DESIGN, DEVELOPMENT AND CHARACTERIZATION OF MOUTH DISSOLVING TABLETS OF CINNARIZINE USING SUPER-DISINTEGRANTS

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1 International Journal of PharmTech Research CODEN (USA): IJPRIF ISSN : Vol.2, No.1, pp , Jan-Mar 2010 DESIGN, DEVELOPMENT AND CHARACTERIZATION OF MOUTH DISSOLVING TABLETS OF CINNARIZINE USING SUPER-DISINTEGRANTS Akbari B.V.* 1, Dholakiya R.B 1, Shiyani B.G 1, Lodhiya D.J 1 1 Shree Dhanvanvantary Pharmacy College, Kim, Surat, Gujarat, India 1 Shree Dhanvanvantary Pharmaceutical analysis and research center, Kim, Surat, Gujarat, India *Corres. author: bhavesh_akbari2003@yahoo.com Mobile: , Fax: ABSTRACT: The demand for mouth dissolving tablets has been growing, during the last decade especially for geriatric and pediatric patients because of swallowing difficulties. Cinnarizine is H1-receptor antagonist and widely used in the treatment of motion sickness, vomiting and vertigo. Mouth dissolving tablets of cinnarizine were prepared by effervescent, superdisintegrant addition and sublimation methods. All the three formulations were evaluated for disintegration time, hardness and friability, among this Superdisintegrant addition method showed lowest disintegration time, hence it was selected for further studies. Further nine batches (B1-B9) were prepared by using crospovidone, croscarmellose sodium and L-HPC in different concentrations such as 5%, 7.5% and 10%. All the formulations were evaluated for weight variation, hardness, friability, drug content, in-vitro disintegration time, wetting time, in-vitro dissolution. Formulation with 10% L-HPC showed the less disintegration time (25.3 seconds) and less wetting time (29.1 seconds). In-vitro dissolution studies showed 100% drug release at the end of 6 minutes. KEY WORDS: Cinnarizine, Crospovidone, Croscarmellose sodium, L-HPC, Mouth dissolving tablet. INTRODUCTION AND EXPERIMENTAL An ideal dosage regimen in the drug therapy of any disease is the one, which immediately attains the desire therapeutics concentration of drug in plasma (or at the site of action) and maintains it constant for the entire duration of treatment. This is possible through administration of conventional dosage form in a particular dose and at a particular frequency. Thus drug may be administered by variety of routes in a variety of dosage forms. Drugs are more frequently taken by oral administration. Although a few drugs taken orally are intended to be dissolved within the mouth, the vast majority of drugs taken orally are swallowed. Compared with alternate routes, the oral route of drug administration is the most popular and has been successfully used for conventional delivery of drug. It is considered most natural, uncomplicated, convenient, safe means of administering drugs, greater flexibility in dosage form design, ease of production and low cost. Swallowing problem is common in children because of their underdeveloped muscular and nervous systems. In some cases like motion sickness, sudden episodes of allergic attack or coughing, and during unavailability of water, swallowing conventional tablets is difficult. To fulfill these medical needs, formulators have devoted considerable efforts for developing a novel type of dosage form for oral administration known as mouth dissolving tablets (MDT). 1, 2 Mouth Dissolving Tablet: 3, 4 This is an innovative tablet technology where the dosage form containing active pharmaceutical ingredients disintegrates rapidly, usually in a matter of seconds, without the need for water, providing optimal convenience to the patient. Innovators and inventor companies have given these tablets various names such as orally disintegrating tablets (ODT), mouth dissolving (MD), fast melting, fast dissolving or Orodisperse. The European

2 Akbari B.V.et al /Int.J. PharmTech Res.2010,2(1) 98 Pharmacopoeia defines Orodisperse as a tablet that can be placed in the mouth where it disperses rapidly before swallowing. Researchers have formulated ODT for various categories of drugs, which are used for therapy in which rapid peak plasma concentration is required to achieve desired pharmacological response. These include neuroleptics, cardiovascular agents, analgesics, anti-allergic and drugs for erectile dysfunction. FORMULATION OF MOUTH DISSOLVING TABLETS OF CINNARIZINE 4, 5 Selection of tablet preparation methodology: Mouth dissolving tablets of Cinnarizine were prepared by following three methods using direct compression method. 1. Effervescent method: Specified quantity of Cinnarizine, mannitol, Avicel 102, aspartame, talc and magnesium stearate were weighed accurately and passed through 60 # screen. Sodium bicarbonate and citric acid were accurately weighed and preheated at a temperature of 70 o C. All the materials were transferred to mortar and triturated till it mixed uniformly. The resulting powder mixture was compressed into tablets using single punch tablet machine. Formulation of tablets was represented in Table Super disintegrants addition method: Specified quantity of Cinnarizine, mannitol, Avicel 102, aspartame, crospovidone, talc and magnesium stearate were weighed accurately and passed through 60 # screen. All the materials were transferred to mortar and triturated till it mixed uniformly. The resulting powder mixture was compressed into tablets using single punch tablet machine. Formulation of tablets was represented in Table Sublimation method: 6, 9 Specified quantity of Cinnarizine, camphor, mannitol, aspartame, talc and magnesium stearate were weighed accurately and were passed through 60 # screen prior to mixing. All the materials were transferred to mortar and triturated till it mixed uniformly. The resulting powder mixture was compressed into tablets using single punch tablet machine. The tablets were dried at 60 o C over till constant weigh obtained. The formulation of these tablets was represented in Table 1.Various methods were tried for formulation of mouth dissolving tablets. The disintegration time of tablets prepared by various methods was shown in Fig.1. It shows that super disintegration addition method exhibits the lowest disintegration time, hence it is the best method as compare to remaining methods. The quicker disintegration time may be attributed to faster water uptake by the tablets. Preparation Of Mouth Dissolving Tablets Using Super Disintegrants: 7, 8 Various superdisintegrants were used for formulation of mouth dissolving tablets. In these formulation crospovidone, croscarmellose sodium and L-HPC were used as a superdisintegrant. Weighed the Cinnarizine, mannitol, Avicel 102, super disintegrants, aspartame, talc and magnesium stearate accurately and passed through 60 # screen. All the materials were transferred to mortar and triturated till it mixed uniformly. The resulting powder mixture was compressed into tablets using single punch tablet machine. Formulations of tablets were represented in Table 2. 10, 11, 12, 13 Evaluation of Powder Blend 1. Bulk Density (D b ): It is the ratio of total mass of powder to the bulk volume of powder. It was measured by pouring the weighed powder (passed through standard sieve # 20) into a measuring cylinder and initial weight was noted. This initial volume was called the bulk volume. From this the bulk density was calculated according to the formula mentioned below. It is expressed in gm/ml and is given by D b = M/ V b Where, M and V b are mass of powder and bulk volume of the powder respectively. 2. Tapped Density (D t ): It is the ratio of total mass of the powder to the tapped volume of the powder. Volume was measured by tapping the powder for 750 times and the tapped volume was noted if the difference between these two volumes is less than 2%. If it is more than 2%, tapping is continued for 1250 times and tapped volume was noted. Tapping was continued until the difference between successive volumes is less than 2 % (in a bulk density apparatus). It is expressed in gm/ml and is given by D t = M / V t Where, M and V t are mass of powder and tapped volume of the powder respectively. 3. Angle of Repose (q): The powder blend was allowed to flow through the funnel freely on to the surface. The diameter of the powder cone was measured and angle of repose was calculated using the following equation. tan (q) = h/r Where, h and r are the height and radius of the powder cone. 4. Carr s index (or) % compressibility: It indicates powder flow properties. It is expressed in percentage and is given by

3 Akbari B.V.et al /Int.J. PharmTech Res.2010,2(1) 99 I = D t D b /D t X 100 Where, Dt and D b are tapped density and bulk density respectively. 5. Hausner ratio: Hausner ratio is an indirect index of ease of powder flow. It was calculated by the following formula. Hausner ratio = D t / D b Where,Dt and D b are tapped density and bulk density respectively. The results were shown in the Table 3. Evaluation of Mouth Dissolving Tablets 1. Weight variation: 20 tablets were selected randomly from the lot and weighed individually to check for weight variation. 2. Hardness: Hardness or tablet crushing strength was measured using Monsanto tablet hardness tester. It is expressed in kg/cm Thickness: Thickness of tablet was measured by using vernier calipers. Three tablets were selected at random from each batch. It is expressed in mm. 4. Friability (F): Friability of the tablet determined using Roche friabiltor. This device subjects the tablet to the combined effect of abrasion and shock in a plastic chamber revolving at 25rpm and dropping a tablet at l height of 6 inches in each revolution. Preweighted sample of tablets was placed in the friabilator and were subjected to the 100 revolutions. Tablets were de-dusted using a soft muslin cloth and reweighed. The friability (F) is given by the formula. F = W initial - W final /W initial X 100 The results of physical parameters of mouth dissolving tablet was shown in Table In-Vitro Disintegration time: 14, 15 A tablet was placed in each of the six tubes of the disintegration test apparatus and one disc was added to each tube. The time in seconds taken for complete disintegration of the tablet with no palatable mass remaining in the apparatus was measured in seconds. The in vitro disintegration time was evaluated and result was summarized in the Table 4 and Fig Wetting time: 14, 15 A piece of tissue paper folded double was placed in a Petri dish containing 6ml of water. The tablet was placed on the paper, and the time for complete wetting of the tablet was measured in seconds. The method was slightly modified by maintaining water at 37 o C. Wetting time corresponds to the time taken for the tablet to disintegrate when kept motionless on the tongue. The Wetting time was evaluated and results are summarized in the Table 4 and Fig Assay: 15, 16 Twenty tablets from each batch were weighed accurately and powdered powder equivalent to 100 mg Cinnarizine was shaken with 100ml of 0.1N Hydrochloric acid in 100 ml amber colored volumetric flask and from this 10 ml was pipette out and than dilute up to 100 ml. From standard solution again 10 ml pipette out and diluted up to 100 ml in 100 ml amber colored volumetric flask. Resulting solution was filtered and assayed at nm and content of Cinnarizine was calculated. The drug content was evaluated and results are summarized in the Table In-Vitro drug release study: 14, 15 In-vitro release rate study of mouth dissolving tablet of Cinnarizine was carried out using the Paddle apparatus method. The dissolution apparatus was covered with the black color polythine to protect the solution from light. The dissolution test was carried out using 900 ml of 0.1 N HCl, at C and 50 rpm. A sample (5 ml) of the solution was withdrawn from the dissolution apparatus at 2, 4, 6, 8 and 10 min and withdrawn volume was replaced with fresh dissolution media.the % release of Cinnarizine was calculated. The observation for different batches was shown in Table 5. The percentage release of Cinnarizine with respect to time for each batch, were graphically shown in Fig Accelerated Stability Testing of Mouth Dissolving Tablets: 14, 15, 16 The stability studies of formulated tablets were carried out at 40 o C and at room temperature for one month. The effects of temperature and time on the physical characteristics of the tablet were evaluated for assessing the stability of the prepared formulations. The different parameters that were studied are in vitro disintegration time, wetting time, drug content and in vitro dissolution rate. The results were summarized in Table 6 & 7. RESULTS AND DISSCUSSION Characterization of the mouth dissolving tablets with various super disintegrants: Crospovidone, Croscarmellose sodium and L-HPC were tried for formulation of mouth dissolve tablets. The concentration of superdisintegrant was taken 5, 7.5 and 10 %. The powder blend was evaluated for angle of repose, hausner ratio and % compressibility. The prepared tablet was evaluated for physical parameter, Wetting time, In vitro disintegration time, Assay and In vitro drug release. Evaluation of powder blend: a) Angle of Repose (q): The angle of repose for the entire formulations blend was found to be in the range o to o. Formulations with crospovidone and croscarmellose sodium as a disintegrants showed angle of repose values 30 o where as formulation containing L-HPC showed angle of repose values > 30 o indicating only fair flow property of the powder blend. b) Compressibility Index: Compressibility index was found to be in the range % to %. All formulations showed good flow properties except formulation containing L-HPC 7.5 and 10 %.

4 Akbari B.V.et al /Int.J. PharmTech Res.2010,2(1) 100 c) Hausner ratio: Hausner ratio was found to be in the range 1.13 to 1.23 and that indicated that all formulation has good flow properties. Physical Parameters a) Weight variation: All the formulated (B1 to B9) tablets were passed weight variation test as the % weight variation was within the IP limits of ±7.5% of the weight. The weights of all the tablets were found to be uniform with low standard deviation values. The prepared formulation complies with the weight variation test. b) Thickness: The maximum thickness of the formulation was found to be 2.62mm. The minimum thickness of the formulation was found to be 2.53mm. The average thickness of the all formulation was found to be 2.58mm. c) Hardness: The hardness of the tablet was found to be 2.5 to 3.0 Kg/cm 2. d) Friability test: The maximum friability of the formulation was found to be 0.8%. The minimum friability of the formulation was found to be 0.65%. The % friability was less than 1% in all the formulations ensuring that the tablets were mechanically stable. e) Drug content: The maximum drug content for the all formulation was found to be % and minimum % drug content from the all formulation was found to be 98.14%. The results were within the limit specified by the IP. e) In vitro Disintegration test: In vitro Disintegration time was found to be in the range 25.3 to 59.4 sec. From all formulations, B9 (10% L-HPC) has minimum disintegration time. Formulations containing croscarmellose sodium has taken more time for disintegration because of its gelling properties. f) Wetting Time: Wetting Time was found to be in the range 29.1 to 89 sec. From all formulations, B9 (10% L-HPC) has minimum wetting time. g) In vitro drug release study: Dissolution data shows that formulation B9 shows improved dissolution as compared to other formulations and total (~25mg) drug release was found at 6 min having 10% L-HPC. h) Stability Study: Stability study was carried out for the optimized formulation according to ICH guide lines at 2 8 C (controlled sample), Room temperature and 40 C for 1 month. The results showed that there was no significant change in physical and chemical parameter of the tablet, hence the formulation was found to be stable. Table 1: Formulation of mouth dissolving tablets by different method Ingredient Method Effervescent Super disintegrant addition Sublimation Cinnarizine Avicel PH Sodium bicarbonate Citric acid Crospovidone Camphor Aspartame Talc Mg stearate Mannitol up to All the quantities are in mg. Table 2: Formulation of mouth dissolving tablets using different super disintegrants Ingredient B1 B2 B3 B4 B5 B6 B7 B8 B9 Cinnarizine Crospovidone Croscarmellose sodium L-HPC Avicel Aspartame Talc Mg stearate Mannitol up to All the quantities are in mg.

5 Akbari B.V.et al /Int.J. PharmTech Res.2010,2(1) 101 Batch code Bulk density Table 3: Evaluation of the Powder Blend Tapped Angle of % compressibility Hausner ratio density repose B B B B B B B B B Table 4: Physical parameters of mouth dissolving Tablet Batch Code Weight Variation Thickness (mm) Hardness (Kg/cm 2 ) Friability (%) In-Vitro Disin. Time (Sec) Wetting Time (Sec) Assay (%) B1 pass ±1.53 B2 pass ±1.00 B3 pass ±1.22 B4 pass ±2.42 B5 pass ±1.25 B6 pass ±2.12 B7 pass ±2.46 B8 pass ±0.50 B9 pass ±0.58 # All the values are expressed as mean ± SD ± ± ± ± ± ± ± ± ±

6 Akbari B.V.et al /Int.J. PharmTech Res.2010,2(1) 102 Time (min) Table 5: Percentage Cumulative drug release profile of batch B1 to B9 Cumulative % drug release B1 B2 B3 B4 B5 B6 B7 B8 B Table 6: Stability parameters of formulation B9 stored at different Temperature Parameters Drug Content (%) In-Vitro Disin. Time (Sec) Wetting Time (Sec) Controlled After 15 days Stored at room Temperature After one months Stored at 40 0 Temperature After 15 days After one months Table 7: Stability study of in-vitro dissolution for formulation B9 stored at Room Temperature Cumulative % drug release Time (min) Controlled After 15 days Stored at room temperature After one months Stored at 40 0 temperature After 15 days After one months

7 Akbari B.V.et al /Int.J. PharmTech Res.2010,2(1) Disintegration time (s) Effervescent Super disintegrant addition Method Sublimation Figure 1: Column graph of disintegration time of mouth dissolving tablets prepared by different method 70 In-Vitro Disin. Time (Sec) B1 B2 B3 B4 B5 B6 B7 B8 B9 Batch no Figure 2: Column graph of the Disintegration time (Sec) of various batches Wetting Time (Sec) B1 B2 B3 B4 B5 B6 B7 B8 B9 Batch no Figure 3: Column graph of the Wetting time (Sec) of various batches

8 Akbari B.V.et al /Int.J. PharmTech Res.2010,2(1) 104 Cum. %Drug Release B1 B2 B3 B4 B5 B6 B7 B8 B Time (min) Figure 4: Cumulative % drug release profile of batch B1 to B9 After 5 Seconds After 25 Seconds Figure 5: Photos of In-Vitro Disintegration Time of Mouth Dissolving Tablet of Formulation B9 REFERENCES 1) Brahmankar D. M., Jaiswal S.B., Biopharmaceutics & Pharmaceutics, First Edition, 1995, ) Howard C. Ansel, Nicholas G. Popvich, Loyd V. Allen, Pharmaceutical Dosage Forms and Drug Delivery System, First Edition, 1995, 78. 3) S. S. Biradar, S. T. Bhagavati and I. J. Kuppasad, Fast Dissolving Drug Delivery Systems: A Brief Overview, Internet J. Pharmacology, 2006, 4(2). 4) Kuccherkar B.S., Badhan A.C., Mahajan H.S., Mouth dissolving tablets: A novel drug delivery system, Phrma Times, 2003, 35, ) Kaushik D, Dureja H., Saini T. R., Mouth Dissolving Tablets: A review, Indian Drugs, 2004, 41(4), ) Amin A. F., Shah T. J., Bhadani M. N., Patel M. M., Emerging trends in orally disintegrating tablets, ) Renon J. P. and Corveleyn S., Freeze-dried rapidly disintegrating tablets, US Patent No. 6,010,719, ) Lailla J. K., Sharma A. H., Freeze-drying and its applications, Indian Drugs, 1993, 31, ) Seager H., Drug delivery products and zydis fast dissolving dosage form, J. Pharm. Phamacol., 1998, 50,

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