DESIGNING AND EVALUATION OF COMPRESSED ... - eJManager

Indo American Journal of Pharmaceutical Research, 2013

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ISSN NO: 2231-6876

INDO AMERICAN JOURNAL OF PHARMACEUTICAL RESEARCH

DESIGNING AND EVALUATION OF COMPRESSED MINI-TABLETS OF RAMIPRIL AS A BIPHASIC DELIVERY SYSTEM Kiran V Mahajan*,1 Anup M Akarte1, Mangesh K Sapate1, Dheeraj T Baviskar1, Dinesh K Jain 2. 1

Department of Pharmaceutics, Institute of Pharmaceutical Education, Boradi, Shirpur 425 428(M.H.) India College of Pharmacy, I.P.S. Academy, Rajendra Nagar, Indore, 452 012, (M.P.), India

2

ARTICLE INFO Article history Received 07/09/2013 Available online 30/09/2013

Keywords Tablet-in-tablet, Zero-order release kinetics, immediate release, HPMC, EC

ABSTRACT Compressed mini-tablets systems are tablet-in-tablet technology which present as a biphasic delivery system; these are premeditated for zero-order sustained drug release. The outer layer that fills the void spaces between the mini-tablets was expressed to release the drug in a very short time fast release, although the mini-tablets delivered a prolonged release. The formulations contained several type of ratio with ramipril and Ethyl cellulose is 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2 and 1:1. As well as ramipril and HPMC is 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8 and 1:9 for mini-tablets in order to extend the release of ramipril throughout 12hr designed for mini-tablets was used to obtain different drug release rates, whereas the drug enclosed in the mini-tablets was released at different rates, depending up on calculated formulation which based on the released kinetic parameters. In vitro performance of these systems exhibited the anticipated biphasic behaviour: the drug contained in the fast releasing phase (powder enrobing the mini-tablets). Batch F5 at the end of 2 hrs near about half percent release found 47.88±0.55% after 12hrs found 96.23±1.41%, it can be concluded that mini-tablets containing HPMC were predominantly suitable impending to zero-order (constant) release over 12 h time periods. Concludes that 1:5 Ethylcellulose and 1:5 Hydroxypropyl methylcellulose was better ratio for drug released hence avoided repeated administration of drug.

Copy right © 2013 This is an Open Access article distributed under the terms of the Indo American journal of Pharmaceutical Research, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Please cite this article in press as Kiran V. Mahajan et.al. Designing and evaluation of compressed mini-tablets of ramipril as a biphasic delivery system. Indo American Journal of Pharm Research.2013:3(9).

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Corresponding author Kiran V. Mahajan Department of pharmaceutics Institute of Pharmaceutical Education Boradi, Tal- Shirpur(M.S.) INDIA 425 428 Phone No. 80875017 Email ID- [email protected]

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INTRODUCTION Oral controlled release drug delivery systems can be classified in two broad groups: single unit dosage forms (SUDFs), such as tablets or capsules, and multiple unit dosage forms (MUDFs), such as granules, pellets or mini-tablets. The concept of MUDFs was initially introduced in the early 1950s. The production of MUDFs is a common strategy to control the release of a drug, as sho wn by the reproducibility of the release profiles when compared to the ones obtained with SUDFs [1]. The development of mini-matrices is a promising area in pharmaceutical research concerned with a high control over the release rate of the drug combined with a high flexibility on the adjustment of both the dose and the release of a drug or drugs [2]. The concept of MUDFs is characterised by the fact that the dose is administered as a number of subunits, each one containing the drug. The dose is then the sum of the quantity of the drug in each subunit and the functionality of the entire dose is directly correlated to the functionality of the individual subunits [3]. Mini-tablets are tablets with a diameter equal to, or smaller than, 2–3mm [4]. The production of mini-matrices using a tabletting technique is an attractive alternative to the production of pellets, as the presence of solvents (e.g. water) is avoided and high production yields like the ones observed in extrusion and spheronization are obtained. This concept can be used to produce a biphasic delivery system combining a fast release together with the slow release period of the drug, provided that the excipient powder that fills the void spaces between the mini-tablets incorporates a part of the total drug dose. This system can produce a rapid rise in the plasmatic concentrations for some drugs (such as analgesic, anti-inflammatory, antihypertensive and antihistaminic agents) that are requested to promptly exercise the therapeutic effect, followed by an extended release phase in order to avoid repeated administrations [5]. The full preparation and characterization of a tablet, as SUDF, with mini-tablets containing Ethylcellulose (EC) or hydroxypropylmethylcellulose (HPMC) are not common. The biphasic delivery system was able to deliver a first fraction of the dose in a short time (a few minutes) and to deliver a second fraction for a longer period of time at a constant rate. The major objectives of this study were: (i) to develop and to evaluate compressed mini-tablets systems, in order to achieve a fast/slow drug release; (ii) to investigate formulation parameters affecting in vitro performance; (iii) to obtain a compressed minitablet formulation, which has the ability to release the drug at a zero-order rate (constant release). In order to delay the drug release, corresponding to the prolonged release component of the biphasic system, EC and HPMC were used as matricial agents to control release of the drug from the minitablets. In matricial systems, the characteristics of the matrix forming agent play an important role in the release mechanism of the drug. Among the hydrophilic polymers, HPMC is one of the most commonly used carriers for the preparation of oral controlled drug delivery systems due to its ability to swell upon jellification once in contact with water. The gel becomes a viscous layer acting as a protective barrier to both the influx of water and the efflux of the drug in solution [6, 7]. In the other hand, hydrophobic polymers, such as EC, can be alternatives to the swelling polymers by forming an inert matrix. When a tablet with a hydrophobic matrix is placed in the dissolution medium, the drug at the surface is released quickly, with a possible burst effect, requiring its replacement by drug from inner layers that must diffuse through the pores until it reaches the surface. Hypertension, commonly referred to as “high blood pressure,” is a medical condition where the pressure is chronically elevated; it is one of the commonly found diseases, affecting most of the populations in the world. So, treating hypertension effectively is the main criterion of this study. For treating hypertension, commonly used drugs include ACE inhibitors [8]. Ramipril inhibit angiotensin converting enzyme (ACE) which is identical to KININASE II catalyzes the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex, thus inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to decreased aldosterone secretion which used to treat hypertension, congestive heart failure. Its long biological half-life (3-16 h) and long elimination phase (9-18 h) it suggest extended action for treating hypertension by controlling blood pressure along with a significant regression of left ventricular hypertrophy [9].

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Dose calculation of immediate-release The pharmacokinetic parameters of drug were utilized for the calculation of theoretical drug release profile for coated mini-tablet-incapsule system. The immediate-release part of ramipril was calculated using the following equation [10]. DL = Cmax Vd Where Cmax is maximum plasma concentration, and Vd is volume of distribution.

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MATERIAL AND METHODS Ramipril, a water insoluble drug (supplied by Khandelwal Laboratories, Mumbai.) was incorporated in both components of the biphasic delivery system. For the preparation of the prolonged release component (mini-tablets), ethylcellulose (EC, Ethocel®, SD Fine Chem Lab, Mumbai ) and Hydroxypropyl methylcellulose (HPMC, Methocel® K100M, Rajesh chemicals Mumbai,) were considered, whereas for the fast release component, microcrystalline cellulose (Avicel PH 102 SD Fine Chem Lab, Mumbai) and sodium croscarmellose (Ac-Di-Sol, SD Fine Chem Lab, Mumbai) were used.

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Dose calculation of sustained release For fast drug release required time, the total dose of drug required was calculated based on the fact that the conventional dose with 5 mg. The total dose was calculated using the following equation 1, Dt = Dose (1 + 0.693 × t/t1/2) (1) Where, Dt = Total dose, Dose = Immediate release dose, t = Total time period for which sustained release is required, t1/2 = Half-life of drug [11, 12]. Preparation of the biphasic delivery system The qualitative and quantitative composition of the different formulations of the biphasic delivery system Biphasic drug delivery system is containing fast release component and slow release component drug. Provided that the excipient powder that fills the void spaces between the mini-tablets incorporates a part of the total drug dose. This system can produce a rapid rise in the plasmatic concentrations in antihypertensive that are requested to promptly exercise the therapeutic effect, followed by an extended release phase in order to avoid repeated administrations. Mini-tablets containing ethyl cellulose (EC) or hydroxypropylmethylcellulose (HPMC) can be seen in table 1 A, 1 B. Prolonged-release component (mini-tablets) The mini-tablets contained either HPMC or EC as controlling agents. All materials were sieved and the fractions below 63µm were considered to minimize the lag time observed during drug release when coarse fractions were used and to prevent changes on properties of the tablets due to changes on the size of particles. The formulations contained various type of ratio between Ramipril and Ethyl cellulose is 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2 and 1:1. As well as Ramipril and HPMC is 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8 and 1:9 for mini-tablets in order to extend the release of ramipril throughout 12hr shown in table 1 B Fast release component Microcrystalline cellulose (Avicel PH 102) was used because of its good compaction and disintegration properties. Sodium crosscarmellose was used as a super disintegrant to obtain an immediate release of the drug. Immediate release component is common for extended release component which in lay in to the fast release component can be seen in table 1 A. Table 1 A): Formulation Composition (mg) Compressed Mini-Tablet of Ramipril as Biphasic Drug Delivery System I) Fast Release Component of Ramipril (Immediate Release) Ingredients Ramipril Croscarmallose sodium Sodium starch glycolate Microcrystalline cellulose PH102 Total

Quantity(mg) 6 6 8 130 150

Table 1 B): Formulation Composition (mg) Compressed Mini-Tablet of Ramipril as Biphasic Drug Delivery System II) Extended Release Component (Sustained Release) F2 5 10 40 2 5 62

F3 5 15 35 2 5 62

F4 5 20 30 2 5 62

F5 5 25 25 2 5 62

F6 5 30 20 2 5 62

F7 5 35 15 2 5 62

F8 5 40 10 2 5 62

F9 5 45 5 2 5 62

Preparation of biphasic drug delivery of Ramipril tablets [13] Drug, polymer and excipients were weighed separately for 100 tablets as shown table 1 A, B. The proposed formulations were coded as F1, F2, F3, F4, F5, F6, F7, F8 and F9. The biphasic drug release Ramipril tablets containing 11 mg of Ramipril was prepared via direct compression after compressing prolong release component (mini tablet) with different proportion of hydroxyl propyl methyl cellulose and Ethyl cellulose and second is fast releasing component containing sodium starch glycolate, crosscarmellose sodium as superdisintegrant. The preparation of the biphasic delivery system the die of the tabletting machine was progressively filled by hand

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F1 5 5 45 2 5 62

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Ingredient Ramipril HPMCk4M Ethyl cellulose Mg. Stearate Talc Total

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with the weighed amounts of the fast release component and the mini-tablets prior to compression. Microcrystalline cellulose PH102 used as filler, talc and magnesium stearate used as glidant and lubricant, before the tablet compression blend was uniformly mixed with HPMC and EC polymers and excipients by using poly bag for 20 min. and directly compressed into tablets using with 12.0mm flat faced punch diameter of 8 station Rimek compression machine (Rimek mini press II), are given in the Table 1 A, B. Preformulation Study Assay of drug Accurately weighed samples (n=3) equivalent to 10mg of drug was taken in a 100ml volumetric flask, a few ml of methanol was added and shaken for few minutes until the drug gets dissolved. The volume was made to 100ml with methanol to get final stock solution of concentration 100μg/ml, accurately pipette out 0.2, 0.4, 0.6, 0.8 and 0.10ml of the above solution into five 10ml standard flasks and the volumes were made up using 0.1N HCl containing 0.1 SLS. And this solution was filtered using 0.45mm membrane filter. Above prepared solution was taken and diluted to 100ml with 0.1N HCl solution. The absorbance of sample solution was determined at 210nm. A series of solution of ramipril in 0.1N HCl concentration of 2, 4, 6, 8, 10μg/ml was prepared. The absorbance of all the solution was measured using ultraviolet spectrophotometer (Schimazdu-1700). A standard plot of absorbance v/s concentration of drug was plotted and calculated the concentration with the help of regression line equation. The percent purity of drug was calculated and values were shown in table 2. Table 2: Assay of Ramipril Sr. No. 1 2 3 4 5

Concentration 2μg/ml 4μg/ml 6μg/ml 8μg/ml 10μg/ml

Absorbance 0.052 0.102 0.143 0.185 0.221

Actual Concentration 1.97μg/ml 4.13μg/ml 6.14μg/ml 8.14μg/ml 9.85μg/ml

% Purity 98.55 104.75 102.33 101.75 98.5

Fourier Transform Infrared Spectroscopy (FTIR) FTIR Spectroscopy of Drug-Excipients Compatibility Study Fourier Transform Infrared spectra were obtained by using an FTIR spectrometer Affinity-1 (Shimadzu). The Samples (Ramipril, Crosscarmellose sodium, Sodium Starch Glycolate, Microcrystalline cellulose, Hydroxypropylmethylcellulose K4M) were previously ground and mixed thoroughly with KBr in mortor pestle in the ratio of 1:100. Fourty five scan were obtained at a resolution of 4 cm-1 from 4500 cm-1 to 400 cm-1. The IR Spectra were shown in Fig. 1 IR ranges were shown in table 3.

Drug- Excipients

1

Ramipril

2

CCNa

3

SSG

4

Ramipril + CCNa

5

Ramipril + SSG

Functional Group N-H (aliphatic) C=O O-H streaching C=O O-H (aromatic) C=O O-H (aromatic) N-H (aliphatic) C-O (aromatic) N-H (aliphatic) C-O (aromatic)

Wave Number (cm-1) 2848.86 1645.28 3630.03 1593.2 2841.15 1558.48 2864.29 2754.34 1190.08 2848.86 1138

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Sr. No.

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Table 3: Data of IR Ranges of Drug-Excipients Compatibility Study.

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Figure 1 : A) Ramipril B)Sodium starch glycolate+Ramipril C)Crosscarmallose sodium+Ramipril D) Microcrystaline cellulose+Ramipril E) Ethylcellulose+Ramipril F) HPMCk4M+Ramipril Determination of Linearity Linearity in 0.1N HCl Solution ranging from 2 to 10µg/ml was prepared using a 0.1N HCl and methanol separately absorbance was measured for each solution at λmax of 210nm using Shimadzu UV/visible 1700 spectrophotometer, graph was plotted for absorbance versus concentration of ramipril. The linear regression analysis for standard curve in 0.1N HCl, the linear regression analysis was done on absorbance data points. The results are as follows:  The slope = 0.019  The intercept = 0.010  The correlation coefficient = 0.990 A straight-Line equation (y = mx + c) was generated to facilitate the calculation for amount of drug. The equation is as follows. Absorbance = 0.019 X, Concentration -0.010

Concentration 0μg/ml 2μg/ml 4μg/ml 6μg/ml 8μg/ml 10μg/ml

Absorbance 0.000 0.058 0.089 0.132 0.165 0.199

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Sr. No. 1 2 3 4 5 6

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Table 4: Concentration and Absorbance Values of Ramipril in 0.1N HCl.

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Figure 2: Standard Calibration Curve of Ramipril in 0.1 N HCl at 210nm RESULT AND DISCUSSION Evaluation of Powder Blend The Ramipril powder blend was evaluated for bulk density, tapped density, angle of repose, Carr’s ratio and Hausner’s ratio. Bulk density Bulk drug were poured into the measuring cylinder using a funnel and weighed (M). Then volume of the powder (Vb) was taken. Bulk density of the granules was calculated using following formula. The Bulk densities were shown in table 5. Bulk density = b= Tapped density Blend was tapped for a fixed (500) number of taps. The minimum volume (Vt) occupied in the cylinder and the weight (M) of the blend was measured. The tapped density (ρt) was calculated using following formula. The tapped density was described in table 5. t= Angle of repose Angle of repose (θ) was determined using funnel method. The blend was poured through a funnel that can be raised vertically until a maximum cone height (h) was obtained. The values of angle of repose are given in table 5. The radius of the heap (r) was measured and angle of repose was calculated. θ = tan‐1 (h/r) Carr’s index Tapped and bulk density measurements can be used to estimate the carr's index of a material. The cars index values are given in table 5 and it was determined by, Carr’s index =

X 100

Hausner’s ratio = Table 5: Evaluation of Powder Blend

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Hausner’s ratio =

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Hausner’s ratio Hausner’s ratio is an index of ease of powder flow; it is calculated by following formula.

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Formulation F1 F2 F3 F4 F5 F6 F7 F8 F9

Bulk Density (gm/ml) ( ±SD) 0.49±0.08 0.51±0.05 0.42±0.04 0.43±0.06 0.50±0.01 0.48±0.05 0.47±0.02 0.55±0.04 0.49±0.01

Tapped Density (gm/ml) ( ±SD) 0.57±0.05 0.59±0.03 0.49±0.04 0.48±0.06 0.57±0.07 0.56±0.04 0.54±0.06 0.65±0.02 0.61±0.01

Angle of Repose (θ) 28.12±0.02 26.27±0.02 25.54±0.01 26.12±0.04 24.25±0.03 26.65±0.05 24.66±0.03 27.20±0.01 28.88±0.04

ISSN NO: 2231-6876 Carr’s Index (%) 14.03±0.5 13.55±0.3 14.28±0.5 10.41±0.6 12.28±0.9 14.29±0.4 12.96±0.2 15.38±0.3 19.67±0.4

Hausner’s Ratio (%) 1.16±0.9 1.15±0.9 1.16±0.6 1.11±0.4 1.14±0.6 1.16±0.3 1.14±0.4 1.07±0.8 1.18±0.2

Evaluation of compressed Mini-Tablet of Ramipril as Biphasic Drug Delivery System Hardness test The hardness of the tablets was determined using Monsanto Hardness tester. It is expressed in kg/cm 2. Six tablets were randomly picked from each formulation and the mean and standard deviation values were calculated [14]. Friability A friability test was accompanied on the mini-tablets using a Roche friabilator made by veego steel. Twenty mini-tablets were selected from each batch and any loose dust was removed with the help of a soft brush. The mini-tablets were initially weighed and transferred into friabilator. The drum was rotated at 25 rpm for 4 min after which the mini-tablets were removed. Any loose dust was removed from the mini-tablets as before and the tablets were weighed again, % Friability of mini-tablets less than 1% is considered acceptable [15]. Weight variation The weight variation test was conducted by weighing 20 randomly selected mini-tablets individually, calculating the average weight and comparing the individual minitablets. The specification of weight variation is 10% [16]. Thickness The tablet thickness was measured by using Vernier Calliper.

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In-vitro disintegration time Drug dissolution study was carried out for all formulated batches of compressed mini-tablet of ramipril as biphasic drug delivery in dissolution test apparatus (USP paddle type II, TDT-08 L Electro lab, Mumbai, India.). Nine hundred millilitres of acidic buffer (pH 1.2) was taken as dissolution medium at 50rpm and 37 oC ± 0.5oC for two hours. Nine hundred millilitres of phosphate buffer (pH 6.8) was taken as dissolution medium at 50rpm and 37oC ± 0.5oC for 6 hours. Five millilitres of aliquots were periodically withdrawn and the sample volume of was replaced with an equal volume of fresh dissolution medium. The samples were analysed spectrophotometrically at 210nm. As well as nine hundred millilitres of phosphate buffer (pH 7.4) was taken as dissolution medium at 50rpm and 37oC ± 0.5oC for next 6 hours and analysed the sample at 210nm [17]. They were shown in table 6 and Fig 3.

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Water absorption ratio (R) The weight of the tablets prior to placement in the Petri dish containing water was noted. The weight of tablets after placing the water also noted. The water absorption ratio, R was then determined according to the following equation. Water absorption ratio, R = 100 Χ (Wa Wb)/Wb Where, Wb = weight of tablets before water absorption Wa = weight of water after absorption

Table 6: In-vitro Dissolution Studies of F1toF9

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%Drug Release Time (Hr)

F1

F2

F3

F4

F5

F6

F7

F8

F9

0

0

0

0

0

0

0

0

0

0

1

36.67

31.56

36.36

37.88

34.56

26.65

41.06

34.45

34.45

2

49.12

48.45

49.88

50.01

47.88

49.56

50.73

50.45

48.96

3

46.67

41.57

57.87

59.33

55.36

43.36

59.35

45.34

58.37

4

59.33

54.71

64.55

59.33

61.25

48.32

66.49

55.43

64.36

5

65.23

62.56

71.37

75.83

69.35

52.65

73.87

61.32

71.34

6

75.33

71.12

76.94

79.43

76.34

60.78

79.35

74.23

78.35

7

81.98

85.43

80.14

82.43

79.45

65.19

85.54

79.18

85.35

8

84.27

89.55

84.34

84.17

82.12

71.65

89.54

82.54

89.34

9

87.34

91.23

86.65

85.34

85.11

76.34

90.98

85.59

91.88

10

90.32

93.87

89.98

87.82

88.13

79.11

93.33

87.21

94.33

11

-

94.44

91.21

89.63

92.32

88.22

98.71

89.32

96.23

12

-

-

95.63

-

96.23

-

99.13

-

98.32

Figure 3: Dissolution Profile of Batch F1-F9

Hardness (kg/cm ) 5.24±0.15 4.35±0.11 4.45±0.13 5.26±0.14 5.61±0.19 5.25±0.15 5.53±0.09 4.52±0.08 5.21±0.05

Thickness (mm) 4.16±0.20 4.21±0.15 4.10±0.17 4.28±0.11 4.15±0.17 4.12±0.15 4.11±0.15 4.10±0.14 4.14±0.18

Weight variation (mg) 213.78±2.39 215.53±1.89 211.97±3.06 216.73±2.56 212.63±3.55 211.56±2.32 210.55±3.86 212.23±1.23 213.23±2.12

Friability % 0.42±0.037 0.45±0.017 0.51±0.015 0.50±0.030 0.40±0.032 0.60±0.020 0.55±0.025 0.45±0.036 0.51±0.025

Drug content % 93.89±0.57 94.45±0.46 93.23±0.52 97.35±0.89 98.23±0.65 91.53±0.58 94.64±0.78 95.35±0.69 92.56±0.89

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Code F1 F2 F3 F4 F5 F6 F7 F8 F9

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Table 7: Evaluation Parameter of Tablets (n=3). 2

Kinetics Modelling of Drug Release Profiles

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Zero-order, first-order, Higuchi, Hixson Crowell and Korsmeyer–Peppas kinetic models were performed to study the drug release kinetic. The model with the highest correlation coefficient was considered to be the best fitting one. The kinetic modelling of different batches of extended released and fast released tablets were shown in table 7). Table 8: Kinetic Modelling of Different Batches (F1 to F9). Zero Order First Order Higuchi Equation Equation Equation r2 r2 r2 F1 0.9711 0.8934 0.905 F2 0.9718 0.8939 0.903 F3 0.9755 0.8921 0.903 F4 0.9735 0.8922 0.906 F5 0.9761 0.8958 0.905 F6 0.9726 0.8903 0.903 F7 0.9725 0.8953 0.906 F8 0.8951 0.9745 0.905 F9 0.8945 0.9753 0.903 r2 = Correlation coefficient, n= Diffusional Exponent.

Formulation code

Korsemeyer-Peppas Equation 2 r n 0.946 0.6343 0.937 0.6375 0.928 0.6321 0.917 0.6381 0.937 0.6345 0.915 0.6354 0.951 0.6387 0.914 0.6352 0.918 0.6351

Release Mechanism non-Fickian non-Fickian non-Fickian non-Fickian non-Fickian non-Fickian non-Fickian non-Fickian non-Fickian

Figure 4: First order Release

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The two different release phases can remain simply adjusted in a wide range of values of both delivery rate and ratio of the dose parts, on the basis of the pharmacokinetics and beneficial requirements, to perform the desired in vivo profile. Key variables of this study included the external powder/mini-tablets ratio and type of matrix mini-tablets. The effects illustrate that the release profile is intensely dependent on the number and/or composition of subunits, making up the drug sustained dose. After the disintegration of this system, the HPMC mini-tablets were capable to release a second fraction of the dose in a prolonged time (12 h) at a constant rate. In the situation of EC mini-tablets, the powder released from fast component in biphasic formulations and/or compression pressure induced some changes in the release mechanism and in the release time, which was prolonged matched to non-compressed minitablets. For future prospects vivo study can be performs. Accelerated Stability Study

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CONCLUSION A biphasic delivery system was developed by compressing mini-tablets into a tablet dosage form. The compressed mini-tablets showed insignificant deformation and no destruction. Because of their physical characteristics, mini-tablets tend to keep their integrity after compression, making more difficult the fracturing process of these subunits. This technology could be attained by fast/slow delivery system. This stays deliberated by an initial rapid release phase, equivalent to the drug release enclosed in the powder layer filled between mini-tablets, followed by a period of slow release, corresponding to the drug release of mini-tablets. F5 batch at the end of 2 hrs near about half percent release found 47.88±0.55% after 12hrs found 96.23±1.41%. The proposed fast/slow delivery strategies show an extensive flexibility in the variation of the delivery program.

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Accelerated stability study was performed as per ICH guidelines on best batch F5 to determine the change in physical characteristics, dissolution study and disintegration time of tablets on storage at 45 oC and 75% relative humidity for 3 months. The accelerated stability studies of sustained release tablets shown in table 8. Table 9: Accelerated stability study of best batch F5 at 45oC and 75% RH Physical parameters 0 Days 30 Days 60 Days 90 Days Weight Variation(mg) 212.63±3.55 212.30±0.45 212.01±0.40 211.98±0.42 Hardness (kg/cm2) 5.61±0.19 5.35±0.08 5.20±0.07 5.05±0.09 Friability (%) 0.40±0.032 0.30±0.013 0.22±0.011 0.10±0.016 Thickness 4.15±0.17 4.10±0.15 4.03±0.16 3.99±0.15 Drug Content (%) 98.23±0.65 97.95±0.65 96.85±0.68 95.97±0.65 Drug Invitro Release (%) 96.23 ±1.41 94.10 ±0.15 93.07 ±0.20 91.71 ±0.65 ACKNOWLEDGEMENTS Any successful task is not an individual’s effort but it is a joint venture of many people who put in their mind and soul for the completion of that work. Firstly I would like to give my humble thanks to my esteemed principal Dr. Dheeraj T. Baviskar, Principal and Professor, Institute of Pharmaceutical Education, Boradi for his valuable guidance, keen interest, inspiration, unflinching encouragement and moral support. I am very much thankful to Mr. Anup M. Akarte, Mr. Mangesh K. Sapate, , Mr. Amarjit P. Rajput for their valuable guidance and inspiration throughout my research work.

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REFERENCES 1. Borgquist P., Nevsten P., Nilsson B., Wallenberg LR., Axelsson A., Simulation of the release from a multiparticulate system validated by single pellet and dose release experiments. J. Contr. Release. 2004; 97: 453–465. 2. Gandhi R., Kaul CL., Panchagnula R., Extrusion and spheronization in the development of oral controlled release dosage forms. PSST. 1999; 2: 160–170. 3. Gross ST., Hoffman A., Donbrow M., Benita S., Fundamentals of the release mechanism interpretation in multiparticulates systems: the prediction of the commonly observed release equations from statistical population models for particle ensembles. Int. J. Pharm. 1986; 29: 213–222. 4. Lennartz P., Mielck JB., and Mini-tabletting: improving the compactability of paracetamol powder mixtures. Int. J. Pharm. 1998; 173: 75–85. 5. Maggi L., Machiste EO., Torre ML., Conte U., Formulation of biphasic release tablets containing slightly soluble drugs. Eur. J. Pharm. Biopharm. 1999; 48: 37–42. 6. Colombo P., Bettini R., Santi P., Peppas NA., Swellable matrices for controlled drug delivery: gel-layer behaviour, mechanisms and optimal performance. PSTT. 2000; 3: 198–204. 7. Kiil S., Dam-Johansen K., Controlled drug delivery from swellable hydroxypropylmethylcellulose matrices: model-based analysis of observed radial front movements. J. Contr. Release. 2003; 90: 1–21. 8. Pharmacopoeia: The Stationary office, MHRA, British Pharmacopoeial Commission office, London 2005. 9. Indian Pharmacopoeia. Ghaziabad. The Indian Pharmacopoeia Commission 2007; 2: p. 1648. 10. Shobha R, Hiramanth R. Text book of Biopharmaceutics and Pharmacokinetics. P. 178. 11. Sonar GS., Jain DK., More DM., Preparation and in vitro evaluation of bilayer and floating-bioadhesive tablets of rosiglitazone maleate. Asian Journal of Pharmaceutical Sciences. 2007; 2 (4): 161- 169. 12. Reddy KR., Mutalik S., Reddy S., Once-Daily Sustained- Release Matrix Tablets of Nicorandil: Formulation and In Vitro Evaluation. AAPS PharmSciTech. 2003; 4 (4) 13. Nadendla S., Nagaraja TS., Effect of various polymers on swelling and in vitro release of ramipril in effervescent system. Int. J. of Pharm. & Life Sci. (IJPLS). 2013; 4(4): 2621-2625. 14. Lopes CM., Loboa Jose MS., Pinto JF., and Paulo C., Compressed mini-tablets as a biphasic delivery system. Int J Pharmaceutics. 2006; 323: 93-100.

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COMPETING INTERESTS “The author(s) declare that they have no competing interests”.

Vol 3, Issue 9, 2013.

Kiran V. Mahajan et al.

ISSN NO: 2231-6876

15. Bhupendra PG., Patel KR., Design and In-vitro evaluation of Nicorandil sustained release matrix tablets based on combination of hydrophilic and hydrophobic matrix system. International Journal of Pharmaceutical Sciences Review and Research. 2010; 1(1):7. 16. Lachman L., Lieberman HA., Kanig JL. The theory and practice of industrial pharmacy. 4rd ed. Mumbai: Varghese Publishing house; 1991. p. 67-68. 17. Kanakadurga DN., Prameela RA., Sai MB., Formulation and evaluation of oral disintegrating tablets of Montelukast sodium: effect of functionality of superdisintegrants. Journal of Pharmacy Research. 2010; 3(4):803-808.

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