Granulation And Plastic Impact On Ranitidine Hydrochloride Release Biology Essay

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ABSTRACT: The effects of plastic, hydrophilic and hydrophobic types of polymers and impact of granulation process were investigated on the release profile of Ranitidine Hydrochloride from matrix systems. A comparative release characteristics were evaluated by the use of polymers from different Ranitidine Hydrochloride matrices. Matrix tablets of Ranitidine Hydrochloride using MEthyl Cellulose K4M, Ethyl Cellulose 20 cps, Kollidon SR were prepared separately by direct compression and wet granulation process. In this investigation the feasibility of wet granulation technique in the development of sustained release matrix tablet of Ranitidine Hydrochloride was studied. The kinetics of the dissolution process was determined by analyzing the dissolution data using various kinetic equations, viz., zero-order, first order, Higuchi, Korsmeyer Peppa's and Hixson Crowell's equations. The mean dissolution time (MDT) was calculated for all the formulations. The analysis of the dissolution data showed that the release process involves erosion and diffusion. Drug release was different from different classes of polymeric matrices and from tablets prepared by different manufacturing processes. The results showed that the profile and kinetics of drug release were the functions of polymer type, polymer content and granulation process.

Key words: Ranitidine Hydrochloride, Wet granulation, Direct compression, MEthyl Cellulose K4M, Ethyl Cellulose 20 cps, Kollidon SR

INTRODUCTION

Sustained-release dosage forms are gaining importance in recent years in terms of clinical efficacy and patient compliance. The matrix system is commonly used method for making sustained release tablets because of its ease of manufacturing. A wide range of polymers have been used in formulating sustained release matrix tablets.

Plastic matrix systems (skeleton matrices) have been widely used for sustaining the drug release from dosage forms due to their chemical inertness and drug embedding ability. The hydrophobic and water- insoluble polymers (waxy materials) control the release of drug through pore diffusion and erosion (3). On the other hand hydrophilic polymers, when exposed to an aqueous medium, they develop a highly viscous gelatinous surface barrier which controls the drug release from the dosage form.

MATERIALS AND METHODS

Materials used in this experiment are Ranitidine Hydrochloride, which was a generous gift from Square Pharmaceuticals Ltd., Starch 1500 (BASF, Germany), HPMC K 100 M (Colorcon, USA), Ethyl Cellulose 20 cps (Dow chemical Co, USA), Kollidon SR (BASF, Germany), Pharmacel PH 101 (FMC Biopolymer, USA), Xysil 200 (Xunyu Chemicals, Chaina), and Magnesium stearate (Wilfrid Smith Ltd, UK). All the other chemicals used were of analytical grade.

Preparation of matrix tablets by direct compression technique

The active ingredient and polymers were blended at dry conditions. Lubricant, glidants were added and compressed to get tablets. The formulations were shown in Table 1.

Table 1. Different formulations of Ranitidine Hydrochloride matrix tablets prepared by direct compression technique

Ingredients

Formulation

F-1

F-2

F-3

F-4

F-5

F-6

Ranitidine Hydrochloride

100

100

100

100

100

100

Povidone k-30

25

25

25

25

25

25

Starch 1500

125

75

125

75

125

75

HPMC K 100 M

50

-

-

-

-

-

HPMC K 100 M

-

100

-

-

-

-

Ethyl Cellulose 20cps

-

-

50

-

-

-

Ethyl Cellulose 20cps

-

-

-

100

-

-

Kollidon SR

-

-

-

-

50

-

Kollidon SR

-

-

-

-

-

100

Xysil 200

4

4

4

4

4

4

Magnesium stearate

2

2

2

2

2

2

Total weight of the tablet

306

306

306

306

306

306

Table 2. Different formulations of Ranitidine Hydrochloride matrix tablets prepared by wet granulation technique

Ingredients

Formulation

F-7

F-8

F-9

F-10

F-11

F-12

Ranitidine Hydrochloride

100

100

100

100

100

100

Povidone k-30

25

25

25

25

25

25

Pharmacel PH 101

125

75

125

75

125

75

HPMC K100M

50

-

-

-

-

-

HPMC K100M

-

100

-

-

-

-

Ethyl Cellulose 20cps

-

-

50

-

-

-

Ethyl Cellulose 20cps

-

-

-

100

-

-

Kollidon SR

-

-

-

-

50

-

Kollidon SR

-

-

-

-

-

100

Xysil 200

4

4

4

4

4

4

Magnesium stearate

2

2

2

2

2

2

Total weight of the tablet

306

306

306

306

306

306

Preparation of matrix tablets by wet granulation technique

The active ingredient and polymers were blended to a damp mass with aid of water. Then moisture absorbing material microcrystalline cellulose (Pharmacel PH 101) was added to absorb any excess water. Then magnesium stearate, Xysil 200 along with granules were taken in a blender and blended for about 10 minutes. Finally granules were compressed using a single punch tablet compression machine. The compression force and compression time were 2 tons and 5 seconds respectively. The formulations for wet granulation technique with their codes are listed in Table 2.

All the formulations were stored in airtight containers at room temperature till use.

In vitro dissolution study

The drug dissolution tests of matrix tablets were carried out by the paddle method specified in the US Pharmacopoeia XXI. Tablets containing Ranitidine Hydrochloride (equivalent to 100 mg of drug) were placed in basket with 900ml of dissolution medium (SGF without enzymes), rotated at 100 rpm and thermostatically controlled at 37oC. Perfect sink conditions prevailed during the dissolution tests. The sample was withdrawn at a suitable interval from the dissolution vessel and assayed using double beam UV/ Visible spectrophotometer (Elico SL 210, India) at 225 nm.

Drug release kinetics

In vitro drug release (kinetics and mechanism)

To know the mechanism of drug release from these formulations, the data were fitted to zero order (cumulative amount of drug released vs. time), first-order (log cumulative percentage of drug remaining vs. time), Higuchi's (cumulative percentage of drug released vs. square root of time), Korsmeyer's Peppa's (log cumulative percentage of drug released vs log time) and Hixson Crowell's equations (percentage Drug Retained) 1/3 Vs. Time. (Kumar, S., Chandrasekar, M., Gopinath, R., Srinivasan, R., Nanjan, M., Suresh, B., 2007. In vitro and in vivo studies on HPMC K-100 M matrices containing naproxen sodium. Drug Deliv. 14, 163- 169.).

Zero order equation

ft = K0t ……… (11)

Where, ft = fraction dissolved at time t, K0 = zero order rate constant.

First-order equation

Log Qt = log Q0 - K1t/2.303 ……… (12)

Where, Qt = amount released at time t, Q0 = initial amount of drug in solution

K1= first order rate constant.

Higuchi's equation

Ft = KH. t ½ ……… (13)

Where, Ft=fraction dissolved at time t, KH= Higuchi dissolution constant.

Korsmeyer Peppa's equation

Mt/M∞ = at n ……… (14)

Where, Mt= amount of drug released at time t, M∞ = amount of drug released after infinite time (total drug in a dosage form), a = Korsmeyer's dissolution rate constant, n =release exponent.

Hixson Crowell's equation

3- 1 mt/m¥ = Kt ----------- (15)

Where mt = Drug release at time t, m¥ = Drug originally present in the tablet.

Accelerated Stability studies

The promising formulation was tested for a period of 3 months at accelerated temperature of 400C with 75% RH, for their drug content 10

RESULTS AND DISCUSSION

To investigate the effects of polymer, their content level and granulation process on drug release twelve formulations were prepared (Table 1 and 2). Formulation F-1, F-2 and F-3 best fits with Korsmeyer kinetic model (R2 =0.996, R2=0.995 and R2 =0.999 respectively) (Table 3). The values of release exponent (n) for the above mentioned formulations are 0.677, 0.620 and 0.551 respectively which indicates anomalous transport mechanism (coupling of the diffusion and erosion mechanism). Formulation F-4, F-5 and F-6 also followed Korsmeyer model (R2 =0.993, R2 =0.996 and R2 =0.997 respectively) (Table 3). The values of release exponent (n) for the Formulation F-4, F-5 and F-6 are 0.551, 0.770 and 0.840 respectively. In the same manner Formulation F-7, F-8, F-9 best fits with Korsmeyer kinetic model (R2 =0.997, R2 =0.997 and R2 =0.991 respectively) (Table 3). The values of release exponent (n) for the Formulation F-7, F-8 and F-9 are 0.7, 0.76 and 0.82 respectively which indicate that the drug was released by anomalous transport. Formulation F-10, F-11 and F-12 followed Korsmeyer model (R2 =0.995, R2 =0.995 and R2 =0.994 respectively) (Table 3). The values of release exponent (n) for the Formulation F-10, F-11 and F-12 are 0.69, 0.81 and 0.83 respectively.

MDT value is used to characterize the drug release rate from the dosage form and the retarding efficacy of the polymer. A higher value of MDT indicates a higher drug retarding ability of the polymer and vice versa. The MDT value was also found to be a function of polymer content, polymer nature and manufacturing process. MDT values for F-1, F-2, F-3, F-4, F-5 and F-6 were 4.36, 5.68, 3.8, 7.59, 3.25 and 7.7 hours respectively (Table 3). MDT values were larger for those formulations which contained highest percentage of polymer. MDT values for F-7, F-8, F-9, F-10, F-11 and F-12 were 6.90, 8.97, 5.12, 13.8, 3.56 and 5.37 hours respectively (Table 3). MDT values for formulations of wet granulation process were larger than those of direct compression.

Effect of granulation technique on drug release. In this investigation Ranitidine Hydrochloride matrix tablets were prepared by different manufacturing technique such as direct compression and wet granulation. It was found that tablets prepared by wet granulation exhibit significant retard release of drug compare to those of direct compression and this technique can effectively be used for sustained release tablet preparation. In case of matrix tablet prepared with hydrophilic polymer such as HPMC K 100 M(Formula F-1 and F-1) drug release was less in wet granulation compare to direct compression (Figure 1a). HPMC K 100 Mis a cellulose derivative and forms a water-soluble gel after contact with water. This polymer forms a very viscous gel as it has a viscosity of 4000 cps.11 Drug diffusion through this viscous gel was difficult and HPMC K 100 Meffectively retarded drug release. Water activate HPMC K 100 Mand result better agglomeration in wet granulation technique. Thus drug release from wet granulation was lower comparing to direct compression. In case of matrix tablet prepared with hydrophobic polymer such as Ethyl Cellulose 20 cps (Formula F-3 and F-9) drug release was also less in wet granulation in comparison to direct compression (Figure 1b). But when Kollidon SR (Plastic polymer) was used as rate-retardant (Formula F-5 and F-11), it was found that granulation process has little impact on drug release (Figure 1c). As Kollidon SR is Plastic polymer granulating water has no effect on its activity. Addition of water couldn't activate Kollidon SR and drug release was similar from tablets prepared by direct compression and wet granulation process.

Table 3. Kinetic parameters of Ranitidine Hydrochloride release from different polymeric matrix tablets

Formulation

Thickness

hardness

Friability

% drug release after 8h

MDT

F-1

8.2±0.03

5.9±0.06

0.15±0.08

77

4.36

F-2

8.1±0.06

6.9±0.05

0.11±0.02

64

5.6

F-3

8.0±0.05

5.8±0.25

0.61±0.03

83

3.8

F-4

8.0±0.02

6.6±0.15

0.22±0.02

50

7.5

F-5

8.1±0.05

7.0±0.21

0.45±0.02

93

3.2

F-6

8.2±0.03

7.0±0.21

0.49±0.05

72

7.7

F-7

8.1±0.06

6.52±0.02

0.50±0.02

57

6.9

F-8

8.0±0.05

6.12±0.52

0.11±0.01

42

8.9

F-9

8.0±0.02

7.51±0.69

0.71±0.02

62

5.12

F-10

8.1±0.05

6.29±0.12

0.49±0.05

35

13

F-11

8.2±0.03

5.58±0.37

0.59±0.04

89

3.5

F-12

8.1±0.06

7.0±0.21

0.49±0.05

65

5.3

Formulation

Zero order

First order

R

R

F-1

0.9147±0.004

0.9835±0.004

F-2

0.9577±0.004

0.9625±0.004

F-3

0.9523±0.004

0.9894±0.004

F-4

0.9648±0.004

0.9138±0.004

F-5

0.9711±0.004

0.9686±0.004

F-6

0.9865±0.004

0.9908±0.004

F-7

0.9945±0.004

0.9842±0.004

F-8

0.9491±0.004

0.9702±0.004

F-9

0.9385±0.004

0.9484±0.004

F-10

0.9895±0.004

0.8884±0.004

F-11

0.9478±0.004

-0.8496±0.004

F-12

0.9720±0.004

0.9714±0.004

Formulation

Higuchi

Korsmeyers peppas

Hixson crowells

R2

n

R2

R2

F-1

0.9909 ±0.005

0.3589

0.9929±0.004

0.9758±0.006

F-2

0.9909±0.004

0.5284

0.9868±0.007

0.9747±0.004

F-3

0.9982±0.003

0.6697

0.9951±0.002

0.9869±0.005

F-4

0.9431±0.001

0.5845

0.9818±0.008

0.8382±0.006

F-5

0.9892±0.003

0.6548

0.9915±0.009

0.9552±0.002

F-6

0.9961±0.005

0.6584

0.9949±0.002

0.9836±0.001

F-7

0.9778±0.004

0.5536

0.9945±0.004

0.9949±0.008

F-8

0.9723±0.005

0.4698

0.9936±0.006

0.9964±0.004

F-9

0.9848±0.006

0.4845

0.9949±0.002

0.9971±0.008

F-10

0.9874±0.007

0.4956

0.9962±0.004

0.9979±0.007

F-11

0.9923±0.001

0.6456

0.9978±0.005

0.9985±0.003

F-12

0.9981±0.002

0.56987

0.9989±0.008

0.9997±0.001

Effect of polymer type on the drug release. The class and nature of the matrix forming polymers influenced the release profile of active ingredient. To explore the effect of polymer variation, formulation F-1, F-3 and F-5 were compared. The above formulations contained MEthyl Cellulose K4M, Ethyl Cellulose 20 cps, Kollidon SR respectively and polymer content was 10% of total tablet weight in all cases. After carrying out dissolution for eight hours, it was found that drug release was highest with Kollidon SR compared to other two polymers (Figure 2). This might be attributed to dissolution of Polyvinylpyrrolidone (PVP) molecules, which are components of Kollidon SR that created pores and channels and thus facilitated solvent front penetration and elevation of drug release.12 Drug release from HPMC K 100 Mwas lowest because it formed a viscous gel layer through which drug diffusion was difficult. After solvation of the polymer chains, the dimensions of the polymer molecule increased due to the polymer relaxation by the stress of the penetrated solvent. This phenomenon is defined as swelling and it is characterized by the formation of a gel-like network surrounding the tablet. This swelling and hydration property of HPMC K 100 Mcaused an immediate formation of a surface barrier around the matrix tablet that impeded the burst release.

Effect of Polymer content on drug release. For all the formulations, it was found that drug release was inversely proportional to the content of rate retarding polymer present in the matrix system, i.e. the rate and extent of drug release increased with decrease in polymer content. It was observed that, formulation F-1 which contained 10% HPMC K 100 Moffered 77.78% drug release at the end of eight hours whereas formulation F-2 which contained 20% HPMC K 100 Moffered 64.03% drug release (Figure 3a). Such increase in the polymer content resulted decrease in the drug release rate due to decrease in the total porosity of the matrices (initial porosity plus porosity due to the dissolution of the drug). Similar phenomena were found for Ethyl Cellulose 20 cps and Kollidon SR. In case of Ethyl Cellulose 20 cps matrix system 79.78% and 50% of Ranitidine Hydrochloride were released from formulation F-3 and F-4 which contained 10% and 20% of polymer respectively (Figure 3b). Again for Kollidon SR matrix system 93.89% and 72.58% of Ranitidine Hydrochloride were released from formulation F-5 and F-6 which contained 10% and 20% of polymer respectively (Figure 3c).

CONCLUSION

From the investigation it was found that tablets prepared by direct compression offered maximum drug release in all types of polymers than those were prepared by wet granulation technique. In case of matrix tablets prepared with plastic polymers wet granulation technique had insignificant impact on drug release. Among the three different types of polymers Kollidon SR showed more drug release than Ethyl Cellulose 20 cps and MEthyl Cellulose K4M. It was also observed that the rate and amount of drug release from all types of polymers were increased with decrease in polymer content. Thus a controlled plasma level profile of drug can be obtained by judicious selection of polymer, Polymer content and granulation process in the matrix system.

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