| Abstract|| |
The aim of this study was to evaluate the effect of increasing crospovidone (superdisintegrant) load on the characteristics of fast-disintegrating tablets for the potential use of the drug for its therapeutic effect. Five tablet formulations, F 0 , F 1 , F 3 , F 7 , and F 10 containing 0%, 1%, 3%, 7%, and 10% (w/w) of crospovidone, respectively, frusemide and microcrystalline cellulose (PH102), were prepared by direct compression, at a different compression forces. Tablet weight variation, content uniformity, crushing strength, disintegration time, wetting time, and in vitro release were measured for each formulation at each compression force. A linear increase in compression force resulted in an exponential increase in hardness for all formulations, a linear increase in disintegration and wetting times was observed for the formulations F 0 , F 1 , F 3 with the increase in compression force. The tablet formulation F 7 indicated, there was no effect of compression force on disintegration and wetting time. The in vitro release of the drug was increased with increase in concentration of crospovidone irrespective the compression force. However, storage under high humidity conditions caused the softening of the tablets containing the high amount of crospovidone, leading to softening of tablets. Fast disintegration of the tablets within 1-2 min is prerequisite for improving the dissolution of frusemide, attributed to increase in speed at which maximum surface area of sparingly soluble drug is exposed to the dissolution medium. However, tablet containing high amount of crospovidone must be protected from the atmospheric moisture because storage of these tablets at high humidity led to softening and losing the tablet characteristics.
Keywords: Compression force, crosspovidone, disintegration, relative humidity, dissolution
|How to cite this article:|
Chaulang GM, Patil KS, Ghodke DS, Yeole PG, Bhosale AV, Hardikar SR. Effect of some physical parameters and crospovidone on directly compressed frusemide tablets. Asian J Pharm 2008;2:235-40
|How to cite this URL:|
Chaulang GM, Patil KS, Ghodke DS, Yeole PG, Bhosale AV, Hardikar SR. Effect of some physical parameters and crospovidone on directly compressed frusemide tablets. Asian J Pharm [serial online] 2008 [cited 2013 Jun 19];2:235-40. Available from: http://www.asiapharmaceutics.info/text.asp?2008/2/4/235/45038
| Introduction|| |
A rapid onset of action of any drug is required in so many diseased conditions to get desired pharmacological response. For a rapid onset of action, fast dissolution and absorption are primary objectives for any dosage form. The tablet dosage forms are very popular among the other dosage forms, showing the need of fast dispersion of drug for rapid dissolution and absorption.  The development of fast dispersible tablet using superdisintegrant has become popular for various reasons. Theoretically, for improvement of dissolution can be achieved by increasing the surface area of the drug by micronization. This phenomenon was attributed to the agglomeration tendency of micronized, poorly soluble, hydrophobic drugs, which effect results in a decreased effective surface for dissolution. ,, For tablet containing sparingly water soluble drugs, the start of dissolution is often delayed by poor wettability of tablet or slow liquid penetration into tablet matrix. , This causes increase in disintegration time and retards the drug release. This can be overcome by addition of superdisintegrant. The shorter disintegration time requirement stimulated continuous efforts in the search for new, more efficient disintegrating agents. ,, Wicking and swelling were found to be the primary mechanisms of action for tablet disintegrants, while other mechanisms, such as deformation recovery, particle repulsion theory, heat of wetting and evolution of a gas etc; may play a role in particular cases of tablets disintegration.  Potential disadvantages of use of disintegrant in tablet formulation, using direct compression as the method of manufacture are - (1) high concentration needed for optimum disintegrating efficiency, (2) poor disintegration, (3) susceptibility to high compression forces which decrease the efficiency, (4) poor compression properties, and (5) decreased disintegrating efficiency in hydrophobic formulations.  A group of superdisintegrants including crosscamellose sodium ( Ac-Di-Sol ) sodium starch glycolate ( Primojel and Explotab ) and crosspovidone ( Polyplasdone XL ) alleviate most of these problems.  Use of the superdisintegrants in fast dispersible tablet is possible as tablet shows optimum physical properties. Factors affecting disintegrant efficiency include tablet solubility,  tablet hygroscopicity, ,, compression force, ,, and storage under high relative humidity.  All the factors are related to accessibility of liquid molecules to disintegrant particles inside the tablet. ,
Furosemide is a loop diuretic and effectively used in problems like hypertension, the drug having low solubility and low bioavailability, hence classified as class IV drug as per biopharmaceutical system. The purpose of this study was to determine the effect of concentration of crosspovidone, compression pressure, and relative humidity on directly compressed furosemide tablet properties like hardness, wetting time, disintegration time, and dissolution profile. The furosemide was chosen for this work because it was proved by several researchers that excipient and processing factors affect the dissolution profile of furosemide. ,,
| Materials and Methods|| |
Furosemide was supplied as gift sample from Samruddha Pharmaceuticals, Thane, Mumbai, Avicel (PH 102) was supplied as gift sample from F.M.C. Biopolymer, Ireland and Crosspovidone from ISP Technologies, INC. Wayane, NJ. All other excipient were of analytical grade.
Standard calibration curve of furosemide
Solutions ranging from 2 to 20 µ g/ml were prepared in simulated gastric fluid (pH 1.2 without enzyme). Absorbance was measured at lmax 274 nm using, double beam UV visible spectrophotometer Model No. UV 2401 PC Shimadzu Corporation, Koyto, Japan.
Formulation of tablets of furosemide
All ingredients were passed through sieve No.100, and blended in glass mortar uniformly. After sufficient mixing of all components, magnesium stearate was added and again mixed for additional 2-3 min. The tablets were compressed using 8 mm flat punch on 16-station rotary tablet compression machine (Type - CMD3 - 16, Cadmach Machinery Pvt. Ltd., Ahamadabad). Each blend was compressed at different compression pressures i.e., 3, 5, 7, and 9 tons at 18 rpm speed. The composition of each formulation using crospovidone as superdisintegrant and Avicel (PH102) as a diluent is given in [Table 1].
Stability study of tablets
The tablets of F 7 batch (containing 7% w/w crospovidone concentration) were stored under different humidity conditions at 25°C for 3 months. The humidity chambers were developed in desiccators by using saturated salt solutions. The tablets were stored in glass petri-dishes similar to condition described as 'open dish' method for stability testing. The following humidity conditions were used for storage of tablets according to climatic zones of the world, specified by ICH guidelines. Zone-I (21°C, 45% relative humidity [RH]), zone-II (25°C, 60% RH), zone-III (25°C, 35% RH) and zone-IV (30°C, 70% RH). ,,
Evaluation of tablet
The tablets were evaluated before keeping at different humidity conditions as well as after three months storing at different humidity conditions. The tablets were evaluated for different parameters viz. weight variation, drug content, disintegration time, crushing strength, wetting time and in vitro release of the drug. The results are reported in [Table 2].
The weight variation study was performed as per the method specified in IP 1996. 
The drug content of all formulated batches was determined as per the procedure specified in IP.  Twenty tablets were weighed accurately and powdered. Powder equivalent to 0.1 g of furosemide was taken to 150 mL of 0.1 M NaOH and shaken for 10 min. To the mixture, 0.1 M NaOH was added again to produce 250 mL. The resultant solution was filtered through Whatman filter paper no. 42. The 5 mL of this solution was taken and diluted up to 200 mL with 0.1 NaOH and the absorbance of resulting solution was measured at 271 nm. A 1% cm value was 580 at 271 nm.
Crushing strength was measured diametrically, using Campbell Electronic Tablet tester. The tablets from each batch were taken and kept on horizontal surface of the jaw of machine, and tablets were crushed mechanically with automatic working and direct reading for the crushing strength was obtained digitally. For each batch three tablets were tested. 
Disintegration test was carried out as described under procedure for uncoated tablets in IP. One tablet each was placed in each of six tubes of the basket of the assembly. Apparatus was operated using water, maintained at 37±2°C as the immersion fluid. 
Wetting time was determined by procedure similar to the one used by Aly AM, et al . A two-fold piece of tissue paper was kept in small culture dish (i.d. - 6.5 cm) containing 6 mL water. A tablet for testing was kept on tissue paper and time required to wet the whole tablet was measured and recorded as the wetting time. 
In vitro dissolution study
The dissolution was studied using USP apparatus II taking 900 ml of dissolution medium, simulated gastric fluid without pepsin (pH 1.2) for one hour. The rotational speed of the paddle was set at 50 rpm at 37±0.5°C. The 5 mL of aliquots was withdrawn at predetermined time interval for every 2, 4, 6, 8, 10, 15, 20, 25, 30, 40, 50, and 60 min and maintaining sink condition. The samples were analyzed for drug content using double beam UV spectrophotometer (Model No. UV 2401 PC Shimadzu Corporation, Koyto, Japan) at 274 nm. The in vitro dissolution study was carried out in triplicate for each formulated batch. 
| Result and Discussion|| |
Primarily the tablets were evaluated for weight variation and content variation and found to be satisfactory as per official standards. The crushing strength of the tablets formulation increased with increasing compression force as shown in [Table 2]. Crushing strength of tablets clearly describes a certain mechanical property of a whole tablet. Crushing strength is obviously a parameter which can be related quite directly to the compression force used as shown in [Table 2]. The disintegration time of the tablet was also increased with increase in compression pressure, and the effect was observed up to the 7% (w/w) concentration of crospovidone. The increase in disintegration time with an increase in compression force may be because of decreased porosity hence reduced penetration of dissolution medium in tablet bulk.  At higher concentration of superdisintegrant 10% (w/w) the disintegration time of the tablet was constant irrespective of compression pressure, though crushing strength was increased with increase in compression force. The results are shown in [Table 2].
The wetting time of tablet was increased with increase in compression pressure as there was decrease in porosity of the tablet, but the effect was leveled off after 7% (w/w) concentration of crospovidone. The results are shown in [Table 2].
In vitro dissolution studies of tablets from each batch were carried out. The percent cumulative drug release at compression force 3 tons, containing 0, 1, 3, 7, and 10% w/w concentration of disintegrant are shown in [Table 2],[Figure 1],[Figure 2],[Figure 3],[Figure 4],[Figure 5]. It was observed that with increase in concentration of superdisintegrant, the release rate of drug was increased. This may be, because of the increase in concentration of superdisintegrant, the particles were exposed to dissolution medium at comparatively faster rate. The presence of the superdisintegrant in dissolution medium kept the drug particles in dispersed condition i.e., agglomeration of drug particles was avoided and also promoted the wetting of dispersed particles due to fixation of hydrophobic drug particles upon hydrophilic crosspovidone during the tabletting process. 
The cumulative percent drug release of batch F 3 (containing 3% of disintegrant) and F 7 (containing 7% of disintegrant) at compression forces 3, 5, 7, and 9 tons are shown in [Table 2],[Figure 3] and [Figure 4]. It was observed that, the drug release was decreased with increase in compression force at fixed concentration of disintegrant, because the increase in compression force decreases the porosity of the tablet.
The in vitro dissolution study showed that there was no significant difference in dissolution profile of batch F 7 . The results are shown in [Table 3],[Figure 6],[Figure 7],[Figure 8],[Figure 9].
From all the above data, as the tablet of F 7 batch (containing 7% w/w crospovidone concentration) showed the critical results, at this concentration the disintegration rate was maximum at different compression pressures viz. 3, 5, 7, and 9 tons. These tablets were selected for the stability studies.
After 3 months, the tablets were evaluated for its physical properties like crushing strength, disintegration time, and wetting time. Also the dissolution study was carried out.
The crushing strength, disintegration time, and wetting time of tablet was observed to be decreased for the tablets stored under the conditions of zone II (60% RH) and zone IV (70% RH), while there was not significant difference for the tablets stored under the conditions of zone I (45% RH) and zone III (35% RH). This was observed as the tablets get soften by absorbing the moisture in humidity zones II and IV. The results are shown in [Table 3].
| Conclusion|| |
From the study for physical properties and dissolution profile of tablets it was concluded that there was increase in dissolution of drug with increase in the concentration of superdisintegrant (crosspovidone) in tablet formulation. The significant difference was observed in dissolution profile between tablets containing 0% and 10% crospovidone.
It was also observed that at fixed concentration of crosspovidone the release of drug decreased as compression pressure was increased.
The above findings showed the need of superdisintegrant for better dissolution of poorly soluble drugs like furosemide. Also tablets stored under different humidity conditions showed softening and indicated the need of proper packaging for the tablets to be marketed in higher humidity zone (II and IV).
| Acknowledgement|| |
The authors thank Samruddha Pharmaceuticals, Thane, Mumbai, for providing the gift sample of furosemide
| References|| |
|1.||McGinity JW, Stavchansky SA, Martin A. Bioavilability in tablet technology. In: Lieberman HA, Lachaman L, editors. Pharmaceutical dosage forms: Tablets, Vol. 2. New York: Marcel Decker Inc; 1981. p. 307-69. |
|2.||Aguir AJ, Zelmer AJ. Deagglomeration behavior of a relatively in soluble benzoic acid and its sodium salt. J Pharm Sci 1967;56:1243-52. |
|3.||Finholt P, Solvang S. Dissolution Kinetics of drugs in human gastric juice-the role of surface tension. J Pharm Sci 1986;57:1322-6. |
|4.||Lin SL, Mening J. Intedependence of physiological surfactant and drug particles size on the dissolution behavior of water in-soluble drugs. J Pharm Sci 1986;57:2143-8. |
|5.||Chebli C, Cartilier L. Effect of some physical parameters on the sustained drug-release properties of substituted amylose matrices. Int J Pharm 2000;193:167-73. [PUBMED] [FULLTEXT]|
|6.||Rambali B, Baert L, Jans BE, Massart DL. Influence of the roll compactor parameter settings and the compression pressure on the buccal bio-adhesive tablet properties. Int J Pharm 2001;220:129-40. |
|7.||Baichawal MR, Moghe BD. Modified cellulose as tablet disintegrant. Indian J Pharm 1971;33:29-31 |
|8.||Deshapande AV, Panya LB. Evaluation of sorghum starch as a tablets disintegrant and binder. J Pharm Pharmacol 1987;39:495-6. |
|9.||El-Khawas M, El-Khodairy KA. Comparative evaluation of plum gum as tablet disintegrant. Acta Pharm 1995;4:539-50. |
|10.||Kanig JL, Rudnic EM. The mechanisms of disintegration action. Pharm Tech 1984;4:50-63 |
|11.||Andries FM, Mingna S, de Villiers MM. Effect of compression force, humidity and disintegrant concentration on the disintegration and dissolution of directly compressed furosemide tablets using croscarmellose sodium as disintegrant. Trop J Pharma Res 2003;2:125-35. |
|12.||Munoz N, Ferrero C, Velasco MV. Effect of Explotab on the tablet ability of a pooly soluble. Drug Dev Ind Pharm 1998;24:785-91. |
|13.||Fitzpatrick AS, James F, McCabe B, Catherine RP, Bootha SW. Effect of moisture on polyvinyl pyrrolidone in accelerated stability testing. Int J Pharm 2002;246:143-51. |
|14.||Nokhodchi A, Rubhinstein MH. The effect of moisture on the properties of ibuprofen tablets. Int J Pharm 1995;118:191-7 |
|15.||Lopez-Solis J, Villafuerte-Robles L. Effect of disintegrants with different hygriscopicity on dissolution of norfloxacin/Pharmatose DCL 11 tablets. Int J Pharm 2001;216:127-35. |
|16.||Khan KA. Concept of dissolution efficiency. J Pharm Pharmacol 1975;27:48-9. [PUBMED] |
|17.||Khan KA, Rhodes CT. Effect of compaction pressure on the dissolution efficiency of some direct compression systems. Pharm Acta Helv 1972;47:594-607. [PUBMED] |
|18.||Adel MA, Semreen M, Mazen KQ. Superdisintegrants for solid dispersion: To produce rapidly disintegrating Tenoxicam tablets via camphor sublimation. Pharm Tech 2005;32:68- 78. |
|19.||Ferrero C, Mufioz N, Velasco MV, Mufioz-Ruiz AR, Jimnez-Castellanos. Disintegrating efficiency of croscarmellose sodium in a direct compression formulation. Int J Pharm 1997;147:11-21. |
|20.||Rubenstein MH, Rughani JM. The effect of four particle characteristics on the dissulion rate, tablet binders on bioavailability of frusemide. Drug Dev Ind Pharm 1989;15:621-7. |
|21.||Akbuga J, Gursoy A. Studies on frusemide tablet I Dissolution of commercial products and different formulations. Drug Dev Ind Pharm 1987;13:2199-208. |
|22.||Akbuga J, Gursoy A. Studies on frusemide tablet II Influence of weight mixing time, binder volume and batch variation on dissolution rate. Drug Dev Ind Pharm 1987;13:2541-52. |
|23.||Fitzpatrick AS, James F, McCabe B, Catherine RP, Bootha SW. Effect of moisture on polyvinyl pyrrolidone in accelerated stability testing. Int J Pharm 2002;246:143-51. |
|24.||Cartensen JT. Drug stability: Principle and practice, 2 nd ed. New York: Marcel Dekker; 1995. p. 538-50. |
|25.||Sarisuta N, Parott EL. Effect of temperature, humidity and aging on the disintegration and dissolution of acetaminophen tablets. Drug Dev Ind Pharm 1988;14:1877-81. |
|26.||Indian Pharmacopoeia. Vol. 2. Delhi: Controller of Publications; 1996. p. 735-6. |
|27.||Riippi M, Osmo A, Tapani N, Jouko Y. The effect of compression force on surface structure, crushing strength, friability and disintegration time of erythromycin acirstrate tablets. Eur J Pharm Biopharm 1998;46:339-45. |
|28.||Indian Pharmacopoeia. Vol. 1. Delhi: Controller of Publications; 1996. p. 332. |
|29.||Adel MA, Semreen M, Mazen KQ. Superdisintegrants for solid dispersion: To produce rapidly disintegrating Tenoxicam tablets via camphor sublimation. Pharm Tech 2005;32:68-78. |
|30.||De Villiers MM, van der Watt JG. Dissolution from ordered mixtures: The effect of stirring rate and particle characteristics on the dissolution rate. Drug Dev Ind Pharm 1989;15:621-7. |
|31.||Julid A, Gursoy A. Studies of furosemide tablet II: Influence of wet-mixing time, binder volume and batch variation on dissolution rate. Drug Dev Ind Pharm 1987;13:2541-52. |
|32.||Makiko F, Hideko O, Yu Suke S, Honami T, Masuo K, Yoshiteru W. Preparation, characterization, and tableting of a solid dispersion of indomethacin with crospovidone. Int J Pharm 2005;293:145-53. |
Ganesh Mahadev Chaulang
SGRS College of Pharmacy, Saswad, Pune, Maharashtra - 412 301
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9]
[Table 1], [Table 2], [Table 3]