Formulation and Evaluation of Buccal Tablet of Ropinirole Hydrochloride

RESEARCH ARTICLE

Formulation and Evaluation of Buccal Tablet of Ropinirole Hydrochloride

Jani Jayesh H1*, Prajapati Amit J1, Shah Dhaval K1, Singh Sudarshan K1

Abstracts: The Ropinirole Hydrochloride is a non‐ergoline dopamine agonist with high relative specificity and full intrinsic activity at the D2 and D3 dopamine receptor subtypes. This action in humans correlates with treatment for Parkinson’s disease due to stimulation of postsynaptic dopamine D2‐type receptors. Ropinirole Hydrochloride after oral administration shows a lesser bioavailability up to 55% and biological half life of 4 to 6 hours. So, present investigation deals with formulation and evaluation of buccal tablet of Ropinirole Hydrochloride. Ropinirole Hydrochloride buccal tablets were prepared by wet granulation method using Polycarbophil and HPMC K15M as mucoadhesive polymers. A 32 full factorial design was applied to investigate the combined effect of concentration of Polycarbophil (X1) and concentration of HPMC K15M (X2). Results of the multiple regression analysis revealed that the independent variables significantly affected the dependent variables (Q7(%), Mucoadhesive strength (gm) and Swelling index). An optimized formulation F6 was found to have good mucoadhesive strength 6.805 ± 0.12 gm, swelling index 106.00 ± 0.03 after 8 hr; mucoadhesive residence time was found to be more than 8 hr and cumulative percentage drug release 98.44 ± 1.47 within 8 hr. Release kinetic model studies indicated that optimized batch followed diffusive mechanism with Zero order release kinetics.

The total dose of Ropinirole Hydrochloride buccal tablet for a sustained release formulation was calculated by following four Robison and Eriksen equations: k0 = Dike……….. (1) Dm = k0T………. (2) Dl=Di‐k0Tp…….. (3) Dt = D l+ Dm……. (4) Where, k0= zero order drug release; ke =0.693/t1/2 Di= initial dose, Dl= loading dose; Dm= maintenance dose; T= time for sustained action; Tp= time to reach peak plasma concentration; Dt= total dose of drug. Therefore, the total dose of the drug is calculated using the equations. k0 = Dike = 0.75×0.693/4 = 0.1299 mg Dm = k0T = 0.1299×8 = 1.0395 mg Dl = Di‐k0Tp = 0.75 ‐ (0.1299×1) = 0.6201 mg Dt = Dl +Dm = 0.6021+1.0395 = 1.7 ≡ 2 mg Hence the matrix tablet should contain a total dose of 2 mg and it should release 0.6201+ 0.1299 = 0.75 (37.5%) mg in 1st hr like conventional dosage form and 0.1299 + 0.0428 (8.6%) mg per hr up to 8 hr. Theoratical profile shown in table 1. PREFORMULATION STUDY FOR DRUGEXCIPIENTS COMPATIBILITY FTIR and DSC Data Analysis Study The FTIR scan was recorded by using FTIR spectrometer (Jasco 4100) coupled with Jasco spectra manager version 2.0 software using KBr as negative control. An adequate quantity of sample & IR grade KBr was thoroughly blended. The sample was then analyzed at a scanning range 400‐ 4000 cm‐1. Ropinirole Hydrochloride Buccal Tablet was Prepared by Wet Granulation5 Buccal tablet of Ropinirole Hydrochloride was prepared by wet granulation method. All the ingredients were weighed accurately and mix well in mortar pestle. The powder mass was mixed with alcoholic solution of PVP K‐30 to obtained

INTRODUCTION Mucoadhesive drug delivery, system has become highly interesting in the last 10‐15 years. The recent development in the drug delivery has intensified investigation of mucosal delivery of drug such route includes oral, buccal, ocular, nasal and pulmonary routes etc.1 Mucoadhesive drug delivery systems are delivery systems, which utilized the property of bioadhesion of certain polymers, which become adhesive on hydration and hence can be used for targeting a drug to particular region of the body for extended period of time. Problems such as high first pass metabolism and drug degradation in gastrointestinal environment can be circumvented by administering the drug via the buccal route 2. Ropinirole is a non‐ergoline dopamine agonist activity at the D2 and D3 dopamine receptor subtypes, used for the treatment of Parkinson’s disease. The absolute oral bioavailability is about 50 to 55%. The half‐life of Ropinirole is 4 to 6 hrs and it undergoes hepatic metabolism. In order to overcome such hepatic metabolism and poor bioavailability the drug is selected as suitable candidate for bioadhesive buccal drug delivery 3. The objective of present work to develop the buccal tablet of Ropinirole using wet granulation technique by using different polymers like Polycarbophil and HPMC K15M. MATERIAL AND METHOD Material Ropinirole Hydrochloride was given by Alembic, Vadodara, India. Polycarbophil and HPMC K15M was given Lubrizol Advanced Materials India Pvt. Ltd and Colorcon Asia pvt. Ltd. Goa, India respectively. All ingredients were used of laboratory analytical grade. METHOD Dose Calculation 4

1Shree H.N.Shukla Institute Pharmaceutical Education And Research, Rajkot, Gujarat, India. E‐mail: [email protected] *Corresponding author

Inventi Rapid: Pharm Tech Vol. 2012, Issue 4 [ISSN 0976‐3783]

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2012 ppt 527, CCC: $10 © Inventi Journals (P) Ltd Published on Web 16/06/2012, www.inventi.in

RESEARCH ARTICLE Table 1: Theoretical Release Profile of Drug % CDR 0 37.5 46.1 54.7 63.3 71.9 80.5 89.1 97.7

Time (Hr) 0 1 2 3 4 5 6 7 8 Table 2: Composition of trial batches Ingredients Ropinirole HCL Polycarbophil HPMC K15M MCC PVP k‐30 IPA Aerosil Talc Total

P1 (mg) 2 5 ‐ 83 5 q.s 3 2 100

P2 (mg) 2 10 ‐ 78 5 q.s 3 2 100

P3 (mg) 2 15 ‐ 73 5 q.s 3 2 100

P4 (mg) 2 20 ‐ 68 5 q.s 3 2 100

P5 (mg) 2 25 ‐ 63 5 q.s 3 2 100

H1 (mg) 2 ‐ 5 83 5 q.s 3 2 100

H2 (mg) 2 ‐ 10 78 5 q.s 3 2 100

H3 (mg) 2 ‐ 15 73 5 q.s 3 2 100

H4 (mg) 2 ‐ 20 68 5 q.s 3 2 100

H5 (mg) 2 ‐ 25 63 5 q.s 3 2 100

PH1 (mg) 2 5 10 73 5 q.s 3 2 100

PH2 (mg) 2 10 5 73 5 q.s 3 2 100

PH3 (mg) 2 20 10 58 5 q.s 3 2 100

PH4 (mg) 2 25 20 68 5 q.s 3 2 100

Table 3: Composition of Factorial Batch F1toF9 F1 F2 F3 F4 F5 F6 F7 F8 Ingredients (mg) (mg) (mg) (mg) (mg) (mg) (mg) (mg) Ropinirole Hydrochloride 2 2 2 2 2 2 2 2 Polycarbophil 15 15 15 20 20 20 25 25 HPMC K15M 10 15 20 10 15 20 10 15 MCC 61 56 51 56 51 46 51 46 PVP K30 5 5 5 5 5 5 5 5 IPA q.s q.s q.s q.s q.s q.s q.s q.s Aerosil 3 3 3 3 3 3 3 3 Talc 2 2 2 2 2 2 2 2 Total 100 100 100 100 100 100 100 100 Table 4: Data of IR Interpretation of Drug and Physical Mixture of Drug and Polymer

F9 (mg) 2 25 20 41 5 q.s 3 2 100

Name of the Compound Ropinirole Hydrochloride Ropinirole HCl + Physical Mixture of Polymers

C=O Streatching 1723 cm‐1 1713.44 cm‐1

Functional Group NH 1o Aliphatic 3415.31 cm‐1 3474.69 cm‐1

Halogen 1455.31 cm‐1 1455.03 cm‐1

a wet mass and passed through sieve no # 18. The prepared granules were dried at 40 ºC for 30 min. The dried granules were screened through sieve no # 22 and stored for further study. The specified quantity of Aerosil and talc were finally added and mixed for the compression. Preliminary Screening Preliminary Screening was carried out using two different bioadhesive polymers. Preliminary Screening was carried out first using single bioadhesive polymer and then combination of two bioadhesive polymer. The formulas of batch P1 to P5 were using Polycarbophil, formulas of batch H1 to H5 were using HPMC K15M and formulas PH1 to PH4

were using Polycarbophil and HPMC K15M combination. All batches Composition shown in Table 2. Optimization Using Full Factorial Design A 32 randomized full factorial design was used in present study. In this design 2 factors were evaluated, each at 3 levels, and experimental trials were performed for all 9 possible combinations. Concentration of Polycarbophil polymer (X1) and concentration of HPMC K 15M (X2) were chosen as independent variables while percentage drug release in 7 hr (Q7), ex vivo Mucoadhesive strength and swelling index after 8 h were taken as dependent variables. The formulation layout for the factorial design batches F1– F9 is shown in Table 3.


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RESEARCH ARTICLE Table 5: Swelling index, exvivo Mucoadhesive Strength, Force of Adhesion, Mucoadhesion Residence Time for Formulations of Trial Batches Mucoadhesive Strength Mucoadhesion Residence Formulation Code SI Time (8 hr)* Force of Adhesion (N)* (gm)* Time (hr)* P1 15 ± 0.15 1.501 ± 0.117 0.014 ± 0.012 1.30 ± 1.01 P2 37 ± 0.26 2.810 ± 0.640 0.027 ± 0.014 3.10 ± 0.51 P3 49 ± 0.04 3.911 ± 0.062 0.038 ± 0.004 5.15 ± 0.26 P4 80 ± 1.13 5.221 ± 0.010 0.051 ± 0.005 7.05 ± 0.53 P5 94 ± 0.64 5.601 ±0.114 0.054 ± 0.004 7.25 ± 0.15 H1 18 ± 1.12 1.321 ± 0.144 0.012 ± 0.012 1.22 ± 0.32 H2 32 ± 0.25 2.511 ± 0.333 0.024 ± 0.015 2.55 ± 0.66 H3 52 ± 0.08 3.620 ± 0.334 0.035 ± 0.010 4.30 ± 0.21 H4 85 ± 1.06 3.801 ± 0.547 0.035 ± 0.009 6.08 ± 0.36 H5 96 ± 0.54 4.126 ± 0.442 0.040 ± 0.010 6.58 ± 0.61 PH1 51 ± 0.23 4.510 ± 0.331 0.044 ± 0.011 5.40 ± 0.04 PH2 45 ± 0.33 5.122 ± 0.121 0.050 ± 0.014 5.55 ± 1.15 PH3 101 ± 0.45 6.615± 0.522 0.064 ± 0.015 7.15 ± 0.63 PH4 124 ± 0.07 8.511 ± 0.124 0.083 ±0.016 >8 *Mean ± SD (n= 3)

Time (hr) 0 0.5 1 2 3 4 5 6 7 8

*Mean ± SD (n= 3)

Time (hr) 0 0.5 1 2 3 4 5 6 7 8

P1 0 49.58 ± .34 69.81 ± 2.16 84.82 ± 1.01 92.1 ± 2.10 98.95 ± 3.15 98.89 ± 0.77 ‐ ‐ ‐

Table 6: %Cumulative Drug Release of Trial Batch of Polycarbophil % Cumulative Drug Release* P2 P3 P4 0 0 0 46.62 ± 3.31 43.17 ± 2.54 36.92 ± 2.56 65.81 ± 2.81 59.68 ± 3.45 58.63 ± 3.12 80.42 ± 3.24 71.63 ± 3.71 72.92 ± 2.79 90.64 ± 1.65 82.12 ± 0.90 78.16 ± 1.89 98.62 ± 2.70 86.12 ± 1.98 88.95 ± 2.98 98.62 ± 1.98 99.12 ± 2.50 93.6 ± 1.54 ‐ 99.12 ± 1.29 99.24 ± 0.98 ‐ ‐ 99.26 ± 1.24 ‐ ‐ ‐

Table 7: % Cumulative Drug Release of Trial Batch of HPMC K15M % Cumulative Drug Release* H1 H2 H3 H4 0 0 0 0 42.68 ± 2.56 45.78 ± 2.0 38.15 ± 3.12 32.35 ± 1.50 78.45 ± 1.54 76.41 ± 3.02 62.71 ± 2.10 53.48 ± 2.12 86.12 ± 0.89 85.09 ± 3.21 74.44 ± 1.29 67.47 ± 2.16 93.02 ± 1.24 92.12 ± 1.25 82.52 ± 1.02 73.62 ± 1.89 97.96 ± 2.57 99.09 ± 0.89 88.93 ± 2.10 79.02 ± 2.89 98.11 ± 1.68 99.9 ± 1.28 99.96 ± 0.82 91.46 ± 3.16 98.16 ± 1.75 99.03 ± 1.02 99.96 ± 0.79 98.16 ± 1.20 ‐ ‐ ‐ 98.16 ± 2.01 ‐ ‐ ‐ ‐

P5 0 30.62 ± 1.02 53.08 ± 2.80 68.01 ± 3.15 76.17 ± 2.89 81.3 ± 1.01 91.62 ± 1.76 100.02 ± 0.89 99.98 ± 1.90 ‐

H5 0 28.12 ± 1.05 52.15 ± 2.10 61.62 ± 3.50 74.16 ± 2.00 80.62 ± 3.21 88.14 ± 1.20 99.42 ± 1.56 99.43 ± 0.79 ‐

*Mean ± SD (n= 3)

POST COMPRESSION EVALUATION PARAMETER OF TABLETS Hardness 6, 7 Tablets require certain amount of strength or hardness, to withstand mechanical shocks of handling in manufacture, packaging, and shipping. The most widely used apparatus to measure tablet hardness (crushing strength) is the Monsento hardness tester. The hardness of five tablets in each batch was measured and the average hardness was calculated. Thickness 8

The thickness of the tables was determined by using vernier callipers. Ten tablets were used, and average values were calculated. Friability9 The friability of the tablets was measured in a Roche friabilator (Camp‐bell Electronics, Mumbai). Tablets of a known weight (W0) or a sample of 20 tablets are deducted in a drum for a fixed time (100 revolutions) and weighed (W) again. Percentage friability was calculated from the loss in weight as given in equation as below. The weight loss should not be more than 1 %. Determination was made in triplicate.


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RESEARCH ARTICLE Table 8: %Cumulative Drug Release of Trial Batch Prepared Using Combination of Polycarbophil and HPMC K15M % Cumulative Drug Release* Time (hr) PH1 PH2 PH3 PH4 0 0 0 0 0 0.5 23.12 ± 2.56 24.12 ± 3.10 24.36 ± 1.56 20.46 ± 2.10 1 33.44 ± 3.15 30.48 ± 2.51 39.65 ± 2.10 36.52 ± 3.20 2 51.62 ± 2.30 48.56 ± 1.06 46.32 ± 2.01 42.68 ± 1.34 3 68.09 ± 1.00 66.42 ± 3.50 55.54 ± 1.66 50.14 ± 1.56 4 79.16 ± 2.56 76.14 ± 3.10 64.78 ± 2.50 55.69 ± 2.69 5 87.39 ± 1.09 85.98 ± 2.10 74.68 ± 1.06 62.92 ± 2.10 6 99.78 ± 1.99 97.35 ± 1.10 85.62 ± 2.07 68.92 ± 1.01 7 99.78 ± 0.79 100.11 ±1.00 93.6 ± .56 75.12 ± 2.16 8 ‐ 100.11 ± 1.20 100.07 ± 1.01 81.44 ± 3.00 Table 9: Post Compression Evaluation Parameter of Batch F1 to F9 Batch Weight Variation Drug Content Hardness(kg/cm2)* Thickness (mm)* Friability (%)* Code (mg)* Uniformity (%)* F1 5.1 ± 0.31 3.13 ± 0.11 0.41 ± 0.02 98.01± 1.03 98.75 ± 1.51 F2 5.4 ± 0.43 3.16 ± 0.05 0.33 ± 0.04 99.24 ± 1.41 97.17 ± 1.34 F3 5.0 ± 0.52 3.30 ± 0.05 0.38 ± 0.01 99.88 ± 1.11 96.34 ± 1.62 F4 5.3 ± 0.46 3.32± 0.09 0.33± 0.05 102.50 ± 1.21 98.26 ± 1.16 F5 5.5 ± 0.37 3.15 ± 0.03 0.45 ± 0.07 100.53 ± 1.26 100.41 ± 1.41 F6 5.6 ± 0.31 3.31 ± 0.11 0.43 ± 0.03 99.04 ± 1.30 99.25 ± 1.54 F7 5.3 ± 0.23 3.20 ± 0.08 0.56 ± 0.04 98.46 ± 1.18 98.43 ± 1.26 F8 5.2 ± 0.19 3.10 ± 0.07 0.32 ± 0.07 99.20 ± 1.12 99.61 ± 2.37 F9 5.6 ± 0.21 3.19 ± 0.09 0.31± 0.08 98.72 ± 1.18 100.97 ± 1.32 *Mean ± SD (n= 3)

Formulation code F1 F2 F3 F4 F5 F6 F7 F8 F9

Table 10: Swelling Index Profile for batch F1 to F9 Time (hr)* 4 25.30 ± 0.05 33.33 ± 0.04 59.59 ± 0.07 46.00 ± 0.04 65.00 ± 0.12 80.00 ± 0.07 75.76 ± 0.06 90.90 ± 0.08 95.96 ± 0.09

8 62.63 ± 0.07 72.70 ± 0.06 82.81 ± 0.07 81.00 ± 0.06 92.00 ± 0.06 106.00 ± 0.12 104.08 ± 0.03 111.12 ± 0.02 117.17 ± 0.05

*Mean ± SD (n= 3)

Table 11: Surface pH, E vivo Mucoadhesive Strength, Force of Adhesion, Mucoadhesion Time for Formulations of F1 to F9 Batches Mucoadhesion Residence Formulation Surface pH* Mucoadhesive Strength (gm)* Force of Adhesion (N)* Code Time (hr)* F1 5.21 ± 0.10 6.00 ± 0.10 0.058 ±0.08 5.30 ± 0.10 F2 6.81 ± 0.23 6.305 ± 0.23 0.061 ±0.10 5.52 ± 0.14 F3 6.91 ± 0.10 6.455 ± 0.10 0.063 ±0.22 6.10 ± 0.15 F4 7.04 ± 0.11 6.390 ± 0.16 0.063 ± 0.14 6.39 ± 0.32 F5 6.11 ±0.14 6.615 ± 0.08 0.064 ± 0.12 7.52 ± 0.22 F6 6.82 ± 0.05 6.805 ± 0.12 0.066 ± 0.009 >8 F7 6.91 ± 0.08 7.605 ± 0.54 0.074 ± 0.010 >8 F8 7.03 ± 0.11 7.620 ± 0.50 0.074 ±0.10 >8 F9 6.72 ± 0.05 7.930 ± 0.48 0.077 ± 0.009 >8 *Mean ± SD (n= 3)

% Friability

W W

W

20 tablets were selected at random from the batches, weighed individually and the average weigh was determined. The percent deviation of each tablets weight against the average weight was calculated. The test

100

Weight Variation Test 10, 11


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RESEARCH ARTICLE

Time (hr) 0 0.5 1 2 3 4 5 6 7 8 *Mean ± SD (n= 3)

Time (hr) 0 0.5 1 2 3 4 5 6 7 8 *Mean ± SD (n= 3)

Time (hr) 0 0.5 1 2 3 4 5 6 7 8

Table 12: % Cumulative Drug Release of Factorial Batch F1, F2 and F3 % Cumulative Drug Release* F1 F2 0 0 35.09 ± 1.50 31.2 ± 2.09 45.1 ± 2.15 44.80 ± 1.29 58.82 ± 3.20 59.62 ± 1.56 78.05 ± 1.89 72.73 ± 2.01 84.55 ± 0.78 86.65 ± 1.05 93.38 ± 2.91 90.1 ± 2.10 97.74 ± 1.01 98.09 ± 1.50 97.75 ± 1.89 98.05 ± 0.79 ‐ ‐

F3 0 28.62 ± 2.89 40.10 ± 0.76 55.62 ± 1.07 63.92 ± 2.89 74.62 ± 4.10 83.42 ± 2.10 87.58 ± 1.56 92.16 ± 2.01 96.09 ± 1.98

Table 13: In vitro % CDR of Factorial Batch F4, F5 and F6 % Cumulative Drug Release* F4 F5 0 0 26.31 ± 2.00 24.36 ± 2.01 41.50 ± 1.89 39.65 ± 1.56 52.68 ± 2.10 46.32 ± 2.39 66.98 ± 1.09 55.54 ± 1.56 78.90 ± 3.69 64.78 ± 3.96 85.96 ± 1.21 74.68 ± 2.98 88.98 ± 2.60 85.62 ± 1.99 94.55 ± 1.98 93.60 ± 0.78 99.62 ± 2.10 101.20 ± 0.99

F6 0 22.41 ± 1.56 37.68 ± 2.03 45.62 ± 0.89 53.71 ± 1.86 64.54 ± 2.16 70.62 ± 3.10 81.09 ± 2.50 90.51 ± 1.21 98.44 ± 3.21

Table 14: Cumulative Drug Release of Factorial Batch F7, F8 and F9 % Cumulative Drug Release* F7 F8 0 0 23.51 ± 3.10 25.62 ± 1.51 40.62 ± 2.90 42.78 ± 1.01 48.78 ± 3.54 45.68 ± 0.88 52.1 ± 1.56 53.08 ± 3.24 58.4 ± 2.01 57.66 ± 4.41 65.21 ± 3.22 61.72 ± 1.56 73.6 ± 3.38 74.76 ± 2.01 87.65 ± 2.89 84.05 ± 0.56 93.61 ± 3.56 90.62 ± 3.01

F9 0 19.2 ± 1.09 39.5 ± 2.00 43.48 ± 3.56 56.62 ± 1.89 61.82 ± 1.29 66.73 ± 3.00 72.08 ± 1.56 79.17 ± 1.60 83.09 ± 2.50

*Mean ± SD (n= 3)

requirements are met, if not more than two of the individual weights deviate from the standard. Drug Content Uniformity The prepared Ropinirole Hydrochloride tablet tested for their drug content. The prepared tablets from each batch were finely powdered, 100 mg of powdered is accurately weighed and dissolved in suitable quantity of Phosphate buffer pH 6.8 and the solution was filtered, after the suitably dilution the drug content was analyzed by UV‐ Visible spectrophotometer at 247.40 nm. This test was done on 10 tablets for each batch. Surface pH Study 12, 13, 14 H of" the tablets The surface pH of the buccal tablets was determined in order to investigate the possibility of any side effects in

vivo. As the acidic or alkaline pH may cause irritation to the buccal mucosa, the pH was maintained to neutral as closely as possible. A combined glass electrode was used for this purpose. The tablet was allowed to swell by keeping it in contact with 1 mL of distilled water (pH 6.5 ± 0.05) for 2 hr at room temperature. The pH was measured by bringing the electrode in contact with the surface of the tablet and allowing it to equilibrate for 1 min. Swelling Study 15, 16 Three Buccal tablets were weighed individually (W1) and placed separately in 2% agar gel plates with the core facing the gel surface and incubated at 37 ± 1 °C. After 4 hr and 8 hr, the tablet was removed from the Petri dish and excess surface water was removed carefully with blotting paper. The swollen tablet was then reweighed (W2) and the


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RESEARCH ARTICLE Table 15: Effect of Independent Variable on Dependent Variable by 32 Full Factorial Design Independent Variable Dependent Variable Batch Codes X1 X2 Q7 (%)* Mucoadhesive Strength (gm)* SI (after 8 hr)* F1 ‐1 ‐1 97.75 ± 0.10 6.00 ± 0.10 62.63 ± 0.07 F2 ‐1 0 98.05 ± 0.79 6.305 ± 0.23 72.70 ± 0.06 F3 ‐1 +1 92.16 ± 2.01 6.455 ± 0.10 82.81 ± 0.07 F4 0 ‐1 94.55 ± 1.98 6.390 ± 0.16 81.00 ± 0.06 F5 0 0 93.60 ± 0.78 6.615 ± 0.08 92.00 ± 0.06 F6 0 +1 90.50 ± 1.21 6.805 ± 0.12 106.00 ± 0.12 F7 +1 ‐1 87.65 ± 2.89 7.605 ± 0.54 104.08 ± 0.03 F8 +1 0 84.05 ± 1.56 7.620 ± 0.50 111.12 ± 0.02 F9 +1 +1 79.17 ± 1.60 7.930 ± 0.48 117.17 ± 0.05 Translation of Coded Levels in Actual Units Real Value Independent Variables Low (1) Medium (0) High (+1) Polycarbophil (X1) 15 20 25 HPMC K15M (X2) 5 10 15 Table 16: Summary of Results of Regression Analysis for Q7 (%) Response Q7 (%) b0 b1 b2 b12 b11 b22 R2 FM 93.952 ‐6.181 ‐3.02 ‐0.722 ‐3.0783 ‐1.603 0.9833 RM 92.883 ‐6.181 ‐3.02 ‐ ‐3.0783 ‐ 0.9604 Table 17: Calculation for Testing the Models in Proportions for Q7 (%) SS MS F DF Regression FM 5 310.1821 62.03641 35.393 Fcal = 2.06 RM 3 302.9527 100.9842 40.433 Ftable = 9.01 Residual DF = (3,5) FM 3 5.258219 1.75274 ‐ RM 5 12.4876 2.49752 ‐ Table 18: Summary of Results of Regression Analysis for Mucoadhesive Strength Response Mucoadhesive Strength (gm) b0 b1 b2 b12 B11 B22 R2 FM 6.603 0.732 0.199 ‐0.0325 0.3825 0.0175 0.995 RM 6.603 0.732 0.199 ‐ 0.3825 ‐ 0.993 Table 19: Calculation for Testing the Models in Proportions for Mucoadhesive Strength DF SS MS F Regression FM 5 3.754 0.750 123.0519 Fcal = 2.75 RM 3 3.7499 1.2499 270.0237 Ftable = 9.01 Residual DF = (3,5) FM 3 2.164886 0.721629 ‐ RM 5 6.140783 1.228157 ‐ Table 20: Summary of Results of Regression Analysis SI (after 8 hr) Response SI (after 8 hr) b0 b1 b2 b12 b11 b22 R2 FM 92.772 19.038 9.711 ‐1.7725 ‐.1.248 ‐1.603 0.991 RM 92.167 19.038 9.711 ‐ ‐ ‐ 0.985

Swelling study shown in figure 1. Determination of the Exvivo Mucoadhesive Strength 17,18,19,20 Bioadhesive strength of the buccal tablets was measured on the “Modified Physical Balance method”. The method used sheep buccal membrane as the model mucosal membrane. The

swelling index (SI) were calculated using the formula given in equation.

Swelling Index W2 W1 W1 Where, W1 = Initial weight of the tablet W2 = Final weight of the tablet

100


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RESEARCH ARTICLE Table 21 : Calculation for Testing the Models in Proportions for SI ( after 8 hr) DF SS MS F Regression FM 5 2756.565 551.31 66.813 Fcal = 0.643 RM 2 2740.648 1370.32 202.153 Ftable = 19.33 Residual DF = (2,6) FM 3 24.7545 8.2515 ‐ RM 6 40.6717 6.77862 ‐ Table 22: Release Kinetic Models of Ropinirole Hydrochloride Buccal Tablets Release Zero Order First Order Higuchi Hixson KPappas Batch Code R2 R2 R2 R2 R2 n F1 0.917 0.996 0.974 0.983 0.990 0.43 F2 0.923 0.943 0.981 0.981 0.996 0.46 F3 0.951 0.992 0.994 0.996 0.998 0.45 F4 0.938 0.985 0.987 0.993 0.991 0.5 F5 0.985 0.912 0.980 0.963 0.973 0.44 F6 0.985 0.805 0.994 0.927 0.983 0.49 F7 0.948 0.877 0.947 0.922 0.934 0.39 F8 0.946 0.905 0.938 0.932 0.921 0.34 F9 0.919 0.977 0.967 0.967 0.925 0.5 Table 23: Exvivo Cumulative Percentage Drug Release of Formulation F6 Time (hr) Exvivo Cumulative Percentage Drug Release Performed on Goat Mucosa 0 0 1 7.10 2 16.29 3 24.48 4 32.5 5 44.97 6 51.16 7 55.21 8 60.11 Table 24: Stability Study of Batch F6 of Post Compression Parameter Parameter Initial* After 30 Days* Hardness (kg/cm2) 5.6 ± 0.031 5.5 ± 0.1 Thickness (mm) 3.31 ± 0.11 3.33 ± 0.02 % Friability 0.43 ± 0.03 0.44 ± 0.02 % Drug Content 99.25 ± 1.59 99.20± 1.07 Surface pH study 6.91 ± 0.08 6.71 ± 0.04 Mucoadhesive Strength (gm) 7.605 ± 0.54 7.598 ± 0.51 SI ( after 8 hr) 104.08 ± 0.03 103.08 ± 0.01 * Mean ± SD (n= 3)

Time (hr) 0 0.5 1 2 3 4 5 6 7 8

Table 25 : Stability Study of Batch F6 (Invitro Drug Dissolution) % Cumulative Drug Release* Initial After 30 days 0 0 22.41 ± 1.56 21.5 ± 2.54 37.68 ± 2.03 36.52 ± 3.05 45.62 ± 0.89 45.54 ± 1.56 53.71 ± 1.86 52.88 ± 2.82 64.54 ± 2.16 62.10 ± 1.84 70.62 ± 3.10 69.60 ± 3.15 81.09 ± 2.50 82.31 ± 1.65 90.51 ± 1.21 88.01 ± 3.45 98.44 ± 3.21 97.80 ± 1.95

* Mean ± SD (n= 3)


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RESEARCH ARTICLE

Initial

After 8 hour

Figure 1: Swelling Study of Ropinirole HCl Tablet

Figure 2: Measurement of Mucoadhesive strength

Figure 3: Determination of Residence Time

Figure 4: Exvivo Permeation Study by Franz Diffusion Cell

fresh sheep buccal mucosa was cut into pieces and washed with phosphate buffer pH 6.8. A piece of mucosa was tied to the glass slide which was moistened with phosphate buffer pH 6.8. The tablet was stuck to the lower side of another

glass slide with glue. The both pans were balanced by adding an appropriate weight on the left‐ hand pan. The glass slide with mucosa was placed with appropriate support, so that the tablet touches the mucosa. Previously


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Figure 5: FTIR spectra of pure drug Ropinirole Hydrochloride

Figure 6: FTIR spectra of drug + physical mixture

weighed beaker was placed on the right hand pan and water (equivalent to weight) was added slowly to it until the tablet detach from the mucosal surface. The weight required to detach the tablet from the mucosal surface gave the bioadhesive strength shows in figure 2. The experiment was performed in triplicate and average value was calculated.

B

Force of adhesion (N) =

medium was composed of 800 mL pH 6.8 phosphate buffer maintained at 37 ºC. The porcine buccal tissue was glued to the surface of a glass slab, vertically attached to the apparatus. The buccal tablet was hydrated from one surface using 0.5 mL of phosphate buffer pH 6.8 and then the hydrated surface was brought into contact with the mucosal membrane. The glass slab was vertically fixed to the apparatus and allowed to run in such a way that the tablet was completely immersed in the buffer solution at the lowest point and was out at the highest point. The time necessary for complete erosion or detachment of the tablet from the mucosal surface was recorded which shows in figure 3 were. The experiments were performed in triplicate and average was calculated.

×9.81 Determination of the Ex vivo Mucoadhesive Residence Time 21 The exvivo residence time was determined using a locally modified USP disintegration apparatus. The disintegration


9


RESEARCH ARTICLE

Figure 7: DSC Spectra of pure drug

Figure 8: DSC Spectra of Drug and Physical Mixture of Drug and Polymers

100

Mucoadhesive strenght

% Swelling index

120

80 60 40 20 P1 P2 P3 P4 P5 H1 H2 H3 H4 H5 PH1 PH2 PH3 PH4

0

Formulation Code Figure 9: Swelling Study of Trial Batches

P1 P2 P3 P4 P5 H1 H2 H3 H4 H5 PH1 PH2 PH3 PH4

10 9 8 7 6 5 4 3 2 1 0

140

Formulation Code Figure 10: Mucoadhesion Strength of Trial Batches

Invitro Drug Release Studies 22, 23 The USP dissolution test apparatus (apparatus II paddle type) was used to study the drug release from the tablets.

The dissolution medium was 500 mL of phosphate buffer pH 6.8. The release was performed at 37 ± 0.5 °C, with a rotation speed of 50 rpm. The buccal tablet was allocated to


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RESEARCH ARTICLE % Cumulative Drug Release of PI to P5

%Cumulative Drug Release of HI to H5 % Cumulative Drug release

% Cumulative Drug Release

120 100 80

P1 60

P2 P3

40

P4

20

P5

0 0

5

100 80

H1

60

H2 H3

40

H4

20

H5

0

10

0

Time (hr) Figure 11: % Cumulative Drug Release of Batch P1 to P

%Cumulative Drug Release of PHI to PH4

10

140

120

120 Swelling index %

100 80 PH1

60

PH2

40

PH3

80 60

4 hr

40

8 hr

20

PH4

20

100

0 F1 F2 F3 F4 F5 F6 F7 F8 F9

0 0

5

10 Formulation code Figure 14: Swelling Study of F1 to F9 Batches % CumulativeDrug Release of F4,F5 and F6 120 % CumulativeDrug Release

Time (hr) Figure 13: % Cumulative Drug Release of Batch PH1 to PH5 %Cumulative Drug Release of F1, F2 and F3 120 % Cumulative DrugRelease

5

Time (hr) Figure 12: % Cumulative Drug Release of Batch H1 to H5


120

100 80

F1 F2

60

F3 40

TARGETED

20

100 80 F4

60

F5

40

F6

20

TARGETED

0

0 0

5

0

10

Time (hr) Figure 15: % Cumulative Drug Release of Batch F1, F2 and F3

5 Time (hr)

10

Figure 16: % Cumulative Drug Release of Batch F4, F5 and F6

the bottom of the dissolution vessel. 10 mL samples were withdrawn at predetermined time intervals and replaced with fresh medium. The samples were filtered through whatman filter paper and analyzed after appropriate dilution by UV spectrophotometer at 247.40 nm.

Release Kinetic Model Study 24,25,26,27 To study the mechanism of drug release from the sustained release matrix tablet, the in vitro drug release data were fitted to various kinetic models like zero‐order as cumulative amount of drug release v/s time, First order as


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RESEARCH ARTICLE % Cumulative Drug Release of F7, F8 and F9 120 100 80 F7

60

F8

40

F9

20

TARGETED

0 0

5

10

Time (hr) Figure 17: % Cumulative Drug Release of Batch F7, F8 and F9

Figure 19: Response Surface Plot of Mucoadhesive strength Exvivo % CDR of Batch F6 70

Figure 20: Response Surface Plot of SI (after 8 hr) Comparative Dissolution Profile 120

60

100

50

80

40

% CDR


Figure 18: Response Surface Plot of Q7 (%)

30

60 40

20 20

10

Initial After 30 day Targated release profile

0

0

0 5 10 6 8 10 Time (hr) Time (hr) Figure 21: Exvivo Cumulative Percentage Drug Release of Figure 22: Comparative Dissolution Profile of Batch F6 for Formulation F6 Stability Study 0

2

4

log cumulative % of drug remaining v/s time, Hixson‐ Crowell, higuchi as cumulative % of drug release v/s square root of time and K‐Peppas equation and coefficient

of correlation (r) values were calculated for linear curves by regression analysis of the above plot. These models used to explain drug release mechanism of the tablet.


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RESEARCH ARTICLE Ex vivo Drug Permeation Study 28, 29 The exvivo permeation studies of mucoadhesive buccal tablets of drug through excised layer of goat buccal mucosa were carried out using Franz diffusion cell having 3.14 cm2 effective diffusional area shows in figure 4. It consists of two compartments one is donor compartment and another is receptor compartment of 17 mL capacity. The cell contents were stirred with a magnetic stirrer and temperature of 37 ± 1 0C was maintained throughout the experiment. The separated buccal epithelium was mounted between two chambers and in receptor chamber phosphate buffer of pH 6.8 (37 0C) was filled and epithelium was allowed to stabilization for the period of 1 hr. After stabilization the tablet was placed into the donor compartment and was wetted with 1mL of phosphate buffer. The amount of drug permeated through the membrane was determined by removing samples periodically and same volume fresh medium was replaced. Then the samples were analyzed by using UV‐Visible spectrophotometer at λmax of 247.80 nm. Stability Study 30, 31 The storage conditions used for stability studies were accelerated condition (40 ºC ± 2 °C / 75% ± 5 % RH).Stability study was carried out for the optimized formulations. Tablets of optimized formulation were striped packed and kept in humidity chamber for 30 days on above mention temperature. RESULTS AND DISCUSSION Preformulation Study FTIR Data Anlysis Study From the FTIR study showed that the drug and excipients are compatible with each other and no interaction between them showed in table 4. DSC Analysis DSC curves obtained for pure Ropinirole Hydrochloride and physical mixture of pure drug and polymers are shown in Figure 7 and 8 respectively. Pure powdered Ropinirole Hydrochloride showed a melting endothermic at 247.66 C, while physical mixture of drug and excipients showed the melting peak of the drug at 244.76 °C which indicates that all ingredients are compatible with each other. Swelling Index, exvivo Mucoadhesive Strength, Force of Adhesion, Mucoadhesion Time for Formulations of Trial Batches Swelling index of trial batch P1 to P5 was calculated. Results indicate that when the polymer concentration increased, swelling index was proportionally increased. Same results observed for trial batches H1 to H5. Results also indicate that tablets prepared by HPMC K15M were more swellable then tablets prepared by Polycarbophil. This result showed due to more hydrophilicity of HPMC K15 M. Here results indicate that Polycarbophil polymer have more mucoadhesive properties due to the polyacrylic acid derivatives showed high bioadhesive strength probably due to the formation of secondary bioadhesion bonds with the mucin. The polymer chains undergo rapid swelling and

interpenetration into the interfacial region while HPMC K15 M polymers exhibit only superfacial adhesion. Quick polymer swelling promotes rapid interaction with the mucin, due to the large adhesive surface, leading to good adhesion. Trial batches PH1 to PH4 were Polycarbophil and HPMC K15M in combination. Results shows that formulation PH1 and PH2 had less mucoadhesion strength and less mucoadhesion residence time as compared to batches PH3 and PH4.All the above result are shown in table 5. In vitro Drug Release of Trial Batches Invitro dissolution study of trial batches P1 to P5 was shows in table 6, which prepared using Polycarbophil. Formulation P1, P2 and P3 were failed to generate sustained release of drug compare to P4 and P5. Trial batches P4 and P5 retards drug release up to 6 h but these batches also failed to generate sustained release of drug up to 8 h. Invitro dissolution study of trial batches H1 to H5 prepared using with HPMC K15M shows in table 7. Formulation H1, H2 and H3 were failed to generate sustained release of drug compare to H4 and H5. Trial batches H4 and H5 retards drug release up to 6 hr but these batches also failed to generate sustained release of drug up to 8 h. In vitro drug release study of polycarbophil and HPMC K15M in combination shows in table 8. Results showed in that PH3 batch has good swelling index, Mucoadhesive strength, Mucoadhesion residence time and drug release profile. So on the basis of these results obtained in the preliminary studies, a factorial design was employed in the present study. RESULTS OF FULL FACTORIAL DESIGN Post Compression Evaluation Parameter of Batches F1 to F9 Result of the batch F! to F9 showed in table 9 have hardness in the range of 5.0 ± 0.31 to 5.6 ± 0.31 kg/cm2 and thickness of the tablet was found to be in the range of 3.10 ± 0.07 to 3.31 ± 0.011 mm and in all the cases the friability was less than 1%. The results of weight variation were found to be within the prescribed official limits as per IP. All the batches showed drug content in the range of 96.34 ± 1.62 to 100.97 ± 1.32%. Swelling Index Profile of Batch F1 to F9 The mucoadhesion and drug release profile are dependent upon swelling behaviour of the tablets. Swelling index increased as the weight gain by the tablets increased proportionally with the rate of hydration. Batch F1 to F9 showed swelling index in table 10, within the range of 25.30 ± 0.05 to 95.96 ± 0.09 for 4 hr and 62.63 ± 0.07 to 117.17 ± 0.05. This observation could be due to higher concentration of Polycarbophil and HPMC K15 M. This may due to both the polymers have higher and faster swelling properties. Determination of Surface pH, Exvivo Mucoadhesive Strength, Force of Adhesion, Mucoadhesion Residence Time for Formulations of F1 to F9 Batches All the formulations were found to be satisfactory when evaluated for surface pH study. The surface pH of all


13


RESEARCH ARTICLE formulations was within a range of 5.21 ± 0.10 to 7.04 ± 0.11, close to neutral pH. These results reveal that all the formulations provide an acceptable pH in the range of salivary pH 5.5 to 7.0. They did not produce any local irritation to the mucosal route. The mucoadhesive strength of all formulations was within a range of 6.00 ± 0.10 to 7.930 ± 0.48 gm. The results indicate that increasing concentration of polymer, increase in the mucoadhesive strength was observed. The mucoadhesion residence time of all formulations was within a range of 5.30 ± 0.10 to more than 8 h. All the above result shown in table 11. Invitro Drug Release Study of 32 Factorial Batches In vitro drug release of batch F1 to F9 showed in table 12, 13 and 14. From the dissolution study formulations F1 and F2 showed 100 % drug release in 7 hr it indicated that less amount of polymer concentration did not retards the drug release from the tablets for desired period of times. While formulations F4, F5 and F6 released 100% drug in 8 hr. Results of formulations F7, F8 and F9 shows that drug release was decrease with increase in Polycarbophil concentration. Effect of Independent Variable on Dependent Variable by 32 Full Factorial Designs of Ropinirole Hydrochloride Buccal Tablets The factorial batches were prepared by using independent variable concentration of Polycarbophil (X1) and HPMC K15M (X2) and check its effect on dependent variable like Q7, mucoadhesive strength and swelling index which shown in table 15. Full and Reduced Model for Q7 (%) The significance level of coefficients b12 and b22 was found to be greater than P=0.05, thus they were omitted from the full model to generate the reduced model. The results of statistical analysis are shown in Table 16. The coefficients b1, b2 and b11 were found to be significant at P > 0.05, thus they were retained in the reduced model. The reduced model was tested in portions to determine whether the coefficients b12 and b22 contribute significant information for the prediction of the cumulative drug release at 7 hr. The results of testing the model in portions are shown in Table 17. The critical value of F for α = 0.05 is equal to 9.01 (df = 3, 5). Since the calculated value (F = 2.06) is less than the critical value (F = 9.01), it may be concluded that the omitted terms do not contribute significantly to the prediction of Q7 (%). The results are shown in the form of response surface plot in Figure 18. Polynomial Equation FM: 93.95X – 6.181X1 – 3.02X2 – 0.722X12 – 3.078X11 – 1.063X22 RM: 92.88X – 6.18X1 – 3.02X2 – 3.078X11 The coefficient of X1 and X2, that is, b1 and b2 respectively, bear a negative sign, and thus both polymers Polycarbophil and HPMC K15M have significant effect on 7 hr drug released.

Full and Reduced Model for Mucoadhesive Strength The significance level of coefficients b12 and b22 were found to be greater than P = 0.05, thus they were omitted from the full model to generate the reduced model. The results of statistical analysis are shown in Table 18. The coefficients b1, b2 and b11 were found to be significant at P 0.05, thus they were retained in the reduced model. The reduced model was tested in portions to determine whether the omitted coefficients contributed significant information for the prediction of disintegration time. The results for testing the model in portions are shown in Table 19. The critical value of F for α = 0.05 is equal to 9.01(df = 3, 5). As the calculated value (F = 2.75) is less than the critical value (F = 9.01), it may be concluded that the omitted terms do not contribute significantly to the prediction of mucoadhesive strength. The results are shown in the form of a response surface plot in Figure 19. Polynomial Equation FM: 6.603X + 0.732X1 + 0.199 X2 – 0.0325X12 + 0.3825X11 + 0.0175X22 RM: 6.603X + 0.732X1 + 0.199 X2 + 0.3825X11 The coefficient of X1 and X2, that is, b1 and b2 respectively, bear a positive sign, and thus both polymers Polycarbophil and HPMC K15M have significant effect on Mucoadhesive Strength. Full and Reduced Model for SI The significance level of coefficients b12, b11 and b22 was found to be greater than P= 0.05, thus they were omitted from the full model to generate the reduced model. The results of statistical analysis are shown in Table 20. The coefficients b1 and b2 were found to be significant at P > 0.05, thus they were retained in the reduced model. The reduced model was tested in portions to determine whether the coefficients b12, b11 and b22 contribute significant information for the prediction of the percent of friability. The results of testing the model in portions are shown in Table 21. The critical value of F for α = 0.05 is equal to 19.33 (df = 2, 6). Since the calculated value (F = 0.643) is less than the critical value (F = 19.33), it may be concluded that the omitted terms do not contribute significantly to the prediction of SI (after 8 hr). The results are shown in the form of response surface plot in Figure 20. The coefficients of X1 and X2, that is, b1 and b2, respectively, bear a positive sign, thus on increasing the concentration of either Polycarbophil or HPMC K 15M, an increase in swelling index is observed. Polynomial Equation FM: 92.77X + 19.038X1 + 9.711X2 – 1.77X12 – 1.248X11 – 1.603X22 RM: 92.77X + 19.038X1 + 9.711X2 The coefficient of X1 and X2, that is, b1 and b2 respectively, bear a positive sign, and thus both polymers Polycarbophil and HPMC K15M have significant effect on swelling index after 8 h. Selection of Optimized Batch The optimized batch was selected on the basis of Q7 (%), mucoadhesive strength and swelling index (after 8 hr). In


14


RESEARCH ARTICLE vitro release profile showed that formulations F4, F5 and F6 release the drug up to 8 hr but F6 formulation showed targeted release at 7 hr and also good mucoadhesive strength and swelling index. Formulations F7, F8 and F9 showed more mucoadhesive strength and swelling index but failed to targeted release at 7 hr and also slow drug release up to 8 hr. Thus, batch F6 fitted all the desired criteria and selected as optimized batch. Release Kinetic Model Study of Ropinirole Hydrochloride Buccal Tablets of most satisfactory batch F6 Result was found that the invitro drug release of Ropinirole Hydrochloride buccal tablet was best explained by Higuchi equation showed the highest linearity (R2 = 0.994), followed by Zero order (R2 = 0.985). The mechanism of drug release is explained by Korsmeyer‐Peppas equation ((log cumulative percent drug release v/s time). Korsmeyer’s plots indicated an n value (slope) of 0.49 which was below 0. 5 and 1, which was indicate combination of drug Fickian diffusion act as a drug release mechanism. Exvivo Drug Permeation Study Exvivo cumulative percentage drug release study of formulation F6 shows in table 23. Results showed that in 8 hr 60.11 % drug was released. This decrease in drug release as compare to invitro drug release was due to the low permeability of drug (class‐III).Also the variation among the used biological membrane could be attributed to the fat content and thickness of the membrane used. As the goat mucosa has more fat deposition and the thickness compare with the porcine mucosa, it might have hampered the drug release through the membrane. Short Term Stability Study of Optimize Batch F6 Stability study of the optimized formulation was carried out for one month. The results of the stability study are tabulated in Table 24and 25. The results of stability study showed that no significant change was observed for hardness, thickness friability, % drug content, surface pH, mucoadhesive strength and swelling index. The stability study also revealed that there was no significant change in drug release profile. This shows that the optimized batch is stable and reproducible. CONCLUSION Development of mucoadhesive buccal drug delivery of Ropinirole Hydrochloride tablets was one of the alternative routes of administration to avoid first pass effect and provide prolong release by increasing the diffusion path length using bioadhesive polymers. From the parameter of in vitro dissolution study, mucoadhesive strength and swelling study of factorial batches conclude that the batch F6 fulfill all the criteria. Hence, it was concluded that buccal tablets of Ropinirole Hydrochloride was successfully prepared.

REFERENCES AND NOTES

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RESEARCH ARTICLE 27. Peppas NA, “Analysis of Fickian and Non‐Fickian Drug Release from Polymers”, Pharm Acta Helv. 60, p.110‐111, 1985. 28. Kumar G, Gauri S, Hooda A, Saini S, Garg A, “Fabrication and Evaluation of Flavoured Mucoadhesive Buccal Tablet of Caffeine As CNS Stimulant.” IJUPLS, 1 (3), p.85‐97, 2011. 29. Mahalaxmi D, Senthil A, Prasad V, Sudhakar V, Mohideen S, “Formulation and Evaluation of Mucoadhesive Buccal Tablets of Glipizide.” International Journal of Biopharmaceutics, 1 (2), p.100‐107, 2010. 30. Kulkarni G, Gowathamarajan K, Rao B, suresh B, “Stability Testing of Pharmaceutical Product: An Overview.” Ind. J of Pharm. Sci. 38 (4), p.194‐202, 2004. 31. Ranade A, Ranpise N, Sanap G, Kulkarni R, “Development and In‐Vitro Evaluation of Buccal Tablet of Quinapril Hydrochloride.” Ind J Pharm Edu Res, 45 (4), p.364‐369, 2011. Cite this article as: Jani Jayesh H, Prajapati Amit J, Shah Dhaval K, Singh Sudarshan K. Formulation and Evaluation of Buccal Tablet of Ropinirole Hydrochloride. Inventi Rapid: Pharm Tech, 2012(4):1‐16, 2012.

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