Development and In Vitro Evaluation of Fast Dissolving Tablets of Tapentadol

 

Prathibha Suvarna1, Ravi Kumar2*, Yamunappa1, Pooja Shetty1, Narayana Swamy V.B.3

1M.Pharm (Pharmaceutics) Research Scholar, Karavali College of Pharmacy Mangalore.

2Department of Pharmaceutics, Karavali College of Pharmacy Mangalore.

3Department of Pharmacognosy, Karavali College of Pharmacy Vamanjoor Mangalore.

*Corresponding Author E-mail: ravikumar300@gmail.com

 

ABSTRACT:

The objective of this research was to formulate fast dissolving tablets of tapentadol that disintegrate in the oral cavity upon contact with saliva and there by improve therapeutic efficacy. Tapentadol is used for the treatment of moderate to severe pain for both acute (following injury, surgery, etc.) and chronic musculoskeletal pain). Fast dissolving tablets of tapentadol were prepared by direct compression method comprising of three different superdisintegrants-Sodium starch glycollate, Crosscarmellose sodium and Crosspovidone (2%, 4%, 6% and 8%) and diluent viz: microcrystalline cellulose. Twelve formulations were prepared and evaluated for hardness, thickness, friability, weight variation, drug content, in vitro disintegration time, in vitro dispersion time, wetting time, water absorption ratio and in vitro dissolution studies. FTIR and DSC studies revealed that there was no chemical interaction between the drug and the excipients. Formulation M12 was found to be the best on the basis of wetting time, in vitro disintegration time and in vitro drug release. The formulation M12 containing microcrystalline cellulose as diluent and crosspovidone (8%) as disintegrant was found to be the optimized combination. Stability studies were carried out at 250C±20C/60%±5% RH and 400C±20C/75%±5% RH for formulation M12 for 60 days. The results of stability studies indicated no significant changes with respect to physicochemical properties, in vitro disintegration time, wetting time and in vitro drug release.

 

KEY WORDS: Fast dissolving tablets, tapentadol, Superdisintegrant, Direct compression, Sodium starch glycollate, Crosscarmellose sodium, Crosspovidone.

 

 

 

 


INTRODUCTION:

The oral route of administration still continues to be the most preferred and popular route about 80% of total dosage forms are administered due to its manifold advantages including ease of ingestion, pain avoidance, versatility and most importantly patient compliance. Many pharmaceutical dosages are administered in the form of pills, granules, powders and liquids.

 

Generally, a pill design is for swallowing intact or chewing to deliver a precise dosage of medication to patients. The pills, which include tablets and capsules, are able to retain their shapes under moderate pressure. However, some patients, particularly pediatric and geriatric patients, have difficulty swallowing (dysphagia) or chewing solid dosage forms. Many pediatric and geriatric patients are unwilling to take these solid preparations due to fear of choking1. In order to assist these patients, several fast-dissolving drug delivery systems have been developed, which include Orally Disintegrating Tablets and Oro Dissolving Films. Oral fast dissolving drug delivery system (OFDDS) is one such novel approach to increase consumer acceptance by virtue of rapid disintegration, self-administration without water or chewing1. Oral cavity is that area of mouth delineated by the lips, cheeks, hard palate, soft palate and floor of mouth. The oral cavity consists of two regions.

(a) Outer oral vestibule, which is bounded by cheeks, lips, teeth and gingival(gums).

(b) Oral cavity proper, which extends from teeth and gums back to the fauces (which lead to pharynx) with the roof comprising the hard and soft palate. The tongue projects from the floor of the cavity. The drug administered via the oral mucosa gain access to the systemic circulation through a network of arteries and capillaries. The major artery supplying the blood to the oral cavity is the external carotid artery. The venous back flow goes through branches of capillaries and veins and finally taken up by the jugular vein. Orally disintegrating tablets (ODT) are solid unit dosage forms like conventional tablets, but are composed of superdisintegrants, which help them to disintegrate the tablet rapidly in saliva and are swallowed without water as tablet disintegrate in mouth, this could enhance the clinical effect of drug through pregastric absorption from the mouth, pharynx, esophagus. This leads to an increase in the bioavailability by avoiding first pass liver metabolism. Oral disintegrating tablets (ODT) are not only indicated for people who have swallowing difficulties, but also are ideal for active people. Orally disintegrating tablets are also called as mouth dissolving tablets, orodispersible tablet’, quick disintegrating tablets, rapid dissolving tablets, porous tablets and rapimelts2.

 

US FDA defined orally disintegrating tablet as A solid dosage form containing medicinal substances, which disintegrates rapidly, usually within a matter of seconds, when placed upon the tongue. Recently European pharmacopoeia also adopted the term ‘orodispersible tablet’ as a tablet that is to be placed in the mouth where it disperses rapidly before swallowing2. Despite various terminologies used, orally disintegrating tablets are here to offer unique form of drug delivery with many advantages over the conventional dosage forms. The US Food and Drug Administration 2008 publication of guidance for industry: Orally Disintegrating Tablets. Three main points stand out in the final guidance3:ODTs should have an in vitro disintegration time of approximately 30 sec o less (using United States Pharmacopeia disintegration test or equivalent). Generally, the ODT tablet weight should not exceed 500 mg, although the combined influence of tablet weight, size, and component solubility all factor into the acceptability of an ODT for both patients and regulators. The guidance serves to define the upper limits of the ODT category, but it does not supersede or replace the original regulatory definition mentioned. In other words, disintegration within a matter of seconds remains the target for an ODT4. The drug selected for investigation is Tapentadol which is  a centrally-acting synthetic opioid analgesic used for moderate to severe pain like labor pain, postoperative surgical pain, traumatic pain and cancer pain. Tapentadol can be administered orally, intravenously or rectally. Tapentadol is rapidly absorbed orally is subjected to first pass metabolism and absolute bioavailability is only approximately 32%. It is bitter in taste. The objective was to formulate taste masked tapentadol fast dissolving tablets leading to an increase in bioavailability of the drug, quick onset of pharmacological action and increase in patient compliance due to ease of administration.

 

MATERIALS AND METHODS:

Materials:

Tapentadol was obtained from Lupin Pharmaceuticals, Mumbai, India as gift sample. All the other solvents, reagents and chemicals used were of either Pharmacopoeial or analytical grade.

 

Methods:

1. Drug excipients compatibility study:

Compatibility of Tapentadol with superdisintegrants was established by infrared spectral analysis. The samples were mixed with potassium bromide in a ratio of 1:99 in agate mortar and pestle and mixed thoroughly. This mixture was then loaded in FTIR to get an IR spectrum. IR Spectral analysis was carried out to investigate the changes in chemical composition of the drug after combining it with the excipients.

 

2. PREPARATION OF TAPENTADOL FAST DISSOLVING TABLETS:

Tapentadol tablets each containing 75 mg of Tapentadol were prepared by direct compression method. The different superdisintegrants used were Sodium starch glycollate, Crosscarmellose sodium and Crosspovidone in different concentrations. The diluent used was microcrystalline cellulose along with other excipients. The study was intended to compare the disintegration efficiency of these superdisintegrants in various concentrations (2%, 4%, 6% and 8%) and to select the best possible diluent-superdisintegrant combination among the various superdisintegrants used. Accurate quantities of Tapentadol, superdisintegrants (preferred superdisintegrants in different concentrations), microcrystalline cellulose, aspartame, talc and magnesium stearate were weighed and passed through mesh #60. All the ingredients except lubricant were thoroughly blended in a glass mortar with pestle for 15 min.


Table 1: Composition of FDT’s of Tapentadol with MCC as diluent

INGREDIENTS (mg/tablets)

FORMULATIONS

M1

M2

M3

M4

M5

M6

M7

M8

M9

M10

M11

M12

Tapentadol

75

75

75

75

75

75

75

75

75

75

75

75

Sodium Starch Glycollate

4

8

12

16

-

-

-

-

-

-

-

-

Crosscarmellose Sodium

-

-

-

-

4

8

12

16

-

-

-

-

Crosspovidone

-

-

-

-

-

-

-

-

4

8

12

16

Microcrystalline Cellulose

113

109

105

101

113

109

105

101

113

109

105

101

Aspartame

2

2

2

2

2

2

2

2

2

2

2

2

Magnesium Stearate

2

2

2

2

2

2

2

2

2

2

2

2

Orange flavour

2

2

2

2

2

2

2

2

2

2

2

2

Talc

1

1

1

1

1

1

1

1

1

1

1

1

Aerosil

1

1

1

1

1

1

1

1

1

1

1

1

Total weight (mg)

200

200

200

200

200

200

200

200

200

200

200

200

 


After sufficient mixing lubricant was added and mixed for additional 2 to 3 min. Before compression, hardness was adjusted. 75 mg of Tapentadol were compressed on 10-station rotary punching machine, each weighing 200 mg. The compositions of Tapentadol fast dissolving tablets was given in table 1.

 

EVALUATION OF FAST DISSOLVING TABLETS

PRE-COMPRESSIONAL STUDIES:5-14

1.     Angle of Repose (Ө):

The frictional force in a loose powder or granules can be measured by angle of repose. Angle of repose is defined as the maximum angle possible between the surface of a pile of the powder and horizontal plane. The angle of repose of API powder was determined by the funnel method. The accurately weighed powder blend was taken in the funnel. The height of the funnel was adjusted in such a way that 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.

 

                               Ө = tan-1 (h/r)

 

Where, Ө is the angle of repose, h is the height of pile and r is the radius of the base of pile.

 

2.     Bulk Density and Tapped density:

Loose bulk density (LBD) and tapped bulk density (TBD) of tablet blends were determined using bulk density apparatus. Tablet blend was passed through #18 sieve to break the clumps and transferred to 100ml graduated cylinder. Initial volume was observed. The cylinder was tapped initially 200 times from a distance of 14 ±2 mm. The tapped volume was measured to the nearest graduated unit. This was repeated for other tablet blends. The LBD and TBD were calculated in g/ml using following formula:

 

LBD = weight of the powder / volume of the packing

TBD = weight of the powder / tapped volume of the packing

 

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 is packed down. The formula for Carr’s Index is as below,

Carr’s Index (%) = [(TBD-LBD) x100]/TBD

Where, LBD = Loose Bulk Density and TBD = Tapped Bulk Density

 

4.     Hausner ratio:

The Hausner’s ratio is a number that is correlated to the flowability of a powder or granular material. The Hausner ratio of the powder was determined by the following:

equation:

Hausner ratio = TBD / LBD

Lower Hausner ratio (<1.25) indicates better flow properties than higher ones (>1.25).

 

5.     Total porosity:

Total porosity was determined by measuring the volume occupied by a selected weight of a granule (Vbulk) and the true volume of the granule (The space occupied by the powder exclusive of spaces greater than the intermolecular spaces).

Porosity (%) = V bulk - V x100

                             Vbulk

 

POST-COMPRESSIONAL STUDIES5-14

A.    General appearance:

The fast dissolving tablets, morphological characterization which includes size, shape, colour, presence or absence of odour, taste surface texture was determined.

B.    Thickness and diameter:

Five tablets were picked from each formulation randomly and thickness and diameter was measured individually. It is expressed in mm and standard deviation was also calculated. The tablet thickness and diameter was measured using vernier calliper.

 

C.    Hardness:

Hardness indicates the ability of a tablet to withstand mechanical shocks while handling. The hardness of the tablets was determined using Monsanto hardness tester. It is expressed in kg/cm2. Five tablets were randomly picked and hardness of the same tablets from each formulation was determined. The mean and standard deviation values were also calculated.

 

D.    Friability test:

Friability test is performed to assess the effect of friction and shocks, which may often cause tablet to chip, cap or break. Roche Friabilator was used for the purpose. Preweighed sample of ten tablets were placed in the Friabilator, which was then operated at 25 rpm for 4 minutes or ran upto 100 revolutions. After 100 revolutions the tablets were dusted and reweighed. Compressed tablets should not lose more than 1% of their weight. The % friability was then calculated by the following formula:

 

Percentage friability =

(Initial weight - Final weight /Initial weight) × 100

 

E.    Weight variation:

20 tablets were selected randomly from each formulation and weighed individually to check for weight variation. The US Pharmacopoeia allows a little variation in the weight of a tablet. The following percentage deviation in weight variation is allowed: In all the formulations the tablet weight was 200 mg, hence 7.5% weight variation was allowed.

 

F.    Drug content uniformity:

Twenty tablets were weighed and powdered. Powder equivalent to 75 mg drug was transferred into a 100 ml volumetric flask. Volume was made with phosphate buffer pH 6.8. After few minutes the solution was filtered; rejecting first few ml of the filtrate. 10ml of filtrate was taken in a 50 ml volumetric flask and diluted up to the mark with phosphate buffer pH 6.8 and analyzed spectrophotometrically at 272 nm. The concentration of Tapentadol (in μg/ml) was calculated by using the standard calibration curve of Tapentadol.

 

G.   Wetting time and water absorption ratio:

A piece of tissue paper folded twice was placed in a small petridish (i.d = 6.5 cm) containing 6 ml of water. A tablet was placed on the paper and the time required for complete wetting was then measured. The water absorption ratio, R, was determined using the following equation,

                       R = Wa - Wb / Wb × 100

Where, Wb is the weight of the tablet before water absorption and Wa is the weight of the tablet after water absorption.

 

H.   In vitro dispersion time:

One tablet was placed in a beaker containing 10 ml of phosphate buffer pH 6.8 at 37 ± 0.5ºC and the time required for complete dispersion was determined.

 

I.      In vitro disintegration time:

In vitro disintegration time was performed by apparatus specified in USP at 50 rpm. Phosphate buffer pH 6.8, 900 ml was used as disintegration medium, and the temperature of which was maintained at 37±2°C and the time in second taken for complete disintegration of the tablet with no palpable mass remaining in the apparatus was measured in seconds.

 

J.     In vitro drug release studies:

In vitro release studies were carried out using tablet dissolution test apparatus USP XXIII. Two objectives in the development of in vitro dissolution tests are to show  that the release of the drug from the tablet is as close as possible to 100% and  that the rate of drug release is uniform batch to batch and is the same as the release rate from those batches proven to be bio available and clinically effective. In vitro drug release studies were carried out using dissolution apparatus USP type XXIII at 50 rpm. The dissolution medium consisted of 900 ml of Phosphate buffer pH 6.8 maintained at 37±10C. The drug release at different time intervals was measured using a double beam UV Spectrophotometer at 272 nm.

 

K.   Data Analysis:

Various models were tested for explaining the kinetics of drug release. To analyze the mechanism of the drug release rate kinetics of the dosage form, the obtained data were fitted into zero-order, first order, Higuchi, Korsmeyer-Peppas release model and Hixson-Crowell equation.

 

L.    Stability Studies:

Stability of a drug has been defined as the ability of a particular formulation, in a specific container, to remain within its physical, chemical, therapeutic and toxicological specifications. The purpose of stability testing is to provide evidence on how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors such as temperature, humidity and light, and enables recommended storage conditions, re-test periods and shelf lives to be established. ICH specifies the length of study and storage conditions:

 

Long term testing 250C ± 20C/60%±5% RH for 12 months

Accelerated testing 400C ± 20C/75% ±5% RH for 6 months

 

In the present study, stability studies were carried out at 250C ± 20C/60% ±5% RH and 400C± 20/75% ± 5% RH for a period of 60 days for the selected formulation (M12). The formulation was then evaluated for changes in the physicochemical properties, wetting time, in vitro disintegration time and in vitro drug release.

 

RESULTS AND DISCUSSION:

The present study was to formulate fast dissolving tablets of Tapentadol using superdisintegrants (sodium starch glycollate, crosscarmellose sodium and crosspovidone) in different concentrations and diluent microcrystalline cellulose along with other excipients by direct compression method. The prepared tablets were evaluated for physiochemical properties, wetting time, water absorption ratio, in vitro dispersion time, in vitro disintegration time, in vitro dissolution studies and stability studies.

 

Drug-Excipients Compatibility Studies:

Fourier Transform Infrared (FTIR) Spectroscopy:

Physical mixture of Tapentadol and formulative ingredients were subjected for IR spectroscopic analysis to ascertain whether there was any interaction between drug and excipients used. The IR spectras showed similar characteristic peaks at their respective wavelengths with minor differences. The similarity in the peaks indicated the compatibility of drug with formulation excipients. IR spectra of the physical mixture of drug with formulative ingredients were depicted in figure 1 to 5.

 


 

 

Figure 1: FT-IR Spectra of Physical mixture of Tapentadol+SSG

Figure 2: FT-IR Spectra of Physical mixture of Tapentadol + CCS

Figure 3: FT-IR Spectra of Physical mixture of Tapentadol + CP

Figure 4: FT-IR Spectra of Physical mixture of Tapentadol + M12

Figure 5: FT-IR Spectra of Physical mixture of Tapentadol + MCC

 

 


Differential Scanning Calorimetry (DSC):

The DSC thermograms of pure Tapentadol HCl showed melting endothermic peak at 205.5°C indicating crystalline nature of Tapentadol HCl, followed by exothermic peak which may be due to decomposition of Tapentadol HCl. The endothermic peak for the drug in physical mixture, showed minor changes in the melting endotherm of drug could be due to the mixing of drug and excipients, which lower the purity of each component in the mixture and may not necessarily indicates potential incompatibility. The result showed that drugs were compatible with excipients. DSC thermograms of drug and physical mixture of drug and excipients were shown in figure 6-7.

 

Figure 6: DSC thermogram of Tapentadol HCl

Figure 7: DSC thermogram of Physical mixture of Tapentadol + Excipients

 

EVALUATION PARAMETERS:

A) PRECOMPRESSIONAL PARAMETERS:

Blended drug/excipient mixture of all the formulations were subjected for various precompressional evaluation parameters such as bulk density, tapped density, compressibility index, hausner’s ratio and angle of repose who’s values were found to be within limit and had favorable flow properties for compression, reported in table 2. All the formulations showed good passable compressibility index and good angle of repose.

 


Table 2: Pre compression evaluation of tapentadol powder blend containing MCC

Formulation Code

Angle of Repose

Bulk Density (gm/cc)

Tapped Density (gm/cc)

Carr’s Index

%

Hausner Ratio

Bulkiness (cc/g)*

M1

27.3±0.02

0.54±0.04

0.73±0.03

22.8±0.01

1.32±0.01

1.75±0.01

M2

27.9±0.03

0.55±0.02

0.72±0.01

18.7±0.02

1.24±0.01

1.75±0.01

M3

26.3±0.04

0.57±0.03

0.67±0.02

19.9±0.01

1.24±0.01

1.72±0.02

M4

26.3±0.02

0.55±0.03

0.67±0.02

16.9±0.03

1.22±0.03

1.79±0.03

M5

27.6±0.04

0.55±0.01

0.70±0.02

19.9±0.04

1.27±0.02

1.82±0.03

M6

26.9±0.05

0.54±0.03

0.73±0.03

21.5±0.02

1.35±0.04

1.72±0.01

M7

 30±0.02

0.53±0.01

0.67±0.01

20.8±0.02

1.26±0.05

1.89±0.02

M8

28.0±0.03

0.57±0.01

0.74±0.02

23.1±0.01

1.29±0.02

1.75±0.04

M9

32.6±0.01

0.56±0.02

0.74±0.02

23.7±0.01

1.30±0.04

1.79±0.05

M10

28.1±0.01

0.57±0.02

0.71±0.03

19.0±0.01

1.24±0.02

1.75±0.02

M11

27.3±0.02

0.54±0.04

0.73±0.03

22.8±0.01

1.32±0.01

1.75±0.01

M12

27.9±0.03

0.55±0.02

0.72±0.01

18.7±0.02

1.24±0.01

1.75±0.01

*All values are expressed as mean ± SD, n=3.

 


B) POST-COMPRESSIONAL PARAMETERS:

All the tablet formulations were evaluated for parameters such as shape, colour, thickness, hardness, friability, weight variation, drug content, in vitro disintegration time, in vitro dispersion time, wetting time, water absorption ratio, in vitro dissolution studies, model fitting of release profile and stability studies.

 

a)    General appearance:

All the fast dissolving tablets from each batch were found to be flat, white in color, circular in shape and having good physical appearance. There was no change in the color and odour of the tablets from all the batches.

 

b)    Thickness and diameter:

Thickness and diameter of all prepared fast dissolving tablets was measured by using calibrated vernier callipers. Tablet thickness should be controlled within ± 0.1% variation of standard value to facilitate packaging and consumer acceptance. The tablets showed thickness and diameter in the range of 2.701 mm to 2.709 mm, 6.01 to 6.03 mm respectively.

 

c)     Hardness:

Tablets require certain amount of strength, hardness to withstand mechanical shocks during manufacture, packaging and shipping. The hardness was found to be in the range of 3.2 to 4.0 kg/cm2. The obtained results revealed that the tablets were having good mechanical strength and compactness.

 

d)    Friability:

Adequate tablet hardness and resistance to friability are necessary to prevent damage to the tablet during manufacture, packing and transport. % Friability of tablets less than 1% was considered acceptable .Percent friability ranged from 0.24 to 0.55%.

 

e)     Weight variation:

The average weight of Tapentadol fast dissolving tablet was 200mg. the weight variation was found to be in the range of 199.17 mg to 203.55 mg. The obtained results indicated that all tablets of different formulations were within the I.P specifications.

f)     Mouth feel:

The prepared formulations were subjected for mouth feel. The volunteers felt good taste in all the formulations. As the drug is bitter the presence of Aspartame and orange flavour in all the formulations showed good, palatable taste.

 

g)    pH:

pH of the solution of all the tablets was found to be between 7.1 to 7.5, which suggest that the tablets can be conveniently administered orally and will not cause any discomfort.

 

h)    Drug content:

To evaluate a tablet’s potential for efficacy the amount of drug in the tablet need to be monitored from tablet to tablet and batch to batch. The percentage drug content was found to be in the range of 98.00% to 99.78 %( table3).

 


 

Table 3: Post compression evaluation of tapentadol FDT’s containing MCC

Formulation

Code

Thickness

(mm)*

Diameter

(mm)*

Hardness

(kg/cm2)*

Friability

(%)**

Weight variation test (mg)***

Drug Content

(%)***

pH

Mouth

feel

M1

2.703±0.01

6.02±0.02

3.4±0.24

0.37±0.01

201.00 ± 1.01

98.70±0.73

7.4

+

M2

2.701±0.04

6.01±0.02

3.5±0.25

0.33±0.02

203.55 ± 1.11

98.55±0.09

7.5

+++

M3

2.705±0.01

6.03±0.02

3.3±0.27

0.39±0.4

200.30 ± 1.12

99.30±0.56

7.4

++

M4

2.709±0.03

6.01±0.01

3.5±0.23

0.24±0.03

202.55 ± 1.17

99.78±0.28

7.2

+

M5

2.704±0.06

6.01±0.03

3.7±0.25

0.27±0.01

201.00 ± 1.05

98.65±0.51

7.5

+++

M6

2.701±0.03

6.01±0.04

3.6±0.26

0.34±0.02

199.80 ± 0.11

98.58±0.44

7.2

+

M7

2.704±0.02

6.03± 0.04

3.2±0.24

0.29±0.01

202.25 ± 1.22

98.29±0.75

7.1

+++

M8

2.701 ± 0.01

6.01±0.03

3.8±0.23

0.35±0.03

200.05 ± 1.15

98.90±0.65

7.1

++

M9

2.702±0.04

6.03±0.02

3.7±0.24

0.32±0.04

201.05 ± 1.17

99.47±0.47

7.2

+++

M10

2.701±0.03

6.02±0.01

3.5±0.25

0.24±0.04

200.30 ± 1.06

99.35±0.53

7.5

++

M11

2.705±0.04

6.01±0.02

3.2±0.23

0.29±0.02

202.11 ± 1.22

98.85±0.63

7.2

++

M12

2.703±0.01

6.01±0.03

3.5±0.24

0.35±0.01

201.55 ± 1.15

98.51±0.71

7.5

++

*All values are expressed as mean ± SE, n=5; **All values are expressed as mean ± SE, n=10; ***All values are expressed as mean ± SE, n=20; += Average; ++= good,        +++= excellent

 

 

 


Water Absorption Ratio:

Water absorption ratio, which is an important criterion for understanding the capacity of disintegrants to swell in presence of little amount of water, was calculated. It was found to be in the range of 53.21 to 78.83 in formulations containing MCC as diluent (figure 8).  The Water absorption ratio increased with increase in the concentration of superdisintegrant from 2-8 %. The water absorption ratio was found to be in the increasing order. This increase was due to the water up taking ability of the superdisintegrants. More the superdisintegrant concentration greater was water absorption.  Water absorption ratios for all these formulation batches varied in the following decreasing order: Crosspovidone > Crosscarmellose sodium > Sodium starch glycollate.

 

 

Wetting Time:

Wetting time is an important parameter related to water absorption ratio, which needs to be assessed to give an

 

insight to the disintegration properties of the tablets. Wetting is closely related to the inner structure of the tablets and the hydrophilicity of the excipients. Wetting time was used as a parameter to correlate with disintegration time in oral cavity. This is an important criterion for understanding the capacity of disintegrants to swell in presence of little amount of water. Since the dissolution process of a tablet depends upon the wetting followed by disintegration of the tablet, the measurement of wetting time may be used as another confirmative test for the evaluation of dispersible tablets.

It was found that formulation containing sodium starch glycollate and MCC (M1) showed wetting time 46 sec. whereas those containing crosspovidone and MCC (M12) showed least wetting time of 25 sec (figure 8).

Figure 8: Comparison of wetting time and water absorption ratio of various formulations of Tapentadol FDT’s containing MCC

 

In vitro Disintegration Time:

Disintegration, the first important step for a drug absorption from a solid dosage form after oral administration was preliminarily focused. The internal structure of tablets that is pore size distribution, water penetration into tablets and swelling of disintegration substance are suggested to be the mechanisms of disintegration. This indicates that the tablets would disintegrate almost instantaneously when they will come in contact with even slight amount of saliva in the mouth. Disintegration time was determined as per I.P. for all the formulations. Least in vitro disintegration time was shown by formulation containing crosspovidone and MCC (M12).  Disintegration time was observed in the increasing order of  Crosspovidone < Crosscarmellose Sodium < Sodium Starch Glycollate.

 

In vitro Dispersion Time:

In vitro dispersion time was measured by the time taken to undergo uniform dispersion. All formulations showed rapid dispersion within seconds. Formulated fast dissolving tablets containing MCC as diluent showed dispersion time less than 59 seconds (figure 9).

Figure 9: Comparison between in vitro disintegration time and   in vitro dispersion time of various formulations of tapentadol FDT’s containing MCC

 

In vitro Dissolution Studies:

The IN VITRO drug release characteristics were studied in phosphate buffer pH 6.8 using tablet dissolution apparatus USP XXIII. The samples were withdrawn at different time intervals and analyzed at 272 nm and the cumulative percentage drug released was determined.

 

Microcrystalline cellulose as diluents:

The IN VITRO dissolution data of formulations were shown in figure 10, 11 and 12. Formulation M1, M2, M3 and M4 released 89.11 %, 92.56 %, 93.76 % and 94.50 % drug respectively in 15 mins. Formulation M5, M6, M7 and M8 released 90.01 %, 92.17 %, 96.34 % and 97.02 % drug respectively in 15 mins. Formulation M9, M10, M11 and M12 released 92.97 %, 95.84 % and 97.87 % and 98.90 % drug respectively in 15 mins. IN VITRO dissolution studies revealed that the release rate of Tapentadol from fast dissolving tablet containing Crosspovidone (M12) was maximum i.e 98.90%.

 

Figure 10: Comparison of dissolution profile of various formulations of Tapentadol FDT’s containing MCC+SSG (M1-M4)

 


Figure 11: Comparison of dissolution profile of various formulations of Tapentadol FDT’s containing MCC+CCS (M5-M8)

Figure 12: Comparison of dissolution profile of various formulations of Tapentadol FDT’s containing MCC+CP (M9-M12)


 

Data Analysis:

The results of in vitro dissolution studies obtained from these formulations were plotted in Zero order, First order, Higuchi and Korsmeyer-Peppas release model and Hixson-Crowell equation to study the mechanism of drug release. The correlation coefficient (r) for drug release kinetic models was tabulated in table 4 for formulations containing microcrystalline cellulose. The formulations M1 showed Higuchi Matrix which described the drug release, as a diffusion process based on the Fick’s law, square root time dependent. Formulations M2 to M11  showed First order Model and formulation M12 showed Hixson Crowell Model which was used to describe that dissolution occurred in planes that were parallel to the drug surface if the tablet dimensions diminished proportionally, in such a manner that the initial geometrical form was kept constant at all time.

 


 

 

Table 4: Model fittings of release profile of formulated Tapentadol FDT’S containing MCC as diluent using different models

FORMULATION CODE

MATHEMATICAL MODELS (KINETICS)

Zero Order

First Order

Higuchi Matrix

Peppas

Hixson Crowell

Best Fit Model

M1

0.826

0.942

0.980

0.776

0.949

Higuchi matrix

M2

0.771

0.985

0.955

0.721

0.938

First order

M3

0.734

0.931

0.929

0.764

0.917

First order

M4

0.726

0.935

0.932

0.749

0.911

First order

M5

0.752

0949

0.942

0.755

0.930

First order

M6

0.736

0.939

0.935

0.748

0.934

First order

M7

0.719

0.940

0.939

0.743

0.920

First order

M8

0.709

0.920

0.918

0.747

0.915

First order

M9

0.721

0.942

0.921

0.749

0.917

First order

M10

0.751

0.930

0.929

0.750

0.920

First order

M11

0.780

0.941

0.932

0.755

0.956

Hixson crowell

M12

0.781

0.944

0.935

0.759

0.959

Hixson crowell

 

 


Stability Studies:

Stability studies of formulation M12 were performed at 250C±20C/60% ±5% RH and 400C ±20C/75% ± 5% RH for a period up to 60 days. The formulations were selected for stability studies on the basis of their high percentage cumulative drug release and also results of          in vitro disintegration time, wetting time and in vitro dispersion studies.  The results obtained for physicochemical properties, wetting time, in vitro disintegration time and in vitro drug release of formulation M12 at 250C ± 20/60%±5% RH and 400C ± 20/75%±5% RH were shown in table 5 to 6. There was no change in color and shape of the tablets when stored at 250C ± 20C /60% ± 5% RH and 400C±20C /75% ±5% RH and observed every 20 days interval upto 60 days. Formulation M12 showed not much variation in any parameter. From these results it was concluded that formulations were stable and retained its original properties.

 


 

Table 5: Results of stability study of formulation M12 stored at 250C ± 20C/ 60% ± 5% RH

Formulation Code

Tested in days

Thickness (mm)

Hardness

(Kg/cm2)

Friability

(%)

Weight variation (mg)

% Drug content

M12

20

2.703±0.01

3.5±0.23

0.32

201.45±1.15

98.45

40

2.702±0.04

3.5±0.24

0.31

201.50±1.10

98.42

60

2.701±0.02

3.5±0.26

0.34

201.10±1.05

98.46

 

 

Table 6: Results of stability study of formulation M12 stored at 400C± 20C/ 75% ± 5% RH

Formulation Code

Tested in days

Thickness

(mm)

Hardness

(Kg/cm2)

Friability

(%)

Weight variation

(mg)

% Drug content

M12

20

2.709±0.04

3.5±0.24

0.32

201.05±1.20

98.49

40

2.703±0.08

3.5±0.23

0.31

201.50±1.79

98.43

60

2.708±0.04

3.5±0.21

0.34

201.21±1.03

98.44

 

 

 


CONCLUSION:

In the present work, an attempt was made to develop fast dissolving tablets of Tapentadol as an improved and better patient compliant dosage form. From the study conducted and from the observations and the results obtained thereof, following conclusions were drawn:

Ø FTIR studies concluded that drug and excipients were compatible with each other.

Ø The formulated tablets were satisfactory in terms of hardness, thickness, friability, weight variation, drug content, wetting time, water absorption ratio, in vitro disintegration time, in vitro dispersion time and in vitro drug release.

Ø Formulations containing superdisintegrant Crosspovidone showed least wetting time and in vitro disintegration time.

Ø As the superdisintegrant concentration increases, the wetting time and in vitro disintegration time on tablets decreases.

Ø Formulation M12 was found to be the best on the basis of wetting time, in vitro disintegration time and in vitro drug release.

Ø The formulation M12 containing microcrystalline cellulose as diluent and crosspovidone (8%) was found to be the optimized combination.

 

REFERENCES:

1.     Parakh S R, Gothoskar A V. A review of mouth dissolving tablet technologies. Pharm Tech 2003;27(11):92-98.

2.     Suresh B, Rajendar KM, Ramesh G, Madhusudan YR. Orodispersible Tablets An overview. Asian Journal of Pharmaceutics 2008;2:10-15.

3.     Guidance for Industry Orally Disintegrating Tablets published by centre for drug evolution and research, accessed at http://www.fda.gov/cder/guidance/index.html.

4.     William RP, Tapash KG. Orally disintegrating tablets. Pharmaceutical Technology 2005.

5.     Subrahmanyam CVS. Textbook of physical pharmaceutics. Delhi: Vallabh Prakashan; 2005:28-32.

6.     Subrahmanyam CVS, Thimmasetty J, Shivanand KM, Vijayendraswamy SM. Laboratory manual of industrial pharmacy. Delhi: Vallabh Prakashan; 2006: 32.

7.     Ministry of Health and Family Welfare (India). Indian Pharmacopoeia. New Delhi: The Controller of Publications; 1996.

8.     Banker SG, Anderson NR. Tablets. In: Lachman L, Lieberman HA, Kanig JL, editors. The theory and practice of industrial pharmacy. 3rd ed. Bombay: Varghese Publishing House; 1991.

9.     United States of Pharmacopeia-National Formulary. USP 30 NF 25. Rockville, MD: The United States Pharmacopeial Convention Inc; 2007. Vol 1.p.644, 242, 645, 731 and 634.

10.  Jacob S, Shirwaikar A, Joseph A, Srinivasan K. Novel Co-Processed Excipients of Mannitol and Microcrystalline Cellulose for Preparing Fast Dissolving Tablets of Glipizide. Indian J Pharm Sci 2007; 69(5): 633-39.

11.  Sweetman SC, editor. Martindale: The Complete Drug Reference. 33rd ed. London: Pharmaceutical Press; 2002:1235--7.

12.  Jha SK, Vijayalakshmi P, Karki P, Goli D. Formulation and evaluation of melt-in-mouth tablets of haloperidol. Asian J Pharm 2008; 2(4): 255-60.

13.  United States Pharmacopoeia, In vitro Dissolution. Asian edition. United States Pharmacy Convention Inc; 2000:1941-3.

14.  Shukla V, Manvi FV. Effect of different superdisintegrants on isoniazid dispersible tablet for oral tuberculosis. Der Pharma Chemica 2010; 2(4): 65-78.

 

 

 

Received on 22.02.2016          Accepted on 15.03.2016        

© Asian Pharma Press All Right Reserved

Asian J. Pharm. Res. 6(1): January -March, 2016; Page 11-21

DOI: 10.5958/2231-5691.2016.00003.4