journal of advanced pharmaceutical sciences

Srinath reddy et al.,

______________________________________________________________________________________ JAPS/Vol.3/Issue.1/2013 www.japsjournal.com 432

Formulation and evaluation of Ketoprofen sustained release pellets

Srinath reddy G, Kumara Swamy S and Agaiah Goud B Department of Pharmaceutics, S.R.R. College of Pharmaceutical Sciences,

Valbhapur, Elkathurthy, Karimnagar - 505 476, Andhra Pradesh, India. Email: [email protected]

Introduction: Most conventional oral drug products, such as

tablets and capsules, are formulated to release the active drug immediately after oral administration, to obtain rapid and complete systemic drug absorption. Such immediate-release products result in relatively rapid drug absorption and onset of accompanying pharmacodynamic effects. However, after absorption of the drug from the dosage form is complete, plasma drug concentrations decline according to the drug's pharmacokinetic profile.

Eventually, plasma drug concentrations fall below the minimum effective plasma concentration (MEC), resulting in loss of therapeutic activity. Before this point is reached, another dose is usually given if a sustained therapeutic effect is desired. An alternative to administering another dose is to use a dosage form that will provide sustained drug release, and therefore maintain plasma drug concentrations.

Modified-release drug products are designed for different routes of administration based on the physicochemical, pharmacologic and

Journal of Advanced Pharmaceutical Sciences

Research Article eISSN 2249-5797

Abstract: Ketoprofen, a propionic acid derivative, is a non steroidal anti inflammatory agent with analgesic and

antipyretic properties. It is chemically designed as 2-(3-benzoylphenyl) propanoic acid. The present invention concerns the development of sustained release pellets of ketoprofen, which are designed to modify the drug release followed by sustained release action. There are so many oral systems in that one of the advance techniques is pelletization. The use of multi particulate system is to provide modified release formulation is ever increasing and provide an ideal way of delivering unit doses of such formulations. The most common approaches to pellet formulation are drug layering. Sustained release capsule of Ketoprofen were formulated by using the pelletization process by drug layering on inert non pareil seeds by using PVPK-30 as binder. The drug layered pellets were coated by using the ECN- 50, HPMCE-5 and Eudragit L100 coated material used as a polymer. The coated pellets were evaluated for SEM analysis micrometrics, percentage yield, in-vitro dissolution studies, and stability studies. The coated pellets size and shape were observed during processing. There is no physical and chemical interaction between drug and excipients compatibility study is carried out for four weeks at different temperature conditions. It may be concluded from the present study that sustained release pellets of ketoprofen releases 98.22±0.49 over a period of 24hrs. The optimized batch is kept under stability conditions as for 3 months as per ICH guidelines in HDPE containers and the product is proved to be stable throughout the period of the storage.

Keyword: Ketoprofen, Pelletization, Druglayring, Sustained release pellets, non steroidal anti inflammatory agent.

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pharmacokinetic properties of the drug and on the properties of the materials used in the dosage form. Several different terms are now defined to describe the available types of modified-release drug products based on the drug release characteristics of the products1.

Modified release delivery systems may be divided into four categories. They are as follows:

1. Delayed Release 2. Site Specific Targeting 3. Receptor Targeting

4. Extended Release

Controlled Release

Sustained Release Sustained Release Drug Delivery Systems:

Most conventional drug products, such as tablets and capsules, are formulated to release the active drug immediately after administration to obtain rapid and complete systemic drug absorption. In recent years, various modified drug products have been developed to release the active drug from the product at a sustained rate. Advantages of Sustained Release Systems: 2

Maintenance of plasma drug concentration within an optimal therapeutic range for prolonged duration of treatment.

Minimization of the need for frequent dose intake.

Improves control of condition i.e., reduced fluctuation in drug level.

Minimize drug accumulation with chronic dosing.

Make use of special effects, e.g. Sustained-release aspirin for morning relief of arthritis by dosing before bed time.

Economy i.e. reduction in health care costs. The average cost of treatment over an extended time period may be less, with lesser frequency of dosing, enhanced therapeutic benefits and reduced side effects.

Disadvantages of Sustained Release Dosage Forms:

Increased variability among dosage units.

Poor in vitro – in vivo correlation.

Toxicity due to dose dumping may occur when more than usual fraction is being released.

Retrieval of drug is difficult in case of toxicity, poisoning or hypersensitivity reactions.

Need for additional patient education and counselling.

Reduced potential for dose adjustment of drugs normally administered in varying strength.

Pellets: Pharmaceutical pellets are agglomerates of

fine powder particles or bulk drugs and excipients, small, free-flowing, spherical or semi-spherical solid units, size ranges from about 0.5mm to 1.5mm (ideal size for oral administration), obtained from diverse starting materials utilizing different processing techniques and conditions4. Desirable Properties of Pellets: Uncoated Pellets:

Uniform spherical shape and smooth surface.

Optimum size, between 600 and 1000 m.

Improved flow characteristics.

High physical strength and integrity.

Good hardness and low friability.

High bulk density.

Ease and superior properties for coating.

Reproducible packing of beds and columns. Coated Pellets:

Maintain all of the above properties.

Contain as much as possible of the active ingredient to keep the size of the final dosage form within reasonable limits.

Have desired drug release characteristics. Advantages of Pellets5:

The smooth surface and the uniform size of the pellets allow uniform coating not only for each pellet but also from batch to batch. Coating of pellets can be done with different drugs to enable a controlled release rate.

In case of immediate release products, larger surface area of pellets enables better distribution.




Chemically incompatible products can be

formed into pellets and delivered in a single dose by encapsulating them.

The beads or granules of different thickness of

coatings are blended in the desired proportions to give the desired effect.

The thickness of the coat on the pellets

dictates the rate at which the drug or contents are released from the coated particles.

By selecting the proper formulation, processing conditions and processing equipment, it is possible to attain smooth surfaced and uniform pellets.

Improved appearance of the product and the core is pharmaceutically elegant.

Pellets can be divided into desired dosage strength without process or formulation changes and also allows the combined delivery of two or more bioactive agents that may or may not be chemically compatible, at the same site or at different sites within the gastrointestinal tract.

They offer high degree of flexibility in the design and development of oral dosage form like suspension, tablet and capsule.

Disadvantages of Pellets:

The manufacturing of multiple unit dosage forms is more complicated and more expensive.

The filling into gelatin capsules is difficult to accomplish, especially in the case where different subunits are involved. Theory of Pellet Formation and Growth: 6, 7

The most classified pelletization process involves three consecutive regions (Fig.1) which include: Nucleation Coalescence and Layering Abrasion transfer Nucleation: Nucleation occurs whenever a powder is wetted with liquid and presents first stage of the pellets growth. The primary particles are drawn together to form three-phase air-water-liquid nuclei and attached together by liquid bridges which are pendular in nature. The size of primary particles, the viscosity of the bonding particles, the moisture content, wettability of the substrate and the processing conditions influence the size, rate and extent of nuclear formation.

Coalescence and Layering: Nucleation is followed by a transition phase with two major mechanisms, coalescence and layering. Coalescence phase is characterized with formation of large-sized particles by random collision of nuclei containing slight excess of moisture. Although the number of nuclei is reduced, the total mass of the system remains unchanged during this step.

Layering involves successive addition of fines and fragments on surface of nuclei. The number of nuclei remains the same, but the total mass of nuclei in the system increases due to increasing particle size as a function of time. The fragments and fine particles that are formed during the process in the stage of particle size reduction due to attrition, breakage and shatter, are picked up by large pellets. Production of fines and subsequent coalescence and layering continues until the number of favourable collisions declines rapidly, thereby leading to a reduction in the rate of growth of the pellets. At this point the third phase, the ball growth is reached.

Abrasion Transfer: In the ball growth phase, the main mechanism affecting the slow growth of agglomeration is the abrasion transfer which involves the transfer of materials from one granule formed to another without any preference in either direction. Particles will experience a change in size as long as the conditions that lead to the transfer of material exist but not change in the total number or mass of the particles.

Fig.1: Pellet Growth Mechanisms. (A)Nucleation (B) Coalescence (C) Layering (D) Abrasion Transfer




There is a continuously growing interest in the pharmaceutical industry for sustained release pellets for oral drug delivery systems. There is also a high interest for design a dosage formulation that allows high drug loading, particularly for actives with high water solubility. The basic rationale of a sustained drug delivery system is to optimize the Biopharmaceutical, Pharmacokinetic and Pharmacodynamics properties of a drug in such a way that its utility is maximized through reduction in side effects and cure or control of condition in the shortest possible time by using smallest quantity of drug, administered by the most suitable route.

This drug has low half life of 2 hr. rapidly eliminated from the body, it is poorly soluble, it shows irregular bioavailability up on oral administration. Ketoprofen lacks to maintain its concentration at the site of action and side effects are more in conventional dosage form. Hence to minimize these effects we found it has an excellent candidate for sustain release oral drug delivery system.

Methodology:

Materials and methods Ketoprofen, Non-Pareil seeds and Sugar

Powder were obtained from Glukem Pharma Ltd, Hyderabad. Eudragit L-100, Ethylcellulose N-50 and HPMC E-5 were obtained from Evonik Degussa Industries, Mumbai, KMV Enterprises, Hyderabad and Colorcon Asia Pvt. Ltd., Goa respectively. PVP K-30 and Aerosil are obtained from Signet Chemicals, Mumbai and Danmed Pharmaceuticals Pvt. Ltd., Hyderabad respectively and all other materials are analytical and pharmaceutical grade used in this study. Preformulation Studies:

Preformulation studies activities range from supporting discovery’s identification of new active agent to characterizing physical properties necessary for the design of dosage form. Critical information provided during preformulation can enhance the rapid and successful introduction of new therapeutic entities for humans. Preformulation testing is an investigation of physical and chemical

properties of a drug substance alone and when combined with excipients. It is the first step in the rational development of dosage form8.

Preformulation studies were performed on the drug, which included identification of pure drug and physicochemical properties of the bulk drug like physical appearance, solubility, bulk density, tapped density, compressibility index, angle repose, melting point, sieve analysis and compatibility studies.

The overall objective of preformulation testing is to generate information useful in developing the formulation, which is acceptable, safe, efficacious, and stable product. Physical Properties: i) Physical Appearance:

The physical appearance can be done by visual identification.

ii) Solubility: Weigh accurately about 1g of pure drug Ketoprofen and dissolve each in 1mi of the solvent system i.e., water, chloroform, ethanol, methanol, IPA, benzene etc., in well closed air tight container. Then add the successive amount of the solvent in to the containers containing drug until the solution became saturated solution9.

iii) Determination of Melting Point: Melting point of Ketoprofen determined by capillary method by using Melting Point apparatus.

iv) Bulk Density(Db): It is the ratio between a given mass of powder and its bulk volume. Db = M / V0

Where, M = Weight of granules (g) V0 = Bulk volume of sample (mL) A given quantity of the powder is transferred to the measuring cylinder and it is tapped mechanically either manually or mechanical device till a constant volume is obtained. This volume is bulk volume (v) and it includes the true volume of the powder and void space among the powder particles.




v) Tapped Density(Dt): Tapped density is defined as the ratio between weight of the sample powder taken and the tapped volume. Dt = M / V Where, M = Weight of sample (g) V = Tapped volume of sample (mL)

vi) Compressibility Index /Carr’s Index: Based on the apparent bulk density and the tapped density, the percentage compressibility index of the powder was determined by using the following formula: Compressibility index = (1- V/ V0) X 100

Where, V0 = Volume of sample before tapping V = Volume of sample after 100 tappings

vii) Hausner’s Ratio: 10

By calculating tapped density and bulk density, the Hausner’s ratio can be calculated as follows: Hausner’s Ratio = Dt / Db

Where, Dt = Tapped density Db = Bulk density

viii) Angle of Repose: 11

Angle of repose is defined as the maximum angle possible between the surface of pile of powder and the horizontal plane. The granule mass should allowed to flow out of the funnel orifice on a plane paper kept on the horizontal surface. This forms a pile of granules on the paper (Table.1). Tan = h/r Where, h= height of the pile r= radius of the pile

ix) Sieve Analysis: A series of standard sieve were stacked one

above the other so that sieves with larger pore size (less sieve number) occupy top position followed by sieves with smaller pore size (greater sieve number towards the bottom). Procedure: A series of sieves were arranged in the order of their decreasing pore diameter (increasing sieve number) i.e. sieve number 20, 30, 40, 60, 100, and 200. 100 grams of drug was

weighed accurately and transferred to sieve number 20 which were kept on top. The sieves were shaken for about 5-10 minutes. Then the drug retained on each sieves was taken, weighed separately and amount retained was expressed in terms of percentage.

Table.1. Flow Properties of Powder

S. No

Angle of

Repose Carr’s

Index Hausner’s

Ratio Properties

1 25-30 5-12 1.00-1.11 Free Flowing

2 30-35 12-16 1.12-1.18 Good 3 35-40 18-21 1.19-1.25 Fair 4 40-55 23-35 1.35-1.45 Poor

5 55-65 33-38 1.46-1.59 Very poor

6 >65 >40 >1.60 Extremely poor

Identification of Ketoprofen Drug: Infra Red Spectroscopy:

The IR absorption spectrum of ketoprofen was determined by FT-IR spectrophotometer using KBr dispersion method. The IR spectrum of the obtained sample of drug was compared with the standard IR spectra of the pure drug. FT-IR spectra help to confirm the identity of the drug and detect the interaction of the drug with polymers was carried out to check the compatibility between drug and polymers12. Formulation Development:

Ketoprofen sustained release pellets were prepared by the process displayed in the following flow chart (Fig.2). Formulation Steps:

Step I: Drug Loading: 1. All the materials as per manufacturing

formula were dispensed. 2. Pulverize the Ketoprofen and mix it with other

excipients. 3. Add PVPK-30, HPMC-E5 in IPA and stir well

still to get the clear solution. 4. Transfer the basic core non-pareil pellets into

coating pan, and then spray with the binder solution prepared above.




5. Over wetting of the cores to be avoided as it may cause agglomeration.

6. Add the Ketoprofen slowly by spraying the binder.

7. The pellets are then dried in a tray drier at about 450 C-550 C to attain the moisture content less than 5%.

8. The dried pellets are sized on a sifter to remove agglomerates, broken pellets and fine powder.

9. After checking the weight of the pellets and noting down the yield they are packed in a HDPE container lined with double polythene bags, labeled and securely tied.

10. The pellets were ready for coating (table 2).

Formulation Trials of Ketoprofen Sustained Release Capsules:

Table.2. Drug Loading Composition for Each Capsule

S.No

Ingredients Quantity in milligrams

1 Ketoprofen 200

2 Non Pareil Seeds(24#30)

52.2

3 Sugar Powder 27.36 4 Aerosil 1.45

5 Poly vinyl Pyrrolidone (PVP) k-30

0.87

6 Hydroxy propyl Methyl cellulose (HPMC) E-5

0.87

7 Sugar 7.25 8 Isopropyl Alcohol Q.S

Step II: Sustained Release Coating of Ketoprofen Pellets: 1. Isopropyl alcohol and dichloromethane in 4:1

ratio was taken into a vessel and required quantity of ethyl cellulose N-50 and Hydroxypropyl methylcellulose E5 or Eudragit L100 as shown in Table.3.was dissolved. Stirring was continued till the clear solution was obtained.

2. Drug loaded pellets were transferred into the FBC and coated with the coating solution.

3. The spray rate, inlet air temperature were adjusted in such a way that the drug coated pellets reached a temperature of about 370C – 420C.

4. Over wetting of the drug coated pellets was avoided as it may cause agglomeration.

5. After quantity of the coating solution was consumed, the fluidization was reduced for a brief post-drying period.

6. The dried pellets were sized on a sifter to remove agglomerates, broken pellets and fine powder by using sieves. The weight of the pellets was checked and the yield was noted, then the pellets were packed in double polythene bags and labeled.

Rational for Selection of the Manufacturing Process: Drug Loading: 13

Drug loading is a simple process using a conventional coating pan has been adopted. This process consists of wetting the core material with a binder solution and loading of drug. This process is continued with intermittent drying till completely the drug is loaded on to the core. This process has been used by us for many similar products. It is easy to adopt and can be conveniently controlled. Coating Process: 14

Coating is carried out in a bottom spray (Wurster) arrangement in a fluid bed processor. The selection of bottom spray was done as per the prior experience with other similar products. The basic principle of Wurster coating is described in the following schematic diagram (Fig.3)

Fig.3: Bottom Spray Coating




Fig.2: Flow Chart for Manufacturing of Ketoprofen Sustained Release Pellets

Table.3. Sustained Release Coating Composition for Each Capsule

Formulation Code

ECN-50 (mg)

Eudragit L-100 (mg)

HPMC E-5 (mg)

DCM:IPA (1:4)

F1 1.16 1.16 - Q.S

F2 1.74 1.16 - Q.S

F3 2.32 1.16 - Q.S

F4 2.90 1.74 - Q.S

F5 3.48 1.74 - Q.S

F6 4.06 1.74 - Q.S

F7 1.16 - 1.16 Q.S

F8 1.74 - 1.16 Q.S

F9 2.32 - 1.16 Q.S

F10 2.90 - 1.74 Q.S

F11 3.48 - 1.74 Q.S

F12 4.06 - 1.74 Q.S

Binder Solution

PVPK-30, HPMC E5, Sugar, in IPA

Drug loading Conventional Coating

pan

Non-Pariel Seeds

Drying

Sieving in #14 and #20

Coating solution ECN-50, Eudragit L100 (or)

ECN-50, HPMC E5 in IPA and DCM (4:1)

Coating in FBC

Sieving

Ketoprofen, Sugar Powder, Aerosil




Drug Loading Process: The drug loading process was identified as a

critical step in the manufacturing process, as this step directly impacts upon size of pellets as well as the content uniformity of final product. The critical process parameters and optimum settings for the drug loading process were identified (Table.4) based on prior knowledge on a similar product in which the drug substance is coated on non-pareil seeds of the same size distribution. In addition, laboratory scale studies (5 kg batches) were performed in an 18 inch coating pan at the optimized and extremes (low and high) for the identified critical process parameters. The critical process parameters identified for the drug layering step were the uniformity and particle size distribution of the drug, the rate of powder application, binder solution spray rate, product bed temperature and atomizing pressure. These studies established that a proper balance of binder solution spray and the drug powder application was important for the size uniformity and surface characteristics of the drug-layered pellets15,16. Coating Process:

As per the intended function of the proposed drug product, the functional coating process was identified as a critical step in the drug product manufacturing process.

The critical process parameters for the coating process were identified and the impact elucidated using a statistical design of experiments (D.O.E.) with the main objective to determine the influence of the process parameters and maximize coating efficiency. A secondary objective was to ensure that the optimized process yields a fully cured product that maintains a consistent release profile through the shelf life of the product. The D.O.E. was set up to challenge extremes of several process parameters, which were chosen based on

prior knowledge of the Wurster coating process for a coated drug product and available literature. Results of the D.O.E. study are summarized below as shown in the Table.5 and Table.6.

The range of process parameter results (Table.7) showed an expected influence on the drug release profile of the coated drug product attributed to variations in coating thickness and coating membrane integrity, based on the range of process parameters. All process parameters were found to have some effect on the coating efficiency, with the maximal effect observed when spray rate and atomizing pressure were varied in the process17.

Table.5. Equipment Parameters Parameters Laboratory Scale

Number/ Diameter/ Number of Spray Guns

1/89 mm/1

Batch size 5 kg

Table.6. Coating Process Variables Process Variable Minimum

Maximum

Inlet Air Temperature 45°C 55°C

Product Bed Temperature

37°C 42°C

Atomizing Air Pressure 1 bar 3 bar

Fluidization Air Volume

70 m3/h 150 m3/h

Spray Rate 10 g/min 70 g/min

SR Coat Solids Content 5 % 20%




Table.4. Drug Loading Process Parameters

Parameters Settings Rationale Particle size

distribution of the drug

Finer than 75 micron

(200# mesh)

In the drug loading process, the finer is the powder being applied on the wet cores, the better is the surface finish and the more uniform is the content of the active. In our process, the drug is pulverized using a 0.5 mm screen.

Atomizing air pressure for the

binder solution spray

1.5 bar At higher atomization pressure, the wetting of the core is not uniform and at lower pressure there is a tendency to form agglomerates.

Table.7. Coating Equipment Parameters Parameter Settings Rationale

Inlet Air Temperature

45-55°C Calculated using the drying/humidity chart of the Wurster. This is a dependent process variable that is calculated based upon consideration of spray rate, fluid bed temperature, fluidizing air volume, incoming air RH%, and outlet air temperature/RH% to ensure sufficient evaporative capacity.

Product Bed Temperature

37–42°C Lower than optimum led to poor evaporation and pellet agglomeration. Higher than optimum led to case hardening of the pellets (trapping moisture in the product matrix), poor adherence of the CR membrane, and rapid drug release.

Atomizing Air Pressure

1.5 Bar At the optimized spray rate of 25-30 g/min, the atomizing air pressure generates a 30µm droplet size that is critical to ensure adequate CR coating. Atomizing air pressures exceeding 3.0 bars should be avoided due to excessive pellet attrition.

Fluidizing Air Volume

80–100 m3/hr Lower and higher than optimum range led to poor fluidization patterns and loss of coating efficiencies.

Spray Rate 30–40 g/min Lower spray rates decreased droplet size, enhancing evaporation resulting in poor coating efficiency and rapid drug release. Faster spray rates increased the droplet size leading to low yield due to product agglomeration.

Coating Solids 5 % w/v Lower coating solids led to less viscous coating suspension which affected spray rate. Higher coating solids resulted in a too viscous suspension that was difficult to spray without maximum air pressure utilization

Characterization of Pellets: Granules are the key process in the production

of many dosage forms involving the controlled release of drug from matrix particles. Prior to compression granules were evaluated for their characteristic parameters such as angle of repose, bulk density (BD), tapped density (TD), and Carr’s index.(13,14,15)

Bulk density: It is the ratio of total mass of granules to the

bulk volume of the granules. It was measured by pouring the weighed (passed through standard sieve #) into a measuring cylinder and the initial volume was noted. This initial volume is called bulk volume. From this, the bulk density is




calculated according to the formula mentioned below. It is expressed in gm/ml and is given by:

b = M/Vo

Where, M is the mass of granules, Vo is the bulk volume of the granules

Tapped density: The measuring cylinder containing known

mass of blend was tapped for a fixed time. The minimum volume (Vt) occupied in the cylinder and weight (M) of the blend was measured. The tapped density ( b) was calculated using the following formula

t = M/Vt

Where, M is the mass of granules, Vt is the tapped volume of the granules

Carr’s Compressibility Index: The simplest way of measurement of free flow

of granules is compressibility, an indication of the ease with which a material can be induced to flow is given by compressibility. The compressibility index of the granules was determined by Carr’s compressibility index, which is calculated by using the following formula

I = Vo-Vt/Vo×100 Angle of repose:

The frictional force in a loose granules can be measured by the angle of repose, . It is an indicative of the flow properties of the granules. It is defined as the maximum angle possible between the surface of pile of granules and the horizontal plane

= tan-1(h/r) Where, is the angle of repose, h is height of pile;

r is radius of the base of pile. The granules mixture was allowed to flow

through funnel fixed to a stand at definite height (h). The angle of repose was then calculated by measuring the height and radius of the heap of granules formed. Care was taken to see that the granules particles slip and roll over each other through the sides of the funnel.

Volume of angle of repose less than 30°usually indicate a free flowing material and

angle greater than 40°suggest a poorly flowing material.

Hausner’s Ratio: 18

By calculating tapped density and bulk density, the Hausner’s ratio can be calculated as follows:

Hausner’s Ratio = Dt / Db

Where, Dt = Tapped density, Db = Bulk density Sieve Analysis

A series of standard sieve were stacked one above the other so that sieves with larger pore size (less sieve number) occupy top position followed by sieves with smaller pore size (greater sieve number towards the bottom). Percentage Yield:

The prepared pellets were collected and accurately weighed. The measured weight of prepared pellets was divided by the total amount of all excipients and drug used in preparation of the pellets, which gives the total percentage yield of pellets. Calculation:

Determination of Moisture Content (% w/w): Take suitable quantity of Methanol in titration

flask of Karl Fischer Titrator and titrate with Karl Fischer reagent to end point. Grind the pellets to fine powder in a dry mortar, weigh accurately about 0.5 g of the sample, transfer quickly to the titration flask, dissolve by stirring and titrate with Karl Fischer reagent to end point. Calculation:

Where, F = Factor of Karl Fischer reagent V = Volume in mL of Karl Fischer reagent

consumed for sample titration. Percentage Friability:

Friability is the loss of weight of pellets in the container/package, due to removal of fine particles from the surface. This in-process quality




control test was performed to ensure the ability of pellets to withstand the shocks during processing, handling, transportation, and shipment. Roche Friabilator was used to measure the friability of the tablets. It was rotated at a rate of 25 rpm. 5 g pellets were weighed collectively and placed in the chamber of the friabilator. In the friabilator, the pellets were exposed to rolling, resulting from free fall of pellets within the chamber of the friabilator. After 100 rotations (4 minutes), the pellets were taken out from the friabilator and intact pellets were again weighed collectively after removing fines using sieve # 44 sieve. Permitted percentage friability limit is 0 - 1% 18,19. Calculation:

Determination of Assay by U.V – Vis Spectrophotometer (% w/w):20

Standard Solution: Accurately weighed quantity of about 100mg

of Ketoprofen working standard is transferred to100mL volumetric flask, add 50mL of methanol to dissolve the drug and diluted to the volume with distilled water and 10ml of above solution was taken in 100mL volumetric flask and diluted to the volume with distilled water. 5mL of the above solution was taken and volume is made up to 10mL with distilled water and the absorbance was measured using U.V Spectrophotometer at max of 258 nm. Sample Preparation:

Accurately weighed quantity of the pellets equivalent to 100mg of Ketoprofen working standard is transferred to100mL volumetric flask, add 50mL of methanol to dissolve the drug and diluted to the volume with distilled water and 10mL of above solution was taken in 100mL volumetric flask and diluted to the volume with distilled water. 5mL of the above solution was taken and volume is made up to 10mL with distilled water and the absorbance was measured using U.V spectrophotometer at max of 258 nm.

Calculation: Calculate the amount of ketoprofen present in pellets, in % using the following formula

The content of individual dosage complies with the test if not more than one individual content is outside the limits of 85 to 115 percent of the average content and none is outside the limits of 75 to 125 percent of the average content. The preparation fails to comply with the test if more than three individual contents are outside the limits of 85 to 115 percent of the average content or if one or more individual contents are outside the limits of 75 to 125 percent of the average content. Loading of Coated Pellets in to Capsules:

The pellets after checking physical parameters can be filled into capsules no.1 by using automatic capsule filling machine and the weight of capsule can be checked in filling of pellets into capsules. The percentage weight variation of capsules is given as 10 % to the total fill weight of capsule no.1 with sugar dummy pellets of same (#16- #20) size. Evaluation of Ketoprofen Capsules Weight Uniformity Test: 21

To determine capsule weight uniformity, 30 capsules were sampled and accurately weighed using an electronic analytical balance. The results were expressed as mean values of 20 determinations. The coefficient of variation was calculated by using the following formula:

Coefficient of variation (%) = Standard deviation / Mean X 100

The capsules meet the USP or IP/BP specifications if not more than 2 capsules are outside the percentage limit and if no capsule differs by more than 2 times the percentage limits (Table.8). Lock Length:

As the pellets was filled in capsule no.1 Specifications of capsule are cap length is




9.78±0.45 mm, body length is 16.61±0.45 mm, cap diameter is 6.91±0.06 mm, body diameter is 6.63±0.06 mm, lock length is 19.4±0.3 mm It was tested by using vernier calipers.

Table.8. Limits of weight variation

IP/BP Limits

USP

80 mg or less 10% 130mg or less

More than 80mg or

Less than 250mg 7.5% 130mg to 324mg

250mg or more 5% More than 324mg

Disintegration Test: The compendia disintegration test for hard and

soft capsules follows the same procedure and uses the same apparatus which is used for uncoated tablets. The capsules are placed in the basket rack assembly, which is repeatedly immersed 30 times per minute into a thermostatically controlled fluid at 37ºc and observed over the time described in the individual monograph. To fully satisfy the test the capsules disintegrate completely into a soft mass having no palpably firm core, and only some fragments of the gelatin shell. Determination of Drug Release by UV –Vis Spectrophotometer (% w/w):

Medium : 0.1 N HCl followed by 7.4 Phosphate Buffer

Apparatus : USP Apparatus I

RPM : 100

Sampling Interval : 1st, 2nd, 3rd, 4th, 6th, 8th, 12th, 16th, 20th, 24th hour

In vitro Drug Release Studies:

In-vitro drug release was studied using dissolution test apparatus USP type I (rotating basket) method. The drug loaded pellets equivalent to 200mg of ketoprofen were filled in empty gelatin capsules. These capsules were introduced into dissolution flasks containing 900mL of 0.1N HCl. The temperature was maintained at 37±0.5 ºC and paddle rotating speed

at 100rpm. 5ml of aliquot was withdrawn at regular predetermined intervals and sink conditions were maintained throughout the study by replacing equal volume of fresh dissolution medium. After 2 hrs, dissolution medium was replaced with pH 7.4 phosphate buffer and dissolution study was carried out until 24 hrs. The collected samples were analyzed spectrophotometrically at 258nm using pH 7.4 phosphate buffer with an appropriate dilutions. All the analysis was carried out in triplicate22,23.

Scanning Electron Microscopy:

The equipment used was Hitachi S3000 N. Powder samples were mounted onto aluminium studs using double sided adhesive tape & then sputter coated with a thin layer of gold. The specimens were scanned with an electron beam of 10 kV acceleration potential & Photomicrographs were taken at 2500X & 5000X magnifications24.

Mathematical Models: 25,26

The success of ECN-50, HPMC E5, and Eudragit L100in controlling the release of drug was studied under following heads to understand the order and probable underlying mechanism involved in release pattern. The various mathematical models studies include:

Zero Order Model:

According to zero order model, release of drug can be represented by following equation

Qt = K0t

Where, Qt is amount of drug dissolved in time t,

K0 is the zero order release constant expressed in units of concentration/time.

To study the release kinetics, data obtained from in vitro drug release studies were plotted as cumulative amount of drug released versus time.

First Order Model:

The release of the drug which followed first order kinetics can be expressed by the equation.

Log F = K1t




Where, F is fraction of drug release at time t,

K1 is first order release constant.

The data obtained are plotted as log cumulative percentage of drug remaining vs. time.

Higuchi Model:

As per Higuchi model, the data obtained were plotted as cumulative percentage drug release versus square root of time. Equation (10) is used for determining release kinetics in Higuchi model.

Qt = KH t1/2

Where, Qt is amount of drug dissolved in time t,

KH is Higuchi dissolution constant.

Korsemeyer-Peppas Model:

To study the release kinetics, data obtained from in vitro drug release studies were plotted as cube root of drug percentage remaining in matrix versus time, which is expressed by following equation.

Mt / M8 = K tn

Where, Mt is represents amount of the released drug at time t,

M8 is the overall amount of drug released after 12 hrs,

K is the release rate constant, n is the release exponent/ diffusional exponent.

In this model, the value of n characterizes the release mechanism of drug as described in Table 9

Table .9. Interpretation of Diffusional Release Mechanisms

Release exponent(n)

Drug transport

mechanism Rate as a

function of time

=0.45 Fickian diffusion t -0.5

0.45 < n < 0.89

Non-fickian diffusion

t n-

1

0.89 < n < 1 Case II transport Zero order release

=1 Super case II transport

t n -1

n = 0.45 corresponds to a Fickian diffusion mechanism,

0.45 < n < 0.89 to non-Fickian transport,

0.89 < n < 1 to Case II (relaxational) transport,

n =1 to super case II transport. To find out the exponent of n the portion of

the release curve, where Mt / M8 < 0.6 should only be used. Stability Studies:

In any rational design and evaluation of dosage forms for drugs, the stability of the active component must be a major criterion in determining their acceptance or rejection. Stability of a formulation can be defined as the time from date of manufacture of the formulation until its chemical or biological activity is not less than a predetermined level of labeled potency and its physical characteristics have not changed appreciably or deleteriously.

The purpose of stability testing is to provide evidence on how the quality of a drug substance or drug product varies with time. Under the influence of a variety of environmental factor such as temperature, humidity, light, enabling recommended storage conditions, re-test periods and shelf lives. Generally, the observation of the rate at which the product degrades under normal room temperature requires a long time. To avoid the undesirable delay, the principles of accelerated stability studies are adopted. The International Conference on Harmonization (ICH) guidelines titled “stability of new drug substances and products” (QIA) describes the stability test requirements for drug registration application in the European Union, Japan, and United States of America27. Stability Protocol:

Aim: Accelerated Stability Study of Sustained Release Pellets of Ketoprofen. Name of API: Ketoprofen. Dosage Form: Sustained Release Capsules of Ketoprofen.




Label Claim: Each Capsule contains Ketoprofen 200mg. Accelerated Stability Conditions: Sustained Release Capsules containing Ketoprofen was stored at 40±2°C/75±5% RH for three months. Parameters Estimated: Moisture Content, Assay, and % Drug Release by UV-Vis Spectrophotometer.

Results and Discussion Preformulation studies:

Preformulation studies were performed on the drug, which included physical properties of the bulk drug like physical appearance, solubility, melting point, bulk density, tapped density, compressibility index, angle of repose and sieve analysis.

Interparticulate interactions influence the bulking properties of powder. A comparison of the bulk density and tapped density can give a measure of the relative importance of this interaction in a given powder; such a comparison is often used as an index of the ability of the powder to flow. The bulk density and tapped density were found to be 0.219 g/cm3 and 0.76g/cm3 respectively.

A simple indication of ease with which a material can be induced to flow is given by application of a compressibility index. The value for % compressibility index of ketoprofen was found to be 36.585 % and Hauser’s ratio of 1.578. The properties of ketoprofen active pharmaceutical ingredient were tabulated in Table.10.

Through sieve analysis results shown in Table.11 we came to know that as large quantity of powder was retained on Sieve No 200, which indicates poor flow of drug. Identification of Ketoprofen Drug: Infra Red Spectroscopy:

Ketoprofen standard drug and ketoprofen + excipients were made into pellets by using KBr at a ratio of 1:100. These pellets were scanned from 4000- 400cm-1 using FT-IR spectrophotometer. Functional groups present in the ketoprofen are C-

H (690-900 cm- 1), C=C (1500-1600 cm-1), C=O (1690-1760 cm-1), O-H (2500-2700 cm-1).

The IR spectrum of pure drug was shown in the Fig.4. IR spectra of pure drug shows characteristic functional peaks at 716.79 cm-1 (C-H stretching for methyl), 1598.12 cm-1(C=C stretching), 1696.60 cm-1 (C=O stretching), 2626.34 cm-1 (O-H stretching).

The IR spectrum of drug along with sugar was shown in Fig.5. It shows characteristic functional peaks at 717.08 cm-1 (C-H stretching for methyl), 1598.31 cm-1 (C=C stretching), 1696.79 cm-1

(C=O stretching), 2645.19 cm-1 (O-H stretching). The IR spectrum of drug along with PVP K-

30 was shown in Fig.6. It shows characteristic functional peaks at 716.93 cm-1 (C-H stretching for methyl), 1598.41 cm-1 (C=C stretching), 1696.66 cm-1 (C=O stretching), 2622.93 cm-1 (O-H stretching).

The IR spectrum of drug along with HPMC E-5 was shown in Fig.7. It shows characteristic functional peaks at 716.90 cm-1 (C-H stretching for methyl), 1598.27 cm-1 (C=C stretching), 1696.94 cm-1 (C=O stretching), 2647.45 cm-1 (O-H stretching).

The IR spectrum of drug along with ECN-50 was shown in Fig.8. It shows characteristic functional peaks at 716.67 cm-1 (C-H stretching for methyl), 1598.16 cm-1 (C=C stretching), 1696.95 cm-1 (C=O stretching), 2622.15 cm-1 (O-H stretching).

The IR spectrum of drug along with Eudragit L-100 was shown in Fig.9. It shows characteristic functional peaks at 716.74 cm-1 (C-H stretching for methyl), 1598.15 cm-1 (C=C stretching), 1698.97 cm-1 (C=O stretching), 2625.35 cm-1 (O-H stretching).

Functional peaks of the pure drug and pure drug along with excipients were with in specified range of frequencies, therefore there is no interaction between drug and excipients.




Table.10. Physical properties of Ketoprofen drug

S. No

Physical properties Specification

1.

Physical

Appearance of Drug Ketoprofen is a white or off-white,

odourless, non hygroscopic and fine to granular powder.

2.

Solubility It is freely soluble in ethanol, chloroform, acetone,

ether and soluble in benzene and strong alkali,

but practically insoluble in water at 20° C 3.

Melting Point 950

C

4.

Bulk Density 0.219 g/mL

5.

Tapped Density 0.346 g/mL

6.

Compressibility Index(%)

36.585

7.

Hausner’s Ratio 1.578

8.

Angle of Repose

380.3451

Table.11. Sieve Analysis values of Ketoprofen:

Sieve No

Empty Sieve (g)

Sample Sieve (g)

Difference (g)

%Retained

Cumulative %Retained

#20 321.4 321.4 0 0 0

#30 328.6 328.8 0.2 0.2 0.2

#40 299 300.0 1.0 1.0 1.2

#60 287.2 297.4 10.2 10.2 11.4

#100 255.0 275.0 20.0 20.0 31.4

#120 274.0 299.0 25.0 25.0 56.4

#200 270.0 303.2 33.2 33.2 89.6

Receiver

348.8 359.0 10.2 10.2 99.8

Weight of sample=100g




Fig.4: FT-IR Report of Ketoprofen Fig.5: FT-IR Report of Ketoprofen with Sugar

Fig.6: FT-IR Report of Ketoprofen with Poly Vinyl Pyrrolidone K-30 Fig.7: with Hydroxypropyl Methylcellulose E-5

Fig.8: FT-IR Report of Ketoprofen with Ethylcellulose N-50 Fig.9: Ketoprofen with Eudragit L-10




Evaluation of Ketoprofen Pellets: Micromeritic Properties: Angle of Repose:

Table.12 shows the results obtained for angle of repose for all the formulations. The values were found to be in the range of 26°.10' to 28°.67'. All the formulations showed the angle of repose below 30°, which indicates good flow. Bulk Density:

The bulk density and tapped bulk density for all the formulations varied from 0.74 gm/cm3 to 0.81 gm/cm3 and 0.81 gm/cm3 to 0.87 gm/cm3

respectively. The values obtained lies within the acceptable range and no large differences found between bulk density and tapped bulk density. These results help in calculating the % compressibility of the powder. Compressibility Index / Carr’s Index:

The percentage compressibility of powder mix was determined by the equation given for Carr’s Consolidation Index. The percentage compressibility for all the formulations lies within the range of 5.0 to 8.64 which indicates that the flow of all the formulations is excellent. Hausner’s Ratio:

The Hausner’s ratio was determined by the data of bulk density and tapped density. The Hausner’s ratio for all the formulations lies within the range of 1.05 to 1.09, which indicates flow of powder is excellent. Evaluation of flow properties of the formulations from F1 – F12 were tabulated in Table.12. Sieve Analysis:

Sieve analysis values of Ketoprofen pellets shown in Table.13 reveals that most of the pellets pass through sieve no. 16 and retain on sieve no. 20 and from this it came to know that the pellets as per specifications. Table.13. Sieve Analysis values of Ketoprofen Pellets

Sieve No % Retain % Pass #14 2 98 #16 15-20 85-90 #18 50 50 #20 95 5

Percentage Yield:

Percentage yield of all formulations was determined by weighing the pellets after drying. Percentage yield was calculated to know the amount of loss occurred during the manufacturing process. The percentage yield of different formulations was in the range of 92.16- 96.27 as shown in the Table.14. Percentage yield values indicate that only small amount of loss is occurred during the formulation development. Moisture Content:

Moisture content of all formulations was calculated to know the amount of moisture present in the pellets. The moisture content of different batches of pellets was in the range of 2.12-2.94%, which was found to be satisfactorily within limits. Moisture content values of all formulations were shown in the Table.14. Percentage Friability:

The friability test is designed to evaluate the ability of the pellets to withstand abrasion in filling, handling, and shipping. Pellets were weighed and placed in tumbling apparatus where they were exposed to rolling and repeated shocks resulting from freefalls within the apparatus. The percentage friability for all the formulations lies in the range of 0.51 % to 0.70 %, which was found to be in limit (i.e. < 1%). Friability values of all formulations were shown in the Table.14. Determination of Assay by U.V – Vis Spectrophotometer (% w/w):

All the formulations were evaluated for the drug content estimation in a pooled sample of capsules using the procedure described in methodology section. The drug content values for all the formulations are in the range of 94.46% to 101.23. The content of all formulations complies with the test because all the assay values are within the limits and the values of all formulations are shown in the Table.14.

Evaluation of Ketoprofen Capsules Weight Uniformity Test:

The result of weight uniformity of these ketoprofen capsules is shown in Table 15. All these formulations met the USP and I.P




specifications for weight uniformity. The coefficient of variation of these capsules varied from 2.25 to 3.22 %. The values of coefficient of

weight variations indicate that filling of capsules carried out properly.

Table.12. Flow Properties of all Formulations

Formulation Code

Angle of Repose*( )

Bulk Density*(g/ml)

Tapped Density*(g/ml)

Carrs Index

Hausner’s Ratio

F1 26.54±0.05 0.74±0.059 0.81±0.047 8.64 1.09 F2 28.42±0.04 0.81±0.063 0.86±0.059 5.81 1.06 F3 26.89±0.05 0.76±0.023 0.80±0.075 5.0 1.05 F4 25.98±0.06 0.75±0.047 0.81±0.084 7.40 1.08

F5 27.45±0.04 0.81±0.048 0.86±0.046 5.81 1.06 F6 25.42±0.03 0.81±0.087 0.87±0.057 6.89 1.07 F7 28.18±0.07 0.76±0.051 0.83±0.035 8.43 1.09 F8 26.38±0.05 0.74±0.042 0.81±0.068 8.64 1.09 F9 25.98±0.07 0.81±0.038 0.86±0.086 5.81 1.06

F10 26.10±0.06 0.77±0.055 0.83±0.026 7.22 1.07 F11 28.67±0.03 0.81±0.034 0.87±0.038 6.89 1.07 F12 27.12±0.06 0.77±0.067 0.84±0.061 8.33 1.09

Table.14. Percentage Yield, Moisture Content, Percentage Friability and Assay of all Formulations

Formulation Code

% Yield Moisture Content (%)

Friability (%) Assay (%)

F1 94.64±1.584

2.83 0.66±0.04 94.46%±0.36

F2 94.0±1.625 2.86 0.65±0.01 99.93%±0.28

F3 92.46±1.891

2.92 0.61±0.05 96.48%±0.14

F4 94.18±1.426

2.78 0.58±0.03 100.61%±0.38

F5 95.68±1.250

2.12 0.53±0.06 98.16%±0.31

F6 96.27±1.276

2.66 0.51±0.04 95.59%±0.16

F7 94.93±1.368

2.94 0.70±0.08 101.23%±0.71

F8 93.68±1.452

2.38 0.68±0.04 99.96%±0.57

F9 94.39±1.328

2.45 0.65±0.07 99.85%±0.16

F10 92.16±1.831

2.68 0.64±0.04 96.82%±0.28

F11 93.58±1.436

2.73 0.62±0.03 100.24%±0.13

F12 94.16±1.831

2.45 0.60±0.06 97.56%±0.61




Table.15. Weight Uniformity Test of all Formulations

Formulation Code

Mean Weight ±S.D

Coefficient of Variation

F1 287.07 ±7.12 2.48

F2 286.46 ±8.78 3.06

F3 286.92 ±8.05 2.80

F4 292.02 ±7.22 2.47

F5 288.66 ±7.08 2.45

F6 290.08 ±8.12 2.799

F7 289.03 ±7.07 2.446

F8 286.18 ±9.12 3.18

F9 288.92 ±9.33 3.22

F10 290.07 ±8.87 3.05

F11 288.14 ±7.18 2.49

F12 286.48 ±6.45 2.25

Coefficient of Variation = (S.D/Mean) × 100

Table.16. Lock Length and Disintegration Test of all Formulations

Formulation Code

Lock Length(mm)

Disintegration Time(min)

F1 19.5 28.25

F2 19.4 26.50

F3 19.6 27.15

F4 19.3 25.75

F5 19.2 26.18

F6 19.6 22.48

F7 19.1 27.85

F8 19.4 26.18

F9 19.7 25.85

F10 19.5 28.10

F11 19.3 23.50

F12 19.6 24.15




Lock Length:

The average lock length of all the formulations was in the range of 19.1 to 19.7. Therefore lock length of all the capsules was within the specifications (capsule size: 1, Limits 19.4±0.3). Lock length values of all the formulations was shown in the Table.16.

Disintegration Time: Disintegration time of all the formulations was

shown in the Table.20. Disintegration time of all capsules was in the range of 22.48 to 28.25. Therefore Disintegration time of all the formulations was within the specifications. In vitro Drug Release Studies:

The results of in-vitro release of drug from formulations F1 – F12 along with the marketed preparation graphs plotted against Time Vs % Drug Release were shown in Fig.10, Fig.11 and Fig.12. The in vitro drug release characteristic were studied in 0.1 N HCl of pH 1.2 for a period of 2hrs followed by phosphate buffer of pH 7.4 for a period up to 24 hrs using USP type I dissolution apparatus. In formulations F1 to F6 pellets was coated with ECN-50 and Eudragit L-100 and in formulations F6 to F12 pellets was coated with ECN-50 and HPMC E-5. ECN-50 and Eudragit L-100 were hydrophobic polymers and HPMC E-5 is hydrophilic polymer.

In formulation F1 to F3 pellets was coated with 0.4% Eudraqgit L-100 and 0.4% ECN-50, 0.4% Eudraqgit L-100 and 0.6 % ECN-50, 0.4% Eudraqgit L-100 and 0.8 % ECN-50 and the drug release from the formulations were observed as 75.25 %, 70.92 % and 68.39 % at the end of 24 hrs of dissolution.

In formulation F4 to F6 pellets was coated with 0.6% Eudraqgit L-100 and 1 % ECN-50, 0.6% Eudraqgit L-100 and 1.2 % ECN-50, 0.4% Eudraqgit L-100 and 1.4 % ECN-50 and the drug release from the formulations were observed as 100.42 %, 98.22 % and 91.11 % at the end of 24 hrs of dissolution.

From the dissolution profiles of Formulations F1 to F6, I came to know that the drug release from the formulation is decreased by increasing

the concentration of ECN-50. Due to increase in the concentration of ECN-50 from formulation F1 to F6 coating thickness is increased and the drug release from the formulation is decreased. A slight increase in the concentration of Eudragit L-100 can cause a reasonable increase in the drug release from the formulation. This occurs because Eudragit L-100 dissolves in the pH > 6.

In formulation F7 to F9 pellets was coated with 0.4% of HPMC E-5 and 0.4 % of ECN-50, 0.4% of HPMC E-5 and 0.6 % of ECN-50, 0.4% of HPMC E-5 and 0.8 % of ECN-50. The drug release from the formulation F7 was observed as 100.33 by the end of 16 hrs of dissolution only. The drug release from the formulation F8 was observed as 100.21 by the end of 16 hrs of dissolution only. The drug release from the formulation F8 was observed as 100.16 by the end of 24 hrs of dissolution.

In formulation F10 to F12 pellets was coated with 0.6% of HPMC E-5 and 1 % of ECN-50, 0.6% of HPMC E-5 and 1.2 % of ECN-50, 0.6% of HPMC E-5 and 1.4 % of ECN-50. The drug release from the formulation F10 was observed as 100.52 by the end of 8 hrs of dissolution only. The drug release from the formulation F11 was observed as 100.11 by the end of 8 hrs of dissolution only. The drug release from the formulation F12 was observed as 100.32 by the end of 16 hrs of dissolution only.

From the dissolution profiles of Formulations F7 to F12, I came to know that the drug release from the formulation is decreased by increasing the concentration of ECN-50. Due to increase in the concentration of ECN-50 from formulation F7 to F12 coating thickness is increased and the drug release from the formulation is decreased.

The formulations F1 to F6 showed better drug release when compared with the formulations F7 to F12 when dissolution was done with objective of formulating sustained drug delivery for 24 hours. In all the formulations drug release was slower during 0 to 4 hrs because of low water affinity of the ECN-50. As the relative composition of ECN-50 increased retards the penetration of dissolution medium by providing




by more hydrophobic environment and thus cause delay in release of drug from pellets.

Formulations F1 to F6 showed low drug release in 0.1 N HCl of pH 1.2 and high drug release in Phosphate buffer of pH 7.4. Formulations F7 to F12 showed high drug release in 0.1 N HCl of pH 1.2 and phosphate buffer of pH 7.4 when compared with F1to F6. By this we came to know that both ECN-50, Eudragit L-100 polymers dissolve in nearly basic or basic pH conditions and HPMC E-5 dissolve in acidic conditions. Formulations F1 to F6 showed better retarding effect on drug release when compared with formulations F7 toF12.

Formulation F5 showed better drug release(98.22%) when compared to other formulations and the marketed SR tablets, so F5 formulation is considered as best formulation.

Fig.10. Comparison of Dissolution Profile of Formulations F1 to F6

Fig.11. Comparison of Dissolution Profile of Formulations F7 to F12

Fig.12. Comparison of Dissolution Profile of Formulation F5 and Marketed Preparation

Scanning Electron Microscopy: Scanning Electron Microscopy

photomicrographs shown in Fig.13 reveal that the pellets were spherical or nearly spherical shape. Normal size range of pellets ranges from about 0.5 to 1.5 mm. From SEM images we can observe that the pellets obtained were in the size range of about 1.08 to 1.44 mm. By this we conclude that the prepared pellets are within the size range limits.

Fig.13. SEM Photomicrographs of Formulation F5




Mathematical Models:

In order to understand the kinetics and mechanism of drug release, the result of the in vitro dissolution study of all formulations was fitted with various kinetic equations like zero order as cumulative percentage released Vs Time, First order as log percentage of drug remaining to be released Vs. Time, and Higuchi’s model, cumulative percentage drug released Vs Square root of time. The R2 values were calculated for the linear curves obtained by regression analysis of the above plots. The mathematical modeling of the in-vitro drug release data for all the formulations were complied in Fig.13, Fig.14, Fig.15, Fig.16, Fig.17, Fig.18, Fig.19, Fig.20 and R2 values of all formulations was shown in Table.17.

It is evident from the R2 values that the drug release from formulations was found to follow first order kinetics. The mechanism of drug release from the formulations was by non-fickian diffusion as the value of n is less than 0.89 and greater than 0.45.

Fig.13. Zero Order Plot for Formulations F1 to F6

Fig.14. Zero Order Plot for Formulations F7 to F12 and Marketed Preparation

Fig.15. First Order Plot for Formulations F1 to F6

Fig.16. First Order Plot for Formulations F7 to F12 and Marketed Preparation




Table.17. Mathematical Models for Ketoprofen Sustained Release Formulations

Formulation Code

Correlation coefficient (R2) Release

Exponent (n) Zero Order

First Order Higuchi

Korsemeyer

Peppas

F1 0.918 0.986 0.980 0.971 0.731

F2 0.919 0.979 0.976 0.977 0.744

F3 0.928 0.983 0.980 0.980 0.731

F4 0.911 0.990 0.962 0.954 0.876

F5 0.919 0.970 0.967 0.960 0.864

F6 0.929 0.996 0.971 0.969 0.838

F7 0.810 0.994 0.942 0.961 0.874

F8 0.831 0.993 0.949 0.921 0.712

F9 0.843 0.992 0.953 0.928 0.728

F10 0.681 0.788 0.846 0.810 0.789

F11 0.705 0.850 0.861 0.823 0.798

F12 0.714 0.903 0.865 0.834 0.805

MP 0.931 0.981 0.969 0.961 0.874

Fig.17Higuchi's Plot for Formulations F1 to F6

Fig.18. Higuchi's Plot for Formulations F7 to F12 and Marketed Preparation




Fig.19. Korsemeyer Plot for Formulations F1 to F6

Fig.20. Korsemeyer Plot for Formulations F7 to F12 and Marketed Preparation

Stability Studies:

Optimized formulation F5 was subjected to stability studies for 3 months at 40±20 C/75±50

RH storage conditions and the formulation was tested for moisture content, assay and dissolution during and after stability studies. The results obtained were as in the following Table.18. The values indicate that there is not much change in moisture content and assay values after stability studies. In-vitro drug release of optimized formulation F5 was compared with the marketed preparation after stability studies and it is better than Marketed Preparation (Fig 21.)

Fig.21. Comparision of Dissolution Profile of Optimized Formulation F5 and Marketed preparation after stability studies for 3 month

Conclusion:

In this study, pellets containing Ketoprofen was prepared successfully using powder layering technique in coating pan followed by coating of the pellets in Fluidized Bed Coater. Coating was done by using Ethyl cellulose N-50, Hydroxypropyl methyl cellulose E-5 and Eudragit L-100 as retarding polymers.

The drug release rate was found to vary among the formulations depending on the composition, percentage of coating material used and solubility of the coating materials in the buffer. The in-vitro release of drug from formulations F1 to F12 along with the Marketed preparation was performed. Formulation F5showed better drug release when compared to other formulation and marketed extended release tablet. It was concluded from the present study that the formulation F5 is the optimized formulation. The formulation F5 was obtained by coating the drug loaded pellets with 1.2% of ECN-50 and 0.6% of Eudragit L-100.

R2 value of optimized formula indicates the drug release form the formulations is found to follow first order kinetics. Release exponent (n) value of optimized formula is 0.864, which indicates that the drug release from the




formulation occurs by non-fickian diffusion as the value of n is greater than 0.45 and less than 0.89. Drug Release from the optimized formulation is better than the marketed extended release tablet even after the stability studies. It is evident from

the results that formulation F5, better system for daily once dose and sustained release coating having higher retardant release profile than marketed product.

Table.18. Moisture Content and Assay Values of Optimized Formulation F5 during and after stability studies

S. No

Test Initial Month 1 Month 2 Month 3

1 Moisture Content (%)

2.12 2.18 2.22 2.24

2 Assay (%) 98.15±0.17

98.09±0.28

97.94±0.38

97.91±0.17

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