International Journal of Innovative Pharmaceutical Sciences and Research

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1 International Journal of Innovative Pharmaceutical Sciences and Research 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 Telangana, INDIA vikramadhitya.g@gmail.com Phone: Available online: August Issue 1837

2 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: August Issue 1838

3 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: August Issue 1839

4 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 NH - stretching 3365 NH - stretching N - stretching N - stretching N - stretching S - stretching 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: August Issue 1840

5 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) 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 Crosspovidone Sodium starch glycolate Croscarmellose Sodium Mcc Flavour Mannitol Aspartame 9 Aerosil 10 Total Wt 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 Crosspovidone Sodium starch glycolate Croscarmellose Sodium Mc c Flavour Mannitol Aspartame 9 Aerosil 10 Total Wt Available online: August Issue 1841

6 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 F F F F F F F F F F F F F F F F 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± ± ±0.035 F 81.4±1.00.4± ± ±0.058 F3 80.7±0.65.8± ± ±0.040 F4 80.1±1.80.4± ± ±0.06 F5 80.3±0.84.4± ± ±0.067 F6 80.8±0.84.4± ± ±0.00 F7 80±0.38.4± ± ±0.06 F8 81.6±0.97.5± ± ±0.035 F9 80.7±1.35.5± ± ±0.035 F ±0.8.4± ± ±0.058 F ±1.81.7± ± ±0.040 F1 81.1±1.6.4± ± ±0.06 F ±.74.4± ± ±0.067 F ±1.04.4± ± ±0.00 F15 8±0.70.4± ± ±0.06 F ±0.83.5± ± ±0.035 Available online: August Issue 184

7 Table 8: Post Compression Evaluation studies of tablets preliminary Batches F1-F16 Code Wetting Water Disintegration Time(Sec) Absorption Time(Sec) Assay (%) F1 34± ± ± ±0.615 F 6± ± ± ±0.45 F3 1± ±1.00 1± ±0.085 F4 54± ± ± ±0.145 F5 48± ± ± ±0. F6 44± ± ± ±0.18 F7 61± ±0.70 6± ±0.438 F8 53±0.71 4± ± ±0.13 F9 4± ± ± ±0.615 F10 6± ± ± ±0.45 F11 1± ± ± ±0.085 F1 34± ±0.80 6± ±0.145 F13 48± ± ± ±0. F14 44± ± ± ±0.18 F15 31± ± ± ±0.438 F16 33±0.71 4± ± ±0.13 *Mean ±SD, n=3 The hardness of the tablets was found to be to 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± to 1.± 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 to 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 Crosspovidone Sodium starch glycolate Croscarmellose Sodium 5 MCC Flavour (vanilla) Mannitol Aspartame 9 Aerosil 10 Total Wt Available online: August Issue 1843

8 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) 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 Crosspovidone Sodium starch glycolate Flavour (vanilla) Mannitol Aspartame 7 Aerosol S.n o Name of the ingredient Ropinrole Croscarmellose Sodium MCC Flavour(vanilla) Mannitol Aspartame 7 Aerosol Table 1:Pre-Compression parameters Evaluation of factorial formulations of Sublingual Tablets BATCH-A parameters Bulk Density Tapped density Carr s ratio Hausner s ratio Angle of Repose * All the values represented as mean ± Standard Deviation (SD), n= Available online: August Issue 1844

9 Table 13:Pre-Compression parameters Evaluation of factorial formulations of Sublingual Tablets BATCH-B parameters Bulk Density Tapped density Carr s ratio Hausner s ratio Angle of 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 Hardness Thickness Friability Disintegration time (sec) Assay (%) Table 15: Post-Compression Evaluation of factorial formulations of Sublingual Tablets Batch B Mixed effect of CCS &MCC Post- compression Parameters Hardness Thickness Friability Disintegration time (sec) Assay (%) Fig.3 & 4: Disintegration time of all formulation Available online: August Issue 1845

10 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 ± 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 to 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), %. 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: August Issue 1846

11 G.Vikramadhitya et.al / IJIPSR / (8), 014, ISSN (online) 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 Batch A Hardness X1 = A: CP X = B: SSG 1.8 B: SSG A: CP B: SSG B: SSG A: CP 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 low= high= Final Equation In Terms Of Coded Factor: Batch A Hardness= Final Equation In Terms Of Actual Factor: Batch A Hardness = Value Of Prob > F Less Than Indicate Model Terms Are Significant Design-Expert Software Factor Coding: Actual Std Error Shading Design-Expert Software Factor Coding: Actual Design Points Std Error Shading X1 = A: CCS X = B: MCC X1 = A: CCS X = B: MCC B: MCC B: MCC 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 low= 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 Indicate Model Terms Are Significant Design-Expert Software Factor Coding: Actual Std Error Shading Design-Expert Software Factor Coding: Actual Design Points Std Error Shading X1 = A: CP X = B: SSG X1 = A: CP X = B: SSG B: SSG A: CP B: SSG Available online: 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

12 B: MCC Design-Expert Software Factor Coding: Actual Std Error Shading X1 = A: CCS X = B: MCC RESEARCH ARTICLE G.Vikramadhitya et.al / IJIPSR / (8), 014, Coefficient Factor estimate intercept. Df. Standard error 95% CI low= high= Final Equation In Terms Of Coded Factor: Batch A Disintegration= Final Equation In Terms Of Actual Factor: Batch A Disintegration = Value Of Prob > F Less Than Indicate Model Terms Are Significant Design-Expert Software Factor Coding: Actual Design Points Std Error Shading X1 = A: CCS X = B: MCC B: MCC A: CCS 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 A-CCS= B-MCC= Final Equation In Terms Of Coded Factor: R1= , * A, * B Final Equation In Terms Of Actual Factor: = , * CCS, MCC Value Of Prob > F Less Than 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 F Available online: August Issue 1848

13 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 F 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 F 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 F Available online: August Issue 1849

14 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± ±0.09.6± ±0.019 Friability (%) 0.63± ± ± ±0.069 Disintegration time(sec) 15± ± ± ±0.834 Drug content (%) 99.89± ± ± ±0.019 In vitro drug release (%) 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: August Issue 1850

15 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: August Issue 1851

16 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: Bradoo, R., Shahani, S., Poojary, S., Deewan, B. and Sudarshan, S., fast dissolving over view, International journal of pharmaceutical sciences 001; 4(10): United States Publication (006) Publication Number US 006/ A1. 4. Bhowmik D (009) Design and characterization of fast dissolving tablet of telmisartan. IJPRR 1: 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: Desai, Kharede SV, Petkar KC, Kuchekar BS (006) Orodispersible tablets of promithazine hydrochloride. Indian J Pharm Edu and Research 40: Available online: August Issue 185

17 8. Vijay KSG, Mishra DN (006) Rapidly disintegrating oral tablets of meloxicam. Indian Drugs 43: Chandrashekar NS, Kulkarni PK, Parimala P (006) Formulation and evaluation of fast dissolving tablets of rofecoxib. Int J Pharma Excip Devi VK, Asha AN, Pai RS, Reddy MCH, Raghvendra MMAV (006) Orodispersible fuconazole tablets-preparation and Evaluation. Indian Drugs 43: 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: Journal of Pharmaceutical Sciences : S 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: Banker GS, Rhodes CT (1996) Modern Pharmaceutics and the pharmaceutical sciences. (4thedn), 11: 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: 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: August Issue 1853