Ranjith Reddy Kondeti et al., Asian Journal of Pharmaceutical Technology & Innovation, 02 (07); 2014; Research Article

Transcription

1 Asian Journal of Pharmaceutical Technology & Innovation ISSN: Research Article Received on: Accepted on: Published on: Corresponding Author: Ranjith Reddy Kondeti* C.L Baid Metha College of Pharmacy, Chennai-97, India. Ph: * A Comparative Study on Different Methods of Granulation on Tablet Properties Ranjith Reddy Kondeti 1 *, Kranti Sri Mulpuri 2, Meghana Koganti 3, Dr.Grace Rathnam 4 ABSTRACT The active ingredient in a formulation represents a very small portion of the overall tablet, then the challenge is to ensure that each tablet has the same amount of active ingredient. Sometimes, blending the ingredients is not enough. The active ingredient may segregate from the other ingredients in the blending process. The ingredients may be incompatible because of particle size, particle density, flow characteristics, compressibility, and moisture content. These incompatibilities can cause problems such as segregation during blending or during transfer of the product to the press as well as separation of the active on the tablet press. Granulating the active ingredient by itself and then blending it with the rest of the ingredients is one solution to the segregation problem. Otherwise, all or most of the ingredients could be granulated together. The best course of action to ensure that each tablet contains the correct amount of active ingredient, especially if the active ingredient is only a small percentage of the tablet ingredients, is to mix the active ingredient thoroughly with some or most of the other ingredients and then granulate the blend (i.e., form the blend into granules). Each granule would contain a little of each of the ingredients, and the active ingredient would be distributed evenly. Different granulation techniques include Wet granulation, Dry granulation and Direct Compression. The method of granulation is chosen based on the ingredient s individual characteristics and ability to flow, compress, eject, and disintegrate. Choosing a method requires thorough investigation of each ingredient in the formula, the combination of ingredients, and how they work with each other. Then, the proper granulation process can be applied. In this study, work was done to evaluate the different process of granulation techniques for the preparation of tablets. Key-words: Wet granulation, paracetamol, in vitro dissolution, direct compression, disintegration Cite this article as: Ranjith Reddy Kondeti, Kranti Sri Mulpuri, Meghana Koganti, Dr.Grace Rathnam, A Comparative Study on Different Methods of Granulation on Tablet Properties, Asian Journal of Pharmaceutical Technology & Innovation, 02 (07); ,2,3,4 C.L Baid Metha College of Pharmacy, Chennai-97 70

2 INTRODUCTION: Tablets are unit dosage forms which contain one or more active medicaments along with additives. Most common solid dosage forms in contemporary use are tablets, this may be defined as unit forms of solid medicaments prepared by compaction. Most consist of a mixture of powders that are compacted in a die to produce a single rigid body. The most common types of tablets are those intended to be swallowed whole and then disintegrated and release their medicaments in gastrointestinal tract. 1 Advantages: Tablets are the unit dosage form and they offer the greatest capabilities of all oral dosage forms for the greatest dose precision and least content variability. Product identification is potentially the simplest and cheapest, requiring no additional processing steps when employing an embossed or monogrammed punch face. They may provide greatest ease of swallowing with least tendency for hang up above the stomach, especially when coated provided that tablet disintegration is not excessively rapid They lend themselves to certain special release profile products, such as enteric or delayed release products. They are easy to administer, easy to dispense. They are more stable and accuracy of dosage forms. They are better suited to large scale production as compared with any other unit oral dosage form. Disadvantages: Some drugs resist compression into tablet form due to their amorphous nature or low density character. Bitter tasting drugs, drugs with objectionable odour or drugs that are sensitive to oxygen or atmospheric moisture may require encapsulation or special type of coating which may increase the cost of finished tablets. Drugs with poor wetting and slow dissolution properties are difficult to convert into tablets which provide full drug bioavailability. Granulation 2 : Most powders cannot be compressed directly into tablets because (a) They lack the characteristics of binding or bonding together into a compact entity and (b) They do not ordinarily posses the lubricating and disintegrating properties required for tabletting. For these reasons, drugs must first be penetrated, either alone or in combination with a filter, to form granules that lend themselves to tabletting. This process is known as granulation. Granulation is any process of size enlargement whereby small particles are gathered together into larger, permanent aggregates to render them into a free-flowing state similar to that of dry sand. Size enlargement, also called agglomeration, is accomplished by some method of agitation in mixing equipment or by compaction, extrusion or globulation as described in the previous section on unit operation. 3 The reasons for granulation as listed by record are to: 1. Render the material free flowing. 2. Density of materials 3. Prepare uniform mixtures that do not separate 3. Improve the compression characteristics of the drug 5. Control the rate of drug release 6. Facilitate metering or volume dispensing 7. Reduce dust 8. Improves the appearance of the tablet 71

3 Reasons for granulation: The reasons why granulation is often necessary are as follows. To prevent segregation of the constituents of the powder mix Segregation is due primarily to differences in the size or density or density of the components of the mix, the smaller and/or denser particles concentrating at the base of a container with the larger and or less dense above them. An idea granulation will contain all the constituents of the mix in the correct proportion in each granule, and segregation of the ingredients will not occur. Figure 1: Different granulation procedures Types of Granulation 4 : Granulation methods can be divided into two types: Wet granulation Dry granulation Wet granulation: Wet granulation involves the massing of a mix of dry primary powder particles using a granulating fluid. The fluid contains a solvent which must be volatile so that it can be removed by drying and be non toxic. Typical liquids include water, ethanol and isopropanol, either alone or in combination. The granulation liquid may be used alone or, more usually, as a solvent containing a dissolved adhesive (also referred to as binder or binding agent) which is used to ensure particle adhesion once the granule is dry. In the traditional wet granulation method the wet mass is forced through a sieve to produce wet granules which are then dried. A subsequent screening stage breaks agglomerates of granules and removes the fine material, which can then be recycled. Variations of this traditional method depend on the equipment used, but the general principle of initial particle aggregation using a liquid remains in all of the processes. Dry granulation: In the dry methods of granulation the primary powder particles are aggregated under high pressure. There are two main processes. Either a large tablet (known as slug)is produced in a heavy-duty tabletting press (a process known as slugging) or the powder is squeezed between two rollers to produce a sheet of material(roller compaction). In both cases these intermediate products are broken using a suitable milling technique to produce granular material, which is usually sieved to separate the desired size fraction. The unused fine material 72

4 may be reworked to avoid waste. This dry method may be used for drugs that do not compress well after wet granulation, or those which are sensitive to moisture. 5 Direct compression: Tablet production by direct compression involves two operations: Powder mixing Tabletting Direct compression process assumes that all materials can be purchased or manufactured to specifications that allow for simple blending and tabletting. The most obvious advantage of direct compression is economy. Although a number of pieces of equipment such as granulators and dryers are not needed in preparing tablets by direct compression, there may be a need for greater sophistication in the blending and compressing equipment. The most significant advantage in terms of tablet quality is that of processing without the need for moisture and heat which is inherent in most wet granulation and the avoidance of high compaction pressures involved in producing tablets by slugging or roll compaction. In addition of primary problem of stability of the active ingredients the variabilities encountered in the process of granulation can lead to innumerable tabletting problems. In direct compression all of the disintegrants is able to perform optimally, and when properly formulated, tablets made by direct compression should disintegrate rapidly to the primary particle state. It is important to use disintegrants to separate each drug particle if ideal dissolution is to occur. Prime particle disintegration in direct compression tablets depends on the presence of sufficient disintegrating agent and its uniform distribution though out tablet matrix. MATERIALS & METHODS: Formulation of Paracetamol Tablets: Table 1: Composition of the tablets S.No Ingredients Quantity (Mg) 1 Lactose 50 2 Paracetamol Microcrystalline cellulose Talc 5 5 Magnesium stearate 5 6 Corn starch q.s Note: q.s quantity sufficient Wet Granulation (F1) 6 Paracetamol, lactose and micro crystalline cellulose were weighed and were size reduced in a mortar by grinding. Starch paste was prepared, by dispersing starch in water and heated till mucilage formation occurred. Mucilage was then added to the fine grinded powder until a wet coherent mass was obtained. The coherent mass was sieved through sieve number 16 and dried at 60 0 C in hot air oven. Dry Granulation (F2) 7 Paracetamol, Microcrystalline cellulose and other excipients were weighed. All the ingredients were mixed in the mortar and grinded. The powder mass was punched into tablets. The compressed tablets are again crushed in mortar and sieved. Thus the granules are obtained by dry granulation. Direct Compression (F3) 8 Paracetamol, microcrystalline cellulose and other excipients were weighed. All of the ingredients were mixed in the mortar and grinded and taken up for compression Evaluation of Granules: The prepared granules were analyzed for Bulk density, tapped density, Carr s index, Hausners ratio and Loss on drying. 73

5 Bulk density and Tapped density: An accurately weighed quantity of the granules (w), was carefully poured into the graduated cylinder and the volume (v0) was measured. The graduated measuring cylinder was tapped for 100 times and after that, the volume (Vf) was measured and continued the operation till the two consecutive readings were equal. Bulk density and tapped density determines the flow properties of the formulation. Bulk density=w/vo Tapped density=w/vf Where, W = weight of powder V 0= Initial volume V f=final volume Carr s Compressibility index: The porosity of the tablet produced under a certain compressive load was a function of initial porosity of the packing in the die. One of the simplest expressions of this packing tendency was compressibility index described in the equation Carr (%) = [{Tapped density-bulk density}/tapped density] X 100 Table 2: Compressibility and Flow properties % Compressibility Flow < 10 Excellent Good Fair >20 Very Poor Hausner s ratio It is a number that is correlated to the flowability of a granular material. It is a measure of tapped density by bulk density. Hausner s ratio = Tapped density/bulk density Loss on drying: The granules were dried at 60 0 C for 3 hours and weight loss on drying was determined. Evaluation of tablets: All the formulations were evaluated for weight variation, friability, hardness, disintegration time, in vitro dissolution test. 9, Weight variation: It is desired that every individual tablet in a batch is uniform in weight and weight variation of any tablet is within permissible limits. (10% for tablets weighing 80 mg or less 7.5% for tablets weighing between 80mg to 250mg, 5% for tablets weighing 250gm or more). Non uniformity in weights may lead to variation in dosing. Formulated paracetamol tablets were tested for weight uniformity. Twenty tablets were selected at a random, weighed collectively and individually. From collective weight average weight was determined. Then each tablet was compared with average weight to ascertain whether it is within permissible limits or not. The results are given in the table 2. Friability: Friability test is carried out to assess the ability of tablets to withstand abrasion in packing, handling and transportation. The Roche friability test apparatus was used to determine the friability of the tablets. This device subjects the tablets to the combined effect of abrasions and shock in a plastic chamber revolving at 25rpm. 10 pre weighed tablets were placed in the apparatus and were subjected to 100 revolutions, after which the tablets were reweighed. The percentage friability was calculated. 3. Hardness: Hardness of a tablet is indicative of its tensile strength and was measured in terms of low pressure required to crush it when placed between plungers. Hardness test is done to find out the 74

6 strength of a tablet to withstand mechanical strength of a tablet encountered during the production, packing, stripping and handling. The tester consists of a barrel containing a compressible spring held between two plungers. The lower plunger was placed in contact with the tablet and zero reading was taken. The upper plunger was forced against the spring by turning a threaded bolt until the tablet fractured. As the spring was compressed a pointer rids along a gauge in the barrel to indicate the force. Hardness or tablet crushing strength (the force required to break a tablet) was measured using Monsanto hardness tester. 4. Disintegration test: Disintegrating test determines whether tablets or capsules disintegrate with in a prescribed time when placed in a liquid medium under the prescribed experimental conditions. The disintegration time was measured using USP disintegration test apparatus. A tablet was placed in each of the 6 tubes of the apparatus maintained at 37 0 C ± C taking distilled water as medium. The time taken for complete disintegration of the tablet was measured. 5. In vitro dissolution studies: Development of dissolution method for fast dissolving tablets is comparable to the approach taken for conventional tablets.usp-2 paddle apparatus is the most suitable and common choice for fast dissolving tablets with the paddle speed of 50rpm commonly used. The USP-1 basket apparatus may have certain application for orally dissolving tablets, but is used less frequently due to physical properties of the tablets. Specifically tablet fragments are disintegrated tablet masses may become trap on the inside top of the basket at the spindle where little or no effective stringing occurs yielding irreproducible dissolution profile. In vitro dissolution studies for all the compressed tablets were carried out using USP paddle method at 50 rpm in 900 ml of 6.8 buffer at 37 0 ± C. Samples were withdrawn at definite time intervals, filtered through whatmann filter paper and assayed spectrophotometrically at 257nm using UV spectrophotometer. An equal volume of fresh medium was replaced into the dissolution medium after each sampling to maintain the constant volume throughout the test. 6. Assay: 20 tablets were weighed and crushed into fine powder. Accurately weighed powder was taken in 100 ml volumetric flask, 25 ml of 0.1M sodium hydroxide and 25ml of water was added. It was shaken for 15 min and made up to 100ml with water and filtered. 10 ml of the filtrate was pipette into 100ml volumetric flask and made up with water and again 10 ml of resulting solution was pipette and 10 ml of 0.1M sodium hydroxide was added, made up to 100 ml. The absorbance was measured at 257 nm and the amount of paracetamol was calculated. RESULTS & DISCUSSION: The obtained micrometric properties of granules are given in Table 3. The bulk density of all the powders was between and tapped density was between The Carr s index was within the range of 10 only for granules prepared by wet granulation showing excellent flow. For granules prepared by dry granulation and direct compression it was found to be between This indicates that dry granulation produces granules with good flow properties and that by direct compression are fair in grading. Table 3: Properties of powder S.No Batch Bulk density (g/ml) Tapped Density (g/ml) Carr s Index (%) Hausner s ratio Loss on drying (%) 1 F1 0.82± ± ± ± F2 0.63± ± ± ± F3 0.57± ± ± ± Note: All values are expressed as mean ±SD, n=3 75

7 Evaluation of tablets: The results are shown in Table 4. The tablets prepared by different methods were evaluated for weight variation, hardness and friability and disintegration time (DT). Hardness for the F1 formulation was between kg/cm while for F2 it was found to be kg/cm and for F3 was between kg/cm. It was seen that the hardness for F1 was the greatest while this was followed by F2 and then F3 formulations respectively. Similarly, based on the results of hardness, the friability was also high for F3 followed by F2 and then F1. The disintegration time for F1 was found to be 14 minutes, while disintegration time for F2 and F3 were found to be 3 minutes and 1 minute respectively. This was due to the formation of stronger bonds between particles in wet granulation process. Table 4: Evaluation of tablets prepared by different granulation methods Hardness Friability (kg/cm) (%) S.No Batch Weight Variation (%) Disintegration Time (min) Assay (%) 1 F % 2 F % 3 F % The assays for all the formulation were within limits as per IP limits. The percentage of drug released at the end of 60 min in case of F1 was 40.6, F2 was 44.6 %, and F3 was 99.8 %. The dissolution profiles of the formulations are shown in Table 5 and represented graphically in Figure 2. It is seen that the dissolution of Paracetamol for F3 is the highest as compared with that of F2 which is followed by F1. This is due to the formation of weak bonds between the particles in case of direct compression and dry granulation as opposed to wet granulation process. Table 5: Dissolution profile of formulations (F1 to F3) Time (min) % Drug Release F1 F2 F ± ± ± ± ± ± ± ± ± ± ± ±0.2 Note: All values are expressed as mean ±SD, n=3 Figure 2: in vitro dissolution profile of F1, F2 and F3 76

8 CONCLUSION: In the present study, efforts have been made to develop paracetamol tablets by different methods of granulation. The various granulation techniques include Wet granulation, Dry granulation and Direct compression. The various granulation techniques have different effect on the tablet properties such as hardness, friability, weight variation, disintegration time and in vitro dissolution. The comparison of drug release profile of different formulations showed that dissolution of Paracetamol prepared by Direct Compression is highest as compared with that of tablets prepared by Dry Granulation and Wet Granulation. This is due to the formation of weak bonds between the particles in case of direct compression and dry granulation as opposed to wet granulation process. ACKNOWLEDGEMENT: We deeply indebted grateful to Aurobindo Pharma Ltd, Hyderabad for providing gift sample of paracetamol. We are deeply thankful to the Management of C.L Baid Metha College of Pharmacy, Chennai for granting us permission and encouraging to utilize the facilities in the college premises and support to bring this research in an effective way. REFERENCES: 1. Gohel M. A Review of Co-processed Directly Compressible Excipients. J Pharm Pharmaceut Sci. 2005; 8(1): Lachman L, Lieberman H, Kanig J. Granulation: In the Theory and Practice of Industrial Pharmacy. Edn 3. Verghese Publishing House, Bombay, pp Solanki H, Basuri T, Thakkar J, Patel C. Recent advances in granulation technology. Int J Pharm Sci Rev Res. 2010; 5(3): Shah K, Hussain M, Hubert M, Farag S. Form Conversion of Anhydrous Lactose during Wet granulation and its Effect on Compactibility. Int J Pharm. 2008; 357: El-say K, Refaey T, Samy A, Badawy A. Comparative Study among Different Techniques to Improve the Physical and Technical Properties Prevailing to Compression of Poorly Flowing and Highly Cohesive Drug. Int J Pharm Sci Rev Res. 2010: 4(1): Litster, J.D., Hapgood, K.P., Michaels, J.N., Sims, A., Roberts, M., Kameneni, and Hsu, T., Liquid distribution in wet granulation: dimensionless spray flux. Powder Technol. 114 (1-3) DE Wurster. J AM Pharm Assoc Sci 1960; 49: Chaudhari PD. Melt Granulation Technique: A Review. Pharmainfo.net. 2006; 4 (1). 9. Ismat U, Jennifer W. Moisture-activated dry granulation: The one pot process.pharma Tech Eur 2010; 22(3). 10. Holm P, Jungersen O, Schæfer T, Kristensen HG. Granulation in high speed mixers. Part I: Effect of process variables during kneading. Pharm Ind 1983;45: