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Transcript of Dissolution Rate Enhancement of Nifedipine and Development of Controlled Release Matrix Tablets of...
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
REFERENCES
1. Fincher, J.H., J.Pharm.Sci., 57(11):1925-35,1969
1. 2 .Lees,KA.,Pharm.J.,191:289-91,1963a. .
2. Dare,J.G.,Australian J.Pharm.,45:S58-S65,1964.
3. Goldberg, E., Midland Macromolecular Symposium, 227, 1978.
4. Hopfenberg, H.B. and Hsu, K. C., Polym. Eng. Sci., 18, 1186, 1978.
5. Nakagami, H. and Nanda, M., Drug Design Discovery, 8, 103, 1991.
6. Motyeka. S. and Naira, J. G., J. Pharm. Sci., 67, 500, 1978.
7. Park, K., Chang, H. s., and Robinson, J. R., Recent advances in Drug Delivery Systems, Plenum Press, Newyork, 163, 1984.
8. Bechgaard, H. and Baggesen, S., J. Pharm.Sci., 69, 1327, 1980.
9. Ford,J.& Robinstein,M.H.,Pharm Acta Helv.,53(11):327-32,1978.
10. Daabis,N.A.,Abd-Elfattan,S.and El-Banna, H.M.Pharmazic,29(6):400-4,1974.
11. Ed-Banna, H.M.,Abd-Elfattan,S.and Daabis, N.A.,Pharmazie,29(6):396-400.1974.
12. Rogers, J.A Anderson, A.J.,Acta pharm.Helv.,57:276-81,1982.
13. Raghuraman, S., Velrajan, G., Palaniappan., Indian. J. Pharm. Sci., 67, 510- 515, 2003.
14. Chowdary,KPR., Reddy, G. k., Indian. J. Pharm. Sci., 64, 142- 146, 2002.
15. Panchagnula, R, Singh, R, Ashok raj, Y., Indian. J. Pharm. Sci., 69, 556- 561, 2007.
16. Farid, D. J, Shoberi, N. S., Hassani, M, Indian. J. Pharm. Sci., 60, 375- 378, 1998.
17. Chowdary,KPR., Nagarajan, M, Nalluri, B. N., Indian. J. Pharm. Sci., 58, 152- 156, 1996.
18. Costa, P., and Lobo, J. N. S., Eur. J. Pharm. Sci., 13, 23, 2001.
19. Bruno, L., Jhon, S. K., Indian. J. Pharm. Sci., 50, 109- 112, 1998.
20. 21 Sood, A., Panchagnula, R., Indian. J. Pharm. Sci., 27, 261, 2003.
21. Desai, A.A, Nayak, V. k., Desai, Nk., Indian. J. Pharm. Sci., 27, 167- 170, 1995.
22. Shnakar. V., Jhonson, D B., Shivanad. V., Indian. J. Pharm. Sci., 65, 510- 515, 2003.