Design and Characterization of Extended Release Ranolazine Matrix Tablet

 

Bawankar DL, Deshmane SV, More SM, Channawar MA, Chandewar AV and  Shreekanth J.

P. Wadhwani College of Pharmacy, Dhamangaon Road, Girija  Nagar, Yavatmal-445001 (M.S.)

*Corresponding Author E-mail:  dlbawankar@rediffmail.com

 

ABSTRACT

The objective of present investigation was to develop a extended release matrix tablet for Ranolazine in the treatment of chronic angina pectoris using wet granulation technology. HPMC E 15, EC, HPMC phthalate and different Eudragit grades form release layer. All lubricated formulation was compressed using 16.5 × 8mm oval shaped punches. Compressed tablets were evaluated for uniformity of weight, content of active ingredients, friability, hardness, thickness, invitro dissolution using paddle in 0.1 N HCl at 50 rpm for 24 hrs study. All the formulation showed compliance with pharmacopoeial standards. The batch number (F8) showed extended release of drug according to USP limits. Selected formulation (F8) was subjected to stability studies for three months at 400c ± 20c and 75% RH and showed stability with respect to release pattern. The kinetic treatment showed that lease of drug follows diffusion release and Higuchi model. The result of current study clearly indicate, a promising potential of  Ranolazine extended release 500 mg tablets as an alternative to conventional dosage form.

 

KEYWORDS: Extended release, matrix tablet, ranolazine, and Angina pectoris.

 

 


INTRODUCTION:

Approximately one quarter of the total global population is affected by at least any one form of the cardiovascular disease.1 cardiovascular disease caused 2.3 million deaths in India in 1990, which may double by year 2020, where hypertension alone contribute for 57% of all stroke death and 24 % of all coronary heart disease.2 Thus management of cardiovascular disease in particular the angina pectoris becomes important to improve the health care system. Several days are prescribed for successful management of cardiovascular disease in which ranolazine a 1-piperazine acetamide derivative is effectively used in management of various cardiovascular disease like chronic angina pectoris, myocardial infraction and arrhythmias.3-5

 

U.S.Pat. No. 5,506,2296 which is incorporated conventional oral and parentral formulation are disclosed including controlled release formulation. U.S. Pat. No.5, 472,7077 which is incorporated a high dose oral formulation employing supercooled liquid ranolazine as a fill solution for a hard gelatin capsule or softgel. Presently preferred route of administration for ranolazine and its pharmaceutical acceptable salts and esters is oral.

 

One problem with conventional oral dosage form is that they are not ideally suited to ranolazine and its pharmaceutical acceptable salts, because the solubility of ranolazine is relatively high at low pH that occurs in the stomach. Furthermore ranolazine also has a relatively short plasma half-life. The high acid solubility property of ranolazine results in rapid drug absorption and clearance, causing large and undesirable fluctuation in plasma concentration of ranolazine and short duration of action, thus necessitating frequent oral administration for adequate treatment. So there is need to formulate ranolazine as extended release dosage form for once or twice daily administration and maintained effective plasma concentration in blood.

 

The simplest and least expensive way to control the release of drug is matrix system where drug is dispersed it within an inert polymeric matrix.8 The dosage release properties of matrix devices may be dependent upon the solubility of drug in the polymer matrix or, in case of porous matrices , the solubility in sink solution within the particle’s pore network.9. Hydroxypropylmethylcellulose (HPMC) is dominant hydrophilic vehicle used for the preparation of oral controlled drug delivery system.10 Various grades of eudragit polymers are used alone or in combination with HPMC, EC in different viscosity grades.11 The objective of present study was to formulate ranolazine ER tablets using various grades of eudragit in combination with HPMC and EC with various viscosity grades and to elucidate the release kinetics of ranolazine ER tablets from polymers. We attempted a systematic approach to develop twice-daily extended release ranolazine matrix tablet.

MATERIALS AND METHODS:

Ranolazine was obtained from Natco Pharma.Pvt.Ltd. Hyderabad. HPMC E5 and EC were procured from colorcon Asia pvt.ltd.Goa, HPMC E 15 was purchased from signet chemicals, worli, Mumbai. A grade of eudragit was procured from S.zhaveri and co., worli, Mumbai. Avicel pH 101 from chemicals, worli, Mumbai. Mg-stearate from union derivatives S.A. barc. Spain. Materials and excipient used in preparing tablets were IP grades. All other ingredients used throught the study were of analytical grade were used as received.

 

Preparation of matrix tablet:

Matrix tablet were prepared by wet granulation technique using Avicel pH 101 as diluent and Mg-stearate as lubricant. All the ingredients were passed through 40µm sieve. The ingredients were accurately weighed and mixed together in a glass mortar for 10 minutes. Binding solution was prepared. Binding solution was added in above materials dough mass was produced. Dough mass was passed through 12 mesh to get wet granules. Wet granules were dried at 65 o c by using tray dryer up to 45 minutes. Dried granules were passed through 18 mesh to get uniform granules. Finally HPMC and magnesium stearate was passed through 40 mesh and added to above granules and then mixed and compressed into tablets on 16 machine ( Rimek) by using oval shaped punches 16.5 × 8 mm. Table No.1 shows composition of each tablet formulation.

 

Evaluation of tablets:

The prepared matrix tablets were evaluated for hardness, Weight variation, Thickness, Friability and Content Uniformity (Table 2). Hardness of the tablets was tested using Dr. schleuniger pharmatron hardness tester. Friability was determined in Roche friabilator. The thickness of the tablets was measured by vernier calipers. Weight variation test was performed according to official method 12. Content uniformity for ranolazine was carried out by using HPLC method 13.

 

In vitro drug release studies:

The In vitro dissolution studies were carried out using USP Type- II (Paddles) apparatus at 50 rpm. Dissolution test was carried out for a total period of 24 h using 0.1 N HCl solution ( 900 ml ) as dissolution medium at 37 0 c± 0.5 0 c. After completion of specified time interval, withdraw 5 ml of solution from zone midway between the surface of  the Dissolution medium and top of the rotating blade, not less than 1 cm from vessel wall and filter through 0.45 µ membrane filter 14-15. Transfer 2.0 ml of solution in to a 10 ml volumetric flask and dilute to volume with Dissolution medium. Measure the absorbance of the standard and sample preparation in 1- cm cells, at the wavelength of maximum absorbance at about 272 nm, with a suitable spectrophotometer using a Hydrochloric acid as blank Preparation

 

Release Kinetic Study:

To describe the kinetics of the drug release from the matrix tablet batches, mathematical models such as zero-order, first order, Higuchi, Hixson-Crowell, Korsmeyer-Peppas models were used. The criterion for selecting the most appropriate model was chosen on the basis of the goodness-or fit test 16-17. The optimized formulation batch i.e. batch F 8 were compared with the marketed extended release Ranolazine tablet (Ranexa ®, CV Therapeutics, USA). The comparison of the % drug release profiles were carried out the similarity factor (F2) was defined by CDER, FDA and EMEA as the ‘logarithmic reciprocal square root transformation of one plus the mean squared difference in percent dissolved between the test and the reference products18. This was calculated to compare the test with reference release profiles

 

The similarity factor (f2) should be always greater than 50 (f2>50).

 

Stability studies:

The tablets from the selected and optimized batch (F8) were studied for stability and kept under the accelerated conditions of temperature and moisture (humidity) for the period of three months. The tablets were studied for stability at 40°C and 75% RH conditions 19-21. Each tablet was individually weighed and wrapped in an aluminum foil and packed in black PVC bottle and put at above specified conditioned in a heating humidity chamber for 3 months. After each month the, the formulation was observed for changes in physical appearance and analyzed for in-vitro drug release. (Table. Stability study)

 

RESULTS:

Compatibility study of ranoazine was studied by taking drug and all excipient in fixed ratio and physical observation done at 55 0c, for period of 1 month (Table No. 4) Interpretation of drug-polymer interaction was done by viewing physical observation and was interpreted that no drug interaction was observed.

 

Formulation of proper powder blend is the key factor in the production of tablet dosage form involving extended release of drug from matrix type particle. Physical parameters such as specific surface area, shape, hardness, surface characteristics and size can be significantly affect the rate of dissolution of drugs contained in a complex system. All the formulations had shown the values of evaluation parameters within the standard limits specified in official books for powder blend, (Table No. 2) The bulk density and tapped density values indicates good packing The values of % compressibility, Hausner ratio and angle of repose were lies in between indicates acceptable flow property and also good packing ability. Therefore, the tablet blend might be used for the preparation of extended release matrix tablets.

 

 


Table No.1: Composition of tablets formulations F 1 to F 8

Ingredients

F1

F2

F3

F4

F5

F6

F7

F8

Ranolazine

500

500

500

500

500

500

500

500

Eudragit L100-55

-

-

-

-

-

-

-

68

Ethyl cellulose

105

-

-

-

-

-

-

-

HPMC E15

-

116

-

-

-

-

-

-

HPMC phthalate

-

-

100

-

-

-

-

-

Eudragit L100

-

-

-

68

-

-

-

-

Eudragit S 100

-

-

-

-

68

-

-

-

Eudragit L-30-L-55(30%w/w)

-

-

-

-

-

60

-

-

Eudragit RS-30D(30%w/w)

-

-

-

-

-

-

60

-

Avicel pH 101

35

37

50

68

68

68

68

68

NaOH

-

-

-

2.67

2.67

2.67

-

2.67

Purified water (ml)

0.15

0.1

0.3

0.2

0.2

-

0.05

0.2

HPMC E 5

13

-

-

13

13

13

13

13

Mg-Stearate

12

12

15

13.33

13.33

13.33

13.33

13.33

Opadry Pink

-

-

-

-

-

-

-

-

 

Table No. 2 : Properties of compressed ranolazine matrix tablets

Formulation

Hardness (Kg/cm2)

Friability (%)

Thickness (mm)

Content Uniformity (%)

Weight Variation Test (mg)

F1

15.5

0.41

6.78

98.0

670

F2

15.4

0.53

6.75

99.0

668

F3

15.3

0.38

6.50

98.1

672

F4

15.4

0.39

6.70

100.1

670

F5

15.2

0.45

6.66

100.4

674

F6

16.1

0.50

6.81

99.7

654

F7

15.7

0.52

6.63

101.3

668

F8

15.2

0.91

6.76

102.0

666

 

 


Table No. 3: Dissolution profiles of Ranolazine ER Tablets (F 8) after 1st to 3rd month at 40ºC/75% RH

Time (hours)

% Drug Released

 

0 Month

1 Month

2 Month

3 Month

0

0

0

0

0

0.5

18.5

18

22

18

1

28.1

28.1

29.1

27.7

2

41.3

42.2

40.3

40.2

4

59.8

60.3

53.4

58.4

6

71.2

73

70.2

70.5

8

78.3

81.6

75.2

79.2

12

88.8

93.3

88.3

92.7

20

96.5

97.2

95.5

98.6

24

96.6

97.4

95.2

95.5

 

 

 

 

 

 

 

 

 

 

 

The tablets of different formulations (F1 to F8) and reference standard were evaluated for various parameters viz., hardness, friability, percentage weight variation and percentage drug content. The results of these parameters are given in (Table No. 2) Hardness values for Formulation were ranged from which indicates good strengths of the tablets. Values also match with innovator. Friability and thickness both were in acceptable range. For content uniformity test, representative samples of 30tablets are selected and 10 are assayed individually. The drug content was determined by HPLC method. At least 9must assay within ±15% of the declared potency and none may exceed ±25% results are shown in (Table No.2)  , six replicate injection and finally taken the mean of retentions time, peak area, tailing factor and plate count. Separately inject equal volumes (about 20 µL) of mobile phase as blank, and sample preparations into the chromatograph, record the chromatograms, and the responses for the major peaks.

 

All the formulations were subjected to in-vitro dissolution studies and results are shown in (graph 1-4).  The drug dissolution data were subjected to release kinetic studies for the determination of mechanism of drug release from the prepared matrices- The drug release kinetics from matrices were calculated, which was illustrated in (Table No. 5) Most of the formulations prepared were found to release by the drug by non-fickian transport (anomalous) since the release exponent values (n) shown in (Table No. 6) Although the drug release fitted better into an anomalous/non-fickian diffusion mechanism, a model representing zero order was also very close.The ‘r’ values for the Higuchi plots were found to be in the (Table No.6) which confirms diffusion controlled drug release from all the prepared matrices.

 

 

The tablets from the selected and optimized batch (F8) were studied for stability and kept under the accelerated conditions of temperature and moisture (humidity) for the period of three months. The tablets were studied for stability at 40°C and 75% RH conditions.The results indicates that no remarkable changes in physical and chemical parameters and in vitro dissolution profiles as shown in (Table No. 3 and 4).

 

Similarity factor was calculated by comparison of F8 formulation batch in-vitro release with marketed product release profile. This value indicated that the in-vitro release of F8 were closely similar to that of marketed tablet release profiles and results are shown in (Table no. 8) and graphs are also shown in (Figure No. 6).

 

 


Table No. 4  : Physical and chemical parameters of Ranolazine ER Tablets (F 8) after 1st to 3rd month at 40ºC/75% RH

Parameter

Initial

1 st month

2 nd month

3 rdmonth

Description

Light orange coloured capsule shaped film coated tablets plane surface on both sides.

Light orange coloured capsule shaped film coated tablets plane surface on both sides.

Light orange coloured capsule shaped film coated tablets plane surface on both sides.

Light orange coloured capsule shaped film coated tablets plane surface on both sides.

Assay

94.8 %

97.1 %

97.4 %

98.6 %

Moisture content

1.956 %

1.976 %

1.570 %

1.988

 

Table No. 5 : Compatibility study by physical observation

S. No

Excipients

Ratio

Description

Initial

Final

1

API- Ethyl cellulose

1:0.5

White to off white powder

White to off white powder

2

API –HPMC E5

1:0.5

Off white coloured powder

Off white coloured powder

3

API – HPMC E15

1:0.5

Off white coloured powder

Off white coloured powder

4

API- HPMC pthalate

1:0.5

Off white coloured powder

Off white coloured powder

5

API-Eudragit L 100

1:0.5

Off white coloured powder

Off white coloured powder

6

API- Eudragit S 100

1:0.5

Off white coloured powder

Off white coloured powder

7

API- Eudragit L-30-L-55

1:0.5

Off white coloured powder

Off white coloured powder

8

API- Eudragit RS 30 D

1:0.5

Off white coloured powder

Off white coloured powder

9

API- Eudragit L 100-55

1:0.5

Off white coloured powder

Off white coloured powder

10

API-Avicel pH 101

1:0.5

Off white coloured powder

Off white coloured powder

11

API-Magnesium stearate

1 :0.1

Off white coloured powder

Off white coloured powder

12

API- Sodium hydroxide

1 :0.1

Off white coloured powder

Off white coloured powder

 

 


 

 

 

 

 

 

 

 

 

 

 

 

 

 

Table No. 6: Various rate order release equations

 

Figure No. 1 : In vitro dissolution of formulation F 1 and F 2

 

DISCUSSION:

Recent advances in novel drug delivery systems aim to enhance safety and efficacy of drug molecules by formulating a convenient dosage form for administration and to achieve better patient compliance. Once daily dosing of drugs having short elimination half life, through design of extended-release oral formulation is the most preferred approach in improving patient convenience, drug therapy and safety. Ranolazine is an antianginal used in the management of chronic angina pectoris and heart failure in doses ranging from 500 mg to 1000 mg. It is slightly water soluble drug with bioavailability of 35-50 % and plasma half-life 7 hours. Hence, conventional tablet is insufficient to achieve the therapeutic plasma concentration for long duration of time and a dosage regime of twice or thrice daily is required.

Zero – order kinetic equation

Q t  =   K 0 t

First – order kinetic equation

Q t  = Q 0 ( 1 – e-k 1 t )

Higuchi equation

Q t  = KH  √ t

Hixson-Crowell cube root law equation

3 √ Q 0 – 3 √ Q t = K HC  t

Korsmeyer-Peppas equation

Q t / Q ∞ = K k tn

 

 

 

 

 

 

 

 

Table No. 7  : Drug Release Kinetic Studies from Formulation

Formulation

n

Zero-order

First-order

Higuchi

F1

0.751

0.947

0.978

0.981

F2

0.750

0.963

0.963

0.973

F4

0.690

0.975

0.992

0.953

F5

0.647

0.974

0.989

0.978

F6

0.711

0.802

0.941

0.954

F7

0.836

0.883

0.982

0.972

F8

0.931

0.990

0.966

0.967

 

Figure No. 2 : In vitro dissolution of formulation F 3 and F4

 

The preformulation study like qualitative analysis of raw materials and drug which includes physical characterization and analytical methodologies, drug interaction studies (compatibility study) and evaluation of tablet blend including determination of bulk density, tapped density, compressibility index, hausner ratio and angle of repose were performed. Interpretation of drug-polymer interaction was done by viewing physical observation and was interpreted that no drug interaction was observed. All the formulations had shown the values of evaluation parameters within the standard limits specified in official books for powder blend. Therefore, the tablet blend might be used for the preparation of extended release matrix tablets.

 

Figure No. 3 : In vitro dissolution of formulation F 5 and F 6

 

Figure No. 4 : In vitro dissolution of formulation F 7 and F 8

 

All the formulations were subjected to in-vitro dissolution studies. The results revealed that formulation F1 contains ethyl cellulose; results not matched as release occurred within 4 Th hour. In the formulation F3 the released was obtained within 1 st hour so that no match with the innovator. The formulation which contains HPMC in high quantity shows initial burst release. The hydration rate of hypromellose polymer relates to its hydroxypropyl substitutes percentage. The hypromellose E 15 contains the higher amount of these groups and produce strongly viscose gel that plays an important role in drug release especially at the beginning of the release profile. Therefore, the quick hydration and subsequent gel formation is a foremost and important property of an excipients for it to be used in extended-release formulations.

Table No. 8 : Table indicating calculation of similarity factor (F2)

 

Time (Hrs.)

Rt

Tt

Rt-Tt

(Rt-Tt)^2

24

92.2

92.0

0.2

0.04

92.2

92.0

0.2

0.04

Number of points

1

 

 

F2

51.1

 

 

 

 

 

 

 

In the formulation F4, F5, F6, F7 and F8 pH dependent polymers were used in combination to retard the release of drug over extended period of time.

 

Formulation F8 has the dissolution profile which matches with the innovator’s release profile so that this formulation was kept for further studies.

 

When the hypromellose combined with the natural gums is used for controlling the drug release, the process of drug release from matrix involves solvent penetration in to the matrix, gelatinization of the polymer, dissolution of the drug and diffusion of the drug through resultant layer. Concomitantly, the outer layer becomes fully hydrated and dissolves, this process is generally referred to as erosion.

 

The mechanism of drug release in these formulations is mainly governed by diffusion and as the drug is so highly soluble, polymer viscosity grade did not significantly affect the diffusion rate. However, when considering in-vivo behaviour of these systems, the erosion rate will also become important (in comparison to the dissolution testing conditions) and thus a higher viscosity grade may produce a more robust formulation. Most of the formulations prepared were found to release by the drug by non-fickian transport (anomalous) since the release exponent values (n) were found to be in the range of 0.647 to 0.931. Although the drug release fitted better into an anomalous/non-fickian diffusion mechanism, a model representing zero order was also very close (‘r’ values form 0.802 to 0.990). The ‘r’ values for the Higuchi plots were found to be in the range of 0.953 to 0.981 which confirms diffusion controlled drug release from all the prepared matrices.

 

The analysis of the dissolution kinetic data for the ranolazine preparations containing hypromellose had shown the first order release kinetic and the release process involves erosion/diffusion and an alteration in the surface area and diameter of the matrix systems as well as in the diffusion path length from the matrix drug load during the dissolution process. This relation is best described by the use of both first-order equation and Hixson-Crowell cube root law.The results of stability studies indicates that no remarkable changes in physical appearance and in vitro dissolution profiles.

 

The optimized formulation batch F 8 showed better drug release profile with Ranexa ® (CV Therapeutics, USA). This was concluded from the similarity factor (F2), which was found to be 58.51.


 

Figure No. 5 : Plot of stability studies on in vitro release at acclerated temperature (40ºC ± 2 ºC at 75 % ± 5 % RH )

 

Figure N0. 6 : Comparison of F8 tablets with marketed tablets (Ranexa ® )

 

 


In conclusion, a stable extended-release swellable matrix tablet formulation of Ranolazine was successfully developed. Moreover, the developed product is less complex with regards to formulation components and processing aspects.

 

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Received on 05.05.2009       Modified on 08.07.2009

Accepted on 03.08.2009      © RJPT All right reserved

Research J. Pharm. and Tech.2 (4): Oct.-Dec. 2009; Page 756-761