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WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES

Vijay.

World Journal of Pharmacy and Pharmaceutical Sciences

SJIF Impact Factor 6.647

Volume 6, Issue 2, 1170-1184

Research Article

ISSN 2278 – 4357

FORMULATION AND DEVELOPMENT OF AMISULPRIDE TABLETS AND IT'S COMPARATIVE EVALUATION OF PHYSICAL AND CHEMICAL PARAMETERS BETWEEN ACCELERATED AND REAL TIME STABILITY Vijay Kumar Panthi* Department of Pharmacy, Sunsari Technical College, Laxmisadak-4, Dharan, Sunsari, Nepal.

Article Received on 09 Dec. 2016,

ABSTRACT Amisulpride used for easing the symptoms of severe or sudden (acute)

Revised on 29 Dec. 2016, Accepted on 19 Jan. 2017

and ongoing or long term (chronic) schizophrenia, a sort of mental

DOI: 10.20959/wjpps20172-8615

health condition which affects the way of thinking, feeling, or action. In this formulation frequent problem were high disintegration and low

*Corresponding Author

hardness. As per formulation elaborated in formulation chart it is

Vijay Kumar Panthi

mainly concluded that the both high disintegration and low hardness

Department of Pharmacy,

problem of amisulpride tablets can be counteracted by mainly MCCP

Sunsari Technical

200, Crospovidone and polyvinylpyrrolidone k-30 but extra more

College, Laxmisadak-4, Dharan, Sunsari, Nepal.

amounts of MCCP 200 was appeared required. In addition, as per trials it is also justified that the dried Maize starch (without paste) was not

appeared effective ingredients in formulation of amisulpride tablets. Although other surfactants were not used, the anionic surfactants i.e. Sodium Lauryl Sulphate is observed good ingredients in this formulation for obtaining the good dissolution from initial phase up to six month stability. Aerosil, crospovidone, kollidon VA 64 were other successful supportive ingredients for the formulation of amisulpride tablets. Although there is higher humidity and temperature in Accelerated stability than Real time, the hardness of tablet is very slightly increased in Accelerated as compared to Real time but rest of the parameters were observed equally stable. No gradual increment of any parameters in both stability, it further illustrated that there is no significant changes in any physical and chemical parameters in both accelerated and real time but disintegration time is increasing very slightly as per gradual basis which can be considered as a negligible impact.

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KEYWORDS: Amisulpride, Physical Parameters, Chemical Parameters, Accelerated stability, Real Time Stability. INTRODUCTION Amisulpride (AMS) belongs to a group of medicines called substituted benzamide antipsychotics. AMS used for easing the symptoms of severe or sudden (acute) and ongoing or long term (chronic) schizophrenia, a sort of mental health condition which affects the way of thinking, feeling, or action. Symptoms of schizophrenia such as hallucinations seeing, hearing or sensing which are not apparent in patient, delusions, unusual suspiciousness, emotional or social withdrawal. People with schizophrenia may also feel into depression, tension, anxiety or uneasiness. AMS can help to get rid of these symptoms. At higher doses it inhibits postsynaptic dopamine D2 and D3 receptors, which results in reducing dopaminergic transmission.[1] Amisulpride may be a partial agonist at dopamine 2 receptors, which would theoretically reduce dopamine output when dopamine concentrations are high and increase dopamine output when dopamine concentrations are low. Unlike other atypical antipsychotics, amisulpride does not have potent actions on serotonin receptors. Psychotic symptoms can improve within 1 week, but it may take several weeks for full effect on behavior as well as on cognition and affective stabilization. Classically recommended to wait at least 4-6 weeks to determine efficacy of drug, but in practice some patients require up to 16-20 weeks to show a good response, especially on cognitive symptoms.[2] Amisulpride and it's relative sulpride have been shown to bind to and activate the GHB receptor at doses that are used for therapeutic purposes. Amisulpride 400-1200 mg/day was found to be as least as effective. At low doses amisulpride demonstrated a similar safety profile to placebo. At higher doses adverse events such as endocrine effects, agitation, insomnia and anxiety occurred at a similar rate to that seen with other antipsychotics. It has no affinity for serotonergic alpha-adrenergic, H1 histaminergic or cholinergic receptors. There are two absorption peaks-one hour post-dose and a second 3-4 hours after taking the tablet. The elimination half life is 12 hours. Absolute bioavailability is 48%. AMS is weakly metabolized by the liver. There are two inactive metabolites. The drug is mainly eliminated unchanged by the kidney.[3] Treatment resistant depression is a complex spectrum of severity rather than a single uniform entity and is difficult to treat successfully and outcomes are inadequate. Approximately 60% patients with major depressive disorder (MDD) do not achieve a sufficient response and

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about two-thirds of patients receiving initial antidepressants therapy do not achieve timely remission.[4] MATERIALS AND METHODS Materials All raw materials (both API and excipients) were used a pharmaceuticals grade supplied by different supplier and parties and study conducted in research and development department of pharmaceutical company. Methods 1. Sifting Amisulpride and Sodium Lauryl Sulphate is sifted through sieve no. 60 and mixed uniformly for 5 minutes. 2. Melting Cremophore RH 25 is melted by applying heat at about 40ºC then added capryol-90 in it with continuous stirring for 5 minutes. 3. Dispersion Dispersed step 2 with step 1 and mixed it properly with continuous stirring with the help of stirrer for 5 minutes. 4. Sifting Maize starch (dried), MCCP 200 and Crospovidone were sifted through mesh no. 60 and mixed these ingredients properly then added to the step 3. 5. Preparation of Binder Solution Polyvinylpyrrolidone k-30 (PVPK-30) is dissolved in Purified water (400 gm) with continuous stirring until dissolved completely then granulate with step 4. After that passed the moistened granules through sieve no. 16 and allowed the granules for drying in tray dryer at 45ºC until completely drying. After final drying granules were sifted through sieve no. 20. 6. Lubrication Kollidon VA 64, Aerosil, Sodium Starch Glycolate and Purified talc were sifted through sieve no. 60 then finally lubricated with step 5 by proper mixing for 5 minutes.

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Evaluation Amisulpride tablets prepared by wet granulation were subject to following physical evaluation. Physical observation At initial phase tablets ejected from compression machine was observed only colour and appearance but after stability period eject the tablets from packed blister strips and observed the characteristics of tablets by naked eye such as colour change, smell, breaking, swelling etc. Hardness The tablet hardness is the force required to break a tablet in a diametric compression force. A Digital hardness tester was used in this study. This tester applies force to the tablet straightly. The test was performed on six tablets and the average was calculated in kilo pound.[5] Thickness The thickness of the tablets was determined using a Vernier caliper. Five tablets from each formulation were used and average values were calculated.[5] In-vitro Disintegration Studies Six Tablet were placed in basket then basket dipped in a beaker containing 800 ml of distilled water at 37 ±0.5°C. Time for complete disintegration of the tablet was measured in minute. Stability studies Stability studies on the best formulation were carried out to determine the effect of presence of formulation additives on the stability of the drug and also to determine the physical stability of the formulation under accelerated storage conditions and Real time conditions. The tablets were stored in an blister strips and subjected to: 

Accelerated stability conditions: Elevated temperature and humidity conditions of 40ºC ± 2ºC & 75% ± 5%.



Real Time conditions: 30ºC± 2ºC & 65%±5%

The samples were withdrawn at the end of month and evaluated for physical parameters viz. physical observation, hardness, thickness, disintegration time and percentage of drug release and also chemical parameters i.e. Assay (drug potency).[6-7]

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Method of Dissolution determination[8] Apparatus: 2, Paddle Revolution/ min: 50 Temperature: 37ºC Time: 45 min Media: 900 ml, 0.1 M hydrochloric acid Procedure 

Measured the absorbance of a 0.0011% w/v solution of standard and test preparation of Amisulpride.



After 45 minutes withdrawn a sample of the medium and measured the absorbance of the filtered sample at 280 nm by Ultraviolet Spectroscopy.

Assay determination 

Concentration of Standard and Test Preparation: 0.005 mg/ml



Wavelength: UV 226 nm

Table 1. Formulation of Amisulpride tablets S.No. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. Total

Materials (mg) Amisulpride Cremophore RH 25 Maize Starch (Dried) MCCP 200 Crospovidone PVPK-30 SLS Aerosil Kollidon VA 64 SSG Capryol-90 Purified Talc Purified Water

F1 50 1.5 38.23 1.77 1.5 4.5 1.0 1.5 qs 100.00

F2 50 2.33 33.79 4.37 2.0 0.77 4.12 1.5 1.12 qs 100.00

F3 50 2.5 14.13 16.5 4.45 1.5 0.85 2.0 4.65 1.42 2.0 qs 100.00

F4 50 3.5 29.68 5.0 1.5 1.0 2.5 1.25 3.0 0.57 2.0 qs 100.00

F5 50 0.85 32.93 2.22 1.5 0.62 4.5 1.33 3.2 0.55 2.30 qs 100.00

RESULTS A. Preformulation Studies Before commencement of Amisulpride formulation, the various preformulation studies were carried out for the convenience of final formulation. Amisulpride itself white or almost white crystalline powder and it's solubility in various solvents, pH, sieve analysis, moisture content

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etc. were performed with the help of their related apparatus. The all performed preformulation studies were illustrated in table 2. B. In-process granules parameter After commencement of Amisulpride formulation, the first step carried out was sifting of API by mixing with sodium lauryl sulphate. The all granules parameters which required inprocess checking were mentioned in table 3. C. Initial and stability observation of both Physical and Chemical Parameters 1. Observation of physical parameters in Accelerated stability from Initial duration up to six month Stability In this research, the total five trials were done including both successful and failure trials. All unsuccessful formulation were observed only physically from initial duration up to six months of stability while only final formulation (F5) was followed by both physically and chemically. The all five trials status of physical parameters in accelerated stability were enumerated in table 4. 2. Observation of physical parameters in Real Time stability from Initial duration up to six month Stability The way of sample follow up was same as accelerated stability. In addition, all the five trials were observed physically in Real Time stability to determine any changes by the affection of humidity and temperature. The all results regarding this statement were elaborated in table 5. 3. Drug release observation of Amisulpride tablets in initial The drug release is found good in case of all six tablets which has shown the release (81110)%. After 45 minutes of stirring in jar, withdrawn a sample of the medium and measured the absorbance of the filtered sample at 280 nm by Ultraviolet Spectroscopy. This result is also enumerated in figure 1. 4. Drug release observation of Amisulpride tablets of First month duration on both Accelerated and Real Time stability The drug release is also found excellent results in case of both accelerated and real time stability in first month but drug release was obtained quite good in real time as compared to accelerated stability. This result is also further justified in figure 2.

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5. Drug release observation of Amisulpride tablets of Second month duration on both Accelerated and Real Time stability The drug release found good up to second month in case of both Accelerated and Real time but in second month slightly different result was obtained i.e. drug release is found higher in accelerated than real time which is exactly differ than first month result but result itself good for both accelerated and real time stability and no significantly decrement was observed. The second month comparative data of drug release is also presented in figure 3. 6. Drug release observation of Amisulpride tablets of Third month duration on both Accelerated and Real Time stability In third months, drug release was observed approximately similar in both accelerated and real time stability. The comparative dissolution profile of third month is mentioned in figure 4. 7. Drug release observation of Amisulpride tablets of Six month duration on both Accelerated and Real Time stability Drug release was found stable up to six months and value is observed higher as compared to initial duration. In initial duration the lower range of drug release was 81% but up to six month it was increased gradually and lower limit was obtained above than 100%. This result is also mentioned in figure 5. 8. Chemical parameter (Assay%) of Amislpride tablets from initial up to six month in both Accelerated and Real time stability The result of chemical parameter is found stable up to six months in case of both Accelerated and Real time stability, assay percentage was obtained above than 100%. Hence on the basis of all physical and chemical parameters it has justified that Amisulpride tablets is stable by both physically and chemically in case of both Accelerated and Real time stability. The comparative chemical parameter value (Assay%) is also illustrated in table 5. Table 2. Preformulation Studies 1. Description of Raw material 2. Solubility a. In water b. In Alcohol c. In Chloroform d. In Acetone e. Methylene Chloride

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White or almost white crystalline powder Partially soluble, particles were dispersed & settle down Soluble Highly soluble Soluble Highly soluble, solution was clear and no dispersion was appeared Vol 6, Issue 2, 2017.

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f. In Propylene Glycol g. In Polyethylene Glycol-400 h. In Glycerine 3. pH (5% Solution) 4. Bulk Density 5. Tapped Density 6. Hausner Ratio 7. Moisture Content (moisture analyzer) 8. Sieve Analysis a. (20#) Retain: 0 % b. (40#) Retain: 76% c. (60#) Retain: 4.2% d. (#80) Retain: 2.4%

Soluble Soluble Slightly soluble 9.52 0.34 gm/cc 0.46 gm/cc 1.35 0.40% Pass: 100% Pass: 10.2% Pass: 6.0% Pass: 3.6%

Table 3. In-process granules parameter Moisture content(%) Unlubricated

Lubricated

Bulk Density (gm/cc)

2.27

2.62

0.455

Tapped Density (gm/cc)

C.I. (%)

Hausner Ratio

0.588

22.62

0.133

Sieve Analysis 20# 40# 60# Retain: Retain: Retain: 9.62% 28.85% 36.53% Pass: Pass: Pass: 90.38% 71.15% 34.62%

Table 4. Physical test comparison of Accelerated stability analysis Parameters Physical observation Hardness(kp) Thickness(mm) D.T(min) Friability(%) Physical observation Hardness(kp) Thickness(mm) D.T(min) Friability(%) Physical observation Hardness(kp) Thickness(mm) D.T(min) Friability(%) Physical observation Hardness(kp) Thickness(mm) D.T(min) Friability(%) Physical observation Hardness(kp) Thickness(mm) D.T(min) Friability(%)

Code F1 F1 F1 F1 F1 F2 F2 F2 F2 F2 F3 F3 F3 F3 F3 F4 F4 F4 F4 F4 F5 F5 F5 F5 F5

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Initial white colour 4-5 3.54 8'40" 0.11 white colour 2-3 3.52 4'25" 0.018 white colour 2.56-3.25 3.52 2'15'' 0.011 white colour 3.55-4.17 3.54 1'22" 0.22 white colour 3.5-4.0 3.54 1'15" 0.45

1st month same 4-5 3.52 8'10" 0.17 same 2-3.5 3.52 5'15" 0.10 same 2.54-3.37 3.52 1'23'' 0.22 same 3.25-4.07 3.54 2'35'' 0.56 same 3.54-3.94 3.54 1'50" 0.35

2nd month same 4.54-4.74 3.56 7'45" 0.24 same 3.56-4.25 3.52 5'37"-6'00" 0.22 same 2.45-3.25 3.54 5'56'' Friable same 3.44-3.49 3.56 3'10'' 0.39 same 3.51-3.98 3.58 2'20" 0.44

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3rd month same 4.5-4.95 3.56 8'25" Fail same 3.50-4.51 3.56 5'30"-7'45" Friable same 2.25-2.55 3.54 4'37'' Friable same 2.27-2.45 3.54 4'07'' 0.33 same 3.45-3.55 3.56 3'10" 0.19

6th month slight change 3-3.5 3.56 10'50" Fail same 2.25-4.0 3.56 6'15"-8'40" Friable same 2.08-2.36 3.54 6'15'' Friable same 2.08-2.56 3.56 3'55'' 0.78 same 3.73-5.43 3.54 3'25" 0.25 1177

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Table 5. Physical test comparison of Real Time stability analysis Parameters Physical observation Hardness(kp) Thickness(mm) D.T(min) Friability(%) Physical observation Hardness(kp) Thickness(mm) D.T(min) Friability(%) Physical observation Hardness(kp) Thickness(mm) D.T(min) Friability(%) Physical observation Hardness(kp) Thickness(mm) D.T(min) Friability(%) Physical observation Hardness(kp) Thickness(mm) DT(min) Friability(%)

Code F1 F1 F1 F1 F1 F2 F2 F2 F2 F2 F3 F3 F3 F3 F3 F4 F4 F4 F4 F4 F5 F5 F5 F5 F5

Initial white colour 4-5 3.54 8'40" 0.11 white colour 2-3 3.52 4'25" 0.018 white colour 2.56-3.25 3.52 2'15'' 0.011 white colour 3.55-4.17 3.54 1'22" 0.22 white colour 3.5-4.0 3.54 1'15" 0.45

1st month same 4-5 3.54 8'55" 0.17 same 2-3.0 3.52 4'10''-5'15'' 0.45 same 3.37-4.55 3.52 2'48'' 0.017 same 3.15-3.66 3.54 1'33-1'55'' 0.11 same 3.50-3.88 3.52 1'28" 0.22

2nd month same 4.54-4.74 3.56 8'12" 0.22 same 2-4.5 3.52 7'17''-8'25'' 0.38 same 3.58-4.61 3.52 2'37'' 0.15 Bad smell 3.08-3.15 3.54 2'15'-2'56'' 0.25 same 3.51-3.84 3.56 1'55" 0.35

3rd month same 4.5-4.95 3.56 10'35" 0.37 same 1.5-3.0 3.54 7'20''-8'22'' 0.55 same 3.55-4.27 3.52 3'42'' 0.25 2.44-2.68 3.56 5'17''-5'45'' 0.55 same 3.65-3.75 3.52 2'37" 0.50

6th month slight change 3-3.5 3.56 9'50" 0.15 same 1.0-1.5 3.52 5'45''-6'55'' 0.37 same 3.25-4.08 3.52 5'22'' 0.33 2.36-2.45 3.52 6'10-8'24'' 0.27 same 3.45-3.75 3.54 3'12" 0.22

Table 6. Assay comparison between Accelerated and Real Time stability test Accelerated Stability Real Time Stability Duration Remarks Assay (%) Assay% 1st month 101.05% 102.27% 2nd month 102.45% 102.86% Initial Assay: 103.05% rd 3 month 104.80% 104.32% 6th month 104.42% 102.25%

Figure 1. Drug release observation of Amisulpride tablets in initial www.wjpps.com

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Figure 2. Drug release observation of Amisulpride tablets of First month duration on both Accelerated and Real Time stability

Figure 3. Drug release observation of Amisulpride tablets of Second month duration on both Accelerated and Real Time stability

Figure 4. Drug release observation of Amisulpride tablets of Third month duration on both Accelerated and Real Time stability www.wjpps.com

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Figure 5. Drug release observation of Amisulpride tablets of Six month duration on both Accelerated and Real Time stability ABBREVIATIONS F

Formulation

AMS

Amisulpride

MDD

Major depressive disorder

MCCP

Microcrystalline Cellulose

SSG

Sodium Starch Glycolate

SLS

Sodium Lauryl Sulphate

PVPK-30

Polyvinylpyrrolidone k-30

D.T

Disintegration Time

LIST OF TABLE S No.

Name of Table

1

Formulation of Amisulpride tablets

2

Preformulation Studies

3

In-process granules parameters

4

Physical test comparison of Accelerated stability analysis in different month

5

Physical test comparison of Real Time stability analysis in different month

6

Assay comparison between Accelerated and Real Time stability test

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LIST OF FIGURE S No. 1 2 3 4 5

Name of Figure Drug release observation of Amisulpride tablets in initial Drug release observation of Amisulpride tablets of First month duration on both Accelerated and Real Time stability Drug release observation of Amisulpride tablets of Second month duration on both Accelerated and Real Time stability Drug release observation of Amisulpride tablets of Third month duration on both Accelerated and Real Time stability Drug release observation of Amisulpride tablets of Six month duration on both Accelerated and Real Time stability

DISCUSSION All the formulations are done by wet granulation method and details of formulation are illustrated in formula code. Amisulpride tablet with different formulation is compressed in 8 station rotatory compression machine. All trials were continuously followed only by physically as per stability schedule but only the final formulation (F4) is followed continuously by both physically and chemically. When at first F1 trial is taken with wet granulation by Purified water the ultimate result in compression was high disintegration time of tablet (8:40 min) but rest of the other compression parameters were satisfactory. Due to high disintegration, processing of F1 is rejected but tablet were completely ejected from compression machine only to follow it in stability hence trial is gone with further attempts. The all details of second attempt (F2) is mentioned in formulation chart. At first step of formulation second (F2), Crospovidone is used a main disintegrator to eliminate the problem of high disintegration time but rest of the other ingredients were kept similar. After this attempt the high disintegration problem is partially solved by only the application of crospovidone which minimizes disintegration time in exactly half (i.e. 4:25 min) but new problem is also appeared in this trial that was low hardness but most of the other compression parameters were found satisfactory. Hence, this trial is also rejected but tablets were compressed for purpose of stability observation. Due to low hardness problem, decided to go further for third trials hence to counteract the previous problem of high disintegration time and low hardness the third attempt is started mainly with the addition of MCCP 200 (16.5%) and Aerosil (2.0%) but couldn't got the desired results. This trial is also appeared same problem as per previous trials (low hardness) hence this trial was also not observed satisfactory so compressed the tablets from remaining granules just for stability observation. After three unsuccessful attempts, the fourth trial is also started by maintaining same of weight with the excess amount of MCCP 200. Approximately 30% total weight of MCCP

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200 was used in this trial to minimize trouble of high disintegration and low hardness but with the addition of new ingredients i.e. Kollidon VA 64 (grades of crospovidone) to maintaining disintegration within desired range. The result was obtained satisfactory and previous problem were approximately eliminated which further stated that all the compression parameters were found as per desired limits and also placed in stability. Due to started with low batch size of formulation, the quantity of tablets were obtained less which might be the insufficient sample to continuously follow as per stability schedule hence by applying same formula of F4 only with slight modification the fifth trial is conducted. The final trial (F5) also showed the desired results hence all the granules were compressed completely and placed in stability. The all five trials were packed (both unsuccess and success) in blister strips constituted from plain aluminium foil and PVC and placed in stability. All five trials were followed only physically as per stability schedule i.e. 1st month, 2nd month, 3rd month and finally 6th month but 4th and 5th month sample is escaped and only the final trial (F5) is followed both physically as well as chemically. All the trial samples were kept in Accelerated and Real time stability chamber by maintaining proper limit of humidity and temperature. Accelerated stability analysis is observed by maintaining 75%±5% humidity and 40ºC±2ºC temperature while Real time is operated at 65%±5% humidity and 30ºC±2ºC temperature then required test were carried out as per basis of stability whose stability results were also elaborated in different part of table and figure on the part of results. CONCLUSION The high disintegration and low hardness problem is appeared frequently in the formulations of amisulpride tablets, which was initially observed that root cause of trouble was lacking proper disintegrator and binder hence after two unsuccessful trials, attempts is tried by the application of crospovidone as a disintegrator and MCCP 200 as a both disintegrator and binder but couldn't obtained the satisfactory results. Maize starch (Dried) is also not appeared effective binder in this formulation. All the compression parameters were found satisfactory except high disintegration and low hardness but frequent problem was low hardness. As per formulation elaborated in formulation chart it is mainly concluded that the both high disintegration and low hardness problem of amisulpride tablets can be counteracted by mainly MCCP 200, Crospovidone and polyvinylpyrrolidone k-30 but extra more amounts of MCCP 200 was appeared required. In addition, as per above attempts it is also justified that

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the dried Maize starch (without paste) was not appeared effective ingredients in formulation of amisulpride tablets. Although other surfactants were not used, the anionic surfactants i.e. Sodium Lauryl Sulphate is observed good ingredients in the formulation of amisulpride for obtaining the good dissolution from initial phase up to few month stability schedule. Aerosil, crospovidone, kollidon VA 64 were other successful supportive ingredients for the formulation of amisulpride tablets. Although there is higher humidity and temperature in Accelerated stability than Real time, the hardness of tablet is very slightly increased in Accelerated as compared to Real time. No gradual increment of any parameters in both stability, it further illustrated that there is no significant change in any physical and chemical parameters in both accelerated and real time but disintegration time is increasing very slightly as per gradual basis which can be considered as a negligible impact. As per data observed in stability schedule, it is concluded that the product is appeared effective in case of both physically and chemically in a accelerated and real time chamber. There is no significant changes between two stability chamber all the parameters were observed within the desired range from initial stage up to the six month stability. Hence it is readily concluded that amisulpride tablets is equally effective up to six months in both accelerated and real time stability. ACKNOWLEDGEMENTS I would highly gratitude thanks to my respected family members for their continuous encouragement and support and gratefulness to all executives, officers, analyst, staff of R&D department of Asian Pharmaceuticals, Nepal for their valuable support in formulation and analysis. REFERENCES 1. Ravisankar P, Rao G. Devala, Novel RP-HPLC method for the determination of Amisulpride in pure and pharmaceutical formulations, ISSN:0975-7384, CODEN (USA): JCPRC5. 2. Stephen M. Stahl, Cambridge University Press: 978-0-521-75900-7-The prescriber's guide: Antipsychotics and mood stabilizers, Third edition. 3. A Kottai M et al. IRJP 1 (1) 2010 247-253, Formulation development and evaluation of amisulpride once daily tablet.

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4. Dar, Wani, Margoob, Haq, Hussain, Chandel et al: Role of amisulpride augmentation on in treatment resistant major depressive disorder; International journal of emergency mental health and human resilience, 17(2): 538-543, ISSN 1522-4821. 5. www.Pharmainfo.net/Evaluation of tablets, Accessed on: 01/02/2016. 6. Jens Cartensen, ICH Guidelines, In drug stability principles and practices, 2 nd edn, New York: Marcel Dekker, Inc., 1995; 68: 541 – 546. 7. SA. Kanvinde, Stability of oral solid dosage forms- a global perspective. Pharma times. 2005; 37: 9-16. 8. British Pharmacopoeia 2014, Amisulpride tablets page No. III-131-132.

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