International Journal of Innovative Pharmaceutical Sciences and Research

International Journal of Innovative Pharmaceutical Sciences and Research www.ijipsr.com FORMULATION DESIGN OPTIMISATION EVALUATION OF ROPINIROLE HYDROCHLORIDE SUBLINGUAL FAST DISSOLVING TABLETS 1 G.Vikramadhitya *, A.Venu, 3 L.Bharat Kumar, 4 M.Santosh Kumar 1,,3 Department of Pharmaceutics Srikrupa Institute of Pharmaceutical Sciences, Siddipet, Medak 5077, Telangana, INDIA 4 Faculty Department of Pharmaceutics Srikrupa Institute of Pharmaceutical Sciences, Siddipet, Medak-5077, Telangana, INDIA Abstract The current investigation is to formulate and optimize Ropinrole Hydrochloride sublingual tablet Sublingual tablets of Ropinrole Hydrochloride were prepared by direct compression technique. Twelve Formulations were formulated using 4* full factorial designs to explore the effects of Croscarmellose sodium and Crosspovidone,Sodium starch glycolate and Microcrystalline cellulose (as independent variables) on Hardness and Disintegration time (as dependent variables). Tablets exhibited drug release in the range of 94.8 to 98.33% in 0 minutes. The formulation was optimized with desirable Hardness and disintegration time by applying Design of experiments D-optimal Response surface design. The optimized Formula F 1showing the hardness about 3 kg/cm and disintegration time about 1 seconds. The drug release profile of this optimized batch was found to be 98.33%. The drug excipients compatibility studies were performed by FTIR. Finally, a check-point batch is prepared to prove the validity of evolved method. Using the contour plot, effect of the independent variables on the responses was represented graphically. The optimized formulation shows good stability at 40 C/75% RH for 6 months period Keywords: Ropinrole HCl, 4* full factorial designs, Dependent variables as independent variables. Corresponding Author: G.Vikramadhitya #4-143 Prasantnagar Raghavendranagar street-10 Siddipet, Medak District 50103. Telangana, INDIA Email: vikramadhitya.g@gmail.com Phone: +91-949301441 Available online: www.ijipsr.com August Issue 1837

INTRODUCTION Ropinirole Hcl is a non-ergotamine dopamine agonist with high in-vitro specificity and full intrinsic activity at D receptors. Based on electrophysiological studies in animals Ropinirole influences the striatal neuronal fringe via activation of dopamine receptors in the striatum, substantia-nigra and at the site of neurons that sends projections to the striatum. Ropinirole has the ability to stimulate these D3 & D receptors in the striatum. Dopaminergic neurons in substantial nigra destroy leading to decline in dopamine levels in basal ganglia. Sublingual route is a useful method of administration when rapid onset of action is desired. The ease of usage, patient compliance and improved bioavailability are other advantages of this route. It has been reported that sublingual administration of Ropinirole is an effective and safe method of balances the dopamine levels in patients with Parkinson s disease. Based on previous researches, Ropinirole reduces off time in patients with motor fluctuations of drug concentration in plasma and more rapid onset of pharmacological effect has been observed after oral administration of Ropinirole. Hence, formulation of a sublingual tablet containing Ropinirole Hcl could be considered as an appropriate method to obtain suitable clinical effect. Different studies have been conducted on using D-optimal design in optimization of various formulations, but no published work was found regarding the formulation and optimization of Ropinirole hydrochloride sublingual tablet. Therefore the present study deals with the design and optimization of formulation variables using mathematical equations and contour plots to prepare a desired sublingual tablet of Ropinirole hydrochloride with suitable physical and chemical characteristics. The concept of Fast Disintegrating Drug Delivery System emerged from the desire to provide patient with more conventional means of taking their medication. It is difficult for many patients to swallow tablets and hard gelatin capsules. Hence they do not comply with prescription, which results in high incidence of non-compliance and ineffective therapy. [1, ] Introduction to Experimental design Types of designs are listed here according to the experimental objective they meet. Comparative objective If you have one or several factors under investigation, but the primary goal of your experiment is to make a conclusion about one a-priori important factor, and the question of interest is whether or not that factor is "significant then you have a comparative problem and you need a comparative design solution. Available online: www.ijipsr.com August Issue 1838

Screening objective: The primary purpose of the experiment is to select or screen out the few important main effects from the many less important ones. These screening designs are also termed main effects designs. Factorial Experiments: Factorial designs allow for the simultaneous study of the effects that several factors like concentration of superdisintegrants and hardness may have on the physical characteristics of the tablets. [3] Contour Plots: Contour plot helps in visualizing the response surface. Contour plots are useful for establishing desirable response values and operating conditions. [4] Response Surface Design Surface Plots Using a surface plot one can visualize the response surface. Surface plots are useful for establishing desirable response values and operating conditions. RSM designs are used to Find improved or optimal process settings Troubleshoot process problems and weak points Make a product or process more robust against external and non-controllable influences. MATERIALS Ropinirole Hydrochloride was gift sample from Cyrex Laboratories Mumbai. Crosspovidone, Croscarmellose sodium were obtained as gift sample from Drug India Bulk Drugs, Hyderabad. Micro crystalline cellulose, Mannitol, Aerosil Aspartame Flavors Vanilla were gift samples from SD Fine Chem. Pvt, Mumbai. METHODOLOGY Method Development Systematic formulation approach by optimization technique using Response surface type of D- optimal design method using Design Expert software. Preparation of Ropinirole hydrochloride Sublingual tablets All ingredients were triturated individually in a mortar and passed through #60 sieve. Then required quantity of all ingredients were weighed for a batch size of 30 tablets and mixed uniformly in a mortar except talc and magnesium Stearate. Finally magnesium Stearate and talc were added as lubricant. This uniformly mixed blend was compressed in to tablets containing 1 mg drug using 6mm flat face surface punches on a cemache rotary tablet machine by direct compression method. Total weight of tablet was kept 80mg. [5] Available online: www.ijipsr.com August Issue 1839

Drug-excipients compatibility study by FTIR A B C Fig.1: IR spectra of A) Ropinirole hydrochloride B) Optimized formulation Ropinirole HCL+MCC+ SSG C) Optimized formulation. Ropinirole HCL + Crosspovidone + Croscarmellose sodium FTIR study was done to verify if there was any interaction between the pure drug and various excipients were employed. The various FTIR graphs both of pure drug and optimization formula formulated into IR pellet and scanned. Ropinirole HCl Table 1: Principal Peaks in FTIR Spectrum Region in cm -1 Type of vibration and Functional groups 1 347 NH - stretching 3365 NH - stretching 3 105 N - stretching 4 1187 N - stretching 5 1199 N - stretching 6 1403 S - stretching 7 1789 Cl - stretching Table : Stability Data Drug Sample and Drug-Polymer Mixture S.No Ingredients Ratio Initial 55 (weeks) 40± c/75±5%rh (4 Weeks) FTIR 1 API 1 Off White No Change No Change Complies Mannitol 1 White No Change No Change Complies 3 MCC 1 Off White No Change No Change Complies 4 Cross povidone 1 White No Change No Change Complies 5 SSG 1 White No Change No Change Complies 6 CCS 1 White No Change No Change Complies 7 API+CP+SSG 1:: Off White No Change No Change Complies Available online: www.ijipsr.com August Issue 1840

Preparation of standard graph for Ropinirole HCl Standard solutions in the range of 3 to 15 mcg/ml were prepared and absorption values were recorded at 49 nm against the reference. From this data, the standard curve of Ropinirole hydrochloride was obtained by plotting absorbance on Y-axis against concentration on X-axis. Table No: 3 Standard graph of Ropinirole HCl Fig.: Calibration curve of Ropinirole HCl Concentration Absorbance (micro gm/ml) 0 0 3 0.153 6 0.7904 9 0.3886 1 0.55934 15 0.6347 Table 4: working formula of the preliminary batches from F1-F8 batches S.no Name of The Ingredient R1 R R3 R4 R5 R6 R7 R8 mg mg mg mg mg mg mg mg 1 Ropinirole 1 1 1 1 1 1 1 1 Crosspovidone 4 6 8 - - - - 3 Sodium starch glycolate - - - - 4 8 1 16 4 Croscarmellose Sodium - - - - - - - - 5 Mcc - - - - - - - - 6 Flavour 1 1 1 1 1 1 1 1 7 Mannitol 7 70 68 66 70 66 6 58 8 Aspartame 9 Aerosil 10 Total Wt. 80 80 80 80 80 80 80 80 Table- 5: working formula of the preliminary batches from F9-F16 batches S.no Name of The Ingredient R9 R10 R11 R1 R13 R14 R15 R16 mg mg mg mg mg Mg mg mg 1 Ropinirole 1 1 1 1 1 1 1 1 Crosspovidone - - - - - - - - 3 Sodium starch glycolate - - - - - - - - 4 Croscarmellose Sodium 4 6 8 - - - - 5 Mc c - - - - 5 10 15 0 6 Flavour 1 1 1 1 1 1 1 1 7 Mannitol 7 70 68 66 69 64 59 54 8 Aspartame 9 Aerosil 10 Total Wt. 80 80 80 80 80 80 80 80 Available online: www.ijipsr.com August Issue 1841

Table-6: Micrometric Properties of Granules (Pre-compression Data) Preliminary Batches F1-F16 Formulation Bulk density (gm/cm 3 ) Tapped density(gm/cm 3 ) Angle of repose(θ) Carr s Index(%) Hausner s ratio F1 0.40 0.47 1.5 14.8 1.17 F 0.41 0.46 0.1 10.86 1.1 F3 0.41 0.47 19.6 1.7 1.14 F4 0.43 0.48 17.8 10.4 1.11 F5 0.41 0.45 19. 8.88 1.09 F6 0.40 0.44 18.4 9.09 1.10 F7 0.44 0.50 18.5 1.0 1.13 F8 0.41 0.46 17.4 10.86 1.1 F9 0.4 0.48 17.8 1.5 1.14 F10 19.9 0.434 0.497 1.67 1.14 F11 1.5 0.50 0.58 10.65 1.15 F1 6.7 0.487 0.561 13.19 1.15 F13 8.34 0.544 0.643 15.39 1.18 F14 7.34 0.510 0.591 13.70 1.15 F15 8.47 0.498 0.58 14.43 1.16 F16 6.7 0.487 0.561 13.19 1.15 Table 7: Post Compression Evaluation studies of tablets preliminary Batches F1-F16 Code Weight Hardness Thickness Variation(mg) (Kg/Cm ) (Mm) Friability (%) F1 80.4±1.00.5±0.08 1.±0.63 0.65±0.035 F 81.4±1.00.4±0.15 1.1±0.1.9 0.66±0.058 F3 80.7±0.65.8±0.057 1.±0.05 0.63±0.040 F4 80.1±1.80.4±0.10 1.±0.135 0.66±0.06 F5 80.3±0.84.4±0.15 1.1±0.057 0.69±0.067 F6 80.8±0.84.4±0.656 1.±0.1 0.65±0.00 F7 80±0.38.4±0.00 1.1±0.045 0.65±0.06 F8 81.6±0.97.5±0.30 1.1±0.115 0.65±0.035 F9 80.7±1.35.5±0.08 1.±0.063 0.65±0.035 F10 79.7±0.8.4±0.15 1.1±0.109 0.66±0.058 F11 81.6±1.81.7±0.057 1.±0.05 0.63±0.040 F1 81.1±1.6.4±0.10 1.±0.135 0.66±0.06 F13 80.9±.74.4±0.15 1.1±0.057 0.69±0.067 F14 81.3±1.04.4±0.656 1.±0.1 0.65±0.00 F15 8±0.70.4±0.00 1.1±0.045 0.65±0.06 F16 80.80±0.83.5±0.30 1.1±0.115 0.64±0.035 Available online: www.ijipsr.com August Issue 184

Table 8: Post Compression Evaluation studies of tablets preliminary Batches F1-F16 Code Wetting Water Disintegration Time(Sec) Absorption Time(Sec) Assay (%) F1 34±1.414 51±0.707 15±0.707 98.0±0.615 F 6±1.069 4±1.57 10±0.577 98.47±0.45 F3 1±1.57 34±1.00 1±0.577 99.89±0.085 F4 54±0.763 41±0.80 16±1.00 98.64±0.145 F5 48±1.101 36±1.159 41±1.57 99.1±0. F6 44±1.014 37±1.418 37±1.137 98.73±0.18 F7 61±1.58 34±0.70 6±1.57 97.5±0.438 F8 53±0.71 4±1.193 4±1.63 98.37±0.13 F9 4±1.414 51±0.707 15±0.0707 98.0±0.615 F10 6±1.069 4±1.57 10±0.577 98.47±0.45 F11 1±1.57 34±1.00 18±0.577 99.89±0.085 F1 34±0.793 41±0.80 6±1.00 98.64±0.145 F13 48±1.101 46±1.159 1±1.57 99.1±0. F14 44±1.014 37±1.418 17±1.137 98.73±0.18 F15 31±1.58 34±0.70 16±1.57 97.51±0.438 F16 33±0.71 4±1.193 13±1.63 98.37±0.13 *Mean ±SD, n=3 The hardness of the tablets was found to be.1 + 0.10 to.7 + 0.057 kg/cm and friability was found to be below 1% indicating good mechanical resistance. The thickness of the tablets was found to be 1.1± 0.057 to 1.± 0.04. All the tablets passed weight variation test, as percentage weight variation was within the Pharmacopoeial limits i.e. ±7.5%. The drug content was found to be 98.0 to 99.89%, indicating uniform distribution of drug in the tablets & in-vitro drug release was found to be 97.831+ 0.93 to 98.98 +0.410. DESIGN OF EXPERIMENTS Table 9: Pre Work Data Formulation of Ropinirole Sublingual Tablet S.n Name of The R1 R R3 R4 R5 R6 R7 R8 R9 R10 R11 R1 o Ingredient 1 Ropinirole HCl 1 1 1 1 1 1 1 1 1 1 1 1 Crosspovidone 4 6 8 - - - - - - - - Sodium 3 - - - - 4 8 1 16 - - - - starch glycolate Croscarmellose 4 - - - - - - - - 4 6 8 Sodium 5 MCC - - - - - - - - - - - - 6 Flavour (vanilla) 1 1 1 1 1 1 1 1 1 1 1 1 7 Mannitol 7 70 68 66 70 66 6 58 7 70 68 66 8 Aspartame 9 Aerosil 10 Total Wt. 80 80 80 80 80 80 80 80 80 80 80 80 Available online: www.ijipsr.com August Issue 1843

S.no Table-10: Analysis of factorial formulation: Working formula of factorial Formulation Mixed effect of CP & SSG [BATCH-A F1-F5] Name of the ingredient ( mg) 1 3 4 Table 11: Analysis of factorial formulation: Working formula of factorial formulation. Mixed effect of CCS &MCC [BATCH-B] In the present study Ropinirole hydrochloride sublingual Fast disintegrating tablets were prepared by using superdisintegrants namely, Crosspovidone, Croscarmellose sodium and sodium starch glycolate. All the formulations were evaluated for various parameters like hardness, friability, drug content, wetting time, water absorption ratio, disintegration time and In-vitro drug release [6-1]. 5 1 Ropinrole HCl 1 1 1 1 1 1 1 1 1 1 1 1 Crosspovidone.8 3..7.6 3.0.4 3..4.5.4.9.4 3 Sodium starch glycolate 4.8 5.8 5.4 6. 5.4 4.8 4.8 6.4 5. 5.6 6.4 4.8 4 Flavour (vanilla) 1 1 1 1 1 1 1 1 1 1 1 1 5 Mannitol 65.4 63. 64.7 65.1 65.5 66.8 66.0 65. 66.4 66.0 65.6 66.8 6 Aspartame 7 Aerosol S.n o Name of the ingredient 1 3 4 5 6 7 8 9 10 11 1 1 Ropinrole 1 1 1 1 1 1 1 1 1 1 1 1 Croscarmellose Sodium 1.6 1.95.19 1.6.4.4 1.6.1. 1.6 1.90 3 MCC 3.15 3.67 4 4 4.75 3.504 4.4 4 Flavour(vanilla) 1 1 1 1 1 1 1 1 1 1 1 1 5 Mannitol 70 68.89 69.80 69 68.9 68 69 68. 69.1 68.9 68 69 6 Aspartame 7 Aerosol Table 1:Pre-Compression parameters Evaluation of factorial formulations of Sublingual Tablets BATCH-A parameters 1 3 4 5 6 7 8 9 10 11 1 Bulk Density 0.41 0.40 0.4 0.36 0.6 0.5 0.7 0.48 0.34 0.45 0.38 0.44 Tapped density 0.4 0.4 0.41 0.48 0.46 0.44 0.5 0.47 0.46 0.54 056 048 Carr s ratio 16.10 18 18.18 19 19.5 17.3 16.66 19.33 16.5 15.8 15.68 18.5 Hausner s ratio 1. 1. 1.3 1.9 1.16 1.17 1.11 1.18 1. 1.1 1.5 1.4 Angle of Repose 14. 13.5 14.15 13.1 1.6 14.8 14.68 15.70 16.4 19 19.1 18. * All the values represented as mean ± Standard Deviation (SD), n=3. 6 7 8 9 10 11 1 Available online: www.ijipsr.com August Issue 1844

Table 13:Pre-Compression parameters Evaluation of factorial formulations of Sublingual Tablets BATCH-B parameters 1 3 4 5 6 7 8 9 10 11 1 Bulk 0.331 0.36 0.386 0.434 0.50 0.487 0.494 0.4 0.481 0.475 0.54 0.488 Density Tapped 0.404 0.384 0.390 0.45 0.46 0.44 0.4 0.531 0.54 0.46 0.484 0.44 density Carr s 14.8 15.38 14.74 16.07 16.6 14.69 13.94 1.11 17 17.17 19.39 19.1 ratio Hausner s 1.11 1.14 1.4 1.0 1.18 1.16 1.13 1.4 1.16 1.8 1.16 1.13 ratio Angle of 14.1 1.1 16.13 18.14 14.64 15.4 13.5 19 1.4 15.5 19. 17.8 Repose * All the values represented as mean ± Standard Deviation (SD), n=3. Table 14: Post-Compression Evaluation of factorial formulations of Sublingual Tablets Batch A Mixed effect of CP & SSG Post-compression Parameters 1 3 4 5 6 7 8 9 10 11 1 Hardness.1.5.8.1.1.3.8. 1.8 1.8.4 Thickness 1.3 1.1 1.4 1. 1.5 1.4 1.6 1.7 1. 1.1 1.3 1.9 Friability 0.6 0.6 0.6 0.56 0.6 0.63 0.65 0.6 0.55 0.58 0.63 0.54 Disintegration time (sec) 11 1 1 13 13 14 15 14 10 11 11 1 Assay (%) 93.1 95. 9.3 95.4 94.3 96.4 95.1 95.9 96. 97.4 97.8 98.9 Table 15: Post-Compression Evaluation of factorial formulations of Sublingual Tablets Batch B Mixed effect of CCS &MCC Post- compression Parameters 1 3 4 5 6 7 8 9 10 11 1 Hardness..1.7.1.1.4.1..1.5.7 Thickness 1.3 1.1 1.4 1. 1.5 1.4 1.6 1.7 1. 1.1 1.3 1.9 Friability 0.6 0.6 0.6 0.56 0.6 0.63 0.65 0.6 0.55 0.58 0.63 0.54 Disintegration time 86 18 8 9 11 9 8 7 16 108 13 14 (sec) Assay (%) 98.5 97.6 97.8 96. 95.4 96.5 98.7 97.8 96.9 97.4 97.45 99.8 Fig.3 & 4: Disintegration time of all formulation Available online: www.ijipsr.com August Issue 1845

The most important parameter that needs to be optimized in the development of fast disintegrating tablets is the disintegration time of tablets. In the present study disintegration time of all batches were found in the range of 15 ± 0.577 sec fulfilling the official requirements (less than1 min) for disintegrating tablets. It was observed that the disintegration time of the tablets decreased with increasing concentration of Crosspovidone, sodium stach glycolate and Croscarmellose sodium. Batch A of F3 and Batch B of F1 Formulation was selected as optimized batch containing Batch A (CP: 3-4%, SSG: 6-8%). Batch B (CCS: -3%, MCC; -5%) as superdisintegrant in above said concentration. It was shown less disintegration time of 1 seconds. It was observed that less disintegration time was observed when Crosspovidone and sodium starch glycolate was used as superdisintegrant, may be due to swelling at faster rate upon contact with water and elimination of lump formation after disintegration when compared with Microcrystalline cellulose and Croscarmellose sodium. Batch A of Formulation F3 was found to be the best as this formulation shown less disintegration time and possessing good tableting properties. In-vitro dissolution study The dissolution study on formulation no : F1 to F1 were carried out using 900 ml of respective dissolution medium at 50rpm using USP.The formulations F1 to F1shown 97.83 + 0.93 to 98.9 +410 in 1 sec respectively the rapid In Vitro dissolution was shown in the Batch A of formulation F3 containing Crosspovidone and Sodium starch glycolate. High dissolution resulted due to faster break down & rapid disintegration of tablet From the dissolution study an important conclusion can be drawn that addition of superdisintegrant technique has improved the dissolution profile of the water soluble drugs besides the disintegration time. Rapidly disintegrating fast dissolving tablets of Ropinrole HCl was prepared using either Ropinrole HCl with various amounts of Super disintegrate mixed effect by direct compression. The physical characteristics of the tablets were as follows: hardness (measured using Monsanto hardness tester),.8 Kg/cmand.6 Kg/cm; friability (determined using a friabilator, Electronics India Ltd., Mumbai), 0.60.35%. Formulation of rapidly disintegrating fast dissolving tablets is based on two principal criteria: the tablets should disintegrate in less than 1 min and 95% of the drug should dissolve in less than 30 min. To optimize the ratios of Superdisintegrant mixed effect that can provide rapid disintegration of tablets with rapid dissolution of the drug contained therein, 1 formulations each Batch A & B were prepared according to the 4 factorial designs (Table ). The design provided an empirical Available online: www.ijipsr.com August Issue 1846

G.Vikramadhitya et.al / IJIPSR / (8), 014, 1837-1853 ISSN (online) 347-154 RESEARCH ARTICLE Department of Pharmaceutics First order polynomial model. Following are the Design Expert Quality by Design statistical model For Independent variables taken as Disintegration and Hardness. n-expert Software r Coding: Actual A Hardness sign points above predicted value sign points below predicted value Design-Expert Software Factor Coding: Actual Design Points Std Error Shading 1.500.8.6 Batch A Hardness.4 8.00 0.500. 7.50 X1 = A: CP X = B: SSG 1.8 B: SSG A: CP B: SSG 1.6 7.00 8.00 6.50 7.50 4.00 7.00 0.800 3.80 B: SSG 1.000 3.60 6.50 3.40 6.00 3.0 6.00 A: CP 3.0 3.40 3.60 3.80 4.00 A: CP Fig. 5 Batch A Hardness of CP and SSG Fig. 6: Batch A Hardness of CP and SSG Contour plot Coefficient Factor estimate intercept. Df. Standard error 95% CI.063333 1 0.08437 low=1.877631 high=.49036 Final Equation In Terms Of Coded Factor: Batch A Hardness=.063333 Final Equation In Terms Of Actual Factor: Batch A Hardness =.063333 Value Of Prob > F Less Than 0.0500 Indicate Model Terms Are Significant Design-Expert Software Factor Coding: Actual Std Error Shading 1.500 Design-Expert Software Factor Coding: Actual Design Points Std Error Shading 1.500 0.500 X1 = A: CCS X = B: MCC 1.400 0.93 0.800 0.500 4.50 1.00 X1 = A: CCS X = B: MCC 1.000 B: MCC 5.00 0.800 4.00 3.50 0.400 5.00 4.50.80 4.00.60 3.50 B: MCC.50.40.50.00.0.40.60.80 A: CCS.0 A: CCS.00 Fig.7. Batch B Hardness of CCS and MCC Fig.8: Batch A Hardness of CCS and MCC Counter plot Coefficient Factor estimate intercept. Df. Standard error 95% CI.35 1 0.144141 low=.007749 high=.6451 Final Equation In Terms Of Coded Factor: Batch B Hardness=.35 Final Equation In Terms Of Actual Factor: Batch B Hardness =.35 Value Of Prob > F Less Than 0.0500 Indicate Model Terms Are Significant Design-Expert Software Factor Coding: Actual Std Error Shading 1.500 Design-Expert Software Factor Coding: Actual Design Points Std Error Shading 1.500 0.500 X1 = A: CP X = B: SSG 1.400 1.000 0.800 0.500 1.00 7.50 1.000 X1 = A: CP X = B: SSG 0.800 B: SSG 8.00 0.400 0.00 7.00 0.000 6.50 4.00 6.00 3.80 6.50 3.60 3.40 A: CP 6.00 7.00 7.50 3.0 B: SSG Available online: www.ijipsr.com 3.40 3.60 3.80 4.00 A: CP 8.00 Fig.9: Batch A Disintegration of CP and SSG 3.0 Fig.10: Batch A Disintegration of CP and SSG Contour plot August Issue 1847

B: MCC Design-Expert Software Factor Coding: Actual Std Error Shading 1.500 0.500 X1 = A: CCS X = B: MCC RESEARCH ARTICLE G.Vikramadhitya et.al / IJIPSR / (8), 014, 1837-1853 Coefficient Factor estimate intercept. Df. Standard error 95% CI 9.5833 1 0.5163 low=8.6166 high=9.780401 Final Equation In Terms Of Coded Factor: Batch A Disintegration= 9.5833 Final Equation In Terms Of Actual Factor: Batch A Disintegration =9.5833 Value Of Prob > F Less Than 0.0500 Indicate Model Terms Are Significant 1.000 0.800 Design-Expert Software Factor Coding: Actual Design Points Std Error Shading 1.500 0.500 5.00 4.50 0.500 0.700 0.400 X1 = A: CCS X = B: MCC 4.00 0.800 0.700 0.00 3.50 0.000 0.700 5.00 4.50 4.00 B: MCC 3.50.50.00.0.40.80.60 A: CCS.50 0.800 0.900.00.0.40.60.80 A: CCS Fig. 11: Batch B Disintegration of CCS and MCC Fig.1: Batch B Disintegration of CCS and MCC Counter Plot Coefficient Factor estimate intercept. Df. Standard error low high VIF 903815 1 0.99645 7.78497 11.4845 A-CCS=1.775765 1 1.11076-0.73695 4.88478 1.01366 B-MCC=-0.156 1 1.09608 -.63551.3351 1.01366 Final Equation In Terms Of Coded Factor: R1= +9.385, 1.775765 * A,-0.156 * B Final Equation In Terms Of Actual Factor: = 0.97067, 3.55153 * CCS,-0.148 MCC Value Of Prob > F Less Than 0.0500 Indicate Model Terms Are Significant Table 16: In vitro Cumulative drug release from factorial formulations of Sublingual Tablets Batch-A (CP & SSG) [F1-F1] S.no Time Cumulative percentage of drug release of formulation (min) F1 F F3 F4 F5 F6 1 0 0 0 0 0 0 0 1 95.61951 96.697 96.3415 95.18049 96.40976 95.7073 3 96.73 97.441 96.89093 96.1489 97.33083 96.4497 4 3 96.978 97.81573 97.54859 96.57616 97.94678 97.1954 5 4 97.49546 98.38778 98.1193 97.3465 99.0489 98.468 6 5 98.15137 99.04807 98.7789 98.1104 99.13676 98.41873 7 10 98.80815 99.6144 99.35034 98.91887 99.847 99.16463 8 15 97.49546 98.38778 98.1193 97.3465 99.0489 98.468 9 0 98.35137 99.4807 98.4789 98.1104 99.53676 98.41873 10 5 99.31741 96.14796 96.76357 97.7449 98.8304 98.913 11 30 97.936 96.41137 97.56456 98.63916 97.46891 98.55867 Available online: www.ijipsr.com August Issue 1848

Table 17: In vitro Cumulative drug release from factorial formulations of Sublingual Tablets Batch-A (CP & SSG) [F1-F1] Sno Time Cumulative percentage of drug release of formulation F7 F8 F9 F10 F11 F1 1 0 0 0 0 0 0 0 1 94.91 95.97 94.30 94.03 94.1 96.40 3 95.70 96.59 95 94.73 95.08 97.0 4 3 96.41 97.3 95.6 95.4 95.79 97.9 5 4 97.06 98.0 96.3 96.3 96.67 98.10 6 5 97.75 98.65 97.1 96.85 97.47 99.7 7 10 98.47 99.33 98.10 97.48 98.0 99.91 8 15 95.70 96.59 95.0 94.73 95.08 97.0 9 0 96.41 97.30 95.61 95.4 95.79 97.9 10 5 97.75 98.65 97.1 96.8 97.47 99.7 11 30 97.5 96.54 97. 98.83 95.5 99.05 Sno Table-18: In vitro Cumulative drug release from factorial formulations of Sublingual Tablets BATCH B (MCC &CCS) Time Cumulative percentage of drug release of formulation F1 F F3 F4 F5 F6 1 0 0 0 0 0 0 0 1 96.93 93.86 93.86 94.56 96.14 96.05 3 97.55 94.60 94.51 95.6 96.85 96.94 4 3 98.08 95.6 95.34 95.97 97.48 97.56 5 4 98.69 95.87 96.05 96.76 98.11 98.8 6 5 99.31 96.14 96.76 97.74 98.83 98.9 7 10 99.93 96.41 97.56 98.63 99.46 99.55 8 15 97.55 94.60 94.51 95.6 96.85 96.94 9 0 98.08 95.6 95.34 95.97 97.48 97.56 10 5 99.31 96.14 96.76 97.74 98.83 98.9 11 30 98.5 96.8 97.5 97.45 98.65 98.45 Table-19: In vitro Cumulative drug release from factorial formulations of Sublingual Tablets BATCH B (MCC &CCS) Sno Time Cumulative percentage of drug release of formulation F7 F8 F9 F10 F11 F1 1 0 0 0 0 0 0 0 1 94.91 95.97 94.30 94.03 94.1 96.40 3 95.70 96.59 95 94.73 95.08 97.0 4 3 96.41 97.3 95.6 95.4 95.79 97.9 5 4 97.06 98.0 96.3 96.3 96.67 98.10 6 5 97.75 98.65 97.1 96.85 97.47 99.7 7 10 98.47 99.33 98.10 97.48 98.0 99.91 8 15 95.70 96.59 95.0 94.73 95.08 97.0 9 0 96.41 97.30 95.61 95.4 95.79 97.9 10 5 97.75 98.65 97.1 96.8 97.47 99.7 11 30 97.5 96.54 97. 98.83 95.5 99.05 Available online: www.ijipsr.com August Issue 1849

13 14 15 16 17 18 Fig.13, 14, 15: BATCH-A Cumulative % drug release of CP & SSG formulations Fig. 16, 17, 18: BATCH-B Cumulative % drug release of CCS & MCC formulations Table-0: Accelerated stability studies Parameters Time in months 0 (Initial) 1 st month nd month 3 rd month Hardness (kg/cm ).6±0.057.6±0.09.6±0.046.6±0.019 Friability (%) 0.63±0.040 0.63±0.060 0.63±0.09 0.63±0.069 Disintegration time(sec) 15±0.577 15±0.739 15±0.68 15±0.834 Drug content (%) 99.89±0.085 99.89±0.059 98.89±0.039 98.89±0.019 In vitro drug release (%) 99.9±0.065 99.9±0.058 99.9±0.049 99.9±0.038 The stability [13-].of this optimized formulation was known by performing stability studies for three months at accelerated conditions of 40 0 C + 75 % RH on optimized formulation. The formulation was found to be stable, because there was no change in the hardness, disintegration time, drug content and in-vitro drug release pattern. Experimental design In the present study, a Four level two factorial design was used to evaluate the efects of the selected independent variables on the responses, to characterize the physical properties of the tablet like disintegration time, the Hardness and to optimize the procedure. Tihs design is suitable for exploration of the quadratic responses and the second order polynomial models, thus helping to optimize the process by using a small number of experimental runs. Available online: www.ijipsr.com August Issue 1850

Optimization results The formulation was designed using 4 factorial design, the materials and compositions used were presented in tables 7,8, In this study, formulation variables i.e, Independent variables: BATCH A : A=Crossprovidone, Dependent variables: B=Sodium Starch Glycolate BATCH B : A= Croscarmellose Sodium, B=Microcrystalline Cellulose Y1=Disintegration time, Y= Hardness. Optimized formulation of the present research: F3 of Batch-A factorial formulations Analysis of contour plots and response surface plots F1 of Batch-B factorial formulations Three-dimensional (3D) plots and Contour plots for the measured responses were formed, based on the model polynomial functions to assess the change of the response surface. Also the relationship between the dependent and independent variables can be further understood by these plots. Since the model has two factors, one factor was held constant for each diagram; therefore, a total of response surface diagrams was produced one for each response. Response surface plots are presented using optimal levels of the factors studied. Considering the greatest difference in model polynomial functions response, the surface plots for responses Y1 and Y are further presented. CONCLUSION Oral disintegrating tablets (ODT) of ROPINIROLE Sublingual tablets was successfully prepared by using direct compression method. In the present study, it was revealed that several combinations of polymer mixed effect of Crosspovidone, Sodium Starch glycolate and polymer mixed effect of Croscarmellose sodium and Micro crystalline cellulose can produce tablets that provide less than 1 min Disintegration Time and less than 30 min t90%. However, use of Superdisintegrant mixed effect of Crosspovidone, Sodium Starch glycolate alone in the lowest quantity studies provided a faster tablet disintegration and drug dissolution (1 sec) than the use of superdisintegrants mixed effect of Croscarmellose sodium and Microcrystalline cellulose (15 sec).the method for ODT of Ropinirole with optimal release properties was determined using experimental design methodology. Available online: www.ijipsr.com August Issue 1851

After determination of significant parameters by using four-level two-factorial design was applied. Analytical parameters investigated in this study were: concentration of two superdisintegrant Crosspovidone (A), sodium starch glycolate (B) for batch A and for batch B Croscarmellose sodium (A) and microcrystalline cellulose (B). The chosen responses were disintegration time and the Hardness. The model reliability and estimation of quantitative effects of different levels of investigated factors was performed using the Design Expert 8.0. The levels of these factors were predicted to obtain an optimal response with reference to set constraints. The observed responses were close to the predicted values for the optimized drug release method. From the above results, it can be concluded that characterization and optimization of the Ropinirole oral disintegrate tablets were performed in a very short time period and with a small number of experimental runs. It is essential that experimental design methodology is a very economical way for extracting the maximum amount of complex information, a significant experimental time saving factor and moreover, it saves the material used for analyses and personal costs as well. The results of 4 factorial design revealed that the different ratio of two superdisintegrants significantly affect the dependent variables disintegration time and hardness. It is concluded that by adopting a systematic formulation approach, an optimum can be reached in the shortest time with minimum efforts. REFERENCES 1. Seager, H., Drug-deliver Products and the Zydis Fast-dissolving Dosage Form",J.Pharm and Pharmacol., 1998;50:375-38.. Bradoo, R., Shahani, S., Poojary, S., Deewan, B. and Sudarshan, S., fast dissolving over view, International journal of pharmaceutical sciences 001; 4(10):7-31. 3. United States Publication (006) Publication Number US 006/0165781 A1. 4. Bhowmik D (009) Design and characterization of fast dissolving tablet of telmisartan. IJPRR 1: 31-40. 5. Gerald Van Belle Biostatistics- A Methodology for the Health Sciences. (ndedn). 6. Gohel M, Patel M, Amin A, Agrawal R, Dave R, et al. (004) Formulation, design and optimisation of mouth dissolving tablets of nimesulide using vaccum technique. AAPS Pharm Sci Tech 5: 10-15. 7. Desai, Kharede SV, Petkar KC, Kuchekar BS (006) Orodispersible tablets of promithazine hydrochloride. Indian J Pharm Edu and Research 40: 17-174. Available online: www.ijipsr.com August Issue 185

8. Vijay KSG, Mishra DN (006) Rapidly disintegrating oral tablets of meloxicam. Indian Drugs 43: 117-11. 9. Chandrashekar NS, Kulkarni PK, Parimala P (006) Formulation and evaluation of fast dissolving tablets of rofecoxib. Int J Pharma Excip 14-17. 10. Devi VK, Asha AN, Pai RS, Reddy MCH, Raghvendra MMAV (006) Orodispersible fuconazole tablets-preparation and Evaluation. Indian Drugs 43: 548-55. 11. Di Martino P, Martelli S, Wehrlé P (005) Evaluation of different fast melting disintegrants by means of a central composite design. Drug Dev Ind Pharm 31:109-11. 1. http://www.rxlist.com/micardis-drug-center.htm 13. Journal of Pharmaceutical Sciences : S146-156 14. Fast Dissolving Drug Delivery System (006). 15. Rowe RC (009) Hand Book Of Pharmaceutical Excipients. (6thedn). 16. United states of pharmacopeia 3 - nf 7, Physical tests for solid dosage form. 17. Indian pharmacopeia (010) III: 186. 18. Banker GS, Rhodes CT (1996) Modern Pharmaceutics and the pharmaceutical sciences. (4thedn), 11: 39-330. 19. Manivannan R (009) Oral Disintegrating Tablets: A Future Compaction. International Journal of Pharmaceutical Research and Development. 0. Gordon MS, Chatterjee B, Chowhan ZT (006) Effect of the mode of croscarmellose sodium incorporation on tablet dissolution and friability. J Pharm Sci 79: 43 47. 1. Guidance for the Industry dissolution testing for the immediate solid oral release dosage forms.. Sanford Bolton, Charles Bon. Pharmaceutical Statistics, Practical and Clinical Applications. Available online: www.ijipsr.com August Issue 1853