DESIGN and IN-VITRO EVALUATION of FAST DISINTEGRATING TABLETS of FLUPIRTINE Sridhar Rao

Sridhar Rao. K*et al. /International Journal of Pharmacy & Technology

ISSN: 0975-766X CODEN: IJPTFI Available Online through Research Article www.ijptonline.com DESIGN AND IN-VITRO EVALUATION OF FAST DISINTEGRATING TABLETS OF FLUPIRTINE Sridhar Rao. K*1, Sreekanth. J2 1Department of Pharmaceutics, Trinity College of Pharmaceutical Sciences, Peddapalli, Karimnagar, Telangana- 505172. 2Director of Research and Development, Progenerics Pharma Pvt. Ltd., Sanathnagar, Hyderabad, Telangana-500018. Email id: [email protected] Received on: 05-03-2017 Accepted on: 08-04-2017

Abstract

Aim:

The main objective of this study was to formulate and evaluate fast disintegrating tablets of Flupirtine (FFDT’s) prepared by direct compression method using super-disintegrants as well as subliming agents with a view to enhance patient compliance.

Materials:

Flupiritine (Perkin pharmaceutical Pvt Ltd, Mumbai), Low-substituted hydroxypropyl cellulose (L-HPC-12), Locust

Bean Gum used as super disintegrates, Camphor and Menthol used as subliming agents, Microcrystalline cellulose (PH-

102) and Sodium xylitol as diluents (DR.Reddy’s Laboratories Hyderabad), Sod. Saccharine and Rasberry Flavor as sweeting agent (SD Fine Chemicals Pvt Ltd, Mumbai), Colloidal silicon di oxide (Aurobindo Pharmaceuticals,

Hyderabad) and Magnesium stearate (Qualikems Fine Chem Pvt. Ltd, Vadodara) as lubricating agents. All the above following materials were either AR/LR grade were used in the above work and which were supplied from the manufacturer.

Results:

Flupirtine is the prototype of a new class of drug and it is selective neuronal potassium channel opener (SNEPCO) which is used as an analgesic for acute and chronic pain, in moderate to severe cases. The main objective of this study was to formulate and evaluate fast disintegrating tablets of Flupirtine (FFDT’s) prepared by direct compression method using super-disintegrants as well as subliming agents with a view to enhance patient compliance. Two different super- disintegrants, such as L-HPC and Locust Bean gum were selected in different ratio (2 and 4 % w/w) and in order to

IJPT| April-2017| Vol. 9 | Issue No.1 | 29307-29319 Page 29307 Sridhar Rao. K*et al. /International Journal of Pharmacy & Technology ensure the disintegrating effect by choosing the different concentrations of subliming agents such as camphor and menthol with alone, as well as combination. FTIR study reveals that there was no drug-excipients interaction between

Flupirtine and used excipients. There after all pre & post compressional studies were evaluated including In-vitro dissolution studies. It was observed that the formulation F10 with 4% of L-HPC having an equal concentration (5% w/w each) of camphor and menthol showed satisfactory results with disintegration time of 30±1.04 seconds, wetting time of

25±1.91 seconds, water absorption ratio 58±1.07 seconds and with highest dissolution rate of 94.68±0.62% in 30 min.

From the above results, it was concluded that a combined equal portions of camphor and menthol has shown faster disintegration and dissolution effect on formulation (F10) having super disintegrant of L-HPC with 4% (w/w) concentration.

Conclusion:

The main objective of present work was to design and In-vitro evaluation of FFDT’s by selecting the super disintegrates such as L-HPC and Locust bean gum along with both subliming agents such as camphor and menthol. By choosing these components F1-12 formulations were fabricated with changing their concentration as alone and combination of both.

Then all the pre & post compressional parameters were carried out including In-vitro dissolution studies to determine the fastest drug release from the dosage forms. Based on these results, F10 formulation was released 94.68±0.62 percentage within 30 minutes compared to all the above formulations so it was confirmed as an optimized formulation.

Key words: Flupirtine, L-HPC-12, Locust Bean Gum, Sod. Xylitol, MCC (PH102), Camphor and Menthol.

Introduction:

Most of pharmaceutical solid dosage forms are fabricated for direct ingestion, chewing, prior dispersion and/or dissolution in water; few of dosage forms are absorbed in the mouth. In past decades patients have difficulty in swallowing when prescribed in conventional tablet and capsule forms [1-3]. The problem of swallowing is also evident in pediatrics, psychiatric as well as traveling patients who may not have ready access to water [4]. The rapidly disintegrating tablet in the mouth or orodispersible tablets overcome all the above problems and thus offer an alternate form of oral medication, which provide patients with a more convenient means of administration of their medication [5].

Addition of super disintegrating agent in the formulation is one of the approaches to formulate oro dispersible tablets [6-

7]. Orally disintegrating tablets (ODTs) rapidly disintegrate in the mouth without chewing on oral administration and

IJPT| April-2017| Vol. 9 | Issue No.1 | 29307-29319 Page 29308 Sridhar Rao. K*et al. /International Journal of Pharmacy & Technology without the need for water, unlike other drug delivery systems, and conventional oral solid immediate-release dosage form. ODT dosage forms, also commonly known as fast melt, quick melts, fast disintegrating and orodispersible systems have the unique property of disintegrating the tablet in the mouth in seconds. The desired criteria for the FDT is to have a pleasant mouth feel, leave minimal or no residue in the mouth after oral administration and not require water to swallow, but it should dissolve or disintegrate in the mouth in a matter of seconds [8, 9]. Most commonly used methods to prepare these tablets are; freeze-drying / Lyophilization [10], tablet molding [11] and direct compression methods [12].

Lyophilized tablets show a very porous structure, which causes quick penetration of saliva into the pores when placed in the oral cavity. Molded tablets dissolve completely and rapidly. However, lack of strength and taste masking are of great concern. Main advantages of direct compression are low manufacturing cost and high mechanical integrity of the tablets

[13].

Therefore, direct compression appears to be a better option for manufacturing of tablets. The key to the rapid disintegration of fast dissolving tablets (FDT) is the preparation of a porous structure in the tablet matrix. To generate such a porous matrix, volatile ingredients are incorporated in the formulation that is later subjected to a process of sublimation. Highly volatile ingredients such as camphor, menthol, and urea may be compressed along with other excipients into a tablet. This volatile material is then removed by sublimation leaving behind a highly porous matrix. In present research work, an attempt has been made to prepare FDT of Flupirtine by using direct compression technique.

Flupirtine is a novel, centrally acting, non-opioid and non NSAID analgesic agent, and is devoid of common adverse effects seen with NSAIDs and opioids. Chemically it was an aminopyridine whose systematic (IUPAC) name is ethyl

{2-amino-6-[(4-fluorobenzyl) amino] pyridin-3-yl} carbamate. Its Formula is C15H17FN4O2 and molecular mass of

304.32 g/mol. In addition to analgesic action, it has also muscle relaxant, antioxidant, neuroprotective and antiparkinsonian effects.

Methodology:

Estimation of Flupirtine by spectrophotometric method: Take and dissolve required quantity of Flupirtine in equal volume of solution (pH 6.8 buffer). From which, subsequent dilutions were prepared to get 2, 4, 6, 8, 10 & 12 mcg/ml concentrations of Flupirtine solution. Thereafter the absorbance was recorded by using UV-visible spectrophotometer at

246 nm.

IJPT| April-2017| Vol. 9 | Issue No.1 | 29307-29319 Page 29309 Sridhar Rao. K*et al. /International Journal of Pharmacy & Technology Drug - Excipient compatibility: These studies were performed by preparing powder blend containing different ratios of excipients with drug by FTIR spectrometer, which is most powerful technique to identify functional groups of the drug in order to ensure suitable chemically compatible excipients. Hence in this present study potassium bromide disc (pellet) method was employed for recording the spectra from 4000 - 400cm-1.

Evaluation of powder blend:

Organoleptic properties:

A small amount of Flupirtine powder was taken on a butter paper and viewed in illuminated place to observe the color, as well as smelled to get odor and tasted with the help of tongue. Shown in table: 01

Table-01: Results of organoleptic properties.

Properties Results

Description crystalline powder

Colour White in color

Taste and odor Bitter and odorless

Bulk density (Db): Take required quantity of powder and carefully poured in to a graduated cylinder, which was previously passed through sieve # 40. Then pour the powder and note down the bulk volume which was produced from the cylinder and the bulk density is calculated by following formula; Bulk density = Weight of powder / Bulk volume

Tapped density (Dt): Tapped volume was noted by tapping the powder for 100 tappings for each time. If two volumes difference was more than 2%, tapping was continued until the successive volumes are less than 2 % in a bulk density apparatus. It was calculated by the following formula; Tapped density = Weight of powder / Tapped volume.

Angle of repose: It is maximum possible angle between the horizontal plane and powder surface. These resistance forces of free powder can be measured by the angle of repose (θ). It was determined by a formula: tan (θ) = h / r

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

Hausner’s ratio = Tapped density / Bulk density.

Compressibility index: The compressibility index (Carr’s Index) was determined by using following equation;

Carr’s Index (%) = [(Dt – Db) × 100] / Dt. where Dt: Tapped density of powder, Db: Bulk density of powder.

IJPT| April-2017| Vol. 9 | Issue No.1 | 29307-29319 Page 29310 Sridhar Rao. K*et al. /International Journal of Pharmacy & Technology Formulation of Flupirtine Fast disintegrating Tablets (FFDT’s)

Direct compression method: It is one of the most convenient methods to fabricate Flupirtine Fast Disintegrating

Tablets. In these formulations of Flupirtine FDTs, two super disintegrates, L-HPC, Locust Bean gum were selected and maintained 2 and 4 percentage in all formulations(shown in table 02). Take required quantities of Flupirtine, super disintegrating agents L-HPC, Locust Bean gum were mixed and passed thorough sieve no 60. Then add powdered camphor, menthol, sodium saccharine and flavoring agent to above mixture. Finally magnesium stearate and talc were added as lubricating agents and glidants. Then the powder mixture was subjected to allow for compression in an electrically driven Tablet punching machine (Rimek, Mumbai) using 8 mm punch to obtain tablets.

Table-02: Flupirtine Fast Dissolving Tablets by Direct compression (F1-F12).

Ingredients F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 F12

Flupirtine 100 100 100 100 100 100 100 100 100 100 100 100

Sod. Xylitol 59.75 47 59.75 47 59.75 47 59.75 47 59.75 47 59.75 47

MCC pH102 50 50 50 50 50 50 50 50 50 50 50 50

L-HPC 5 10 * * 5 10 * * 5 10 * *

Locust Bean * * 5 10 * * 5 10 * * 5 10

Gum

Camphor 25 25 25 25 * * * * 12.5 12.5 12.5 12.5

Menthol * * * * 25 25 25 25 12.5 12.5 12.5 12.5

Sod. Saccharine 2.5 5 2.5 5 2.5 5 2.5 5 2.5 5 2.5 5

Rasberry Flavor 0.25 0.5 0.25 0.5 0.25 0.5 0.25 0.5 0.25 0.5 0.25 0.5

Colloidal 5 10 5 10 5 10 5 10 5 10 5 10

Silicon dioxide

Magnesium 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5

Stearate

Total Weight 250 250 250 250 250 250 250 250 250 250 250 250

IJPT| April-2017| Vol. 9 | Issue No.1 | 29307-29319 Page 29311 Sridhar Rao. K*et al. /International Journal of Pharmacy & Technology Evaluation of Flupirtine Fast Disintegrating Tablets (FFDT’s)

Tablet thickness: Tablets dimension was calculated by using a calibrated vernier caliper. For this, randomly picked out five tablets from each formulation and thickness was measured.

Tablet hardness: For each formulation, the hardness of 6 tablets was determined by using the Monsanto hardness tester

(Cadmach, Ahmadabad, India).

Friability test: The friability test was performed using the Roche friabilator (Campbell Electronics, Mumbai, India).

Twenty tablets were selected and tested at a time. After 100 turns, the tablets were evaluated by weighing.

Weight variation test: Ten tablets were randomly selected from each batch and weighed on an electronic balance and mean weight was taken. Each tablet was then weighed individually and standard deviation in weight was calculated for each batch (as per IP).

Wetting time and water absorption ratio:

A piece of tissue paper folded twice was placed in a small petridish containing 10 ml of water. A tablet was placed on the paper, and the time for complete wetting was measured. The wetted tablet was again weighed. Water absorption ratio, R, was calculated using the formula; R = 100(Wa-Wb) Wb. Where, Wa and Wb are the weight after and before water absorption, respectively.

Disintegration time: It was performed by using modified disintegration apparatus. First place the tablet in a beaker containing 900 ml of 0.1 N Hcl medium and basket was positioned in a beaker. The beaker was placed at 37±2°C temperature. Then the time required for the tablet to disintegrate completely was noted.

In-vitro Dissolution studies: The percentage dug release was estimated by using USP apparatus II rotating paddle

(Electrolab TDT-08L, India). It was carried out in 900 ml of 0.1 N HCl as a medium. The paddle was rotated at 75 rpm at 37 ± 0.5 ºC. Aliquots of 5 ml were withdrawn and replaced with equal volumes of fresh dissolution medium at specified time intervals ( 5, 10, 15, 20, 25 and 30 min). Then samples were adequately diluted, filtered through a 0.22µm filter and analyzed photometrically at 246 nm (Systronics UV–Vis spectrophotometer 2202-India). The experiments were done in triplicates (n=3) for each of the selected formulation.

Stability studies: Stability study was done for the optimized formulation for a period of three months at 40±2oC, 70±5%

RH to provide evidence on how the quality of a drug substance varies with time under the influence of a variety of

IJPT| April-2017| Vol. 9 | Issue No.1 | 29307-29319 Page 29312 Sridhar Rao. K*et al. /International Journal of Pharmacy & Technology environmental factors such as temperature and humidity enables recommended storage conditions, re-test periods and shelf-lives to be established.

Results and Discussion:

Flupirtine works as an analgesic for various types of acute and chronic pain like headache, trauma, migraine and gynecology. Due to its muscle relaxant properties it is widely used for backache and other orthopedic pain. In this condition, patients require immediate response in order to minimize their clinical illness. Hence in the present research work, several attempts have been made to prepare FDT of Flupirtine (F1-F12) choosing with few super disintegrating agents (L-HPC, Locust Beam Gum) and subliming agents such as (Camphor and Menthol) using direct compression technique. From the above discussion, Flupirtine standard calibration curve was plotted by considering parameters between the concentration and absorbance. The results were producing a straight fitting line having regression (r2) value was found to be 0.998 (Figure: 01). IR spectra for Flupirtine pure drug and powder excipients were recorded with KBr pellets (Figure: 02). According to the IR studies, Flupirtine amine (NH) stretching was found at 3000.14cm-1, aromatic

(CH) stretching was obtained at 2965.98 cm-1, carbonyl (C=O) stretching was existed at 1651.73 cm-1 and finally aromatic (C=C) stretching was at 1576.52 cm-1. The obtained all characteristic functional group peaks were observed in figure: 03. So it has indicated that there was no incompatibility reactions found between the drug and excipients used in the formulations.

Figure: 01 Standard graph for Flupirtine

1 0.9 y = 0.085x + 0.006 0.8 R² = 0.999 0.7 0.6 0.5 0.4 Absorbance 0.3 Ряд1 0.2 0.1 0 0 5 10 15 Concentation (mcg/ml)

IJPT| April-2017| Vol. 9 | Issue No.1 | 29307-29319 Page 29313 Sridhar Rao. K*et al. /International Journal of Pharmacy & Technology Figure: 02 FTIR spectrum of pure Flupirtine.

Figure: 03 FTIR spectrum of pure Flupirtine with excipients.

The prepared Flupirtine fast disintegrating Tablets (FFDT’s) tablets were determined for various physical properties

(Table 03). The bulk densities for the powder blend of FFDT’s tablets of various formulations (F1-F12) ranged between

0.373±0.10gm/ml and 0.495±0.09gm/ml; and tapped density ranged between 0.40±0.01gm/ml and 0.57±0.11gm/ml as determined by the tap densitometer. These values of bulk density indicated good packing characteristics. The Carr’s index (CI) for all the formulations was ranged from 11.45±0.02 to 14.27±0.06, indicating desirable flow properties. The value of Hausner’s ratio was ranged from 1.09±0.01 to 1.17±0.01. The flow properties of powder blends were further analyzed by determining the angle of repose for all formulations and were ranged between 23.98±0.14 and 32.13±0.01.

The values indicated satisfactory flow behavior.

IJPT| April-2017| Vol. 9 | Issue No.1 | 29307-29319 Page 29314 Sridhar Rao. K*et al. /International Journal of Pharmacy & Technology Table-03: Evaluation of Pre compressional parameters of FFDT’s.

Formulation Bulk density Tapped density Angle of Hausner’s CI

(gm/ml) (gm/ml) repose (θ) ratio

F1 0.395±0.01 0.56±0.05 27.23±0.02 1.10±0.01 13.92±0.08

F2 0.489±0.02 0.45±0.03 25.51±0.07 1.11±0.04 11.58±0.03

F3 0.390±0.02 0.50±0.04 27.12±0.01 1.16±0.04 12.34±0.04

F4 0.410±0.05 0.45±0.06 25.34±0.09 1.09±0.01 13.85±001

F5 0.495±0.09 0.57±0.11 32.13±0.01 1.17±0.01 14.27±0.06

F6 0.389±0.11 0.40±0.08 29.23±0.05 1.12±0.05 11.59±0.07

F7 0.391±0.07 0.42±0.12 26.48±0.03 1.12±0.09 14.22±0.03

F8 0.373±0.10 0.40±0.01 23.81±0.04 1.15±0.01 12.26±0.01

F9 0.494±0.06 0.40±0.03 24.13±0.07 1.13±0.02 11.45±0.02

F10 0.383±0.17 0.47±0.12 23.98±0.14 1.13±0.09 12.22±0.07

F11 0.392±0.09 0.52±0.12 26.81±0.09 1.14±0.04 13.16±0.08

F12 0.342±0.15 0.49±0.12 27.41±0.06 1.12±0.05 13.63±0.05

All the formulations (F1-F7) were produced under similar conditions to avoid processing variables. The weight variation, hardness, friability, thickness, wetting time and disintegration time of all formulations were found to be within acceptable limits as per official specifications. Weight of the optimized fast disintegrating tablet formulation (F10) was

250.1±18 mg, hardness was 3.05±0.246 kg/cm2 and thickness was 3.09±0.195 mm. The percentage friability of all the formulations was ranged from 0.37±0.047 to 0.58±0.052 which was less than 1% of their weight. The values of the hardness and percent friability indicated good handling properties of the prepared FFDT’s. The disintegration time was found to be between 30±1.04 to 95±1.05 seconds, wetting time as well as water absorption ratios were ranged between

25±1.91to 92±1.65 and 58±1.07 to 189±1.23 seconds. The obtained results were tabulated in Table: 04

IJPT| April-2017| Vol. 9 | Issue No.1 | 29307-29319 Page 29315 Sridhar Rao. K*et al. /International Journal of Pharmacy & Technology Table-04: Evaluation of Post compressional parameters of FFDT’s.

Formulation Thickness Hardness Friability Avg.wt Disintegration Wetting Water

(mm) (kg/cm2) (%) (mg) time (sec) time(sec) absorption

ratio (sec)

F1 3.51±0.221 3.14±0.205 0.55±0.031 250.6±15 60±1.05 58±1.15 115±1.12

F2 3.43±0.215 3.19±0.044 0.56±0.025 251.7±17 51±1.07 49±1.32 104±1.14

F3 3.81±0.163 3.17±0.265 0.46±0.032 244.3±16 72±1.02 70±1.21 140±1.15

F4 3.95±0.154 3.19±0.265 0.58±0.052 247.7± 31 80±1.00 78±1.14 157±1.21

F5 3.66±0.178 3.17±0.245 0.47±0.043 251.7±.10 89±1.08 84±1.36 178±1.34

F6 3.55±0.210 3.15±0.313 0.51±0.045 250. 3±01 83±1.04 80±1.57 165±1.04

F7 3.53±0.217 3.19±0.252 0.45±0.031 249.3±12 95±1.05 92±1.65 189±1.23

F8 3.81±0.243 3.08±0.223 0.37±0.047 251.9±1.9 92±1.08 90±1.83 182±1.09

F9 3.37±0.168 3.09±0.229 0.42±0.56 250.5±22 45±1.07 41±1.78 90±1.19

F10 3.09±0.195 3.05±0.246 0.47±0.052 250.1±18 30±1.04 25±1.91 58±1.07

F11 3.01±0.169 3.14±0.226 0.53±0.073 251.7±17 55±1.03 53±1.19 105±1.27

F12 3.08±0.208 3.25±0.249 0.48±0.014 244.6±36 52±1.07 49±1.53 104±1.42

In-vitro Dissolution profile:

In the present study Flupirtine fast dissolving Tablets (F1-F12) were formulated by using two different concentrations of super disintegrating agents (L-HPC and Locust bean gum) as well as two subliming agents (Camphor and Menthol).

There after all fabricated formulations were carried out for determining the percentage drug release followed by using

USP-II paddle type dissolution apparatus. From the formulations of F1-F4, F2 has shown greater percentage of drug release with 83.46±1.27 percentage in 30 minutes (figure: 4.0). Because the above formulation consisting the high amount of L-HPC with a very good subliming agent such as camphor. Camphor was responsible for the formation of porous structure on the surface of solid dosage form and was responsible for intake of more water with faster rate.

Finally this mechanism facilitated greater wicking action of L-HPC to bring about faster rate of disintegration.

IJPT| April-2017| Vol. 9 | Issue No.1 | 29307-29319 Page 29316 Sridhar Rao. K*et al. /International Journal of Pharmacy & Technology Figure: 4.0 In-vitro dissolution profile of FFDT’s from F1-F4

100

60 F1 F2 40 release(%) F3 F4

20 Cummulative Cummulative percentage drug 0 0 10 20 30 Time in minutes

In case of formulations F5-F8, which were designed by using same super disintegrates with small change of subliming agent such as menthol. From the prepared tablets F5 has shown 64.96±4.02 percentage, F6 was 70.5±1.86 percentage, F7 showed 70.6.5±1.59 percentage and finally F8 released a very least drug release with 68.5±1.35 percentage only in 30 minutes (figure: 4.1). It was due to the poor action of menthol which predominately suppressed the wicking action of poor super disintegrating agent of Locust bean gum compared to L-HPC.

Figure: 4.1 In-vitro dissolution profile of FFDT’s from F5-F8.

100

60 F5 F6 40 F7 F8 20

Cummulative Cummulative percentage drugrelease (%) 0 0 10 20 30 Time in minutes

Unlike the above formulations, F9-F12 FFDT’s were designed with equal amount of both subliming agents such as camphor and menthol with same super disintegrates. In which F10 has shown a greater significant percentage drug release with 94.68±0.62 percentage within 30 minutes, because of presence of both camphor and menthol in optimum

IJPT| April-2017| Vol. 9 | Issue No.1 | 29307-29319 Page 29317 Sridhar Rao. K*et al. /International Journal of Pharmacy & Technology concentrations, which had produced the synergetic effect to a super disintegrating agent L-HPC and was induced more amount of drug release from the dosage form (figure: 4.2).

Figure: 4.2 In-vitro dissolution profile of FFDT’s from F9-F12.

100

60 F9 F10 40

release (%) release F11

20 F12 Cummulative Cummulative percntage drug 0 0 10 20 30 Time in minutes

Stability studies:

The accelerated stability studies were carried out on the optimized formulation, i.e., F10. The formulation was stored at

40±2oC/75±5% RH for 3 months to assess their long term stability. After stability studies, all the post-compressional properties of FFDT’s were evaluated for various tests like thickness, friability, hardness, disintegration time and in vitro drug release study. The results were revealed that, there were no changes observed in tablets characteristics after three months of stability study.

Summary:

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