A Research Article: Formulation and Evaluation of By-Layered Tablet of Divalproex Sodium

Objective: To Formulate and Evaluate bi-layered tablet of Divalproex Sodium.

In the last decade, interest in developing a combination of two or more active pharmaceutical ingredients (API) in a single dosage form has increased in the pharmaceutical industry, promoting patient convenience and compliance. Bi-layered tablets can be a primary option to avoid chemical incompatibilities between API by physical separation, and to enable the development of different drug release profiles. 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. Bi- layered 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 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. 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.

Figure 1: General Bi-layered tablet

Bi-layer tablets

Bilayer tablets are formulated with one drug layer for immediate release, while the second layer is designed for a later release of the drug, either as a second dose or in a prolonged-release manner. Bilayer tablets are acceptable for sequential release of two combination drugs, separating two incompatible components, and extended-release tablets where one layer is the immediate release as the initial dose and the second layer is the maintenance dose.The primary goal of therapy is to achieve stable blood levels of the drug over a more extended period of time Epilepsy is an abnormal, high-frequency electrical discharges in the brain that cause seizures with or without loss of consciousness and characteristic body movements (convulsions). Worldwide, epilepsy is the third most prevalent neurological disorder after cerebrovascular disease and Alzheimer's disease.

Figure 2: Bi-layered tablet

Drugs with poor wetting, slow dissolution properties, optimum absorption high in GIT may be difficult to formulate as a tablet that will still provide adequate or full drug bioavailability

1. Bitter tasting drugs, drugs with an objectionable odor or drugs that are sensitive to oxygen may require encapsulation or coating.

2. Difficult to swallow in case of children and unconscious patients.

3. Drugs with poor wetting, slow dissolution properties, optimum absorption high in GIT may be difficult to formulate as a tablet that will still provide adequate or full drug bioavailability.

Advantage of Bi-layered tablets over conventional tablets

1. Blood level of a drug can be held at consistent therapeutic level for improved drug deliver, accuracy, safety and reduce side effects.

2.Reduction of adverse effect can be accomplished by targeting the drug release to the absorption site as well as controlling the rate of release, enabling the total ddrug content to be reduced.

3. Patient convenience is improved because fewer daily doses are required compated to traditional systems. Patient compliance is enhanced leading to improved drug regimen efficacy.

4. Bi-layered tablets readily lend themselves to repeat action products; where in one layer provide initial dose, the other layer provide maintenance dose.

Ideal characteristics of Bi-layered tablets

1. A Bi-layered tablet should have elegant product identity while free of defects like chips, cracks, discoloration and contamination.

2. It should have sufficient strength to with stand mechanical stock during its production packaging, shipping and dispensing.

3. It should have the chemical and physically stability to maintain its physical attributes over time. The Bi-layered tablet must be able to release the medicinal agents in a predictable and reproducible manner.

4. It must have a chemical stability shelf-life, so as not to follow alteration of the medicinal agents.

Since the development cost of a new drug molecule is very high, efforts are now being made by pharmaceutical companies to focus on the development of new drug dosage forms for existing drugs with improved safety and efficacy together with reduced dosing frequency, and the production of more cost- effective dosage forms. Bi-layered tablet concept has long been utilized to develop sustained released formulation. The pharmacokinetic advantage relies on the criterion that, drug release from the fast releasing layer leads to a sudden rise in the blood concentration. However the blood level is maintained at steady state as the release from sustained layer. Particularly bilayer tablets are commonly used to avoid chemical incompatibilities of formulation components by physical separation, and release profile [7]. After stoke and dementias, epileptic seizures constitute the 3rd most frequent neurologic disorders encountered in elderly in developed countries [8]. The aim of the present research work was to develop the different immediate and sustained release formulation of Divalproex sodium and compare their release profile, from above formulation select a best formulation for manufacturing bi-layered tablet.  Hence, in  the  present research investigation attempt was made to formulate and evaluate bi-layered tablet of Divalproex sodium.

Figure 3: Drug Divalproex Sodium

Structure of Divalproex sodium

Divalproex sodium contains not less than 98% and not more than 102% of available valproic acid, C8H16O2.

Chemical Name:2-propyl-pentanoic acid sodium salt (2:1). Sodium hydrogen bis (2- propylvalerate) oligomer.

CAS Number: 76584-70-8

Brand name: Depakote, Depakote CP, Depakote ER, Epival, Stavzor.

Category: Anticonvulsant.

Molecular Formula: C8H16O2C8H15O2Na

Molecular weight: 310.41.

Description: Odorless, white or off-white crystalline powder.

Melting Point: 222 °C.

Solubility: soluble in ethanol (95%), methanol, Isopropyl alcohol, partially soluble in water, ether.

Storage: Store protected from moisture at a temperature not exceeding 30 °C.

MECHANISM OF ACTION

Divalproex sodium is broad-spectrum anticonvulsant. It increases the availability of gamma- amino butyric acid (GABA), an inhibitory neurotransmitter. It has inhibitory action against GABA transaminase which breakdown GABA, it leads to increased concentration of GABA in the synapses. Other propose mechanisms of action that account for their anticonvulsant properties is it either enhance the action of GABA or mimic its action at postsynaptic receptor sites. It also block voltage gated sodium channels and T-type calcium channels, and cause inhibitory activity in the brain.

Pharmacokinetics

Absorption: Rapid absorption from gastrointestinal tract.

Distribution: Protein binding 80-90%

Metabolism: Metabolized almost entirely by the liver.

Excretion: Both bile and urine

Half Life: 9-16 hours

Bioavailability (oral): 84%

Materials and Methods Preparation Of IRL

IRL of Divalproex sodium (DS) was prepared by wet granulation by using different Superdisintegrants 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. Manufacturing steps-

• Pass all the ingredients though sieve #80.

• Mix Divalproex sodium with MCC geometrically and then mix with lactose.

• Add Superdisintegrants and mix for 10 to 15 min in mortar and pestle.

• Make wet mass using binding agent PVP K 30 solution containing color.

• Pass the cohesive mass through sieve # 16 to get uniform granules.

• Dry the granules at 50 °C for 15 min in hot air oven.

• Lubricate the granules with lubricating agent and compressed into 250 mg each tablet weight by adjusting hardness. The formulations are shown on table no 1.

Preparation Of SRL

Accurately weighed Divalproex sodium and polymer and others ingredients were taken in mortar and pestle and mixed well. The powder were mixed with sufficient quantity for PVP K30 solution until wet mass formed. The cohesive mass obtained was passed though sieve # 16 and the granules were dried in a hot air oven at 50 °C for 20 min. The dried granules again passed through sieve # 22 to break the large lumps. Then granules were mixed with talc and magnesium stearate and compressed into 300 mg each tablet by adjusting hardness. The formulations were shown on table no 2.

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 prepared formulations

Evaluation of Divalproex sodium IRL, SRL and bi-layered tablet on following parameter

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. Then tablets were removed from the friabilator dusted off the fines and again weighed and the weight was recorded.

Percentage friability was calculated by using the formula.

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. Vernier caliper consists of metric and imperial scales. The main matric scale is read first then read “hundredths of mm” of imperial scale (count the number of divisions until the lines concedes with the main metric scale. The imperial scale number is multiply with 0.02. Then that number obtained from imperial scale added with main metric scale to get final measurement

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±0.50 °C. A 5 ml was withdrawn at specific time intervals and same volume of fresh medium was replaced. The withdrawn samples were diluted with pH 6.8, filtered and analyzed on UV spectrophotometer at 210 nm using pH 6.8 as a blank. Percentage cumulative drug release was calculated.

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 ±0.5 °C and then at phosphate buffer pH 6.8 in 900ml for another 18 hour. A 5 ml was withdrawn at different time intervals and replaced with an equal volume of fresh medium. The samples were suitably diluted with blank dissolution medium, filtered and analyzed on UV spectrophotometer at 210nm.

RESULT

Post-Compression Evaluation Parameters

The selected formulation of immediate and sustained release layer was prepared as bi- layered tablet and the post- compression parameters tabulated in 3 & Hardness and friability showed 7.05±0.15 and less than 1% respectively indicating the stability against physical stokes. Thickness was found to be 5.75±1.83 mm and content of uniformity 99.23±0.53 indicate uniform distribution of drug in both layer. In vitro drug release showed in table no 3.

In-vitro dissolution study

In vitro drug release profile of the immediate release and sustained release formulations were given in table no 5 and 6 respectively. Among all formulations of immediate release layer, formulation IF1, IF2, IF3 and IF4 showed the least drug release 80.40, 83.44, 82.68 and 94.82 respectively in 20 min as they consist of 5% SSG, 6% SSG, 5% CD and 6% CD respectively. Formulation IF6 releases 98.62% drug in 20 min. The release profile of the formulation IF6 was believed be due to combination of SSG and CD. The result indicated that increase in the concentration of Superdisintegrants and combination of super disintegrants increases the release profile of drug. In sustained release formulation, the formulation SF1 (15% HPMC K4M) showed highest release in 16 hours compare to the formulations SF2 and SF3 (17.5 and 20% HPMC K4M) which showed the drug release of 97.81 and 84.11% in 18 hours. The formulations SF4 and SF5 containing 15% and 17.5% of HPMC K100M showed 98.82 and 97.69% drug release in 18 hours. SF8 was selected as best sustained release formulation based on dissolution profile as they showed more than 90% after 18 hours. The formulations found to contain combination of HPMC K4M and HPMC K100M in ratio 1:1 of the concentration 17.5% of total weight. The formulation SF9 showed floating behavior which consists of polymers in 20% of total weight so withdrawn the batches from the dissolution studies.

DISCUSSION

Divalproex sodium a broad-spectrum antiepileptic drug was chosen as a model drug as it is a right candidate for immediate as well as sustained release formulations. Both immediate and sustained release formulations were prepared by wet granulation method using PVP K30 solution as binding agent. Six batches (IF1-IF6) of immediate release layer and nine batches (SF1-SF9) of sustained release layer were developed by altering the excipients ratio as given in table number 13 and 14 respectively. Immediate release tablet were prepared by using Superdisintegrants such as sodium starch glycolate and croscarmellose sodium and Sustained release tablet were prepared by using polymer like HPMC K4M and HPMC K100M. The tablets were evaluated for weigh variation, friability, thickness, drug content and in vitro dissolution parameters using standard procedure as shown in tablet number 24. Best formulations for preparation of bi-layered tablet were selected depending upon the dissolution profile as all the formulation showed good content uniformity, friability. The selected formulation of immediate and sustained release layer was prepared as bi- layered tablet and the post- compression parameters tabulated in 3. Hardness and friability showed 7.05±0.15 and less than 1% respectively indicating the stability against physical stokes. Thickness was found to be 5.75±1.83 mm and content of uniformity 99.23±0.53 indicate uniform distribution of drug in both layer. In vitro drug release showed in table no 4. The release pattern of the drug from bi-layered tablet showed same as the individual layer tablets of immediate and sustained release.

Table 1: Formulation of immediate release layer (IRL)

Table 2: Formulation of sustained release layer (SRL)

Table 3: Post-compression parameters for IRL and SRL

Table 4: Post-compression parameters for bi-layered tablet

Table 5: In vitro dissolution study of IRL

Table 6: In vitro dissolution study of SRL

Table 7: Dissolution study of Bi-layered Tablet

Fig 4: Release profile of immediate release layer

Fig 5: Release profile of sustained release layer