Title of Invention

A NOVEL METHOD FOR PREPARATION OF MOUTH DISSOLVE TABLET OF NIMESULIDE FROM GRANULES PREPARED BY EUTECTIC BLEND

Abstract

A novel method for preparation of mouth dissolve tablet of nimesulide from granules prepared by eutectic blend of camphor, menthol and/or thymol comprising the steps of: (a) separately preparing granules of nimesulide by wet granulation technique using alcoholic solution of Polyvinylpyrrolidone (PVPK40) binder; (b) separately preparing Lactose granules by wet granulation technique using PVP K40 binder in eutectic blend of camphor, menthol and/or thymol of equal amount; (c) mixing both, the Lactose granules obtained from step (b) and the granules containing nimesulide from step (a); (d) adding extragranular ingredients such as 4% w/w Crospovidone, 2% w/w Magnesium Stearate, 2% w/w Talc to the granules obtained from step (c); and (e) compression of granules from step (d).

Full Text

FORM-2 THE PATENTS ACT, 1970 COMPLETE SPECIFICATION [SECTION 10] 1. A NOVEL METHOD FOR PREPARATION OF MOUTH DISSOLVE TABLET OF NIMESULIDE FROM GRANULES PREPARED BY EUTECTIC BLEND. 2. (a) L. M. COLLEGE OF PHARMACY, run by Ahmedabad Education Society, a Registered Trust (b) P.O. Box NO. 4011, Navrangpura, Ahmedabad-380 009. Gujarat, India. (c) INDIA. The following specification particularly describes and ascertains the nature of the invention and the manner in which it is to be performed. This invention relates to A NOVEL METHOD FOR PREPARATION OF TABLET OF ACTIVE PHARMACEUTICAL INGREDIENTS FROM GRANULES PREPARED BY EUTECTIC BLEND. More particularly, it describes the preparation of mouth dissolve tablet by using eutectic blend comprising of camphor, menthol and thymol or any two of them. Background of Invention Infant survival rate and life expectancy rate for geriatric patients have increased significantly in the recent years due to advancements in medical sciences. Pediatric and geriatric patients generally consume more drugs as compared to that by the adults. The widely used liquid dosage forms for these groups of patients are difficult to formulate, less stable and they show poor patient compliance due to objectionable taste in many cases. Geriatric and pediatric patients experience difficulty in swallowing tablets, which leads to poor patient compliance. To overcome this weakness of tablets, scientists have developed innovative drug delivery system known as "melt in mouth" or "mouth dissolve" tablets. When they are used by a patient, they disintegrate, dissolve or disperse in oral cavity. Their characteristic advantages such as administration without water, anywhere, anytime lead to their suitably to geriatric and pediatric patients and to those patients who are mentally ill or bed ridden. They are also preferred by the patients who do not have an easy access to water (e.g. army). Their benefits in terms of patient compliance, rapid onset of action, increased bioavailability and good stability makes them popular in the current market. Tablets are the most widely used for the oral delivery of drugs, vitamins and minerals. The popularity of tablets is attributed to compactness, uniformity of weight, temper-proofness, ease of administration, stability during storage, economy and ease in packing and transportation. Compressed tablets are also used for the marketing of non pharmaceutical materials such as laundry detergents, artificial sweeteners, fish foods, plant growth regulators, pesticides, herbicides, bleaching agents and dyes. The actual characteristics of various tablets differ depending on the formulation. Majority of the drugs do not possess adequate flow and/or compressibility. The flow can be improved by size enlargement and the compressibility 3 can be improved by using binder. Those who are skilled in art know this as a granulation process. The classical and most preferred method of size enlargement is wet granulation. The amount of drug that can be tableted using the wet granulation technique is high compared to direct compression and dry granulation. In wet granulation one can modulate the release profile of the drug substance more easily than the other methods. The taste masking is possible by using the suitable polymer. Due to granulation the bulk density of the material increases and hence the flow and compressibility increases. A wet granulation technique requires preparation of a powder blend, wetting the blend with a sufficient amount of binder solution (water, alcohol or suitable solvent), milling the wet mass into moist granules and drying the granules, followed by further milling and blending with other inactive ingredients. For drugs that are not compressible and lack required flow characteristics, this process of agglomeration with a binder results in a compressible granulation. Melt granulation technique requires higher operating temperature and hence it is unsuitable for many drugs. The second method of obtaining agglomerates is dry granulation. The slugs are prepared by compressing a dry powder admixture of active ingredient, filler, and binder using roller compactor or chilsonator. These slugs are then milled to yield granules. The granules are then mixed with other inactive ingredients. This method is commonly used for the drugs that are compressible but do not have required flow characteristics or for drugs that have marginal compressibility, e.g., aspirin. Compounds that undergo elastic recovery on removal of applied pressure, show difficulties in roller compaction. Dry granulation method is expensive, requires specialized equipment, labour and high power consumption compared to direct compression. The technique, moreover, does not always provide suitable tablets. The third method for the production of tablets is direct compression. In this method the drug is blended with the readyniade adjuvant/s and compressed into the tablets. The method is less time consuming but it requires the costly adjuvant as well as it has very low dilution potential for drug like paracetamol. Majority of tablets are prepared by direct compression contain about 30% of drug/s. Hence, the final weight and volume of the tablets will become quite large that a patient may have difficulty in swallowing. So, the direct compression is suitable for the low dose drugs only. Due to the size difference between the drug and adjuvant, there are chances of segregation and subsequent problem of content uniformity. Only a very limited number of pharmaceutical substances possess enough cohesive strength and flowability to allow direct compression without previous granulation. Direct compression is less suitable method for the tablets that are to be coated. Majority of the conventionally available tablets are prepared by wet granulation. The most crucial step for the production of granules having ideal characteristics is the selection of binder and control of variables like the concentration of binder, mixing time, etc., Table 1 shows the commonly used binders in the preparation of pharmaceutical tablets {Encyclopedia of Pharmaceutical Technology, Volume I, pp.451 -464). These binders have their own advantages and disadvantages. Binders are solid materials used in the manufacture of solid dosage forms because of their adhesive and cohesive properties. They are also referred to as adhesives. The role of binders is to assist size enlargement by adding cohesiveness to powders, thereby providing granules and tablets with the necessary bonding strength. Although binders improve the appearance, hardness and friability of these preparations, they are usually not intended to adversely influence the disintegration or dissolution rates of the active substance. The commonly used binders are hydrophilic polymers which because of their properties as film formers and viscosity builders are used in pharmaceutical formulations for a number of different purposes. In wet granulation, the role of the binder is primarily to improve the strength and friability of the dried granules and to facilitate the subsequent tablet compression. In wet granulation method, aqueous binder solutions are preferred, considering the factor of cost. Nonaqueous solutions are necessary in many cases because of the properties of the drug substance and the formulation. A drug candidate may be sensitive to moisture with regard to its chemical stability. If the substance is readily soluble in water, granulation with aqueous binder solutions gives rise to partial dissolution of the drug substance and subsequent crystallization or deposition during drying. This may have consequences to the quality attributes of the final product. In effervescent tablets, the use of aqueous binders is not recommended since premature reaction between an acid and alkali will occur. Water or organic solvent such as alcohol, dichloromethane, etc. may be used as a granulating agent if the drug exhibit satisfactory solubility in the solvent and if it shows good spreading behaviour. Those good at art knows that ciprofloxacin HC1 is granulated in water. Commonly used binders and granulating agents Binder Concentration %of Formulation Granulating System Solvent Concentration (%) Sugar Sucrose 2-25 Water 50-67 Glucose 2-25 Water 25-50 Sorbitol Water 2-25 Binder of Natural origin Acacia 3-5 Water 10-15 Alginic acid 1-5 Water - Sodium Alginate 1-3 Water 3-5 Gelatin 1-3 Water 5-10 Starch 2-5 Aqueous paste Dry addition Pregelatinized starch 2-5 (5-10) Water Dry addition Microcrystalline cellulose 5-20 Dry binder 10-15 Magnesium aluminum silicate 3-5 Water slurry Semi synthetic and Synthetic binders Carboxymethyl cellulose sodium 1-5 (5-10) Water 2-10 Methylcellulose 1-5 (5-10) Water 2-15 Hydroxypropyl methyl cellulose 1-5 (5-10) Water or Hydroalcoholic solution 5-10 Ethylcellulose 1-5 (5-10) Ethanol 5-10 Povidone 2-5 (5-10) Water or Hydroalcoholic solution 5-10 Polyethylene glycol 10-15(3-5) Melt granulation - Values in parent incorporated by a lesis refer to concentration used when the binder is dry mixing process. Table 1 Table 1 reveals the novel use of eutectic mixture consisting of acceptable pharmaceutical in the present invention. The compressed tablets must release the active pharmaceutical ingredient/s in predetermined fashion. To ascertain this, disintegration and in-vitro dissolution tests are conducted. In most cases rapid disintegration of the tablet is desired. For example, a tablet embodying a COX-2 inhibitor such as nimesulide, should rapidly break down in the digestive fluid of the stomach to make the active ingredient promptly available to the central compartment i.e. blood. Other important characteristics are friability and hardness. They are somewhat related to each other. Friability decreases as the hardness increases. Excessive friability is undesirable, since dusting and crumbling of the tablet results in at least some diminution in active ingredient, unattractive tablet appearance, and poor consumer • appeal. The effectiveness of any tablet markings is also reduced. Insufficiently hard tablets, in addition to exhibiting the effects of excessive friability, are prone to breakage and chipping, particularly during transportation due to repeated mechanical shock. Accordingly, for most purposes, and particularly for pharmaceutical application, a hard, non-friable tablet possessing acceptable disintegration characteristics is the goal of the tablet manufacturer. Other properties are, of course, important such as color stability and non-hygroscopicity. In order to prepare ideal tablets, it becomes mandatory for the pharmaceutical formulator to include adjuvants in the formulation. Lubricants, disintegrants, fillers, glidants, colorants, flavours, etc. may be added. When tablets containing suitable disintegrant is placed in the proper fluid environment, the tablet breaks into small pieces (Tablet into granules and then in to small particle). A typical disintegrant employed in tableting is granular starch, however, granular starch is not freely flowable and will not form a hard, non-friable tablet. Hence, superdisintegrants are used today. One of the important factors that significantly affect disintegration is water uptake rate by tablets. The disintegration time of tablet is dependent upon water uptake rate of the tablet. Porous tablets are likely to pick up water at a faster rate. Heinemann et al (US Patent 3,885,026) and Roser et al (US Patent 5,762,961) developed a technique to develop porous tablets that dissolve quickly and exhibit good mechanical strength. Heinemann et al incorporated one inert readily volatile solid ingredient in the blend for tableting. The volatile solid ingredient is removed after compression. In the present invention, liquid volatile agents are used and are removed by evaporation before compression of granules in the tablet form. Moreover, our objective is to use the eutectic blend as a solvent for binder such as Polyvinylpyrrolidone (PVP). Roser et al used volatile salts such as ammonium bicarbonate , ammonium acetate, etc. The salts were removed from the compressed tablets. Salts we were not used in the present study in solid form. Instead of this, we used the volatile blend of camphor, menthol and thymol as a solvent for binder in the present invention. Maximizing the pore structure of tablet matrix and incorporation of efficient disintegrating agent/s and/or highly watcr soluble excipient/s in the tablet formulation are the basic approaches in the development of mouth dissolve tablets. Freeze drying and vacuum drying are the most commonly used techniques to maximize the pore structure of tablet matrix. Freeze drying yields fragile and hygroscopic tablets. The dosage form is to be freeze dried in the final package. Moreover, due to scale-up difficulties faced in the freeze-drying, in the present invention vacuum drying technique is used for the removal of volatile agent such as camphor, menthol and/or thymol. Wet granulation was adopted for the preparation of mouth dissolve tablets considering their advantages such as content uniformity and improved wettability of poorly flowable and hydrophobic drugs, fn wet granufation, either aqueous or convenfibna/ organic solutions of binders are in used. Aqueous binders are unsuitable in many cases. Ethyl alcohol, dichloromethane, wopropyl alcohol, etc. are commonly used organic solvents. These organic solvents pollute the environment. Regulatory agencies restrict the presence of traces of organic solvent above certain specified levels i.e. parts per million (ppm). Solvent recovery is mandatory considering health and safety hazards. In the present invention rapidly disintegrating tablet of nimesulide is prepared by eutectic blend consisting of camphor, menthol and/or thymol as a novel solvent for binder. Camphor, menthol and thymol are used in ayurvedic system of medication for internal use. Hence, volatile agents remain after vaporization do not harm regulatory restrictions. The performance of tablets prepared by novel method was compared to that of the tablets prepared by conventional wet granulation technique and a commercially available tablets. The invention is described with respect to the accompanying figures. Fig. 1 : Represents comparison of effectiveness of disintegrants on disintegration time. Fig. 2 : Represents comparison of effectiveness of disintegrants on wetting time. Fig. 3 : Represents effect of volatile agent on disintegration time Fig. 4 : Represents effect of volatile agents on % friability. Fig. 5 : Represents comparison of disintegration time after addition of nimesulide. Fig. 6 : Represents comparison of % friability after addition of nimesulide. Example 1: Preparation of Lactose tablets by selection of superdisintegrant. Wet granulation was adopted using alcoholic solution of polyvinylpyrrolidone (PVP K40) for the preparation of granules. Alternatively, PVP was dissolved in an eutectic mixture containing equal proportion of camphor, menthol and thymol for use as a binder. In the present invention, three superdisintegrants namely croscarmellose sodium (CRS), sodium starch glycolate (SSG) and crospovidone (CRP) were evaluated and the best one was selected for further studies. Initially three batches (A1-A3) were prepared, where each of the superdisintegrant was added at 4 % by weight of the lactose tablet. Another three batches (A4-A6) were prepared using combination of the disintegrants. Polyvinylpyrolidone (PVP K40, binder), magnesium stearate (lubricant) and talc (anti-adherent) were used in all the six formulations. The composition of the preliminary batches (A1-A6) is shown in Table 2. Evaluation of Superdisintegrants in Lactose Tablets Formulation Al A2 A3 A4 A5 A6 Sodium starch glycolate+ 4 - - 2 - 2 Croscarmellose+ - 4 - 2 2 - Crospovidone+ - - 4 - 2 2 PVP K40 (in alcohol)^ 1.1 1.1 1.1 1.1 1.1 1.1 Magnesium stearate 1 1 1 1 1 1 Talc 2 2 2 2 2 2 Lactose q.s. to 100 100 100 100 100 100 Crushing strength (kg) 4 4 4 4 4 4 Friability (%) 1 1 1 1 1 1 Wetting time (sec) 90 95 40 210 55 50 Disintegration time (sec) 120 110 90 170 80 90 All the quantities are expressed in mg. ^Binder: 5% w/v PVP in ethyl alcohol +Intragranular 50%, extragranular 50% Table 2 The ingredients were passed through a 100# screen prior to mixing. Lactose and the intragranular fraction of disintegrant/s were mixed by trituration. Alcoholic solution of PVP K40 (5 % w/v) was added to the mixture in a quantity just enough to bind the mass. The lactose granules were prepared by passing the wet mass through a 44#. The granules were dried at 60°C for 30 minute in a hot air oven. The granules were then sized through 44/100#. The fraction of granules that passed through 100# was considered as fines. The granules retained on 100 mesh were blended with the extragranular fraction of the disintegrant/s, the lubricant, anti-adherent and the required proportion of fines (10% w/w). The resulting granules were then compressed into round tablets using a single punch tablet machine. The tablets (batches A1-A6) were stored in sealed glass jars till further use. The crushing strength of the tablets was measured using a Monsanto hardness tester. The friability of a sample of 10 tablets was measured using Roche type friabilator. The tablets were rotated for a period of 4 minute at 25 rpm. After de-dusting, the tablets were weighed again and the percentage loss in tablet weight was calculated. The nearest integer values of friability are shown in Table 2. A commercially available nimesulide mouth dissolve tablet was also evaluated for friability in order to compare the performance of the formulated tablets. Ten ml. of water was placed in a petri dish of 10 cm. diameter. A piece of tissue paper was placed in the petri dish after folding it so that it fits well in the petri dish. A tablet was placed in the centre of the petri dish and the time for water to migrate up to the upper surface of the tablet was noted as a wetting time. The disintegration time (dt) was measured using a modified disintegration method. For the purpose, 10 ml. of water was added to a petri dish of 10 cm. diameter. A tablet was carefully placed in the centre of the petri dish and the time for the tablet to completely disintegrate into particles was noted as disintegration time. The test was terminated at 240 seconds and the results were noted as >240 seconds if the tablet failed to disintegrate within 240 seconds. Mouth dissolve tablets are designed to disintegrate rapidly in oral cavity. The insoluble diluents such as dicalcium phosphate and microcrystalline cellulose were not used in the present investigation since they are expected to cause unacceptable feeling of grittiness in the mouth. Koizumi et al (Koizumi, K., Watanabe, Y, Morita, K, Utoguchi, N, and Matsumoto, M., Int. J. Pharmaceutics, 1997, 152, 127) reported that patients sometimes feel a rough texture in their mouth due to the incomplete solubilization of tablets containing insoluble diluent/s. Mannitol and camphor powder were selected by them as diluent and subliming agent respectively. The objective of using camphor in powder form was to alter porosity of the tablet. Hyun et al (Patent WO 01 89485) used mannitol and menthol powder for the development of rapid dissolve tablets using different drugs. The sublimablse agent was tableted together with drug and adjuvant and later vaporized directly from solid state to vapour state. We used liquid volatile agents for dissolving the binder PVP. The liquid was evaporated before compression. Amongst the soluble diluents, lactose was selected as a model diluent considering its advantages in terms of easy availability, cost effectiveness and relative moisture insensitivity. Soluble diluents in a formulation, as lactose, are considered to act as a passive disintegrants. Hydrogen bond annihilation is responsible for passive mechanism. Lactose may also augment compressibility of poorly compressible drug such as nimesulide. The requirement of the mouth dissolve tablets to disintegrate within fraction of seconds in the limited amount of saliva in the oral cavity demands the use of superdisintegrants. The effect of type of superdisintegrant on disintegration time was evaluated and the results are summarized in Fig. 1. The wetting study is important because the displacement of air by water or aqueous liquid leads to hydration of involved particles. Disintegration of the tablet or dissolution of the drug is facilitated due to rapid wetting. The crushing strength, friability and disintegration time of the commercially available mouth dissolve tablets of nimesulide were found to be 2 kg. 1.3% and 60 seconds respectively. It was decided to consider any batch as acceptable if the parameters are either number of adjuvants. Multiple disintegrant should be used if substantial reduction in disintegration time occur. The blends of the disintegrants did not show improved wetting and/or disintegration. Fig. 1 reveals that the tablets containing 4% w/w crospovidone (CRP) showed quick disintegration. Crospovidone, a water insoluble disintegrant, is generally used at a concentration of 5-10% w/w. It exhibits high capillary activity and pronounced hydration capacity with little tendency to gel formation. Any disintegrant, where the small water-soluble portion results in gel formation, is unsuitable for formulating mouth dissolve tablets. The quicker disintegration time of tablets of batch A3 may be attributed to faster water uptake by the tablet. The batches containing crospovidone, alone or in combination with other disintegrants, showed 100 sec disintegration time. The results of wetting study are depicted in Fig. 2. The tablets of batch A3 showed the least wetting time. Hence, crospovidone was used at a level of 4% w/w for further studies. The crushing strength and the friability of the formulated products were found to be acceptable. Example 2: Preparation of lactose tablets using volatile agents/ eutectic blend Batch Bl was prepared by the classical wet granulation method. Three batches (B2-B4) were prepared using different volatile agents in powder form. Batch B5 was prepared using solution of PVP in the eutectic blend as a binder. It is worthwhile to emphasis here that the use of eutectic blend has not been explored earlier by any researcher. The method of preparation of tablets was identical to that described earlier. The volatile agent was incorporated intragranularly and the granules were vacuum dried at 60°C, instead of drying in a hot air oven in order to facilitate vaporization of volatile agents. Formulation of Lactose Tablets Prepared using Volatile Agent/s Formulation Bl B2 B3 B4 B5 Camphor (C) - 5 - - - Menthol (M) - - 5 - - Thymol (T) - - - 5 - PVP K40 (in eutectic mixtures) - - - - 1.1 PVP K40 (in alcohol)^ 1.1 1.1 1.1 1.1 - Crospovidone+ 4 4 4 4 4 Magnesium stearate 1 1 1 1 1 Talc 2 2 2 2 2 Lactose q.s. to 100 100 100 100 100 Crushing strength (kg) 4 4 4 4 4 Friability (%) 0.76 0.78 0.94 0.99 1.1 Wetting time (sec) 45 40 40 15 15 Disintegration time (sec) 90 55 70 30 30 All the quantities are expressed in mg *Binder 1: 5% w/v PVP in eutectic mixture (1:1 :1 mixture of C:M:T) Camphor, menthol and thymol evaporate during drying. ^Binder 2 : 5% w/v PVP in ethyl alcohol +Intragranular 50%, extragranular 50% Table 3 The results of the formulations prepared using volatile agent/s (camphor, menthol, thymol or eutectic mixture) are shown in Table 3. The effect of volatile agents on disintegration time and wetting time was evaluated and the results are summarized in Fig. 3 and Fig. 4 respectively. The batches Bl and B3 showed relatively higher disintegration time as compared to the commercial formulation, which disintegrated in 60 seconds. While the remaining batches showed acceptable disintegration time. Considering the values of friability and disintegration time, batch B2 containing camphor may be ranked as the best batch amongst four batches (B1-B4). Batch B5 was retained for further studies since the main purpose of this investigation was to explore the use of eutectic blend in granulation. Batch B5 meet the selection criteria of crushing strength (> 2Kg), friability ( Fig. 3 reveals that the disintegration time of the tablets was in the order of "no volatile agent" > menthol > camphor > thymol/eutectic mixture. The results may be attributed to the fact that upon vaporization of volatile agent porosity of the tablet increases. The increased porosity lead to increased water uptake and subsequent disintegration of the wet tablet. It may be concluded that mouth dissolve tablets of water-soluble model drug (lactose) can be developed by the proposed novel method, where eutectic blend was used as a solvent for binder. Another advantage of the proposed method is uniform dispersion of the volatile agents such as camphor, menthol and thymol in the powder blend for granulation since they are present in the dissolved state. This point is important from validation view point. Example 3: Preparation of tablet of active pharmaceutical ingredient Nimesulide using volatile agents/eutectic blend The batches containing camphor and eutectic mixture were formulated again after addition of a model hydrophobic drug- nimesulide. The batches C2 and C3 were prepared to evaluate the effect of percentage of camphor. To evaluate the binding potential of eutectic mixture, a trial batch (C4) was prepared where binding was achieved using the eutectic mixture. Batch C5 was prepared using solution of PVP in eutectic blend as a binder. The formulation and results of the trials are shown in Table 4. Effect of Addition of Nimesulide Formulation CI C2 C3 C4 C5 Camphor - 10 20 - - Eutectic mixture" - - - Q.S. - PVP K40 (in eutectic mixture)* - - - - 4.4 PVP K40 (in alcohol*) 4.4 4.4 4.4 - - Crospovidone+ 8 8 8 8 4 Magnesium stearate 2 2 2 2 2 Talc 2 2 2 2 2 Nimesulide 100 100 100 100 100 Lactose q.s. to 200 200 200 200 200 Crushing strength (kg) 4 4 4 4 4 Friability (%) 0.88 1.09 1.08 0.93 1.03 Wetting time (sec) 110 45 45 60 105 Disintegration time (sec) 200 90 90 >240 >240 "Camphor: menthol: tymol (1:1:1); (0.045ml per tablet) evaporates during drying Binder : * 10 % w/v PVP in ethyl alcohol/eutectic blend Intragranular 50%, extragranular 50% Table 4 The results of batches C1-C5 containing nimesulide are shown in Table 4. Nimesulide is a poorly compressible drug and hence the concentration of PVP was increased from 5 to 10% in the binder. The weight of the drug containing tablets was double than that of the lactose tablets. Hence, relatively larger volume of binder was required to obtain a wet coherent mass for granulation. Therefore, a higher amount of PVP (4.4 mg/tablet of 200 mg weight) was present in these batches. Batch CI, prepared by the classical wet granulation technique, showed higher wetting and disintegration time as compared to the batches C2 and C3. It is certain that the disintegration time of the nimesulide tablets can be modulated by using camphor as a volatile agent (Batch C 1=200 sec, Batch C2=90 sec). The batches C2 and C3 showed almost identical parameters. It may be concluded that optimum percentage of camphor shall be used to modulate the evaluation parameter/s. The tablets of lactose, prepared using solution of PVP in eutectic blend as a binder, showed short disintegrating time while the tablets of nimesulide plus lactose, prepared using solution of PVP in eutectic blend as a binder, showed higher disintegration time. The increase in the disintegration time of the tablets (> 240 sec, Fig. 5) may be attributed to partial solubilization of nimesulide in the eutectic mixture or due to increase in percentage of PVP in the binder solution. The formulations C4 and C5 may be less suitable for mouth dissolve tablet because of higher disintegration time than the control tablets. However, it can be successfully used for development of tablets to be swallowed. Further trials were carried out to reduce the disintegration time of drug containing tablets. Example 4: Preparation of tablet of active pharmaceutical Ingredient Nimesulide by separate granulation technique To overcome the problem of delay in disintegration time when nimesulide was granulated with eutectic mixture, a trial was carried out where nimesulide granules were prepared separately using alcoholic PVP as a binder. Lactose granules were also prepared separately using either alcohol or eutectic blend as a solvent for binder. The composition and results of batch Dl are summarized in Table 5. Evaluation of Nimesulide Tablets Formulation Dl Lactose granules PVP K40 (in eutectic mixture) 4.4 Crospovidone 2 Lactose q.s. to 100 Nimesulide granules Nimesulide 100 PVP K40 (In alcohol) 4.4 Crospovidone 2 Nimesulide granules Lactose granules .. .q.s. to 106.4 200 Magnesium stearate 2 Talc 2 Crospovidone 4 Crushing strength (kg) 4 Friability (%) 0.8 Wetting time (sec) 95 Disintgration time (sec) 180 Table 5 When nimesulide granules were prepared separately by granulating them with ethyl alcohol instead of eutectic mixture, a decrease in disintegration time was obtained. The disintegration time of batch Dl can be decreased further by reducing the crushing strength of the tablet (from 4 kg. to 2 kg.) or by using a higher percentage of superdisintegrant. A batch containing 16 mg of crospovidone was prepared and it showed a disintegration time of 100 seconds. It is clear from the experiments that the characteristics of mouth dissolve tablets of nimesulide can be modulated by properly choosing the type and percentage of superdisintegrating agent and volatile agent. Crospovidone and camphor proved to be superior superdisintegrating agent and volatile agent respectively. Eutectic blend consisting of equal amount of camphor, menthol and thymol also yielded satisfactory tablets. The solubility of the drug in binder solution is also an important parameter affecting the characteristic of the tablets. Eutectic blend can serve as an attractive alternative to the classical organic solvent for the preparation of various dosage forms and in various processes. We claim, 1. A novel method for preparation of mouth dissolve tablet of nimesulide from granules prepared by eutectic blend of camphor, menthol and/or thymol comprising the steps of: (a) separately preparing granules of nimesulide by wet granulation technique using alcoholic solution of Polyvinylpyrrolidone (PVPK40) binder; (b) separately preparing Lactose granules by wet granulation technique using PVP K40 binder in eutectic blend of camphor, menthol and/or thymol of equal amount; (c) mixing both, the Lactose granules obtained from step (b) and the granules containing nimesulide from step (a); (d) adding extragranular ingredients such as 4% w/w Crospovidone, 2% w/w Magnesium Stearate, 2% w/w Talc to the granules obtained from step (c); and (e) compression of granules from step (d). 2. A novel method as claimed in claim 1 (a) wherein granules are prepared by passing nimesulide through 100# and then granulated using alcoholic solution of PVP K40 (10% w/v), passing the wet coherent mass through 44# and wet granules are obtained, further wet granules are drying at 60° C for 30 minute in hot air oven and dried granules are sized through 44/100#. 3. A novel method as claimed in claim 1 (b) wherein Lactose granules are prepared by passing of Lactose through 100# and then granulated using solution of PVP K40 (10% w/v) in said eutectic blend, passing the wet coherent mass through 44# and wet granules are obtained, further wet granules are drying at 60° C for 30 minute in hot air oven and dried granules are sized through 44/100#. 4. A novel method as claimed in claim 1(b) & 3 wherein the blend of eutectic compounds used as solvent for binder. 5. A novel method for preparation of mouth dissolve tablet of nimesulide from granules prepared by eutectic blend of camphor, menthol and/or thymol as substantially herein described with foregoing description, 3rd & 4th example and 6 drawings. Dated this on 29th of June 2002. Dr. Rajeshkumar H. Acharya. Advocate & Patent agent For and on behalf of the applicant.

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