STUDIES ON DISSOLUTION RATE ENHANCEMENT OF NIFEDIPINE AND DEVELOPMENT OF CONTROLLED

RELEASE MATRIX TABLETS OF NIFEDIPINE DISPERSIONS

Dissertation submitted toThe Acharya Nagarjuna University, Nagarjuna Nagar,

In partial fulfillment for the award of degree of

BACHELOR OF PHARMACY

By

PRATHYUSHA. G (Y5PH935)

Under the Guidance ofDr. S. Vidyadhara, M. Pharm., Ph.D.,

Professor and Principal.

APRIL 2009

CHEBROLU HANUMAIAHINSTITUTE OF PHARMACEUTICAL SCIENCES

GUNTUR- 19

CERTIFICATE

This is the bonafide dissertation work on “studies on Dissolution Rate Enhancement

of Nifedipine and Development of Controlled Release Matrix Tablets of Nifedipine

Dispersions” by Leena. A, Pavanaraghava. G, Prathyusha. G and Sireesha. K The work

mentioned in this dissertation was carried out at Chebrolu Hanumaiah Institute of

Pharmaceutical Sciences, under the supervision of Dr. S. Vidyadhara, M.Pharm.,Ph.D.,

Professor and Principal.

Dr. S. Vidyadhara, M.Pharm.,Ph.D., Professor and Principal,

Chebrolu Hanumaiah Institute of Pharmaceutical Sciences, Guntur- 19.

CERTIFICATE

This is the bonafide dissertation work on “studies on Dissolution Rate Enhancement

of Nifedipine and Development of Controlled Release Matrix Tablets of Nifedipine

Dispersions” has been carried out by Leena. A, Pavanaraghava. G, Prathyusha. G and

Sireesha. K in Chebrolu Hanumaiah Institute of Pharmaceutical Sciences, under my

guidance and supervision.

Dr. S. Vidyadhara, M.Pharm.,Ph.D., Professor and Principal, Chebrolu Hanumaiah Institute of Pharmaceutical Sciences, Guntur- 19.

DECLARATION

We here by declare that the work incorporated in this dissertation has been carried out

at Chebrolu Hanumaiah Institute of Pharmaceutical Sciences, Guntur, A.P, India. The work is

original and has not been submitted in part or full for any other diploma or degree of this or

any other university.

Place: GunturDate: Leena. A (Y5PH922)

PavanaRaghava. G (Y5PH932)

Prathyusha. G (Y5PH935)

Sireesha. K (Y5PH944)

Acknowledgement

It is our pleasant duty to express my deep sense of gratitude and indebtedness to my

beloved research guide Mr. R. L. C. Sasidhar, M. Pharm., Lecturer, Chebrolu Hanumaiah

Institutte of Pharmaceutical sciences, who have suggested and guided all through the work

but also kept my spirit high up with their valuable suggestions and constant encouragement.

We express my sincere thanks and gratitude to our Principal Dr. S. Vidyadhara for

providing all the resources to complete this work successfully.

We are thankful to Dr. k. Basavapunnaiah, President, CHIPS, Dr.M. GopalKrishna,

Secretary and Correspondent, CHIPS, Sri. CH. Narendranath, Vice president, CHIPS and

other members of Nagarjuna Educational Society, Guntur, for their encouragement in

research work.

We are greatly indebted to Sri. J. Ramesh Babu, Sri. R. Rambabu, Sri. A. Ramu, Sri.

S. Siva Prasad and all other staff members for giving their valuable suggestions for successful

completion of my project work.

It is our pleasure to express my warm regards and wishes to my friends M. Nagasree,

Navya.k and P. Chandana for their help and co-operation during my work.

We express our special thanks to Mr. P. Kishore, Mrs. CH. Uma Devi and other non

teaching staff for their help during my work.

We conclude my acknowledgement by regarding my deep sense of affection to my

beloved family for their encouragement and cheerful company throughout this endeavor,

without which this work would not have been completed in stipulated period.

Leena. A (Y5PH922) PavanaRaghava. G (Y5PH932) Prathyusha. G (Y5PH935) Sireesha. K (Y5PH944)

DEDICATED TO MY

FAMILY

CONTENTS

Pg No:

CHAPTER 1: Introduction

CHAPTER 2: Literature Review

CHAPTER 3: Materials and Methods

CHAPTER 4: Experimental Results

CHAPTER 5: Discussion of Results

CHAPTER 6: Summary and Conclusions

CHAPTER 7: References

CHAPTER I

INTRODUCTION

INTRODUCTION

The bioavailability of most of the drugs depends on dissolution rate and these inturn

depend on particle size1. The rate of absorption depends on concentration gradient which is

done by increasing dissolution rate and is seen in drugs with limited solubility.

The particle size plays an important role in parentral therapy 23.Absorption of drugs

appears to increase with increase in surface area. The viscosity of suspensions increase with

decrease in particle size and leads to delayed absorption.

In semisolids improved dissolution rate leads to greater bioavailability and absorbed

in to the systemic circulation, The size of droplets governs the deposition of respiratory track

in inhalation therapy.

Particle size reduction is achieved by

1. Conventional trituration and grinding.

2. Ball milling.

3. Fluid energy micronization.

4. Controlled precipitation by change of liquid solvents or temperature.

5. Administration of liquid solutions from which, up on dilution with gastric

fluids, the dissolved drug may precipitate in very fine particles.

6. Administration of water soluble salts of poorly soluble compounds from

which the parent neutral forms may precipitate in ultramarine form in GI fluids.

Theoritically, the solvent method seems to be an ideal approach to achieve particle

size reduction. How ever it is not frequently employed in the commercial market due to such

reasons as selection of noin toxic solvets, limitation of drugs with loow dose and the high

cost of production.

A unique approach of solid dispersion is to reduce the particle size and to increase the

rate of dissolution and absorption was first demonstrated in 1961. In addition to absorption

enhancement the solid dispersion technique has numerous othe pharmaceutical applications

such as homogenous distribution of a small amount of drugs at solid state, to stabilize

unstable drugs, to dispense liquid or gaseous compounds, to formulate a fast releasing

promising dose in a sustained release regimen of soluble drugs by using a poorly soluble or

insoluble carriers.

DEFINITION: It is a science of dispersing one or more active ingredients in an inert matrix

using in the solid state in order to achieve increased dissolution rate, sustained release of

drugs, altered solid state properties and enhances release of drugs from ointment and

suppository bases and improves solubility and stability.

TYPES OF SOLID DISPERSIONS:

Simple eutectic mixtures: An eutectic mixture of a sparingly water soluble drug and a

highly water soluble carrier may be regarded thermodynamically as an intimately blended

physical mixture of its two crystalline components. The increasing surface area is responsible

for increased rate of dissolution.

Solid solutions: The solid solution consists of a solid solute dissolved in a solid solvent. A

mixed crystal is formed because the two components crystallise together in a homogenous

one phase system. Hence this system would expect to yield much higher rate of dissolution

than simple eutectic systems.

Glass solutions of suspensions: It is a homogenous system in which a glassy or a

vitreous of the carrier solubilises drug molecules in its matrix. PVP dissolved in organic

solvents undergoes a transition to a glassy state up on evaporation of the solvent

.

Compound or complex formation: This system is characterised by complexation of

two components in a binary system during solid dispersion preparation. The availability of

the drug from the complex depends up on the solubility, dissociation constant and intrinsic

absorption rate of the complex.

Amorphous precipitation: It occurs when the drug precipitates as an amorphous form

in the inert carrier. The high energy state of the drugs in this system generally produces much

greater dissolution rates than the corresponding crystalline forms of the drugs.

INTRODUCTION TO CONTROLLED RELEASE DRUG DELIVERY

SYSTEMS

During the past 30 years as the expenses and complications involved in marketing new drug

entities have increased, with concomitant recognition of the therapeutic advantages of

controlled drug delivery, greater attention has been focused on the development of

controlled-release drug delivery systems (CRDDS). There are several reasons for the

attractiveness of these dosage forms. It is generally recognized that for many disease states, a

substantial number of therapeutically effective compounds already exist. The effectiveness of

these drugs, however, is often limited by side effects or the necessity to administer the

compound in a clinical setting. The goal in designing controlled release systems is to reduce

the frequency of dosing or to increase effectiveness of the drug by localization at the site of

action, reducing the dose required or providing uniform drug delivery.

An Ideal drug delivery system must have two prerequisites

1) It would be a single dose for the duration of treatment, whether it be for days or weeks

as with infection or for the lifetime of the patient as in hypertension or diabetes.

2) It should deliver the active entity directly to the site of action, thereby minimizing or

eliminating side effects. This may necessitate delivery to specific receptors or to

localization to cells or to specific areas of the body.

Thus the controlled delivery attempts to deliver the therapeutic agent to a specific site, for a

specific time. In other words, the objective is to achieve both spatial and temporal placement

of drug. Currently, it is possible to only partially achieve both of these goals, with most drug

delivery systems.

Advantages and disadvantages of controlled release systems

Advantages:

1. Decreased incidence and/or intensity of adverse effects and toxicity

2. Better drug utilization.

3. Controlled rate of release

4. More uniform blood concentrations.

5. Improved patient compliance.

6. Reduced dosing frequency.

7. More consistent and prolonged therapeutic effect.

8. A greater selectivity of pharmacological activity.

Disadvantages:

1. Increased variability among dosage units.

2. Stability problems.

3. Toxicity due to dose dumping.

4. Increased cost

5. More rapid development of tolerance.

6. Need for additional patient education and counseling.

Characteristics of drugs suitable for controlled release:

1. Uniform absorption throughout the gastrointestinal tract (GIT)

2. Administered in relatively small doses.

3. Possess a good margin of safety.

4. For the treatment of chronic therapy.

Characteristics of drugs unsuitable for controlled release

1. Not effectively absorbed in the lower intestine (riboflavin)

2. Absorbed and excreted rapidly, short biological half lives <1 hr (penicillin G,

furosemide)

3. Long biological half-lives > 12 hr (diazepam, phenytoin)

4. Large doses required. 1 g (sulfonamides)

5. Drugs with low therapeutic index (Phenobarbital, digoxin)

6. Precise dosage titrated to individuals required (anticoagulants, cardiac glycosides)

7. No clear advantages for sustained release formulation (griseofulvin)

TYPES OF CONTROLLED DRUG DELIVERY SYSTEMS

Controlled drug delivery systems are broadly classified as follows.

Oral controlled release systems

Targetted delivery systems

Dental systems

Ocular systems

Transdermal systems

Vaginal and Uterine systems

Injections and Implants.

Oral controlled-release systems

The majority of oral controlled release systems rely on dissolution, diffusion or a

combination of both mechanisms, to generate slow release of drug to the gastro intestinal

tract.

1) Dissolution-controlled systems: Controlled release preparations of drugs could be made

by decreasing their rate of dissolution. The approaches to achieve this include, preparation of

appropriate salts or derivatives, coating the drug with a slowly dissolving material or

incorporating it into a tablet with a slowly dissolving carrier.

Dissolution controlled systems can be made in several different ways. By alternating

layers of drug with rate controlling coats, a pulsed delivery can be achieved If the outer layer

is a quickly releasing bolus of drug, initial levels of drug in the body can be quickly

established with pulsed intervals following. An alternative method is to administer the drug

as a group of beads that have coatings of different thicknesses. Since the beads have different

coating thicknesses, their release will occur in a progressive manner. Those with the thinnest

layers will provide the initial dose. The maintenance of drug levels at later times will be

achieved from those with thicker coatings. This is the principle of the spansuIe technology or

micro encapsulation.

2) Diffusional systems: Diffusion systems are characterized by the release rate of a drug

being dependent on its diffusion through an inert membrane barrier usually, this barrier is

an insoluble polymer In general, two types of diffusional systems are recognized. They are

reservoir devices and matrix devices.

a) Reservoir devices: Reservoir devices are characterized by a core of drug, the reservoir

surrounded by a polymeric membrane. The nature of the membrane determines the rate of

release of drug from the system

The advantages of reservoir diffusional systems are zero-order delivery is possible

and release rate variable with polymer type The disadvantages of reservoir diffusional

systems are system must be physically removed from implant sites, difficult to deliver high-

molecular weight compounds, generally increased cost per dosage unit and potential toxicity

if the system fails.

b) Matrix devices: A matrix device consists of drug dispersed homogeneously

throughout a polymer matrix. In this model, drug in the outside layer exposed to the bathing

solution is dissolved first and then diffuses out of the matrix. This process continues with the

interface between the bathing solution and the solid drug moving towards the interior.

Obviously, for this system to be diffusion controlled, the rate of dissolution of drug particles

within the matrix must be much faster than the diffusion rate of dissolved drug leaving the

matrix.

3) Bioerodible and combination of diffusion and dissolution systems: These systems can

combine diffusion and dissolution of both the matrix material and the drug. Drug not only can

diffuse out of the dosage form, as with some previously described matrix systems but the

matrix itself undergoes a dissolution process. The complexity of the system arises from the

fact that as the polymer dissolves; the diffusional path length for the drug may change. This

usually results in a moving boundary diffusion system. Zero-order release can occur only if

surface erosion occurs and surface area does not change with time. The inherent advantage of

such a system is that the bioerodible property of the matrix does not result in a ghost matrix

and removal from implant sites is not necessary. The disadvantages of this system include,

difficulty to control kinetics owing to multiple processes of release, potential toxicity of

degraded polymer must be considered.

Another method of bioerodible systems is to attach the drug directly to the polymer by

a chemical bond 4 generally, the drug is released from the polymer by hydrolysis or

enzymatic reaction.

A third type, which in this case utilizes a combination of diffusion and dissolution. is

that of a swelling-controlled matrix 5Here the drug is dissolved in the polymer but instead of

an insoluble or eroding polymer, as in previous systems, swelling of the polymer occurs This

allows entrance of water, which causes dissolution of the drug and diffusion out of the

swollen matrix In these systems the release rate is highly dependent on the polymer-swelling

rate, drug solubility and the amount of soluble fraction in the matrix 6 This system usually

minimizes burst effects, since polymer swelling must occur before drug release.

4) Osmotically controlled systems: In these systems, osmotic pressure provides the driving

force to generate controlled release of drug. Consider a semi permeable membrane that is

permeable to water, but not to drug. A tablet containing a core of drug surrounded by such a

membrane and when this device is exposed to water or any body fluid, water will flow into

the tablet owing to the osmotic pressure difference.

These systems generally appear in two different forms. The first one contains the drug

as a solid core together with electrolyte, which is dissolved by the incoming water. The

electrolyte provides the high osmotic pressure difference. The second system contains the

drug in solution in an impermeable membrane within the device. The electrolyte surrounds

the bag. Both systems have single or multiple holes bored through the membrane to allow

drug release. In the first example, high osmotic pressure can be relieved only by pumping

solution, containing drug, out of the hole Similarly in the second example, the high osmotic

pressure causes compression of the inner membrane and drug is pumped out through the hole.

The advantages of osmotically controlled devices are, zero-order release is obtainable

Reformulation is not required for different drugs and release of drug independent of the

environment of the system. The disadvantages of these systems include, systems can be much

more expensive than conventional counterparts, quality control is more extensive than

conventional tablets

5) Ion-exchange systems: Ion-exchange systems generally use resins composed of water-

insoluble, cross-linked polymers. These polymers contain salt-forming functional groups in

repeating positions on the polymer chain. The drug is bound to the resin and released by

exchanging with appropriately charged ions in contact with the ion-exchange groups.

Resin+ - drug - + X - resin+ - X - + drug -

Conversely,

Resin - - drug+ + Y+ resin - - Y+ + drug+

Where X- and Y+ are ions in the Gl tract. The free drug then diffuses out of the resin. The

drug-resin complex is prepared either by repeated exposure of the resin to the drug in a

chromatography column or by prolonged contact in solution.

The rate of drug diffusing out of the resin is controlled by the area of diffusion,

diffusional path length and rigidity of the resin, which is a function of the amount of cross-

linking agent used to prepare the resin.

This system is advantageous for drugs that are highly susceptible to degradation by

enzymatic processes, since it offers a protective mechanism by temporarily altering the

substrate This approach to controlled release, however, has the limitation that the release rate

is proportional to the concentration of the ions present in the area of administration

Although the ionic concentration of the Gl tract remains rather constant with limits, the

release rate of the drug can be affected by variability in diet, water intake and individual

intestinal content.

An improvement in this system is to coat the ion-exchange resin with a hydrophobia

rate-limiting polymer, such as ethyl cellulose or waxes 7These systems rely on the polymer

coat to govern the rate of drug availability.

6) pH - independent formulations: The granules are designed for the oral controlled

release of basic or acidic drugs at a rate that is independent of the pH in the Gl tract They

are prepared by mixing a basic or acidic drug with one or more buffering agents, granulating

with appropriate pharmaceutical excipients and finally coating with a gastrointestinal fluid

permeable film-forming polymer. When the Gl fluid permeates through the membrane, the

buffering agents adjust the fluid inside to a suitable constant pH, thereby rendering a constant

rate of drug release.

7) Altered density formulations: It is reasonable to expect that unless a delivery system

remains in the vicinity of the absorption site until most, if not all of its drug contents is

released, it would have limited utility. At this end, several approaches have been developed

to prolong the residence time of drug delivery systems in the Gl tract. One such approach is

the bioadhesion approach 8 which is based on the adherence of bioadhesive polymers to the

mucin/epithelial surface of the Gl tract. The other approach is to alter the formulation's

density by using either high or low density pellets.

a) High - density approach: In this approach, the density of the pellets must exceed that of

normal stomach content and should therefore be at least 1.4 9 In preparing such formulations,

drug can be coated on a heavy core or mixed with heavy inert materials such as barium

sulfate, titanium dioxide, iron powder and zinc oxide. The weighed pellet can then be covered

with a diffusion controlled membrane.

b) Low-density approach: Globular shells which have an apparent density lower than that of

gastric fluid can be used as a carrier of drug for controlled release purposes Polystyrol

poprice and even popcorn are all candidates as carriers The surface of these empty shells is

undercoated with sugar or with a polymeric material such as methacrylic polymer and

cellulose acetate phthalate. The undercoated shell is then coated by a mixture of drug with

polymers such as ethyl cellulose and hydroxypropylcellulose. The final product floats on the

gastric fluid for a prolonged period, while slowly releasing drug.

METHOD OF SOLID DISPERSION EMPLOYED IN THIS STUDY IS FUSION

METHOD:

In fusion method of preparation, the carrier is heated to a temperature just above its melting

point and the drug is incorporated into the matrix. The mixture is cooled with the constant

stirring to homogeneously disperse the drug through out the matrix. If the drug has high

solubility in the carrier, the drug could remain dissolved in the solid state, yielding a solid

solution. Particle size reduction leads to molecular dispersion of the drug in the carrier

matrix. These systems have high drug dissolution rates compared to control samples. If the

solubility of the drug in solid state is not so high, crystalinity of the drug become dispersed in

the matrix, such systems show moderate increase in the dissolution rates. A third mechanism

is the conversion of the drug to an amorphous form in the presence of matrix, exhibiting

different dissolution rates and solubility.

An important limitation of this method of preparation is the exposure of drugs to elevated

temperatures, particularly if the carrier is a high melting solid and the drug is heat sensitive.

The fusion method is less difficult method, provided the drug and the carrier are miscible in

the molten state.

CHARACTERIZATION OF SOLID DISPERSIONS

Thermo Microscopical Analysis: This is a visual method of analysis using a polarised

microscope with a hot state to determine the thaw and melting point of solids. Its dis

advantages are only small amount of sample required and direct observations of the changes

taking place in the samples through the thaw and melt stages. This technique has been used to

support DTA. 10, 11

Different Thermo Analysis (DTA): Differential heat changes that accompany

physical and chemical changes are recorded as a function of temperature as the substances is

heated at a uniform rate. In addition to thawing and melting polymorphic transitions,

evaporation, sublimation, dissovation and other types of changes such as decomposition of

the sample can be detected. DTA records energy changes ocuring in the sample as it is being

heated either exothermic or endothermic. DTA has been used routinely to identify types of

solid dispersions.12, 13

Power X-ray Diffusion: X- rays have been studied in crystal structure studies in two

different ways. 1) Single crystal X ray crystallography Dealing with the determination of

bond angles and inter atomic distances. 2)P Powder X- Ray diffraction dealing with the study

of crystal lattice parameters, where the X- Ray diffraction intensity from a sample is

measured as a function of the diffraction angles. Thus, changes in the diffraction pattern

indicate changes in crystal structure. The relationship between the wavelength of X- Ray and

angle of diffraction, distance between each set of atomic planes of crystal lattice is given by

the equation:

Mλ = 2dsinθ

M represents the order of diffraction x-ray spectra of simple eutectic system show peaks of

each crystalline component X- Ray diffraction can also be used in detecting complex

formation.

Dissolution methods: The rotating basket dissolution method was included as the first

official compendial diisolution test. The USPXX in 1980 included a modification of this

method and also introduced the paddle method as an official compendial test. The

disintegration test apparatus for dissolution has been deleted from the USPXXI.

ORAL CONTROLLED RELEASE SYSTEM ADOPTED FOR SOLID

DISPERSION PREPARATION IN THE PRESENT STUDY:

Bioerodible and Combination Diffusion and Dissolution Systems

Strictly speaking, therapeutic systems will never be dependent on dissolution only or

diffusion only.

However, in the foregoing systems, the predominant mechanism allows easy

mathematical description. In practice, the dominant mechanism for release will overshadow

other processes enough to allow classification as either dissolution rate-limited or diffusion-

controlled. Bioerodible devices, however, constitute a group of systems for which

mathematical descriptions of release characteristics can be quite complex. Characteristics of

this type of system are listed in typical system is shown in Figure. The mechanism of release

from simple erodible slabs, cylinders, and spheres has been described. A simple expression

describing release from all three of these erodible devices is

Where n = 3 for a sphere, n = 2 for a cylinder, and n =1 for a slab. The radius of a sphere, or

cylinder, or the half-height of a slab is represented by a. M t is the mass of a drug release at

time t, and M is the mass released at infinite time. As a further complication, these systems

can combine diffusion and dissolution of both the matrix material and the drug. Not only can

drug diffuse out of the dosage form, as with some previously described matrix systems, but

the matrix itself undergoes a dissolution process. The complexity of the system arises from

the fact that, as the polymer dissolves; the diffusional path length for the drug may change.

This usually results in a moving-boundary diffusion system. Zero-order release can occur

only if surface erosion occurs and surface area does not change with time. The inherent

advantage of such a system is that the bioerodible property of the matrix does not result in a

ghost matrix. The disadvantages of these matrix systems are that release kinetics are often

hard to control, since many factors affecting both the drug and the polymer must be

considered.

Another method for the preparation of bioerodible systems is to attach the drug

directly to the polymer by a chemical bond. Generally, the drug is released from the polymer

by hydrolysis or enzymatic reaction. This makes control of the rate of release somewhat

easier. Another advantage of the system is the ability to achieve very high drug loading, since

the amount of drug placed in the system is limited only by the available sites on the carrier.

A third type, which in this case utilizes a combination of diffusion and dissolution, is

that of a swelling-controlled matrix. Here the drug is dissolved in the polymer, but instead of

an insoluble or eroding polymer, as in previous systems, swelling of the polymer occurs. This

allows entrance of water, which causes dissolution of the drug and diffusion out of the

swollen matrix. In these systems the release rate is highly dependent on the polymer-swelling

rate, drug solubility, and the amount of soluble fraction in the matrix, This system usually

minimizes burst effects, since polymer swelling must occur before drug release,

Time = 0

Time = 1

Drug Dispersed in Matrix

Drug Dispersed in Matrix

Representation of a bioerodible matrix system. Drug is dispersed in the matrix before release

at time = 0. At time = l, partial release by drug diffusion or matrix erosion has occurred.

Characteristics of Bioerodible Matrix Systems

Description:

A homogeneous dispersion of drug in a credible matrix

Advantages:

All the advantages of matrix dissolution system Removal from implant sites not

necessary

Disadvantages

Difficult to control kinetics owing to multiple processes of release Potential toxicity

of degraded polymer must be considered.

DRUG USED IN PRESENT STUDY:

Drug name: Nifedipine

Chemical nomenclature: 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-pyridine-3,5-

dicarboxylicacid-dimethyl ester; Dimethyl 1,4-dihydro-2,6-dimethyl-4-(o-nitro-phenyl)-

3,5-pyridine-dicarboxylate.

Chemical formula: C17H18N2O6

Molecular structure:

Molecular weight: 346.30

DESCRIPTION: It is a dihydropyridine calcium-channel blocker. It is a peripheral and coronary

vasodilator. Physical properties: It is yellow, odourless and tasteless crystalline powder,

thermostable, non-hygroscopic.

Solubility: Nifedipine is freely soluble at 200c in acetone, in methylene chloride, in

chloroform in ethylacetate, slightly soluble in methanol and ethanol,

insoluble in water.

Loss on drying: Losses not more than 0.5% of its weight when dried at 105oc to

constant weight. Melting point: 171-175OC

Light sensitivity: The substance is sensitive to light in solid form and extremely

sensitive to light in dissolved state in solution.

Sensitivity to Temperature: Should not be stored above 25oc,should be protected from frost.

PHARMACOKINETICS: Absorption: It is almost completely absorbed from gastrointestinal tract but

undergoes hepatic first pass metabolism. Absorption affected by

administration with food. Bioavailability and serum concentrations

either increase or decrease when a modified released tablet was

given after a meal. Absorption of nifedipine from tablets is slower

than from capsules. The biological half life of nifedipine is 6-11 hrs.

DISTRIBUTION: It is about 92-98% bound to plasma proteins. It is distributed

into breast milk.

METABOLISM: It is metabolized in the liver. EXCRETION: It is excreted in the urine almost entirely as inactive metabolites.

Uses:

Used in the management of raynaud’s syndrome

It is used in treatment of hypertension, anginapectoris , Atherosclerosis.

Cardiomyopathies, Cough, Hiccup, Kidney disorders, Migrane and Cluster head ache,

Oesophageal motility disorders, peripheral vascular disorders, phaeochromocytoma

NIFEDIPINE MARKETED FORMULATIONS: ADALAT-ORS: CAP 10mg, CAP 20mg, and CAP 30mg ANGIBLOCK: TAB 20mg, CAP 5mg, CAP 10mg

CALBLOC: CAP 10mg

CALBLOC RETARD: TAB 10mg, TAB 20mg

CALCIGARD: RTD-TAB 10mg, RTD-TAB 2Omg CARDIPIN: SR-TAB 20mg

CARDULES: CAP 10mg

CARDULES RETARD: CAP 10mg, CAP 20mg DEPIN: CAP 5mg, CAP 10mg, and CAP 20mg

MYOGARD: TAB 5mg, TAB 10mg, and TAB 20mg

DEPIN RETARD: TAB 20mg NIFCARD: SR-TAB 10mg, SR-TAB 20mg NICARDIA XL: EXT-TAB 30mg NICARDIA-CD-RETARD: TAB 30mg

POLYMERS USED IN PRESENT STUDY:

In present study PEG 6000 was used for preparing solid dispersion and

Methocel K 15M was used as a controlled release polymer for preparing nifedipine matrix

tablets.The properties of these two polymers are as follows:

POLYETYLENEGLYCOL

Non proprietary names: Macrogol (BP)

Polyethyleneglycol (USPNF) Synonyms: Carbowax, carbowaxsentry, polyoxyethylene

Description: The USPNF23 describes polethyleneglycol as being an addition polymer of

ethylene oxide and water. Polyetyleneglycol grades 200-600 are liquids; grades 1000

and above are solids at ambient temoeratures. Liquid grades (PEG 200-600) occur as

clear, colourless or slightly yellow coloured, viscous liquids. They have slight but

characteristics odour and a bitter, slightly burning taste. PEG 600 can occur as a solid

at ambient temperatures. Solid grades (PEG > 1000) are white or off-white in colour,

and range in consistency from pastes to waxy flakes, They have a faint, sweet

odour. Grades of PEG 6000 and above are available as free-flowing milled powders.

Solubility: All grades of polyethyleneglycol are soluble in water and miscible in all

proportions with other polyethylene glycols.

Stability and Storage Conditions: Polyethyleneglycols are chemically stable in air and in solution, although

grades with a molecular weight less than 2000 are hygroscopic. Polyetylene glycols

do not support microbial growth and they do not become rancid.

Incompatibilities:

Liquid and solid polyetyleneglycol grades may be incompatible with

some colouring agents.

Safety: Polyetyleneglycols are widely used in a variety of pharmaceutical formulations.

Generally they are regarded as non-toxic and non-irritant materials.

Applications In Pharmaceutical Formulations:

1. PEG’s are widely used in a variety of pharmaceutical formulations including

parenterals, topical, ophthalmic, oral and rectal preparations.

2. It has been used experimentally in biodegradable polymeric materials used in

Controlled-release systems.

3. Solid grades are generally employed in topical ointments, with the consistency

of the base being adjusted by the addition of liquid grades of polyethylene

glycol.

4. Mixtures of PEG’s can be suppository bases, for which they have many

advantages over fats.

5. Aqueous PEG solutions can be used ether as suspending agent or to adjust

viscosity and consistency of other suspending vehicles.

6. Liquid polyethylene glycols are used as water miscible solvents for the

contents of soft gelatine capsules.

7. In concentrations upto approximately 30% v/v, PEG 300, 400, have been used

as the vehicle for parenteral dosage forms.

8. PEG’s can also be used to enhance the aqueous solubility or dissolution

characteristics of poorly soluble compounds by making solid dispersions.

9. In film coatings, solid grades of PEG can be used alone for the film coating of

tablets.

HYDROXYPROPYL METHYLCELLULOSE:

Synonyms: Benecel MHPC Cellulose, hydroxypropyl methyl ether; E464: HPMC; Methocel;

methylcellulose propylene glycol ether, methyl hydroxypropylcellulose; Metolose;

Pharmacoat

Description:

Hydroxypropyl methylcellulose is an odorless and tasteless white or creamy-white

colored fibrous or granular powder.

It is available in several grades which vary in their viscosity. The grade of methocel

used in the present study is K15M

Viscosity:

K15M: 15,000 – 17,600 CP (nominal value 16,000 CP)

Solubility: Soluble in cold water, forming a viscous colloidal solution, practically insoluble

in chloroform, ethanol (95%) and ether, but soluble in mixtures of ethanol and

dichloromethane, mixtures of methanol and dichloromethane and mixtures of water and

alcohol. Certain grades of hydroxypropyl methylcellulose are soluble in aqueous acetone

solutions, mixtures of dichloromethane and propan-2-ol and other organic solvents.

Stability and storage conditions:

Hydroxypropyl methylcellulose powder is a stable material although it is hygroscopic

after drying. Hydroxypropyl methylcellulose powder should be stored in a well-closed

container, in a cool and dry place.

Incompatibilities:

Hydroxypropyl methylcellulose is incompatible with some oxidizing agents. Since it

is nonionic, hydroxypropyl methylcellulose will not form complexes with metallic salts or

ionic organics to form insoluble precipitates.

Safety:

Hydroxypropyl methylcellulose is widely used as an excipient in oral and topical

pharmaceutical formulations. It is also used extensively in cosmetics and food products

Hydroxypropyl methylcellulose is generally regarded as a nontoxic and nonirritant material.

Applications in pharmaceutical formulation or technology:

Hydroxypropyl methylcellulose is widely used in oral and topical pharmaceutical

formulations. Methocel C.R premium grade (Methocel K15M) are widely used in controlled

release hydrophilic matrix systems and controlled release coatings, as granulation binders and

as viscosity modifiers and suspending agents in liquid systems.

In oral products, hydroxypropyl methylcellulose is primarily used as a tablet binder,

in-film -coating. Concentrations of between 2-5% w/w may be used as a binder in either wet

or dry granulation processes. High viscosity grades may be used to retard the release of drugs

from a .matrix at levels 10-80% w/w in tablets and capsules.

Depending upon the viscosity grade, concentrations between 2-20% w/w are used as

film-forming solutions to film-coating tablets. Lower viscosity grades are used in aqueous

film-coating solutions while higher viscosity grades are used with organic solvents.

Hydroxypropyl methylcellulose is also used as a suspending and thickening agent in

topical formulations, particularly ophthalmic preparations. Compared with methylcellulose,

hydroxypropyl methylcellulose produces solutions of great clarity, with fewer undispersed

fibres present and is therefore preferred in formulations for ophthalmic use. Concentrations of

between 0.45-1.0% w/w may be added as a thickening agent to vehicles for eye drops and

artificial tear solutions.

Hydroxypropyl methylcellulose is also used as an emulsifying and suspending agent

and stabilizing agent in topical gels and ointments. As a protective colloid, it can prevent

droplets of particles from coalescing or agglomerating, thus inhibiting the formation of

sediments.

In addition hydroxypropyl methylcellulose is used in the manufacture of capsules, as

an adhesive in plastic bandages and as a wetting agent for hard contact lenses. It is also

widely used in cosmetics and food products.

AIMS AND OBJECTIVES OF THIS WORK:

One of the areas of current interest in pharmaceutical technology that has significant

impact on clinical therapy is enhancement of dissolution rate and bioavailability of insoluble

and poorly soluble drugs. The very poor aqueous solubility and wetability of these drugs

gives rise difficulty in the design of pharmaceutical formulations which leads to variable oral

bioavailability. Hence enhancement of dissolution rates and oral bioavailability is needed for

their clinical efficacy.

Controlled realised drug delivery systems have received much attention in the past two

decades with numerous technologically sophisticated products on the market place. Such

advancements have come about by the simultaneous convergence of many factors, including

the discovery of novel polymers, formulation optimisation, better understanding of

physiological and pathological constraints, prohibitive cost of developing new drug entities

and introduction of bio technology and bio pharmaceutics in drug product designs. The major

benefits of these products lie in the optimisation of the drug input rate into the systemic

circulation in order to achieve an appropriate pharmacodynamic response. This in turn should

add to product safety and reduce the extent and incidence of major adverse drug reactions due

to more strict control of blood levels. Further more , with less frequent dosing, it is speculated

that this should improve patient compliance and possibly maximise drug product efficacy in

therapeutics.

Recently numerous hydrophilic polymers have been investigated and are currently

used in the design of complex controlled release systems. In many cases the formulator

depends on the inherent rate controlling mechanisms of the polymer to provide constant rate

drug delivery. Among desirable features the polymer should posses inherent physico

chemical characteristics which provide for the attainment of high gel state viscosity upon

swelling, ability to maintain constant gel layer integrity over a prolonged period of time and

hence low erosion rate, and complete dissolution of polymer upon exhaustion of drug release.

Alternatively, the high programmed system is sought for which swelling and erosion are the

key factors in controlling drug liberation. The ideal polymer would permit these processes to

operate synchronously, i.e. affording a balance between the principle process of swelling,

erosion and dissolution. Among the most widely used polymers, such as non ionic hydroxyl

propyl methyl cellulose(HPMC), hydroxy propyl cellulose (HPC), polyethylene oxide(PEO)

types, the cationic chitosan types and anionic alginate types, the attainment of high gel state

viscosity, maintenance of constant gel layer in a monolithic sense for linear drug release over

a prolonged period of time is not easily achievable and still remains a challenge. Since the

various dynamic phases in the rate process of polymer relaxation, disentanglement and/or

erosion during dissolution are manifested in a non-constant manner, realisation of zero order

drug relase from such monolithic devices is difficult.

This limitation of hydrophilic polymers may be circum vented through modification of

the physical and chemical infrastructure of the polymeric gel system. In the present work

reliable process has been established for inducing in situ reactions between pharmaceutically

acceptable electrolytes and drug which influences the intra gel swelling dynamics and relative

physical integrity of the swollen matrix structure. Further more, this may produce

heterogeneous domains with in the swollen gel boundary.

The aim of the work was to desing solid dispersion of nifedinpine by using PEG 6000 as

carrier for improving its dissolution rate characteristics. Futher the nifedipine solid dispersion

were then reengineered as monolithic matrix controlled release formulations using HPMC

K15M as a controlled release polymer and MCC as a diluent so as to achieve the study state

drug release over a prolonged period of time.

THE MAJOR OBJECTIVES OF WORK ARE AS FOLLOWS:

1) prepare nifedipine solid dispersion by fusion method using PEG6000 as a

polymer at a drug: polymer ratio of 1:1.5 and 1:2.

1) To evaluate the flow properties of prepared solid dispersion by estimating

angle of repose, cars index, particle size.

2) To evaluate the drug release from solid dispersion by invitro dissolution

studies

Based on the above studies the optimized formulation was selected for

formulating it as controlled release matrix tablet.

3) To prepare controlled release matrix tablets of nifedipine solid dispersion by

using methocel K15 as a polymer and MCC as diluent by direct compression

method.

4) To evaluate physical parameters of prepared matrix tablets by weight

uniformity, hardness, friability.

5) To perform the dissolution studies on the prepared matrix tablets

6) To estimate the invitro pharmaco kinetic parameters such as 1st order rate

constant, Higuchis constant, pappas constant by using dissolution data

obtained.

The drug nifedipine is used as antihypertensive drug. It is effective in

patients whose anginal episodes are due to coronary vasospasm. It is used in the treatment of

vasospastic angina aswell as classic angina pectoris. Systemic availability of the oral dose of

the drug may be up to 6 hrs.

CHAPTER I

LITERATURE REVIEW

LITERATURE REVIEW:

1) Evaluation of nifedipine formulation with pre gelatinized starch solid dispersion was

prepared with pre gelatinized and formulated into tablets and evaluated. These tablets

show improvement in dissolution rather than pure form. 14

2) Complex formation of nifedipine with beta cyclo dextrin and hydroxyl propyl beta cyclo

dextrin was studied. The formulations employing these gave slow, controlled and

complete release spread over a period of 12 hrs.15

3) An Invitro evaluation of modified release formulations marketed in India was conducted

and compared their performance with a novel matrix based on multi particulate system. It

was concluded that novel matrix based multi particulate system were found to be

superior with respect to the therapeutic advancement as well as manufacturing

feasibility.16

4) The effects of various polymers on the release of nifedipine from their matrices have

been evaluated. In vitro release profile of nifedipine from Eudragit RS matrices show

that increase in the concentration of Eudragit RS resulted in reduction in the release rate

of nifedipine. 17

5) Microencapsules containing solvent deposited systems of micro crystalline cellulose as

core are evaluated. They gave slow, sustained and complete release of nifedipine over a

period of 12 hrs which was not possible with microencapsules of nifedipine alone.18

6) Nifedipine and its solvent deposited systems on micro crystalline cellulose were micro

encapsulated with cellulose acetate by an emulsification solvent evaporation method and

micro encapsules were studied. These micro capsules gave release depending on the

proportion of micro crystalline cellulose in the solvent dispersion systems used as core.

Release was diffusion controlled.19

7) Spectro photometric methods based on the reaction with vaniline in methanol in

phosphoric acid medium and folin ciocilters reagent in strongly acidic medium are

reported for the determination of nifedipine and its dosage form.20

8) Different approaches were done to analyze the invitro dissolution behaviour of different

dosage forms containing nifedipine. A new sustained release dosage form formulated in

two different strengths 30 and 60 mg were tested and compared with an extended release

commercial product21

9) Affect of nifedipine and aspirin on plat let aggregation was studied. Both these drugs

inhibited the platelet aggregation when administered alone or in combination in

hypertensive individuals 22

10) Recent investigations have been done for the design and evaluation of nifedipine

transdermal patches. It was concluded that faster release was absorbed from ethyl

cellulose patches containing glycerol as plasticizer23

CHAPTER III

MATERIALS AND

METHODS

MATERIALS AND METHODS:

The following materials were used:

1) Nifedipine

Gift sample from M/S NATCO pharma limited.hyderabad.

2) HPMC K15 M

Gift sample from M/S COLOROCON Asia private limited.Mumbai

3) Potassium dihydrogen phosphate

S.D.Fine Chem. Ltd.Mumbai

4) Sodium hydroxide

S.D.Fine Chem. Ltd.Mumbai

5) Methanol

High-pure fine chem.Chennai

6) Hydrochloric acid

S.D.Fine Chem. Ltd.Mumbai

7) Potassium chloride

S.D.Fine Chem. Ltd.Mumbai

INSTRUMENTS AND EQUIPMENTS

1. Weighing balance (sensitivity) axis AGN204-PO

2 .Heating mantle KEMI

3. Orbital shaking incubator- REMI (R15-24BL)

4 .Magnetic stirrers- REMI(IMLDX)

5. Doublecone blender (PHARMACON)

6. Tray dryer-JAINSON(DTC-96)

7. 16 station rotatory tablet punching machine(ELITE)- (CMD-16)

8. 8 digital dissolution testing apparatus- optics technology

9. U.V. spectrophotometer (ELICO SLV – 159

10. Friability – PHARMACON (FTA- 023)

11. Disintegration – THERMONIK (CAMPBELL ELECTRONICS)

12. Double Distillation plant – (JSGW)

13. PH meter – ELICO( LI120)

14. Hot plate- KEMI

15. Digital balance – SHIMADZU( ELB300)

ANALYTICAL METHODS:

1) ESTIMATION OF NIFEDIPINE:

A simple, sensitive and accurate spectrophotometric method was used for the

measurement of Nifedipine at a λmax of 238nm. The absorbance of standard

dilutions were measured at 238nm.PREPARATION OF STANDARD SOLUTION:

100mg of nifedipine was dissolved in methanol in 100ml volumetric flask and the

solution was made up to volume with methanol.PROCEDURE:

The standard solutions of nifedipine was subsequently diluted with 6.4 pH buffer and

0.5% SLS to obtain series of dilutions containing 2,4,6,8,10 µg of nifedipine

per ml of solution. The absorbance of the above dilution were measured in ELICO

Double beam UV spectrophotometer at 238 nm using 6.4pH buffer and 2 % SLS as a

blank. The concentration o nifedipine and the corresponding absorbance values are

given in table 1. The absorbance values were plotted against concentration of drug as

shown in graph 1. The method was found to be suitable for the estimation of nifedipine in

Dissolution fluids calibration curve shown in graph 1 was used for this purpose

2) PREPARATION OF NIFEDIPINE SOLID DISPERSION BY FUSION

METHOD:

Required quantities of PEG, Nifedipine were weight accurately and pass through sieve

number 100. Materials passed through the sieve were taken and PEG is transferred into a

clean and dry china dish.

Then PEG is melted at its melting point, 50 0C on a heating mantle and nifedipine is

added in small amounts with trituration. Then the mixture was triturated and then dried. The

dried mixture was allowed to pass through sieve number 80 and material is collected and

packed in white mouthed amber coloured glass containers and hermetically sealed and stored

at an ambient conditions.

3) ESTIMATION OF FLOW PROPERTIES OF SOLID DISPERSION:

ANGLE OF REPOSE: It is the maximum angle that is obtained between the free standing surface of a powder heap and horizontal plane.

COMPRESSIBILITY INDEX: A single indication of the case with which a material can

be induced to flow is given by application of Carr’s index.

4) DISSOLUTION STUDIES ON NIFEDIPINE SOLID DISPERSION:

Dissolution rate studies of pure nifedipine marketed conventional tablet and solid

dispersions of nifedipine were performed in 8 stage Toshiba dissolution test apparatus

with rotation paddles at 75rpm employing 900ml of 6.4 pH buffer and 0.5% SLS and the

temperature of the bath was maintained at 37 ± 2 °c through out the experiment. 2ml of

the samples were with drawn at various time intervals and were further diluted with 6.4PH

buffer and 0.5% SLS medium. The absorbance of the samples were measured at 238 nm

for determining the amount of drug released at various time intervals. Each time the same

volume of buffer was added to the dissolution media for maintaining the constant volume

of dissolution medium. The dissolution studies were carried out in triplicate.

5) PREPARATION OF CONTROLLED RELEASE MATRIX TABLETS

OF SOLID DISPERSIONS:

Four different formulations of controlled release matrix tablets were prepared by direct

compression using different concentrations of HPMC K15 as a polymer and MCC&

Magnesium stearate as diluents with solid dispersions of nifedipine.

6) PHYSICAL PARAMETERS EVALUATED FOR CONTROLLED

RELEASE TABLETS:

The physical parameters that are evaluated includes weight variations, hardness, friability and

disintegration type

7) DISSOLUTION RATE STUDIES ON CONTROLLED RELEASE

NIFEDIPINE TABLETS:

Dispersions of nifedipine were performed in 8 stage Toshiba dissolution tes Dissolution rate

Studies of pure nifedipine marketed conventional tablet and solid apparatus

With rotation paddles at 75rpm employing 900ml of 6.4 pH buffer and 0.5% SLS and the

Temperature of the bath was maintained at 37 ± 2 °c through out the experiment. 2ml of

the samples were with drawn at various time intervals and were further diluted with 6.4PH

buffer and 0.5% SLS medium. The absorbance of the samples were measured at 238 nm

for determining the amount of drug released at various time intervals. Each time the same

volume of buffer was added to the dissolution media for maintaining the constant volume

of dissolution medium. The dissolution studies were carried out in triplicate.

8) IN VITRO PHARMACOKINETICS EVALUATED:Based upon the data obtained from the dissolution studies the invitro pharmacokinetic

Parameters such as T50, T90, DE30 and first order release rate constant for each and every

curve obtained from cumulative % drug release vs. time profile. First order release rate

constant was calculated from the log % undissolved vs. time curve. The % drug released

at time, T50,T90, DE30 and first order release rate constant values were given in table 5

and shown in graphs

CHAPTER IV

EXPERIMENTAL

RESULTS

TABLE 1: Calibration curve for estimation of nifedipine in 6.4 pH buffer (N=8)

S.No CONC( µg/ml) ABSORBANCE

1

2

3

4

5

2

4

6

8

10

0.142

0.264

0.387

0.523

0.652

TABLE 1: Calibration Curve for Estimation of Nifedipine

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0 5 10 15

concentration

abso

rban

ce

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0 5 10 15

concentration

abso

rban

ce

TABLE 2: composition of various solid dispersions

S.NO Composition Ratio

1.

2.

Nifedipine +PEG 6000

( NFF1)

Nifedipine + PEG 6000

(NFF2)

1:1.5

1:1.2

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0 5 10 15

concentration

abso

rban

ce

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0 5 10 15

concentration

abso

rban

ce

TABLE 3: Flow properties of Nifedipine solid dispersions

S.NO Solid

dispersion

Angle of

repose

Carrs index Particle size % drug

recovered

1.

2.

NFF1

NFF2

25.5

28.3

15.2

15.6

178

178

99.3±2

99.7±2

TABLE 4: Dissolution parameters for Nifedipine solid dispersions

S.NO Solid

dispersion

% drug

released

at 90

mins

T50(min) T90(min) DE30 K R2

1.

2.

NFF1

NFF2

99.0

99.5

3

1

12

4

29.41

31.03

0.011

0.0172

0.993

0.995

TABLE 5: compositions of various controlled release matrix tablets of nifedipine

S.No Ingredients(mg/tablet) Formulations

NFD1 NFD2 NFD3 NFD4

1

2

3

4

Nifedipine(solid dispersion)

Methocel K 15M

Micro crystalline cellulose

Magnesium sterate

60mg 60mg 60mg 60mg

60mg 80mg 100mg 120mg

79mg 59mg 39mg 19mg

1mg 1mg 1mg 1mg

Total wt. of tablet 200 mg 200 mg 200 mg 200 mg

TABLE 6: Physical parameters of nifedipine matrix tablets

S.No Formulation Wt uniformity

(mg)

Hardness

(kg/cm2 )

Friability

(%)

Drug Content

(Mg/tablet)

1

2

3

4

NFD 1

NFD 2

NFD 3

NFD 4

200 ± 2.0

199 ± 2.0

203± 2.0

198 ± 2.0

7.5 ± 0.3

7.5 ± 0.4

7.5 ± 0.1

7.5 ± 0.3

0.20

0 .18

0 .20

0.19

20.4 ± 0.5

19.9 ± 0.2

20.2 ± 0.3

20.8 ± 0.5

TABLE 7: Release of nifedipine from controlled release matrix tablets containing

methocel K15M

S.No Time Cumulative % of nifedipine released

NFD1 NFD 2 NFD 3 NFD 4 MARK

1

2

3

4

5

6

7

8

30 mins

1 hr

2 hr

4 hr

6hr

8hr

10 hr

12 hr

2.92 2.2 1.8 1.2 2.35

6.04 5.2 3.8 2.6 6.02

10.7 7 6.6 5 10.3

14.02 10 9.4 7.8 14.4

16.46 12.8 12.4 10.4 16.4

18.48 15.2 15 12.6 18.2

19.9 18 17.2 15.2 18.9

- 19.8 19 17 19.1

GRAPH 2: Drug Release Profiles of Controlled Release Tablet Formulations of Nifedipine

0

2

4

6

8

10

12

14

16

18

20

0 2 4 6 8 10 12

time(hr)

cum

ulat

ive%

drug

rel

ease

d

nfd1

nfd2

GRAPH 3: Drug Release Profiles of Controlled Release Tablet Formulations of Nifedipine

0

2

4

6

8

10

12

14

16

18

20

0 2.5 5 7.5 10 12.5 15time(hrs)

cum

ulat

ive%

dru

g re

leas

ed

nfd3

nfd4

GRAPH 4: Drug Release Profiles of Controlled Release Tablet Formulations of Nifedipine

0

5

10

15

20

25

0 2.5 5 7.5 10 12.5 15

time(hr)

cu

mu

lati

ve%

dru

g r

elea

sed

mark

TABLE 8: kinetic parameters of nifedipine matrix tablets

S.No Formulation First order

(min-1)

R2 Higuchis

constant

R2 Pappas

constant

R2

1

2

3

4

5

Marketed

NFD 1

NFD 2

NFD 3

NFD4

0.126

0.050

0.160

0.077

0.0021

0.142

0.821

0.988

0.951

0.902

6.086

6.667

5.834

5.760

5.168

0.957

0.9823

0.991

0.989

0.978

0.4576

0.4956

0.5451

0.6370

0.7390

0.9505

0.9676

0.9934

0.9964

0.9959

GRAPH 5: First Order Kinetic Profiles of Nifidipine Controlled Release Matrix

Tablets.

0

0.5

1

1.5

2

2.5

0 5 10 15

time(hr)

log

%d

rug

un

dis

solv

ed

nfd1nfd2Linear (nfd1)Linear (nfd2)

GRAPH 6: First Order Kinetic Profiles of Nifidipine Controlled Release Matrix Tablets

0

0.5

1

1.5

2

2.5

0 5 10 15

time(hr)

log

%d

rug

un

dis

solv

ed

nfd3nfd4Linear (nfd3)Linear (nfd4)

GRAPH 7: First Order Kinetic Profiles of Nifidipine Controlled Release Matrix Tablet

0

0.5

1

1.5

2

2.5

0 2.5 5 7.5 10 12.5 15

time(hr)

log

%d

rug

un

dis

solv

ed

markLinear (mark)

GRAPH 8: Sqaure root of Time V/S Amount of Drug Released Plot of Nifidipine

Controlled Release Matrix Tablets.

-5

0

5

10

15

20

25

0 0.5 1 1.5 2 2.5 3 3.5 4

square root of time

amo

un

t o

f d

rug

dis

solv

ed

nfd1nfd2Linear (nfd2)Linear (nfd1)

GRAPH 9: Sqaure root of Time V/S Amount of Drug Released Plot of Nifidipine

Controlled Release Matrix Tablets.

0

2

4

6

8

10

12

14

16

18

20

0 1 2 3 4

square root of time

amo

un

t o

f d

rug

dis

solv

ed

nfd3nfd4Linear (nfd4)Linear (nfd3)

GRAPH 10: Sqaure root of Time V/S Amount of Drug Released Plot of Nifidipine

Controlled Release Matrix Tablets.

0

5

10

15

20

25

0 1 2 3 4

square root of time

amo

un

t o

f d

rug

dis

solv

ed

markLinear (mark)

CHAPTER V

DISCUSSION OF

RESULTS

In the present investigation, studies were undertaken for the design and

development of oral controlled release matyrix tablets of Nifidipine solid dispersions with

HPMC K15 M by direct compression process. Initially Nifedipine was formulated as a solid

dispersion with poly ethylene glycol 6000 to enhance its dissolution rate and bioavailability

and then the solid dispersions were compressed as matrix tablets.

The enhancement of oral bioavailability of poorly soluble drugs remain one

of the most challenging aspects of drug development. Although salt formation, solubilization

and particle size reduction have commonly been used to increase dissolution rate and thereby

oral absorption and bioavailability of such drugs. There are some practical limitations of

these tyechniques. The solid dispersion approach has been widely and successfully applied to

improve solubility, dissolution rate and consequently the bioavailability of poorly soluble

drugs.

The drug selected for investigation was nifedipine which is a yellow

powder practically insoluble in water and sparingly soluble in dehydrated alcohol , freely

soluble in acetone.

Analytical methods used in present studies for estimation of nifedipine

was simple and wellknown UV spectrophotometric method. This method was adopted for

estimation of solubility studies, drug content in dispersions and in invitro dissolution studies.

Nifedipine was estimated at 238nm in different media. This method obeyed beer’s law in

concentration range of 0-10µg/ml. reproducibility of the method was tested by analysing 6

seperately weighed samples of nifedipine. This method was found to be suitable for

estimation of nifedipine in dissolution fluids. The absorbance values were given in table 1

and calibration ciurve was shown as graph 1.

The solid dispersions of nifedipine with PEG 6000 at different ratios were

prepared by fusion method. The dispersions prepared were finally screened through sieve no

100 to achieve uniform size dispersions. The compositions of various slid dispersions were

given in table 2. the dispersions prepared by fiusion were stable, having uniform size

dispersions with good flow properties.

The solid dispersions prepared were analysed for their flow properties by

angle of repose, carrss index ,methods. All the dispersions exhibited good flow

characteristics.

All the solid dispersions were further analysed to determine the uniformity

of particle size. The particle size determination was determined by simple sieve analysis

method. All these solid dispersions were found to be uniform in size with good particle size

reduction.

The amount of nifedipine present in solid dispersions prepared were

analysed by UV spectrophotometric method. The actual amount of drug present in solid

dispersions were given in table 4. all the dispersions prepared were having stated amount of

drug.

Nifedipine release from solid dispersions were studied in 6.4 ph phosphate

buffer containing 0.5%w/w SLS for a period of 90 mins. The nifedipine dispersions were

found to release the drug faster than in the dissolution media. Amoing the solid dispersions

poreapared by fusion method drug to polymer ratio 1:1 was found to release the drug at a

faster rate than other solid dispersions. The rapid release of poorly soluble nifedipine from

solid dispersions was influenced by the proportion of polymer and the method employed for

its preparation. As the concentration of PEG 6000 increases the release of nifedipine in

dissolution media was found to be increased. In fusion method the drug is entrapped into long

chain polymeric structure and there by reducing the lipophillicity of drug, which enabled the

poorly soluble nifedipine to release at faster rate in dissolution media. The dissolution

parameters for solid dispersions were tabulated. The dissolution profiles of solid dispersions

were shown in graphs 2-4. the first order release rate plots were shown in 5-7. the release of

drug from solid dispersions were linear with first order kinetics. The release rate constants

and other dissolution rate parameters were depicted in table 5.

Controlled release drug delivery systems have recievemuchattention in the

past 2 decades with numerous technologically sophisticated products on the market place.

Such advancements have come about by simultaneous convergents of many factors, including

the discovery of novel polymers, formulation optimisation and better drug understanding of

physiological constraints, prohibitive cost of developing new drug entities and the

introduction biotechnology and biopharmaceutics in drug product design and the major

benefits of these products lie in the optimisation of drug input rate into systemic circulation in

order to achieve an appropriate pharamacodynamic response. This inturn should add to

product safety and reduce the extent and incidence of major adverse druig reactions due to a

more strict control of blood levels. Furthermore, with less frequent dosing, it is speculated

that this should improve patient compliance and possible maximize drug product efficacy and

drug products.

Controlled release matrix tablets of nifedipine were prepared by direct

compression process using 16 station rotary compression machine. The composition of

various tablet formulations of nifedipine were given in table 2. the direct compression process

was used for making matrix tablets were found to be ideal and easy to produce. Polym,er

such as Methocel K 15 M, diluent such as MCC were used for making the matrix tablets of

nifedipine solid dispersions. All the excipients exhibited good flow p[roperties, which

enables the process very easy. All the batches of matrix tablets were compressed under

identical conditions to minimize processing variables. Then these matrix tablets were

evaluated for physical properties, hardness, friability and drug content uniformity.

The controlled release matrix tablets prepared by direct compression

process were having good quality and have a smooth texture without cracks on the tablet

surface. The physical parameters evaluated for matrix tablets were highlyt uniform and the

results obtained were within the limits of official compendiums.

Nifedipine release from the matrix tablet was studied in 6.4 ph buffer as

the medium over the period of 12 hrs. the matrix formulations with HPMC K15 M and

diluent such as MCC were found to release the drug at a steady state over a prolonged period

of time. The release characteristics of the nifedipine in matrix tablets were varied with

polymer concentration. As the concentration of polymer increased the drug release from the

matrix tablet were correspondingly increased and extended the drug release over a prolonged

period of time.

Among the formulations NFD 2 was found to release the drug at a steady

state over an extended period of time upto 12 hrs. The drug release from this formulation was

meeting the USP test 2 profiles specified for nifedipine extended release formulations.

The cumulative percentage of drug release values for different

formulations were given in table 4 and the dissolution profiles for all the formulations were

given in graphs 2-5. The invitro pharmacokinetic parameters such as first order rate

constants, higuchi dissolution rate constant, pappas rate constant were calculated for all the

formulations found to be linear with first order release rate kinetics. Higuchi dissolution rate

constant values indiacted that the drug release from matrix tablet were linear with the druig

diffusion from the matrix. The N values obtained by Pappas constant were within 0.5- 0.9

indicated that the drug release follows non fickian anomalous drug release. Thus the release

of drug from matrix tablet follows dissolution of diluents by erosion followed by diffusion of

the drug from the matrix tablet in all the formulations. The invitro pharmacokinetic

parameters estimated were in table 5 and shown in graphs 5-10.

CHAPTER VI

SUMMARY AND

CONCLUSIONS

The enhancement of oral bioavailability of poorly soluble drugs remain one of the

most challenging aspects of drug development. Although salt formation, solubilisation and

particle size reduction have commonly been used top increase dissolution rate and there by

oral absorption and bioavailability of such drugs. There are some practical limitations of

these techniques. The solid dispersion approach has been widely and successfully applied to

improve solubility, dissolution rate and consequently the bioavailability of poorly soluble

drugs.

Further investigations on formulating controlled release matrix tablets were

performed. Controlled release drug delivery systems have received much attention in the past

two decades with numerous technologically sophisticated products on the market place. Such

advancements have come about by simultaneous convergence of many factors, including the

discovery of novel polymers, formulation optimization, better drug understanding of

physiological constraints, prohibitive cost of developing new drug entities and the

introduction biotechnology and biopharmaceutics in drug product design. The major benefits

of these products lie in the optimization of drug input rate into systemic circulation in order to

achieve an appropriate pharamacodynamic response. This inturn should add to the product

safety and reduce the extent and incidence of major adverse drug reactions due to a more

strict control of blood levels. Further more, with less frequent dosing, it is speculated that

this should improve patient compliance and possibly maximize drug product efficacy in

therapeutics.

Nifedipine by formulating as solid dispersions with PEG 6000 as a carrier by fusion

method to enhance the dissolution rate and bioavailability.

Further nifedipine dispersions were formulated as controlled release matrix tablets by

HPMC K 15 M as a polymer MCC as diluent by direct compression method. Based on the

results obtained the following conclusions were drawn:

1. The solid dispersions of Nifedipine with PEG 6000 as a carrier prepared by fusion

method were found to be stable, having uniform particle size with free flowing

characters.

2. The drug content estimated in all the solid dispersions were uniform.

3. The dissolution rate of all the solid dispersions were rapid when compared to the

dissolution rate of a pure drug.

4. Dissolution rate of all the solid dispersions followed first order kinetics.

5. All the dissolution parameters estimated such as T50, T90, DE30, K values indicated

faster dissolution of drug from the solid dispersions than that of pure drug.

6. Nifedipine solid dispersions can be directly compressed into controlled release matrix

tablets with HPMC K 15 M along with diluents such as MCC. This method was found

suitable for direct compression as matrix tablets.

7. Weight uniformity of all the matrix tablets were uniform in all the cases and were

with in IP specified limits.

8. Hardness of matrix tablet formulations were constant for all batches and maintained at

6-7 kg/cm2.

9. Friability loss for the formulations was negligible and was less than 0.5% loss for all

the batches.

10. Drug content was uniform in all the batches of matrix tablet formulations.

11. The matrix tablet formulations gave slow release of drug from 8-12 hrs.

12. The formulations NFD 2 was found to extend the drug release in a steady state

manner over a period of 12 hrs.

13. First order plots for all the formulations were found to be linear with R2 values of

0.998.

14. Higuchi plots for all the matrix tablets formulations were found to be linear with R 2

values of 0.999.

15. The Pappas constant value obtained from the plots were linear with the N value

ranging from 0.5-0.9.

16. The drug release from the matrix tablets were found to follow first order kinetics.

17. The mechanism of drug release indicated anomalous drug release with non fickian

diffusion model and hence the drug release is by diffusion an dissolution controlled

systems.

From the results obtained, formulation NFD 2 was found to extend

the drug release over an extended period of time which followed USP test 2 profiles of

Nifedipine extended release formulations. Hence this formulation can be further evaluated for

invivo studies such as pharmacokinetic and pharmacodynamic studies in a suitable animal

model.

CHAPTER VII

REFERENCES

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