FORMULATION AND EVALUATION OF BILAYER TABLETS OF EZETIMIBE AND METFORMIN HCL

BILAYER TABLETSFORMULATION AND EVALUATION OF BILAYER TABLETS OF EZETIMIBE AND METFORMIN HCL

 

N.S.V. SUSHMA

 

ABSTRACT:

 

Tablets are the unit solid dosage forms. Bi-layered tablets are one of the extended-release tablets. Metformin HCl belongs to this category of tablets which was prepared by using hydrophilic matrix polymers such as HPMC K15M, HPMC K4M, HPMC K100M, and Ezetimibe as immediate-release layer tablet.

 

The combination of Ezetimibe and Metformin Hcl is used for the treatment of TYPE-II DIABETES MELLITUS which is non-insulin dependent. Drug release from the matrix was found to decrease the increase in polymer concentration. According to the angle of repose, bulk density, tapered density, and compressibility index results show that the formulation is suitable for wet granulation. The drug release kinetics of the optimized bi-layered tablets corresponding best to Kornsmeyer-Peppas model and the drug release mechanism as per the ‘n’ value of Kornsmeyer-Peppas are anomalous diffusion and the tablet showed no significant change in physical appearance, drug content or in-vitro dissolution pattern.

 

It concludes that the bi-layered tablet technology can be successfully applied for sustained release of Metformin Hcl and immediate release of Ezetimibe.

 

INTRODUCTION:

 

TABLET DEFINITION: Tablets are the solid dosage form containing medicament or medicaments, usually circular in shape and may be flat or biconvex. Tablets are prepared by the compression method and are hence called the “Compressed Tablets.”

ADVANTAGES OF TABLET:

1) The tablets are easy to administer.

2) These are a more stable dosage form.

3) They maintain the accuracy of dosage.

4) They have longer expiry periods due to lower moisture content.

5) These are an economical dosage form.

DISADVANTAGES OF TABLETS:

1) Some drugs resist compression into tablet form due to their amorphous nature or low density 

character.

2) Bitter tasting drugs, drugs with objectionable odor or drugs that the sensitivity to oxygen or atmospheric moisture may require encapsulation or a special type of coating which may increase the cost of the finished tablets.

3) Drugs with poor wetting and slow dissolution properties are difficult to convert into tablets that provide full drug bio-availability.

4) The tablets cannot be used in case of emergency cases, because the rate at which active ingredient reaches the site to be treated slow.

5) Bio-availability of some drugs may be low due to poor absorption from the gastric tract.

BILAYERED TABLET DEFINITION: Bi-layered tablets are those which can provide immediately or sustain release of two drugs or different release rates of the same drug in one dosage form.

ADVANTAGES OF BILAYERED TABLETS:

1) The release of both drugs starts immediately.

2) Combination of incompatible drugs.

3) Combination of different release profiles.

4) Reduce the side effects by using a combination of one drug for this patient.

5) Treat different ailments in the same patient, at the same time and with one pill.

 

Fig.01: BILAYERED TABLETS

 

LIMITATIONS OF BILAYERED TABLETS:

1) Drugs with poor wetting, slow dissolution properties, optimum absorption high in GIT may be difficult to formulate or manufacture as a tablet that will provide adequate or full drug bio-availability.

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

3) Administration of sustained-release bi-layer tablet does not permit the prompt termination of therapy.

4) Bitter testing drugs, drugs with an objectionable odor or drugs that are sensitive to oxygen may require encapsulation or coating.

5) The physician has less flexibility in adjusting the dose regimens.

 

GENERAL PROPERTIES OF BI-LAYER TABLET DOSAGE FORMS:

1) A bi-layer tablet should have sufficient strength to withstand mechanical shock during its production, packaging, shipping, and dispensing.

2) A bi-layer tablet should have elegant product identity while free of defects like chips, cracks, discoloration, and contamination.

3) A bi-layer tablet should have the chemical and physical stability to maintain its physical attributes over time.

 

TYPES OF TABLETS:

 Tablets are classified according to their route of administration or function. The following are the 4 main classification groups: -

(A) Tablets ingested orally

(i)  Compressed tablets

(ii)  Multiple compressed tablets or press coated tablets

    (iii)  Bi-layered tablets

          (a) Bi-layer modified-release tablet

          (b) Bi-layer floating tablet

          (c) Bi-layer Bucco adhesive tablet

    (iv) Multilayered tablets

    (v) Sustained action tablets

    (vi) Enteric-coated tablets

    (vii) Sugar-coated tablets

    (viii) Film-coated tablets

    (ix) Chewable tablets

(B)  Tablets used in the oral cavity

    (i) Buccal tablets

(ii) Sub-lingual tablets

    (iii) Lozenge tablets and traches

    (iv) Dental cones

(C) Tablets administered by other routes

(i) Implantation tablets

(ii) Vaginal tablets

(D) Tablets used to prepare solutions

(i) Effervescent tablets

(ii) Dispensing tablets

(iii) Hypodermic tablets

(iv) Tablet triturates

 

ESSENTIAL QUALITIES OF A GOOD TABLET:

1) The size and shape should be reasonable for easy administration.

2) They should be chemically and physically stable during storage.

3) Should be attractive in appearance.

4) They should not break during transportation or crumble in the hands of the patient.

5) The drugs should be uniformly distributed throughout the body.

 

IDEAL CHARACTERISTICS OF BILAYER TABLETS:

1) The drug produces an additive/synergistic effect.

2) Drugs having opposite side effects, may reduce the side effect.

3) Incompatible drugs.

4) Low biological half-life (ideal for modified released bi-layer).

5) Unstable at intestinal pH (ideal for bi-layer floating).

6) High first-pass metabolism with a low biological half-life (ideal for Bucco adhesive bi-layer).

 

FORMULATION OF TABLETS:

 Compressed tablets usually consist of active medicaments mixed with a number of inert substances known as excipients or additives. These additives are added to give the qualities of a good tablet. Although these additives are termed as inert but they have a great influence on stability, bio-availability and the process by which the dosage forms are prepared.

According to the functions of additives, these may be classified as follows:

             (i) Diluents

             (ii) Binders

             (iii) Granulation agents

             (iv) Disintegrating agents

             (v) Lubricants

             (vi) Coloring agents

             (v) Flavoring agents

             (vi) Sweetening agents

     One additive may serve 2 or more functions e.g. Starch may serve as a diluent, binding agent and disintegration agent in one form or the other.

 

1. Diluents: When the quantity of the drug for an individual dose is very small and it is not able to 

Compress such a small amount in the form of a tablet then the inert substances which are added to increase the bulk of powders to be easily compressed are known as diluents. Various diluents used are lactose, sodium chloride, starch, powdered sucrose, mannitol, calcium carbonate, calcium carbonate, calcium sulphate, calcium phosphate, etc.

 

2. Binders: Some substances which are available in the crystalline form can be compressed directly but the majority of the drugs will have to be converted to granules before compression. The agents used during granulation to impart cohesiveness to the powdered substances are known as binders. They keep the tablet intact after compression. Various commonly used binders are starch, acacia, tragacanth, gelatin, glucose, lactose, sucrose, methylcellulose, etc.

     In some formulations, binders are used in the dry form whereas in others they are used as liquids by dissolving them in a suitable solvent like water, alcohol, or a mixture of these two.

 

3. Granulating agents: Granulating agents are the substances that are added to powders during the granulating process to convert the fine powders into granules. Insufficient quantity of granulating agents may be led to poor adhesion, soft tablets, and ‘capping’, whereas excessive quantity may lead to hard tablets with greater disintegration time. The commonly used granulating agents are water, mucilage’s of acacia, tragacanth and starch, liquid glucose, syrup, and alcohol in various dilutions.

 

4. Disintegrating agents: Disintegrating agents or disintegrators are the substances or a mixture of substances which are added to tablets to facilitate their disintegration or breaking apart into small particles in G.I.T. after administration, thus facilitating dissolution. Commonly used disintegrating agents are methylcellulose, agar, bentonite, carboxymethyl cellulose, etc.

 

5. Lubricants: Lubricants are the substances which are added to granules before compression to improve the flow of granules from the hopper to the die cavity by reducing interparticle friction, to prevent adhesion of the powders to the surface of dies and punches thus reducing wear and tear of dies and punches and to facilitate the ejection of the tablet from the die cavity after compression. Commonly used lubricants are magnesium stearate, calcium stearate, stearic acid, and talc.

 

6.Coloring agents: Coloring agents are used to imparting elegance to the tablets. Sometimes they are also used to identify the different types of tablets. Approved colors are only used. These colors may be added either in the mixed powders before granulation or they may be dissolved in the vehicles used for making the granules.

 

7. Flavoring agents: Generally, flavors are added to all lozenges, chewable tablets, and effervescence tablets. Volatile oils, volatile substances, and fruit flavors are used for this purpose. The volatile substances are dissolved in a suitable organic solvent and sprayed over the granules before compression. Fruit flavors and spray dried beadles are incorporated into the mixed powders before granulation.  

 

8. Sweetening agents: Sweetening agents are added to the tablets which are required to be dissolved cavity. ex. mannitol, lactose, and sucrose.

 

METHODS OF PREPARATION OF TABLETS:

     In the preparations of tablets, the fine powders are not used but they are prepared in the form of granules which are then compressed. There are three methods by which compressed tablets can be prepared.

1.      Direct Compression

2.      Dry Granulation

3.      Wet Granulation

1. Direct Compression: The materials which are available in crystalline form and have free-flowing and binding characteristics can be compressed directly, but the majority of drugs cannot be compressed easily in this way because sometimes they produce tablets which may not disintegrate. To overcome this difficulty directly compressible vehicles can be incorporated into the drug and compressed. Such vehicles include calcium phosphate, compressible sugar, mannitol, and microcrystalline cellulose. The drugs which can be compressed directly are sodium chloride, sodium bromide, sodium salicylate, potassium chloride, etc. These materials possess necessary cohesive and flow properties thereby they can be easily compressed.

 

2. Dry Granulation: This method is also known as slugging, precompression, or double compression method. In this method, the blend of powders is compressed into slugs on specially designed tablet machines. The slugs are the flat-faced large size tablets which are prepared under heavy pressure on a tablet press. These slugs are then broken to suitable size granules by passing through an oscillating granulator or other suitable device fitted with NO.10 or No.20 sieve. The resultant granules are mixed with lubricants and other necessary additives, then they are compressed into finished tablets.

 

3. Wet Granulation: The most widely and generally used method. This method meets all the qualities required for a good tablet. In this method, the crystalline substances are reduced to fine powder, they are mixed with other ingredients, a major portion of the disintegrating agent is incorporated and mixed uniformly. The mixed powders thus obtained are passed through a sieve No. 30 to 60.

A rough method to determine the proper quantity of granulating agent to be added Can be determined by pressing a portion of the mass in the palm of the hand, if the ball breaks under moderate pressure, the mixture is ready for screening. After adding the proper quantity of the granulating agent to the powders they are mixed continuously until a uniform mass is obtained. The wet mass so obtained is then passed through sieve No. 6 to20. The wet granules obtained after passing through the various sieves are spread in thin layers in trays and dried in an oven at a temperature not exceeding 60-degree centigrade. The dried granules are then passed through a proper screen to obtain the granules of uniform size. These are then mixed with other additives.

 

FORMULATION OF EZETIMIBE TABLETS:

       It can be prepared by using a direct compression method.

 

FORMULATION INGREDIENTS:

1) Ezetimibe

2) Sodium starch glycolate

3) Lactose

4) Micro-crystalline cellulose

5) Aerosil

6) Magnesium stearate

7) Red oxide of iron

 

STEPS INVOLVED IN DIRECT COMPRESSION METHOD:

   The Ezetimibe tablets were prepared as follows:

1) All ingredients (Ezetimibe + Avicel PH 102+ SSG + Lactose + MCC +Red oxide of iron) were weighed accurately and co-shifted by passing through #40 sieve, blended in a Poly Bag for 15 min.

2) The above blend was lubricated with #40 sieve passed Aerosil and Magnesium stearate.

3) The final blend was then compressed into tablets using a single station tablet compression machine with an average hardness of 3.5kg/sq.cm, by using 8mm-12mm dies.

 

FORMULATION OF METFORMIN HCl TABLETS:

        It can be prepared by using the wet granulation method.

 

FORMULATION INGREDIENTS:

1) Metformin HCl

2) Eudra gir RS 100

3) PEO

4) Carbapol

5) Micro-crystalline cellulose

6) Magnesium stearate

7) Talc

 

STEPS INVOLVED IN WET GRANULATION METHOD:

     The Metformin Hcl tablets were prepared as follows:

1) All ingredients (Metformin HCl+ Polymer) were weighed accurately and co-shifted by passing through #22sieve, blended in a Poly Bag for 5 min.

2) The above blend was granulated with PVP K30w/v solution in isopropyl alcohol.

3) The above granules were lubricated with#40 sieve passed Magnesium stearate and Talc.

4) The final blend was then compressed into tablets using a single station tablet compression machine with the hardness of 7.0-8.0kg/sq.cm, by using 8mm-12mm dies.

 

²  Punch the tablets of the best formulations of both layers together.

EVALUATION TESTS:

A) Pre compression studies:

(i) Angle of Repose

(ii) Density

         (a) Bulk Density

         (b) Tapped Density

(iii) Carr’s Index

(iv) Hausner’s Ratio

 

B) Post compression studies:

(i) Average weight / Weight Variation

(ii) Thickness

(iii) Hardness test

(iv) Friability test

(v) Drug content / Assay

(vi) In vitro dissolution study

 

A) Precompression studies:

  1) Angle of Repose: It is defined as the maximum angle possible between the surface of a pile of 

powder and the horizontal plane.

Angle of Repose of granules was determined by the funnel method. Accurately weighed powder

blend was 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 the angle of repose was calculated using the following equation.

The angle of repose has been used to characterize the flow properties of solids.

 

 

Flow property	Angle of Repose (Degrees)
Excellent	25-30
Good	31-35
Fair-aid not needed	36-40
Passable-may hang up	41-45
Poor-must agitate, vibrate	46-55
Very poor	56-65
Very, very poor	>66

                    Table no.01: Angle of repose limits

2)Density:

a) Bulk density (BD): It is the ratio of the total mass of powder to the bulk volume of powder. Weigh accurately 25 g of granules, which was previously passed through 22#sieve and transferred in 100 ml graduated cylinder. Carefully, level the powder without compacting, and read the unsettled apparent volume. Calculate the apparent bulk density in gm/ml by the following formula.

 

Bulk density = weight of powder/Bulk volume

 

b) Tapped density (TD): It is the ratio of the total mass of powder to the tapped volume of powder. Weigh accurately 25g of granules, which was previously passed through 40#sieve and transferred

    in 100 ml graduated cylinder of tap density tester which was operated for a fixed number of taps

    until the powder bed volume has reached a minimum thus was calculated by the formula.

 

Tapped density = Weigh of powder/Tapped volume

 

3) 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:

     

Compressibility index = 100 x Tapped Density-Bulk density/Tapped density

 

4) Hausner’s Ratio: Hausner’s Ratio is the number that is correlated to the flowability of a powder.

 

Hausner’s Ratio = Tapped density/Bulk density

 

 

 

Compressibility Index (%)	Flow Character	Hausner’s Ratio
<10	Excellent	1.00-1.11
11-15	Good	1.12-1.18
16-20	Fair	1.19-1.25
21-25	Passable	1.26-1.34
26-31	Poor	1.35-1.45
32-37	Very poor	1.46-1.59
>38	Very, very Poor	>1.60

                    Table no.02: Compressibility index limits

 

B) Post compression studies:

 

1. General appearance: The formulated tablets were assessed for its general appearance and observations were made for shape, color, texture, and odor.

2.Average weight/weight variation: 20 tablets were selected and weighed collectively and individually. From the collective weight, the average weight was calculated. Each tablet weight was then compared with the average weight to assure whether it was within permissible limits or not. Not more than two of the individual weights deviated from the average weight by more than 7.5% for 300 mg tablets and none by more than double that percentage.

 

Average weight = weight of 20 tablets / 20

 

% weight variation = (Average weight – weight of each tablet *100 )/

Average weight

 

 

Average weight tablet(mg)	% difference allowed
130 or less than	± 10
130-324	± 7.5
More than 324	± 5

                  Table no.03: Weight variation table for uncoated tablets

 

3. Thickness: Thickness of the tablets (n=3) was determined using a Vernier calipers

 

4. Hardness test: Hardness of the tablet was determined by using the Monsanto hardness tester (n=3) the lower plunger was placed in contact with the tablet and a zero reading was taken. The plunger was then forced against a spring by turning a threaded bolt until the tablet fractured. As the spring was compressed a pointer ride along with a gauge in the barrel to indicate the force.

5. Friability test: This test is performed to evaluate the ability of tablets to withstand abrasion in packing, handling, and transporting.

The initial weight of 20 tablets is taken and these are placed in the Friabilator, rotating at 25rpm for 4min. The difference in the weight is noted and expressed as a percentage.

               It should be preferably between 0.5 to 1.0%.

% Friability = [(W1 – W2)/W1] x 100

Where, W1 = weight of tablets before the test,

W2 = weight of tablets after the test.

 

6. Content uniformity test

               Drug content estimation: Ten tablets were weighed and powdered, a quantity of powder equivalent to 100 mg of Drug was transferred to a 100ml volumetric flask and 10ml methanol is added. The drug is dissolved in methanol by vigorously shaking the volumetric flask for 15 minutes. Then the volume is adjusted to the mark with distilled water and the solution is filtered. From prepared solution take 0.1 ml solution in 10 ml volumetric flask and makeup to mark with distilled water. The drug content was determined by measuring the absorbance at a suitable wavelength after appropriate dilution. The drug content was calculated as an average of three determinations.

 

Calculate the quantity in mg of drug in the portion taken by the formula

 

Assay = (Test absorbance * standard concentration * Average weight * % purity of drug * 100) /

standard absorbance * sample concentration * label claim * 100

 

7. In-vitro Dissolution Study for Ezetimibe

900 ml of 0.1N HCL was placed in the vessel and the USP-II apparatus (Paddle method) was assembled. The medium was allowed to equilibrate to the temperature of 37˚C±0.5˚C. A tablet was placed in the vessel and was covered; the apparatus was operated up to 60 minutes at 50 rpm. A definite time intervals, 5 ml of dissolution medium was withdrawn; filtered and again replaced with 5 ml of fresh medium to maintain sink conditions. Suitable dilutions were done with dissolution medium and were analyzed spectrophotometrically at λmax = 256nm using a UV-spectrophotometer.

Parameter	Details
Dissolution apparatus	USP – type II(Paddle)
Medium	0.1N HCL
Volume	900 ml
Speed	50rpm
Temperature	37˚C±0.5˚C
Sample volume withdrawn	5ml
ime points	5,10,15,30,45 and 60
Analytical method	Ultraviolet-Visible Spectroscopy
λmax	265nm

Table no.04: Dissolution parameters for Ezetimibe

 

8. Invitro Dissolution Study for Metformin HCl

900 ml of 0.1N HCL was placed in the vessel and the USP-II apparatus (Paddle method) was assembled. The medium was allowed to equilibrate to a temperature of 37˚C±0.5˚C. A tablet was placed in the vessel and was covered; the apparatus was operated up to 2hours at 50 rpm. After completion of 2hours remove the 0.1N HCL and add 6.8 phosphate buffer then continue the apparatus up to 12hours. At definite time intervals, 5 ml of dissolution medium was withdrawn; filtered, and again replaced with 5 ml of fresh medium to maintain sink conditions. Suitable dilutions were done with dissolution medium and were analyzed spectrophotometrically at λmax = 232 nm using a UV-spectrophotometer.

 

 

Parameter	Details
Dissolution apparatus	USP – type II(Paddle)
Medium	0.1N HCL and 6.8 Phosphate buffer
Volume	900 ml
Speed	50rpm
Temperature	37˚C±0.5˚C
Sample volume withdrawn	5ml
ime points	1,2,3,4,6,8,10 and 12hrs
Analytical method	Ultraviolet-Visible Spectroscopy
λmax	232nm

             Table no.05: Dissolution parameters for Metformin HCL

 

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