Venugopal P. et al. / International Journal of Biopharmaceutics. 2014; 5(4): International Journal of Biopharmaceutics

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1 258 e- ISSN Print ISSN International Journal of Biopharmaceutics Journal homepage: IJB DEVELOPMENT OF FORMULATION AND EVALUATION OF RAMIPRIL POROUS TABLET BY SUBLIMATION TECHNIQUE Venugopal P 1, Gnanaprakash K* 1, Kumar B 1, Gobinath M 1, Narendra Reddy B 2 1 Department of Pharmaceutics, Ratnam Institute of Pharmacy, Pidathapolur, Nellore , Andhra Pradesh, India. 2 Brige Pharmaceutical Pvt. Ltd., Santhosh Nagar, Hyderabad, Andhra Pradesh, India. ABSTRACT Ramipril was an Angiotension-Converting enzyme inhibitor. It is an Antihypertensive drug. Insoluble in water used to treatment of Hypertension, Conjective heart failure patients. The present investigation was to development of formulations of porous tablet of Ramipril by sublimation technique. Porous tablets of Ramipril were prepared by using subliming agent like different concentrations of menthol by using direct compression method. The technique is to increase the porosity of the tablets where s by subliming material was sublimed from the granules by exposing the granules to vacuum. Alternatively, tablets were first prepared and later exposed to vacuum. It is suitable dosage form for paediatric and geriatric patients. The drug and excipients were characterized using FTIR techniques. The blend was examined for angle of repose, bulk density, tapped density, compressibility index and Hausner s ratio. The prepared tablets were evaluated for general appearance, content uniformity, hardness, friability, wetting time, In vitro and in vivo disintegration time, and In vitro dissolution studies. Tablets with menthol at 13% and crospovidone 6% concentration have shown quick disintegrating features, i.e., within 20 s, which is very characteristic of orodispersible tablets. The In vitro drug release study revealed that menthol at a concentration of 13 % and crospovidone 6% (F1) of the dosage form weight was able to fast the release of Ramipril within 10 minutes. Further optimized formulations (F1) were subjected to stability testing for 3 months at temperatures 25±5ºC/60±5%RH and 40±5ºC/75±5%RH. Optimized tablets have shown no appreciable changes with respect to taste, disintegration, and dissolution profiles. In conclusion, the results of this work suggest that sublimation is a useful technique to enhance the solubility and dissolution rate of poorly water-soluble drug like Ramipril. Key words: Ramipril; Direct compression; Sublimation; Super disntigrates; Menthol; Porous tablet. INTRODUCTION Patients, particularly paediatric and geriatric patients, have difficulty in swallowing solid dosage forms. These patients are unwilling to take these solid preparations due to a fear of choking. In order to assist these patients, several mouth dissolving drug delivery systems has been developed. Porous tablets can be prepared by direct compression, wet granulation, Corresponding Author K. Gnanaprakash pharmagp@gmail.com moulding, spray drying, freeze drying or sublimation methods (Biradar SS et al., 2006). Porous tablets dissolve rapidly in the saliva without the need for water, releasing the drug (Kaushik D et al., 2004). Some drugs are absorbed from the oral cavity as the saliva passes down into the stomach. In such cases, bioavailability of drug is significantly greater than those observed from conventional tablet dosage. Form the basic approach used in the development of the Porous tablet is the use of superdisintegrants. Croscarmellose sodium, sodium starch glycollate, and crospovidone were screened in the present study, and the best one was used for further studies. Another approach used in developing Porous

2 259 tablets is maximizing pore structure of the tablets. We chose menthol as a subliming material. (Wilson K. R. W. et al., 1996) Ramipril (2S, 3aS, 6aS) -1-[ (2S) -2-{[ (2S) - 1-ethoxy-1-oxo-4-phenylbutan-2-yl] amino} propanoyl] octahydrocyclopenta[b]pyrrole-2-carboxylic acid is a widely used antihypertensive drug available as tablets for oral administration. Each tablet contains 5 mg or 20 mg Ramipril. The empirical formula is C 23 H 32 N 2 O 5 and the molecular weight is (g/mol) ; Ramipril is insoluble in water. The melting point is 105 C. Its pharmacological activity consists ACE inhibitor inhibits the actions of Angiotension converting enzyme thereby lowering the production of Angiotension II and also decreasing the breakdown of bradykinin. The decrease in Angiotension II results in relaxation of arteriole smooth muscle leading to a decrease in total peripheral resistance, reducing blood pressure as the blood is pumped through widened vessels. Solubility and permeability are the fundamental parameters controlling the rate and extent of drug absorption. According to the Bio pharmaceutics Classification System (BCS), Ramipril is a Class II having low solubility and high permeability. Bioavailability of in the present study, an attempt was made to develop porous tablets of Ramipril and to investigate the effect of various subliming agent on the disintegration time, wetting time and release profile of the drug in the tablets. (Sharma S, 2008). MATERIALS AND METHODS Ramipril was supplied as a gift sample from Bridge Pharmaceuticals (Hyderabad, India). Crospovidone, Megnesiumstearate (ISP chemical Inc, Hyd, India). Sodium starch glycollate, Talc (Roquette, Mumbai), Croscaramellose (DowChemicalInc, Mumbai), menthol (Nutrasweet, Vadodara) Micro crystalline cellulose (Bramhar cellulose products, Tamilanadu) were provided from Industry. Methods of preparation of ramipril porous tablets sublimation method Sifting: Sift Ramipril, Micro crystalline cellulose, Crospovidone, Sodium saccharin; Menthol and Talc through mesh #40 separately. Pre-Lubrication: Loaded the sifted materials of step no.1 into suitable into polythene bag and blend for 10 minutes. Sifting: Sift Magnesium stearate through mesh #40 separately. Lubrication: Loaded the sifted Magnesium Stearate of step no. 2 and 3 into polythene bag and mixed for 5 minutes. Compression: The lubricated blend of step no.4 was compressed using following parameters. The compressed tablets were than subjected to sublimation at 80 c for 30 min. Characterization of drug and excipients Fourier transforms infra red spectroscopy (FTIR) FTIR spectra of pure Ramipril and physical mixture of drug and excipients were recorded on Shimadzu Corporation, (Tokyo, Japan) Model-1601 PC. Potassium bromide pellet method was employed and background spectrum was collected under identical situation. Each spectrum was derived from single average scans collected in the region cm-1 at spectral resolution of 2cm-2 and ratio against background interferogram. Spectra were analyzed by software supplied by Shimadzu. Evaluation of granule blend Angle of repose (θ): It is defined as the maximum angle possible between the surface of pile of the powder and the horizontal plane. Fixed funnel method was used. A funnel was fixed with its tip at a given height (h), above a flat horizontal surface on which a graph paper was placed. Powder was carefully poured through a funnel till the apex of the conical pile just touches the tip of funnel. These studies were carried out before and after incorporating lubricant/glidant. The angle of repose (θ) was then calculated. θ = tan -1 (h/r) Where, θ - Angle of repose; h - Height of pile; r - Radius of the base of the pile. Bulk density (D b ): Bulk density was determined by using bulk density apparatus, during measurement accurately weighed quantity of the dried granules were taken in a measuring cylinder and recording the volume and weight of the total granules. Bulk density is expressed in gm/ml and is given by, D b = M / Vo Where, Db - Bulk density (gm/ml); M - Weight of granules (gm); Tapped density (D t ):Tapped density was determined by using Tapped density apparatus during measurement accurately weighed quantity of the dried granules were taken in a measuring cylinder and recording the volume of granules after 100 tapping and weight of the total granules. D t = M / V Where, D t - Tapped density (gm/ml); M - Weight of granules (gm); V - Tapped volume of granules (ml). Compressibility index: It is the propensity of a powder to be compressed. Compressibility index was determined by placing the dried granules in a measuring cylinder and the volume (V 0 ) was noted before tapping, after 100

3 260 tapping s again volume (V) was recorded. The flow properties are tabulated. Compressibility index = (1- V/ V 0 ) X 100 Where, V 0 -Volume of powder/granules before tapping; V- Volume of powder/granules after 100 tapping. Hausner s ratio: The hausner s ratio is a number that is correlated to the flow ability of a powder or granular blend. (Ramesh Kannuri et al., 2011). Hausner s Ratio = TD / BD Where, TD -Tapped density; BD -Bulk density Evaluation of prepared tablets General Appearance and Organoleptic Properties: The control of a general appearance of a tablet involves the measurement of a number of attributes such as a tablet s size, shape, colour, presence or absence of an odour, taste, surface texture, physical flaws and consistency, and legibility of any identifying markings. Thickness: Thickness was determined for 20 pre weighed tablets of each batch using a digital venire scale and the average thickness was determined in mm. Average of three readings were taken and the results were tabulated. (Furtado S et al., 2008). Weight Variation: 20 tablets were selected randomly from a batch and were individually weighed and then the average weight was calculated. The tablets meet the USP specifications if not more than 2 tablets are outside the percentage limit and if no tablet differs by more than 2 times the percentage limits. Hardness Test: Prepared tablets were evaluated for their hardness by using Pfizer hardness tester. Scale was adjusted to zero; load was gradually increased until the tablet fractured. The value of the load at that point gives a measure of hardness of the tablet. Hardness was expressed in Kg/cm 2. Triplicate readings were taken and average was computed. (Yourong Fu et al., 2004). Percentage Friability: In friability testing the tablets are subjected to abrasion and shock. It gives an indication of the tablets ability to resist chipping and abrasion during transportation and shipping. If the tablet weight is 650 mg 10 tablets were taken and initial weight was noted. The tablets were rotate in the Roche friabilator for 100 revolutions at 25 rpm. The tablets were dedusted and reweighed. For conventional tablets the percentage friability should be less than 1% whereas friability values of up to 4% are acceptable for oral disintegrating and chewable tablets. (Gattu Jyothi et al., 2011). The percentage friability is expressed as the loss of weight and is calculated by the formula: Content Uniformity: The content uniformity test is used to ensure that every tablet contains the amount of drug substance intended with little variation among tablets within a batch. Five tablets were selected randomly and average weight was calculated. Tablets were crushed in a mortar and accurately weighed and the amount of average tablet was taken from the crushed blend. Then, the samples were transferred to three 100 ml volumetric flasks and were diluted up to the mark 0.1N HCl solution. The content was shaken periodically and kept for 24 hours for dissolution of drug completely. The mixtures were filtered and appropriate dilutions were made. The drug content in each tablet was estimated at max nm against blank reference and reported. (Pranati et al., 2010). Disintegration Time: Disintegration time is the time taken by the tablet to break into smaller particles. The disintegration test is carried out in an apparatus containing a basket rack assembly with six glass tubes which consists of a 10 mesh sieve. The basket is raised and lowered times per minute in the medium of 900 ml of purified water which is maintained at 37±2 o C. Six tablets were placed in each of the tubes and the time required for complete passage of tablet fragments through the sieve (# 10) was considered as the disintegration time of the tablet. The time for disintegration of porous tablet is generally <1min and actual disintegration time that patience can experience ranges from 5 to 30s. Wetting Time: Wetting time of dosage form is related with the contact angle. Wetting time of the mouth dissolving tablets is another important parameter, which needs to be assessed to give an insight into the disintegration properties of the tablets; a lower wetting time implies a quicker disintegration of the tablet. The wetting time of the tablet can be measured using a simple procedure. Method: Five circular tissue papers of 10 cm diameter were placed in a petri dish with a10 cm diameter. 10 ml of water was added to Petri dish and 2 drops of eosin red dye was added. A tablet was placed on the surface of the tissue paper. The time required for water to reach upper surface of the tablet was noted as wetting time. Water absorption ratio (R): The weight of the tablet before keeping in the Petri dish was noted (W b ). The wetted tablet from the Petri dish was taken and reweighed (W a ) using the same. The water absorption ratio, R, was determined according to the following equation: R = 100 (Wa W b ) / W b Where W b andw a are the weight before and after water absorption respectively

4 261 In-vitro dispersion time: Tablet was added to 10ml of distilled water at 37±0.5 0 C. Time required for complete dispersion of a tablet was measured. Moisture Content: The moisture content was determined by Karl-Fisher apparatus and in the method 30ml of dried methanol was taken in KF apparatus beaker, and neutralized with fresh KF reagent. Accurately weighed quantity of powdered tablet has been transferred into the neutralized methanol present in the beaker. The titer value is noted. Dissolution studies: Dissolution is a process by which the disintegrated solid solute enters the solution. The test determines the time required for a definite percentage of the drug in a tablet to dissolve under specified conditions. In-vitro drug release studies were carried out by using USP XXIII dissolution apparatus II (paddle type) at 50 rpm. The drug release profile was studied in 500 ml of 6.8 maintained at 37 ± 0.5 o C. Aliquots of 5 ml of dissolution medium were withdrawn at PH 6.8 buffer specific time intervals (2, 4, 6, 8, 10minutes) filtered and the amount of drug released was determined by UV- Visible spectrophotometer. 5 ml of fresh PH6.8 buffer was replaced as soon as the drug samples were withdrawn. Samples withdrawn were analyzed for the percentage of drug release. Stability Conditions: Stability study of tablets containing Ramipril was performed at following temperatures for one month and three months Long term testing: 25 o C / 60% RH (1 Month) (3 Month ) Accelerated testing: 40 o C / 75% RH (1 Month) (3 Month) Parameters estimated: Moisture content, assay, disintegration time and dissolution. (Leon Lachman, Herbert et al., 2009) RESULTS AND DISCUSSION Stability studies of the optimized formulation F1 Optimized formulation F 1 was subjected to stability studies for 1and 3months and the tablets were tested for moisture content, assay, disintegration and dissolution. The results obtained were as in the following. Table 1. Composition of s for Sublimation Method Ingredients F1 F2 F3 F4 F5 F6 F7 F8 F9 Ramipril (API) (mg) Crosspovidane (CP) (mg) Cross caramellose sodium (CCS) (mg) Sodium starch glycolate (SSG) (mg) Menthol (mg) Sodium saccharine (mg) Talc (mg) Micro crystalline cellose (MCC) (mg) Megnisium stearate (mg) Table 2. Flow properties of powders S. No Flow Properties Angle of Repose ( ) Compressibility Index (%) Hausners Ratio 1 Excellent < Good Fair Passable Poor Very poor Very very poor >66 >38 >1.60

5 262 Table 3. Percentage deviations allowed for the tablets Average weight of tablet (mg) % deviation allowed 130 or less 10 From 130 to > Table 4. Results of precompression properties Angle of Bulk Density Repose (ө) (g/cc) code Tapped Density (g/cc) Compressibility index (%) Hausner's ratio F ± ± ± ± ±0.06 F ± ± ± ± ±0.02 F ± ± ± ± ±0.03 F ± ± ± ± ±0.02 F ± ± ± ± ±0.04 F ± ± ± ± ±0.06 F ± ± ± ± ±0.04 F ± ± ± ± ±0.05 F ± ± ± ± ±0.04 Table 5. Evaluation of post compression parameters of formulations: code Weight variation (mg) Hardness (kg/cm 2 ) Thickness (mm) Friability (%) F ± ± ± ±0.17 F ± ± ± ±0.15 F ± ± ± ±0.14 F ± ± ± ±0.12 F ± ± ± ±0.16 F ± ± ± ±0.14 F ± ± ± ±0.13 F ± ± ± ±0.18 F ± ± ± ±0.16 Table 6. Evaluation of Ramipril porous tablet by using superdisintegrants Code Water absorption Ratio (%) Wetting time (sec) Disintegration time (sec) Drug content (%) F F F F F F F F F Table 7. Tests for stability studies of the optimized formulation Initial Month 1 Month 3 S No. Test 25 o C, 25 o C, 40 o 25 o C, 40 o C, C, 75 %RH 60 % RH 60 %RH 60 % RH 75 %RH 1 Moisture content 9.5% 9.54 % 9.59% 9.61 % 9.65 % 2 Assay ± 0.17 % ± 0.09 % ± 0.28 % ± 0.25 % ± 0.38 % 3 Disintegration (sec) 10 ± ± ± ± ± Dissolution at 30 min ± 0.42 % ± 0.59 % ± 0.59 % ± 0.84 % 98.2 ± 0.89 %

6 263 Table 8. In vitro % Cumulative drug release (F1-F9) Code Time in min 2 min 4min 6min 8min 10min F F F F F F F F F Figure 1. Plot for In vitro % Cumulative drug release (F1-F9) Figure 2. FTIR spectra of pure Ramipril and physical mixture of drug and excipients CONCLUSION From the experimental result can be concluded that the menthol is used as the sublimation agent so it form the effective porous in the Ramipril tablet. The F1 is show the effective amount of cumulative drug relies 97.2% within 10 minutes compared to the other formulations. It show the post compression parameters as fallowed values weight variation ±0.57, Hardness 3.4±0.4, friability 0.30±0.17, water absorption ratio 61.7%, Wetting time 36 sec, disintegration time 24 sec, drug content uniformity 99.12%. Comparative studies with the marketed formulations is reviled that the F1 show the cumulative % of drug relies ± 0.26% within time period of 8 minutes but marketed formulation show the drug relies 98.93±0.26 within the time period of 22 minutes. The stability studies doing up the 3 mounts in different temperatures 25 c to 75 c &relative humidity 60% to 75% in this criteria it shown the moisture content initially 9.5% finally 9.65%, assay initially ±0.17 finally 99.65±3.8% of purity, disintegration time

7 264 intially10±0.58 sec finally 99.65±0.38 and dissolution initially ±0.42%, finally 98.2±0.87.The above all parameters are concluded that the F1 is the best formulation compared to the all other formulations and marketed formulation and also it show the good stability in all conditions. REFERENCES Biradar SS, Bhagavati ST, Kuppasad IJ. Fast dissolving drug delivery systems: a brief overview. The Int. J. Pharmacol. 2006; 4 (2): Furtado S, Deveswaran R, Bharath S. Development and characterization of orodispersible tablets of famotidine containing a subliming agent. Trop J Pharm Res. 2008; 7(4): Gattu Jyothi and Lakshmi PK. Comparative evaluation of natural and synthetic superdisintegrants with newer superdisintegrant Kyron T-314. Acta Pharmaceutica Sciencia. 2011; 5 (3): Kaushik D, Dureja H, Saini TR. Mouth dissolving tablets: A review. Indian Drugs-Bombay. 2004; 41: Leon Lachman, Herbert A. Liebermann. The Theory and Practice of Industrial Pharmacy, Special Indian Edition; 2009: Pranati Srivastava, Rishabha Malviya, Sharad Visht. Development and Evaluation of Atenolol Fast Disintegrating Tablets for Treatment of Hypertension. J of Chronotherapy and Drug Delivery. 2009; 1(1); Ramesh Kannuri, Threveen Challa, Hareesha Chamarthi. Taste Masking and Evaluation for Orodispersible Tablets. Int. J. Pharm & Ind. Res. 2011; 1(3): Sharma S, Gupta GD. and characterization of fast- dissolving tablet of promethazine theoclate. Asian Journal Pharmaceutics. 2008; 2: Wilson KRW, Mona Piplani, Prabodh C. Sharma, Dhirender Kaushik and Sanju Nanda. Orally Disintegrating Tablets Friendly to Pediatrics and Geriatrics. Arch. Apll. Sci. Res, 2010; 2 (2); Yourong Fu, Shicheng Yang, Seong Hoon Jeong, Susumu Kimura & Kinam Park. Orally Fast Disintegrating Tablets: Developments, Technologies, Taste-Masking and Clinical Studies. Critical Reviews in Therapeutic Drug Carrier Systems. 2004; 221(6);