Formulation and Evaluation of By-Layered Tablet

Since many decades’ treatment of acute and chronic disorders have been done with the help of conventional drug delivery systems like tablets, capsules, solutions, suspensions, creams, ointments, suppositories, liquids and injectable. These types of conventional therapy are most widely used and it is available commonly on prescription as well as over the counter. The conventional therapy is regarded as prompt release therapy. In order to maintain and achieve drug concentration within effective therapeutic range the conventional therapy has to be administered several times in a day and slight delay causes fluctuation in drug concentration which leads to poor patient compliance as well as poor aesthetic value. In order to avoid fluctuation or disadvantages of conventional therapy several new techniques have been developed to improve patient compliance which is capable of controlling rate of drug delivery to the site of action. Oral route is one of the best and most widely used routes for administering drug to site of action. Tablets and capsules are the most widely used conventional therapy for the patients because they can be easily administered without any problem.

Bilayer tablet is suitable for sequential release of two drugs in combination, separate two incompatible substances and also for sustained release tablets in which one layer is immediate release which act as loading dose and second layer is sustained release which act as maintenance dose. Bilayer tablet is the most recent form of tablet which comprises of combination of immediate release tablets and sustained release tablets. It is a type of once a day oral dosage form which acts immediately upon administration and provides the action for prolonged period of 12-24hrs. Bilayer tablets can be an excellent technique to avoid all types of incompatibilities between drugs, API and excipients etc.

Figure 1: Bi-layer tablet

Advantages of bilayer tablet

• Release of both drugs start immediately.
• Combination of incompatible drugs can be easily composed
• Combination of different release profile drugs can be formulated.
• Pill burden can be reduced by reducing dose of individual drug due to additive effect.
• Side effects can be reduced by using combination of drugs which can nullify the adverse effects of each other.
• Provides elegance to the products.
• Treats different disorders in same patient at the same time by administering one pill.
• This type of tablet only allows synergistic combination.

Limitations of bilayer tablet

• Capping
• Hardness problem
• Layer separation
• Order of layer sequence
• Cross contamination between layers
• Elastic mismatch of adjacent layers.

Ideal candidates of bilayer tablet

• Drugs which produces additive or synergistic effect i.e. antiasthamatic drugs like salbutamol + theophylline.
• Drugs having opposite side effects may reduce the side effects of each othere.g. omeprazole + NSAIDS, hydrochlorothiazide + amiloride.
• Incompatible drugs.
• Low biological half-life (ideal for modified release bilayer).
• Unstable at intestinal pH (ideal for bilayer floating).
• High first pass metabolism with low biological half-life (ideal for buccoadhesive bilayer).

Approaches for bilayer tablet

It consists of two drugs in same tablet having different layers. One layer is immediate release layer and other layer is sustained release layer.

Different types of bilayer tablet

• Bilayer modified release tablet
• Bilayer floating tablet
• Bilayer buccoadhesive tablet.

Bilayer modified release tablet

This type of bilayer tablet consists of two different types of release profile layers. One layer is immediate release layer in which drug will release 90% of concentration within 30 minutes. Other layer is sustained release layer where drug will release slowly up to 12-24 hrs.

e.g. Metaclopramide HCl+ Ibuprofen.

Bilayer floating tablet

This type of bilayer tablet consists of such type of combination of drugs which are sensitive to gastrointestinal pH. One layer of drug gets metabolized in stomach, while other layer gets degraded in intestine.

e.g. Rosiglitazone Maleate.

Bilayer buccoadhesive tablet This type of bilayer tablet consists of drugs which have mucoadhesion and have the property to get attached to mucous membrane of buccal region and sustain the release of drug.

e.g.Propanolol HCl

Reasons for selecting bilayer tablet by pharmaceutical industry

• To get synergistic effects.
• To inhibit drug interaction.
• Drug incompatibility.
• Patent extension.
• Therapeutic justification.
• To reduce capital investments.
• To get sustained release tablets preparation in combination in which one layer is immediate release form and second layer may be extended release form.

Various techniques of bilayer tablet

• OROS push pull technology.
• L-OROS tm technology.
• EN SOL TROL Technology.
• DUROS technology.
• Dual release drug delivery system.

MATERIALS AND METHODS

Preparation of IRL IRL of Divalproex sodium (DS) was prepared by wet granulation by using different Super disintegrates 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 Super disintegrates 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.

Dual release drug delivery system

This tablet provides immediate release and sustained release of two drugs in one dosage form.

Prefomulation studies to be carried out before formulation of bilayer tablet

• Solubility of drug.
• Particle size determination.
• Bulk density.
• Tapped density.
• Carr’s index
• Hausner’s ratio.
• Angle of repose.
• Drug excipients compatibility studies.

Solubility of drug

The solubility of drugs to be formulated as bilayer tablets should be determined in various types of mediums like distilled water, 0.1N HCl, 0.1 N NaOH, ethanol, methanol, PBS pH 6.8, PBS pH 7.2 etc.

Particle size determination.

Particle size can be determined by two methods. It can be either determined with the help of Malvern particle size analyzer or by sieving on a mechanical sieve shaker.

Bulk density

Weigh accurately 25g of drug and pass through sieve no 20. Transfer it in a 100ml graduated measuring cylinder. Without disturbing measuring cylinder note the initial apparent volume (Vo).

Calculate bulk density by the following formula: -

                             Bulk density =          ????????????????????? ???????? ????????????????

                                                                              ???????????????? ????????????????????

Tapped density

Weigh accurately 25g of drug, pass through sieve # 20 and transfer it in a 100ml graduated measuring cylinder. Measure initial volume (Vo), now tap the cylinder for about 100 times. Then measure final volume (V1).

Calculate the tapped density by the following formula: -

                                   Tapped density =                ????????????????????? ???????? ????????????????

                    T???????????????????? ????????????????????????

Hausner ’s ratio

It is ratio of tapped density and bulk density. It can be calculated by the formula: -

                                        Hausner’s ratio =           ???????????????????????? ????????????????????????????

                                                                                ???????????????? ????????????????????????????

Carr‘s index

It is a measure for compressibility index developed by carr and Neumann. It can be calculated by the formula: -

                         Carr’s index =           ???????????????????????? ????????????????????????????−???????????????? ???????????????????????????? × 100

                                                                                       ???????????????????????? ????????????????????????????

Angle of repose

Weigh 10g of drug accurately. Prepare an assembly consisting of tripod stand, funnel and paper. Pour the drug through the funnel freely and now calculate height and diameter of heap with scale and pencil. Angle of repose can be calculated by the formula: -

                                                      Angle of repose =          tan-1 ?

                                                                                                 ????

Drug –excipient compatibility studies

This test is carried out to find out a stable storage condition for drug in solid state. In this method different excipients were selected and mixed separately with drug in proportion generally used for tablet formulation. Three mixtures of each set is prepared for measurement at different RH and temperatures. Keep for one month in same condition and check for colour changes in each combination. This is mainly determined by FT-IR study or DSC.

Formulation of bilayer

tablet Bilayer tablet is formulated by mainly two methods: -

Wet granulation method

Direct compression method.

Wet granulation method

Weigh all drugs and excipients accurately and pass through sieve# 100. Prepare binder solution. Wet massing of mixture with the binder solution is done in a pestle mortar. Screen wet mass with the help of sieve# 10. Dry the granules. After drying blend with the help of lubricants and disintegrants to produce running powder. Compress the mixture into tablets with the help of flat punch.

 Direct compression method

Weigh accurately all the excipients and drugs and pass through sieve# 100. Mix all the components in a pestle mortar and compress them in the form of tablet directly.

Compression cycle of bilayer tablet

Figure 2: Compression cycle of bilayer table