problems, to reduce

dose dependent side effects and frequency of administration. The optimized formulation SAF

exhibited an in vitro drug release of 94% in 8 h along with satisfactory bioadhesion strength

(4.6 gm). Short-term stability studies (40±2 C/75±5% RH for 3 months) on the promising

formulation indicated that there are no significant changes in drug content and in vitro

dissolution characteristics (p<0.05). IR spectroscopic studies indicated that there are no drug

excipient interactions. Formulation Design and Evaluation of Bilayer Buccal Tablets of

Granisetron Hydrochloride, Indian Journal of Pharmaceutical Education and Research 2010-

2011.

11. ma naeem et al., developed and characterized bilayer tablet formulations of tramadol HCl

(TmH) and acetaminophen (AAP) microparticles. Higuchi model produced the best fit, with

regard to release profile, for both drugs, with correlation coefficient (R2) of 0.966 and 0.960

for AAP and TmH, respectively. Microencapsulated TmH and AAP can be developed into

suitable bilayer tablets that are stable and capable of releasing the drugs over 12 h.



Development and Evaluation of Controlled-Release Bilayer Tablets Containing

Microencapsulated Tramadol and Acetaminophen, Tropical Journal of Pharmaceutical

Research 9 (4), 347-354, August 2010.

12. Anindita De et al, Bilayer tablets of Domperidone (IR) Rabeprazole (SR) were formulated

for the management of gastro disintegrant. For sustained release of Rabeprazole HPMC as

the rate controlling polymers was used. Preformulation studies were performed prior to

compression. The individual layers of the bilayer tablets were evaluated for weight variation,

dimension, hardness, friability, drug content, and disintegration time and invitro drug release

using USP dissolution apparatus type II (paddle). It was found that the optimized formulation

showed 12.8%, 18.0%, 38.8%, 59.5%, 74.9%, 88.5% and 98.9%release for rabeprazole in

0.5,1,2, 4, 6, 8, 12 hours respectively. However, domperidone released 98.28% at the end of

30 minutes. The IR spectrum studies revealed that there is no disturbance in the principal

peaks of pure drugs. This further confirms the integrity of pure drugs and no incompatibility

of them with excipients. The stability studies were carried out for the optimized batch for

three months and it showed acceptable results. The kinetic studies of the formulations

revealed that diffusion is the predominant mechanism of drug and release follows first order

kinetics, Design, Development and In-Vitro Evaluation of Floating Bilayer Tablet of

Domperidone and Rabeprazole for the Treatment of Gastro Esophageal Reflux Disorder,

international journal of pharmaceutical and chemical sciences, Vol. 2 (2) Apr-Jun 2013.

13. Metkar Vishal et,al. The objective of the present study was to develop bi-layer tablets of

lornoxicam, a highly potent nonsteroidal anti-inflammatory drug with short half-life, that are

characterized by initial burst drug release in the stomach and comply with the release

requirements of sustained-release products. Each of the proposed bi-layer tablets is composed

of an immediate-release layer and a sustained-release layer, anticipating rapid drug release

that starts in the stomach to rapidly alleviate the symptoms and continues in the intestine to

maintain protracted analgesic effect. Immediate release layer prepared by using dry

granulation method in which ac-di sol used as a disintigrant for immediate release of drug,

roll compaction of drug with sodium citrate which act as buffering agent and create basic

microenvironmental pH inside the tablets favorable to drug release in acidic conditions.

Sustained release layer formulated by using HPMC as release retardant, two grades of

HPMC that are HPMC K4M and HPMC K100M used to get sustained release profile for 24



hr. various trial batches are taken to get desiredrelease profile. Batch F8 formulate as bilayer

tablet in which 24.67 % for 1 hr in immediate release layer and drug release 98 % for 24 hr

in sustained release layer is selected as optimized batch of bilayer tablet formulation. All the

prepared bilayer tablets showed acceptable physical properties before , Formulation

development and evaluation of Bilayer tablets of Lornoxicam, International Journal of Drug

Development & Research April-June 2012 | Vol. 4 | Issue 2.

14. nabin karna , This bi-layer matrix tablets were formulated to show quick onset of action as

well as SR delivery systems is limited to the lower gastrointestinal tract which consequently

leads to a delayed onset of its analgesic action. To provide complete drug release that starts

in the stomach to rapidly alleviate the painful symptoms and continues in the intestine to

maintain protracted analgesic effect, use basic pH modifiers like sodium bicarbonate &

magnesium oxide to create basic micro-environmental pH inside &give a favorable acidic

condition for tablets to release the drug. Different types and levels of hydrophilic matrixing

agents, like HPMC K4 & HPMC K 15 were used to control the release of the drugs. The UV

Spectroscopy, particle size and FTIR analysis of pure drug were performed. The tablets were

prepared by wet granulation. In-Vitro drug release study was carried out for different

formulations. design, development and evaluation of novel sustained release bi-layer tablets

of lornoxicam based on the combination of hydrophilic matrix formers and basic ph

modifiers, int j pharm bio sci 2012 oct; 3(4): (p) 392 – 402.

15. Rajesh Sahota et al, Diabetes, being one of the most prevalent disease in India, accounts for

several other complications like development of atherosclerosis, hypertension and many

other physiological complications which cannot be treated using single drug therapy. The

low compliance and high cost are the major hindrance blocks for multiple drug therapy. The

main aim of present work is to develop an optimized bilayer tablets of metformin

hydrochloride and atorvastatin calcium for overcoming the problem associated with multiple

drug therapy. The prepared tablets were evaluated for uniformity of weight, friability and

drug release characteristics. The stability studies revealed that developed tablet can be stored

at room temperature, Development and Characterization of Bilayer Tablets Containing

Metformin Hydrochloride in Sustained Release Layer and Atorvastatin Calcium in

Immediate Release Layer, IPP, Vol 1 (3), 220-229, 2013.



16. M.Sowmya, M.Saritha(2011)..Has developed and optimized bilayered sustained release

matrix tablets of Valsartan. The tablets contained an immediate releasing layer with the

loading dose of the drug and a sustaining layer with maintenance dose of drug prepared by

wet granulation method. The immediate releasing layer is directly compressed on to the

sustaining layer. Sodium starch glycholate was used as super disintegrant and Eudragit RSPO

and Eudragit RLPO were used as polymers. The drug polymer interaction was investigated

by FTIR and DSC and their results directed further course of formulation. Valsartan tablets

were evaluated for various post compression parameters like Tablet hardness, Friability,

Weight variation, Drug content and In vitro dissolution. Kinetic treatment to the in vitro

release data revealed that the drug release followed zero order non – fickian diffusion with n

value greater than 0.45.

17. Narendra et al (2006)developed an optimized bilayer gastric floating tablet containing

metoprolol tartrate using soluble starch for immediate loading dose layer and HPMC was

used for sustained release layer with SCMC was used for floating the tablet. Fickian release

transport was confirmed as the release mechanism from the optimized formulation. The

results demonstrate the feasibility of the model in the development of GFDDS. The results

demonstrate the feasibility of the model in the development of GFDDS.

18. Vishnu M Patel., Bhupendra G. et al. (2007) studied the mucoadhesive bilayer tablets of

propanolol hydrochloride using the bioadhesive polymers sodium alginate and Carbopol

934P (CP) along with ethyl cellulose as an impermeable backing layer. Tablets containing

Na-alginate and CP in the ratio of 5:1 (F2) had the maximum percentage of in vitro drug

release without disintegration in 12 hours. The swelling index was proportional to Na-

alginate content and inversely proportional to CP content. The mechanism of drug release

was found to be non-Fickian diffusion and followed zero-order kinetics.

19. Girish S. Sonara., Devendra K. Jaina. et al(2007). prepared the bilayer and floating - bio

adhesive tablets of rosiglitazone maleate. HPMC was used for the sustained release layer and

Sodium bicarbonate was used for the floating layer. The floating ability was studied by

gamma scintigraphy. The release of rosiglitazone maleate from the tablets followed the

matrix first-order release model. The tablet was buoyant for up to 8 h in the human stomach.

20. Pandey H. et al. developed sustained release bilayer tablet of domperidone using

hydrophilic matrix material such as HPMC, carbapol and poly-ethylene oxide. The results



indicated that the formulation with HPMC could extend the drug release upto 24hr. All the

formulations show diffusion dominated drug release.

21. Shirwaikar A. et al. formulated sustained release of Diltiazem hydrochloride tablets by

utilizing the bilayer concept using matrix material rosin and ethyl cellulose. The formulation

produce an initial burst effect followed by sustained release for 12hr which indicate bimodal

release of diltiazem HCL from matrix tablet and the drug release involved both diffusional

and dissolutional mechanism.

22. Vishnu M. Patel et al.,(2007) The purpose of this research work was to establish

mucoadhesive buccal devices of propranolol hydrochloride (PRH) in the forms of bilayered

and multilayered tablets. The tablets were prepared using sodium carboxymethylcellulose

(SCMC) and Carbopol-934 (CP) as bioadhesive polymers to impart mucoadhesion and ethyl

cellulose (EC) to act as an impermeable backing layer. Buccal devices were evaluated by

different parameters such as weight uniformity, content uniformity, thickness, hardness,

surface pH, swelling index, ex vivo mucoadhesive strength, ex vivo mucoadhesion time, in

vitro drug release, and in vitro drug permeation. As compared with bilayered tablets,

multilayered tablets showed slow release rate of drug with improved ex vivo bioadhesive

strength and enhanced ex vivo mucoadhesion time. The mechanism of drug release was found

to be non-Fickian diffusion (value of n between 0.5 and 1.0) for both the buccal devices. The

stability of drug in both the optimized buccal devices was tested for 6 hours in natural human

saliva; both the buccal devices were found to be stable in natural human saliva. The present

study concludes that mucoadhesive buccal devices of PRH can be a good way to bypass the

extensive hepatic first-pass metabolism and to improve the bioavailability of PRH.

23. Bhavesh Shiyani et al.,(2008) The aim of this study was to prepare bi-layer tablet of

Metoclopramide Hydrochloride (MTH) and Ibuprofen (IB) for the effective treatment of

migraine. MTH and IB were formulated as immediate and sustained release layer

respectively. MTH was formulated as immediate release layer by using various disintegrants

like Ac-Di-Sol, Polyplasdone XL, Explotab, Agar and Gellan Gum. Treated form of gellan

gum and agar was prepared and compared for their disintegrant efficiency with other

disintegrants. IB was formulated as sustained release layer using hydrophilic matrix

(hydroxypropylmethylcellulose [HPMC K4M]). The effect of concentration of hydrophilic

matrix (HPMC K4M), binder (polyvinylpyrollidone [PVP K304]) and buffer (sodium



bicarbonate) on IB release was studied. The dissolution study of sustained release layer

showed that an increasing amount of HPMC or PVP K304 results in reduced IB release. The

inclusion of buffer (sodium bicarbonate) enhanced the release of IB from sustained release

layer. The rational for formulation of bi-layer tablet of these two drugs in combination was

(1) MTH increases the absorption of acidic non-steroidal anti-inflammatory drug (NSAID)

by increasing gastric motility. So sequential release of MTH (as immediate release) and IB

(as sustained release) was suitable for treatment of migraine. (2) MTH was degraded when

prolonged contact with acidic NSAID. Bi-layer tablet was suitable for preventing direct

contact of these two drugs and thus to maximize the efficacy of combination of two drugs for

migraine.

24. Lauretta M et al.,(1999) A new biphasic release system for slightly soluble drugs has been

proposed. To enhance the dissolution rate, the drug was milled with superdisintegrant. Then,

double-layer tablets were prepared. One layer was formulated to release the drug in a very

short time (fast-release). The other consisted of an extended-release

hydroxypropylmethylcellulose (HPMC) matrix. Different HPMC concentrations (10, 16 and

22%) and viscosity grades (Methocel K 4, K 15 and K100 M) were used to obtain different

release rates of the drug from the extended-release layer, Ketoprofen and praziquantel were

used as slightly soluble model drugs. The in vitro dissolution tests of the prepared double-

layer systems, showed the desired biphasic behaviour: the drug contained in the fast releasing

layer dissolved within the first 15 min, while the drug contained in the prolonged-release

layer was released at different times, depending on the formulation of the hydrophilic matrix.

In particular, an increase in the percentage and viscosity grade of HPMC, in the extended

release layer, leads to a decrease in the drug delivery rate and produces a wide range of

different release rates from only a few hours up to 24 h.

25. Jayabalan Nirmal et al.,(2008) formulated bilayer tablets consisting of atorvastatin calcium

(AT) as an immediate release layer and nicotinic acid (NA) as an extended release layer. The

immediate release layer was prepared using super disintegrant croscarmellose sodium and

extended release layer using hydroxypropylmethyl cellulose (HPMC K100 M). Both the

matrix and bilayer tablets were evaluated for hardness, friability, weight variation, thickness,

and drug content uniformity and subjected to in vitro drug release studies. The amount of AT

and NA released at different time intervals were estimated by HPLC method. The bilayer



tablets showed no significant change either in physical appearance, drug content or in

dissolution pattern after storing at 40°C/75% relative humiding (RH) for 3 months. The

release of the drug from the tablet was influenced by the polymer content and it was much

evident from thermogravimetry/differential thermal analysis (TG/DTA) analysis. The results

indicated that the bilayer tablets could be a potential dosage form for delivering AT and NA.

AIM AND OBJECTIVE

The main aim of the present work is to overcoming the problem associated with multy

drug theraphy and improve patient compliance.



The primary object of the work is to formulate and evaluate the capecitabine and

metoclopramide bilayer tablets in order to produce a single tablet containing two different

classes of drugs.

PLAN OF WORK

Review of literature

Selection of drug and polymers

Preformulation studies

Preparation of bilayer tablets

Evaluation of bilayer tablets

DRUG PROFILE:

CAPECITABINE

Name Capecitabine

Type small molecule

Description Capecitabine is an orally-administered chemotherapeutic



agent used in the treatment of metastatic breast and

colorectal cancers. Capecitabine is a prodrug, that is

enzymatically converted to fluorouracil (antimetabolite)

in the tumor, where it inhibits DNA synthesis and slows

growth of tumor tissue.

Structure

Brand names Xeloda

Categories

Antineoplastic Agents

Antimetabolites

Prodrugs

Antimetabolites, Antineoplastic

WeightAverage: 359.3501

Monoisotopic: 359.149263656

Chemical Formula C15H22FN3O6

IUPAC Name

pentyl N-{1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-

methyloxolan-2-yl]-5-fluoro-2-oxo-1,2-

dihydropyrimidin-4-yl}carbamate



.

Mechanism of action

Capecitabine is a prodrug that is selectively tumour-activated to its cytotoxic moiety,

fluorouracil, by thymidine phosphorylase, an enzyme found in higher concentrations in many

tumors compared to normal tissues or plasma. Fluorouracil is further metabolized to two active

metabolites, 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP) and 5-fluorouridine

triphosphate (FUTP), within normal and tumour cells. These metabolites cause cell injury by two

different mechanisms. First, FdUMP and the folate cofactor, N5-10-methylenetetrahydrofolate,

bind to thymidylate synthase (TS) to form a covalently bound ternary complex. This binding

inhibits the formation of thymidylate from 2'-deaxyuridylate. Thymidylate is the necessary

precursor of thymidine triphosphate, which is essential for the synthesis of DNA, therefore a

deficiency of this compound can inhibit cell division. Secondly, nuclear transcriptional enzymes

can mistakenly incorporate FUTP in place of uridine triphosphate (UTP) during the synthesis of

RNA. This metabolic error can interfere with RNA processing and protein synthesis through the

production of fraudulent RNA.

Absorption:

Readily absorbed through the GI tract (~70%)

Protein binding:

< 60% (mainly albumin)

Route of elimination:

Capecitabine and its metabolites are predominantly excreted in urine; 95.5% of administered

capecitabine dose is recovered in urine. Fecal excretion is minimal (2.6%). The major metabolite

excreted in urine is FBAL which represents 57% of the administered dose.About 3% of the

administered dose is excreted in urine as unchanged drug.

Half life:

45-60 minutes for capecitabine and its metabolites.



METOCLOPRAMIDE:

Type: small molecule

Description: A dopamine D2 antagonist that is used as an antiemetic.

Structure:



Synonym:

Categories: Antiemetics, Dopamine Antagonists.

Weight:Average:299.796

Chemical Formula: C14H22ClN3O2

IUPAC Name: 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-methoxybenzamide.

Pharmacodynamics:

Metoclopramide, although chemically related to procainamide, does not possess local anesthetic

or antiarrhythmic properties. Metoclopramide is used to enhance GI motility, to treat diabetic

gastroparesis, as an antinauseant, and to facilitate intubation of the small bowel during radiologic

examination. Metoclopramide may be used to treat chemotherapy-induced emesis and as a

radiosensitizing agents in the treatment of non-small cell lung carcinoma and glioblastomas in

the future.

Mechanism of action:

Metoclopramide inhibits gastric smooth muscle relaxation produced by dopamine, therefore

increasing cholinergic response of the gastrointestinal smooth muscle. It accelerates intestinal

transit and gastric emptying by preventing relaxation of gastric body and increasing the phasic

activity of antrum. Simultaneously, this action is accompanied by relaxation of the upper small

intestine, resulting in an improved coordination between the body and antrum of the stomach and


Metoclopramida

Metoclopramidum

http://structures.wishartlab.com/molecules/DB01233/image.png


the upper small intestine. Metoclopramide also decreases reflux into the esophagus by increasing

the resting pressure of the lower esophageal sphincter and improves acid clearance from the

esophagus by increasing amplitude of esophageal peristaltic contractions. Metoclopramide's

dopamine antagonist action raises the threshold of activity in the chemoreceptor trigger zone and

decreases the input from afferent visceral nerves. Studies have also shown that high doses of

metoclopramide can antagonize 5-hydroxytryptamine (5-HT) receptors in the peripheral nervous

system in animals.

Absorption: Rapidly and well absorbed (oral bioavailability 80±15.5%).

Volume of distribution: 4.4±0.65 L/kg.

Protein binding: 30%

Metabolism: Hepatic

Route of elimination: Approximately 85% of the radioactivity of an orally administered dose

appears in the urine within 72 hours.

Half life: 5-6 Hrs.

HYDROXY PROPYL METHYL CELLULOSE



Hydroxy propyl methyl cellulose is mixed alkyl hydroxyl alkyl cellulosic ether and may be

regarded as the propylene glycol ether of methylcellulose.

Chemical Name : Cellulose, 2-hydroxypropyl methyl ether.

Grades : E6,E15, E50, E4M, F50, F4M, K4M, 15M

Description : It is an odorless, tasteless, white or creamy-white

fibrous or granular powder

Solubility : Soluble in cold water, forming a viscous colloidal

solution,

insoluble in alcohol, ether and chloroform, soluble

in

CH3OH:CH2Cl2 (50:50) mixture, soluble in

mixtures of CH2Cl2 and isopropyl alcohol and

other organic solvents.

Density : 0.25 to 0.70 g/cm3

pH : 6.0 to 8.0(1% aqueous solution)



Viscosity : HPMC E 5 cps, 15 cps (2% aq. Solution) HPMC

E4M, 4000 cps (2% aq. solution) HPMC K4M,

4000 cps (2% aq. Solution)

Stability : Very stable in dry conditions, solutions are stable

at pH 3.0-11.0. Aqueous solutions are liable to be

affected by micro-organisms and film

Uses : 1. Suspending agent, viscosity increasing agent

forming agent.

2. Tablet binder and adhesive ointment ingredient.

ETHYL CELLULOSE

Nonproprietary Names

BP: Ethylcellulose

PhEur: Ethylcellulose

USP-NF: Ethylcellulose

Synonyms

Aquacoat ECD;Aqualon;Ashacel; E462;Ethocel; ethylcellulosum; Surelease.

Chemical Name

Cellulose ethyl ether

Empirical Formula and Molecular Weight

Ethylcellulose is partially ethoxylated. Ethylcellulose with complete ethoxyl

substitution (DS = 3) is C12H23O6(C12H22O5)nC12H23O5 where can vary to provide a

wide variety of molecular weights. Ethylcellulose, an ethyl ether of cellulose, is a

long-chain polymer ofb-anhydroglucose units joined together by acetal linkages.

Structural Formula



Functional Category

Coating agent; flavoring agent; tablet binder; tablet filler; viscosityincreasing agent.

GUAR GUM

Nonproprietary Names:

BP, PhEur : Guar Galactomannan

USP-NF : Guar Gum

Structural Formula :

Synonyms : Galactosol, Guarflour, Jaguargum, Meyprofin.

Chemical name : Galactomannan polysaccharide.

Molecular Formula : (C6H12O6)n

Molecular Weight : 220 000

Density : 1.492g/cm3

Viscosity : 4.86 Pa s (4860 cP) for a 1% w/v dispersion.

Description : Occurs as an odorless, white to yellowish color, bland taste.

Solubility : Practically insoluble in organic solvents. In cold or hot

water, disperses and swells almost immediately to form

a highly viscous, thixotropic solution.

Functional category : Suspending agent, binder, disintegrator and viscosity agent.



Safety : Guar gum is widely used in foods, and oral and topical

pharmaceutical formulations. Excessive consumption may

cause gastrointestinal disturbance such as diarrhea or

nausea[42]. It is nontoxic and nonirritant material.

Pharmaceutical Applications

1. Guar gum is commonly used in cosmetics, food products and pharmaceutical

formulations[43].

2. It has also been investigated in the preparation of sustained release matrix tablets[43].

3. Guar gum is used in solid dosage forms as a binder and disintegrant[44].

4. It is used by suspending, thickening, and stabilizing agent.

5. Guar gum also used by controlled released carrier[45].

6. It has also been examined for use in colonic drug delivery.

MICROCRYSTALLINE CELLULOSE

Nonproprietary Name: Microcrystalline Cellulose.

Synonyms: Avicel PH; celex; cellulose gel; crystalline cellulose; emcocel; tabulose.

Chemical Name: Cellulose

Empirical Formula: (C6H10O5) n where n ~ 220

Molecular Weight: ~36 000

Functional Category: Adsorbent; suspending agent; tablet and capsule diluent; tablet

disintegrant.

Description: Microcrystalline cellulose is a purified, partially depolymerized cellulose that

occurs as a white, odorless, tasteless, crystalline powder composed of porous particles. It is

commercially available in different particle sizes and moisture grades that have different

properties and applications.

Solubility: Slightly soluble in 5 % w/v sodium hydroxide solution; practically insoluble in water,

dilute acids, and most organic solvents.



Stability and Storage Conditions: Microcrystalline cellulose is a stable though hygroscopic

material. The bulk material should be stored in a well-closed container in a cool, dry place.

Incompatibilities: Microcrystalline cellulose is incompatible with strong oxidizing agents.

Applications: Microcrystalline cellulose is widely used in pharmaceuticals, primarily as a

binder/diluent in oral tablet and capsule formulations where it is used in both wet-granulation

and direct-compression processes. It also has some lubricant and disintegrant properties that

make it useful in tableting. It is also used in cosmetics and food products.

Related Substances: Microcrystalline cellulose and carrageenan; microcrystalline cellulose and carboxy methyl cellulose sodium; microcrystalline cellulose and guar gum; powdered cellulose.

TALC

Non-Proprietary Name:

BP: Purified Talc

JP: Talc

PhEur: Talc

USP: Talc

Synonym:

Altalc; E553b; hydrous magnesium calcium silicate; hydrous magnesium silicate; Imperial;

Luzenac Pharma; magnesium hydrogen metasilicate; Magsil Osmanthus; Magsil Star; powdered

talc; purified French chalk; Purtalc; soapstone; steatite; Superiore; talcum.

Molecular Weight = 379.27 gm

Chemical Name: Talc.

Empirical Formula: Mg3Si4O10 (OH) 2

Structural Formula:



Category

Anti caking agent, glident, tablet & capsule lubricant and diluent. Also used to clarify liquids.

Physical Properties

Color: Pale green, White, Gray white, Yellowish white, Brownish white.

Density: 2.7 - 2.8, Average = 2.75 g/cm3

Moisture Content: Talc absorbs insignificant amount of water at 25 degree and relative

humidity up to about 90%.

Applications

Dusting powder 9-99 (%) (In Topical preparations)

Glidant 1-10 (%)

Tablet Lubricant 1-10 (%)

Tablet & Capsule Diluent 5-30 (%)

MAGNESIUM STEARATE

Synonyms : Magnesium octadecanoate; Octadecanoic acid, magnesium salt;

Stearic acid, magnesium salt.

Functional Category : Tablet and capsule lubricant.



Description : It is a very fine, light white, precipitated or milled, impalpable powder of

low bulk density, having a faint odor of stearic acid and a

characteristic taste. The powder is greasy to the touch and readily

adheres to the skin.

Flowability : Poorly flowing, cohesive powder.

Melting range : 117–150°C (commercial samples);

126–130°C (high purity magnesium stearate).

Solubility : Practically insoluble in ethanol, ethanol (95%), ether and water;

slightly soluble in warm benzene and warm ethanol (95%).

Stability and Storage : It is stable and should be stored in a well-closed container in a cool,

dry place.

Incompatibilities : Incompatible with strong acids, alkalis, and iron salts. Avoid mixing with

strong oxidizing materials. It cannot be used in products containing

aspirin, some vitamins, and most alkaloidal salts.

Safety : Nontoxic following oral administration. However, oral consumption of

large quantities may produce a laxative effect or mucosal irritation.

Uses : It is widely used in cosmetics, foods, and pharmaceutical formulations. It is

primarily used as a lubricant in capsule and tablet manufacture at

concentrations between 0.25% and 5.0% w/w. It is also used in barrier

creams.

STARCH

Non proprietary names

Maize starch

Potato starch

Rice Starch

Tapioca Starch



Wheat Starch

Description

A very fine, white or slightly yellowish powder or irregular white masses which are

readily reducible to powder, creaks when pressed between the fingers; odorless and tasteless.

Empirical formula:

(C6 H10 O5) n

Where n= 300-1000.

Functional category:

Glidant, tablet and capsule diluents; tablet and capsule disintegrant; tablet binder.

Applications in Pharmaceutical Formulation Technology

Starch is used as an excipient primarily in oral solid –dosage formulations where it is

utilized as a binder, diluents, and disintegrant. As diluent, starch is used for the preparation of

standardized triturates of colarants or potent drugs to facilitate subsequent mixing or blending. In

tablet formulations, freshly prepared starch paste is used at a concentration of 5-25% w/w in

tablet granulation as a binder. Starch is one of the most commonly used tablet disintegrants at

concentrations of 3-15%w/w. Starch is also used in topical preparations such as dusting powders,

oinment,starch mucilage also been applied to skin as an emollient, and also in the treatment of

iodine poisonings.

Contamination of surgical wounds with the starch glove powder used by surgeons has

also resulted in the development of granulomatous lesions. Allergic reactions to starch are

extremely rare and individuals apparently allergic to one particular starch may not experience

adverse effects with a starch from a different botanic source. LD50 (mouse, IP): 6.6 g/kg

CROSCARMELLOSE SODIUM

1. Nonproprietary Name: Croscarmellose sodium

2. Synonyms:

Ac-di-sol; carmellosum natricum conexum; Crosslinked carboxymethylcellulose sodium;

Explocel:modified cellulose gum; Nymcel ZSX; Pharmacel XL; Primellose; Solutab; Vivasol.



3. Chemical Name: Cellulose, carboxy methyl ether, sodium salt.

4. Functional Category: Tablet and capsule disintegrant.

5. Description: Croscarmellose sodium occurs as an odorless, white or grayish-white powder.

6. Solubility:

Insoluble in water, although Croscarmellose sodium rapidly swells to 4-8 times its original

volume on contact with water. Practically insoluble in acetone, ethanol and toluene.

7. Stability and Storage Conditions:

Croscarmellose sodium is a stable though hygroscopic material. A model tablet formulation

prepared by direct compression, with Croscarmellose sodium as a disintegrant, showed no

significant difference in drug dissolution after storage at 3000C for 14 months. Croscarmellose

sodium should be stored in a well closed container in a cool, dry place.

8. Incompatibilities:

The efficacy of disintegrant such as Croscarmellose sodium, may be slightly reduced in tablet

formulations prepared by either the wet-granulation or direct compression process that contain

hygroscopic excipients such as sorbitol. Croscarmellose Sodium is not compatible with strong

acids or with soluble salts of iron and some other metals such as aluminum, mercury and zinc.

9. Applications:

Croscarmellose sodium is used in oral pharmaceutical formulations as a disintegrant for

capsules, tablets and granules. In tablet formulations, Croscarmellose sodium may be used in

both direct-compression and wet-granulation processes. When used in wet granulations, the

Croscarmellose sodium should be added in both the wet and dry stages of the process (intra and

extra- granularly) so that the wicking and swelling ability of the disintegrant is best utilized.

Croscarmellose sodium at concentrations up to 5% w/w may be used as tablet disintegrant,

although normally 2% w/w is used in tablets prepared by direct compression and 3%w/w in

tablet prepared by wet granulation process.

10. Related Substances: Carboxy methyl cellulose calcium: Carboxy methyl cellulose sodium.

SODIUM STARCH GLYCOLATE (SSG)

1. Synonyms:



Explotab; Primogel; Vivastar. Carboxymethyl starch, sodium salt.

2. Chemical Name:

Sodium carboxymethyl starch.

3. Description:

It is a white or almost white free-flowing very hygroscopic powder. The PhEur states that when

examined under a microscope it is seen to consist of: granules irregularly shaped, ovoid or pear-

shaped, 30–100 mm in size, or rounded,10–35 mm in size; compoundgranules consisting of 2–4

components occur occasionally; the granules have an eccentric hilum and clearly visible

concentric striations. Between crossed nicol prisms, the granules show a distinct black cross

intersecting at the hilum; small crystals are visible at the surface of the granules. The granules

how considerable swelling in contact with water.

4. Functional Category:

Tablet and capsule disintegrant.

5. Solubility:

Practically insoluble in water and insoluble in most organic solvents.

6. Incompatibilities:

Sodium starch glycolate is incompatible with ascorbic acid.

7. Stability and Storage Conditions:

Tablets prepared with sodium starch glycolate have good storage properties.Sodium starch

glycolate is stable although very hygroscopic, and should be stored in a well-closed container in

order to protect it from wide variations of humidity and temperature, which may cause caking.

The physical properties of sodium starch glycolate remain changed for up to 3 years if it is stored

at moderate temperatures and humidity

8. Applications in Pharmaceutical Formulation :

Sodium starch glycolate is widely used in oral pharmaceuticals as a disintegrant in capsule and

tablet formulations. It is commonly used in tablet prepared by either direct compression or wet

granulation processes.

POVIDONE



Nonproprietary Name: Povidone

Synonyms: Kollidon; plasdone; polyvinylpyrrolidone

Chemical Name: 1-Ethenyl-2-pyrrolidinone homopolymer

Empirical Formula: (C6H9NO) n

Molecular Weight: 2500–3 000 000

Functional Category: Disintegrant; dissolution enhancer; suspending agent; tablet binder.

Description: Povidone occurs as a fine, white to creamy-white colored, odorless or almost

odorless, hygroscopic powder. Povidone with K-values equal to or lower than 30 are

manufactured by spray-drying and occur as spheres. Povidone K90 and higher K value povidone

are manufactured by drum drying and occur as plates.

Solubility: Freely soluble in acids, chloroform, ethanol (95 %), ketones, methanol, and water;

practically insoluble in ether, hydrocarbons, and mineral oil.

Stability and Storage Conditions: Povidone darkens to some extent on heating at 150°C, with a

reduction in aqueous solubility. It is stable to a short cycle of heat exposure around 110–130°C.

Povidone may be stored under ordinary conditions without undergoing decomposition or

degradation. As the powder is hygroscopic, it should be stored in an airtight container in a cool,

dry place.

Incompatibilities: Povidone is compatible in solution with a wide range of inorganic salts,

natural and synthetic resins, and other chemicals. It forms molecular adducts in solution with

sulfathiazole, sodium salicylate, salicylic acid, phenobarbital, tannin, and other compounds.

Applications: Although povidone is used in a variety of pharmaceutical formulations, it is

primarily used in solid-dosage forms. It is used as a tablet binder, tablet diluent or coating agent

in the concentration of 0.5-5 %. Povidone is used as a suspending and dispersing agent in the

concentration of 5 %



FORMULATION OF SUSTAIN RELEASE TABLET FOR 10 TABLETS

INGREDIENTS (mg) F1 F2 F3 F4 F5 F6

Capecitabine 1500 1500 1500 1500 1500 1500

Hydroxy Propyl Methyl

Cellulose

300 - - 225 - 225

Ethyl Cellulose - 300 - 225 225 -

Guar Gum - - 300 - 225 225

Microcrystalline

Cellulose

900 900 900 700 700 700

Talc 75 75 75 75 75 75

Starch 150 150 150 150 150 150

Magnesium Stearate 75 75 75 75 75 75

TOTAL 3000 3000 3000 3000 3000 3000

FORMULATION OF IMMIDIATE RELEASE TABLET FOR 10 TABLETS

INGREDIENTS (mg) F1 F2 F3 F4 F5 F6

Metoclopramide 100 100 100 100 100 100

Croscarmellose Sodium 100 100 - - 150 150

SodiumStarch Glycolate

(Ssg)

- - 100 100 - -

Starch 100 - 100 - 100 -

Povidone - 100 - 100 - 100

Talc 50 50 50 50 50 50



Magnesium Stearate 50 50 50 50 50 50

Microcrystalline

Cellulose

1600 1600 1600 1600 1550 1550

TOTAL 2000 2000 2000 2000 2000 2000

METHODOLOGY

PREFORMULATION STUDIES

Preparation of linearity plot of Capecitabine in distilled water

Determination of λ max of Capecitabine in distilled water

Capecitabine was dissolved in distilled water and the λmax was obtained at 303 nm against

the blank primary stock solution concentration of Capecitabine 1000 µg/ml was prepared.

All measurements were made at room temperature.

Standard Stock solution: 10 mg of Capecitabine was dissolved in 10 ml distilled water to give a

concentration of (1000 μg/ml)

Scanning: From the stock solution 1000μg/ml was prepared in distilled water and UV scan was

taken between 200 to 400 nm. The absorption maximum was found to be 303 nm and was used

for the further analytical studies.

Calibration curve of Capecitabine in distilled water

The standard solutions were prepared by proper dilutions of the primary stock solution with

absolute distilled water to obtain working standards in the concentration range of 2-10µg/ml

of pure sample of Capecitabine. The concentration of Capecitabine present in the

microspheres was obtained from the calibration curve.

Construction of Standard Graph of Metaclopramide (0.1 N Hcl)

Preparation of stock solution:



Accurately weighed amount of 10 mg was transferred into a 10 ml volumetric flask. Few

ml of water was added to dissolve the drug and volume was made up to 100 mL with 0.1 N Hcl .

The resulted solution had the concentration of 1mg/ml which was labeled as ‘stock’.

Preparation of working standard solution:

From this stock solution 10ml was taken and diluted to 100 mL with 0.1 N Hcl which has

given the solution having the concentration of 1000 mcg/mL.

Preparation of serial dilutions for standard calibration curve:

Necessary dilutions were made by using this second solution to give the different

concentrations of metaclopramide (5-35mcg/mL) solutions

The absorbances of above solutions were recorded at max (257nm) of the drug using

double beam UV-Visible spectrophotometer. Standard graph was plotted between the

concentration (on X-axis) and absorbance (on Y-axis).

Drug – Excipient Compatibility Study:

FTIR Studies

FTIR studies were performed on drug and the optimized formulation using Shimadzu

FTIR (Shimadzu Corp., India). The samples were analyzed between wavenumbers 4000 and 400

cm-1.

FORMULATION DEVELOPMENT

The pharmaceutical development studies have to be carried out with the purpose of selecting

right dosage form and a stable formulation. These studies give detailed description of all the

steps involved in the process of formulation development. Such details are intended towards

identifying critical parameters involved in the process, which have to be controlled in order to

give reliable and reproducible quality product.

Formulation of Bilayer Matrix Tablet (Sustained Release Layer)



The sustained release tablets containing 5mg Metaclopramide were prepared with a total tablet

weight of 350mg.

Manufacturing Procedure

Micro crystalline cellulose, Maize starch and different polymers were weighed and sifted

through 40 mesh according to the formulation table.

To the above blend Metaclopramide was added and sifted through 18 mesh.

The sifted materials were mixed for 10min.

Magnesium Stearate and talc was weighed and sifted through 40 mesh.

To the above mixture lubricated blend was added and mixed properly.

Then the blend was compressed using 9mm round punches.

DIRECT COMPRESSION FOR IMMEDIATE LAYER

All the ingredients were passed through sieve and mixed in a motor and pestle for 30min for

uniform mixing. The addition of ingredients was done in a geometrical manner. Then the

capecitabine layer was compressed using 8mm round punch.

BILAYERED TABLET PUNCH

After the batch was optimized in both immediate release layer ( F8) and sustained release layer

(F5).The optimized batch in both was compressed by using same ingredients.

Evaluation of Precompression Blend

Flow Properties:

Angle of Repose8:

The flow property was determined by measuring the Angle of Repose. In order to

determine the flow property, the Angle of Repose was determined. It is the maximum angle that

can be obtained between the free standing surface of a powder heap and the horizontal.

Angle of repose= tan-¹ (h/r)



where,

h = height of a pile (2 cm)

r = radius of pile base.

Procedure:

20gms of the sample was taken

The sample was passed through the funnel slowly to form a heap.

The height of the powder heap formed was measured.

The circumference formed was drawn with a pencil on the graph paper.

The radius was measured and the angle of repose was determined. This was repeated three

times for a sample.

Bulk density8:

Bulk density is ratio of given mass of powder and its bulk volume. Bulk density was

determined by measuring the volume of known mass of powder sample that has been passed

through the screen in to graduated cylinder or through volume measuring apparatus in to cup.

Bulk density = M / V0

Where M= mass of the powder;

V0=bulk volume of the powder.

Limits:

It has been stated that the bulk density values having less than 1.2 g/cm3 indicates good packing

and values greater than 1.5 g/cm3 indicates poor packing.



Tapped density8:

A known quantity of powder was transferred to a graduated cylinder and volume V0 was

noted.The cylinder fixed to a density determination apparatus, tapped for 500 times then reading was

observed. The density is achieved by mechanically tapped by a measuring cylinder containing

the powder sample. After observing the initial volume the cylinder is mechanically tapped and

volume reading were taken until little further volume changes is observed.

Tap density = M / Vr

Where M = mass of the powder,

Vr = final tapping volume of the powder.

Compressibility index and Hausner ratio:

The compressibility index and hausner ratio may be calculated using measured values of bulk density and tapped density as follows:

Compressibility index = 100 × tapped density / bulk density

Hausner ratio = tapped density / bulk density

Flow properties and corresponding Angle of repose, Compressibility index and Hausner ratio:

TABLE NO. : ACCEPTANCE CRITERIA OF FLOW PROPERTIES

S. No Flow properties Angle of repose(θ) Compressibility Index (%) Hausner ratio



1. Excellent 25-30 <10 1.00-1.11

2. Good 31-35 11-15 1.12-1.18

3. Fair 36-40 16-20 1.19-1.25

4. Passable 41-45 21-25 1.26-1.34

5. Poor 46-55 26-31 1.35-1.45

6. Very poor 56-65 32-37 1.46-1.59

7. Very very poor > 66 >38 >1.6

EVALUATION OF TABLETS:

The quantitative evaluation and assessment of a tablets chemical, physical and bioavailability

properties are important in the design of tablets and to monitor product quality. There are various

standards that have been set in the various pharmacopoeias regarding the quality of

pharmaceutical tablets. These include the diameter, size, shape, thickness, weight, hardness,

Friability and invitro-dissolution characters.

1. Physical Appearance:

The general appearance of a tablet, its identity and general elegance is essential for consumer

acceptance, for control of lot-to-lot uniformity and tablet-to-tablet uniformity. The control of

general appearance involves the measurement of size, shape, color, presence or absence of

odour, taste etc.

2. Size & Shape:

It can be dimensionally described & controlled. The thickness of a tablet is only variables. Tablet

thickness can be measured by micro-meter or by other device. Tablet thickness should be

controlled within a ± 5% variation of standard value.

3. Weight variation test:

This is an in process quality control test to ensure that the manufacturers control the variation in

the weight of the compressed tablets, different pharmacopoeia specify these weight variation



tests.. These tests are primarily based on the comparison of the weight of the individual tablets

(xi) of a sample of tablets with an upper and lower percentage limit of the observed sample

average (x-mean). The USP has provided limits for the average weight of uncoated compressed

tablets. These are applicable when the tablet contains 50mg or more of the drug substance or

when the latter comprises 50% or more, by weight of the dosage form.

Method:

Twenty tablets were weighed individually and the average weight was calculated. The individual

tablet weights are then compared to the average weight. Not more than two tablets should differ

in their average weight by more than percentages stated in USP. No tablet must differ by more

than double the relevant percentage.

Table 8: Limits for Tablet Weight variation test:

Average weight of tablet (mg) % Difference allowed

130 or less 10 %

From 130 to 324 7.5 %

> 324 5 %

Friability8:

Friction and shock are the forces that most often cause tablets to chip, cap or break. The friability

test is closely related to tablet hardness and designed to evaluate the ability of the tablet to

withstand abrasion in packaging, handling and shipping. It is usually measured by the use of the

Roche friabilator.

Method:

A number of tablets are weighed and placed in the apparatus where they are exposed to rolling

and repeated shocks as they fall 6 inches in each turn within the apparatus. After four minutes of



this treatment or 100 revolutions, the tablets are weighed and the weight compared with the

initial weight. The loss due to abrasion is a measure of the tablet friability. The value is

expressed as a percentage. A maximum weight loss of not more than 1% of the weight of the

tablets being tested during the friability test is considered generally acceptable and any broken or

smashed tablets are not picked.

The percentage friability was determined by the formula:

% loss = [(Initial wt. of tablets –

Final wt. of tablets)/ Initial wt. of tablets] ×100

(OR)

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

W1 = Weight of tablets before test

W2 = Weight of tablets after test

Thickness:

The thickness of the tablets was measured by vernier calipers. It is expressed in mm.

FORMULATION IR SR

F1 3.33 3.82

F2 3.28 3.88

F3 3.37 3.80

F4 3.41 3.90

F5 3.28 3.74



F6 3.59 3.78

IR: Immediate Release, SR: Sustain Release

Hardness:

Tablets require a certain amount of strength or hardness and resistance to friability, to withstand

mechanical shocks of handling in manufacture, packing and shipping. The hardness of tablet was

measured by Monsanto hardness tester. The tablets from each batch were used for hardness

studies and results are expressed in Kg/cm2.

HARDNESS (Kg/cm2 )

FORMULATION IR SR

F1

F2

F3

F4

F5

F6

AVG

IR: Immediate Release, SR: Sustain Release

DISSOLUTION STUDIES

In vitro Dissolution Studies for sustained release layer of capecitabine

TIME (Hrs)

FORMULATIONS (% OF RELEASE)

F1 F2 F3 F4 F5 F6

0 0 0 0 0 0 0

1/2 27.85 33.35 26.65 10.28 10.56 8.78

01 40.71 61.71 29.35 17.35 10.71 11.14

02 46.71 77.14 44.35 18.20 11.40 12.08



03 51.73 77.78 52.92 19.51 13.02 13.96

04 56.78 79.71 54.42 20.78 15.00 15.42

05 57.11 81.11 56.78 21.60 18.06 18.67

06 60.12 82.29 57.22 22.89 19.14 19.39

07 62.59 85.11 59.16 24.12 21.29 22.12

08 65.24 86.97 64.28 25.99 23.00 23.59

09 68.18 88.11 65.24 27.12 24.12 25.92

10 71.32 92.51 67.34 28.75 25.92 26.78

11 76.15 96.50 71.34 30.12 27.22 28.92

12 79.51 97.79 75.32 32.24 28.96 29.34

16 - - - 38.14 35.11 37.12

20 - - - 45.42 41.24 42.26

24 - - - 52.33 46.78 44.51

In vitro drug release studies were carried out using USP XXIV dissolution apparatus

type II, with 900ml of dissolution medium maintained at 37±1°C for 24 hr, at 50 rpm, distilled

water was used as a dissolution medium. 5ml of sample was withdrawn at predetermined time

intervals replacing with an equal quantity of drug free dissolution fluid. The samples withdrawn

were filtered through 0.45µ membrane filter, and drug release in each sample was analyzed after

suitable dilution by UV/Vis Spectrophotometer at 303nm.

In vitro Dissolution Studies for immediate release layer of Metaclopramide

TIME

(Min)

FORMULATIONS (% OF RELEASE)

F1 F2 F3 F4 F5 F6

0 0 0 0 0 0 0

05 40.40 19.51 21.44 19.30 23.80 17.58

10 42.31 24.87 35.88 26.94 34.02 29.45

15 45.53 3.52 44.34 35.95 47.53 38.24

20 48.18 40.31 48.82 42.96 54.61 48.25



25 50.11 44.53 50.82 45.52 62.11 58.63

30 54.22 54.18 54.72 50.25 73.39 65.32

35 62.11 59.12 61.12 58.39 79.84 67.82

40 72.41 68.11 67.11 66.11 88.88 76.32

45 79.42 74.59 72.32 73.22 97.37 88.32

50 86.22 82.33 84.11 86.12 - 95.14

55 93.54 88.11 91.09 87.11 - 98.59

60 98.78 95.59 97.34 94.32 - -

In vitro drug release studies were carried out using USP XXIV dissolution apparatus

type II, with 900ml of dissolution medium maintained at 37±1°C for 1 hr, at 50 rpm, 0.1 N HCl

was used as a dissolution medium.5ml of sample was withdrawn at predetermined time

intervals replacing with an equal quantity of drug free dissolution fluid. The samples withdrawn

were filtered through 0.45µ membrane filter, and drug release in each sample was analyzed after

suitable dilution by UV/Vis Spectrophotometer at 257 nm.

REFERENCE

1. Priyamvada barthwal*, g ganarajan and preeti kothiyal bilayer: a review international

journal of pharmaceutical and chemical sciences issn: 22775005.

2. Balaji G*,Ggnana prakash k, bilayer tablet: a review , international journal of research

and reviews in pharmacy and applied science.

3. Singh KP and Kumar S. Bilayer and Floating Bioadhesive Tablets: Innovative Approach

To Gastroretention. Journal of Drug Delivery and Therapeutics. 2011;1(1):32-35.



4. Kulkarni A and Bhatia M. Developments And Evaluation Of Bilayer Floating Tablets Of

Atenolo And Lovastatin For Biphasic Release Profile, Iranian Journal of Pharmacy and

Research. 2009; 8(1);15 -25.

5. Shaikh TK, Gadhave MV and Jadhav SL. Different Techniques In Bilayer Tablets : A

Review., International Journal of Universal Pharmacy And Life Sciences. 2012;1(1):1-8.

6. Rohan D. Deshpande et al, bi-layer tablets- an emerging trend: a review, IJPSR, 2011;

Vol. 2(10): 2534-2544.

7. Motarwar s.s.*, jadhav s.b. ,kadam v. S. , muttepawar s.s, bharkad v.b.,Md. Zamiruddin,

review on - bilayer tablet, world journal of pharmacy and pharmaceutical science.

8. Banker GS, Rhodes CT,1995, Modern pharmaceutics. 3rded.,Marcel deccker . (2):21.

9. B. Nilesh, et al., 2010. physiology of pain (chapter 3), International Association for

the study of pain.

10. Panchal H, et al. 2012, A novel approaches of bilayer tablet technology: a review.

A.Pharm.J.Res.8, 3(2).

11.Chaudhari S, Divya A, 2009 Bilayer tablet technology; an overview, J. of Applied

Pharma.Sci.,01(08).

12.Vyas S P, Khar R K, 2005, Controlled drug delivery and advances,1 st

edition.delhi, Vallabh prakashan.

13.Lachmann and Liebermann, 1991,The theory and practice of industrial

pharmacy.3rd Indian edition, , pages.293- 294, 325-9.) .

14.Habeeb MD, Vasanth PM, Suresh K, et al., 2012, Formulation and evalution of

bilayer sustained release tablet of Tramadol HCl by using natural and synthetic

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