1. INTRODUCTION:

1.1 Epilepsy

An epileptic seizure itself is one of the many pathological forms of reaction which can take place in the brain; it is the brain’s "response" or reaction to a disturbing, irritating or damaging stimulus. This reaction to the stimulus is accompanied by abnormal electrochemical excitatory processes in the cerebral nerve cells. This pathological process takes place when suddenly an unnaturally large number of nerve cells are stimulated simultaneously, causing a difference in voltage between the outer side of the cell wall and the inside of the cell (membrane potential). This voltage difference is then suddenly discharged, creating a kind of "storm in the brain", or, to put it another way, "making a fuse blow".¹

1.1.1 Symptoms⁴

Early Symptoms (auras or warnings)

Unusual smell, sound, taste, or visual perception, Fear/panic, Dizziness, headache, light headedness, nausea, numbness, sometimes no warnings.

Seizure Symptoms

Confusion, loss of consciousness, spaceyness, Visual, smelling, and/or hearing difficulties, Twitching, shaking, stiffening, tongue biting, incontinence, falling, drooling, eyelid fluttering.

After Seizure Symptom

Confusion, memory loss, Writing difficulties, Depression, fear, frustration/shame, Nausea, headache, pain, thirst, weakness, Injuries, Exhaustion/sleeping.

1.1.3 Types ⁶

a) Absence (petit mal): It is most common in children. It is characterized by a blank stare lasting about half a minute; the person appears to be daydreaming. During this type of seizure, the individual is unaware of his or her surroundings.

b) Atonic (drop attack): A childhood seizure in which the child loses consciousness for about ten seconds and usually falls to the ground because of a complete loss of muscle tone.

c) Complex partial (temporal lobe): A blank stare, random activity, and a chewing motion are characteristic of this type of seizure. The person may be dazed and unaware of his or her surroundings, and may act oddly. There is no memory of this seizure. A person may experience a distinctive warning sign called an aura before this type of seizure.

d) Generalized tonic-clonic (grand mal): It is characterized by sudden cries, a fall, and rigidity and jerking of the muscles, shallow breathing, and bluish skin. Loss of bladder control is possible. The seizure usually lasts two to five minutes, and is followed by confusion, fatigue, and/or memory loss. It can be frightening to witness, especially for the first-time observer.

e) Myoclonic: Brief, massive muscle jerks occur.

f) Simple partial (Jacksonian): Jerking begins in the fingers and toes and progresses up through the body. The person remains conscious.

g) Simple partial (sensory): The person may see, hear, or sense things that do not exist. This may occur as a preliminary symptom of generalized seizure.

1.2 Controlled release Drug delivery system

Conventional drug therapy requires periodic doses of therapeutic agents. These agents are formulated to produce maximum stability, activity and bioavailability. For most drugs, conventional methods of drug administration are effective, but some drugs are unstable or toxic and have narrow therapeutic ranges. Some drugs also possess solubility problems. In such cases, a method of continuous administration of therapeutic agent is desirable to maintain fixed plasma levels

To overcome these problems, controlled drug delivery systems were introduced three decades ago. These delivery systems have a number of advantages over traditional systems such as improved efficiency, reduced toxicity, and improved patient convenience. The main goal of controlled drug delivery systems is to improve the effectiveness of drug therapies.⁸

The oral controlled-release system shows a typical pattern of drug release in which the drug concentration is maintained in the therapeutic window for a prolonged period of time, thereby ensuring sustained therapeutic action. Thus, the release commences as soon as the dosage form is administered as in the case of conventional dosage forms. Controlled drug delivery is delivery of drug at a rate or at a location determined by needs of body or disease state over a specified period of time. Ideally two main objectives exist for these systems: Spatial delivery, which is related to the control over the location of drug release. Temporal drug delivery, in which the drug is delivered over an extended period of time during treatment.^{9, 10}

Advantages of Controlled Drug Delivery System ^{8, 11, 12}

· Avoid patient compliance problems.

· Employ less total drug.

· Minimize or eliminate local rate effects.

· Minimize or eliminate systemic side effects.

· Obtain less potentiation or reduction in drug activity with chronic use.

· Minimize drug accumulation with chronic dosing.

· Improve efficiency in treatment.

· Cure or control condition more promptly.

· Improve control of condition, i.e., reduce fluctuation in drug level.

· Improve bioavailability of some drugs.

· Make use of special effects, e.g. sustained-release aspirin for morning relief of arthritis by dosing before bedtime.

· Economy.

1.2.1 Types of Non-immediate release drug delivery system

The conventional dosage forms are immediate release type. Non-immediate release delivery systems may be divided conveniently into three categories: ^12-16

a) Delayed release drug delivery systems:

Repeat action DDS

Timed release DDS

b) Sustained release drug delivery systems:

Controlled release DDS

Prolonged release DDS

c) Site specific and receptor release drug delivery systems:

Organ targeting DDS

Cellular targeting DDS

Sub cellular targeting DDS

1.2.2 Classification of controlled release systems

(A)Monolithic Systems (Matrix System)

Monolithic (matrix) devices are the most common of the devices for controlling the release of drugs. This is because they are 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 formed by the compression of a polymer/drug mixture or by dissolution or melting. The dosage release properties of monolithic devices may be dependent upon the solubility of the drug in the polymer matrix or, in the case of porous matrixes, the solubility in the sink solution within the particle's pore network, and also the tortuosity of the network (to a greater extent than the permeability of the film), dependent on whether the drug is dispersed in the polymer or dissolved in the polymer. 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).

• Diffusion controlled by Flick’s law.

Where,

J = flux of the drug across a membrane in the direction of decreasing concentration,

D = Diffusion coefficient of the drug, and dCm /dx = Change in the concentration of the drug in the membrane.

Figure: 1.5 Rate Control: Matrix System

(B) Reservoir Systems

A typical approach to controlled release is to encapsulate or contain the drug entirely e.g., as a core within a polymer film or coat (i.e., microcapsules or spray/pan coated cores). The various factors that can affect the diffusion process may readily be applied to reservoir devices (e.g., the effects of additives, polymer functionality {and, hence, sinksolution pH} porosity, film casting conditions, etc.) and, hence, the choice of polymer must be an important consideration in the development of reservoir devices. Modeling the release characteristics of reservoir devices (and monolithic devices) in which the transport of the drug is by a solution-diffusion mechanism therefore typically involves a solution to (unsteady-state conditions; concentration dependent flux) for the relevant boundary conditions. When the device contains dissolved active agent, the rate of release decreases exponentially with time as the concentration (activity) of the agent (i.e., the driving force for release) within the device decreases (i.e., first order release). If, however, the active agent is in a saturated suspension, then the driving force for release is kept constant (zero order) until the device is no longer saturated. Alternatively the release-rate kinetics may be desorption controlled, and a function of the square root of time. ^22-25

4.2 Methodologies that are adopted in present work

4.2.1 Pre-formulation studies:

4.2.1.1 Solubility:

Add measured volumes of different medias at physiological pH to 1 gm of API (Antiepileptic drug + its sodium salt) until it dissolve and produce saturated solution. Calculate the mg of API that goes into per ml of solvent or media. Solubility is carried out at temperature between 15-25° C

4.2.1.2 Drug-Excipients Compatibility study:

DSC study was carried out using DSC TA-60 instrument (M/s Shimadzu) to check the compatibility of ingredients with drug. DSC thermograms of pure drug, physical mixtures of drug and each excipient and final formulation were studied for their interactions. DSC thermograms were taken.

Procedure :Samples were placed in pierced aluminum pans and hold for 1 minute at 50ºC and then heated gradually at 10ºC min-1 from 50ºC to 350ºC. The onsets of melting points were calculated by the instrument.

4.2.2 Method for Evaluation of blend ready for compression

4.2.2.1 % Loss on drying:

On wet-weight basis the water content of materials is calculated as a percentage of the weight of the wet solid. Loss on Dry is an expression of moisture content on a wet-weight basis, which is calculated as follows:

% LOD = wt. of water in sample /total wt. of wet sample x 100

A weighed sample is placed on the moisture balance and allowed to dry until it is at constant weight. The water lost by evaporation is read directly from the percent LOD scale.

4.2.2.2 Flow Property:

I. Bulk Density:

a) Loose Bulk Density: Weigh accurately 25 g of drug (M), which was previously passed through 20 # sieve and transferred in 100 ml graduated cylinder. Carefully level the powder without compacting, and read the unsettled apparent volume (V0).

Calculate the apparent bulk density in gm/ml by the following formula

b) Tapped bulk density: Weigh accurately 25 g of drug, which was previously passed through 20 # sieve and transfer in 100 ml graduated cylinder. Then mechanically tap the cylinder containing the sample by raising the cylinder and allowing it to drop under its own weight using mechanically tapped density tester that provides a fixed drop of 14± 2 mm at a nominal rate of 300 drops per minute. Tap the cylinder for 500 times initially and measure the tapped volume (V1) to the nearest graduated units, repeat the tapping an additional 750 times and measure the tapped volume (V2) to the nearest graduated units. If the difference between the two volumes is less than 2% then final the volume (V2).Calculate the tapped bulk density in gm/ml by the following formula

II. Carr’s Index

The Compressibility Index of the powder blend was determined by Carr’s compressibility index. It is a simple test to evaluate the BD and TD of a powder and the rate at which it packed down. The formula for Carr’s Index is as below:

III. Hausne r’s Ratio

The Hausner’s ratio is a number that is correlated to the flowability of a powder or granular material.

IV. Angle of repose

The angle of repose of API powder was determined by the funnel method. The accurately weight powder blend were taken in the funnel. The height of the funnel was adjusted in such a way the tip of the funnel just touched the apex of the powder blend. The powder blend was allowed to flow through the funnel freely on to the surface. The diameter of the powder cone was measured and angle of repose was calculated using the following equation.

Table 4.2 Effect of Angle of repose (Φ) on Flow property

Angle of Repose (Φ)	Type of Flow
< 20	Excellent
20-30	Good
30-34	Passable
>35	Very poor

4.2.2.3 Method for Particle size distribution:

Particle size distribution was carried out by sieving method. The procedure involves the mechanical shaking of a sample through a series of successively smaller sieve. The size of particles retained on the sieve is taken as the arithmetic or geometric mean of the two sieves.

4.2.2.4 Blend Uniformity:

As shown in figure 5.6 and table 5.14, samples (in duplicate) are withdrawn from 10 different locations after the lubrication stage to validate the mixing of the API with the excipients with the help of sampling rod. If RSD is < 5.0, for n = 10, indicates that all blends for compression are homogenous with respect to the distribution of API, indicating good mixing is achieved.

4.2.3 Method for preparation of CR tablet of Antiepileptic drug

Tablets are prepared by Wet granulation method. In Wet granulation method, drug and excipients are sifted through 40 #, then blending of drug and other excipients are carried out. Prepared binder solution is slowly added into blend to form a cohesive mass, which is passed through 8-12 # using Oscillating granulator. Drying of granules are carried out using tray drier or FBD at or below 60° C. then dried granules are passed through #. Mix and lubricated the sieved granules in blender, which are ready for compression. Then blend is compressed into tablet using Rotatory compression machine. Coating of tablets is carried out by using Gansons Coater.

4.2.4 Methods for Evaluation of Tablet

Prepared tablets were evaluated for certain physical properties like Tablet wt. variation, %Assay, hardness, friability, dissolution study etc.

Tablet weight variation: Every individual tablet in a batch should be in uniform weight and weight variation within permissible limits. Weight control is based on a sample of 20 tablets. Twenty tablets were randomly selected and accurately weighed using an electronic balance (Metteler Toledo electronic balance:Model PG 03-S). The results are expressed as mean values of 20 determinations.

Dimensions: The thickness of ten randomly selected matrix tablets was determined using a digital vernier caliper (mitutoyo). The results are expressed as mean values of 10 determinations.

Hardness: The hardness of the tablets was determined using a Hardness testing

apparatus (Batch top Tablet Tester, Model: 5y, tablet tester, Dr. Schleuniger Pharmatron).

Friability: The friability of the tablets was measured in a Roche friabilator (Model:ED- 2, Electrolab). Tablets of a known weight (W0) or a sample of 10 tablets are dedusted in a drum for a fixed time (100 revolutions) and weighed (W) again. Percentage friability was calculated from the loss in weight as given in equation as below. The weight loss should not be more than 1 % w/w.

% Friability = (W0 - W)/W0 * 100

4.2.5 % Assay of prepared tablet:

% Assay of prepared tablet was carried out by Chromatographic method using Liquid chromatograph. (Model: LC-2010C HT, Shimadzu).

Preparation of Buffer solution 1:

Dissolve 0.4 gm of Citric acid monohydrate and 4 gm anhydrous disodium hydrogen phosphate in 1000 ml of water.

Preparation of Buffer solution 2:

Dissolve 6.8 gm of Potassium dihydrogen phosphate and 1.7 gm sodium hydroxide in 1000 ml of water and adjust the pH to 7.5 with phosphoric acid.

Buffer solution: Mix equal volumes of Buffer solution 1 and Buffer solution 2 and mix.

Preparation of Mobile Phase:

Prepare a mixture of buffer solution and Acitonitrile in the ratio of 70:30. Adjust the Ph to 2.5 with phosphoric acid and mix.

Standard preparation:

Weigh accurately about 87 mg of standard drug (Antiepileptic drug) working standard and transfer to a 100 ml volumetric flask. Dilute to volume with water and mix.

Sample preparation:

Accurately weigh 20 tablets and calculate the average weight. Powder the tablets and immediately transfer a quantity of powder equivalent to 2500 mg of Sodium salt of VALPROIC ACID into a 250 ml volumetric flask. Add 125 ml of Acetonitrile and sonicate for 45 mins with intermittent shaking. Cool and dilute to volume with water and mix. Dilute 5 ml of this solution to 50 ml with water and mix. Filter this solution through 0.45 μ Millipore PVDF filter, discarding first few ml of the filtrate.

Chromatographic system:

Column :Nova pack Phenyl, 150 mm x 3.9 mm, 4μ

Detector : 210 nm

Flow rate : 1.2 ml/min

Injection volume: 50μl

Temperature : 45 ºC

System suitability:

Chromatograph the standard preparation and record the peak responses. The column efficiency determined for analyte peak is not less than 2000 theoretical plate and the tailing factor for analyte peak is not more than 2.0. The relative standard deviation for five replicate standard injections is not more than 2.0 %.

Procedure:

Separately inject mobile phase, dissolution medium, standard and sample preparation in single into the chromatograph, record the chromatograms and measure the responses for the measure peak. Calculate quantity in percentage of sodium salt of AED determined by using following formula.

AT WS DT P 144.2

% Sodium salt of AED = ------ X ------- X ------- X ------X ------ X 100

AS DS LC 100 166.2 -- (6)

Where,

AT = Peak area of sample injection,

AS = Peak area of standard injection,

DS = Dilution of standard,

DT = Dilution of sample,

WS = Weight of working standard taken in mg

LC = Label claim,

P = Percentage purity of working standard,

144.2 = Molecular weight of Valproic acid,

166.2 = Molecular weight of Sodium valproate.

4.2.6 Method for In vitro dissolution study

Dissolution tests were performed in a USP Dissolution Tester Apparatus I (Basket method) (TDT-08 L, Electrolab, Mumbai, India.) at 37 ± 0.5°C. The baskets were rotated at a speed of 100 rpm. The prepared tablets, in addition to commercially available Epilim CR 500mg tablets (Sanofi-Synthelab Ltd., South Africa), were placed in the baskets and then submerged into 500 ml of 0.1 N HCl solution (pH 1.2) for 45 mins. These were then transferred to 900 ml of phosphate buffer (pH 7.5) and continue dissolution. Automated sampling of aliquots, at time intervals of 45 mins, 2, 4, 6, 8, 10, 12, 14, 16, and 18 hrs was transferred HPLC, where the content of drug was determined as an area of peak. Peak area of sample and standard were put into below equation to calculate the % of drug release.

Acid Phase: 500 ml, 0.1 N HCL

Buffer phase: 900 ml, 7.5 PH Phosphate Buffer, 0.05M

RPM: 100 rpm

Apparatus: USP type 1(Basket)

Time point: 45 mins, 2, 3, 4, 6, 8, 10, 12, 14,16, 18 hrs.

Temperature: 37°C ± 0.5°C

Preparation of dissolution medium: Dissolve 68 gm of Potassium Di hydrogen phosphate in 10 liters DM water; adjust the pH to 7.5 with sodium hydroxide solution and mix.

Preparation of Mobile Phase:

Prepare a mixture of buffer solution and Acito nitrile in the ratio of 70:30. Adjust the pH to 2.5 with phosphoric acid and mix. Transfer an accurately weighed quantity of about 60 mg of sodium salt of AED working standard into a 100 ml volumetric flask. Add about 50 ml of dissolution medium and sonicate to dissolve. Make a volume up to the mark with dissolution medium and mix.

Standard preparation:

Weigh accurately about 55 mg of sodium salt of AED working standard and transfer to a 100 ml volumetric flask. Add 50 ml of the dissolution medium and sonicate to dissolve. Cool and dilute to volume with the dissolution medium and mix.

Chromatographic system:

Column :Nova pack Phenyl, 150 mm x 3.9 mm, 4μ

Detector : 210 nm

Flow rate : 1.2 ml/min

Injection volume: 50μl

Temperature : 45 ºC

System suitability:

Procedure:

AT WS DT P 144.2

% Sodium valproate= ------ X ------- X ------- X ------X ------ X 100

AS DS LC 100 166.2 ---- (7)

Where,

AT = Peak area of sample injection,

AS = Peak area of standard injection,

DS = Dilution of standard,

DT = Dilution of sample,

WS = Weight of working standard taken in mg

LC = Label claim,

P = Percentage purity of working standard,

144.2 = Molecular weight of Valproic acid,

166.2 = Molecular weight of Sodium valproate.

4.2.7 Comparison of In vitro dissolution of prepared tablet with Market product

The similarity factor (f2) given by SUPAC guidelines for modified release dosage form was used as a basis to compare dissolution profile. The dissolution profiles are considered to be similar when f2 is between 50 and 100. A value of 100% for the similarity factor suggests that the test and reference profiles are identical. This similarity factor was calculated by following formula,

f₂= 50 x log {[1+(1/n)∑_t=1ⁿ ( R_t- T_t )²]^-0.5 x 100}

Where, n is the number of dissolution time and R_t and T_t are the reference and test dissolution values at time t.

Table 4: Specification of Similarity factor value and its significance

Similarity factor (f2)	Significance
< 50	Test and reference profiles are dissimilar
50 – 100	Test and reference release profiles are similar
100	Test and reference release profiles are identical
> 100	The equation yields a negative value

A value of 100% for the similarity factor suggests that the test and reference profiles are identical. Values between 50 and 100 indicate that the dissolution profiles are similar whilst smaller values imply an increase in dissimilarity between release profiles.

4.2.8 Stability study

The stability study was carried out for selected formulation as per ICH guidelines. Various ICH storage conditions are available which are as 250C ± 20C (60% ± 5%RH), 300C ± 20C (65% ± 5%RH) and 400C ± 20C (75% ± 5%RH). The tablets of the final formulation were placed in HDPE container and stored at various storage conditions for a period of 1month. The samples were analyzed for physical appearance, In-vitro dissolution, assay and RS at regular interval.

5.0 Experimental work:

To develop a controlled release matrix tablet of Antiepileptic drug using combination of hydrophilic and hydrophobic rate retardant material by wet granulation technology that gives desired in-vitro release profile comparable to market product . The strength to be developed is 500 mg/tablet.

5.1 Selection of Excipients

Excipients for controlled release matrix tablet of Antiepileptic drug were selected based on the data collected during the literature survey.

5.2 Formulation development process

The present formulation of controlled release matrix tablet of Antiepileptic drug was developed by previously taken preliminary batches that give the desired in-vitro drug release profile comparable to market product. All batches were taken by the defined manufacturing process.

5.3 Pre-formulation Study:

5.3.1 Description of API:

API was evaluated by physical appearance.

Refer section 5.1.1

5.3.2 Solubility of API:

Refer section 5.2.1.1

5.3.3 Drug-Excipients Compatibility study:

As shown in table 6.1, Pure API, excipients and API with excipients were filled in vials and as per shown in table 6.2 few were sealed with rubber closure and aluminum tip for ‘Closed’ condition, while others were remained open for ‘Open’ condition. Each set of 11 vials for open and closed conditions was placed as ‘INITIAL’ at room temperature and as 40°C ± 2°C / 75% RH ± 5% RH and 50°C ± 2°C / 80% RH ± 5% RH in stability chamber (Thermolab stability chamber, Mumbai, India) for time period of 1 month. After 1 month, Samples were withdrawn from stability chamber for analysis.

Table 5.1 Ratio of API with Excipients for Compatibility study

Sr No.	Ingredients	Ratio
1	API (Valporic acid + Sodium Valporate) (1 : 2.3)	1
2	HPMC (MethocelK 4 M)	1
3	Ethyl cellulose 20 cps	1
4	Colloidal Silicon Dioxide (Aerosil 200)	1
5	Hydrated Silica (Sylysia 350 FCP)	1
6	Magnesium Stearate	1
7	API + HPMC (MethocelK 4 M)	1:0.5
8	API + Ethyl cellulose 20 cps	1:0.1
9	API + Colloidal Silicon Dioxide (Aerosil 200)	1:0.01
10	API + Hydrated Silica (Sylysia 350 FCP)	1:0.3
11	API + MagnesiumStearate	1:0.02

Table 5.2 Storage condition for Drug-Excipients Compatibility study

Sr No.	Conditions		Time period
1	INITIAL (At Room Temperature)	Open	1 Month
1	INITIAL (At Room Temperature)	Closed	1 Month
2	40°C ± 2°C / 75% RH ± 5% RH	Open	1 Month
2	40°C ± 2°C / 75% RH ± 5% RH	Closed	1 Month
3	50°C ± 2°C / 80% RH ± 5% RH	Closed	1 Month

Refer section 5.2.1.2 for method for analysis of samples.

5.3.4 Flow properties:

Refer section 5.2.3.2 for method.

5.3.5 Melting point of API:

Melting point of API (AED + Sodium salt of AED) and Blend ready for compression was carried out using DSC.

DSC study was carried out using DSC TA-60 instrument (M/s Shimadzu) to check the M.P. of mixture of drugs and blend. DSC thermograms were taken.

Procedure: Samples were placed in pierced aluminum pans and hold for 1 minute at 50ºC and then heated gradually at 10ºC min-1 from 50ºC to 200ºC. The onsets of melting points were calculated by the instrument.

5.4 Method for preparation of CR tablet of Antiepileptic drug:

Antiepileptic drug CR tablets were prepared by wet granulation technique.

i) Dispensing: All the materials was Dispensed as per required weight.

ii) Binder Preparation: Antiepileptic drug (liquid in nature) was transferred in a stainless steal container. Propeller blade of Lab stirrer (Rimi motors Ltd.) was placed in container and started at high speed until a vortex was formed. Ethyl cellulose was added to AED slowly into vortex and continued stirring until a clear solution was observed.

iii) Sifting: Sodium salt of Drug, HPMC K 4 M, Aerosil 200 and Hydrated silica (Sylysia 350 FCP) were passed through 10# sieve and transferred into RMG (Rapid Mixer Granulator, Saral motors Ltd., 3 Liters)

iv) Wet granulation:

a) Dry Mixing: All the above ingredients were mixed for 10 mins with slow Impeller (150 RPM) and chopper off.

b) Binder addition: Prepared Binder was added into the mixture of ingredients within 2 mins with slow Impeller (150 RPM) and slow Chopper (1500 RPM). Then discharge the materials.

v) Drying: Drying of materials was carried out by using FBD (Fluid Bed Dryer, Alliance engineering Co., Model:-E 200) with Inlet air Temperature NMT 60 °C and Outlet air Temperature NMT 40 °C until % LOD (By IR/moisture halogen analyser) less than 1% was achieved.

vi) Blending: Dried granules and Hydrated silica (Sylysia 350 FCP) was transferred into cage blender and blending was carried out for 30 mins. Blend was carefully packed in double line poly bag with alu-alu pouches, silica gel 100G Blue was added between two poly bags and sealed the bag to protect from moisture. The blend was quarantined for approximately 12 hrs or more.

vii) Screening: Granules was passed through OG (Oscillating Granulator, CMJ-08, Cadmech machinery Co. Pvt. Ld., Ahmedabad) equipped with 16#.

viii) Blending and Lubrication: Size reduced granules were transferred into Cage blender (Model: SS 316, Bectochem consultants and engineering PVT Ltd.). Blending of materials was carried out for 5 mins. After blending, Magnesium stearate (60# sieved), was added to blend and mix again for 5 mins, packed and labeled it.

ix) Compression: Humidity in compression area was controlled below 30 % RH using dehumidifier (Tropical nortec, model No. TM 3000SS, Worli, Mumbai). The prepared blend was compressed (using 18 X 8 mm, Capsule shaped standard concave punches) using 16 station rotatory compression machine (Cadmech, Ahmedabad).

x) Coating: Compressed tablets were coated by using Gans coater. (Model: GAS 375/250, Gansons Ltd.).

5.5 Methods for Evaluation of Tablet:

Refer section 4.2.4 for Tablet weight variation, Dimensions, Hardness, and Friability.

5.6 % Assay of prepared tablet:

Refer section 4.2.5

5.7 In vitro dissolution study:

Refer section 4.2.6

5.8 Stability study:

Refer section 4.2.8

5.9 Formulation of Batches B1 to B10:

Formula for Trial Batches B1 to B5 (Table 6.3) and B6 to B10 (Table 6.4) is as follow.

Batch size is 1500 tablets for batches B1 to B9 and 1, 00,000 tablets for Batch B10 on pilot scale.

Table 5.3 Formula of batches (B1 to B5)

Ingredient	B1		B2		B3		B4		B5
Intragranulation	%	mg	%	mg	%	mg	%	mg	%	mg
Valporic acid	20.69	145.00	22.37	145.00	19.94	145.00	18.66	145.00	19.94	145.00
Sodium Valporate	47.51	333.00	51.38	333.00	45.79	333.00	42.85	333.00	45.79	333.00
HPMC (MethocelK 4 M)	23.08	161.76	-	-	24.20	176.00	22.65	176.00	24.20	176.00
Ethyl cellulose 20 cps	-	-	9.09	58.92	1.65	12.00	1.54	12.00	1.65	12.00
Colloidal Silicon Dioxide (Aerosil 200)	0.57	4.00	0.62	4.00	0.55	4.00	0.51	4.00	0.55	4.00
Hydrated Silica (Sylysia 350 FCP)	7.13	50.00	15.43	50.00	6.88	50.00	12.87	100.00	3.44	25.00
Extragranulation
Hydrated Silica (Sylysia 350 FCP)	-	-	-	-	-	-	-	-	3.44	25.00
Magnesium Stearate	1.03	7.20	1.11	7.20	0.99	7.20	0.93	7.20	0.99	7.20
Total	100.00	700.96	100.00	648.12	100.00	727.20	100.00	777.20	100.00	727.20
(mg) is mg /Tablet and (%) is %W/W. For B1 to B5, batch size was 1500 tablets / Lot. For B1 to B5, batches were coated using in-house formula (as per table 6.5). %W/W was calculated with respect to weight of uncoated tablet. Actual quantity of API was based on actual assay and % LOD. Quantity of extra granular materials was based on% yield achieved.

Table 5.4 Formula of batches (B6 to B10)

Ingredient	B6		B7		B8		B9		B10 #
Intragranulation	%	mg	%	mg	%	mg	%	mg	%	mg
Valporic acid	18.66	145.00	19.30	145.00	19.41	145.00	19.51	145.00	19.97	145.00
Sodium Valporate	42.85	333.00	44.33	333.00	44.57	333.00	44.81	333.00	45.86	333.00
HPMC (MethocelK 4 M)	22.65	176.00	19.97	150.00	20.07	150.00	20.18	150.00	17.21	125.00
Ethyl cellulose 20 cps	1.54	12.00	1.60	12.00	1.07	8.00	0.54	4.00	1.65	12.00
Colloidal Silicon Dioxide (Aerosil 200)	0.51	4.00	0.53	4.00	0.54	4.00	0.54	4.00	0.55	4.00
Hydrated Silica (Sylysia 350 FCP)	3.22	25.00	3.33	25.00	3.35	25.00	3.36	25.00	3.44	25.00
Extragranulation
Hydrated Silica (Sylysia 350 FCP)	9.65	75.00	9.98	75.00	10.04	75.00	10.09	75.00	10.33	75.00
Magnesium Stearate	0.93	72.00	0.96	7.20	0.96	7.20	0.97	7.20	0.99	7.20
Total	100.00	777.20	100.00	751.20	100.00	747.20	100.00	743.20	100.00	726.20
* (mg) is mg /Tablet and (%) is %W/W. # For B10, Batch size was 1 lac tablets on pilot scale For B6 to B10, batches were coated using in-house formula (as per table 6.5) %W/W was calculated with respect to weight of uncoated tablet. Actual quantity of API was based on actual assay and % LOD. Quantity of extra granular materials was based on% yield achieved.

Calculation for Potency adjustment of API (AED/ Sodium salt of AED):

Qty of API required per batch (gm) (B) = Calculated Qty x 100 x 100

X x (100 - Y)

X = % assay of AED /Sodium salt of AED on dried basis,

Y = % LOD of AED/ Sodium salt of AED.

5.10 General Coating formula for Batches B1 to B10:

Sr No.	Ingredients	Mg/tabs	Qty. taken (gm)*
	(Wt. gain 1.5%)		(7 %w/w solid content)
1	HPMC E 15 LV	7.76	11.64
2	Glycerol	3.38	5.07
3	Titanium dioxide	0.51	0.765
4	Methanol (60%)	q.s	139.30
5	Water (40%)	q.s	92.87
* 30% extra coating materials added to compensate for the loss during coating process. * Calculation of coating solution was carried out for a batch of 1500 tablets.

Batch B7 was charged for stability as per shown in previous section 5.2.8. After 2 months of accelerated study, samples were withdrawn and observed that tablet was found to change physical appearance from white to light yellowish, which indicate stability failure because improper moisture barrier coating. So, another coating trial was required. Batch B10 was found to match dissolution rate with Marketed product. So, B10 was selected as an optimized batch for further new coating trials.

5.11 Formula of Coating Trials:

Optimized Batch B10 was chosen for different coating trials for moisture protection.

5.11.1 Opadry-amb Coating (Wt. gain 4%):

Table 5.6 Formula of coating using Opadry-amb Coating (4%)

Sr no.	Ingredients	Quantity taken (gm) for solid content 7% w/w*
1	Opadry- amb	56.64
2	Water	752.55

5.11.2 Insta-coat moist shield Coating (4%) + Eudragit E 100 Coating (7%):

Table 5.7 Formula of coating using Insta-coat Moist shield + Eudragit E 100Coating
Sr. No.	Ingredients	Quantity taken (gm) *
Sr. No.	Insta-coat Moist shield Coating (4%)	Solid content 12% w/w
1	Insta-coatMoist shield	56.64
2	IPA (60%)	249.23
3	Water (40%)	166.15
	Eudragit E 100 Coating (4%)	solid content 7% w/w
4	Eudragit E 100	58.34
5	IPA	775.13

5.11.3 Opadry Yellow Coating (4%) + Eudragit E 100 Coating (4%):

Table 5.8 Formula of coating using Opadry Yellow Coating +Eudragit E 100 Coating
Sr. No.	Ingredients	Quantity taken (gm) *
Sr. No.	Opadry Yellow Coating (4%)	Solid content 12% w/w
1	Opadry Yellow	56.64
2	IPA (60%)	249.23
3	Water (40%)	166.15
	Eudragit E 100 Coating (4%)	solid content 7% w/w
4	Eudragit E 100	58.91
5	IPA	782.65

5.11.4 Opadry Clear Coating (4%):

Table 5.9 Formula of coating using Opadry Clear Coating (4%)
Sr. No.	Ingredients	Quantity taken (gm) for solid content 15% w/w*
1	Opadry clear	56.64
2	IPA (60%)	192.59
3	Dichloro methylene (40%)	128.39

5.11.5 Opadry White Coating (4%) in IPA: Water + Eudragit E 100 Coating (4%):

Table 5.10 Formula of coating using Opadry White Coating +Eudragit E 100 Coating
Sr. No.	Ingredients	Quantity taken (gm) *
Sr. No.	Opadry White Coating (4%)	Solid content 12% w/w
1	Opadry Yellow	56.64
2	Ferric oxide Yellow (0.5%)	0.283
3	IPA (60%)	249.23
4	Water (40%)	166.15
	Eudragit E 100 Coating (4%)	solid content 7% w/w
5	Eudragit E 100	58.91
6	IPA	782.65

5.11.6 Opadry White Coating (4%) in IPA: DCM + Eudragit E 100 Coating (4%):

Table 5.11 Formula of coating using Opadry White Coating +Eudragit E 100 Coating
Sr. No.	Ingredients	Quantity taken (gm) *
Sr. No.	Opadry White Coating (4%)	Solid content 12% w/w
1	Opadry Yellow	56.64
2	Ferric oxide Yellow (0.5%)	0.283
3	IPA (60%)	249.23
4	DCM (40%)	166.15
	Eudragit E 100 Coating (4%)	solid content 7% w/w
5	Eudragit E 100	58.91
6	IPA	782.65

5.11.7 Opadry Violet Coating (4%):

Table 5.12 Formula of coating using Opadry Violet Coating
Sr. No.	Ingredients	Quantity taken (gm)*
Sr. No.	Opadry Violet Coating (4%)	solid content 12% w/w
1	Opadry Violet	56.64
2	Water	752.55

5.11.8 Opadry Violet Coating (4%) + Eudragit E 100 Coating (4%):

Table 5.13 Formula of coating using Opadry Violet Coating +Eudragit E 100 Coating
Sr. No.	Ingredients	Quantity taken (gm)*
Sr. No.	Opadry Violet Coating (4%)	Solid content 12% w/w
1	Opadry Violet	56.64
2	Water	752.55
	Eudragit E 100 Coating (4%)	solid content 7% w/w
3	Eudragit E 100	58.91
4	IPA	782.65

NOTE: *30% extra coating materials added to compensate for the loss during coating process.

* Quantity taken (gm) was calculated for batch size of 1500 tablets.

5.12 Exposure study of coated tablets at room temperature and humidity:

Batch B10 was coated with using different coating materials to protect the tablets from moisture as shown in section 6.11. Three tablets from each coating trial with marketed product removed from packing were put into a Petri dish for 6 days exposure study at roomtemperature and humidity. Observation was carried out and noted in table.

6.0 Results:-

6.1 Blend Uniformity:-

Table 6.1 Blend Uniformity for Batches B5 And B10
Sampling Location	% Drug content
Sampling Location	B5	B10
S1	99.3	101.2
S2	100.4	96.2
S3	97.4	99.8
S4	69.5	102
S5	94	99.1
S6	99	98
S7	100	100.5
S8	99.1	99.1
S9	100.3	103
S10	105.9	98.2
MEAN	99.19	99.71
MAX	105.9	103
MIN	94	96.2
SD	3.62	2.24

6.2 Exposure study of coated tablets at room temperature and humidity

Tablet 6.2 Exposure study of coated tablets at room temperature and humidity
Sr. No.	Coating material	Days
	Single Coat	1	2	3	4	5	6
1	Opadry-amb (4%)	Ok	Ok	Start to Swell	Swell	Swell	Swell
2	Opadry violet (4%)	Ok	Ok	Pin hole	Pin hole	Pin hole	Pin hole
	Double Coat
3	Instracoat MS (4%) + Eu. E100 (4%)	Ok	Ok	Ok	Ok	Swell	Swell
4	Opadry yellow (4%) + Eu. E100 (4%)	Ok	Ok	Ok	Swell	Swell	Swell
5	Opadry white (4%) (IPA:water) + Eu. E100 (4%)	Ok	Ok	Crack on surface	Crack on surface	Crack on surface	Crack on surface
6	Opadry white (4%) (IPA:DCM) + Eu. E100 (4%)	Ok	Ok	Ok	Ok	Crack on surface	Crack on surface
7	Opadry violet (4%) +Eu. E100 (4%)	Ok	Ok	Ok	Ok	Ok	Ok
8	Finished Product	Ok	Ok	Ok	Ok	Ok	Ok

6.3 Melting point of API (Mixture of AED + Sodium salt of AED 1:2:3)

Figure 6.3 DSC thermogram of melting point of API

From above DSC thermogram, it was concluded that melting point of API was found to be 99.69° C.

6.4 Evaluation of tablets:-

Table 6.4 Evaluation of tablet of batches B1 to B10
Batch code	*Avg. Wt (mg)**	*Hardness (kp)**	*Thickness (mm)**	*Friability (%)**	*Assay (%)**
B1	705.8 ± 0.72	13.9 ±0.89	5.2 ±0.12	0.020 ±0.03	99.4 ±0.57
B2	650.1 ± 0.22	14.0 ± 0.76	4.50 ± 0.15	0.0198 ± 0.06	99.7 ± 0.24
B3	729.4 ± 0.62	16.0 ± 0.42	5.75 ± 0.10	0.0147 ± 0.04	99.1 ± 0.29
B4	776.8 ± 0.44	16.3 ± 0.56	6.25 ± 0.15	0.015 ± 0.03	101.2 ± 0.37
B5	728.3 ± 0.37	16.1 ± 0.43	5.60 ± 0.09	0.0151 ± 0.04	99.2 ± 0.40
B6	777.9 ± 0.31	16.0 ± 0.31	6.50 ± 0.10	0.016 ± 0.05	100.4 ±0.32
B7	753.5 ± 0.25	15.8 ± 0.37	6.29 ± 0.08	0.0152 ± 0.03	100.2 ± 0.29
B8	748.2 ± 0.33	16.2 ± 0.33	6.26 ± 0.06	0.0149 ± 0.06	989 ± 0.49
B9	742.8 ± 0.23	16.5 ± 0.28	6.20 ± 0.08	0.0141 ± 0.04	99.9 ± .021
B10	727.6 ± 0.21	16.3 ± 0.27	6.23 ± 0.06	0.0162 ± 0.05	99.7 ± 0.23

6.5 Flow properties of blend ready for compression:

Table 6.5 Evaluation of Powder blends
Powder Blend	% LOD at 85° C	Angle of Repose (°)	Bulk Density (gm/ml)	Tapped Density (gm/ml)	Carr’s Index (%)	Hausner’s Ratio
B1	2.1	31.3	0.500	0.666	24.92	1.33
B2	2	18.4	0.396	0.426	7.04	1.08
B3	1.8	31.6	0.510	0.685	25.55	1.34
B4	1.3	29.9	0.425	0.526	19.20	1.24
B5	0.86	33.1	0.510	0.685	25.55	1.34
B6	0.85	32.8	0.416	0.555	25.05	1.33
B7	0.76	32.9	0.409	0.546	25.09	1.33
B8	0.79	33.0	0.406	0.513	20.86	1.26
B9	0.83	33.4	0.406	0.513	20.86	1.26
B10	0.80	29.8	0.400	0.500	20.00	1.25

6.6 Particle size distribution of blend ready for compression:-

Table 6.6 Particle size distribution of blend ready for compression
Sr.No.	Micron (μm )	Mesh U.S.STD	Wt retained on sieve (gm)	% Retained	Particle Size (μm)
1	1410	14	0	0	› 1410
2	1000	18	4.93	10.27	1205
3	840	20	2.63	5.48	920
4	710	25	4	8.33	775
5	350	45	17.9	37.28	530
6	297	50	2.85	5.93	323.5
7	210	70	6.64	13.82	253.5
8	177	80	0.81	1.69	193.5
9	149	100	1.57	3.27	163
10	Retainer	-	6.69	13.93	‹ 149
Total			48.02	100.00%

Total Wt. of powder = 48.02 gm taken as 100%

Blend Uniformity:- Table 6.7: Blend uniformity for batches B5 to B10

Sampling location	% Drug release
Sampling location	B5	B10
S1	99.3	101.2
S2	100.4	96.3
S3	97.4	99.5
S4	96.4	102.2
S5	94.2	99.2
S6	98.8	98.5
S7	100.1	100.2
S8	99.6	99.5
S9	100.2	103.2
S10	104.8	98.6
MEAN	99.19	99.84
MAX	104.8	103.2
MIN	94.2	96.3
SD	3.62	2.24

6.1 In vitro release profile of batches:-

For batches B1 to B5:-

Table 6.7 Result of In vitro release profile of batches B1 to B5 with Market Product
Time	% CDR
Time	B1	B2	B3	B4	B5	Market Product
0	0	0	0	0	0	0
45 min	7.8	1.3	4	3.2	2.3	6.3
2 hrs	42.7	9.4	10.6	19.1	18.6	25.3
4 hrs	59.2	17.5	34.1	32.8	32.6	42.3
6 hrs	79.2	23.82	44.6	45.2	45.6	58.2
8 hrs	93.6	29.03	52.0	33.2	50.2	69.5
10 hrs	99.3	34.52	60	62.5	60.2	77.5
12 hrs	101.52	37.13	65.8	60.3	65.2	82.2
14 hrs	103.2	42.34	71	71.5	72.3	87.5
16 hrs	103.02	48.65	75	76.8	76.3	90.2
18 hrs	102.81	54.21	78.3	79.6	81.3	92.5
f1	25.18	52.92	20.20	18.25	19.36
f2	38.31	22.20	43.04	45.71	44.45

Figure 6.7 : Comparison of dissolution profile of B1 to B5 with market Product For batches B6 to B10:-

Table 6.8 Result of In vitro release profile of batches B6 to B10 with Market Product
Time	% CDR
Time	B6	B7	B8	B9	B10	Market Product
0	0	0	0	0	0	0
45 min	2	3.5	4.1	5.2	5.7	6.3
2 hrs	22.1	25.4	24.5	26.6	25.5	25.3
4 hrs	38.2	40.1	44.5	47.8	43	42.3
6 hrs	49.5	52.2	59.8	63.2	56.2	58.2
8 hrs	58.2	62.3	72.4	76.3	65.3	69.5
10 hrs	65.9	69.8	80.6	83.1	73.8	77.5
12 hrs	72.1	78.5	85.5	87.5	82.6	82.2
14 hrs	76.9	83.6	89.4	92.9	89.4	87.5
16 hrs	80.5	84.2	93.7	96.1	93.1	90.2
18 hrs	83.2	87.8	98.2	98.6	94.8	92.5
f1	17.36	7.14	3.64	7.34	3.08
f2	46.69	64.65	78.20	64.50	79.25

7.0 CONCLUSION:

The present study concludes that combination of hydrophilic polymer such as Hydroxy propyl methyl cellulose and hydrophobic polymer such as Ethyl cellulose in the ratio of 10:1 can be utilized for designing and development of controlled release solid dosage form. It has been also concluded that coating of core tablet with Opadry violet followed by eudragit E100 with 4% weight gain of tablet are best coating materials for moisture protection. Using selected polymers and coating materials, the developed controlled release table of antiepileptic drug was found to be equivalent with regard to dissolution profile with marketed product.

8.0 SUMMARY:

The aim of dissertation entitled “Formulation and evaluation of controlled release tablets of Antiepileptic Drugs.” was to formulate a stable, safe and convenient oral solid dosage form, whose dissolution profile match with marketed product. Present Drug is classified as an Antiepileptic drug; affect the function of the neurotransmitter GABA (as a GABA transaminase inhibitor) in the human brain. So it decreases the neuronal membrane excitability and it reverses the transamination process to form more GABA. As an anticonvulsant drug is used to control absence seizures, tonic-clonic seizures (grand mal), complex partial seizures, juvenile myoclonic epilepsy and the seizures associated with Lennox-Gastaut syndrome. In the present work an attempt has been made to develop controlled release matrix tablets of Antiepileptic drug using hydrophilic polymer such as hydroxyl propyl methyl cellulose and hydrophobic polymer such as Ethyl cellulose in the different ratio to formulate batches from B1 to B10.

Strength of tablet developed was equivalent to 500 mg of sodium salt of AED, which contains 145mg of AED and 333 mg of sodium salt of AED. Solubility of API (AED and Sodium salt of AED, 1:2.3) was carried out in pH 1.2 0.1 N HCl, pH 4.5 Acetate buffer, pH 6.8 and 7.4 Phosphate buffer by defined procedure. Solubility of API in pH 7.4 Phosphate buffer was found to be 76.5394 mg/ml, which indicate that API is soluble in pH 7.4 Phosphate buffer. Drug-Excipients compatibility study was carried out by DSC method. Drug, excipients and ratio of drug-excipients were stored at initial (open and closed), 40° C / 75% RH (open and closed) and 50°C / 80% RH (closed) for 1 month. After 1 month, from DSC thermogram and physical observation, it was concluded that there was no significant Drug- Excipient interaction was observed, which indicates that drug and other excipients are compatible with each other.

Blend was prepared by Wet granulation technique. In this method, ethyl cellulose was dispersed in AED (Liquid in nature) by lab stirrer at high speed until clear solution was observed, which was used as binder. Sodium salt of AED, HPMC, colloidal silicon dioxide and hydrated silica previously passed through 10 # were transferred into RMG followed by dry mixing for 10 mins. Prepared binder was added into RMG within 2 mins with slow impeller and chopper to form wet mass, which was dried in FBD until % LODwas obtained less than 1%. Dry granules and extra granular hydrated silica were blend for30 mins in cage blender and quarantined for 12 hrs or more. Dry granules were passed through Oscillating Granulator, equipped with 16#. Then lubricated with magnesium stearate for 5 mins in cage blender. Bend ready for compression was evaluated for various physiochemical parameters as follows. Bend ready for compression was evaluated for angle of repose, bulk density, tapped density, Carr’s index and Hausner's Ratio It was found that blend ready for compression has Angle of repose from 29.8° to 33.4° according to fixed funnel method, Carr’s index from 20% to 25.55% and Hausner's Ratio from 1.25 to 1.34, which indicate that blend ready for compression has passable flow property and compressibility property.

For blend uniformity, samples (in duplicate) are withdrawn from 10 different locations from cage blender after the lubrication stage to validate the mixing of the API with the excipients with the help of sampling rod. These 10 samples were analyzed for assay of drug and %RSD of assay was found to be 3.65 % and 2.25 % for Batches B5 and B10 respectively, which was < 5.0, for n = 10, indicates that all blends for compression were homogenous with respect to the distribution of API, indicating good mixing was achieved.

Blend ready for compression was evaluated for Particle size distribution by Sieve analysis method. Result indicates that particle size distribution of Blend was found between 149 to 1410 μm. Lubricated blend was compressed into tablets using 18 x 8 mm punch set by 16 station rotatory compression machine with controlled humidity (<30%RH) in compression area.

The compressed tablets were coated using inhouse coating formula (as shown in table 6.5) containing HPMC E 15 LV followed by Eudragit E100 and Eudragit NE 30 D by using Gansons coater.

The coated tablets were evaluated for weight variation test, dimension, hardness, friability by official methods. The weight variation test indicates that all the tablets were uniform with low standard deviation values. The thickness of tablets for all the batches with low standard deviation values was found. The hardness of all the tablets was between 13.9 ± 0.89 and 16.5 ± 0.28 Kps. The loss in total weight in friability test was in the range of 0.141 to 0.20 %. The percentage assay for different batches (B1 to B10) were carried out by Chromatographic method using Liquid chromatograph, which found to be varied from 98.9 ± 0.49 to 101.2 ± 0.37 indicating the uniformity in drug content within tablets.

Formulations B1 to B10 were evaluated for % release of drug in pH 1.2, 0.1 N HCl for 45 mins followed by pH 7.5 Phosphate buffer over a period of 18 hours using USP type I dissolution apparatus at 100 rpm. The dissolution profile of the batches (B1 to B10) was compared with that of marketed product. From the dissolution profile, Similarity Factor (F2) values was calculated and from those values optimize batch was selected. Batch B10 contained HPMC 125 mg and ethyl cellulose 12 mg per tablet. B10 showed 94.8% drug release at the end of 18 hrs and F2 value was 79.28. So B10 showed more comparable dissolution profile with respect to marketed product. Therefore B10 was selected as optimized batch.

Batch B7 was charged for stability as per shown in section 5.2.8. After 2 months of accelerated study, samples were withdrawn and tablet was found to change physical appearance from white to light yellowish, which indicate stability failure because improper moisture barrier coating. So, other coating trials were required. B10 was selected as an optimized batch for other coating trials.

From the result of 6 days exposure study of coated tablets with different coating materials, tablet coated with Opadry violet (4%) followed by Eudragit E100 coating (4%) was observed to remain intact after 6 days. Therefore Opadry violet (4%) followed by Eudragit E100 coating (4%) was considered as suitable coating as a moisture barrier.

9.0 REFERENCE:

1) http://www.epilepsiemuseum.de/alt/introen.html.

2) L.J. Wilmore, J. A. Ferrendelli. Scientific American Medicine: Epilepsy New York, NY: Scientific American. 1997. p. 11. XII-1-14.

3) Commission on Epidemiology and Prognosis, International League against Epilepsy (1993). "Guidelines for epidemiologic studies on epilepsy. Commission on Epidemiology and Prognosis, International League against Epilepsy". Epilepsia 34 (4): 592–6.

4) http://neurologicalillness.suite101.com/article.cfm/what_is_an_epileptic_seizure.

5) http://www.indianwomenshealth.com/Epilepsy-25.aspx.

6) http://www.healingwithnutrition.com/edisease/epilepsy/epilepsy.html

7) Brannon PL., L. Med. Plast. & Biomater, Med. Plast. & Biomater; 1998; 199(6); 34-46.

8) Lee TW., Robinson JR., In Remington: The science and practice of pharmacy; Gennaro, Ed.; LippincottWilliams and Wilkins: Baltimore; 2000; (2); 903-929.

9) Swarbrick J., Boylan JC., Encyclopedia of Pharmaceutical Technology; 1990; 3;281-286.

10) Vyas SP, Khar RK. Controlled drug delivery: concepts and advances. 1st Ed. Vallabh prakashan, Delhi; 2002; 1-150, 167.

11) Li. Xiaoling, Design of controlled release drug delivery system, J.R.Bhaskara; 120-121.

12) Robinson JR., Lee LH., Controlled Drug Delivery: Fundamentals and Applications; 1987; 2nd edition; 29; 312-319.

13) Lachman L., Lieberman HA., Kanig JL., The theory and practice of industrial pharmacy; Varghese Publishing House Bombay; 1987; 293-345, 430.

14) M Flu Lu et al., Drug Development and Industrial Pharmacy; 1991; 17(4); 1987-2004.

15) Nicholson S. J. et al., Journal of pharmacy and Pharmacology; 1990; 42; 21-26.

16) Nigayale A. G. et al., Drug Development and Industrial Pharmacy; 1990; 16; 2-8.

17) Yie WC, Rate controlled drug delivery systems; Marcel Dekker; New York, Revised and expanded, 2005; 2; 210.

18) Singh P., Desai SJ., Simonelli AP., HiguchiWI., Role ofWetting on the Rate of Drug Release from Inert Matrices; Journal of Pharmaceutical Science; 1968; 57 (2); 217-226.

19) Nakagami H., Keshikawa T., Matsumura M., Tsukamoto H., Application of Aqueous Suspensions and Latex Dispersions of Water-Insoluble Polymers for Tablet and Granule Coating; Chemistry and Pharmaceutical. Bulletin; 1991; 39 (7), 1837-1842.

Received on 22.05.2014 Accepted on 15.06.2014

Asian J. Pharm. Tech. 2014; Vol. 4: Issue 3, Pg 117-130

Sr. No.	Ingredient Name	Purpose of Use	Supplier/Vendor Name
1	Valproic acid	API	Anjan Drug PVT.LTD.Chennai
2	Sodium valproate	API	Alembic. PVT.LTD
3	HPMC	Rate retardant polymer	DOW
4	Ethyl cellulose 20 cps	Rate retardant polymer	Signet Chemical Corporation Pvt. Ltd.
5	Colloidal Silicon Dioxide (Aerosil 200)	Glidant	Signet Chemical Corporation Pvt. Ltd.
6	Hydated Silica	Adsorbent	Nagase Singapore Pvt.Ltd.
7	Magnesium Stearate	Lubricant	Signet Chemical Corporation Pvt. Ltd.
8	HPMC (Methocel E 15 LV)	SealCoat	Colorcon Asia Pvt. Ltd.
9	Glycerol Ph. Eur	Plastisizer	Teknirvana Tradelink Pvt. Ltd.
10	Titanium Dioxide USP	Opacifier	Signet Chemical Corporation Pvt. Ltd.
11	Methyl alcohol BP	Solvent	Finar Chemicals Ltd.
12	Eudragit E 100	Moisture barrier coat	S. Zaveri Pharmakem Pvt. Ltd.
13	Eudragit NE 30 D	Moisture barrier coat	S. Zaveri Pharmakem Pvt. Ltd.
14	Talc Micronized Ph. Eur. (Luzenac)	Glidant in Coating	Signet Chemical Corporation Pvt. Ltd.
15	Opadry-amb (OY-B- 28920)	Moisture barrier coat	Colorcon Asia Pvt. Ltd.
16	Insta Coat Moist Shield (ICR-MS-0310)	Moisture barrier coat	Ideal cure Pvt. Ltd.
17	Opadry yellow (03B82943)	Moisture barrier coat	Colorcon Asia Pvt. Ltd.
18	OpadryWhite (03F58991)	Moisture barrier coat	Colorcon Asia Pvt. Ltd.
19	Opadry Clear (03F9016)	Moisture barrier coat	Colorcon Asia Pvt. Ltd.
20	Opadry Violet (OY-S- 6705)	Moisture barrier coat	Colorcon Asia Pvt. Ltd.