formulation and evaluation of felodipine sublingual

www.wjpps.com Vol 3, Issue 6, 2014.

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Bhavik et al. World Journal of Pharmacy and Pharmaceutical Sciences

FORMULATION AND EVALUATION OF FELODIPINE SUBLINGUAL

TABLET

Rohit J. Patel, Bhavik N. Patel*, Dasharath M. Patel and Chhagan N. Patel

Department of Pharmaceutics and Pharmaceutical Technology, Shri Sarvajanik Pharmacy College,

Mehsana-384001, Gujarat, India.

ABSTRACT

Objective: Felodipine is the drug of choice in hypertension and

congestive heart failure.Its bioavailability is very low about 15%.

Present investigation was undertaken to formulate sublingual tablet of

Felodipine to overcome the first pass metabolism and provide fast

onset of action. Experimental Work: The solid dispersion of

Felodipine were prepared with β-cyclodextrin, poloxamer 407, PEG

6000 and PVP K-30 in various ratios (1:2, 1:4, 1:6 1:8) and phase

solubility study was performed to select the carrier. The selected solid

dispersion was then utilized for the preparation of sublingual tablet by

direct compression utilizing different superdisintegrant like Cross

carmelose sodium, Crosspovidone, Kyron T-314 and Sodium starch

glycolate. Prepared tablets were evaluated for weight variation, thickness, friability, content

uniformity, hardness, disintegration time, wetting time and in-vitro drug release. Stability

study of optimized formulation was performed as per ICH guideline. Result: The optimized

formulation (batch F3) containing Drug-Poloxamer-407 (1:6) complex and Kyron-T314(5%)

showed greater drug dissolution (87% in 15 min) and satisfactory in vitro disintegration time

(22 sec). Stability study of optimized formulation showed that optimized formulation was

stable at accelerated environment condition. Conclusion: Felodipine sublingual tablet were

prepared successfully by the use of solid dispersion of Felodipine-poloxamer 407 (1:6)

complex using Kyron-T314 as a superdisintegrant.Thus, sublingual tablet of Felodipine could

be an alternative route to avoid gastrointestinal side effect as well as bypass hepatic first pass

metabolism. The formulated sublingual tablets may act as a potential alternate for the

Felodipine oral tablet.

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Article Received on 25 March 2014, Revised on 15 April 2014, Accepted on 07May 2014

*Correspondence for Author

Bhavik N. Patel

Department of Pharmaceutics

and Pharmaceutical

Technology, Shri Sarvajanik

Pharmacy College, Mehsana-

384001, Gujarat, India.


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Keywords: Felodipine, Solid Dispersion, Poloxamer-407, Sublingual Tablet, Hypertension

INTRODUCTION

The oral route of administration is considered as the most widely accepted route. The unique

environment of the oral cavity offers its potential as a site for drug delivery. Because rich

blood supply and direct access to systemic circulation, the oral mucosal route is suitable for

drugs, which are susceptible to acid hydrolysis in the stomach or which are extensively

metabolized in the liver. The continuous secretion of saliva results in rapid removal of

released drug and this may desire that the oral cavity be restricted to the delivery of drugs,

which have a short systemic circulation. Tablets that disintegrate or dissolve rapidly in the

patient’s mouth are convenient for young children, especially elderly and patients who are

unable to swallow, and in some cases where potable liquids are not available. The drug can

be easily disintegrate in the presence of small volume of saliva in oral cavity. Then the

medication can be absorbed partially or entirely into the systemic circulation from blood

vessels in the sublingual mucosa, or it can be swallowed as a solution to be absorbed from

gastrointestinal tract. The sublingual route usually produces a faster onset of action than

orally administered tablets and the amount absorbed through sublingual blood vessels bypass

the hepatic first- pass metabolic processes[1-3]

Felodipine is a calcium-channel blocker used in the treatment of hypertension and angina

pectoris. Being a dihydropyridine derivative Felodipine has the advantage of being more

selective as vasodilator and having less cardiac effects than non-dihydropyridine calcium

antagonists. This benefit is abolished by the poor bioavailability of the drug, which– although

being almost completely absorbed from the gastrointestinal tract-is only 15% bioavailable

after oral administration.[4-5]

The poor oral bioavailability of Felodipine was attributable to its extensive first-pass

metabolism and the very low water solubility of the drug. The aqueous solubility of a given

drug is a very critical factor affecting drug efficacy and safety as it affects the drug

dissolution parameters and the oral bioavailability. The efficacy of a drug can be severely

limited by its poor aqueous solubility. Moreover, for poorly soluble drugs, the dissolution

step may be the rate-limiting process for drug absorption. In addition, the poor aqueous

solubility and wettability of the drug adds to the difficulties encountered in drug formulation.

As a result, many attempts have been made to improve the aqueous solubility of insoluble

drugs in order to increase drug efficacy and/or reduce side effects.[6]


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MATERIALS AND METHODS

Felodipine was purchased from Torrent Pharmaceuticals Limited, Gujarat, India.Sodium

Starch Glycolate (SSG), Crospovidone, Microcrystalline Cellulose (MCC) were procured

from Yarrow Chem. Products, Mumbai, India. Kyron-314 was received as a gift sample from

Corel pharma, Ahmedabad, India. Poloxamer 407 was purchased from BASF chemical

company, Germany. Polyethylene Glycol 6000was purchased from S. D. Fine Chemical

Limited, Mumbai, India. All other materials used were of pharmaceutical or analytical grade.

Drug-Excipients Compatibility Study

The drug-excipient compatibility study was carried out by using Fourier Transform Infrared

(FTIR) spectroscopy. FTIR study was conducted using KBr powder mixing method on FTIR

spectrophotometer (FTIR-1700, Shimadzu, Kyoto, Japan) and the spectrums were recorded in

the wavelength region of 4000 - 400 cm-1.

Preparation of solid dispersion[7]

Solid dispersions were prepared by solvent wettingmethod using different ratio (1:2, 1:4, 1:6,

and 1:8) of drug with solubility enhancing agent like poloxamer-407, PVP k-30, Beta-

cyclodextrinand PEG-6000. Felodipine, dissolved in an appropriate amount of ethanol. After

complete dissolution of Felodipine, solutions were dropped onto polymeric carriers. Solvents

were removed under vacuum at room temperature. The solid dispersions obtained were

ground in a mortar and passed through sieve no.60.

Phase solubility study[8]

The excess amount of drug or solid dispersion was added to conical flasks containing 10 ml

of phosphate buffer 6.8 pH and subjected to shaking on a rotary shaker for 48 hours at 37°C.

Then the flasks were removed and content was filtered by 0.45µm membrane filter paper and

filtrate was analyzed for the drug content after appropriate dilution with phosphate buffer 6.8

pH and compared with pure drug solubility.

Differential scanning calorimetry (DSC) of solid dispersion

The thermogram of solid dispersion was obtained by differential scanning calorimeter (DSC),

on Shimadzu TA-60 model. Sample holder: DSC aluminum cell. Amount of sample taken: 5-

8 mg. Temp. Rangestudied: 30°C to 300°C. Nitrogen flow rate: 40-50 ml /min. Reference

sample: Blank DSC aluminum cell.


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Preparation of sublingual tablets by direct compression method[9]

All the ingredients were passed through # 80-mesh separately. Then the ingredients were

weighed and mixed in geometrical order and compressed into tablets of 120mg by direct

compression method using 6 mm flat punches on a Rotary Tablet Compression Machine. For

optimization of super disintegrant different types of disintegrants were selected like sodium

starch glycolate, crospovidone, crosscarmalose sodium and kyron T-314 in concentration 3%.

Composition of batches A1 to A4 shown in Table 01.

Table 01: Composition of batches A1 to A4

Ingredient Quantity per tablet (mg) A1 A2 A3 A4

Drug+ poloxamer407 35 35 35 35 Cross carmelose sodium 3.6 - - - Cross povidone - 3.6 - - Kyron-T314 - - 3.6 - Sodium starch glycolate - - - 3.6 Microcrystalline cellulose 53.8 53.8 53.8 53.8 Mannitol 24 24 24 24 Talc 2.4 2.4 2.4 2.4 Aerosil 1.2 1.2 1.2 1.2 Total weight 120

Evaluation of tablets

Hardness [10]

The test was done as per the standard methods. The hardness of three randomly

selectedtablets from each formulation (F1 to F15) was determined by placing each tablet

diagonallybetween the two plungers of tablet hardness tester (with the nozzle) and applying

pressureuntil the tablet broke down into two parts completely and the reading on the scale

was noteddown in Kg/cm2. The results are presented in Tables 04.

Thickness [10]

The thickness of three randomly selected tablets from each formulation was determined

inmm using a micrometre screw. The average values were calculated. The results

arepresented in Table 04.


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Weight variation[10]

Weight variation test was done as per standard procedure. Twenty tablets from each

formulationwere weighed using an electronic balance and the average weight was

calculated.The results are shown in Table 04.

Friability [10]

The friability of tablets using 10 tablets as a sample was measured using a Roche

Friabilator.Tablets were rotated at 25 rpm for 4 minutes or up to 100 revolutions. The tablets

were takenout, deducted and reweighted. The percentage friability was calculated from the

loss inweight as given in equation below. The weight loss should not more than 1%.The

results areshown in Table 04.

%Friability = (initial weight – final weight) x 100 (initial weight)

Drug Content [10]

Ten randomly selected tablets from each formulation were finely powdered andpowder

equivalent to 5mg of Felodipine was accurately weighed andtransferred to 100 ml volumetric

flasks containing 50 ml of methanol. Theflasks were shaken to mix the contents thoroughly.

The volume was made up to the markwith methanol and filtered. Two ml of the filtrate was

suitably diluted andFelodipine content was estimated at 360 nm using a double beam UV-

visiblespectrophotometer. The results are presented in Tables 04.

Wetting Time [11]

The tablets wetting time was measured by a procedure modified from that reported by Bi etal.

The tablet was placed at the centre of two layers of absorbent paper fitted into a dish. Afterthe

paper was thoroughly wetted with distilled water, excess water was completely drainedout of

the dish. The time required for the water to diffuse from the wetted absorbent

paperthroughout the entire tablet was then recorded using a stopwatch. The results are

presented inTable 04.

In- vitro Disintegration Time [11]

In- vitro Disintegration times for sublingual tablets were determined using USP

tabletdisintegration apparatus with phosphate buffer of pH 6.8 as medium. The volume of

mediumwas 900 ml and temp was 37± 2 °C. The time in seconds taken for complete

disintegration ofthe tablets with no palatable mass remaining in the apparatus was measured.

The results arepresented in Table 04.


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In- vitro drug release study [11]

In-vitro release rate of Felodipine sublingual tablets was carried out usingUnited State

Pharmacopoeia (USP) dissolution testing apparatus (Paddle method). Thedissolution test was

carried out using 900 ml of 6.8 pH phosphate buffer, at 37± 20‘C and 50rpm. A sample (5

ml) of the solution was withdrawn from the dissolution apparatus at 5, 10, 15, 20, 25 and 30

min. The samples were replaced with fresh dissolution medium of samequantity. The samples

were filtered through whatman filter paper No 40 and analysed forFelodipineafter appropriate

dilution by UV spectrophotometer at 364 nm. Thepercentage drug release was calculated

using an equation obtained from the calibration curve.The results are presented in Fig 07.

Selection of concentration of super disintegrant in tablet formulation

Sublingual tablets of Felodipine were prepared by direct compression. All the ingredients

were passed through # 80-mesh separately. Then the ingredients were weighed and mixed in

geometrical order and compressed into tablets of 120mg by direct compression method using

6 mm flat punches on a Rotary Tablet Compression Machine (Rimek 10 station minipress).

For selection of concentration of super disintegrantkyron T-314 in 3%, 4% and 5% were

taken. Composition of batches F1 to F3 shown in Table 02

Table 02: Formula for different concentration of superdisintegrant

Ingredient Quantity per tablet (mg)

F1 F2 F3 Drug+ poloxamer407 35 35 35 Kyron-T314 (3%) 3.6 Kyron-T314 (4%) 4.8 Kyron-T314 (5%) 6 Microcrystalline cellulose 53.8 52.6 51.4 Mannitol 24 24 24 Talc 2.4 2.4 2.4 Aerosil 1.2 1.2 1.2 Total weight 120

Stability studies of the optimized formulation

Stability testing of drug products begins as a part of drug discovery and ends with the demise

of the compound or commercial product. To assess the drug and formulation stability,

stability studies were done according to ICH guidelines Q1C. The stability studies were

carried out on the optimized formulations as per ICH guidelines Q1C. The optimized


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formulation sealed in aluminum packaging and kept in humidity chamber maintained 40 ± 2

°C / 75 ± 5 % RH for 1 month. The optimized formulation sealed in aluminum foil was also

kept at room temperature and humidity condition. At the end of studies, samples were

analyzed for the % drug release and drug content.

RESULT AND DISCUSSION

Drug-excipientscompatibility study

The FTIR spectra of Felodipine showed a characteristic peaks of Felodipine appeared at 3355

cm-1(N-H stretching), 800 cm-1 (C-Cl stretching), 1500–1415 cm-1 (skeleton vibration of

aromatic C=C ring stretching), 1000-1300 cm-1 (C-O stretching).

The incompatibility between the Drug and Excipients were studied by FTIR

spectroscopy.The spectral data of pure drug and drug-excipient mixtures are presented in

‘Fig.01-02’.The results indicate that there was no chemical incompatibility between drug and

excipients used in formulation.

Figure 01: FTIR spectra of Felodipine

Figure 02: FTIR spectra of Felodipine + Excipients


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Phase solubility study

Phase solubility study of Felodipine was conducted in phosphate buffer (pH 6.8) and the

result of phase solubility study are given in Table 03. The solubility of pure drug was only

19.17µg/mL.Solubility of Felodipine in phosphate buffer (pH 6.8): 20.56 µg/mL.The

solubility of Felodipine-poloxamer 407 (1:6) and Felodipine-poloxamer 407 (1:8) complex

was 410.58µg/mL and 429.41 µg/mL respectively. Above both complex there is no much

more difference in solubility so Felodipine-poloxamer-407 (1:6) was optimized.

Table 03: Solubility study of drug-carrier complex

Drug-Carrier

Complex

Method Poloxamer 407

PVP K-30

PEG 6000 Betacyclodextrin

Solubility(µg/ml) 1:2 PM 27.05 7.05 10.58 9.41

1:4 PM 103.52 9.41 12.94 14.11

1:6 PM 212.94 12.94 11.76 16.47

1:8 PM 321.17 10.58 8.23 17.64

1:2 SD 52.94 34.11 25.88 21.17

1:4 SD 195.29 47.05 42.35 24.70

1:6 SD 410.58 32.94 63.52 25.88

1:8 SD 429.41 36.47 56.47 27.05

Figure 03: Comparison of solubility study

DSC of solid dispersion

The DSC thermogram of felodipine is shown in figure 05 exhibited an sharp

endothermicpeak at 151.37°C, corresponding to its melting point, whereas nosuch peak was


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observed in solid dispersion particles prepared with poloxamer-407, suggesting thatfelodipine

was molecularly dispersed and in an amorphous form. From the aboveobservation it may be

suggested that the physical state of felodipine changed from crystallineto amorphous during

the solvent evaporation process. It has been known that transforming thephysical state of the

drug to the amorphous or partially amorphous state lead to a high energystate and high

disorder, resulting in enhanced solubility and faster dissolution.

Figure 04: DSCof Poloxamer 407

Figure 05: DSCof Felodipine


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Figure 06:DSCof Poloxamer+Felodipine SD

Table 04: Evaluation of Tablet (batch A1 to A4)

Parameter Batch (direct compression) A1 A2 A3 A4

Hardness (Kg/cm2) 3.46±0.11 3.66±0.11 3.40±0.20 3.53±0.11 Wetting time (Sec) 58.90±1.61 54.26±1.11 43.64±0.59 67.42±1.06 Disintegration time (Sec) 45.48±1.20 43.06±1.08 33.59±1.72 55.66±1.52 Assay(%) 101.20 99.80 100.74 99.66 % friability 0.23 0.20 0.29 0.27 Thickness 3.25±0.026 3.26±0.015 3.27±0.01 3.25±0.011 Weight variation 120.14±1.67 119.32±1.92 119.45±1.76 120.17±1.43

All values are mean ± S.D

The parameters of all formulations A1-A4 was found to be satisfactory and all were

withinpharmacopeias limits. The Hardness for all formulations found to be 3.40±0.20kg/cm2

to3.66±0.11kg/cm2. The Thickness of tablet was found to be between 3.25±0.011mm

to3.27±0.01mm.The Friability was found to be 0.20% to 0.29%.The Weightvariation was

found to between 119.32±1.92 % to 120.17±1.43 %. Assay values of the formulationswere

observed in the range of 99% to 101%.The results are shown in Table 04.

The wetting time which is the important criteria for determiningthe capacity of disintegrates

to swell in presence of little water. By using differentsuperdisintegrant the wetting time in the

formulations A1 to A4were found to be in the range of 43.64±0.59sec to 67.42±1.06sec. The

results are shown in Table 04. The best result has been shown by batch A3tablets, it showed

wetting time was 43.64±0.59sec. Thus the results indicated that the preparation was

minimum wetting time, so it will take less time for disintegrating.


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The disintegration time of sublingual tablets should be less because in a very short time

itshould be totally disintegrates. By using different superdisintegrant, disintegration time in

theformulations A1 to A4 were found to be in the range of 33.59±1.72sec to 55.66±1.52sec.

Theresults are shown in Table 04.The best result has been shown by batch A3 tablets, it

showedthe disintegration time was 33.59±1.72 seconds.So, kyron T-314 selected for further

study.

Table05: Cumulative percentage release(A1 to A4)

Time (min) A1 A2 A3 A4

0 0 0 0 0

5 38.1 39.63 42.37 35.42

10 55.19 58.91 61.18 51.82

15 71.23 77.64 80.64 69.09

20 85.74 89.32 94.75 81.48

25 92.82 96.31 98.82 90.33

30 97.78 98.04 99.64 95.98

Figure 07: Cumulative percentage release

All the batches contain 3% super disintegrant. Among all batches, batch A3 showed highest

drug release as compared to other batches. Batch A3 showed above 90% drug release in 20

min. So, kyron T-314 selected for further study.


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Selection of concentration of super disintegrant

Table 06: Evaluation of batch F1 to F3

Parameter F1 F2 F3 Hardness(Kg/cm2) 3.60±0.20 3.87±0.23 3.93±0.115 Wetting time(Sec) 40.56±1.08 34.79±0.52 32.43±0.67 Disintegration time (Sec) 32.62±0.43 26.94±0.59 22.86±0.79 Assay (%) 100.22 99.56 99.87 % friability 0.31 0.29 0.25 Thickness 3.26±0.015 3.27±0.020 3.25±0.011 Weight variation 120.27±1.89 119.33±1.75 120.54±1.57

All values are mean ± S.D The optimization of super disintegrant was done based on the evaluation parameterslike

hardness, disintegration time, wetting time, % friability and % assay. Batch F3 contain kyron

T-314 (5%) shown minimum disintegration time and wetting timeamong all

tabletformulation.

Table 07: Cumulative percentage release for batch F1 to F3

Time(min) F1 F2 F3 0 0 0 0 5 41.12 43.12 46.59

10 61.64 64.75 67.32 15 79.88 83.47 87.48 20 93.56 94.53 96.83 25 97.91 98.19 99.14 30 99.45 99.89 99.91

Figure 08: Cumulative percentage release for batch F1 to F3


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Batch F1, F2 and F3 contain 3%, 4% and 5% super disintegrant respectively. Among all

batches, batch F3 showed highest drug release as compared to other batches. Batch F3

showed above 87.48% drug release in 15 min. So, formulation F3 was optimized.

STABILITY STUDIES OF THE OPTIMIZED FORMULATION

The stability studies were carried out on the most satisfactory formulations (Batch F3) as per

ICH guidelines Q1C. At the end of studies, samples were analyzed for the weight variation,

thickness, friability, hardness, wetting time, Disintegration time, drug content and in vitro

dissolution. The optimized formulations stored at 40 ± 2 °C / 75 ± 5 % were found stable.

After storage at 40 ± 2 °C / 75 ± 5 %, no shape deformation in the tablets was found. Assay

of drug as well as cumulative percentage drug release was nearly similar before and after

storage. (Figure 09) So, it was clear that drug was thermally stable as well as not affected by

high humidity at 40 ± 2 °C / 75 ± 5 %.

Table 08: Evaluation data after stability study of optimized batch (F3)

Parameter F3 weight variation (mg) 119.62±1.46 Thickness 3.25±0.015 Diameter 6.14±0.010 Friability 0.27 Hardness 4.20±0.43 Wetting time (Sec) 35.56±1.52 Disintegration time (Sec) 24.66±0.57 Assay 99.83

All values are mean ± S.D

Table 09: In-vitro drug release studies after stability study

Time (min)

CPR (Initial)

CPR (After storage at

40 ± 2 °C / 75 ± 5 %) 0 0 0 5 46.59 45.66

10 67.32 68.12 15 87.48 86.30 20 96.83 97.74 25 99.14 99.06 30 99.91 99.67


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Figure 09: Plot of In-vitro drug release studies after stability study

CONCLUSION

From this research study, it was concluded that development of Sublingual tablet of

Felodipine is one of the alternatives routes of administration to avoid gastrointestinal side

effects andfirst pass metabolism. In addition, solubility of Felodipine successfully enhanced

by poloxamer-407. It was also concluded that there was no physical and chemicalinteraction

between drug and excipients. The prepared formulation is stable at40 ± 2 °C / 75 ± 5 % for 1

month.

ACKNOWLEDGEMENTS

Authors are very much thankful to Principal of Shri Sarvajanik Pharmacy College, Mehsana

for extending laboratory and instrumental facilities to carry out the work. Authors are also

thankful to Corel pharma for providing Kyron-314.

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