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Journal of Drug Delivery and Therapeutics

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Open Access Full Text Article                                                                                                  Research Article

Formulation and Evaluation of Ketorolac Tromethamine Mouth Dissolving Tablets

Bindal Rishabh* and Indurkhya Arpna

Sri Aurobindo Institute of Pharmacy, Indore, Madhya Pradesh (India) 453555

INTRODUCTION

Over the past few years, extensive efforts have been made in designing dosages forms with improved patient compliance, enhanced therapeutic effectiveness, reduced side effects, and reducing dosage regimen with less toxicity to treat many acute and chronic diseases. Several rapidly disintegrating drug delivery systems are developed and commercialized ^1-3. The oral drug delivery segment has resulted in the transition from simple conventional tablets or capsules to modified release tablets or capsules into Mouth dissolving tablets (MDTs). Mouth dissolving tablet technology has gained a lot of attention among the plenty of avenues explored for rapid drug release products ^4-7.

The diseases like short term management of moderate to moderately severe acute pain, including post-surgical pain (such as general orthopedic and dental surgery), and acute musculoskeletal trauma pain need to be treated with pain killers. Presently wide range of NSAIDs is available to treat such pain and analgesia. Ketorolac tromithamine (KRT) is a member of the pyrrolopyrrole group of NSAIDs that exhibits analgesic, anti-inflammatory and antipyretic activity ^8-10. It inhibits the cyclooxygenase enzyme system and hence prostaglandin synthesis. It has more pronounced analgesic activity than most NSAIDs. The present investigation was focused on formulation and evaluation of mouth dissolving tablets of Ketorolac tromithamine and thus relieving pain immediately.

MATERIALS AND METHODS

Materials

Ketorolac tromethamine was received as a gift sample from McW Healthcare Private Limited, Indore. Crospovidone, Croscarmellose sodium, and Sodium starch glycolate were purchased from SD–Fine chemicals, Mumbai. All other chemicals and reagents were of analytical reagent grade.

Methods

Pre-formulation studies

Particular fundamental physical and chemical properties of the drug molecule and other derived properties of the drug powder must be determined before producing dosage forms. The preformulation procedure is the first step in the production of a drug's dosage forms.

Melting point determination

A capillary melting point apparatus (Tempo, Mumbai) was used to determine the melting point of the drug. Capillary tube was filled with drug sample and placed in melting point apparatus with a thermometer and the temperature was noted when the drug started melting.

Preparation of Calibration Curve

Accurately weighed 100 mg of KRT was dissolved in PBS pH 6.8 and volume was made up to 100 ml, resulting in a stock solution of 1000µg/ml. Then, 10 ml of this stock solution was further diluted to 100ml with PBS pH 6.8 to get stock solution of 100µg/ml concentration. Stock solution was taken in aliquots of 0.5 ml, 1.0 ml, 1.5 ml upto 2.5 ml in to a series of 10 ml volumetric flasks and volume was made up to the mark with PBS pH 6.8. The solutions were filtered through Whatman filter paper no. 1 and filtrate was analyzed at λmax 322nm using UV visible spectrophotometer ¹⁰. PBS pH 6.8 was used as blank solution. The standard curve was plotted between absorbance and concentration.

Formulation of mouth dissolving tablets of Ketorolac Tromethamine

All the ingredients were powdered separately in a dry, clean porcelain mortar and passed through # 60 mesh sieve and mixed well in geometrical ratio. Different preliminary batches of MDT tablets were prepared by mixing all ingredients with different superdisintegrants (Table 1). Powder mixture of KRT, with one of the superdisintegrant crospovidone, crosscarmellose sodium and sodium starch glycollate were dry blended for 20min followed by addition of mannitol and aspartame. The mixtures were then mixed with magnesium stearate and talc and further blended for 10 min and resultant powder blend was directly compressed using rotary tablet machine with 9 mm flat round punches to obtain the MDT tablets containing 10mg of KRT ^11-12.

Table 1: Composition of MDTs of Ketorolac tromethamine

Evaluation of prepared mouth dissolving tablets

Pre Compression Parameters

Bulk density (BD)

It is the ratio of total mass of powder to the bulk volume of powder. 25g of KRT blend with excipients was weighed and transferred into 50ml measuring cylinders without tapping during transfer the volume occupied by blend was measured. Bulk density was calculated by following formula:

Bulk density = Mass of the blend / Untapped Volume

Tapped density (TD)

It is the ratio of total mass of the powder to the tapped volume of the powder. 25g of KRT blend were weighed and taken into graduated measuring cylinders. Initial volume occupied by drug blends was noted down. Then cylinder was subjected to 500 taps in tapped density tester (Electro Lab USPII) according to USP. Tapped density was calculated using the tapped volume and mass of powdered drugs using following formula:

Tapped density = Mass of the blend/ Tapped Volume

Flow properties (Angle of Repose)

The angle of repose of powder was determined by the funnel method. 25g accurately weighed drug blend with excipients was taken in a funnel. The height of the funnel was adjusted in such a way that the tip of the funnel just touches the apex of the heap of the powder. The powder was allowed to flow through the funnel freely onto the surface. The diameter of the powder cone was measured and angle of repose was calculated using the following equation.

q = tan^-1(H / R)

Where, H and R are the height and radius of the pile.

Compressibility Index (Carr's index-CI)

It is indirectly related to the relative flow rate, cohesiveness and particle size. It is simple, popular and fast method of predicting powder flow characteristics. It is based on the apparent bulk density and the tapped density, the percentage compressibility of the bulk drug was determined by the following formula-

X 100

Determination of Hausner ratio (HR)

The Hausner’s ratio is a number that is correlated to the flow ability of a powder or granular material. It is measurement of frictional resistance of the drug. It was determined by the ratio of tapped density and bulk density.

Post Compression Parameters ^13-14

Hardness

The tablet should be stable to mechanical stress during handling and transportation. Hardness (Kg/cm²) of MDTs was determined by Monsanto hardness tester.

Friability (F)

MDT formulations (20) were weighed and placed in the Roche Friabillator that revolves at 25 rpm for 4 minutes dropping the from a distance of six inches with each revolution. After operation the tablets were de-dusted and reweighed. The % friability was then calculated by the following formula-

Weight variation test

MDT formulations (20) were individually weighed, calculated the average weight, and compared the individual tablet weights to the average. The tablets met the USP tests that were not more than 2 tablets were outside the percentage limit and no tablets differed by more than 2 times the percentage limit. The percentage difference in the weight variation should be within the permissible limits (±7.5%).

Thickness

Tablets of each batch were selected and measured for thickness using verniour caliper.

Disintegration time

Disintegration time was measured using disintegration test apparatus (Electrolab ED-2L, Mumbai, India). Single tablet was placed in each of the six tubes of the basket, insert disc and operate the apparatus for the specified time, using distilled water maintained at 37±2°C as the immersion fluid. The time in second was noted when tablets disintegrate completely.

Drug content

Total 10 tablets were weighed and powder equivalent to 10mg of KRT was weighed and dissolved in PBS pH 6.8 then filtered through Whatman filter paper. Solution was analyzed for KRT content by UV Spectrophotometer at 322nm using PBS pH 6.8 as blank.

Wetting time

The wetting time of the tablets can be measured using a simple procedure. Five circular tissue papers of 10cm diameter are placed in a petridish with a 10cm diameter. 10 ml of PBS pH 6.8 was poured into the tissue paper placed in the petridish. A tablet is carefully placed on the surface of the tissue paper. The time required for water to reach upper surface of the tablet is noted as a wetting time.

In Vitro Dissolution Studies of MDTs

The developed MDT formulations of ketorolac were subjected to release studies using USP-II dissolution apparatus (Electrolab TDT-06 P, Mumbai, India) at 50 RPM ^14-15. Dissolution medium used was 900 ml PBS pH 6.8 maintained at 37±0.5^oC, which was found to provide sink conditions. The 5 ml samples were withdrawn at different time intervals and replaced with an equivalent amount of fresh medium. The dissolution samples, after filtration through 0.45-mm filters, were analyzed using a validated UV spectroscopic method at 322nm.

Stability Studies

The studies were conducted as per ICH guidelines which recommend a temperature of 40±2^oC, a relative humidity of 75±5% and period of 3 months for accelerated stability studies. However, the stability was also assessed at 4±1^oC (refrigerated condition) and at 25±2^oC with 60±5% relative humidity. The sampling time was kept at 1, 2 and 3 months. The studies were performed using stability chamber (Thermo Lab, Mumbai). Changes in the appearance and drug content of the stored films were investigated during the period and after 3 month ¹⁵.

RESULTS AND DISCUSSION

Preformulation studies

It was observed that the melting point of the drugs was found to be 166^oC which is similar to the reported value and proved that the received drug sample meets the reported properties. The absorption maximum of KRT was measured by UV/Visible spectrophotometer and found to be 322nm. Calibration curve was prepared and linearly regressed. The correlation coefficient for standard curves was found to be very near to one which indicates good co-linear correlation between concentration 5-25µg/ml (Table 2 and Figure 1). Hence, drugs are following Beer Lambert Law in the above range.

Table 2: Calibration curve of KRT in PBS pH 6.8 at 322nm

Figure 1: Calibration curve of KRT in PBS pH 6.8 at 322nm

Pre-compression evaluations

Pre-compression evaluations were done to ensure the flow properties of the powder blend. The powder blend's good flow properties will yield the tablets of desired quality and ease the tableting process. The bulk density of all formulations ranges from 0.36g/cm³ to 0.45g/cm³. The tapped density of all the formulations ranges from 0.45g/cm3 to 0.56g/cm3. The angle of repose of all formulations was found in a range of 25˚.5’ to 29˚.6’. The compressibility index of all the formulations ranges from 8.69 to 30.35. The Hausner’s ratio for powder blends of all nine formulations ranges from 1.09 to 1.43. The results indicate that the powder blends of all nine formulations had good flow properties. The various pre-compression parameters are shown in Table 3.

Table 3: Pre-compression characterization of KRT blend

Post-compression evaluations

The hardness for tablets of all the formulations was found to be less than 3 kg/cm². The results friability indicated that tablets of all batches have friability below 1% and hence passes the test. The weight variation test was carried out to ensure that the tablets of each formulation were of uniform weight, which will indicate the uniform distribution of contents of each formulation's powder blends. The weight variation for tablets of all formulations was found to be within the range of 7.5%. The results indicate that all tablets of each formulation were of uniform weight. The thickness for tablets of all nine formulations was found to be 2.2 to 2.5mm. The drug contents for tablets of all the formulations ranges from 95.46% to 98.84%.  (Table 4).

The disintegration time was the time taken by the tablet to break down into small particles, in the presence of an aqueous medium. It varies with the type and concentration of the superdisintegrants incorporated in the formulation. As the name implies, disintegration time was the prime most criteria for mouth dissolving tablet, which should be less than 30 secs to 3 minutes as per the standards. The results indicate that the disintegration time for tablets of all formulations is within limits. Results of wetting time test indicated that wetting time of all tablets and the water absorption ratio were within limits (Table 4).

Table 4: Post-compression evaluation of MDTs of KRT

In vitro drug release from MDTs was carried out in pH 6.8 phosphate buffer. The superdisintegrants were added to the solid dosage formulations to enhance the disintegration time, thereby enhancing the faster release of active drug from its dosage form, which ultimately resulted in enhanced absorption and bioavailability of the drug. The maximum drug release at a period of five minutes was noted for all the formulations. The results indicate that all the formulation's drug release was found to be above 80% in five minutes except for formulations (F1 and F2). The release rate of the three superdisintegrants was in the order of Crospovidone> Sodium Starch Glycolate> Croscarmallose (Table 5 and Figure 2-4).

Table 5: In vitro drug release from MDTs of KRT

Figure 2: Comparative drug release from formulations F1-F3

Figure 3: Comparative drug release from formulations F4-F6

Figure 4: Comparative drug release from formulations F7-F9

Stability studies were performed on best selected formulation F3 on the basis of drug release profile. Formulation F3 was exposed to different storage conditions to determine any changes in final formulation. Initial drug content was considered to be 100%. It was found that the percent drug content after a period of 3 months for KRT was 99.61±0.34% at 4±1^oC whereas it was 99.52±1.3% at 25±2^oC & 60±5% respectively. On the other hand it was 99.14±1.6% at 40±2^oC & 75±5%. These observations indicate that the formulation is fairly stable with respect to the drug content at all temperatures and conditions of storage.

CONCLUSIONS

The aim of the present study was design formulation and evaluation of mouth dissolving tablets of Ketorolac tromethamine using various superdisintegrants. Mouth dissolving tablets were prepared by direct compression method and evaluated for different physicochemical properties. All formulations showed good results for pre-compression and post-compression parameters. The tablets of all the batches were found to release more than 80% in 5 minutes, which is the desired quality of mouth dissolving tablets that helps in faster absorption of the drug and quick onset of therapeutic effect. The dissolution pattern of various disintegrants used in the formulation was found to be in the order of Crospovidone˃ SSG˃ CCS.  Based on physicochemical parameters and in vitro release profile formulation F3 was considered as the best formulation. The conclusion from all encouraging results reaches that mouth dissolving tablets of Ketorolac tromethamine may be more suitable for quicker onset of action and better patient compliance.

ACKNOWLEDGMENT

The authors would like to thank Sri Aurobindo institute of Pharmacy, Indore for the support and providing all facilities to perform the above research work.

CONFLICTS OF INTEREST

There are no conflicts of interest.

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