INTRODUCTION:

For decades an acute disease or chronic illness is being clinically treated through delivery of drug to the patient in the form of some pharmaceutical dosage forms like tablets, capsules, pills, creams, liquids, ointment, aerosols, injectable and suppositories^[^1]. A Successful drug delivery requires consideration of numerous aspects. Depending on the route of administration, the properties of the drug, and many other aspects, various strategies have to be developed. Without doubt the most generically important aspects of any therapy is its efficacy and safety. First and foremost, the drug concentration should be sufficiently high at the site of action in order to have a therapeutic effect, but at the same time it should not be too high, since this may result in side effects. For a safe and efficient therapy, the drug concentration should preferably lie essentially constant within this ‘‘therapeutic window’’ over the time of action. The goal of a constant drug concentration within the therapeutic window at the site of action over a suitable therapeutic time puts requirements not only on the drug but also on the drug formulation.

The drug delivery system should preferably be designed such that a preferential accumulation of the drug is reached at the site of action, whereas the drug concentration elsewhere in the body should be as low as possible^[2]. The science of drug delivery may be described as the application of chemical and biological principles to control the in vivo temporal and spatial location of drug molecules for clinical benefit. Today’s world requires that drug delivery systems be precise in their control o of drug distribution and, preferably, respond directly to the local environment of the pathology in order to achieve a dynamic and beneficia interaction with the histopathology^[3].Oral route has been the most widely used and most convenient route for the drug delivery. Oral route of administration has received more attention in the pharmaceutical industry and research field because of the flexibility in designing of dosage form and constraints like sterility and potential damage at the site of administration are minimized. The novel drug delivery system involves a new technique of formulation for existing drug substances. In recent years attention has been focused on the development of new drug delivery systems. The reasons are summarized as follows. 1) Synthesis of new drug is more expensive, time consuming than formulation of the existing drugs. 2) These dosage forms achieve better therapeutic efficacy & safety of drugs, because these forms will maintain constant plasma drug concentration. Therefore discovering how to use existing drugs to their fullest potential is also having equal importance & scope as that of creating a new drug molecule. All the pharmaceutical formulation for systemic effect via oral route of administration must be developed within intrinsic characteristics of gastrointestinal physiology. The needs of GI physiology. Pharmacodynamics, pharmacokinetics and formulation design is essential to achieve a systemic approach to the successful development of an oral formulation dosage form. The scientific framework required for the successful development of an oral drug delivery system consists of basic understanding of the following three aspects: 1) Physicochemical properties of the drug.2) The Anatomy and physiological characteristics of GIT.3) Dosage form characteristic. The first truly effective oral drug delivery system, the “Spansule” was introduced in the 1950s. This prolonged-release system was marketed by Smith Kline & French Laboratories and consisted of small coated beads placed in a capsule. The 50 to 100 or more beads per capsule were designed to release at a different rate^[4]. A Historically, the oral route of drug administration has been the one used most for both conventional as well as novel drug delivery. The reasons for this preference obvious because of the ease of administration and widespread acceptance by patients. Major limitations of oral route of drug administration are as follows: Drugs taken orally for systemic effects have variable absorption rates and variable serum concentrations which may be unpredictable. This has led to the development of sustained release and controlled-release systems^[5]. Thus, various modified drug products have been developed to release the active drug from the product at a controlled rate. The term controlled release drug products was previously used to describe various types of oral extended-release dosage forms, including sustained release, sustained action, prolonged action, slow release, long action, and retarded release^[6,7,8].

MATERIALS AND METHODS:

Mefenamic acid was obtained as a gift sample from Ajanta Pharmaceuticals, Aurangabad, India. Sodium lauryl sulphate, Tween80 and other chemicals were procured from SD fine chemicals, Mumbai.

Preparation of SR Matrix Tablets:

SR matrix tablets, each containing 100 mg Mefenamic acid, were prepared by direct compression technique. The drug polymer ratio was developed to adjust drug release as per theoretical release profile and to keep total weight of tablet constant for all the fabricated batches under experimental conditions of preparations. The total weight of the SR matrix tablets was 300 mg with different drug polymer ratios. The composition of tablets is shown in Table 1. Microcrystalline cellulose was incorporated as filler excipients to maintain tablet weight constant. This water insoluble filler was incorporated also to counterbalance the faster solubility of the drug in presence of hydrophilic polymer and to provide a stable monolithic matrix. The ingredients were passed through sieve # 30 and thoroughly mixed in a polythene bag. The powder blend was then lubricated with aerosol and magnesium stearate and compressed 90 into tablets on a 8 station single rotary Cadmach machine.

Table No. 1: Composition of Tablet Formulation.

Ingredient	D1	D2	D3	D4	D5
Mefenamic acid	100.00	100.00	100.00	100.00	100.00
HPMC	60.00	90.00	120.00	130.00	140.00
MCC	137.00	107.00	77.00	67.00	57.00
Aerosil	01	01	01	01	01
Magnesium Stearate	02	02	02	02	02
Total weight	300	300	300	300	300
Drug : Polymer ratio	1:0.60	1:0.90	1:1.20	1:1.30	1:1.40

Evaluation of Physical Properties:

All prepared matrix tablets were evaluated for uniformity of weight, hardness, thickness, friability and drug content, as per I.P. method. Hardness was measured by using Pfizer hardness tester. Friability was determined using Roche friabilator. Thickness was measured by Vernier calipers. Weight variation test was performed according to official method. Drug content for Mefenamic acid was carried out by measuring the absorbance of samples at 285 nm using UV/Visible spectrophotometer and comparing with standard Mefenamic acid in the same medium.

Characterization of the tablet:

The prepared tablet were subjected to various quality control test to characterization them.

Weight Variation:

The weight variation test of the tablets was done as per of the tablets was done as per the guidelines of Indian pharmacopoeia .Weight of the twenty tablets (selected at random) and their individual weights were noted and the mean weight was also calculated

Thickness:

Once the tablet size and shape have been established ,tablet thickness remains the only overall within 5% or less of an establish standard value excessive variation in tablet thickness can result in problems with packaging as well as consumer acceptance variation in tablet thickness can also indicate formulation or processing problems such as change in die fill and motion.

Hardness:

Tablets require a certain amount of mechanical strength to withstand the shock of handling during its manufacturing, packaging, shipping and dispensing. It may be especially important to monitor the tablet hardness for sustained release drug products or other product that posses potential bioavailability problems or are sensitive to variations in drug release profile. The crushing strength that just causes the tablet to break was recorded by means of Monsanto hardness tester.

Friability:

Friability is the measure of the tablets ability to withstand both shock abrasion with without crumbling during manufacturing, packing, shipping and consumer use. Tablets that tend powder, chip and fragment when handled lack elegance and hence, consumer acceptance. The weight of ten tablets was noted and they were then placed in Roche type friabilator. The pre-weighed tablet sample was removed after 100 revolutions, dusted and reweighed. Tablets that loose than 0.5 to 1% in weight are generally considered acceptable.

Drug content estimation:

From each batch 5 tablets were triturated to form fine powder after knowing the individual weight of each tablet. The powder equivalent to 100mg of Mefenamic acid was weighed and transfer in to 100ml volumetric flask and dissolved in phosphate buffer of ph 6.8 to get concentration of 10ug/ml .The absorbance of this solution was measured at 285nm UV-visible spectrophotometer. The drug content was estimation by using calibration curve.

In Vitro Release Study:

The in vitro dissolution studies were carried out using USP 24 dissolution apparatus type II 16 (paddle method) at 100 rpm. Dissolution test was carried out for a total period of 12 hours using 0.1N HCl (pH 1.2) solution (750 ml) as dissolution medium at 37 ± 0.50 for first 2 hours, and pH 6.8 Phosphate buffer solution (1000 ml) for the rest of the period. 10 ml of the sample was withdrawn at regular intervals and replaced with the same volume pre warmed (37 ± 0.50) fresh dissolution medium. The samples withdrawn were filtered through 0.45 u membrane filters and drug content in each sample was analyzed after suitable dilution by spectrophotometer at 285 nm. The actual content in samples was read from a calibration curve prepared with standard Mefenamic acid^[^9,10].

RESULTS AND DISCUSSION:

The prepared SR matrix tablets of Mefenamic acid met the standard Pharmacopoeial requirement of uniformity of weight. All the matrix tablets conformed to the requirement of assay, as per I.P, Hardness, % friability and thickness was well within acceptable limits (Table 2).

All formulation showed very low drug release in 0.1N HCl (pH 1.2). This was due to the very low solubility of Mefenamic acid at pH 1.2. Sustained but complete drug release was displayed by all formulations in phosphate buffer (pH 6.8). Thus it can be concluded that drug dissolution was a function of drug solubility of Mefenamic acid is well known. When pH rises above pKa, rapid increase in solubility occurs. The dissociation constant (pKa) of Mefenamic acid is 4.55 ± 0.06 at 25⁰C in water. Mefenamic acid release from tablets was slow and extended over longer periods of time. The results of dissolution studies of formulations D1, D2, D3, D4 and D5 are shown in Table 3. Drug release from the matrix tablets was found to decrease with increase in drug polymer ratio. Formulation D1 composed of drug polymer ratio of 1: 0.6, failed to sustain release beyond 8 hours. Formulation D3 with higher tablet hardness gave slower (t50 is 3.2 Hour) and complete release of Mefenamic acid over a period of 12 hour compared to D2 (t50 is 2.2 Hour) shown in Figure 1. Hence we concluded that there is a direct relationship between tablet hardness and sustaining of the drug release.

The release of drug depends not only on the nature of matrix but also upon the drug polymer ratio. As the percentage of polymer increased, the kinetics of release decreased. This may be due to structural reorganization of hydrophilic HPMC polymer. Increase in concentration of HPMC may result in increase in the tortuosity or gel strength of the polymer. When HPMC polymer is exposed to aqueous medium, it undergoes rapid hydration and chain relaxation to form viscose gelatinous layer (gel layer). Failure to generate a uniform and coherent gel may cause rapid drug release.

In vitro release studies demonstrated that the release of Mefenamic acid from all the formulated SR matrix tablets can generally be sustained. The mechanism of release of Mefenamic acid from tablets D1 to D3 was quasi (Fickian) diffusion, while D4 showed behavior of Fickian diffusion. As shown in Table 4. The n values increased as the drug polymer ratio of the tablets increased. Formulation D5 showed average linearity (R2 values 0.9622), with slope n value of 0.538. This n value appears to indicate a coupling of diffusion and erosion mechanism (known as anomalous non–Fickian diffusion). Hence, diffusion coupled with erosion may be the mechanism of Mefenamic acid release from D5.

Table No. 3.Percentage cumulative release of drug and other formulations.

Time (hrs)	D1	D2	D3	D4	D5
0	0	0	0	0	0
1	45.12	38.15	33.62	25.25	20.55
2	55.45	46.62	41.23	35.10	28.12
4	63.22	61.22	60.21	54.62	40.21
6	76.99	74.44	70.44	68.12	51.96
8	87.22	79.62	75.65	72.12	62.69
10	99.12	81.37	79.15	78.19	75.22
12	--	99.65	99.05	99.02	99.98

Fig 1: Dissolution profile of formulations

Table 4: Mathematical modeling and drug release mechanism of Mefenamic acid SR tablets.

Formulation	n	r	Mechanism
D1	0.286	0.9765	Quasi-Fickian Diffusion
D2	0.320	0.9892	Quasi-Fickian Diffusion
D2	0.398	0.9979	Quasi-Fickian Diffusion
D3	0.497	0.9849	Fickian Diffusion
D4	0.538	0.9879	Anomalous (Non-Fickian) Diffusion

CONCLUSION:

It may be concluded from the present study that slow, controlled and complete release of Mefenamic acid over a period of 12 hours was obtained from matrix tablets D5 formulated employing drug polymer ratio of 1:1.40. It is also evident from the results that formulation D5 is a better system for SR of Mefenamic acid. Formulations D1 to D4 exhibited diffusion to quasi diffusion mechanism of drug release, whereas the mechanism of drug release from D5 was anomalous.

REFERENCES:

1. Vyas S. P, Roop K. Khar, “Controlled Drug Delivery Concepts and Advances”. Vallabha Prakashan; 2002:156.

2. Martin Malmsten, “Surfactants and Polymers in Drug Delivery.” Markel Dekker Inc; 2002:22-23.

3. Ijeoma F. Uchegbu, “Polymers In drug delivery” Taylor and Francis Group, LLC; 2006:1, 39, 40.

4. Keval K. Jain, “Drug Delivery Systems” Humana Press: 217-222.

5. Shargel L. Andrew B.C. Yu. In, “Applied Biopharmaceutics and Pharmacokinetics” New York. 4^thedition, Prentice- Hall International; 1999:139-142.

6. Lachman Leon, Liberaman H. A. and Kanig J.L, “The Theory and Practice of Industrial Pharmacy” 3^rdedition, Varghese publishing house Bombay: 296-302,430.

7. Chein, Y.W. “text Book of Novel Drug delivery system.”2^nd Edition Marcel Dekker Inc; 1992:1-2, 8-9, 44-45, 50.

8. Lione D. Edward, Andrew J. Fletch Anthony W. Fox and Peter D. Stonier. “Principles and Practice of Pharmaceutical Medicine.” 2^ndEdition, John Wiley Sons, Ltd.2007:55.

9. Xialoing Li Bhaskara R. Jasti “Design of Controlled Release Drug Delivery System” McGraw Hill Publication: 108-118.

10. Brahmankar D. M., Jaiswal S. B., “Biopharmaceutics and Pharmacokinetics: A Treatise.” Delhi. 1^stedition. Vallabha Prakashan; 2002:335-337.

Received on 11.07.2014 Modified on 20.08.2014

Res. J. Pharm. Dosage Form. and Tech. 6(4):Oct.- Dec.2014; Page 249-252

FORMULATION	DRUG CONTENT (%)	THICKNESS (mm)	HARDNESS (kg/cm2)n=5	WEIGHT (mg)	FRIABILITY (%)
D1	97.7 ± 0.4	3.81	4.7 ± 0.20	290.0 ±1.55	0.35
D2	99.5 ± 0.3	3.86	4.8 ± 1.20	300.1±1.52	0.40
D3	98.3 ± 0.9	3.86	5.0 ± 0.10	280.3±1.69	0.45
D4	99.6 ± 0.5	3.85	4.8 ± 1.20	290.5±1.70	0.18
D5	99.9 ± 0.3	3.86	4.9 ± 0.50	290.8±1.31	0.21