Formulation And Evaluation of Bi-Layered Tablet of Divalproex Sodium

Oral route is most commonly employed route of drug administration. Although different route of administration is used for the delivery of drugs, due to flexibility in dosage form design and patient compliance oral route is preferred.¹ The popularity of the oral route is attributed ease of administration, patient acceptance, accurate dosing, cost effective manufacturing method and generally improved shelf-life of the product.There are several techniques of conventional drug delivery system where tablets, capsules, pills, liquids, are used as drug carrier. Among them, solid formulation does not require sterile conditions and are therefore, less expensive to manufacture. The tablet is the most widely used dosage form because of its convenience in terms of self-administration, compactness and ease in manufacturing. Tablets are solid dosage forms containing medicinal substances with or without suitable diluents.⁵ According to Indian Pharmacopoeia Pharmaceutical tablets are solid, flat or biconvex dishes, unit dosage form, prepared by compressing a drugs or a mixture of drugs, with or without diluents.They are varying in size and weight, depending on amount of medicinal substances and the intended mode of administration. It is most popular dosage form and 70% of the total medicines are dispensed in the form of tablet. There are different types of tablets are available in market conventional tablet, immediate tablet, fast dissolving tablet, controlled release tablet, sustained release tablet, delayed release tablet. Immediate release tablets are those which disintegrate rapidly and get dissolved to release the medicaments. For immediate release formulation, super disintegrants play key component. Super disintegrants are used to improve the efficacy of solid dosage form. This achieved by various mechanisms, swelling, porosity and capillary action, heat of wetting, particle repulsion forces, deformation recovery, enzymatic reaction by which the tablets are broken into small particles. Categories of the drug which are preferable for immediate release are analgesic and anti-inflammatory drugs such as Ibuprofen, Diclofenac sodium. Anti-coagulants such as Dicoumarol, Dipyridamol. Anti-Depressants such as Amoxapiine. Anti-diabetic such as Glipizide. Antihypertensive drug such as Amlodipine, Minoxidil, Nifedipine are most preferable for the immediate release.

Sustained release systems include any drug over an extended period of time. If the system is successful in maintaining constant drug levels in the blood or target tissue, it is considered as a controlled release system. If it is unsuccessful of this day nevertheless extends the duration of action over that achieved by conventional delivery, it is considered as a prolonged released system.

Drug in the outside layer exposed to the bathing solution is dissolved first and then diffuses out of the matrix. This process continues with the interface between the bathing solution and the solid drug moving toward the interior. It follows that for this system to be diffusion controlled, the rate of dissolution of drug particles within the matrix must be much faster than the diffusion rate of dissolved drug leaving the matrix.

Bi-layer tablets are prepared with one layer of drug for immediate release while second layer designed to release drug later, either as second dose or in an extended-release manner. Bilayered tablet is suitable for sequential release of two drugs in combination, separate two incompatible substances, and also for sustained release tablet in which one layer is immediate release as initial dose and second layer is maintenance dose. The basic goal of therapy is to achieve a steady state drug in blood level for an extent period of time.

MATERIAL AND METHOD

MATERIALS-

Table 1: List of materials

LIST OF INSTRUMENTS-

Table 2: List of Equipment’s

PRE-FORMULATION STUDIES

Pre-formulation testing is the first step in rational development of dosage forms of a drug substance. Pre-formulation study is the process of optimizing the delivery of drug through determination of physicochemical properties of the excipients that could affect drug performance and development of as efficacious, stable and safe dosage form.

1. Determination of λ max 

Divalproex sodium was dissolved in methanol further diluted with the same and scanned for maximum absorbance in UV double beam spectrophotometer (Shimadzu 1800) in the range from 190 to 380 nm.

2. Solubility

The solubility of Divalproex sodium was determined in distilled water, methanol, ethanol, acetone, chloroform and pH 6.8 phosphate buffer by shake flask method. An excess amount of Divalproex sodium is added to each vial containing 10 ml of selected solvent till the saturation of the solution.

3. Melting point

Melting point of the Divalproex sodium was determined by capillary method in triplicate.

4. Standard Curve for Divalproex sodium

100 mg of Divalproex sodium was accurately weighted and dissolved in 100 ml of methanol to prepare first stock solution. 10 ml of above solution was taken and diluted to 100 ml with the same solvent to prepare II stock solution. .

Formulation Design

Calculation of dose

The total dose of Divalproex sodium for once daily formulation was calculated by the following equation, using available pharmacological data.

Dt = Dose (1+0.693xt/t1/2)

Where, Dt = Total dose of drug,

Dose = Dose of immediate release part.

 t = time in hr during which the sustained release is desired (18 hrs)

t1/2 = half life of the drug (9 hrs)

Therefore,

Dt = 125(1+0.693x18/9), Dt ≈ 298.25

Therefore, maintenance dose = 298.25-125 = 173.25 mg.

Hence, the formulation should release 125 mg drug within 1 hour and 173.25 mg drug in 18 hours.

1.  Formulation of Immediate release layer

Table 4: Formulation of immediate release layer (IRL)

2.  Formulation of sustained released layer

Table 5: Formulation of sustained release layer (SRL)

Preparation of IRL

IRL of Divalproex sodium (DS) was prepared by wet granulation by using different Super disintegrants such as SSG and Croscarmellose sodium. PVP K30 solution with containing coloring agent was used as binding solution. As DS was oily in characteristics, MCC was used as adsorbent.

Preparation of SRL

Accurately weighed Divalproex sodium and polymer and others ingredients were taken in mortar and pestle and mixed well. The powder was mixed with sufficient quantity for PVP K30 solution until wet mass formed.

Preparation of bi-layered tablet

By the study of disintegration and drug release profile of IRL and SRL, best formulations of each layer were chosen and bi-layered tablet were prepared by double compression in single rotatory tableting machine.

Evaluation of Pre-formulation Parameters:

1. Angle of Repose:

The angle of repose of granules was determined by the funnel method the accurately weighed granules were taken in a funnel. The height of the funnel was adjusted in such a way that the tip of the funnel just touched the apex of the heap of the granules. The granules were allowed to flow through the funnel Greely onto the surface.  

θ =tan-1 (h/r)

Where, θ = the angle of repose

h = height of the heap of the powder

r = radius of the heap of the powder

Table 6: ANGLE OF REPOSE

2. Determination of bulk density and tapped density: 

A quantity of 2 g of the powder (W) from each formula was introduced into a 25 ml measuring cylinder. After the initial volume was observed, the cylinder was allowed to fall under its own weight onto a hard surface from the height of 2.5 cm at 2 sec intervals. The tapping was continued until no further change in volume was noted. The bulk density, and tapped density were calculated using following formulas.

3. Carr’s index: 

It helps in measuring the force required to break the friction between the particles and the hopper. It is expressed in % and given by     

Table 7: % COMPRESSIBILITY INDEX

4. Hausner’s ratio:

Hausner’s ratio is an indirect index of ease of powder flow. Hausner’s ratio was measured by the ratio of tapped density to bulk density.

Table 8: HAUSNER’S RATIO

Evaluation of prepared formulations Evaluation of Divalproex sodium IRL, SRL and bi-layered tablet

The tablets prepared were evaluated for the following parameters:

Weight Variation Test:

To study weight variation, 20 tablets of each formulation were weighted using electronic balance and the test was performed according to the official method.

Hardness:

The resistance of tablets to shipping or breakage under condition of storage, transportation and handling before usage depends on its hardness. The hardness of each batch of tablet was checked by using Monsanto hardness tester. The hardness was measured in the terms of kg/cm². 5 tablets were chosen randomly and tested for hardness. The average hardness of 5 determinations was recorded.

Friability:

Friability generally refers to loss in weight of tablets in the containers due to removal of fines from the tablet surface. Friability generally reflects poor cohesion of tablet ingredients. 10 tablets were weighed and the initial weight of these tablets was recorded and placed in Roche friabilator and rotated at the speed of 25 rpm for 100 revolutions.     

Tablet thickness:

Thickness of the tablet is important for uniformity of tablet size. Thickness was measured using Vernier Calipers. It was determined by checking the thickness of ten tablets of each formulation.

In-vitro dissolution studies of immediate release layer:

The in-vitro dissolution studies were performed using USP-II (paddle) dissolution apparatus at 100 rpm. Phosphate buffer pH 6.8 dissolution media is maintained at 37±0.500C. A 5 ml was withdrawn at specific time intervals and same volume of fresh medium was replaced.

In vitro dissolution studies of sustained release layer:

The in vitro release of sustained release layer was carried out for 18 hours using USP type-II apparatus (DT-1200) at 100 rpm for the first 45 minute in 900 ml 0.1N HCL maintaining at 37 ±0.50C and then at phosphate buffer pH 6.8 in 900ml for another 18 hour.

Drug Content for IRF, SRF and Bi-layered tablet:

Ten tablets were weight and average weight is calculated. All tablets were crushed and powder equivalent to 100 mg drug was dissolved in pH 6.8 phosphate buffer and the volume was made up to 100 ml with pH 6.8 phosphate buffer.

Stability Studies:

The optimized formulation was subjected for two-month stability study according to standard guidelines. The selected formulations were packed in aluminum foils, which were in wide mouth bottles closed tightly. They were stored at 40⁰C / 75% RH for 3 months and evaluated periodically.

RESULT AND DISCUSSION-

Determination of λmax

The λmax of Divalproex sodium was found to be 210 nm in methanol and phosphate buffer pH 6.8.

Standard curve of Divalproex sodium.

The absorbance was measured in a UV spectrophotometer at 210 nm against methanol.

Figure 4: Standard graph of Divalproex sodium

The solubility studies of drug were done by using various media like distilled water, methanol, chloroform and phosphate buffer pH 6.8. The result shows maximum solubility in chloroform.

Table 11: Solubility of Divalproex sodium

Result showed that Divalproex sodium is more soluble in chloroform in compare to other solvents.

Melting Point

Melting point of drug was determined by capillary method. The result is found to be 219- 2230C.

EVALUATION OF PRE-COMPRESSION PARAMETERS

Table 12: Pre-compression parameters for IRL and SRL

POST-COMPRESSION EVALUATION PARAMETERS:

Table 13: Post-compression parameters for IRL and SRL

Table 14: Post-compression parameters for bi-layered tablet

In-vitro dissolution study

Table 15: in vitro dissolution study of IRL

Figure 5: Release profile of immediate release layer

Figure 6: Release profile of sustained release layer

Figure 7: Release profile of Bi-layered Tablet

Stability Studies:

Table 18: Stability data