DOI: http://dx.doi.org/10.26510/2394-0859.pbe.2017.25

Research Article

Formulation and evaluation of orodispersible tablet of ivabradine hydrochloride

D. B. Patel*, K. J. Patel, P. D. Bharadia

Department of Pharmaceutical Technology, Ratnamani College of Pharmacy, Shankhalpur, Gujarat, India

*For correspondence

Mr. D. B. Patel,

Department of Pharmaceutical Technology, Ratnamani College of Pharmacy, Shankhalpur, Gujarat, India.

Email: pdhaval327@ yahoo.com

 

 

 

 

 

 

 

Received: 02 April 2017

Revised: 22 April 2017

Accepted: 24 April 2017

ABSTRACT

Objective: The objective of present research work was to develop formulation of orodispersible tablets of Ivabradine HCl and evaluate it for different evaluation parameters.

Methods: The tablets were prepared by direct compression method. The formulation of the tablets were evaluated before compression for characterization of flow properties and after compression for different parameters of orodispersible tablet formulation.

Results: Ivabradine hydrochloride orodispersible tablets were developed with considerable increase in drug release as compared to marketed formulations; nine formulations were developed and studied. The difference in drug release values was found to be 100.88 ± 0.10 respectively. The drug was characterized according to different compendial methods, on the basis of identification by HPLC, pH, organoleptic properties and other tests. Parameters evaluated were within prescribed limits and indicated good free flowing properties. The F6 batch with disintegration time 21 ± 3.0 and dissolution 99.29% was selected as optimized formulation. This was compared with conventional marketed formulation and was found superior. Batch F6 was also subjected to stability studies for two months and was tested for its hardness, wetting time, disintegration time, drug contents and dissolution behaviour monthly.

Conclusions: By appropriate selection of excipients, it was possible to develop orodispersible tablets of Ivabradine HCl.

 

Keywords: Orodispersible tablets, Ivabradine HCl, Superdisintegrants, Direct compression

Introduction

Orodispersible drug administration is perhaps most useful and important route for drug delivery. Tablets are the most favoured oral solid dosage form mainly because of several advantages like, ease of administration, good chemical and microbiological stability, easy to swallowing, lowest cost among all other solid dosage form, dose precision and least content variability, ease of packing, self-medication, patient compliance.1-4

Ivabradine hydrochloride is used in the treatment of mild to severe chronic heart failure and also used instable angina pectoris which causes chest pain. Ivabradine is also known as heart rate lowering agent.5-7 Angina pectoris is the disease characterized by inadequate supply of oxygen. An angina attack needs to be immediate balance of the oxygen supply so, as to diminish the chest pain. Oxygen supply can by decreasing oxygen demand. Ivabradine is the drug that decrease the oxygen demand and hence balancing oxygen supply demand

Hence the present work was aimed at increasing the onset of action of ivabradine hydrochloride thus providing faster rate of absorption by adding potential superdisintegrants like Crospovidone, Croscarmellose sodium and Sodium starch glycolate in different concentrations.

Materials and Methods

Ivabradine HCl was procured from Shashi Pharma, Chhatral, Gujarat, India, Croscarmellose Sodium, Cross povidone, Sodium starch glycolate, Microcrystalline Cellulose, Magnesium stearate, Talcum, Aspartum, Pineapple flavour were procured from Shashi Pharma, Chhatral, Gujarat, India.

Table 1: Composition of formulation of F1-F9 for orodispersible tablet.

Ingredients (mg) Quantity in mg/tablet
Formulation Code F1 F2 F3 F4 F5 F6 F7 F8 F9
Ivabradine HCl 8.084 8.084 8.084 8.084 8.084 8.084 8.084 8.084 8.084
Microcrystalline cellulose 91.686 92.786 94.986 90.586 88.386 86.186 92.786 90.586 88.386
Sodium starch glycolate 6.6 - - 4.4 5.5 6.6 4.4 5.5 6.6
Cross carmellose sodium - 5.5 - 3.3 4.4 5.5 - - -
Cross povidone - - 3.3 - - - 1.1 2.2 3.3
Magnesium stearate 0.99 0.99 0.99 0.99 0.99 0.99 0.99 0.99 0.99
Talcum powder 1.1 1.1 1.1 1.1 1.1 1.1 1.1 1.1 1.1
Aspartum 0.88 0.88 0.88 0.88 0.88 0.88 0.88 0.88 0.88
Flavour (pineapple) 0.66 0.66 0.66 0.66 0.66 0.66 0.66 0.66 0.66
Total 110 110 110 110 110 110 110 110 110

Formulation of ivabradine hydrochloride orodispersible tablets

Direct compression

Orodispersible tablets of Ivabradine HCl were prepared by direct compression method using; superdisintegrant in addition to combined approaches according to the formula given in Table 1. Ivabradine HCl 7.5 mg equivalent to Ivabradine 8.084 mg were taken. In all formulations microcrystalline cellulose were used as diluent. The specified quantity of the drug and the other excipients were weighed accurately and passed through 60 # screen prior to mixing. All the materials were transferred to mortar in geometrical order and co-grounded for 15 min. The resulting powder mixture was compressed into tablets using tablets compression machine (Riddhi trading company 10 station D-tooling machine) using 8 mm flat surface round punches. The compression force was adjusted to give tablet hardness in the pharmacopeial range of orodispersible tablets (2–4 kg/cm3).

Analytical method development

Preparation of 0.05M potassium dihydrogen ortho phosphate, ph-6.5 solution

Take about 6.8 gm potassium dihydrogen ortho phosphate reagent into a 1000 ml beaker. Add 800 ml methanol and dissolve. Adjust pH 6.5 of this solution with 0.1N NaOH. Make up volume upto 1000ml with methanol (Use this solution as buffer).8

Preparation of standard stock solution:

Standard drug solution of Ivabradine HCl was prepared by dissolving 10mg of Ivabradine HCl with 100ml methanol in volumetric flask to give stock solution of 100 μg/ml. 1ml of stock solution was withdrawn and further diluted with 10 ml mobile phase to give stock solution of 10 μg/ml concentration.8

Determination of Ivabradine Hydrochloride

The chromatogram of the solutions was measured at 286 nm by using UV detector. A graph of area vs. concentration (µg/ml) was plotted and standard curve was obtained.8

Calibration curve of Ivabradine Hydrochloride

Accurately weighed (10 mg) Ivabradine Hydrochloride was dissolved with 100ml methanol in volumetric flask to give stock solution of 100 μg/ml. Aliquots of 0.5, 0.75, 1.0, 1.25, 1.5 ml was withdrawn and volume was made up to 10 ml with methanol to obtain a concentration in the range from 5 to 15 µg/ml. The chromatogram of the solutions was measured at 286 nm by using UV detector. A graph of area vs. concentration (µg/ml) was plotted and standard curve was obtained. The equation for linearity was also be detected using excel software.8

Drug-excipient compatibility study

Fourier transform infrared spectroscopy

The FTIR spectra of Ivabradine Hydrochloride pure drug powder and Ivabradine HCl + Excipients were recorded on a FTIR spectrophotometer (Shimadzu), in the wavelength region of 4000 – 600 cm. Samples (about 1% w/w) were mixed with KBr powder and suitable amount of sample was placed in sample holder. The KBr discs were prepared by compressing the powders at a pressure of 5 tons for 5 min in a hydraulic press. Thirty scans were obtained at a resolution of 2 cm-1, from 4000 to 600 cm1. The sample holder was placed in the light path and the spectrum was obtained.9

Differential scanning calorimetry

Thermal analysis of Ivabradine Hydrochloride and Ivabradine HCl + Excipients, was carried out using differential scanning calorimetric method. Samples were examined using a DSC instrument. Samples equivalent to approximately 8 mg Ivabradine HCl were placed in aluminium pans and heated from 25 to 300˚C with a heating rate of 10˚C/min.

Evaluation method

Pre-compression evaluation parameter

The flow property of solid formulation was studied by bulk density, tap density, compressibility, angle of repose and Hausner's ratio.

Bulk density1-4

Ten gram of powder mixtures was placed into 100ml measuring cylinder and volume noted. The bulk density was calculated by following equation.

Bulk density = Weight of powder
Bulk volume

Tapped density1-4

The sample powder was placed into 100 ml measuring cylinder. The cylinder was then subjected to a fixed number of taps (100). The final volume was recorded and the tapped density was calculated by the following equation.

Tapped density = Weight of powder
Tapped volume

Carr's index1-4

It is one of the most important parameter to characteristic the nature of powders and granules. It can be calculated from the following equation and category of carr's index given in Table 2.

Table 2: Significance of carr's index.

Carr's Index

Types of flow

05-12

Excellent

12-16

Good

18-21

Fair

23-35

Poor

35-38

Very poor

More than 40

Extremely poor

Hausner's ratio1-4

Hausner's ratio of powder mixture was found out using the following equation.

Hausner's ratio =

Tapped density

Bulk density

Lower Hausner's ratio (<1.25) indicates better flow properties than higher ones (>1.25)

Angle of repose1-4

Angle of repose was found out by fixed height funnel method. The funnel height was kept constant 2 cm (h) and the diameter (D) of the circle was measured and angle of repose was find out by the equation and type of flow is given in Table 3.

θ = tan-1 h
r

Table 3: Angle of repose.

Angle of repose

Type of flow

<20

Excellent

20-30

Good

30-40

Fair

>40

Poor

Table 4: Specification of uniformity of weight.

Sr no.

Avg.wt.of tablet

% Deviation

1

80 mg or <80

10

2

>80 mg to 250 mg

7.5

3

>250 or more

5

Post-compression evaluation parameter.

Weight variation 1-4

The tablet weight was measured using digital weighing balance. 10 tablets from each batch was used and average weight was calculated. Specification of uniformity of weight given in Table 4.

Hardness1-4

Monsanto hardness tester was used for the determination of the hardness. The tablet was placed in contact between the plungers and the handle was pressed, the force of the fracture will record. In this work, for each formulation the hardness of 3 tablets were evaluated.

Thickness1-4

The thickness of the tablet was measured by using digital Vernier scale. Thickness was express in mm.

Friability1-4

Friability of the tablets was determined using Digital friability test Apparatus (pharmatronics, Sunil Corporation).

%Friability =

W0 - W

× 100

W0

Where, W0 is the weight of the tablets before the test,

W is the weight of the tablet after the test

Wetting time1-4

The method was followed to measure tablet wetting time. A piece of tissue paper (12 cm * 10.75 cm) folded twice was placed in a small petridish (ID= 6.5 cm) containing 6 ml of Sorenson's buffer pH 6.8. A tablet was put on the paper, and the time for complete wetting was measured. Three trials for each batch and the standard deviation were also determined.

In vitro disintegration test1-4

The process of breakdown of a tablet into smaller particles is called as disintegration. In vitro dispersion time was measured by dropping a tablet in a beaker containing 50 ml of phosphate buffer pH 6.8 Three tablets from each formulation were randomly selected and in vitro dispersion time was performed.

Estimation of drug content17

Weigh and powdered 20 tablets. Take tablet powder equivalent to 10mg ivabradine in to a 100ml volumetric flask. Add 60 ml methanol. Shake for 15 minutes and sonicate for 10 minutes. Make up volume with methanol. Filter this solution with Whatman filter paper no-1. (Ivabradine-100 mcg/ml).

Table 5: Calibration curve of Ivabradine Hydrochloride.

Stock solution of Ivabradine

Conc (mcg/ml)

Area

ml. ------>

ml make up

   
0.5

10

5

952.954

0.75

10

7.5

1429.819

1

10

10

1892.799

1.25

10

12.5

2341.242

1.5

10

15

2816.864

Correlation coefficient = 0.9995
Absorbance = 185.5x + 31.03

Working sample preparation

Take 1 ml from sample stock solution into a 10ml and make up with mobile phase. (Ivabradine-10 mcg/ml)

Chromatographic condition

Mobile phase: buffer (pH 6.5)-Methanol 40:60

Buffer prepn: (0.05M potassium dihydrogen ortho phosphate, pH- 6.5)

Flow rate: 1 ml/min

Injection volume: 20 microlit.

Column: 250*4.6mm C18, Hypersil BDS

Wavelength-286nm

In-vitro dissolution study17

Dissolution

It is the amount of the solid substance goes into the solution per unit time under standard conditions of the temperature and pressure.

Method

Dissolution media was taken as 0.05M potassium dihydrogen ortho phosphate, pH-6.5, 500 ml was placed in the vessel and the USP apparatus- 2 (paddle) was assembled. The medium was allows to equilibrate to temp of 37 + 0.50 C. tablet was placed in the vessel; the apparatus was operated at 50 rpm. At definite time intervals, 5 ml of the fluid was replaced. The samples were analyzed using HPLC.

Dissolution parameters

Medium: 0.05M potassium Dihydrogen ortho phosphate, pH-6.5: 500ml

Apparatus: USP type 2 (paddle)

Rotation speed: 50 RPM

Temperature: 37 + 50C

Time: 0, 2, 5, 10, 15, 20 min

Results and Discussion

Calibration curve of Ivabradine Hydrochloride using HPLC method.

Estimation of Ivabradine Hydrochloride was carried out using the method describe in calibration curve shown in Figure 1.

Drug excipients compatibility study

Fourier transform infrared spectroscopy

The possible interaction between the drug and the excipients was studied by IR spectroscopy. The spectra of drug and drug + excipients showed in figure 2 and figure 3 were identical and no any sifting of characteristic absorption bands of ivabradine hydrochloride in IR spectra of produced with excipients. The FTIR spectra of all the tested samples showed the prominent characterizing peaks of pure Ivabradine hydrochloride and drug+physical mixture. This indicated that there was no difference between the internal structures.

Figure 1: Calibration curve.

Figure 2: FTIR of pure ivabradine drug.

Figure 3: FTIR of Pure ivabradine + Excipients.

Differential scanning calorimetry

DSC curves obtained for pure ivabradine and mixture of ivabradine + excipients is shown in Figure 4 and 5. Pure powdered ivabradine showed a sharp melting point at 194.02˚C. DSC thermo grams of ivabradine and excipients showed the melting peak of the drug at 196.83˚C.

Figure 4: DSC of Pure ivabradine drug.

Figure 5: DSC of Pure ivabradine + Excipients.

Presence of peak indicated that superdisintegrant and ivabradine were compatible with each other means there is no incompatibility between the selected superdisintegrant and drug.

Pre-compression parameters

Orodispersible tablets of Ivabradine HCl were prepared by direct compression method using cross carmellose sodium, sodium starch glycolate, cross povidone. Pre-compression parameter given in Table 6.

Table 6: Pre-compression parameters of F1-F9.

Formulation code no.

Bulk density (gm/ml)

Tapped density(gm/ml)

Carr's

index*(%) ±SD

Hausner's

ratio* ±SD

Angle of

repose*(0)±SD

F1

0.567±0.010

0.682±0.005

16.86±1.985

1.20±0.028

30.50±0.805

F2

0.545±0.009

0.647±0.07

15.76±1.168

1.18±0.425

29.64±0.856

F3

0.563±0.010

0.667±0.009

15.59±2.696

1.18±0.037

31.20±1.205

F4

0.566±0.007

0.662±0.008

14.50±1.628

1.16±0.023

29.73±0.693

F5

0.567±0.008

0.675±0.010

16.00±1.495

1.19±0.035

30.18±1.500

F6

0.554±0.009

0.673±0.007

17.68±2.168

1.21±0.425

30.71±1.281

F7

0.537±0.008

0.651±0.007

17.51±0.462

1.21±0.006

30.17±1.189

F8

0.563±0.008

0.684±0.006

17.69±1.777

1.21±0.026

30.74±1.336

F9

0.529±0.006

0.665±0.007

20.45±0.259

1.25±0.004

29.93±1.063

Table 7: Post-compression parameter of batches F1-F9.

Formulation code no.

Hardness*

(kg/cm2)±SD

Friability (%)±SD

Thickness

(mm)±SD

Avg. wt (mg) ±SD

F1

2.8±0.36

0.822±0.04

2.2±0.002

109±2.34

F2

3.2±0.36

0.886±0.03

2.6±0.016

112±2.51

F3

3.5±0.24

0.868±0.03

2.6±0.006

111±3.21

F4

2.8±0.30

0.724±0.05

2.3±0.011

108±2.43

F5

2.6±0.27

0.725±0.02

2.2±0.013

110±1.91

F6

3.4±0.33

0.792±0.04

2.6±0.006

113±2.47

F7

3.2±0.27

0.843±0.07

2.4±0.004

111±1.36

F8

3.2±0.27

0.823±0.06

2.6±0.019

110±3.71

F9

3.0±0.24

0.791±0.06

2.4±0.007

109±2.35

Table 8: Post-compression parameter of batches F1-F9.

Formulation code no.

Average Wetting time(sec) ±SD

Disintegration time(sec) ±SD

%Drug content ±SD

F1

35±1.0

47±4.0

99.49±0.02

F2

27±2.0

32±1.0

98.99±0.40

F3

32±1.0

38±2.0

100.09±0.07

F4

32±4.0

36±2.0

99.19±0.06

F5

23±1.0

27±1.0

99.68±0.10

F6

18±3.0

21±3.0

100.88±0.10

F7

31±3.0

35±1.0

100.28±0.10

F8

27±2.0

31±2.0

100.17±0.02

F9

22±2.0

28±1.0

99.47±0.04

Post-compression parameters

Post compression parameter is given in Table 7 and Table 8.

In-vitro dissolution study

In-vitro Dissolution study

In – vitro drug release study for optimized batches (F6) is given in Table 9 and Figure 6.

Comparison of optimized formulation with marketed formulation

The in vitro drug release of optimized formulation was found to be 99.29% at 15 min and in vitro drug release of marketed formulation was found to be near to 97.87%. Hence, studies indicate that optimized formulation shown better dissolution as compared to marketed formulation.

Stability study for optimized formulation

The direct compressed orodispersible tablet of ivabradine containing batch F6 was optimized batch and as per formula of optimized batch were subjected to stability studies.

Figure 6: In vitro dissolution studies of optimized batch.

Table 9: In vitro drug release study for optimized batch.

Sr. No.

Time (min)

% Drug release

F6

1

0

0

2

2

19.81 ±0.01

3

4

37.74 ±0.06

4

6

62.70 ±0.09

5

8

68.03 ±0.07

6

10

75.35 ±0.10

7

12

93.45 ±0.08

8

15

99.29 ±0.10

9

20

-

The prepared orodispersible tablet of ivabradine was packed in aluminium strip and subjected for short term stability studies at 40 ± 2°c and 75 ± 5° RH for 30 and 60 days in humidity chamber. Sample withdrawn after 30 and 60 days showed no significant change in appearance of tablets drug release CPR profile of stability studies are shown disintegration time was 23 and 27 sec, wetting time was 19 and 21 sec and optimized batch drug release profile was 99.12% and 98.89%. The results of short term stability studies indicated that the formulation was stable on required storage condition.

Conclusions

This research work was done with an aim to design an orodispersible tablet of ivabradine HCl and evaluation of the tablets for various parameters including in vitro drug release studies.

The results of experimental studies of Ivabradine HCl Orodispersible tablets proved that the Powder blend of ivabradine showed good flow properties, tablet evaluation tests are within the acceptable limits.

IR spectral & DSC analysis proved that there was no drug- excipients interaction.

Orodispersible tablets formulated using three superdisintegrants Sodium starch glycolate, Croscarmellose sodium and Crospovidone by direct compression method. The formulation F6 was found to be better in terms of rapid disintegration and maximum percentage drug release when compared with all other formulations. Overall results indicated that F6 is better one which satisfied all the criteria for Orodispersible tablets of ivabradine HCl.

The optimized formulation was evaluated for their stability studies. The optimized formulation was stable at room temperature and environmental condition.

The optimized formulation was compared with the marketed formulation. The optimized formulation is fast action than marketed formulation. The future scope of the work includes clinical study of the formulation.

Funding: No funding sources

Conflict of interest: None declared

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