FORMULATION AND EVALUATION OF HYDROCHLOROTHIAZIDE AND RAMIPRIL MOUTH DISSOLVING TABLET USING DIFFERENT SUPERDISINTEGRANTSHTML Full Text
Received on 14 August, 2013; received in revised form, 19 September, 2013; accepted, 26 December, 2013; published 01 January, 2014
FORMULATION AND EVALUATION OF HYDROCHLOROTHIAZIDE AND RAMIPRIL MOUTH DISSOLVING TABLET USING DIFFERENT SUPERDISINTEGRANTS
R. Vani* and Anas Rasheed
School of Pharmacy, Deccan Group of Institutions, Aghapura, Nampally, Hyderabad-500001, Andhra Pradesh, India
ABSTRACT: The purpose of this research was to develop mouth dissolve tablets of Hydrochlorothiazide and Ramipril, were prepared by direct compression technique. Ramipril is an Angiotensin Converting Enzyme (ACE) inhibitor. It is an inactive prodrug that is converted to ramiprilat in the liver, the main site of activation, and kidneys. Thiazides such as hydrochlorothiazide promote water loss from the body (diuretics). They inhibit Sodium and Chlorine (Na+ and Cl-) reabsorption from the distal convoluted tubules in the kidneys. The tablets were prepared using microcrystalline cellulose and dicalcium phosphate as diluents along with three different levels of disintegrant. The superdisintegrant used in this study were CCS and Maize Starch. The tablets were evaluated for weight variation, hardness, friability, wetting time, water absorption ratio, disintegration time (DT) and dissolution study. Formulation prepared with 30% of CCS showed Disintegration time of 20seconds in vitro. Also the hardness, friability, dissolution rate of prepared tablets (batch F4) was found to be acceptable according to standard limits.
Ramipril, Hydrochlorothiazide, Superdisintegrants, Direct compression
INTRODUCTION:The antihypertensives are a class of drugs that are used to treat hypertension. Evidence suggests that reduction of the blood pressure by 5 mmHg can decrease the risk of stroke by 34%, of ischaemic heart disease by 21%, and reduce the likelihood of dementia, heart failure, and mortality from cardiovascular disease. There are many classes of antihypertensives, which lower blood pressure by different means; among the most important and used in the present study are the thiazide diuretics and the Angiotensin Converting Enzyme (ACE) inhibitors 1-12.
The type of medication to use initially for hypertension has been the subject of several large studies and resulting national guidelines. The fundamental goal of treatment should be the prevention of the important endpoints of hypertension, such as heart attack, stroke and heart failure.
Patient age, associated clinical conditions and end-organ damage play a part in determining dosage and type of medication administered. The several classes of antihypertensive differ in side effect profiles, ability to prevent endpoints, and cost. As of 2009, the best available evidence favors the thiazide diuretics as the first-line treatment of choice for high blood pressure when drugs are necessary. An Angiotensin Converting Enzyme (ACE) inhibitor is recommended by National Institution of Healthcare and Excellence (NICE) in the UK for those under 55 years old 13-28.
Ramipril is an angiotensin-converting enzyme (ACE) inhibitor, used to treat high blood pressure and congestive heart failure. Ramipril is an Angiotensin Converting Enzyme (ACE) inhibitor similar to benazepril, fosinopril and quinapril. It is an inactive prodrug that is converted to ramiprilat in the liver, the main site of activation, and kidneys. Ramiprilat confers blood pressure lowering effects by antagonizing the effect of the Renin-Angiotensin-Aldosterone System (RAAS).
Hydrochlorothiazide, abbreviated HCTZ, HCT, or HZT, is a diuretic drug of the thiazide class that acts by inhibiting the kidneys' ability to retain water. This reduces the volume of the blood, decreasing blood return to the heart and thus cardiac output and, by other mechanisms, is believed to lower peripheral vascular resistance 29-37.
MATERIALS AND METHODS: Ramipril and Hydrochlorothiazide were obtained as gift sample by Aurobindo Pharma and Hetero Pharma labs, Hyderabad, India. Dicalcium Phosphate, Magnesium Stearate, Mannitol, Maize Starch, Ferric Oxide, Ascorbic Acid, Butylated Hydroxyanisole, Butylated Hydroxytoulene, Croscarmellose sodium, Microcrystalline and Cellulose were also obtained from S.R. pharmaceuticals Ltd. Hyderabad. All other chemicals used were of suitable analytical grade.
METHODS: Ramipril & Hydrochlorothiazide were prepared by Direct Compression method. All the formulations contained 5 mg of Ramipril and 12.5 mg of Hydrochlorothiazide and by using different superdisintegrants. Various batches prepared shown in Table 1. All the ingredients were passed through 20-mesh sieve separately and collected, finally compressed into tablets after lubrication with magnesium stearate (1.5%) and talc (2.5%) by using 8 mm flat bivel edged punch using RIMEK 8 station tablet compression machine. The mixture was compressed into 50-mg tablets. The prepared tablets were evaluated for various parameters like hardness, friability, wetting time, uniformity of dispersion, disintegration time, and dissolution study.
Table 1: Batches prepared using different concentration of each disintegrant.
Evaluation of the granules:
- Angle of repose: The angle of repose of granules was determined by the funnel method. The accurately weighed granules were taken in a funnel. The height of the funnel was adjusted in such a way that the tip of the funnel just touched the apex of the heap of the granules. The granules were allowed to flow through the funnel freely onto the surface. The diameter of the powder cone was measured & angle of repose was calculated using the following equation: tanⱷ = h/r where, h & r are the height & radius of the powder cone.
- Bulk density: Both loose bulk density (LBD) & tapped bulk density (TBD) were determined. A quantity of 2 g of powder from each formula, previously lightly shaken to break any agglomerates formed, was introduced into a 10 ml measuring cylinder. After the initial volume was observed, the cylinder was allowed to fall under its own weight onto a hard surface from the height of 2.5 cm at 2 second intervals. The tapping was continued until no further change in the volume was noted. LBD & TBD were calculated using the following formulas:
LBD = weight of the powder / volume of the packing
TBD = weight of the powder / tapped volume of the packing
- Compressibility Index: The compressibility index of the granules was determined by Carr’s compressibility Index:
Carr’s index (%) = [(TBD – LBD) * 100] / TBD
Where: LBD = weight of the powder / volume of the packing
TBD = weight of the powder / tapped volume of the packing
Evaluation of the prepared tablets
- Weight uniformity: Twenty randomly selected tablets were weighed individually and the average weight and the standard deviation were calculated.
- Hardness: Hardness of the tablets was measured using Monsanto hardness tester.
- Friability: Friability of the tablets was determined using Roche friabilitor at 25 rpm/min for 4 min. Twenty tablets were weighed and loss in weight (%) was calculated.
- Wetting time and water absorption ratio: Procedures similar to those used by Bi Y et al were used to measure tablet wetting time and water absorption ratio. A piece of tissue paper folded twice was placed in a small culture dish (i.d. = 6.5 cm) containing 6 ml of water. A tablet was placed on the paper, and the time for complete wetting was measured. The wetted tablet was again weighed. Water absorption ratio, R, was calculated using the formula;
R = 100(Wa- Wb)/Wb
Where, Wa and W b are the weight after and before water absorption, respectively.
- Disintegration time (in vitro): The disintegration time for six tablets was measured, and the average time and standard deviation were calculated for each. Three batches for each disintegrant SSG, CCS with varying concentration were prepared and analyzed.
- Dissolution studies: For the dissolution studies, dissolution apparatus USP type II used for drug Ramipril and drug Hydro-chlorothiazide. One tablet was placed in each basket; Paddles rotated at 100 rpm in 900 ml o the dissolution medium (0.1 N HCl at37+0.50 C). The samples were withdrawn at suitable time interval. Samples were assayed by HPLC.
RESULTS AND DISCUSSION:
Physical properties of the formulation: The prepared tablets were evaluated for physical parameters such as, hardness was 3-4 kg/cm2 and friability was observed between 0.36-0.81%, which was below 1% indicating the sufficient mechanical integrity and strength of the prepared tablets (Table 2). Percent weight variation was observed between 1.8 and 3.6, well within the acceptable limit as per USP Wetting time and water absorption ratio was determined using the method described by Bi et al. (Table 2).
The results obtained by evaluating the powder blends of drug and excipients are shown in (Table 3). Values for angle of repose were found in the range of 24 to 27° showing that the blend of powder was free flowing and can be used for direct compression. The value for Carr’s index was less than 1, indicating that all the batches of powder blends were having good compressibility. Lower HR (<1.25) indicates better flow properties than higher ones (>1.25).
The result of in vitro disintegration of all the tablets were found to be within prescribed limit satisfies the criteria of Fast Dissolving Tablet. All the formulated tablets have shown in vitro dispersion time of less than 60sec, among all the formulations, F4 formulation prepared with Crosscarmellose were shows 20sec. of dispersion time. The comparison between the wetting time & disintegration time of all the formulation is showed in figure 3. There was no significant variation in the physicochemical parameters, in vitro disintegration time, and in vitro dissolution profiles after 1.5 months stability (table 4) study as per ICH guidelines Q1C. It was observed that formulations F1, F2 and F5 containing maize starch had higher water absorption ratio and take more time for wetting of tablets (Table 2).
Crosscarmellose had less wetting time and minimum water absorption ratio for hydrophilic combination of Ramipril and Hydrochlorothiazide. The disintegration times for formulation F1-F5 was compared (Table 2) that indicates the formulation (F4) containing Crosscarmellose disintegrated the fastest with no mass left and had good hardness.
TABLE 2: THE PHYSICAL PARAMETERS OF PREPARED FORMULATION:
|Formulation||Hardness Test (Kg/cm2)||Friability Test (%)||Weight Variation Test||Drug Content uniformity||Disintegration Time Sec||Wetting Time sec||Water Absorption ratio|
TABLE 3: PRE COMPRESSION EVALUATION PARAMETERS
|Formulation||Angle of repose||LBD||TBD||Carr’s index||HR||Test for dispersion|
TABLE 4: STABILITY DATA OF SELECTED FORMULATION (F4)
|Formulation code||Time (Days)||Hardness (Kg/cm2)||Friability||Disintegration Time (sec)||Drug content||Wetting time||Dissolution studies|
FIGURE 1: DISSOLUTION PROFILE FOR RAMIPRIL USING CCS AND MAIZE STARCH
FIGURE 2: DISSOLUTION PROFILE FOR HYDRO-CHLOROTHIAZIDE USING CCS AND MAIZE STARCH
FIGURE 3: COMPARISON OF WETTING TIME AND DISINTEGRATION TIME
CONCLUSION: Direct compression method can be considered as an important method for the formulation of fast dissolving. Various percentage of the superdisintegrant was also used to get best formulations with high bioavailability. Formulation having the better superdisintegrant will have better in vitro disintegration time and dissolution along with lesser friability and weight variation. The use of superdisintegrants for preparation of fast-dissolving tablet is to get dispersed in the mouth quickly and releases the drug early as compared to its formulated conventional tablet.
Figure 1 & 2 shows the cumulative percentage of ramipril and hydrochlorothiazide tablet with different concentration of CCS and Maize Starch released from formulation. It is clear that the dissolution has improved considerably in formulation F4 as compared to formulation F1, F2, F3, and F5. Thus, it may be concluded that the fast dissolving tablets of Ramipril and Hydro-chlorothiazide can be successfully prepared and undoubtedly the availability of various technologies and manifold advantages of fast dissolving tablets will surely enhance patient compliance and its popularity in the near future.
ACKNOWLEDGEMENT: The authors thank Dr. B. Vijaya Kumar, Principal, Jangaon Institute of Pharmaceutical Sciences, Jangaon, Warangal, India; and Dr. G. Krishna Mohan, Head & Professor, Center for Pharmaceutical Sciences, JNTU Hyderabad, India for their scientific help.
- R. Vani*, B. Vijaya Kumar, Anas Rasheed; Analytical Development And Formulation Of Ramipril And Hydrochlorothiazide In Combination With Selective Excipients, R. Vani, et al. Int J Pharm 2013; 3(2): 348-35
- Bi Y., Sunada H., Yonezawa Y., Danjo K., Otsuka A., Iida K., Preparation and evaluation of compressed tablet rapidly disintegrating in oral cavity. Chem. Pharm. Bull. 1996;44, 2121-27.
- P.S.Mohanchandran, P.G. Sindhumol ,T.S. Kiran. Superdisintegrants: an overview. IJPSRR. 2011;6(1):105-9.
- TejveerKaur, Bhawandeep Gill, Sandeep Kumar, G.D. Gupta. Mouth Dissolving Tablets: A Novel Approach to Drug delivery. Int J Curr Pharm Res. 2011;3(1):1-7.
- Shukla D, Chakraborty S, Singh S, Mishra B. Mouth dissolving tablets I: An overview of formulation technology. Sci Pharm 2009; 77: 309-26.
- Anantha Lakshmi Pallikonda, RavindarBairam, M. Motilal, MekalaShubashKumar. Formulation and Evaluation of Mouth Dissolving Tablets, Der Pharmacia Lettre, 2010: 2 (1), 342-46 .
- Tripathi KD; Essentials of Medical Pharmacology; 6th Ed (2008) Jaypee Brothers Medical Publishers(P )Ltd; 561-574.
- British Pharmacopoeia, H.M. Stationery Office, London, 2000, 1331.
- David A. Williams, William O. Foye, Thomas L. Lemke; Foye's principles of medicinal chemistry; 6th Ed (2008) Wolters Kluwer Health; 698-728.
- Ramipril: a review of its use in the prevention of cardiovascular outcomes, Warner GT, Perry CM. 2002; 62(9):1381-405; PMID:12076194
- Ramipril for the Prevention and Treatment of Cardiovascular Disease April D Vuong, PharmD, Laura G Annis, PharmD. Ann Pharmacother September 2004 38:S7; Published ahead of print June 29, 2004, doi:10.1345/aph.1E216
- Ramipril: A Review of its Use in Preventing Cardiovascular Outcomes in High-Risk Patients, Anderson, Vanessa R.; Perry, Caroline M.; Robinson, Dean M. American Journal of Cardiovascular Drugs:2006 - Volume 6 - Issue 6 - pp 417-432
- Comparison between nebivolol and ramipril in patients with hypertension and left ventricular hypertrophy: a Randomized Open Blinded End-point (ROBE) trial, Caglar N, Dincer I. 2011 Dec;15(12):1359-68. PMID:22288296.
- Effect of Telmisartan–Amlodipine Combination at Different Doses on Urinary Albumin Excretion in Hypertensive Diabetic Patients with Microalbuminuria, Roberto Fogari, Giuseppe Derosa, Annalisa Zoppi, Paola Preti, Pierangelo Lazzari, Maurizio Destro, Elena Fogari, Andrea Rinaldi and Amedeo Mugellini; Journal of cardiovascular pharmacology therapeutics; March 2012 17: 34-43, first published on February 18, 2011.
- Comparative effects of N-acetyl-L-cysteine and ramipril on arterial hypertension, insulin resistance, and oxidative stress in chronically glucose-fed rats, Adil El Midaoui, Mahmoud Ali Ismael, Huogen Lu, I. George Fantus, Jacques de Champlain, Rejean Couture. Canadian Journal of Physiology and Pharmacology (2008); Volume: 86, Issue: 11, Pages: 752-760; PubMed: 19011670.
- Benazepril. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in hypertension and congestive heart failure. Balfour JA, Goa KL. 1991 Sep; 42(3):511-39. PMID: 1720384.
- Hydrochlorothiazide versus Chlorthalidone Evidence Supporting Their Interchangeability, Barry L. Carter, Michael E. Ernst, Jerome D. Cohen. Hypertension. 2004; 43: 4-9 Published online before print November 24, 2003, doi: 10.1161/01.HYP.0000103632.19915.0E.
- Potassium and Cardiovascular Disease Thiazide Diuretics, Potassium, and the Development of Diabetes A Quantitative Review, Alan J. Zillich, Jay Garg, Sanjib Basu, George L. Bakris, Barry L. Carter. Hypertension; 2006; 48: 219-224 Published online June 26, 2006, doi: 10.1161/01.HYP.0000231552.10054.aa.
- Hydrochlorothiazide Versus Chlorthalidone in the Management of Hypertension, Kimberly M. Neff, Pharm D, and James J. Nawarskas, Pharm D, BCPS. Chobanian AV, Bakris GR, Black HR, et al. Seventh report of the Joint, Committee on prevention, detection, evaluation, and treatment of high blood pressure. Hypertension. 2003; 42:1206 –1252.
- Neutropenia in an infant secondary to hydrochlorothiazide therapy: with a review of hematologic reactions to "thiazide" drugs, Marilyn G. Schotland, Melvin M. Grumbach. Pediatrics; Vol. 31 No. 5 May 1, 1963 pp. 754 -757
- Metoprolol succinate extended release hydrochlorothiazide combination tablets James W Hainer and Jennifer Sugg. Vasc Health Risk Managment. 2007 June; 3(3): 279– 288. Published online 2007 June. PMCID: PMC2293963.
- Antihypertensive Efficacy of Angiotensin Receptor Blockers in Combination With Hydrochlorothiazide: A Review of the Factorial-Design Studies, C. Venketa S; Ram, MD.Current Hypertension Reports; Volume 11, Number 4 (2009), 292-298, DOI: 10.1007/s11906-009-0049-year.; Publication Date: 03 Jun 2010; Journal: Clinical Medicine Reviews in Vascular Health; Citation: Clinical Medicine Reviews in Vascular Health 2010:2; doi: 10.4137/CMRVH.S4614.
- First-line treatment of hypertension: critical appraisal of potential role of aliskiren and hydrochlorothiazide in a fixed combination; Konstantinos Savvatis, Dirk Westermann, Heinz-Peter Schultheiss, and Carsten Tschope. Integr Blood Press Control. 2010; 3: 163–170. Published online 2010 December 1. D oi: 10.2147/IBPC.S13448PMCID: PMC3172061.
- Telmisartan Hydrochlorothiazide in Comparison with Losartan Hydrochlorothiazide in Managing Patients with Mild-to-Moderate Hypertension; Joel M Neutel, Thomas W Littlejohn, Steven G Chrysant and Ashish Singh on behalf of the Telmisartan Study Group. Journal Article: Hypertension Research (impact factor: 2.95). 08/2005; 28(7):555-63.
- E.J. Matthews, N.L. Kruhlak, M.C. Cimino, R.D. Benz, J.F. Contrera, An analysis of genetic toxicity, reproductive and developmental toxicity, and carcinogenicity data: I. Identification of carcinogens using surrogate endpoints, Regul. Toxicol. Pharmacol. 44 (2006) 83-96.
- A. Hartmann, E. Agurell, C. Beevers, S. Brendler-Schwaab, B. Burlinson, P. Clay, A. Collins, A. Smith, G. Speit, V. Thybaud, R. Tice, Recommendations for conducting the in vivo alkaline Comet assay, Mutagenesis 18 (2003) 45-51.
- M.M. Moore, M. Honma, J. Clements, G. Bolcsfoldi, M. Cifone, R. Delongchamp, M. Fellows, B. Yoshimura, Mouse lymphoma thymidine kinase gene mutation assay: International Workshop on Genotoxicity Tests Workgroup report – Plymouth, UK 2002. Mutat. Res. 540 (2003) 127-140.
- R.R. Tice, E. Agurell, D. Anderson, B. Burlinson, A. Hartmann, H. Kobayashi, Y. Miyamae, E. Rojas, J-C Ryu, Y.F. Sasaki, Single cell gel/comet assay: Guidelines for in vitro and in vivo genetic toxicology testing, Environ. Mol. Mutagen. 35 (2000) 206-221.
- Van Gyseghem, E., Jimidar, M., Sneyers, R., Redlich, D., Verhoeven, E., Massart, D. L., and Vander Heyden, Y. (2008) Journal of Chromatography A 1042, 69-80.
- Dehouck, P., Visky, D., Heyden, Y. V., Adams, E., Kovacs, Z., Noszבl, B., Massart, D. L., and Hoogmartens, J. (2008) Journal of Chromatography A 1025, 189-200.
- Neue, U. D., Tran, K. V., Mיndez, A., and Carr, P. W. (2009) Journal of Chromatography A 1063, 35-45.
- Mohammadi, A., Mehramizi, A., Moghaddam, F., jabarian, L., pourfarzib, M., and Kashani, H. (2007) Journal of Chromatography B 854, 152-157.
- Schirmer, R. (1991) Modern Methods of Pharmaceutical Analysis, CRC Press.
- Neue, U. D., Walter, T. H., Alden, B. A., Jiang, Z., Fisk, R. P., Cook, J. T., Glose, K. H., Carmody, J. L., Grassi, J. M., and Cheng, Y. (1999) American Laboratory 31, 36-39.
- O'Gara, J. E., Alden, B. A., Walter, T. H., Petersen, J. S., Niederlaender, C. L., and Neue, U. D. (2005) Analytical Chemistry 67, 3809-3813.
- Sofuni, M. Aardema, S. Albertini, D. Eastmond, M. Fenech, M. Ishidate Jr., S. Kirchner, E. Lorge, T. Morita, H. Norppa, J. Surrallés, A. Vanhauwaert, A. Wakata, Report from the in vitro micronucleus assay working group, Mutat. Res. 540 (2003) 153-163.
- Pedraglio, S., Rozio, M. G., Misiano, P., Reali, V., Dondio, G., and Bigogno, C. (2007) Journal of Pharmaceutical and Biomedical Analysis 44, 665-673.
How to cite this article:
Vani R and Rasheed A: Formulation and evaluation of Hydrochlorothiazide and Ramipril Mouth Dissolving Tablet using different Superdisintegrants. Int J Pharm Sci Res 2014; 5(1): 207-12.doi: 10.13040/IJPSR. 0975-8232.5(1).207-12
All © 2013 are reserved by International Journal of Pharmaceutical Sciences and Research. This Journal licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License.
R. Vani* and Anas Rasheed
School of Pharmacy, Deccan Group of Institutions, Aghapura, Nampally, Hyderabad-500001, Andhra Pradesh, India
14 August, 2013
19 September, 2013
26 December, 2013
01 January, 2014