formulation and evaluation of orodispersible tablets of

W OR MACJournal Y ANDofP HARMAand CEPharmaceutical UTICAL SCIENCES Shailesh et L al.D JOURNAL OF PHAR World Pharmacy SJIF Impact Factor 5.210 Sciences Volume 4, Issue 05, 1526-1539. Research Article ISSN 2278 – 4357

FORMULATION AND EVALUATION OF ORODISPERSIBLE TABLETS OF CILNIDIPINE BY SPRAY DRYING TECHNIQUE Dr. Shailesh T. Prajapati*, Priyank D. Maheshwari and Chhaganbhai N. Patel Department of Pharmaceutics and Pharmaceutical Technology, Shri Sarvajanik Pharmacy College, Near Arvind Baug, Mehsana-384 001, Gujarat, India.

Article Received on 07 March 2015, Revised on 29 March 2015, Accepted on 19 April 2015

ABSTRACT Cilnidipine is a novel dihydropyridine calcium antagonist and its calcium antagonistic activity is lasting longer than those of Nifedipine and Nicardipine. Cilnidipine has been used for the treatment of hypertension. It is a BCS Class-II drug. Therefore, it is necessary to

*Correspondence for Author

enhance the solubility and dissolution rate and minimize the variability

Dr. Shailesh T. Prajapati

in absorption of Cilnidipine. Diverse water soluble carriers viz.

Department of

Polyethylene glycols (PEG 4000, 6000), Hydroxypropyl Methyl

Pharmaceutics and

cellulose (HPMC E5 LV), Chitosan, Carrageenan, Poloxamer 188,

Pharmaceutical

Na.CMC and β‐cyclodextrin were used for this purpose. Phase

Technology Shri Sarvajanik Pharmacy

solubility studies revealed an increase in drug solubility with PVP

College Near Arvind

K30, Na.CMC. Spray drying of Cilnidipine with PVP K30 and

Baug, Mehsana-384 001,

Na.CMC in order to determine the potential effect on solubility

Gujarat, India

Cilnidipine. Preformulation studies were conducted to select the appropriate carriers and drug:carrier ratio for preparing the spray dried

compositions. The solid state interactions of the spray dried mixtures were evaluated by DSC. DSC studies showed that the Drug polymer complex formed by spray drying. Results show that increase in solubility was achieved for Cilnidipine by preparing spray dried dispersion using PVP K30 in ratio of (1:1) with pure drug. Optimized SDDs was further compressed into as orodispersible tablet by direct compression method. The prepared tablets were evaluated for the drug content, weight variation, wetting time, in vitro disintegration, hardness, friability, thickness and in vitro dissolution. Results revealed that Kyron T314 showed least disintegration time compare other disintegrant. Hence spray drying technique can be used for formulation of tablets of Cilnidipine by direct compression technique.

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Shailesh et al. Sciences

World Journal of Pharmacy and Pharmaceutical

KEYWORDS: Cilnidipine, Spray drying Technique, Orodispersible tablet, PVP K 30, Kyron T314. INTRODUCTION Cilnidipine is a novel dihydropyridine calcium antagonist and its calcium antagonistic activity is lasting longer than those of Nifedipine and Nicardipine. Cilnidipine has been used for the treatment of hypertension and hypertensive-associated vascular disorders. Its adult dose is about 40 to 80 mg once daily.[1] Cilnidipine has a very low solubility (BCS Class-II drug Low solubility high permeability) and compliance to the medication is always very poor. Compared with other techniques, like solvent evaporation, fusion method, hot Stage extrusion method, melt agglomeration, freeze-drying, supercritical fluid method, co-precipitation method, dropping method, fusion-solvent method.[2] it has many advantages, including shorter duration, reliability and reproducibility, cost effectiveness of process preparation, particle size control, good yield of production and the possibility of being free of organic solvent. Examples of successfully tested drugs which improved their dissolution by spray drying technique are Raloxifene hydrochloride,[3] Piroxicam,[4] Tinidazole.[5] A few attempts to enhance the solubility of Cilnidipine like inclusion complex of Cilnidipine with β‐cyclodextrin,[6] Coevaporation with PVP, PVP/VA and Soluplus,[7] solid dispersions by melting method were prepared using different carriers (PEG, PVP and poloxamer)[8] have appeared in the literature. Reported methods are having limitation of solvent residue as well as not feasible for large scale in industry. Hence, the objective of the present investigation was to improve solubility of Cilnidipine by spray drying method and develop Orodispersible tablets by direct compression method. Orodispersible Tablets (ODTs) which disintegrate rapidly in saliva, usually in a matter of seconds, without the need to take water. Drug dissolution and absorption as well as onset of clinical effect and drug bioavailability may be significantly greater than those observed from conventional dosage forms.[9] MATERIAL AND METHODS Cilnidipine was purchased from Pure Chem Pvt. Ltd. Gujarat, India, Kyron T314 received as gift sample from Corel Pharma, Ahmedabad, Gujarat, India, MCC procured from Chemdyes

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Corporation Ahmedabad, Gujarat, India), Aspartame purchased from Yarrow Chem. Products, Mumbai, India. Phase-solubility studies[10] Phase Solubility study was conducted as per the method reported by M. Cirri et.al. Excess quantity (50 mg) of drug was selected for study. Drug and carrier as per the specified drug: carrier ratio were weighed accurately and added to pure drug with 10 ml of water in screw capped bottles. All the bottles were shaken in incubator shaker at 37 °C and 24 °C for 24 hrs. The container with drug and water was used as control. After 24 hours the solutions were filtered using (0.45 μ) filter and the filtrates were diluted. The absorbance was measured in spectra at 240 nm. From the absorbance the solubility of the drug was calculated. Preparation of Spray dried dispersion Solid dispersions of Cilnidipine and various polymers in 1:0.75 to 1:1 ratios were prepared using spray drying method. Polymers were dissolved in ethanol and a solution of Cilnidipine in ethanol was added. This mixture was homogenized with a magnetic stirrer at 300-600 rpm. The solutions obtained by this procedure were dried in a laboratory-scale spray dryer. Spray dried all batches mentioned below using mentioned set parameters. Table No 1: Polymer Screening feed system Formulation Codes Components S1 S2 S3 (g) (g) (g) Drug 10 10 10 PVP K 30 7.5 10 Na. CMC 10 Ethanol(ml) 300 300 300

S3 (g) 10 20 300

Characterization of Cilnidipine Solid dispersions Determination of Percent Yield The percent yield of Cilnidipine solid dispersions was determined by using the following formula, Percent yield= (Weight of prepared solid dispersion/weight of drug + carriers)* 100 Evaluation of solid dispersion for solubility The solid dispersion was added to conical flasks containing 10 ml of media and subjected to shaking on a rotary shaker for 48 hours at 37°C. Then the flasks were removed and content

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was filtered by 0.45μm membrane filter paper and analyzed for the drug content after appropriate dilution with media and compared with pure drug solubility. Characterizations of Drug polymer complex Complex characterized by DSC Dug polymer complex were studied by Differential Scanning Calorimetry (DSC). Thermal behavior of Cilnidipine and Spray dried dispersion of Cilnidipine was recorded using a Differential Scanning Calorimeter (Shimadzu DSC TA 60 WS). Preparation of Orodispersible Tablets Preliminary screening of superdisintegrants Orodispersible tablets containing Spray dried dispersion of Cilnidipine:PVP K30 (1:1) using four superdisintegrants (Sodium starch glycolate, Crosscarmelose sodium, Cross povidone and Kyron T314) were prepared using direct compression method. All the ingredients as per formula were taken in mortar-pestle and mix well. Then it was compressed directly in rotary tablet compression machine (Rimek mini press, 10 stations, Karnavati, Ahmadabad. Table No 2: Formula for Preliminary screening of Superdisintegrant Sr. No. 1 2 3 4 5 6 7 8 9

Ingredients

P1

S.D eq. to 10 mg Cilnidipine S.S.G Crosspovidone Kyron T314 Ac-Di-Sol Mannitol Aspartame Talc Mg. Stearate Total Weight

Quantity Per tablet (mg) P2 P3

P4

20

20

20

20

3 73 1 2 1 100

3 73 1 2 1 100

3 73 1 2 1 100

3 73 1 2 1 100

Drug Excipient Compatibility Study FTIR Study Infrared (IR) spectra of drug and drug excipients mixture were obtained by using FTIR8400S (Shimadzu, Tokyo, Japan) using the KBr disk method. The scanning range was 4000 – 400 cm-1.

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Optimization of Orodispersible tablets From the results of preliminary screening studies the optimization was carried out using design of expert (DOE) approach. To study the effect of 2 independent variables i.e. disintegrant concentration (X1) and type of diluent (X2) on responses 32 full factorial design was used. In this design disintegration time, %CPR at 6 minutes and hardness were selected as response variables. Trials were taken at all possible combinations. The Composition of factorial batches is shown in Table 3. Table No. 3: Composition of Factorial batches (F1 to F9) Ingredients (mg)

F1

F2

F3

F4

F5

F6

F7

F8

F9

Cilnidipine SDDS eq. to 10 mg

20

20

20

20

20

20

20

20

20

Kyron T- 314

2%

2%

2%

3%

3%

3%

4%

4%

4%

Lactose DCL 11

73

Pearlitol SD 200

72 73

MCC

71 72

73

71 72

71

Aspartame

2

2

2

2

2

2

2

2

2

Mg. Stearate

1

1

1

1

1

1

1

1

1

Talc

2

2

2

2

2

2

2

2

2

100

100

100

100

100

100

100

100

100

Total weight

Polynomial equation for 32full factorial design: Y = ß0+ ß1X1+ ß2X2+ ß11X11+ ß22X22+ ß12X1X2 was used. In this equation Y is the dependent variable, ß0 is the arithmetic mean response of the nine runs, ß1 to ß12 are the coefficients for factors. The significant factors in the equations were selected using a stepwise forward and backward elimination for the calculation of regression analysis. The terms of full model having nonsignificant p value (p > 0.05) have negligible contribution and they were neglected. Evaluation of Orodispersible Tablets Drug Excipient Compatibility Study FTIR Study Infrared (IR) spectra of drug and drug excipients mixture were obtained by using FTIR8400S (Shimadzu, Tokyo, Japan) using the KBr disk method. The scanning range was 4000–

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400 cm-1. Pre-compression parameters[11] It contains Bulk density, Tapped density, Compressibility index and hausner’s ratio, Angle of repose. Post-compression parameters include[11] Weight variation, Thickness and diameter, Hardness, Friability, Assay Wetting time[12] Five circular tissue papers of 10 cm diameter are placed in a petridish with a 10 cm diameter. Ten millimeters of water containing Eosin, a water-soluble dye, is added to petridish. A tablet is carefully placed on the surface of the tissue paper. The time required for water to reach upper surface of the tablet is noted as a wetting time. In vitro disintegration study Disintegration time was determined using the disintegration apparatus USP in water maintaining the temperature at 37 ± 2°C. In vitro drug release Standard USP dissolution apparatus USP-II (Paddle) has been used to study in vitro release profile using rotating paddle. In release rate study of orodispersible tablets carried out using the USP Apparatus 2 (Paddle apparatus) method. The dissolution test was carried out using 900 ml Deionized Water Containing 0.25% W/V SLS, at 37±0.5°C and 50 rpm. A sample of the solution was withdrawn from the dissolution apparatus at 0, 2, 4, 6, 8, 10 minutes and withdrawn volume was replaced with fresh dissolution media, filtered and assayed spectrophotometrically. Stability Study[13] The prepared ODT tablet was packed in aluminum pouch and charged for short term stability studies at 40 °C and 75% RH for 1 month in a humidity chamber. Samples withdrawn after 1 month showed no significant change in appearance of tablets, % drug content, disintegration time, hardness and drug dissolution profile.

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RESULTS AND DISCUSSION Table No. 4: Solubility results of physical mixture of drug with different carriers Sr. No. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.

Polymers Drug PVP K 30 PEG 4000 PEG 6000 Chitosan Carrageenan Poloxamer 188 β‐cyclodextrin HPMC E5 LV Na. CMC

Ratio (D:P) 1:0 1:1 1:1 1:1 1:1 1:1 1:1 1:1 1:1 1:1

Solubility (µg\ml) 33.99 139.10 46.68 40.00 35.30 36.50 43.90 38.43 40.06 105.40

Fig. 1: Comparison of solubility of drug with different polymer From the Solubility results of drug with different carriers it was found that drug showed maximum solubility in PVP K-30 and Na. CMC. So, both carriers were used for further studies. Spray dried dispersion of drug with PVP K-30 and Na. CMC Table No. 5: Evaluation of Spray Dried Dispersion of drug with PVP K-30 and Na. CMC Sr. No.

Ratio Conc. of feed Solubility % Yield (D:P) System (%) (µg/ml) 1:0.75 5.83 48.00 534.1 1 PVP K30 1:1 6.66 52.00 819.2 1:1 6.66 45.65 712.8 2 Na. CMC 1:2 10.22 34.06 672.1 From all above batches SDD containing PVP (1:1) ratio showed highest solubility. Polymer

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Complex Characterized By DSC.

Fig.2: DSC Thermogram of Cilnidipine and DSC Thermogram of Cilnidipine SDDs The DSC Thermograms of plain drug, drug polymer complex are shown in figure 3. The Thermogram of API exhibited sharp endothermic peak at 111◦C indicated melting point which is reported in literature. in case of the DPC there observed shift in the peak 97◦C, that indicates there is complex was formed between the drug and polymer Optimization of Superdisintegrant in Tablet Formulations Table No. 6: Evaluation of P1 to P4 Batch Hardness Weight Variation Friability Wetting Drug Content D.T 2 (mg)(n=20) (%) Time (Sec.) (%) (Sec.) (Kg/cm ) 101.11±0.21 3.12±0.11 0.76 19.20±0.23 97.27±0.47 25±1.10 99.88±0.31 2.78±0.15 0.77 17.25±0.31 99.12±0.58 116±1.14 100.17±0.23 3.18±0.09 0.88 10.11±0.14 98.41±0.24 15±1.17 100.14±0.33 2.77±0.14 0.80 18.63±0.29 98.57±0.55 52±1.74 *All values are mean ± S.D. (n=3) except in weight variation where n=20

Batch* P1 P2 P3 P4

From above evaluation of tablets, it was found that KyronT-314 has lesser disintegration time and other parameter also found liable for good tablet formulation. So it was use for further optimization by Factorial design. Drug Excipient Compatibility Study FTIR Study The frequencies of functional groups of the drug Cilnidipine remained intact in physical

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mixture containing different excipients. So, it was concluded that there was no major interaction occurred between the drug and excipients used in the study.

Fig.3: FTIR Spectra of Cilnidipine

Fig.4: FTIR Spectra of Cilnidipine + Excipients Optimization of Orodispersible tablets (F1 to F9) Table No. 7: Pre compression Characteristic Batch* F1 F2 F3 F4 F5 F6 F7 F8 F9

Angle of repose(◦)

Bulk density (gm/cm3) 26.37±0.34 0.45±0.02 31.08±0.32 0.43±0.02 29.37±0.34 0.41±0.01 22.12±0.24 0.48±0.03 25.33±0.24 0.46±0.03 19.73±0.18 0.47±0.01 24.11±0.21 0.46±0.02 24.98±0.55 0.48±0.01 21.37±0.41 0.44±0.01 *All values are mean ± S.D. (n=3)

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Tapped Density (gm/cm3) 0.53±0.02 0.58±0.02 0.56±0.01 0.56±0.03 0.57±0.03 0.51±0.04 0.55±0.02 0.59±0.03 0.52±0.04

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Hausner’s Ratio 1.17±0.18 1.34±0.53 1.36±0.37 1.16±0.31 1.23±0.29 1.08±0.33 1.19±0.47 1.22±0.57 1.18±0.41

Compressibility (%) 17.77±0.52 25.86±0.17 26.78±0.16 14.28±0.23 19.29±0.14 7.48±0.18 16.36±0.21 18.64±0.31 15.38±016

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From above data, it was concluded that all powder blends show good flow properties and good compressibility. Post compression Characteristic All the formulated batches were found to be within the limits as per Indian pharmacopeia. The hardness was found to be within 3-4 Kg/cm2 in all the formulations. In all the formulations, the friability value is less than 1% giving an indication that tablets formulated are mechanically stable. All the tablet formulations compile the weight variation test. The weight of all the formulations was found to be within the limits. The assay of all the formulations was found to be within the pharmacopoeial limit (Table 8). Table No. 8: Evaluation of factorial batches of tablets Parameter* Hardness (kg/cm2) Thickness (mm) % Friability

F1 3.1 ± 0.10 2.21 ± 0.22 0.26

F2 3.2 ± 0.10 2.12 ± 0.27 0.39

F3 3.2 ± 0.05 2.43 ± 0.18 0.71

F4 3.3 ± 0.10 2.80 ± 0.19 0.77

F5 3.4 ± 0.10 2.88 ± 0.21 0.19

F6 3.5 ± 0.05 3.08 ± 0.25 0.20

F7 3.6 ± 0.05 2.59 ± 0.32 0.35

100.29 99.97 100.77 100.0 100.02 100.09 100.1 ± ± ± ± ± ± ± 0.57 0.21 0.37 0.77 0.63 0.71 0.44 99.83 97.73 98.12 99.12 96.92 99.03 101.0 ± ± ± ± ± ± ± 0.5 0.46 0.13 0.46 0.5 0.41 0.46 31.60 23.32 26.98 13.52 12.37 4.53 14.78 ± ± ± ± ± ± ± 0.27 0.21 0.24 0.21 0.32 0.27 0.24 54.20 39.80 43.00 21.00 19.24 7.19 21.31 DT time ± ± ± ± ± ± ± (Sec.) 0.67 0.51 0.39 0.87 0.99 0.59 0.77 *All values are mean ± S.D. (n=3) except in weight variation where n=20. Weight variation (mg) Content Uniformity (%) Wetting time (Sec.)

F8 3.8 ± 0.15 2.94 ± 0.21 0.89 100.14 ± 0.39 98.91 ± 0.37 7.77 ± 0.20 12.25 ± 0.48

F9 3.8 ± 0.15 3.16 ± 0.18 0.63 99.87± 0.31 99.43± 0.34 3.86 ± 0.21 5.45 ± 0.42

Fig. 5: In vitro drug release studies of batches www.wjpps.com

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In vitro release All the formulation was studied and it was found that the batch F9 showed 91.90 % CPR at 6 minutes which was maximum compared to other batches. Statistical analysis of 32 factorial batches Disintegration time Full Model: Y 1 = 14.75 - 16.33 X 1 - 6.81 X 2 – 1.16 X 1 2 + 13.52 X 2 2 + 1.60 X 1 X 2 Reduced Model: Y1 =14.75 – 16.33 X1 - 6.81 X 2 + 13.52 X 2 2 Cumulative Percentage Drug Release at 6 minutes Full Model: Y2 = 86.99 + 8.68 X1 + 3.70 X2 + 1.32 X12 – 8.10 X22 - 1.63 X 1X2 Reduced Model: Y1 =86.99 + 8.68 X 1 + 3.70 X2- 8.10 X22 Hardness Full Model: Y3 = 3.47 + 0.30 X1 + 0.093 X2 + 0.037 X12 +0.042 X22 - 0.043 X 1X2 Reduced Model: Y3 =3.47 + 0.30 X 1 + 0.093 X2 Table No. 9: ANOVA for dependent variables of the 32 full factorial design Source

DF

Regression Residual Total

5 3 8


5 3 8


5 3 8

SS MS F-value Disintegration time (sec) 2255.10 451.02 20.79 65.03 21.68 2320.16 % CPR at 6 min. 678.16 135.63 18.89 24.08 8.02 702.25 Hardness (kg/cm2) 0.635 0.1271 33.78 0.011 0.0037 0.648

R2

p-value

0.9720

0.0155 Significant

0.9657

0.0209 Significant

0.9826

0.0077 Significant

From the ANOVA table it was found that, variable X1 i.e. concentration of Kyron T314 shows negative effect on disintegration time. As its concentration increases, disintegration time decreases. Variable X2 i.e. Type of diluent also shoes negative effect on disintegration time. It can be qualitatively concluded that X1 had the largest effect on the response of Y1, which indicated that X1 was important parameters to regulate disintegration time.

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Variable X1 i.e. concentration of Kyron T314 shows positive effect on the % CPR at 6 min. As its concentration increases, % CPR at 6 min. of the tablet increases. Variable X2 i.e. Type of diluent also shows positive effect on the %CPR at 6 min. It can be qualitatively concluded that X1 and X2 both had significant effect on the response. Variable X1 i.e. concentration of Kyron T314 shows positive effect on the Hardness. As its concentration increases, Hardness of the tablet increases. Variable X2 i.e. Type of diluent also shows positive effect on the hardness. It can be qualitatively concluded that X1 and X2 both had significant effect on the response. Design-Expert® Software Factor Coding: Actual D.T (Sec) Design points above predicted value Design points below predicted value 54.2 5.45

60 X1 = A: A X2 = B: B

50

D .T (S e c )

40 30 20 10 0

1

-1 0.5

-0.5 0

0

X1: Disintegrant(%) Design-Expert® Software Factor Coding: Actual Hardness (kg/cm2) Design points above predicted value Design points below predicted value 3.88

Design-Expert® Software Factor Coding: Actual %CPR (%) Design points above predicted value Design points below predicted value 91.9

-0.5

0.5

(A) (k g /c m 2 )

3.12 X1 = A: A X2 = B: B

64.33

100

90

H a rd n e s s

% C P R

(% )

X1 = A: A X2 = B: B

80

70

60

1

X2: Type of Diluent

1 -1

4 3.8 3.6 3.4 3.2 3

1 0.5

0.5 0

X2: Type of Diluent

1

0 -0.5

-0.5 -1 -1

X1: Disintegrant(%)

0.5

0

X2: Type of Diluent

(B)

-0.5

-1 -1

-0.5

0

0.5

1

X1: Disintegrant(%)

(C)

Fig. 6: 3-D surface plot for A) Disintegration time, B) %CPR and C) Hardness Short Term Stability Study of Optimized Formulation

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The result of short term stability studies indicates that the formulation was stable on the required storage condition. CONCLUSION From the above discussion it is clear that improvement in solubility and dissolution rate of Cilnidipine can be achieved from polymer based spray dried dispersions. From evaluation parameters and formulation characterization, it was concluded that solubility of drug was improved in spray dried dispersion compared to pure drug. The results of present study indicated that Kyron T-314 could be used as a disintegrant for formulation of orodispersible tablet containing Cilnidipine. On the basis of data obtained from in-vitro dissolution studies that F9 is promising formulation suitable for the immediate release of Cilnidipine. The formulation batch F9 was found to be stable for a period of one month at 40 ºC/ 75% RH. Orodispersible tablet can be a potential novel drug dosage form for pediatric, geriatric and also for general population. ACKNOWLEDGEMENT The authors are very thankful to Institute of Pharmacy Nirma University, Ahmedabad (Faculty & Management) for providing facilities to carry out this research work on Spray Dryer and also thankful to Corel Pharma Pvt. Ltd. for providing Kyron as a gift sample for our work. REFERNCES 1. Cilnidipine

drug

information,

DrugsUpdate

India,

http://www.drugsupdate.com/generic/view/1129/Cilnidipine. 2. Patil R M, Maniyar A H, Kale M T, Akarte A M and Baviskar D T.“Solid dispersion: strategy to enhance solubility.” Int J Pharm Sci Rev Res, 2011; 8: 66-73. 3. Rajinikanth P S, Balasubramaniam J, Thilek M.“Spray drying as an approach for enhancement of dissolution and bioavailability of Raloxifene hydrochloride” Int J Drug Del, 2012; 4(2): 246-256. 4. Ashwini G, Dixit M, Kulkarni P.“Enhancement of solubility and dissolution rate of poorly water soluble drug by spray drying using different grade of chitosan” In. J Pharm Pharma Sci, 2011; 3(2): 231-235. 5. Chhaprel P, Talesara A, Jain A.“Solubility enhancement of poorly water soluble drug using Spray Drying technique” J Pharma Stu Res, 2012; 3(1): 01-05. www.wjpps.com

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6. Hu L, Zhang H, Song W, Gu D, Hu Q., “Investigation of inclusion complex of cilnidipine with hydroxypropyl-β-cyclodextrin.”, http://www.ncbi.nlm.nih.gov/pubmed/22944438. 7. Chen C, Xiabing X, Yang L, Chen Z, Yang S, Zhixiang Y, and Xinghao Y.“Influence of different polymers on crystallization tendency and dissolution behavior of cilnidipine in solid dispersions” Drug Dev Ind Pharm, 2013; 1–11. 8. Hu L, Weihua S, Feng N, Kuiliang J and Zheng J. “Preparation, characterization and tableting of cilnidipine solid dispersions” Pak J Pharm Sci, 2013; 26(3): 629-636. 9. Deshpande K B. “Orodispersible Tablets: An Overview of formulation and Technology”, Int J phrma Bio, 2011; 2(1): 726-734. 10. Cirri M, ”Characterization of Ibuproxam binary and ternary dispersions with hydrophilic carriers”, Drug Dev Ind Pharm, 2004; 30(1): 65–74. 11. Soumya M, Madhu Babu M, Aparna K and Himabindu P. “A Review on Fast dissolving drug delivery system- A Pioneering Drug Delivery Technology.” Bull Env Pharmacol Life Scien, 2012; 1(12): 8-20. 12. Arora P, Arora V,“ Orodispersible Tablets: A Comprehensive Review“ Int J Res Dev Pharm Life sci, 2013; 2(2): 270-284. 13. Food and drug administration Federal register, “Stability testing for new dosage forms” , http://www.ich.org/products/guidelines/quality/article/quality-guidelines.html

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