Evaluation Of Sustaining Action And Swelling Behaviour Of Some Hydrophilic Polymer Based Matrix Tablets

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1. General Introduction

 

The drug delivery technology landscape is highly competitive and rapidly evolving.  Drug dosage forms are keeping pace with high-tech times. Historically, drug delivery has taken the form of injection, infusion, ingestion and inhalation, with additional variations in each category. The focus of pharmaceutical research is being steadily shifted from the development of new chemical entities to the development of novel drug delivery systems of existing drug molecules to maximize their effectiveness in terms of other therapeutic action and patent protection. This shift has been made possible by the discovery of various compatible polymers. These polymers, when used in the formulation, control the temporal and/or spatial delivery of a drug.  The challenge for both drug and drug delivery companies is deliver both existing and emerging drug technologies in a manner that improves the benefits to the patients, healthcare workers and the healthcare system (Charles S. Brunner, 2004).

 

Areas that are being targeted for improvements through device development include:

{C}·         Improved efficacy

{C}·         Reduced side effects

{C}·         Continuous dosing (sustained release)

{C}·         Reduced pain from administration

{C}·         Increased ease of use

{C}·         Increased use compliance

{C}·         Improved mobility

{C}·         Decreased involvement of healthcare workers

{C}·         Improved safety for healthcare workers

{C}·         Reduced environmental impact (elimination of CFC’s)

 

To provide these benefits, worldwide a number of approaches are being (or in some cases have been) developed. The common thread running through the approaches is the concept of self-administered, targeted, sustained release with increased bioavailability. Many drug delivery scientists view oral delivery as the ideal drug delivery method. Although oral delivery meets the need for self-administered drugs, targeted, sustained release and increased bioavailability present the areas of difficulty in meeting the emerging value position. In recent years, in association with progress and innovation in the field of pharmaceutical technology, there has been an increasing effort to develop prolonged release forms for many drugs. So, an important subset of the historical development of pharmaceutics is the sustained or controlled drug release systems.

There is given one main category of sustain release drug system

 Sustained drug action

Figure1.1: Sustained release dosage form

 

Sustained release dosage forms are the pharmaceutical dosage forms formulated to retard the release of a therapeutic agent such that its appearance in the systemic circulation is delayed and/or prolonged.

1.2: Synonyms of Sustained-Release Dosage Forms

{C}Ø  {C}Sustained action/release(SR)

{C}Ø  {C}Prolonged action/release

{C}Ø  {C}Depot dosage forms(Depot)

{C}Ø  {C}Respiratory dosage forms

{C}Ø  {C}Delayed action/release

{C}Ø  {C}Retardate release(Retard)

{C}Ø  {C}Timed release(TR)

The systemic drug level far exceeds the therapeutic level for a brief period after ingestion or injection (in typical cases). The drug level then gradually declines from therapeutic to ineffective levels. This is an undesirable effect, especially when the therapeutic and toxic levels of a drug are close (that is the therapeutic index is low).

Controlled drug delivery can help reduce this "sawtooth" profile. The flip side of reducing negative effects is the promotion of positive effects. Controlled drug delivery can also be used to provide a consistent and sustained dosage. The therapeutic effectiveness of certain drugs can be greatly improved through sustaining an appropriate level of the drugs over time.

1.3: Components of a Sustained-Release delivery system:

These include:

{C}Ø  {C}Active drug

{C}Ø  {C}Release-controlling agent(s):matrix formers, membrane formers

{C}Ø  {C}Matrix or membrane modifier, such as channeling agents for wax matrices and solubilizers, and wicking agents for hydrophilic matrices.

{C}Ø  {C}Solubilizer, pH modifier and/or density modifiers

{C}Ø  {C}Lubricant and flow aid such as magnesium stearate, stearic acid, hydrogenated vegetable oil,talc, colloidal silicon dioxide

{C}Ø  {C}Supplementary coatings to extend lag time, further reduce drug release

{C}Ø  {C}Density modifiers (if required)

1.4: Classification of Sustained-Release Dosage Forms:

 

1.4.1: Rate-Preprogrammed Drug Delivery System

{C}Ø  {C}Polymer Membrane Permeation-Controlled DDS

{C}Ø  {C}Polymer Matrix Diffusion- Controlled DDS

{C}Ø  {C}Microreservoir Partition- Controlled DDS

 

1.4.2: Activation-Modulated Drug Delivery System

Physical means Osmotic Pressure activated DDS

{C}Ø  {C}Hydrodynamic Pressure activated DDS

{C}Ø  {C}Vapor Pressure activated DDS

{C}Ø  {C}Mechanically activated DDS

{C}Ø  {C}Magnetically activated DDS

{C}Ø  {C}Sonophoresis activated DDS

{C}Ø  {C}Iontophoresis activated DDS

{C}Ø  {C}Hydration activated DDS

Chemical means

{C}Ø  {C}pH activated DD

{C}Ø  {C}Ion activated DDS

{C}Ø  {C}Hydrolysis activated DDS

Biochemical means

{C}Ø  {C}Enzyme activated DDS

{C}Ø  {C}Biochemical activated DDS

1.4.3: Feedback-regulated Drug Delivery System

{C}Ø  {C}Bioerosion-regulated DDS

{C}Ø  {C}Bioresponsive DDS

{C}Ø  {C}Self-regulating DDS

1.4.4:  Site-targeting Drug delivery system

1.5:   Formulation of Sustained-Release dosage Forms

For convenience of description oral sustained-release delivery system can be considered under the following headings:

{C}Ø  Monolithic or Matrix system

{C}Ø  Reservoir membrane-controlled systems

{C}Ø  Osmotic pump systems

1.6: Methods of Sustaining Drug Action

Two general set of methods have been developed for implementation of practical sustained release dosage form designs:

 

{C}q  {C}Method based on modification of the physical and or chemical properties of the drugs.

{C}q  {C}Method based on modification of the drug release rate characteristics of the dosage forms that affect the bioavailability of the drug.

The basic methods of sustaining action are:

Slowing or inhibiting inactivation of drugs producing pharmacological reaction.

{C}·        Slowing excretion or elimination of drug from the body.

{C}·        Changing physico-chemical properties of drug crystals.

{C}·        Controlling the release rate of drug from the dosage forms.

 

1.7: Different drug formulation methods used to obtain the desired drug release rate from sustained release dosage form includes:

 

1.7.1: Increasing the Particle Size;

Increasing the particle size causes decrease in surface area of the particles and decrease in release rate of the drug from the dosage form, as we know dissolution rate is directly proportional to the surface area exposed to the solvent.

 

1.7.2: Matrix System:

Matrix system is that system, where the drug is dispersed in solid, which is less soluble or insoluble in fluid depot, making a continuous external phase of dispersion and effectively retards the passage of the drug from matrix system. It is one of the least complicated approaches to the manufacture of sustained release dosage forms that consist of a drug dispersed in a polymer, the polymer playing the role of a matrix.

{C}{C}

Fig1.2:  Matrix System

 

 

1.7.3: Coating System:

The dosage form or individual particles are coated with materials that retard the drug release into the depot fluid and control the rate of availability of drug from dosage form. Drug release rate is dependent on the physico-chemical properties of the coating material.

1.7.4: Beads & Sphere

                                  
                                             Fig1.3:  Beads

This kind of dosage form contains Beads or Spheres of drug, which are coated with material. The thickness of the coating material determines the times at which the drug will be released by diffusion through their pores.

 

1.7.5: Enteric Coated Beads In Capsules:

The drug is incorporated in to beads or spheres of uniform size & uniformly coated with a suitable enteric materials, thus the rate of drug release depends on the stomach emptying rate of beads

                                           .

                                            Fig 1.4: Enteric Coated Beads

                     (Ref :http://www.eurand.com/upload/orbexa.jpg)

 

1.7.6:  Repeat -action Tablet :

Repeat-action tablets contain fraction of drug that dissolved or release of different times. They usually contain an immediate release fraction and other fractions periodically release the drug.

 

1.7.7: Erosion Core with Initial Dose :

In this kind of sustained product the drug is usually incorporated into tablet with insoluble materials such as high molecular weight Fats and Waxes. This is non-disintegrating tablets that maintain its geometric

 1.7.8:  Erosion Core Only:

The dosage form is formulated to contain only the sustained release component. The primary purpose is to maintain a therapeutic consideration once therapy has been initiated.

1.7.9: The Ion Exchange Resins:

The ion exchange method involves the administration of dosage form containing salt of drug complexes with an ion exchange resin that exchanges the drug for ions as it passes through the gastrointestinal tract

                                                {C}{C}

                                         Fig1.5:IonExchangeResins       

(Ref: http://www.epuro.fr/images/standard/96/ion_exchange_resin_03.jpg)

1.7.10: Complexation: The preparation of complex or salt of active drug that are highly soluble in the gastrointestinal fluid is the strategy used in this method of producing sustained release product

                                            

 

Fig1.6:  Dinuclear Complexation – (CO)5MnRe(CO)5

 

1.7.11: Micro encapsulation

Microcapsules are small particles that contain an active agent or core materials surrounded by a coating or shell. The release of the drug through the microencapsulated particles takes place by diffusion rather than by simple dissolution or disintegration. The drug diffuses through the wall of the microcapsules and dissolved in the gastrointestinal fluid

{C}{C}

Fig1.7:  Dinuclear Complexation

1.7.12:  Osmotic tablet:

The osmotic tablet consists of core tablet and semi-permeable coating with a hole, produced by a laser beam. The drug exists through the hole due to the osmotic pressure, which occurs when the gastrointestinal fluid passes the semi-           

Permeable membrane and reaches the core 

                                                         {C}{C}

Fig1.8: Osmotic tablets (www.wikipedia.org)

 

1.7.13:  Encapsulated Slow Release Granules:

In this type of dosage form the non-peril seeds are initially coated with adhesive and followed by powdered drug. The step is repeated until desired amount of drug has been applied. Then the granules are coated with mixture of solid hydroxylated lipids, which helps to sustain the release of active ingredient.

                                           

Fig 1.9:  Encapsulated  Granules

 

1.7.14:  Gel forming Hydrocolloids:

In this kind of dosage form the capsules are filled with dry mixture of drug and hydrocolloids. Upon dissolution the gastric fluid swells the outer most hydrocolloids to form gelatinous area, which acts as barrier and prevents the further penetration of gastric fluids. The gelatinous core erodes and new barrier layer forms. This process is continuous, releases the drug as each layer continues to erode and forms new layer.

 

 

1.8: Advancement in Methods of Sustaining Drug Action

Milo Gibaldi, Ph.D., Dean of the University of Washington's School of Pharmacy in Seattle, writes in ‘Biopharmaceutics and Clinical Pharmacokinetics’ that:  

" The early history of the prolonged-release oral dosage form is probably best forgotten. Products were developed empirically, often with little rationale, and problems were common. Today, the situation has improved; many of the available products are well-designed drug delivery systems and have a defined therapeutic goal. In some cases, the prolonged-release dosage form is the most important and most frequently used form of the drug."

In recent years, there have been numerous developments in polymeric carriers and controlled release systems (some commercially available devices have been described by Lonsdale, 1982). A few examples mentioned in the literature include:

{C}v  {C}Films with drug in a Polymer Matrix / Monolithic Devices (Singh et al., 1988).

{C}v  {C}The drug contained by the polymer that acts as Reservoir Devices (Nakagami and Matsumura, 1991). 

{C}v  {C}Polymeric colloidal particles or microencapsulates (Microspheres or Nanoparticles) in the form of reservoir and matrix devices (Giddings and Farquaharson, 1975). 

{C}v  {C}Drug contained by a polymer containing a Hydrophilic or Leachable Additive eg, A second polymer, surfactant or plasticizer, etc. (Nicholas, 1987; Udeala and Aly, 1989; Gardner, 1983)

{C}v  {C}Enteric Coatings, ionize & dissolve at suitable pH (Gregoriadis et al., 1984)

{C}v  {C}Soluble polymers with covalently attached 'Pendant' Drug molecules

     (Poznansky et al, 1984; Tomlinson et al, 1986)

{C}v  {C}Devices where release rate is controlled dynamically, eg, the Osmotic Pump

( Patrick, O’Donnell and James, 1997

 

1.9: Matrix Granules:

Th.e matrix system is commonly used for manufacturing sustained release dosage forms because it makes such manufacturing easy. In this system, the drug in the form of fine powder and a matrix forming components are mixed and the mixtures are then shaped in an appropriate mold. Nonbiodegradeble polymer and wax are commonly used as matrix forming components. The use of wax seems to have a particular advantage due to its wax matrix. Drugs however, are, sometimes unstable under heating. So manufacturing machines and operational conditions have to be carefully specified to obtain wax matrices with desired properties.

1.10: Monolithic Devices (Matrix Devices)

Monolithic (matrix) devices are possibly the most common of the devices for controlling the release of drugs. This is possibly because they are relatively easy to fabricate, compared to reservoir devices, and there is not the danger of an accidental high dosage that could result from the rupture of the membrane of a reservoir device. In such a device the active agent is present as dispersion within the polymer matrix, and they are typically formed by the compression of a polymer/drug mixture or by dissolution or melting. For low loadings of drug, (0 to 5% W/V) the drug will be released by a solution-diffusion mechanism (in the absence of pores). At higher loadings (5 to 10% W/V), the release mechanism will be complicated by the presence of cavities formed near the surface of the device, as the drug is lost.

Matrix type drug delivery systems are an interesting and promising option when developing an oral controlled release system. Matrix tablets are easy to manufacture by direct compression. The kinetics often follows the laws described by Higuchi. Diffusion is the dominant mechanism controlling the dissolution of water-soluble drugs and erosion of the matrix is the dominant mechanism controlling the release of water insoluble drugs. However, generally the release of drugs will occur by a mixture of these two mechanisms. The swelling behavior of swellable matrices is mechanistically described by front positions. Front indicates the position in the matrix where the physical conditions sharply change ( Bettini and  Peppas, 1998).

 

Fig 1.10:  Different Front Positions in a Swellable Matrix

.11: Matrix Tablet System

 

 

 

 

 

 

Figure 1.11: Sustained Release matrix.

The term matrix tablet describes a tablet in which the drug is applied in a skeleton of nondissolving material. It needs simply direct compression of blended drugs and retarding additives to form tablets. It is one of the least complicated approaches too the manufacture of sustained/controlled release dosage forms, which consists of a drug dispersed in a polymer, the polymer playing the role of a matrix (Fessi et al. 1982; Focher et al.1984; Heller, 1984; Armand et al.1987Matrix systems are relatively easy to formulate. Tablets are manufactured with existing, conventional equipment and processing methods. Matrix controlled release tablets are relatively simple systems that are more forgiving of variations in ingredients, production methods and end-use conditions than coated controlled – release tablets and other systems.

Direct compression is an accepted pharmaceutical manufacturing technique because of its many advantages such as low equipment costs, short processing time and limited steps, low labor and energy requirements, and use of non-solvent processes. Considerable efforts have been made and are being continued to develop new drug concepts in order to achieve zero order or near zero order kinetics. To alter the kinetics of drug release from inherent non-linear behavior, the use of matrices with erosion, diffusion and swelling controlled mechanisms have changed the release rate (Khan and Zhu, 2001).

There may be different classes of retardant materials used to formulate a matrix tablet, which is given below in table 1.3:

Table 1.1. Materials used as retardants in matrix tablets
Matrix characteristics	Material
Insoluble, Inert (Plastic matrix)	Polyethylene Polyvinyl chloride Ethyl cellulose Methyl acrylate –methacrylic acid copolymer Cellulose acetate Vinyl acetate/vinyl chloride copolymer
Insoluble, erodable (Fat-Wax matrix)	Carnauba wax Bees wax Stearic acid Paraffin wax High molecular weight polyethylene glycols Guar Gum Triglycerides
Hydrophilic	Methyl cellulose Sodium carboxymethyl cellulose Hydroxypropyl methylcellulose Sodium alginate Gelatin
Hydrogel	Poly vinyl alcohol Poly hydroxyl alkyl methacrylates Ethylene vinyl alcohol and their copolymers.

Several other workers (Desai et al, 1965) have also reported that the rate of drug released from a matrix is affected by:

{C}·        Drug solubility

{C}·        The composition of the matrix

{C}·        P^H of the dissolution fluid

{C}·        Shape

{C}·        External agitation

{C}·        Mass of the drug and

{C}·        The porosity of the matrix

There are two other problems also of interest:

{C}1)      {C}When the solubility of the drug is low in the acid gastric fluid as well as the rate of dissolution & when it is necessary to help the drug dissolve in this liquid by provoking the extraction of the drug out of the dosage form.

{C}2)      {C}When the solubility is very low in the acid gastric liquid & rather high in the intestine where the pH is around 8.

{C}3)      {C}The polymer is rather complex, especially, with dosage forms made of an erodible polymer, as not only erosion of the polymer takesp lace, but also diffusion of the liquid through the polymer & even diffusion of the drug through the liquid located within the polymer (Liu. et al., 1988)

There are four basic release systems for matrix formulations:

{C}a.       {C}Inert Non-Bioerodible Matrix System

{C}b.      {C}Bioerodible Matrix System

{C}c.       {C}Swelling Controlled System

{C}d.      {C}Magnetically Controlled System

In matrix system, the release is controlled by a combination of several physical processes. These include:

{C}·         {C}Permeation of the matrix by water

{C}·         {C}Leaching (extraction or diffusion) of the drug from the matrix

{C}·         {C}Erosion of the matrix material

Alternatively, the drug may dissolve in the matrix material & be related by diffusion through the matrix material or partitioned between the matrix & extracting flui(Higuchi, 1963)

1.12: Release Mechanism from Matrices

Various theories have been elaborated by considering either diffusion (Armand et al., 1987) in the case of non-erodible polymers, or erosion with erodible polymers (Bidah and Vernaud, 1991)

 In fact, the release mechanism from the polymer is rather complex, specially, with dosage forms made of an erodible polymer, as not only erosion of the polymers takes place, but also diffusion of the liquid through the polymer & even diffusion of the drug through the liquid located within the polymer also takes place.

 

 Table 1.2: Release mechanism   from matrix

 

Inert Non-Bioerodible Matrix System Drug diffusion through the Polymer matrix tablet is the rate limiting step	{C}{C}
Bioerodible Matrix System The drug dispersed in a polymer and releases according to the rate of polymer bioerosion.	{C}{C}
Swelling Controlled System Water penetrates into the matrices; the polymer particles swell modifying the matrix dimensions according to the leaded drug & polymer.	{C}{C}
Magnetically Controlled System Drug & small magnetic beads are uniformly dispersed to viscous medium; drug is released exposure to an oscillating internal magnetic field (Langer et al., 1980)	{C}{C}

In matrix system, the release is controlled by a combination of several physical processes. These include:

{C}·         {C}Permeation of the matrix by water

{C}·         {C}Leaching (extraction or diffusion) of the drug from the matrix

{C}·         {C}Erosion of the matrix material

1.13: Matrix devices with hydrophilic polymer

The third group of matrix formers represents non-digestible materials that form gels in situ. Drug release is controlled by penetration of water through a gel layer produced by hydration of the polymer and diffusion of drug through the swollen, hydrated matrix, in addition to erosion of the gelled layer. Formulations of this type release 100% of drug. Release rate can be adjusted for low-milligram-potency formulation by replacing polymers with lactose. Generally, their release rate modulation is achieved using different grades of polymers (Nakano et al., 1983), different types of polymers (Baveja et al., 1987), soluble fillers (Ford et al., 1985), or insoluble fillers (Rao et al., 1990)  One of the major drawbacks of bioerodible systems is that as the release is eroded the surface area of the implant decreases. Bioerodiblep olymers release active drugs at a controlled rate via three major mechanism ( J.Heller, 1980).

{C}·         {C}Water-soluble polymers insolubilized by degradable cross-links

{C}·         {C}Water insoluble polymers solubilized by hydrolysis, ionization or protonation of pendant side groups

{C}·         {C}Water insoluble polymers solubilized by back-bone-chain cleavage in small water-soluble molecules. In most cases, the mechanism of solubilization is a combination of all three mechanisms.

2.1 Materials and Method:

Materials that are used throughout the experiment are listed below with their 

Table 2.1: List of ingredients used in experiment

 

Sl No.	Name of experiments	Category	Country of origin
1	Naproxen	Drug	Incepta Pharmaceuticals Ltd,
2	Methocel K  4M CR	Sustaining polymer	Incepta Pharmaceuticals Ltd,
3	Povidone k30	Binder	Albright & Wilson Ltd,
5	Methocel K15M CR	Sustaining polymer	Incepta Pharmaceuticals Ltd,
6	Pre gelatinized starch	Diluent of compressable grade	China
7	CMC-50,000 cps	Sustaining polymer	China
8	Ethyl cellulose(20 premium)	Sustaining polymer	China
9	Isopropyl Alcohol(IPA)	Granulating solvent	Merck,  Gemany
10	Na CMC	Sustaining polymer	China
11	Aerocel-2000	glident	China

 

Table 2.2: List of Instruments used in the preparation and evaluation of Naproxen based matrix tablets

 

Table 2.3: List of reagents used in experiment

 

 

2.2      DRUG PROFILE:

2.2.1   Drug Profile – Naproxen

Naproxen is one of the most potent non steroidal anti-inflammatory agents: it also presents analgesic and antipyretic properties. The anti-inflammatory effects of naproxen and most of its other pharmacologic effects are generally through to be related to its inhibition of cyclooxyginase and consequent decrease in prostaglandin

          {C}{C}

                                                      Fig: 2.1:  Naproxen

Formula: C₁₄H₁₄O₃,

Molecular Mass: 230.259g/mol

Chemical Properties: 

Naproxen is a member of the arylacetic acid group of non steroidal anti-inflammatory drugs (NSAIDs). The chemical name of naproxen is (S)-6-methyloxy-a-methyl-2-naphthaleneacetic acid. Its empirical formula is C₁₄H₁₄O₃, requested with the following structure:

 

DRUG CLASS AND MECHANISM:

Naproxen belongs to a class of drugs called non-steroidal anti-inflammatory drugs (NSAIDs). Other members of this class include ibuprofen (Motrin), indomethacin (Indocin), nabumetone (Relafen) and several others. These drugs are used for the management of mild to moderate pain, fever, and inflammation. They work by reducing the levels of prostaglandins, chemicals that are responsible for pain, fever and inflammation. Naproxen blocks the enzyme that makes prostaglandins (cyclooxygenase), resulting in lower concentrations of prostaglandins. As a consequence, inflammation, pain and fever are reduced. Naproxen was approved by the FDA in December, 1991.

Physical Properties:

Naproxen is an odorless, white to off-white crystalline substance. It is lipid soluble, practically insoluble in water at low pH and freely soluble in water at pH 7.4 is 1.16 to 1.8. Naproxen has a melting point of 153 K.

Clinical Pharmacology:

Pharmacodynamics:

 Naproxen is a non steroidal anti-inflammatory drug (NSAID) with analgesic and antipyretic properties. As with other NSAIDs, its mode of action is not fully understood: however, its ability to inhibit prostaglandin synthesis may be involved in the anti-inflammatory effect.

Pharmacokinetics:

Naproxen is itself is rapidly and completely absorbed in gastrointestinal tract with an in vivo bioavailability of 95%. The different dosage forms of Naproxen are bioequivalent in terms of extent of absorption (AUC) and peak concentration (C_max):. Steady state levels of naproxen are reached in 4 to 5 days, and the degree of accumulation is consists with this half-life.

 

Absorption:

After administration of naproxen tablets, peak plasma levela are attained in 2 to 4 hours. After oral administration of naproxen sodium tablets, peak plasma levels are attained in 1 to 2 hours.

Distribution: Naproxen has a volume of distribution of 0.16 L/kg; At therapeutic levels naproxen is greater than 99% albumin-bound. At doses of naproxen greater than 500 mg/day there is a less than proportional increase in plasma levels due to an increase in clearance caused by saturation of plasma protein binding at higher doses.

Metabolism: Naproxen is extensively metabolized to 6-Q-desmethyl naproxen and both

parent and metabolites do not induce metabolizing enzymes.

Excretion:

The clearance of naproxen is 0.13 ml/min/Kg. Approximately 95% of the naproxen from any dose is excreted in the urine, primarily as naproxen (less than 1%), 6-o-desmethyl naproxen (less than 1%) or their conjugates (66% to 92%). The plasma half-life of naproxen anion in human ranges from 12 to 17 hours. The corresponding half-lives of both naproxen's metabolites and conjugates are shorter than 12 hours.

Special Populations:

Pediatric Use: No pediatric studies have been performed with naproxen sodium extended-release tablets, thus safety of naproxen sodium extended- release tablets in pediatric populations have not been established.

Renal Insufficiency: Naproxen pharmacokinetics has not been determined in subjects with renal insufficiency. Given that naproxen is metabolized and the kidneys primarily excrete conjugates, the potential exists for naproxen metabolites to accumulate in the presence of renal insufficiency. Elimination of naproxen is

decreased in patients with severe renal impairment, Naproxen -containing products are not recommended for use in patients with moderate to severe renal impairment (creatinine clearance < 30 ml/min).

 

Indication

Naproxen Is Indicated for the relief the signs and symptoms of

• Rheumatoid Arthritis

• Osteoarthritis

• Ankylosing spondylitis

• Juvenile arthritis

• Tendinitis

• Bursitrs

• Acute Gout

• Management of Pain

• Primary Dysmenorrhea

 

Dosage and Administration:

The usual adult dose is 250-500 mg twice daily using regular naproxen tablets. The usual dose for Naproxen controlled release tablets is 500 to 1000 mg given once daily. For EC-Naprosyn (Naproxen Enteric coated tablet), the usual dose is 375-500 mg-twice daily. Naproxen should be given with food to reduce upset stomach.

 

Contraindication

All naproxen products are contraindicated in patients who have had allergic reactions to prescription as welt as to over-the-counter products containing naproxen. Anaphylactoid reactions may occur in patients without previous known exposure or hypersensitivity to aspirin, naproxen, or other NSAIDs, or in individuals with a history of angioedema, urticaria, bronchospastic reactivity (e.g. asthma), and nasal polyps. Anaphylactoid reactions, like anaphylaxls, may have a fatal outcome.

PRESCRIBED FOR:

Naproxen is used for the treatment of mild to moderate pain, inflammation and fever.

DRUG INTERACTIONS:

Naproxen is associated with several suspected or probable interactions that affect the action of other drugs. The following examples are the most common suspected.

Naproxen interactions may reduce the blood pressure lowering effects of blood pressure medications. This may occur because prostaglandins play a role in the regulation of blood pressure.

When naproxen is used in combination with aminoglycosides (e.g., gentamicin) the blood levels of the aminoglycoside may increase, presumably because the elimination of aminoglycosides from the body is reduced. This may lead to more aminoglycoside-related side effects.

PREPARATIONS:

Nanprox (tablets): 275 and 550 mg; Naprosyn (tablets): 250, 375, and 500 mg; Naprosyn suspension: 125 mg/5ml; EC-Naprosyn: 375 mg, Aleve: 220 mg; Naprelan (controlled-release tablets): 375 and 500mg.

STORAGE

Room temperature: 15-30°C (59-86°F).

SIDE EFFECTS

The most common side effects from naproxen are rash, ringing in the ears, headaches, dizziness, drowsiness, abdominal pain, nausea, diarrhea, constipation, heartburn, fluid retention and shortness of breath. Naproxen also may cause stomach and intestinal bleeding and ulcers.

2.3: Excipient   profile:

2.3.1 Profile of METHOCEL 

Nomenclature

METHOCEL is a trademark of the Dow Chemical Company for a line of cellulose ether products. An initial letter identifies the type of cellulose ether, its “chemistry”. ‘A’ identifies methylcellulose (MC) products. “E”, “F”, and “K” identify different hydroxypropyl methylcellulose (HPMC) (Figure: 3.1. METHOCEL E). And K is the most widely used for controlled release drug formulation.

 

The number that follows the chemistry designation identifies the viscosity of that product in millipascal-seconds (mPa.s), measured at 2% concentration in water at 20° C. In designating viscosity, the letter “C” is frequently used to represent a multiplier of 100, and the letter “M” is used to represent a multiplier of 1000.

 

Several different suffixes are also used to identify special products. “P” is sometimes used to identify METHOCEL Premium products, “LV” refers to special low-viscosity products, “CR” denotes a controlled-release grade, and “LH” refers to a product with low hydroxypropyl content. “EP” denotes a product that meets European Pharmacopoeia requirements; “JP” grade products meet Japanese Pharmacopoeia requirements.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Fig 2.2 : Example of nomenclature for METHOCEL E cellulose ether

Description

The flexibility in using METHOCEL products in controlled release matrix tablets stems from the different types of polymer grades. The two polymer grades of METHOCEL most commonly used in controlled release applications are K (HPMC 208, USP) and E (HPMC2910, USP). Only METHOCEL Premium products can be used in controlled-release formulations (table 2.4). Typical products used in controlled release include METHOCEL K4M Premium, K15 M Premium, K100 M Premium, E4M Premium and E10 M Premium CR.

  

Table 2.4: Properties of selected METHOCEL products for use in experiment

 

Polymer Structure

METHOCEL products are available in two basic types: methylcellulose and hydroxypropyl methylcellulose. Both types of METHOCEL have the polymeric backbone of cellulose, a natural carbohydrate that contains a basic repeating structure of anhydroglucose units (Figure: 3.2). During the manufacture of cellulose ethers, cellulose fibers are treated with caustic solution, which in turn is treated with methyl chloride and/or propylene oxide. The fibrous reaction product is purified and ground to a fine powder.

Substitution Effect on Polymer

The family of METHOCEL products consists of products that vary chemically and physically according to the desired properties. The major chemical differences are in degree of methoxyl substitution (DS), moles of hydroxylpropoxyl substitution (MS) and degree of polymerization (measured at 2% solution viscosity).

                  

Fig 2.3: Typical chemical structures of METHOCEL Products

Methylcellulose is made using only methyl chloride. These are METHOCEL A cellulose ethers (methylcellulose, USP). For hydroxypropyl methylcellulose products, propylene oxide is used in addition to methyl chloride to obtain hydroxypropyl substitution on the anhydroglucose units. Hydroxypropyl methylcellulose products include METHOCEL E (HPMC 2910, USP), METHOCEL F (HPMC 2910, USP) and METHOCEL K (HPMC 2208, USP) CELLULOSE ETHERS.

The Hydroxypropyl substituent group, -OCH₂CH(OH)CH₃, Contains a secondary hydroxyl on the number two carbon and may be also considered to form a propylene glycol ether of cellulose. These products possess varying ratios of hydroxypropyl and methyl substitution, a factor which influences properties such as organic solubility and the thermal gelation temperature of aqueous solutions.

HPMC products such as METHOCEL Premium cellulose ethers are widely used in hydrophilic matrix system for controlled drug delivery. HPMC polymers are non-ionic and tolerant of most formulation variables. They deliver consistent reproducible performance and they quickly form strong, viscous gels that control diffusion of water and drug release.According to industrial data (Colombo 1993), 40 to 50 percent of all potential new drug entities are poorly soluble in water. Many promising new compounds never make it to market because of poor solubility. Others are marketed in less than optimal formulations, resulting in decreased performance and a greater risk of side-effects. By utilizing precise controlled release systems, formulators can improve the performance of existing drugs and keep other potentially valuable products from being abandened. METHOCEL Premium methyl cellulose and hydroxypropyl methylcellulose products (Pharma coat) are water soluble cellulose ethers used in a variety of pharmaceutical applications. They allow developers and pharmaceutical manufacturers to create reliable formulas for tablet coating, granulation and controlled release as well as for viscosity control in liquid formulations.

2.3.2 Profile of ETHYLCELLULOSE 20 premium

ETHOCEL* ethylcellulose (EC) is derived from cellulose. Like cellulose, the backbone of the molecule of ETHOCEL is based on repeating anhydroglucose units.

{C}{C}{C}

Fig 2.4 : Structural formula of ethyl cellulose

Synonyms: Aquacoat, E462, Ethocel, Surelease

Chemical name: Cellulose ethyl ether

Empirical formula & molecular weight: Ethylcellulose with complete ethoxyl substitution (DS =3) is:

C₁₂H₂₃O₆(C₁₂H₂₂O₅)_nC₁₂H₂₃O₅

Where n can can vary to provide a wide variety of molecular weights.

 

Pharmaceutical application:

EC is widely used in oral & topical pharmaceutical formulations (table3.7)

Table 2.5: Uses of typical concentrations of ethylcellusose

The main use of ethyl cellulose in oral formulation is as a hydrophobic coating agent for tablet & granules. EC coatings are used to modify the release of a drug, to mask an unpleasant taste, or to improve the stability of a formulation, as in the case where the granules are coated with EC to inhibit oxidation. Midified release tablet formulations may also be produced using EC as matrix former (Kibbe A., 2000).

Characteristics
Non proprietary name:	BP: Povidone USP: Povidone
Synonyms:	Kollidon, plasdone, polyvinyl pyrrolidone, PVP
Chemical name:	1- Ethenyl-2- pyrrolidone homopolymer
Empirical formula:	(C6H9NO)n
Molecular weight:	2500-3000000
Description:	Povidone occurs as a fine, White to creamy white colorless odorless, hygroscopic powder. Povidones with K –values equal to or lower than 30 are manufactured by spray –drying and occur as spheres. Povidones with K –values equal to or lower than 90 are manufactured by drum drying and occur as plates.
pH(1%w/w in water):	3.0-5.0
Functional category:	Disintegrant, dissolution aid, tablet binder.
Applications in pharmaceutical industry:	In tableting, povidone solutions are used as binders in wet granulation process. , povidone solutions may also be used as coating agents.

2.3.3: Profile of Povidon K30

 

2.3.4: Profile of Starch 1500

Nonproprietary name: Pre gelatinized starch (USP)

Synonyms: Compressible starch, Inststarch, Lycatab PGS, Pharma gel, Sepistab ST 1500, Starch 1500.

Empirical formula, molecular weight: (C₆H₁₀O₅) _n

Where, n = 300-1000

Pre gelatinized starch is a starch that has been chemically and/or mechanically processed to rupture all or part of the starch granules & so render the starch flowalable & directly compressible. Typically pre gelatinized starch contains 5% free amylase, 15% free amylopectin & 80% unmodified starch.

Structural Formula

{C}{C}

 

Fig 2.5: Chemical structure of Pre gelatinized starch

Application in Pharmaceutical formulation: Pre gelatinized starch is a modified starch used in capsule & tablet formulations as a binder, diluents and disintegrant. In comparison to starch, grades of pre gelatinized starch may be produced with enhanced flow & compression characteristics such that the pre gelatinized material may be used as a tablet binder in dry compression processes. In such processes pre gelatinized starch is self-lubricating. However when used with other recipients It may be necessary to add a lubricant to a formulations. Pre gelatinized starch may also be used in wet granulation processes.

Table 2.6: Application of Starch 1500 according to its content

Typical properties

• Acidity/alkanity: pH = 4.5-7.0 for a 10% w/v aqueous dispersion.
• Angle of repose: 40.7^o
• Density (true): 1.516 g/cm³
• Moisture content: it is hygrospic
• Particle size distribution: 30-150 µm
• Solubility: Practically insoluble on organic solvent. Slightly soluble in cold water, depending upon the degree of pregelation.
• Viscosity: 8-10 mPa s (8-10 cP) for a 2% w/v aqueous dispersion 3.3.8 Profile of Aerosil 2000

 

 

Table 2.3.5: Aerosil at a glance

Feature	Description
Nonproprietary names	BP:     Colloidal anhydrous silica USP:   Colloidal silicon dioxide PhEur:  Silica colloidalis anhydrica
Synonyms	Cab-O-Sil Colloidal silica Fumed silica
Chemical name	Silica
Empirical formula	SiO2
Structural formula	SiO2
Molecular weight	60.08
Appearance	Colloidal silicon dioxide is submicroscopic fumed silica with a particle size of about 15 nm. It is a light, loose, bluish-white colored, odorless, tasteless, nongritty amorphous powder.
Acidity/alkalinity (pH)	3.5-4.4 (4% w/v aqueous dispersion)
Density	0.029-0.042 g/cm3 (Bulk)
Solubility	Practically insoluble in organic solvents, water, and acids, except hydrofluoric acid; soluble in hot solutions of alkali hydroxide. Forms a colloidal dispersion with water.
Specific gravity	2.2
Refractive index	1.46
Functional category	Adsorbent, Glidant, Ant caking agent, Tablet disintegrant Suspending agent.

 

2.4:  Methods:

Table 2.8: Formulations of Naproxen matrix tablets.

 

 

2.4.1: Preparation of Naproxen matrix tablets:

Step-1: Preparation of binder solution

Iso propyl alcohol (IPA) was taken in a beaker. Then, povidone K30 was weight out & added to the IPA. The mixer was continuously prepared binder solution in organic solvent.

 

Step-2: Mixing of powder

Naproxen & the other exipients(except aerosol)was weigh mentioned in the formula by electric balanc, taken in motor & mixed gradually using pastle.

Step-3: Preparation of wet mass

Power mix was added in the IPA solution gradually, stirring with a glass rod was prepared.

 Step-4: Preparation of granules

The wet mass was sieved through 1 mm mesh size sieve & the granules were collected & taken on a tray dryer at 45`c for 30 minutes.

Step-5: Collection of granules

After drying, the granules were weighed out & again sieved by <1mm mesh size (125nm) sieve. From the differences of the weight, we can find out how much drug is lost here.  Finally the granules were granulated.

Step-6: Mixing with glidient

The collected were taken granules in a photo flim pot. Now aerosol added to it and finally the granules mixing were prepared.

Step-7:  Preparation of tablets by direct Compression

 Amount of the granules were weighed & taken in single punch machine for direct compression. Finally, tablets were prepared.

2.4.2: Evaluation of flow property of the powder mix:

2.4.2: Carr’s Index:

Neumann (1967) & Carr (1965) developed a simple test to evaluate flow ability of a powder by comparing the poured (fluff) density & tapped density of a powder & the rate at which it is packed down. A useful empirical guide is given by Carr’s Compressibility Index. Here ‘Compressibility’ is a misnomer since compression is not involved. Density was measured using ‘Pharmatest’ (Germany) densitometer maintaining 1250 tapping frequencies.

CI (%) = (TD-PD) X 100 / TD

Where,

            TD = Tapped Density

            PD = Poured Density

CI = Carr’s Index.

It is a simple index that can be determined in simple quantities of powder & may be incorporated as in Table

Table 2.9: CI as an indication of powder flow properties

CI (%)	Type of Flow
5 to 15	Excellent
12 to 16	Good
18 to 21	Fair to passable*
23 to 25	Poor*
33 to 38	Very poor
> 40	Excellently poor

 

 * May be improved by addition of glidant, e.g. 0.2% Aerosil (Aulton, A.E., 2002)

2.4.2.2: Hausner Ratio  

A similar index has been defined by Hausner (1967):

Hausner Ratio = TD/PD

 

            Where,        TD = Tapped Density

                                PD = Poured density

Hausner Ratio	Type of Flow
< 1.25	Good flow
> 1.25	Poor flow
1.25 to 1.5	Added glidant normally improves flow

Table 2.10 : Hausner ratio as an indicator for powder flow (Aulton, A.E., 2002)

2.4.2.3: Angle of repose:

A glass funnel (75mm) was secured with its tip at a given height (H) above a graph paper placed on a horizontal surface. Powder or granules (2.5gm) was poured through the funnel until the apex of conical pile touched the tip of the funnel and then the angle of repose (θ) was calculated using the following formula,

Tan θ =H/R

                    Where R is the radius of conical pile (Gohel et al., 2007)

Table 3.11 : Angle of repose as an indication of powder flow properties (Aulton, A.E., 2002)

*May be improved by glidant (Aulton M. E., 2^nd edition, 2002)

{C}{C}

Fig 2.6: Measurement of angle of repose by fixed funnel method.

2.4.3: Evaluation of some physical parameters of Naproxen matrix tablets:

2.4.3.1: Hardness

The ability of a tablet to withstand mechanical handling & transport has been evaluated by various types of tests: abration, bending, indentation, hardness, diameter crushing. However the data from these tests seldom can be correlated in a precise manner. Hardness depends on the weight of the material & the space between the upper & lower punches at the moment of compression. If volume of the material or the distance between punches varies, hardness is like inconsistent.

Five tablets of each of the formulations were taken and hardness was measured by Hardness tester (Type PTB 311,511-E). The average value was calculated and the testing unit was kp.

2.4.3.2: Thickness Measurement

Six tablets of each of the formulations were taken and thickness was measured by Type PTB 311(511)-E. The values were reported in millimeter (mm). Mean was calculated.

2.4.3.3: Diameter Measurement

Six tablets of each of the formulations were taken and diameter was measured by . PTB 311(511)-E. The values were reported in millimeter (mm). Mean was calculated.

2.4.3.4. Friability Test

Six tablets of each of the formulations were taken and friability was measured by Friability tester (pharmatest, Germany). Weights of six tablets were taken. The tablets were introduced into the rotating disk and it was allowed to rotate at 25 rpm for 4 minutes. At the end of the rotation, tablets were collected, dedusted and reweighed.The friability was calculated as the percent of weight loss.

Tablet integrity is determined by calculating the percent of friability by using the following formula

            Percent of friability = (M₁ – M₂) / M₁ X 100%

Where;

M₁ = Average weight of the tablets before the rotation

M₂ = Average weight of the tablets after the rotation.

2.4.4 Preparation standard curve of Naproxen in methanol

To prepare a standard solution, 50 mg of Naproxen measured in  an  analytical balance weighing Naproxen was taken in a 100ml volumetric flask. Then methanol was added to dissolve the Naproxen and then make the volume up to 100ml by methanol to produce a solution of 500 mg / ml. 1 ml of  each this solution were taken in 6 different 100ml conical flasks and 24,19,14,11,9, and 4 ml of methanol was added to them respectively for the purpose of serial dilution. 10 ml of standard solution is also taken in a conical flask. The solutions were mixed well using shaker. These serial dilutions allowed naproxen concentration to be made in the range of 2 mg / ml to 20 mg / ml. Then absorbance of the solutions was measured at 230 nm using Single Beam UV-visible spectrophotometer. A plot was constructed showing concentration at X- axis and absorbance at the Y- axis.

The standard curve of naproxen for assay was prepared in concentration range of 5 μg/ml to 34 μg/ml. Then the absorbance of these standard solutions of different concentration was observed with Single Beam Spectrophotometer at 230nm

 

Table 2.12: Data for Standard curve in methanol

 

 

 

 

 

 

 

 

 

 

 

 

Fig 2.7: Standard Curve of Naproxen in methanol at 230 nm

2.4.5:  Evaluation of Swelling Characteristics of HPMC K4M & HPMC K15M CR based matrix Naproxen tablets:

 Swelling behaviour of SR matrix tablets: The extent of swelling was measured in terms of % weight gain by the tablet. The swelling behaviour of formulationsF1, F2, F3, F4, F5, F6 , F7.F8,F9 & F10 of Naproxen matrix core tablets were studied .In this test, one tablet from each formulation was kept in a Petri dish containing pH 7.4 phosphate buffer. At the end of 1 hour, the tablets were withdrawn, soaked with tissue paper, and weighed. Then for every 1 hour, weights of the tablet were noted, and the process was continued till the end of 7 hours, % weight gain by the tablet was calculated by formula;

S.I = {(M_t-M_o) / M_o} X 100

where, S.I = swelling index,

M_t = weight of tablet at time‘t’ and

M_o = weight of tablet at time t = 0.

2.4.6: Dissolution study of Naproxen matrix tablets:

 

Dissolution media:

The dissolution process was carried in 750ml 0.1 N HCl media at first 2 hours but the release of Naproxen was poor. Then the dissolution was carried out by adding pH 7.4fer (0.2 molar tribasic sodium phosphate) up to 8hr in 1000ml pH 7.4 phosphat buffer (which was prepared by adding 780ml 0.3M tribasic sodium phosphate and 50ml water).  The total process was continued for 10 hrs.

• Preparation of 0.1N HCl:

For preparing 0.1 N HCl , 8.3 ml concentrated HCl was taken in a  volumetric flask and add distilled waterwas added to make the volume upto 1000 ml

Calculation:

Molecular weight of HCl= 36.5gm

1litre 1N HCl = 36.5gm

1 litre 0.1N HCl = 36.5 * 0.1

                       = 3.65 gm

in 37% HCL-

                      100ml = 37gm HCl

                       1 ml   = 37/100 * 1.19gm of HCl

                                 = 0.4403gm of HCl

0.4403 gm of HCl present in =1ml of 37%HCl

3.65gm of HCl present in =1ml of 1 * 3.65/0.4403

                                     = 8.28 ml

                                     = 8.3ml

• Preparation of dissolution media (pH 7.4 Phosphate Buffer):

1. At first 1000 mL 0.3M tribasic Sodium Phosphate was prepared by dissolving 114.04 gm of Tribasic Sodium Phosphate with distilled water & then the volume was made 1000 mL. The pH of 1000mL 0.3M tribasic Sodium phosphate was 11.45.

2. In a beaker 750 mL 0.1N HCl was taken & 180 mL of previously prepared 0.3M Tribasic Sodium Phosphate was added & rest amount of water was added up to 1000 mL.  pH was checked 7.4 with pH meter. .

Calculation:

Molecular weight of Tribasic sodium phosphat(Na3PO4.12H2O)= 380.12gm

1 molar Tribasic sodium phosphat(Na3PO4.12H2O)= 380.12gm

0.3 molar Tribasic sodium phosphat(Na3PO4.12H2O)= 380.12* 0.3gm

                                                                                 =114.04gm

pH adjustment

pH adjustment can done by 2 ways

     ● Addition method

     ● pouring method

 Here, we used addition method. Taken 750 ml 0.1N HCl, added NA3PO4.12H20 by addition method to adjust the PH up to 7.4.

Finally, we found 185/165 ml of NA2PO4.12H20 is acheived the desire PH.

   ● 750 ml HCL + 180 ml Na₃PO₄.12H₂0  =PH 7.4

 

 

2.4.7: Preparation of Standard Curve of Naproxen for Dissolution Study

 

2.4.7.1: Preparation of Standard Curve of Naproxen by 0.1N HCL

To prepare a standard solution, 50 mg of Naproxen  was measured in an analytical balance after weighing  Naproxen was taken in a 100ml volumetric flask then 5ml methanol was added drop by drop by pipette for dissolve the Naproxen and then  Prepared 0.1N HCL was added to make the volume up to 100ml to produce a solution of 500 mg / ml. 1 m1each of this solution were taken in 5 different 100ml conical flasks 50 and 69, 79, 99, and  ml of 0.1N HCL was added to them respectively for the purpose of serial dilution. 10 ml of standard solution is also taken in a conical flask. The solutions were mixed well using shaker. These serial dilutions allowed Naproxen concentration to be made in 50 mg / ml. Then absorbance of the solutions was measured at 230 nm using Single Beam UV-visible spectrophotometer. A plot was constructed showing concentration at X- axis and absorbance at the Y- axis.

 

Table 2.13:  Data for Standard curve in 0.1N HCL

 

Fig 2.8:  Standard curve of Naproxen in 0.1N HCL

 

2.4.7.2: Preparation of Standard Curve of Naproxen by pH 7.4 phosphat Buffer

To prepare a standard solution, 50 mg of Naproxen was measured in an analytical balance after weighing Naproxen was taken in a 100ml volumetric flask Prepared buffer solution (pH 7.4 ) was added to make the volume up to 100ml. to produce a solution of 500 mg / ml. 1 ml of this solution were taken in each 6 different 100ml conical flasks and 9, 19, 24, 39, 49 and 9.9ml of buffer was added to them respectively for the purpose of serial dilution. 10 ml of standard solution is also taken in a conical flask. The solutions were mixed well using shaker. These serial dilutions allowed Naproxen concentration to be made in the range of 5 mg / ml to 50 mg / ml. Then absorbance of the solutions was measured at 230 nm using UV-visible spectrophotometer. A plot was constructed showing concentration at X- axis and absorbance at the Y- axis.

 

Table2.14 : Data for Standard curve of Naproxen in pH 7.4 phosphat Buffer

 

                    

               Fig 2.9: Standard curve of Naproxen in 7.4 phosphat buffer

 

2.4.7.3: In vitro release studies of the Naproxen SR in 0.1Nn 7.4 phosphate buffer:

Acid stage: The release rate of Naproxen tablets was determined by using Tablet Dissolution Tester (paddle method). The dissolution test was performed using 750 ml 0.1N HCL solution at 37°C± 0.5^oC using 50 rpm. for first 2 hours. For determining the release rate of Ranitidine HCL & Naproxen in HCL the 10 ml sample was withdrawn at 30 minutes time intervals for 2 hours, replacing with 10 ml of the fresh medium to maintain the volume constant. The samples were filtered through a Whatmaan filter paper and diluted to a suitable concentration with required media.

Buffer stage: After 2 hours, the acid stage was changed into buffer stage followed by addition of 180mL 0.3 M trisodium phosphate & 50 ml of distilled water into 750 ml of 0.1N HCL to raise the pH to 7.4. Now the release rate of Naproxen in buffer was measured for next 9 hours, withdrawing 10 ml of sample at 2 hour interval & replacing with 10 ml of the fresh medium to maintain the volume constant. The samples were filtered through a Whatmaan filter paper and diluted to a suitable concentration with required media. The peak area of the solutions was measured at 230 nm for drug Naproxen UV machine. By finding out the area produced by Naproxen & Ranitidine, percentage of drug release was calculated using an equation obtained from the standard curve. The dissolution study was continued for 2 hour in acid and 9 hours in buffer to get a simulated picture of the drug release in the in-vivo condition and drug dissolved at specified time periods was plotted as percent release.

2.4.8: Drug content assay

Drug content of the sample solution i.e. the quantity of the released drug was determined by UV analysis and the absorbance was measured at 230 nm. For each value of absorbance, the concentration of the corresponding solution was calculated by using equation of the standard curve and then the amount of drug of each vessel was determined. Finally the % of drug present in the tablet was calculated of each batch.

 

2.4.9: Data analysis method

2.4.9.1: Interpretation of Dissolution Profile

Absorbance values obtained from the dissolution studies were converted into percent release of drug from the formulations of matrix tablets. This is done by comparing the absorbance values with the standard curve.

2.4.9.2:  Kinetic Modeling of Drug Release

The dissolution profile of all the batches was fitted to zero order (Mockel and Lippold 1993), first-order, Higuchi (Higuchi 1963), and Korsmeyer (Korsmeyer 1983) equations to ascertain the kinetic modeling of drug release.

As percent release of naproxen in acid media is very less, kinetic modeling was done considering duration of dissolution in acid media as one hour. The time of two hours in acid media is considered as initial time (one hour) for such kinetic Modeling. So the responses obtained (T_25%, T_50%, T_80% & MDT) show one hour less than the actual value. After linear transformation of dissolution curves, the results were tested with the following mathematical models

{C}Ø  {C}Zero order release profile:

The Zero order equation assumes that drug release is constant:

M = M_o  – K_ot   ———————————— (I)

In this equation M is the amount of drug remaining undisclosed at time t, M_o is the amount of drug undissolved at t=0 and K_o is the corresponding release rate constant. Zero order plot of drug release is obtained by plotting percent release of drug versus time in hour.

{C}Ø  {C}Higuchi release profile:

A form of the Higuchi Square Root Law is given by equation:

Q= K_H√t ———————————————    (II)

Where Q (Q = 100 – M) is the amount of drug dissolved at time t and K_H is the corresponding rate constant. Hence drug release is proportional to the square root of time. Here cumulative percentage of drug release is plotted vs. time. The Higuch’s model which describes release by Fickian diffusion through a porous matrix (Higuchi, 1963).Two factors, however, diminish the applicability of Higuchi’s equation to matrix systems. This model fails to allow for the influence of swelling of the matrix (upon hydration) and gradual erosion of the matrix (Abd-el-Kader H et al, 2007).

{C}Ø  First order release kinetics:

Release behavior generally follows the following first order release equation:

In M = In M_o – K₁t ———————————————    (III)

 

Where M is the amount of drug undissolved at time t, M_o is the amount of drug undissolved at t=0 and K₁ is the corresponding release rate constant.

{C}Ø  Korsmeyer release profile:

The Korsmeyer’s equation is:

M_t / M_α = K_ktⁿ ———————————————    (IV)

Where M_t/M_o is the fraction of solute release, t is the release time, K_k is the kinetic constant characteristic of the drug/polymer system and n is the diffusion exponent or release exponent that characterizes the mechanism of release tracers. Log fraction release as a function of log of time (hour) gives the Korsmeyer release pattern from various formulations of Naproxen tablets.

Ritger and Peppas have defined the exponent n as a function of the aspect ratio for 1- dimentional to 3- dimentional systems (slabs, cylinders, and sphere). The aspect ratio (2a/l) is defined as the ratio of diameter (2a) to thickness (L) (Abdelkader H et al, 2007)

Table 2.15: Geometric dependence of diffusion exponent (n) and variation of n values with mechanism of diffusion
Diffusion exponent (n)			Mechanism of transport
Cylinder	Sphere	Slab
< 0.45 or 0.45	< 0.43 or 0.43	< 0.5 or 0.5	Fickian (class I) diffusion
>0.45 or < 0.89	>0.43 and <0.85	>0.5 and <1.0	Anomalous / non – Fickian transport
0.89	0.85	1.0	Class II / Zero order transport
>0.89	>0.85	>1.0	super Class II transport

For tablets, depending on the aspect ratios, n is bellow 0.45, the Fickian diffusion phenomenon dominates, and n between 0.45 and 0.89 is an anomalous transport (coupled diffusion & polymer matrix relaxation) often termed as first-order release.  Purely matrix relaxation or erosion mediated release occurs for n = 0.89 (zero-order kinetics). After the n value reaches 0.89 and above, the release can be characterized by case II and super case II transport, which means the drug release rate does not change over time and the release is characterized by zero-order release. In this case, the drug release is dominated by the erosion and swelling of the polymer (Peppas, 1985; Chueh et al., 1995). The release exponent, n, is the slope of log fraction of drug release vs. log time curve.

 

2.4.10: Successive Fractional Dissolution Time

To characterize the drug release rate in different experimental conditions, T_25%, T_50% (mean dissolution time) and T_80% were calculated from dissolution data according to the following equation

T_25% = (0.25/k)^1/n

 T_50% = (0.5/k)^1/n

 T_80% = (0.8/k)^1/n

Mean Dissolution Time can also be calculated by the following equation (Mockel and Lippold 1993).  

MDT = (n/n+1). K^-1/n

Mean dissolution time (MDT) value is used to characterize the drug release rate from the dosage form and the retarding efficiency of the polymer. A higher value of MDT indicates a higher drug retaining ability of the polymer and vice-versa. The MDT value was also found to be a function of polymer loading, polymer nature and physico-chemical properties of the drug molecule. (Mockel and Lippold 1993)

 

 

Fig 2.10: Naproxen matrix tablets before drying

 

 

Fig 2.10: Naproxen matrix tablets after dissolution for 3 hrs

 

 

       

Fig 2.11:  Naproxen matrix tablets after dissolution for 6 hrs

 

3.1: Characterization of granules

 Naproxen tablets were prepared by wet granulation process prior to compression; granules were evaluated for their characteristic parameters. Angle of repose was measure by fixed funnel method. Bulk density and tapped density were determined by cylinder method, and Carr’s index and Hausner ratio were calculated.

 

Table3.1: Characteristics of granules of formulations of 1- to 10

Formulation	CI (%)	HR	Angle of repose
F-1	16.67	1.2	23.94
F-2	18.18	1.222	25.64
F-3	16.67	1.2	29.68
F-4	18.18	1.22	27.02
F-5	20.00	1.25	17.58
F-6	18.18	1.222	19.03
F-7	15.38	1.182	21.35
F-8	14.29	1.167	23.94
F-9	16.67	1.2	23.94
F-10	15.38	1.182	21.4

 

From the above table, it is found that only F-7 & F-10 shows CI(%) 15.38 & 15.38 respectively ,As the good flow property is observed within the range was 12 to 16.   F-7.& F-10 has good flow property. Again, F-8 gives an excellent flow property. F-2, F-4 & F-6 give a good result (range-15 to 18) and F-1, F-9 ,F-5 & F-3 were give a flow of fair to passable, means that the flow may be increase by addition of glidient such as aerosol.

 

According to Hausner ratio, the range of good flow property range is <1.25 It is  found from the above table, that all the formulations except F-5 follow these range, means that their flow property is good. Only F-5 shows that flow property may be increased by adding glident.

 

From the angle of repose range, F-5 & F-6 were shown the excellent flow property (<20). Besides them all the formulation were shown good flow property, here the range is 20-30.

 

Fig 3.1: Relationship between Car’s index (%) and angle of repose of granules of F-1 to F-10

 

3.2: Characteristics of tablets

 “Single punch compression machine” with 10mm diameter punch and die were used to compress Naproxen mixture as stated earlier. The properties of the compressed matrix   tablets, such as hardness, friability  were determined. Pharma test, Type PTB 311(511)-E was used to measure the diameter and the thickness of the tablets disc. The average thickness and the diameter were found as 2.14 mm and 7.93 mm for all formulations. Hardness of 3 matrix tablets from each formulation was tested using Type PTB 311(511) -E hardness tester. The hardness of tablets was measured in kp.

 

Friability means the ability to produce a solid substance into a smaller piece with little effort. The integrity of the tablets formulation was assessed by rotating 3 tablets trom each formulation in a tablet friability tester. Tablet friability tester was equiped with a specific rotating disk. Weigh of tablets were taken. The tablets were introduced into a rotating disk and it was allowed to rotate at 100 rpm for 1 minute. At the end of the rotation, tablets were collected and weigh of the tablets were taken. The average % friability was found less than 0.4%, which was well within the acceptable range of 1% and indicates the  tablet surfaces are strong enough to withstand mechanical shock or attrition during stroge and transportation until they are consumed (Merchant al,2006)

 

Table 3.2: : Physical properties of Naproxen based matrix tablets

 

 

Table 3.3:  Data of hardness of formulations of Naproxen

Formula	Hardness(kp)
F-1	1.8
F-2	4.5
F-3	1.5
F-4	2.9
F-5	17.5
F-6	5.5
F-7	2.7
F-8	9
F-9	12.4
F-10	11.6

 

 

Fig 3.2:  Bar diagram of hardness of various formulations of Naproxen matrix tablets

 

3.3: Swelling property of HPMC based matrix tablets :

Swelling study of different formulations of Naproxen matrix tablets are performed. Among the five formulations, F-5 swells more than others. As F-5 contains 5% Methocel K4M and 10% CMC-50,000cps, both of them are strong hydrophilic polymer. Among the formulation, 6 to 10, we found that F-8 shows more swelling action for 3 hours. In F-8 formulation, Methocel K15M, Na-CMC and CMC polymer are used in 1: 1:1 ratio. For this, it shows most swelling property.

 

Table 3.4: : Data for swelling index of F-1 to F-5

Time(hr)	SI (%) of Formulations
	F-1	F-2	F-3	F-4	F-5
0 hr	0	0	0	0	0
1 hr	36.308	21.875	58.493	74.952	138.314
2 hrs	21.572	4.297	83.683	76.207	142.184
3 hrs	–	–	–	–	133.870
4 hrs	–	–	–	–	133.908

 

 

Fig 3.3: Comparison of swelling index of Methocel K4M  CR & K15M based matrix tablets

 

 

Table 3.5: Data for swelling index of F-6 to F-10

SI (%)	Formulations
	F-6	F-7	F-8	F-9	F-10
0 hr	0	0	0	0	0
1hr	126.832	106.836	140.708	143.548	183.861
2hr	126.336	139.258	192.168	152.137	167.442
3hr	109.160	171.875	196.991	165.726	116.744
4hr	–	171.484	183.407	167.137	112.558
5hr	–	137.5	–	154.0323	81.86047

 

 

Fig 3.4: Comparison of swelling index of Methocel K4M CR & K15M based matrix tablets

 

3.4: In vitro dissolution study of Naproxen matrix tablets:

Naproxen matrix tablets were formulated according to different formulations, Their dissolution studies were performed with a rpm of 50 rpm at 37.5c using apparatus -2 (paddle method) placed in 750ml of 0.1N HCL for 2 hrs, followed by 100 ml pH 7.4 phosphat buffer media. In 0.1N HCL, the drug release was very poor or very negligible. So  it’s result was not shown here. For this, the result of the drug action in phosphate buffer was present here. Each formulation is used in dissolution study and the release patterned of Naproxen was monitored up to 9 hrs.

 

Table 3.6: Data for zero order kinetics of Methocel K4M based Naproxen matrix tablets

 

Time (hours)	% Release
	F-1	F-2
0	0.000	0
2	7.17	18.30
4	27.80	47.35
6	50.27	61.60
8	57.85	74.38
9	79.24	91.48

 

 

Fig 3.5: Zero order plot of release kinetics of Naproxen from Methocel K4M based matrix tablets

 

Table 3.7: Data for Highuchi release kinetics of Methocel K4M based Naproxen matrix tablets

 

Time(hr)	Square root of time (hr)	%  release
		F-1	F-2
0	0	0	0
2	1.414	7.17	18.30
4	2	27.80	47.35
6	2.449	50.27	61.60
8	2.828	57.85	74.38
9	3	79.24	91.48

 

 

Fig 3.6: Highuchi plot of release kinetics of Naproxen from Methocel K4M based matrix tablets

 

 

 

Table 3.8: Data for 1^st order kinetics of Methocel K4M based Naproxen matrix tablets

 

Time(hour)	Log % Remaining
	F-1	F-2
0	2	2
2	1.968	1.912
4	1.859	1.721
6	1.697	1.584
8	1.625	1.409
9	1.317	0.930

 

 

 

Fig 3.7: 1^st order plot of release kinetics of Naproxen from Methocel K4M based matrix tablet

 

Table 3.9: Data for korsmeyer release kinetics of Methocel K4M based Naproxen matrix tablets

 

Log Time (hours)	Log fraction release
	F-1	F-2
0.301	-1.145	-0.738
0.602	-0.556	-0.325
1.778	-0.299	-0.210
0.903	-0.238	-0.129
0.954	-0.101	-0.039

 

 

 

Fig 3.8: Korsmeyer plot of release kinetics of Naproxen from Methocel K4M based matrix tablets

3.5:  Effects of MethocelK4M on release kinetics of Naproxen from Naproxen based matrix tablets

 

For these experiments  Methocel K4M was used for  Naproxen matrix tablets, It is shown that F-1 gives 79.24% release of Naproxen at 9 hrs and F-2 shows 91.48% release at 9 hrs.  Here F-1 shows more rate retarding action than F-2 as F-1 contains 20% Methocel K4M and F-2 contains 15%.   

  

Table 3.10: Data for zero order release kinetics of Methocel K15M based Naproxen matrix tablets

 

Time (hours)	% Release
	F-3	F-4
0	0.000	0
2	5.66	17.73
4	22.13	35.46
6	39.27	50.72
8	52.65	63.52
9	72.02	85.53

 

 

Fig 3.9: Zero order release profile of Naproxen from Methocel K15M based        matrix tablets

Table 3.11: Data for Highuchi plot of release kinetics of Methocel K15M based        matrix tablets

 

Root of time	%  release
	F-3	F-4
0.000	0	0
1.414	5.66	17.73
2.000	22.13	35.46
2.449	39.27	50.72
2.828	52.65	63.52
3	72.02	85.53

 

Fig 3.10: Highuchi plot of release kinetics of Naproxen from Methocel K15M based matrix tablets

 

 

Table 3.12: Data for 1^st order plot of release kinetics of Methocel K15M based Naproxen matrix tablets       

Time(hour)	Log % Remeaning
	F-3	F-4
0	2	2
2	1.975	1.915
4	1.891	1.810
6	1.783	1.693
8	1.675	1.562
9	1.447	1.161

                   

 

Fig 3.11: 1^st order plot of release kinetics of Naproxen from Methocel K15M based matrix tablets

 

Table 3.13: Data for korsmeyer plot of release kinetics of Methocel K4M based Naproxen   matrix tablets

 

   

 

Fig 3.12: Korsmeyer plot of release kinetics of Naproxen from Methocel K4M based matrix tablets

 

3.6: Effects of MethocelK15M on release kinetics of Naproxen from Naproxen based matrix tablets

 

 For these formulations, Methocel K15M was used for Naproxen matrix tablets. It is shown that F-3 gives 70.02% release of Naproxen at 9 hrs and F-2 shows 85.539% release at 9 hrs.  Here F3 shows more rate retarding action than F-4, as F-3 contains 20% Methocel K15M and F-4 contains 15%.Though Methocel K15M is more viscous so it shown more retarding property than F-1.     

 

Table 3.14: Zero order release profile of MethocelK4M, CMC-50,000cps and Na-CMC based Naproxen matrix tablets

 

Time (hours)	% Release
	F-5	F-6
0	0.000	0.000
2	19.715	29.336
4	20.289	54.344
6	37.461	74.871
8	45.462	79.319
9	60.349	91.624

 

Fig3.13: Zero order plot of release kinetics of Naproxen from Methocel K4M, Na-CMC & CMC based matrix tablets

 

Table 3.15: Highuchi plot of release kinetics of MethocelK4M, CMC-50,000cps and Na-CMC based Naproxen matrix tablets

        

root of time	%  release
	F-5	F-6
0	0	0
1.414	19.715	29.336
2.000	20.289	54.344
2.449	37.461	74.871
2.828	45.462	79.319
3	60.349	91.624

 

 

 

  

Fig 3.14: Highuchi plot of release kinetics of Naproxen from Methocel K4M,Na-CMC & CMC based matrix tablets

 

Table 3.16: Data for 1^st order plot of release kinetics of MethocelK4M, CMC-50,000cps and Na-CMC based Naproxen matrix tablets

 

Time(hour)	Log % remeaning
	F-5	F-6
0	2	2
2	1.905	1.849
4	1.902	1.660
6	1.796	1.400
8	1.737	1.316
9	1.598	0.923

              

 

 Fig 3.15: 1^st order plot of release kinetics of Naproxen from Methocel K15M, Na-CMC & CMC based matrix tablets

 

 

Table 3.17: Data for korsmeyer plot of release kinetics of MethocelK4M, CMC-50,000cps and Na-CMC based Naproxen matrix tablets

 

Log Time (hours)	Log fraction release
	F-5	F-6
0.301	-0.705	-0.533
0.602	-0.693	-0.265
0.778	-0.426	-0.126
0.903	-0.342	-0.101
0.954	-0.219	-0.038

 

 

Fig 3.16: Korsmeyer plot of release kinetics of Naproxen from Methocel K4M CMC-50,000cps and Na-CMC based Naproxen matrix tablet

 

 

3.7:  Effects of Methocel K4M, Na-CMC & CMC (50,000cps) on release kinetics of Naproxen from Naproxen based matrix tablets

 

For these formulations, Methocel K4M, Na-CMC & CMC (50,000) were used for preparing Naproxen matrix tablets, It is shown that F-5 gives 60.349% release of Naproxen at 9 hrs & F-6 shows 91.62% release at 9 hrs.  Here F-6 shows more rate retarding action than F-5, as F-6 contains 5% Methocel K4M, 5%  CMC CMC(50,000 cps) & Na-CMC5%   and F-5 contains 5% Metocel K4M & CMC(50,000 cps).

 

Table 3.18: Data for zero order release profile of Methocel K15M, Na-CMC & CMC (50,000cps) Naproxen matrix tablets

 

Time (hours)	% Release
	F-7	F-8
0	0	0
2	24.242	13.678
4	34.106	57.300
6	37.485	69.431
8	55.554	89.546
9	68.657	90.878

 

Fig 3.17: Zero order release profile of Naproxen from Methocel K15M, CMC & Na-CMC based matrix tablets     

Table 3.19: Data for Highuchi plot of release kinetics of  Methocel K15M, Na-CMC & CMC (50,000cps) Naproxen matrix tablets

   

root of time	%  release
	F-7	F-8
0	0	0
1.414	24.242	13.678
2.000	34.106	57.300
2.449	37.485	69.431
2.828	55.554	89.546
3	68.657	90.878

 

 

Fig 3.18: Highuchi plot of release kinetics of Naproxen from Methocel K15M , Na- CMC & CMC based matrix tablets

 

Table 3.20: Data for 1^st order plot of release kinetics of  Methocel K15M, Na-CMC & CMC (50,000cps) Naproxen matrix tablets

 

Time (hours)	Log% Remaining
	F-7	F-8
0	2	2
2	1.879426	1.936
4	1.818844	1.630
6	1.795983	1.485
8	1.647836	1.019
9	1.496141	0.960

 

 

Fig 3.19: 1^st order plot of release kinetics of Naproxen from Methocel K15M, Na-CMC & CMC based matrix tablets

Table 3.21: Korsmeyer plot of release kinetics of Methocel K15M, Na-CMC & CMC based matrix tablets

 

Log Time (hours)	Log fraction release
	F-7	F-8
0.301	-0.615	-0.864
0.602	-0.467	-0.242
0.778	-0.426	-0.158
0.903	-0.255	-0.048
0.954	-0.163	-0.042

 

 

 

Fig 3.20: Korsmeyer plot of release kinetics of Naproxen from Methocel K15M, Na- CMC & CMC based matrix tablets

 

3.8: Effects of MethocelK15M, Na-CMC, & CMC on release kinetics of Naproxen from Naproxen based matrix tablets

 

For these formulations, Methocel K15M, Na-CMC & CMC (50,000cps) were used for  preparing Naproxen matrix tablets, It is shown that F-7 gives 68.657% release of Naproxen at 9 hrs & F-8 shows 90.88% release at 9 hrs.  Here F-7 shows more rate retarding action than F-8, as F-8 contains 5% Methocel K15M, 5% CMC & 5%Na-CMC and F-7 contains 5% Metocel K15M & CMC (50,000 cps). So, from the zero order plot of F-5, F-6, F-7 & F-8, it shows that CMC-50,00cps itself is a good rate retarding polymer.

 

Table 3.22: Data for zero order release profile from Na- CMC,EC & CMC based Naproxen matrix tablets

Time(hrs)	% Release
	F-9	F-10
0	0	0
2	35.373	45.089
4	67.704	69.971
6	87.361	85.025
8	93.522	90.550
9	93.522	95.792

 

Table 3.21: Zero order release profile of Naproxen from Na-CMC, EC & CMC based  matrix tablets 

Table 3.23: Data for Highuchi plot of release kinetics of Na-CMC, EC & CMC based  Naproxen matrix tablets 

 

root of time	%  release
	F-9	F-10
	0	0
1.414	35.373	45.089
2.000	67.704	69.971
2.449	87.361	85.025
2.828	93.522	90.550
3	93.522	95.792

 

 

 

Fig 3.22: Highuchi plot of release kinetics of Naproxen from Na-CMC, EC& CMC based matrix tablets

Table 3.24: Data for 1^st order plot of release kinetics of Na-CMC, EC& CMC based Naproxen matrix  tablets

 

Time (hours)	Log% Remaining
	F-9	F-10
0	2	2
2	1.810	1.740
4	1.509	1.478
6	1.102	1.175
8	0.811	0.975
9	0.811	0.624

 

 

 

Fig 3.23: 1^st order plot of release kinetics of Naproxen from Na-CMC, EC & CMC based matrix tablets

Table 3.25: Data for korsmeyer plot of release kinetics of Na-CMC, EC & CMC based matrix tablets Naproxen

 

Log Time (hours)	Log fraction release
	F-9	F-10
0.301	-0.451	-0.346
0.602	-0.169	-0.155
0.778	-0.059	-0.070
0.903	-0.029	-0.043
0.954	-0.029	-0.019

 

 

Fig 3.24: Krosmeyer plot of release kinetics of Naproxen from Methcel K15M & CMC based matrix tablets

 

3.9: Effects of Na-CMC, EC & CMC on release kinetics of Naproxen from Naproxen based matrix tablets

For these formulations, Na-CMC, EC& CMC (50,000cps) were used for preparing Naproxen matrix tablets, It is shown that F-9 gives 93.52% release of Naproxen at 9 hrs& F-10 Shows 95.792 %release at 9 hrs.  Here F-9 shows more rate retarding action than F-9, as F-10 contains, 5%CM (50,000cps), 5% Na-CMC & 5%EC and F-9 contains 10% CMC (50,000cps) & 5% Na-CMC. Though all the ratio of polymer used in F-10 were more viscous, so it shows more retarding properties than F-10.

 

Table 3.26: Interpretation of release rate constants and R-sqare values for different release kinetics of Naproxen matrix tablets

 

Formulation	Zero order		First order		Korosmeyer			Higuchi
	K0	R2	K1	R2	Kk	R2	n	KH	R2
F-1	7.976	0.960	0.158	0.877	0.028	0.975	1.540	20.353	0.797
F-2	10.019	0.984	0.240	0.871	0.098	0.974	1.015	26.078	0.908
F-3	6.989	0.948	0.130	0.879	0.020	0.989	1.634	17.705	0.761
F-4	8.754	0.981	0.183	0.843	0.089	0.988	0.988	22.637	0.869
F-5	6.230	0.952	0.091	0.916	0.099	0.839	0.745	16.202	0.870
F-6	10.868	0.939	0.251	0.942	0.185	0.978	0.737	28.717	0.968
F-7	7.324	0.940	0.112	0.913	0.145	0.901	0.640	19.221	0.916
F-8	10.982	0.956	0.286	0.956	0.072	0.913	1.234	28.618	0.890
F-9	12.217	0.867	0.334	0.982	0.244	0.943	0.658	32.569	0.973
F-10	12.272	0.810	0.332	0.982	0.333	0.976	0.496	32.947	0.992

 

Table 3.27: Successive fractional dissolution time (hrs)

 

Formulation
	T25%	T50%	T80%	MDT
F-1	4.172	6.544	8.880	6.223
F-2	2.503	4.953	7.869	4.939
F-3	4.713	7.203	9.604	6.829
F-4	2.805	5.749	9.251	5.762
F-5	3.469	8.793	16.521	9.517
F-6	1.510	3.867	7.316	4.202
F-7	2.340	6.913	14.407	7.968
F-8	2.750	4.821	7.056	4.670
F-9	1.039	2.981	6.091	3.393
F-10	0.561	2.270	8.880	3.045

 

 

Fig 3.25: Successive fractional dissolution times (hrs) of Naproxen matrix tablets from F-1 to F-5

Fig 3.26:  Successive fractional dissolution times (hrs) of Naproxen from F-6 to F-10

Table 3.28: Data   treatment of Naproxen from Methocel K4M based matrix tablets in light of rate constant, R-square, n and MDT value:   

 

Formulation	Best fitted model	n Value	Release mechanism
F-1	Korsmeyer  model	1.540	Complate zero order(erosion through viscoelastic relaxation of polymer
F-2	Zero order	–	Concentration independent
F-3	Korsmeyer  model	1.634	Complate zero order(erosion through viscoelastic relaxation of polymer
F-4	Korsmeyer  model	0.988	Complate zero order (erosion through viscoelastic relaxation of polymer
F-5	Zero order	–	Concentration independent
F-6	Korsmeyer  model	0.737	Complate zero order(erosion through viscoelastic relaxation of polymer
F-7	Zero order	–	Concentration independent
F-8	Zero order	–	Concentration independent
F-9	1st order	–	Release rate depends on the concentration of drug in the depot
F-10	Higuchi release	–	Diffusion through pore formation

 

3.10: Discussion:

 From the above table, it is observed that most of the formulations are fitted to korsmeyer mode with the n value greater than 0.89. so, in most cases the release of drug from the hydrophilic polymer based matrix tablets take place due to complete zero order or release through erosion of viscoelastic relaxation of polymer.

 

From the successive table it shown that the MDT values of different formulations manifest affect of various polymers. The F-1 contains large amount of Methocel K4 M  (20%) and the MDT value was 6.223. In F-2, Methocel K15M (15%) was used and the  MDT value was 4.94. In F-3, contains large amount of Methocel K4M (20%) and the MDT value was 6.829. In F-4, In this formulation Methocel K15M (15%) was used and    the MDT value was 5.76. Among F-1, F-2,   F-3 & F-4, it is shown that, F-1 & F-3 highest value of MDT as they contain highest (20%) amount of greter viscosity grade of HPMC.

 

The F-5 contains least amount of Methocel K4M (5%) and CMC, the MDT value was 9.517. In F-6, In this formulation Methocel K15M (5%), 5%CMC & Na-CMC (5%) were used and  the MDT value was 4.202.The F-7 contains least amount of Methocel K15M (5%), Na-CMC and  CMC(10%), the MDT value was 7.96. In F-8, In this formulation Methocel K15M (5%), CMC (5%), Na-CMC(5%), are used and  the MDT value was 4.670. Among F-5, F-6, F-7 & F-8, I t shows, F-5 gives highest of MDT, where          CMC 50,000cps)  in large amount which gives more retarding action .

 

The F-9 contains least amount of EC (5%) and greater amount (10%) CMC (50,000cps), the MDT value was 3.393.I n F-10, In this formulation EC (5%), CMC (50,000cps) (5%) & Na-CMC (5%) are used and the MDT value are 3.045. Between F-9 & F-10, it is found that F-9 gives more MDT value. In this formulation we used CMC (50,000cps)(10%) which are more retarding polymer.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Fig 3.27: Effect of hydrophilic polymers (F-1 to F-4)

 

 

Fig 3.27: Effect of hydrophilic polymers (F-1 to F-5)

Fig 3.28: Effect of hydrophilic polymers (F-5 to F-10)

3.11: Discussion

 From the fig(3.27), we found that  F-1 & F-2 contains Methocel K4M (20%) &(15%) respectively, where F-1 gives 79.24% rate retarding action & F-2 gives 91.48%  rate retarding action. From the among result we can saw that F-1 gives more sustained release action because it contains Methocel K4M (20%) which has more rate retarding action.

 

 From the fig(3.28), we found that F-5 contains a combination (Methocel K4M5% & CMC 10%). F-6 contains Methocel K4M 5% & CMC 5% & EC 5%. Among this combination F-5 gives more rate retarding action because the ratio of CMC polymer was more than F-6. Again, F-7 contains Methocel K15M 5% & CMC 10% where F-8 contains Methocel K15M 5%, Na CMC 5% & CMC 15%. Between these formulations  F-7 gives more rate retarding action because the ratio of CMC(50.000cps) polymer was more than F-6. Again, F-9 contains EC 5% & CMC 10%, where F-10 contains Methocel K15M 5%, Na CMC 5% & CMC 15%. Though the combination of F-9, was more than F-9, but the ratio of CMC (50.000cps) polymer was more F-10.

 

 

Conclusion

 

Hydrophilic polymers are very commonly used now- a- days for preparing various sustained released release tablets. Here naproxen is used as a model drug. Naproxen matrix tablets were prepared by wet granulation method. It was taken for swelling study and dissolution testing. The % release was calculated by UV method at 230 nm  both in acid media & in buffer media. The following results were observed:

{C}Ø  {C} The average diameter, thickness, and hardness were 7.93, 2.14 and 10 kp respectively.

{C}Ø  {C}Most of the formulations showed good flow properties.

{C}Ø  {C}Among ten formulations, F-8 showed highest swelling (196.99% at 3 hrs) as the formulation contains 5% Methocel15M, 5% CMC-50,000cps and 5% Na-CMC.

{C}Ø  {C}Among F-1 to F-4, (containing defferent percentages of single polymer), F-3 showed more sustained action (72.02% at 9 hrs) which contain 20% Methocel K4M and K15M CR. Among MethocelK4M & K15M, K15M is the higher viscosity grade polymer. So it’s highest contain (20%) shows much sustained action.

{C}Ø  {C}Among F-5 to F-10 (containing various percentages of mixed polymers) F-5 sustained much (60,349% at 9 hrs) as it contains 5% MethocelK4M and 10% CMC-50,000cps.

{C}Ø  {C}Of all the formulation, the best fitting was observed with Korsmeyer model and least fitting with first order and Highuchi model.

{C}Ø  {C}Formulation fitting with Korsmeyer model showed n value greater than 0.89. That is release mechanism was complete Zero order.

{C}Ø  {C}Their MDT values   show   that with the increasing polymer concentration and viscosity grade the values were increasing.

{C}Ø  {C}Among ten, F-5 showed the highest MDT value (9.517 hrs) as it contains 5% Methocel K4M and 10% CMC-50,000cps.

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