Formulation Development and Evaluation of Amisulpride FDT

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FABAD J. Pharm. Sci. 43 2 15-25 2018 Formulation Development and Evaluation of Amisulpride Fast Dissolving Tablets Raghavendra KUMAR GUNDA º Jujjuru Naga SURESH KUMAR RESEARCH ARTICLE 15 Department of Pharmaceutics Narasaraopeta Institute of Pharmaceutical Sciences Narasaraopet Guntur Dt Andhra Pradesh India-522601 ° Corresponding Author Mr.Raghavendra Kumar Gunda M.Pharm.Ph.D Assistant Professor Department of Pharmaceutics Narasaraopeta Institute of Pharmaceutical Sciences Narasaraopet GunturD.t A.P . India-522601. E-mail: raghav.gundagmail.com Mob: +91-9666705894. Formulation Development and Evaluation of Amisulpride Fast Dissolving Tablets SUMMARY Te main objective of current research work was to formulate Amisulpride fast dissolving tablets. Amisulpride a second generation antipsychotic agent belongs to BCS class-II drug and used to treat psychoses paranoid productive schizophrenias dysthymia. Fast dissolving tablets of amisulpride were prepared employing diferent concentrations of crospovidone and croscarmellose sodium in diferent combinations as a superdisintegrants by direct compression technique using 32 factorial design. Te concentration of crospovidone and croscarmellose sodium was selected as independent variables X1 and X2 respectively whereas wetting time Disintegration time t50 t90were selected as dependent variables. nine formulations were designed and are evaluated for hardness friability thickness Assay Wetting time Disintegration time In-vitro drug release. From the Results concluded that all the formulation were found to be with in the Pharmacopoeial limits and the In-vitro dissolution profiles of all formulations were fitted in to diferent Kinetic models the statistical parameters like intercept a slope b regression coeficient r were calculated. Polynomial equations were developed for Wetting time Disintegration time t50 t90. Validity of developed polynomial equations were verified by designing 2 check point formulations C1 C2. According to to SUPAC guidelines the formulation F1 containing combination of 9 crospovidone and 9 croscarmellose is the most similar formulation similarity factor f285.384 dissimilarity factor f1 2.098 No significant diference t 0.0585 to marketed product SOLIAN-100. Te selected formulation F1 follows First order Higuchi’s kinetics mechanism of drug release was found to be Non-Fickian Difusion Super Case-II Transport n 1.445. Key Words: Amisulpride 32 factorial design super disintegrants Wetting time Disintegration time Non-Fickian difusion. Received: 05.12.2017 Revised: 10.02.2018 Accepted: 15.02.2018 Hızlı Çözünen Amisülpirid Tabletlerin Değerlendirilmesi ve Formülasyon Geliştirilmesi ÖZET Mevcut araştırma çalışmalarının temel amacı Amisulpride hızlı çözünen tabletleri formüle etmektir. Amisulpride ikinci nesil antipsikotik bir ajandır BCS sınıf II uyuşturucuya aittir ve psikozları paranoyak üretken şizofreni distimiyi tedavi etmek için kullanılır. Amisülpirid’in hızlı çözünen tabletleri 32 faktöriyel tasarım kullanılarak doğrudan sıkıştırma tekniği ile farklı derişimlerde süper dağıtıcı olarak farklı konsantrasyonlarda krospovidon ve kroskarmeloz sodyum kullanılarak hazırlandı. Bağımlı değişken olarak krospovidon ve kroskarmeloz sodyum konsantrasyonu sırasıyla bağımsız değişken X1 ve X2 olarak seçilirken ıslanma süresi parçalanma zamanı t5o t90 seçildi. Dokuz formülasyon tasarlanmış ve sertlik ufalanabilirlik kalınlık ıslatma süresi parçalanma süresi in-vitro ilaç salınımı için değerlendirilmiştir. Sonuçlardan tüm formülasyonun farmakope sınırları içinde olduğu ve tüm formülasyonların in-vitro çözünme profillerinin farklı kinetik modellere uyduğu kesişim noktası a eğim b ve regresyon katsayısı r hesaplandı. Islatma süresi parçalanma süresi t50 t90 için polinomiyal denklemler geliştirildi. Geliştirilmiş polinom denklemlerinin geçerliliği 2 kontrol noktası formülasyonu C1 C2 tasarlayarak doğrulanmıştır. SUPAC kılavuzlarına göre 9 krospovidon ve 9 kroskarmellozun kombinasyonunu içeren formülasyon F1 pazarlanmış ürüne en benzer formülasyondur benzerlik faktörü f2 85.384 farksızlık faktörü f1 2.098 ve önemli fark yok t 0.0585Amisülpirid-100. Seçilen formülasyon F1 takip edildi. Birinci mertebeden Higuchi’nin kinetiği ilaç salınım mekanizması Non-Fickian Difüzyon Süper Durum II Nakil n 1.445 olarak bulundu. Anahtar Kelimeler: Amisülpirid 32 faktöryel tasarım süper dağıtıcılar Islanma zamanı Dağılma zamanı Non Fickian difüzyon.

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16 Kumar Gunda Suresh Kumar INTRODUCTION Fast dissolving tablets are suitable for numerous kind of people including for people who have swal - lowing difculties pediatric geriatric and bedridden patients. Tey are also useful for active patients who are busy travelling and may not have access to water. Fast dissolving tablets are also popular as orodispers- ible tablets mouth-dissolving tablets orally disinte- grating tablets melt-in mouth tablets rapimelts po- rous tablets quick dissolving etc Kavitha et al. 2013. Orally disintegrating tablets ODT are formulat - ed by utilizing several processes which difer in their methodologies and the ODTs formed vary in various properties such as mechanical strength of tablet taste and mouth feel swallowability drug dissolution in saliva bioavailability and stability. Various processes employed in formulating ODTs include freeze-dry - ing or lyophilization cotton candy process molding spray drying mass extrusion and compaction wet granulation dry granulation direct compression. In the present study the direct compression meth- od was adopted to manufacture the ODT tablets since it was very simple and do not require any sophisticat- ed equipment’ s. Te direct compression represents the simplest and most cost efective tablet manufacturing technique Tanda venkataramudu et al. 2012. ODT by direct compression technique is a simple approach of drug delivery systems that proved to be rational in the pharmaceutical arena for its ease com - pliance faster production avoid hydrolytic or oxida - tive reactions occurred during processing of dosage forms. Amisulpride is a benzamide analogue. Te chem- ical name of Amisulpride is 4-Amino-N-2RS- 1-thylpyrrolidin-2-ylmethyl-5-ethylsulpho- nyl-2-methoxybenzamide Nirvesh Chaudari et al. 2015 Hitesh P . Dalvadi et al. 2016. It blocks cerebral dopamine D 2 and D 3 receptors. When administered at an oral daily dose of 50 mg it improves the dopa - minergic neurotransmission with a D 2 dopaminergic receptors pre-synaptic inhibition and it is used in the treatment of schizophrenia. Amisulpride ODT which when placed in the tongue disintegrates or dissolves rapidly in the saliva without the need of drinking wa - ter. As tablet disintegrates in the mouth this could en- hance the clinical efect of the drug through pregastric absorption from the mouth pharynx and esophagus. Tis leads to an increase in bioavailability by avoiding frst pass metabolism M.A.Shende et al. 2014. It is an important task to design an optimized formulation with an appropriate dissolution rate in a short time period with a minimum number of trials or runs. Many statistical experimental designs have been recognized as useful techniques to optimize the process variables. For this purpose response surface methodology RSM utilizing a polynomial equation has been widely used. Diferent types of RSM designs include 3-level factorial design central composite design CCD Box-Behnken design and D-optimal design. Response surface methodology RSM is used when only a few signifcant factors are involved in experimental optimization. Te technique requires less experimentation and time thus proving to be far more efective and cost-efective than the convention - al methods of formulating rapid release dosage forms Schwartz BJ et al. 1996 Raghavendra Kumar Gunda . 2015. Hence an attempt is made in this research work to formulate Fast Dissolving Tablets of Amisulpride us - ing crospovidone and croscarmellose sodium. Instead of normal heuristic method a standard statistical tool design of experiments is employed to study the efect of formulation variables on the release properties. Large scale production needs more simplicity in the formulation with economic dosage form. Te fast dissolving tablets formulation by direct compression method is most acceptable in industrial scale produc- tion. A 3 2 full factorial design was employed to system - atically study the drug release profle . A 3 2 full fac - torial design was employed to investigate the efect of two independent variables factors i.e the amounts of crospovidone and croscarmellose on the depen - dent variables i.e. Disintegration time Wetting time t 50 t 90 time taken to release 50 90 respective- ly. MATERIALS AND METHODS Materials used in this study were obtained from the diferent sources. Amisulpride was a gif sam - ple from Dr.Reddy’s Laboratories Hyderabad India. Avicel pH-101 crospovidone croscarmellose were procured from Loba Chemie Pvt.Ltd Mumbai. Other excipients such as magnesium stearate talc vanillin and sucralose were procured from S.D. Fine Chem. Ltd. Mumbai. Formulation development of amisulpride fast dissolving tablets: Te factorial design is a technique that allows identifcation of factors involved in a methodology and assesses their relative priority. In addition any interaction between factors chosen can be identifed. Construction of a factorial design involves the selec - tion of parameters and the choice of responses Ramji Anil Kumar Arza et al. 2016 NG RaghavendraRao et

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17 FABAD J. Pharm. Sci. 43 2 15-25 2018 al. 2010. A selected three level two factor experimental design 3 2 factorial design describe the proportion in which the independent variables Crospovidone and Croscarmellose sodium are used in formulation of Amisulpride fast dissolving tablets. Te time re - quired for 50 t 50 90 t 90 drug dissolution Dis- integration Time and Wetting Time were selected as dependent variables. Signifcance terms were chosen at 95 confdence interval p0.05 for Final Equa - tions. Polynomial equations were developed for t 50 t 90 Disintegration time and Wetting time step-wise backward linear regression analysis. Te three levels of factor X 1 crospovidone at a concentration of 9 7 5.Tree levels of factor X 2 croscarmellose at a concentration of 9 7 5. with respect to average weight of tablet i.e 200 mg was taken as the rationale for the design of the Amisul - pride fast dissolving tablet formulation. Amisulpride fast dissolving tablet formulations were prepared em - ploying selected combinations of the two factors i.e X 1 X 2 as per 3 2 factorial design and evaluated to fnd out the signifcance of combined efects of X 1 X 2 to select the best combination and the concentration re- quired to achieve the desired fast release/ dissolution of drug by providing large surface area and improved solubility from the dosage form. Preparation of Amisulpride Fast Dissolving T ab - lets: Amisulpride tablets were prepared by direct com- pression method. Te composition of each tablet is shown in Table No 2. Te drug diluents superdisite - grants were passed through sieve 60 separately. All the above ingredients were properly mixed together in a poly-bag. Talc and Magnesium stearate were passed through mesh 80 mixed and blended with initial mixture in a poly-bag. Te powder blend was compressed into tablets on a 8 station rotary punch tableting machine minipress using 8 mm circular punches and same hardness was used for the required number tablets. Compressed tablets were examined as per ofcial standards and unofcial tests. Tablets were packaged in well closed light resistance and moisture proof containers. Experimental Design: Experimental design utilized in present investi- gation for the optimization of superdisintegrant con - centration such as concentration of crospovidone was taken as X 1 and concentration of croscarmellose sodium was taken as X 2 . Experimental design was giv- en in the Table 1. Tree levels for the concentration of crospovidone were selected and coded as -1 5 07 +19. Tree levels for the concentration of croscarmellose sodium were selected and coded as -1 5 07 +19. Formulae for all the experi - mental batches were given in Table 2 Schwartz BJ et al. 1996 Shiv Shankar Hardenia et al. 2014. Table 1: Experimental design layout Formulation Code X 1 X 2 F 1 1 1 F 2 1 0 F 3 1 -1 F 4 0 1 F 5 0 0 F 6 0 -1 F 7 -1 1 F 8 -1 0 F 9 -1 -1 C 1 -0.5 -0.5 C 2 +0.5 +0.5 Table 2: Formulae for the preparation of Amisulpride fast dissolving tablets as per experimental design Name of Ingredients Quantity of ingredients per each tablet mg F 1 F 2 F 3 F 4 F 5 F 6 F 7 F 8 F 9 Amisulpride 100 100 100 100 100 100 100 100 100 Avicel pH-101 50 54 58 54 58 62 58 62 66 Crospovidone 18 18 18 14 14 14 10 10 10 Croscarmellose sodium 18 14 10 18 14 10 18 14 10 Magnesium Stearate 5 5 5 5 5 5 5 5 5 Talc 5 5 5 5 5 5 5 5 5 Sucralose 3 3 3 3 3 3 3 3 3 Vanillin 1 1 1 1 1 1 1 1 1 Total Weight 200 200 200 200 200 200 200 200 200

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18 Kumar Gunda Suresh Kumar Evaluation of amisulpride fast dissolving tablets: Hardness Te hardness of the tablets was tested by diamet - ric compression using a Monsanto hardness tester. A tablet hardness of about 2-4 Kg/cm 2 is considered ad- equate for mechanical stability. Friability Te friability of the tablets was measured in a Roche friabilator Camp-bell Electronics Mumbai. 20 Tablets were taken Weighed and Initial weight was noted W 0 arededusted in a drum for a fxed time 100 revolutions in a Roche friabilator and weighed W again. Percentage friability was calculated from the loss in weight as given in equation as below. Te weight loss should not be more than 1 . Friability Initial weight- Final weight / Initial weight x 100 Content Uniformity In this test 20 tablets were randomly selected and the percent drug content was determined the tab- lets contained not less than 92.5 or not more than 107.5 100±7.5 of the labeled drug content can be considered as the test was passed. Assay Drug content was determined by weighing ran- domly selected tablets pulverizing to a fne powder. Te powder equivalent to 100 mg Amisulpride was weighed and dissolved in 10 ml of Distilled water in volumetric fask the volume was adjusted to 100 ml with Phosphate bufer pH 6.8 and the solution was fl - tered. An aliquot of 1.0 ml of solution were diluted to 10 ml Phosphate bufer pH 6.8 in separate volumetric fask. Te drug content was determined spectropho - tometrically at 226 nm. Tickness Tickness of the all tablet formulations were mea - sured using vernier calipers by placing tablet between two arms of the vernier calipers. Wetting time To measure Wetting time of the tablet a piece of tissue paper folded twice was placed in a small petri dish internal diameter is 6.5 cm containing 5 ml of distilled water. A Tablet placed on the paper and the time for complete wetting of the tablet was measured in seconds. In vitro dissolution study Te In vitro dissolution study for the Amisul - pride fast dissolving tablets were carried out in USP XXIII type-II dissolution test apparatus Paddle type using 900 ml of Phosphate bufer pH 6.8 as dissolu - tion medium at 50 rpm and temperature 37±0.5°C. At predetermined time intervals 5 ml of the samples were withdrawn by means of a syringe ftted with a pre-flter the volume withdrawn at each interval was replaced with same quantity of fresh dissolution me - dium. Te resultant samples were analyzed for the presence of the drug release by measuring the absor - bance at 226 nm using UV Visible spectrophotometer afer suitable dilutions. Te determinations were per - formed in triplicate n3. Disintegration test Disintegration of fast disintegrating tablets is achieved in the mouth owing to the action of saliva however Quantity of saliva in the mouth is limited and no tablet disintegration test was found in USP and IP to simulate in vivo conditions. A modifed method was used to determine disintegration time of the tablets. A cylindrical vessel was used in which 10 mesh screen was placed in such way that only 2 ml of disintegrat - ing or dissolution medium would be placed below the sieve. To determine disintegration time 6 ml of Sorenson’s bufer pH 6.8 was placed inside the ves - sel in such way that 4 ml of the media was below the sieve and 2 ml above the sieve. Tablet was placed on the sieve and the whole assembly was then placed on a shaker. Te time at which all the particles pass through the sieve was taken as a disintegration time of the tab - let. 6 tablets were chosen randomly from the compos - ite samples and the average value was determined. Kinetic modelling of drug release Te dissolution profle of all the formulations was ftted in to zero-order frst-order Higuchi and Kors - meyer-peppas models to ascertain the kinetic model- ing of drug release Notari RE. 1987Higuchi. 1963 Peppas. 1985. RESULTS AND DISCUSSION Fast dissolving tablets of Amisulpride were pre - pared and optimized by 3 2 factorial design in order to select the best composition of superdisintegrants crospovidone croscarmellose sodium and also to achieve the desired rapid release of drug from the dos - age form by disintegrating quickly. Te two factorial parameters involved in the development of formula - tions are quantity of crospovidone croscarmellose sodium as independent variables X 1 X 2 and In vi- tro dissolution parameters such as t 50 t 90 Wetting time and Disintegrating Time as dependent variables . 9 formulations were prepared using 3 levels of 2 fac - tors and all the formulations containing 100 mg of Amisulpride were prepared as a Fast dissolving tablet dosage form by Direct Compression technique as per the formulae given in Table 2.

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19 FABAD J. Pharm. Sci. 43 2 15-25 2018 All the prepared tablets were evaluated for difer - ent post compression parameters drug content mean hardness friability mean thickness as per ofcial methods and results are given in Table 3. Te hard - ness of tablets was in the range of 3.31±0.57-3.81±0.28 Kg/cm 2 . Weight loss in the friability test was not more than 0.63. Drug content of prepared tablets was within acceptance range only. Te wetting time of tablets was in the range of 25.5±1.3-90.0±1.6 sec. Te disintegration time of tablets was in the range of 35.5±1.5-106.0±1.7 sec. Results for all Post-compres - sion parameters were tabulated or shown in Table 3. In-vitro dissolution studies were performed for prepared tablets using Phosphate bufer pH 6.8 as a dis - solution media at 50 rpm and temperature 37±0.5°C. Te In-vitro dissolution profles of tablets are shown in Fig.1-4 kinetic plots wetting time chart disintegra- tion time charts were shown in Fig.5-6. Te dissolution parameters are given in Table 4. Cumulative drug release of factorial design formu - lations F 1 -F 9 at 25 mins were found to be in the range of 89.06-99.33 . From the result it reveals that the release rate was higher for formulations containing high level of crospovidone/croscarmellose sodium compared with other formulations containing lower level due to high concentration of superdisintegrant in combination shows various disintegration mecha- nism such as wicking and swelling etc more compared with lower concentration and alone drug may release rapidly and shows improved bioavailability. Excess of superdisintegrant also prone to friable. therefore re - quired release of drug can be obtained by manipulat - ing the composition of crospovidone and croscarmel - lose sodium. variation was observed in the Wetting time Dis- integrating time t 50 and t 90 due to formulation vari - ables. formulation F 1 containing 18 mg of crospo - vidone 18 mg of croscarmellose sodium showed promising dissolution parameter Wetting time 25.5±1.3sec Disintegrating time 35.5±1.5 sec t 50 2.679 min t 90 8.902 min. Te diference in burst efect of the initial time is a result of the diference in the concentration of superdisintegrants mixtures. Tis reveals that increased concentration of super - disintegrants resulted in a corresponding decrease in the Wetting time which might be due to the result of wicking and other possible disintegrating mecha - nisms. Disintegration time is directly proportional to wetting time. Te In vitro dissolution data of Amisulpride fast dissolving formulations was subjected to goodness of ft test by linear regression analysis according to zero order and frst order kinetic equations Higuchi’s and Korsmeyer-Peppas models to assess the mechanism of drug release. Te results of linear regression anal - ysis including regression coefcients are summarized in Table 4. It was observed from the above that disso - lution of all the tablets followed First order kinetics with co-efcient of determination R 2 values in the range of 0.974-0.999. Te values of r of factorial for - mulations for Higuchi’s equation was found to be in the range of 0.958-0.994 which shows that the disso - lution data ftted well to Higuchi’s square root of time equation confrming the release followed difusion mechanism. Kinetic data also treated for Peppas equa - tion the slope n values ranges from 0.871-1.479 that shows Non-Fickian difusion mechanism with super case-II transport system. Polynomial equations were derived for Wetting time Disintegrating time t 50 and t 90 values by back- ward stepwise linear regression analysis using PCP Disso sofware and Response surface plots were con - structed using SIGMAPLOT V13 sofware. Te Re - sponse surface plots were shown in Fig.7-10 for Wet - ting time Disintegrating time t 50 and t 90 using X 1 and X 2 on both the axes respectively. Te dissolution data Kinetic parameters of factorial formulations F 1 to F 9 are shown in Table 5. Polynomial equation for 3² full factorial designs is given in Equation Y b 0 +b 1 X 1 +b 2 X 2 +b 12 X 1 X 2 +b 11 X 1 ²+b 22 X 2 ²… Where Y is dependent variable b 0 arithme- tic mean response of nine batches and b 1 estimated co-efcient for factor X 1 . Te main efects X 1 and X 2 represent the average result of changing one factor at a time from its low to high value. Te interaction term X 1 X 2 shows how the response changes when two factors are simultaneously changed. Te polyno - mial terms X 1 ² and X 2 ² are included to investigate non-linearity. Validity of derived equations was veri - fed by preparing two check point formulations of in - termediate concentrationC 1 C 2 . Te equations for Wetting time Disintegrating time t 50 and t 90 developed as follows Y 1 49.00-13.25X 1 -19X 2 +8.75 X 1 2 +17.5 X 2 2 for Wetting time Y 2 62.33-16.25X 1 -19X 2 +11.75 X 1 2 +13.5 X 2 2 for Disintegration time Y 3 3.441-0.605X 1 -0.331X 2 +0.017 X 1 X 2 +0.407 X 1 2 +0.07 X 2 2 for t 50 Y 4 11.435-2.01X 1 -1.099X 2 +0.057 X 1 X 2 +1.35 X 1 2 +0.233 X 2 2 for t 90 Te positive sign for co-efcient of X 1 in Y 1 Y 2 Y 3 and Y 4 equations indicates that as the concentration of crospovidone decreases Wetting time Disintegrat-

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20 Kumar Gunda Suresh Kumar ing time t 50 and t 90 value increases. In other words the data demonstrate that both X 1 quantity of crospo - vidone and X 2 quantity of croscarmellose sodium afect the time required for drug release W etting time Disintegrating time t 50 and t 90 . From the results it can be concluded that and increase in the quantity of the superdisintegrant leads to decrease in disintegra- tion time of the dosage form and drug release pattern may be changed by appropriate selection of the X 1 and X 2 levels. Te dissolution parameters for predict - ed from the polynomial equations derived and those actual observed from experimental results are sum - marized in Table 6. Te closeness of predicted and observed values for Wetting time Disintegrating time t 50 and t 90 indicates validity of derived equations for dependent variables. Te response surface plots were presented to show the efects X 1 and X 2 on Wetting time Disintegrating time t 50 and t 90. Te fnal best Optimized formulation F 1 is compared with mar- keted product SOLIAN-100 shows similarity factor f 2 85.384 diference factor f 1 2.098 Tere is no signifcant diference in drug release because p0.05. Comparative dissolution plots for best formulation F 1 and marketed product shown in fg 11. CONCLUSION Te present research work envisages the applica- bility of superdisintegrants such as crospovidone and croscarmellose sodium in the design and develop- ment of fast dissolving tablet formulations of Amisul - pride utilizing the 3 2 factorial design. From the results it was clearly understand that as the concentration of superdisintegrant increases the release rate of drug was RAPID Improved Solubility and both of these superdisintegrants can be used in combination since do not interact with the drug which may be more helpful in achieving the desired fast dissolving of the dosage form for rapid action and improved bioavail - ability. Te optimized formulation followed Higuchi’s kinetics while the drug release mechanism was found to be Non-Fickian difusion with super case-II trans - port frst order release type. On the basis of evalu - ation parameters the optimized formulation F 1 may be used for the efective management of psychoses paranoid productive schizophrenias dysthymia. Tis may improve the patient compliance by showing rapid action via disintegration without difcult in swallow- ing and side efects which will ultimately improve the therapeutic outcome. We could be able to minimize the per oral cost of the Formulation. Table 3: Post-compression parameters for the formulations ± indicates standard deviation S.No Formulation Code Hardness kg/cm 2 n3 Tickness mm n3 F ria b i li ty n3 Drug Content n3 Wetting Time sec n3 Disintegration Time sec n3 1 F 1 3.49±0.38 3.11±0.16 0.575±0.12 99.24±0.25 25.5±1.3 35.5±1.5 2 F 2 3.41±0.57 3.08±0.76 0.585±0.13 98.68±0.30 27±1.4 41.0±1.6 3 F 3 3.65±0.42 3.06±0.44 0.465±0.1 97.85±0.50 63.5±1.6 73.5±1.8 4 F 4 3.60±0.24 3.08±0.67 0.585±0.12 99.04±.40 30±1.4 40.0±1.4 5 F 5 3.55±0.43 3.05±1.27 0.595±0.13 98.48±0.90 31.5±1.5 45.5±1.5 6 F 6 3.81±0.28 3.03±0.95 0.475±0.05 97.65±0.70 68±1.7 78.01±1.7 7 F 7 3.35±0.38 3.07±0.54 0.375±0.13 98.72±0.25 52±1.3 68.0±1.4 8 F 8 3.31±0.57 3.04±1.14 0.385±0.13 98.16±0.30 53.5±1.5 73.5±1.5 9 F 9 3.55±0.43 3.02±0.82 0.265±0.14 97.33±0.50 90±1.6 106.0±1.7

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21 FABAD J. Pharm. Sci. 43 2 15-25 2018 Table 4: Regression analysis data of 3 2 factorial design formulations of Amisulpride fast dissolving tablets S.NO Formulation Code KINETIC P ARAMETERS ZERO ORDER FIRST ORDER HIGUCHI KORSMEYER- PEPP AS a b r a b r a b r a b r 1 F 1 18.395 7.750 0.941 2.016 0.112 0.988 0.137 29.718 0.992 1.445 0.532 0.984 2 F 2 19.434 7.340 0.932 2.000 0.103 0.999 1.209 28.452 0.994 1.459 0.504 0.986 3 F 3 10.734 7.846 0.968 2.035 0.091 0.987 5.690 29.019 0.985 1.233 0.719 0.985 4 F 4 20.315 7.295 0.922 1.993 0.105 0.994 1.788 28.469 0.990 1.466 0.500 0.977 5 F 5 21.355 6.885 0.906 1.977 0.096 0.993 3.134 27.202 0.985 1.479 0.474 0.961 6 F 6 12.656 7.391 0.956 2.018 0.086 0.996 3.765 27.769 0.988 1.255 0.688 0.979 7 F 7 9.462 7.695 0.974 2.020 0.078 0.983 6.166 28.241 0.984 1.212 0.724 0.986 8 F 8 10.504 7.284 0.973 2.010 0.073 0.998 4.818 26.973 0.991 1.228 0.694 0.993 9 F 9 1.799 7.792 0.986 2.043 0.066 0.974 11.722 27.542 0.958 0.871 1.043 0.986 Table 5: Dissolution parameters of Amisulpride fast dissolving tablets 3² full factorial design batches S.NO FORMULATION CODE KINETIC P ARAMETERS t 1/2 Min t 90 Min WTSec DTSec 1 F 1 2.679 8.902 25.5 35.5 2 F 2 2.922 9.711 27 41 3 F 3 3.315 11.015 63.5 73.5 4 F 4 2.872 9.545 30 40 5 F 5 3.123 10.377 31.5 45.5 6 F 6 3.515 11.681 68 78 7 F 7 3.850 12.794 52 68 8 F 8 4.138 13.750 53.5 73.5 9 F 9 4.555 15.136 90 106 Table 6: Dissolution parameters for predicted and observed values for check point formulations FORMULATION CODE PREDICTED V ALUE ACTUAL OBSERVED V ALUE WTSec DTSec t 50 min t 90 min WTSec DTSec t 50 min t 90 min C 1 71.688 86.268 4.033 13.395 72.03 85.75 4.128 13.524 C 2 39.438 51.018 3.097 10.295 40.02 52.34 3.121 10.351

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22 Kumar Gunda Suresh Kumar Figure 1. Comparative Zero order plots for Formulation F 1 -F 9 Figure 2. Comparative First order plots for Formulation F 1 -F 9 Figure 3. Comparative Higuchi plots for Formulation F 1 -F 9

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23 FABAD J. Pharm. Sci. 43 2 15-25 2018 Figure 4. Comparative Korsemeyer-Peppas plots for Formulation F 1 -F 9 Figure 5. Wetting Time Chart for Formulation F 1 -F 9 Figure 6. Disintegration Time Chart for Formulation F 1 -F 9

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24 Kumar Gunda Suresh Kumar Figure 7. Response Surface plot for W etting Time Figure 8. Response Surface plot for Disintegration Time Figure 9. Response Surface plot for t 50 Figure 10. Response Surface plot for t 90 Figure 11. Comparative Dissolution plots for F 1 Solian-100

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25 FABAD J. Pharm. Sci. 43 2 15-25 2018 ACKNOWLEDGEMENTS: Te author would like to thank the Principal Management Staf of Narasaraopeta Institute of Pharmaceutical Sciences Narasaraopet Guntur D.t A.P. India for providing support for successful com - pletion of research work. REFERENCES A. A. Kharia S. N. Hiremath A. K. Singhai . K. Om- ray and S. K. Jain. 2010 Design and Optimization of Floating Drug Delivery System of Acyclovir In- dian J. Pharm. Sci. 72 5 599-606. Gunda Raghavendra Kumar J.N.Suresh Kumar V. Satyanarayana G.Swarupa Rani B.Satya Prasad. 2016 Formulation Development and Evaluation of Clopidogrel Fast Dissolving Tablets. Iranian J Pharm Sci. 12 2 61-74. Hitesh P. Dalvadi Jitendra J. Jaiswal Abhirajsinh J. Solanki Suryabali K. Yadav.2016 Formulation and evaluation of amisulpride orodispersible Tab - let. Int J Pharm Sci Res.73126-133. K Kavitha Kumutha Subramaniam BoeyJiaHui K. Santhi SA Dhanaraj and M Rupesh Kumar. 2013 Potential Drug Candidates for Fast Dis - solving Drug Delivery - A Review. Res J Pharm Bio Chem Sci. 44 1510-1526. M.A.Shende R.P.Marathe S.B. Khetmalas P. N. Dhabale. 2014 Studies on development of Sus - tained release Diltiazem hydrochloride matrices through jackfruit mucilage. Int J pharm pharmas- ci. 6 7 72-78. NG RaghavendraRao UpendraKulkarni. 2010 Development of Carbamazepine Fast Dissolv - ing Tablets: Efect of Functionality of Hydrophil - lic Carriers on Solid Dispersion Technique Asian J Pharm Clin Res. 32114-117. Nirvesh Chaudhri Girish C. Soni S. K. Prajapati. 2015 Formulation of Amisulpride loaded Na - noemulsion Drug Delivery System for the Treat - ment of Schizophrenia. J Biomed Pharm Res. 4 617-20. Notari RE. 1987 Biopharmaceutics and clinical pharmacokinetics. 4th ed. New York: Marcel Dek- ker Inc 6-21. Peppas NA. 1985 Analysis of Fickian and non-Fick - ian drug release from polymers. Pharm Acta Helv 60110-1. Raghavendra Kumar Gunda. 2015. Formulation De- velopment and Evaluation of Rosiglitazone Ma - leate Sustained Release Tablets Using 3 2 Factorial Design Int PharmTech Res 84 713-724. Ramji Anil Kumar Arza B. Vijaya Kumar. 2016 Development and evaluation of gastroretentive foating matrix tablets of moxifoxacin HCl. Der Pharmacia Lettre.8 10140-149. Schwartz BJ Connor RE.Optimization technique in pharmaceutical formulations and processing. 1996 J Drugs and Pharm Sci in Modern Pharma- ceutics.723:727-54. Shiv Shankar Hardenia G.N. Darwhekar ShaileshSharma and Anu Hardenia. 2014 De- signing and Pharmaceutical Evaluation of Fast Dissolving Tablet of Fexofenadine Using Copro - cessedSuperdisintegrants International Journal of Pharmaceutical Sciences and Research. 57 3018- 3030. T Higuchi. Mechanism of sustained-action medica - tion. 1963. Teoretical analysis of rate of release of solid drugs dispersed in solid matrices. J Pharm Sci 511145-9. Tanda venkataramudu R. Arun Kumar S.M. Imroz T. Murali Krishna Swamy Hanumesh. 2012 sol - ubility enhancement of amisulpride by complex - ation technique and preparation of fast dissolving tablet. Int J Biopharm. 31 32-39. ABBREV ATIONS AND SYMBOLS USED ODT - Oral Disintegrating Tablet CCS - CrosCarmellose Sodium CP - Crospovidone Kg - Kilo Gram Cm - Centi Meter - Percentage mg - milli gram ml - milli litre CDR - Percentage Cumulative Drug Release BCS - Biopharmaceutical Classifcation UR - Un Released Min - Minute ºC - Degree Centigrade mm - milli meter t 1/2 - Half Life DT - Disintegration Time WT - Wetting Time t 50 - Time taken to release 50 drug from dos - age form t 90 - Time taken to release 90 drug from dos - age form Running title: Formulation and Evaluation of Fast Dissolving Tablets of Amisulpride.

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