Introduction
Oral drug delivery is the delivery of a drug formulation through the mouth into the systemic circulation for its intended action. The drug is used to treat various chronic disorders that require long term use of the drug. Its primary goal is to deliver the active medicaments of the drug to its site of action through the systemc circulation. Several formulations are seen to be used in the oral route of delivery such as tablets, capsules, solutions and elixirs.
For efficient delivery of this therapeutic agents, oral administration is the preferred as it is considered easy to use, affordable and patient compliant. Obtaining a maximum concentration of a specific drug at the required duration is important for designing a therapeutic system, to achieve this is quite challenging thus creating the attention in the past few years. However, factors like gastro intestinal absorption and irritation create drawbacks in the administration of the drugs thereby making the oral drug delivery systems to suffer. To achieve success in the oral delivery of drugs, the avoidance of GIT should be a priority.1, 2
Intended for oral administration and are obtained by compressing uniform volumes of ingredients. The objective of the design and manufacture of the compressed tablet is to deliver orally the correct amount of drug in the desired location and to have its chemical properties protected to the point.
Tablets may vary in size, shape, weight, hardness, thickness, and disintegration characteristics and in other aspects, depending upon the intended use of the tablets and their method of manufacture.3
According to CDER and FDA a fast dissolving tablet is a solid dosage form containing medicinal substances that disintegrate rapidly, usually within a matter of seconds, when placed on the tongue.
The basic approach used in development of FDDTS is incorporating the use of Superdisintegrants like cross linked carboxymethylcellulose (croscarmilose), sodium starch Glycolate (primogel, Explotab). Polyvinylpyrrolidone (polyplasdone) etc. which provide instantaneous disintegration of tablet after putting on tongue, thereby releasing the drug in saliva. The bioavailability of some drug may be increased due to absorption of drugs in oral cavity and also due to pregastric absorption of saliva containing dispersed drugs that pass down into the stomach. Moreover, the amount of drug that is subjected to first pass metabolism is reduced as compared to standard tablets.4, 5
Requirements of fast dissolving tablets
A perfect fast dissolving tablets should dissolve/disperse/disintegrate in mouth in a matter of seconds without the need of water. 6
Advantages of mouth dissolving tablets
Beneficial in case such as motion sickness, sudden dose allergic attack or coughing, when an ultra rapid on set of action required.
Some drugs are absorbed from mouth, pharynx and oesophagus as the saliva pass down in to the stomach.
An increased bioavailabilty, particularly in case of insoluble and hydrophobic drugs, due to rapid disintegration and dissolution of these tablets.
Improved patient compliance
Rapid onset of action and may offer an improved bioavailability
Patient having difficulty in swallowing tablets can easily administer this type of dosage form
New business opportunity like product promotion, patent extension and life cycle management7, 8
Objectives
To develop and evaluate the Fast Dissolving Tablet of Irbesartan.
To Formulate FDTs of Irbesartan by using superdisintegrants as croscarmellose sodium and Sodium Starch Glycolate.
Analysing the various parameters of the Fast Dissolving Tablets.
To carry out the stability studies in different temperatures like room temperature and accelerated temperature on FDTs.
Materials and Methods
Materials
Lactose Monohydrate which was used as a filler and a diluent was obtained from (Loba chemical, Hyderabad, India). Croscarmellose Sodium that was used as a superdisintergrant was procured from (Loba chemical, Hyderabad, India). Microcrystalline Cellulose (MCC Ph103) was purchase from (Cadila healthcare, Hyderabad, India). Sodium Starch Glycolate used as a super disintergrant was from (Signet chemical, Hyderabad, India). Aspartame a lubricant was a gift from (Cadila healthcare, Hyderabad, India), Magnesium Stearate which was used as a lubricant was obtained from (Loba chemical, Hyderabad, India) and Talc an anti-caking agent was purchased from (Signet chemical, Hyderabad, India). The Active pharmaceutical ingredient Irbesartan was obtained from (Arabintho Pharmaceutical Ltd, Hyderabad, India). The other chemicals were used as received.
This research was conducted at Vinayaka Missions College of Pharmacy, Salem, Tamilnadu.
Preparation of fast dissolving tablet
Method: Direct compression technique
All the ingredients were weighed accurately as given in the table. The drug, Crosspovidone and Sodium starch glycolate were swifted through sieve no 60 and the mixture was mixed in a poly bag for 15 minutes. Simultaneously talc and magnesium stearate were passsed through sieve no 60. It was then added to the previous mixture of the drug for lubrication and was blend for 20 minutes untill it was ready for compression. The blend was then compressed using multiple tolling twenty station single rotary with single puch (8mm), on labpress machine to produce round shaped tablets weighing 200mg each. The compression force is adjusted to obtain tablets with hardness 3-5kg/cm2. 9, 10
Table 1
Composition of fast dissolving tablets
Solubility studies
Solubility studies were performed in distilled water, Ethanol, Methanol, Acetonitrile, Phosphate Buffer pH 7.4 phosphate buffer by water bath shaker method. To each of these Medias an excess amount of drug was added. Then these solutions were kept in the shaker for 24 hours. After 24 hours samples were centrifuged the supernatant was suitably diluted and estimated for Irbesartan concentration using UV spectrometer at 224 nm.
UV spectrophotometer analysis
Drug was dissolved in 10 ml of Acetonitrile & Phosphate Buffer pH 7.4. It’s stirred for 15mm, sonicated and then filtered through membrane filter paper. Samples were taken from stock solution and serial dilutions were made and UV absorbance was analyzed for l max.
FTIR studies of irbesartan and excipients
The pellets were made by mixing 1gm of drug or excipients and 100gm of dried potassium bromide powder. The mixture was then compressed under 10-ton pressure in a hydraulic press to form a transparent pellet. The thin pellet was put on pellet disc to get IR spectra. 11
Bulk density
The term bulk density refers to a measure used to describe the packing of particles. It is given in (gm/ml) and was determined using balance and measuring cylinder. Initially the weight of the measuring cylinder was taken. Then, 4 gm pre sieved bulk drug was poured into the measuring cylinder using a funnel. Then volume of the powder was taken. Bulk density of the granules was calculated using following formula.12
Bulk density = weight of powder / volume of powder.
Tapped density
Tapped density is determined by placing a graduated cylinder containing same mass of powder used for B.D on a mechanical tapper apparatus which is operated for a fixed number of taps (approximately 500) until powder bed volume has reached a minimum volume.
Tapped density = Weight of powder / Min volume of powder
Angle of repose
Angle of repose in the tan inverse of angle between height (h) of pile of powder and the radius of the base of conical pile. It can be obtained between the free standing surface of the powder heap and the horizontal pale. The fixed funnel that is secured with its tip at a given height h above the graph paper, placed on the flat horizontal surface. Powder is carefully poured through funnel until the apex of conical pile just touches the tip of the funnel.13
Tan q = h/r
Hardness test
The hardness of tablets for fast dissolving tablets is usually kept low for easy disintegration in the mouth. The hardness of the prepared Irbesartan tablet was measured using shulinger hardness tester.14
Thickness
The thickness of tablets was determined using a Vernier callipers. 6 tablets from each batch were used and average values were calculated.15
Friability test
The friability of tablets was determined using Roche Friabilator. It is expressed in percentage (%)
10 tablets were initially weighed and revolved at 25 rpm for 4 min. The tablets were then reweighed after removal of fines and the percentage of weight loss was calculated.
The % friability was then calculated by,
Acceptance criteria for % friability, % weight loss should be less than 1%
Weight variation test
Twenty tablets were selected randomly from each batch and weighed individually on electronic balance. The individual tablet is weighed and then compared with average weight for the weight variations.
Disintegration time testing
It was determined using tablet disintegration test apparatus, using 900 ml of distilled water without disk at room temperature. Test was performed on 6 tablets. Limit set for the disintegration should not be more than 30 seconds. 16
Wetting time of tablet
Wetting time is used to show the porosity, compressibility as well as absorption capacity of the tablets. 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 tablets.
Procedure
For determination of wetting time, a piece of tissue paper folded twice was placed in a small petri dish (internal diameter of 5 cm) containing 6 ml of water. A tablet was carefully placed on the surface of tissue paper. The time required for water to reach the upper surface of tablets was noted as wetting time. The test was repeated on three other tablets of the same batch in same petridish and average of the three readings gives the mean wetting time of the tablets.
Water absorption ratio
Test as done with the same procedure as that of wetting time. In this test, initial weight of tablet was taken before placing on petridish. After complete, wetting, the wetter tablet was then weighed water absorption ratio, R was determined using the equation.
R=100 (wb – wa)/wa
Where wa is weight of tablet before water absorption wb is weight of tablet after water absorption.
In vitro dispersion time
For determination of in vitro dispersion time, one tablet was placed in a beaker containing 10ml of Phosphate Buffer pH7.4 at 370C ±0.50C and the time required for complete dispersion was determined. The test was repeated on three other tablets of same batch, the average gives in vitro dispersion time.
In vitro drug release study
The release rate of drug from FDT was determined using USP dissolution testing apparatus. (II paddle method). The dissolution modern was maintained at 37oC ± 0.5oC the rotation speed was 50 rpm. A sample (5ml) of the solution was withdrawn from the dissolution apparatus at 5, 10, 15, 30, 45 minute, and the samples were replaced with fresh dissolution medium to maintain the sink condition. The samples were filtered through a membrane filter and absorbance of there solutions was measured at 224 nm using a UV – visible double beam spectrophotometer. Cumulative percentage drug release was calculated using linear equation obtained from a standard curve.17
Stability studies
In any design and evaluation of dosage forms for drugs, the stability of the active component must be a major criteria in determining their acceptance or rejection.
Results and discussion
Solubility studies
The solubility studies were conducted in different solvents and the results are shown in Table 5.
FTIR studies
Identification of drug (Irbesartan) sample
The drug was identified and confirmed by FTIR spectrum. FT-IR spectrum of Irbesartan. The characteristic absorption peaks of Irbesartan are within the pharmacopeial limits.18
Drug excipients compatibility study
Compatibility of the drug with recipients was determined by FT-IR spectral analysis, this study was carried out to detect any changes on chemical constitution of the drug after combined it with the recipients. The samples were taken for FT-IR study.
The principle peaks were observed at 2956.50 cm-3 for (N-H stretching), 1760.36 cm-3 for (C=O stretching), 1557.38 cm-3 for (C=C stretching) and 1615.03 cm-3 for (C-N stretching)
The absorption peaks of both the drug and excipients were observed indicating there was no interaction.
Preformulation studies
The flow properties of the pure drug of Irbesartan and irbesartan granules were carried out and the results are shown in tables
Table 4
Flow properties of pure drug
|
Drug |
Bulk density (gm/ml) * |
Tapped density (gm/ml) * |
Compressibility index (%) * |
Hausners ratio * |
Angle of repose * |
|
|
Irbesartan |
0.250 |
0.310 |
24.01 |
1.32 |
24º.41’ |
|
Table 5
Physical characteristics ofIrbesartan granules
The physical parameters of drug as well as excipients concluded that these were considerably good to formulate the Fast Dissolving Tablets using direct compression technique.
Evaluation parameters of the prepared formulation
The evaluation parameters were carried out and the results are shown in Table 6.
Table 6
Physical characteristics of FDT’S of Irbesartan
Discussion
The tablets were compressed at the average weight of 200mg. The maximum weight variation of the tablets was 199.7 to 203.4 %. Hardness for tablets of all batches was in the range of 3.37 to 3.67 kg/cm². The thickness of the tablets of all the batches was found in the range of 3.25 to 3.36 mm. The friability of the tablets of all batches was found in the range of 0.31 to 0.28 %. All the parameters are indicated that the, physical parameters of formulated tablets were within the Pharmacopeial specifications.
Comparative study of disintegration time of formulations F1 to F5
Disintegration time is the main parameter to be evaluated in fast dissolving tablets. The effect of two different superdisintegrants and their functional differences is graphically represented in the below figure. Among all the formulations, tablets containing sodium starch glycolate in 5% concentration were found to show the least disintegration time, it was due to the rapid intake of water within second without formation of lumps and produces a burst effect. It was observed that as the concentration of superdisintegant increased the disintegration time also increased. With the reference to the type of superdisntegrant, the disintegration time to the following flow order.
Crosspovidone < Sodium Starch Glycolate
Comparative study of wetting time of formulations of F1-F5
Wetting time of the formulation is the important criteria of fast dissolving tablet. The time taken for the water to reach the surface of tablets indicates the wetting time of concerned tablets. It indicates the hydrophilicity of the drug as well as the effect of superdisintegrant. The less time taken for completer wetting indicates the rapid uptake of water through capillary action mainly in the case of wicking type of superdisintegrant like sodium starch glycolate. In the present investigation of wetting time of different superdisintegrants, sodium starch glycolate as showed the least time 14.5sec. It is also depicted in the below figure through graphically by comparing the formulation from F1-F2. In this study as the ratio of superdisintegrant is increased the wetting time is decreased in the case of all the batches. The wetting time of all formulation is in the following order.
Crosspovidone < Sodium Starch Glycolate
In vitro dissolution studies
Table 9
In vitro % dissolution studies of FDT of irbesartan and marketed formulation
Stability studies
The Stability studies were undertaken in the investigation of stability of solid oral dosage forms to support post formulation strategies as per ICH guidelines. The accelerated stability studies data of selected formulation (F5) shown in Table 10. The drug content, weight variation, thickness, friability, hardness and in vitro drug release were closely monitored and analyzed at regular intervals (1month). There were no significant changes observed in the drug content thickness, weight variation, hardness, friability and in vitro drug release during and period of stability studies. 19