Scholarly article on topic 'Development and evaluation of gastroretentive floating tablets of an antidepressant drug by thermoplastic granulation technique'

Development and evaluation of gastroretentive floating tablets of an antidepressant drug by thermoplastic granulation technique Academic research paper on "Chemical sciences"

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{"Venlafaxine HCl" / Gastroretentive / "Carnauba wax" / Buoyancy / "Thermoplastic granulation"}

Abstract of research paper on Chemical sciences, author of scientific article — Harshal Ashok Pawar, Rachana Dhavale

Abstract The present study was undertaken with an aim to formulate, develop and evaluate gastroretentive floating tablets of an antidepressant drug, Venlafaxine HCl (hydrochloride), which release the drug in a sustained manner over a period of 24 h. Three different hydrophobic retardants namely hydrogenated cottonseed oil, carnauba wax, cetyl alcohol and a hydrophilic polymer Methocel® (hydroxy propyl methyl cellulose (HPMC)) K15M were used in different combinations at different ratios for the preparation of tablets. The tablets were prepared by Hot Melt or Thermoplastic granulation method and evaluated for tablet thickness, hardness, weight variation, friability, floating lag time and in vitro drug release. Formulation F8 with hydrophilic polymer (Methocel® K15M) and hydrophobic retardant (carnauba wax) in the ratio 1:2.6 (approx.) was considered as an optimized formulation. The optimized formulation showed satisfactory sustained drug release and remained buoyant on the surface of the medium for more than 24 h and its release profile was comparable with the marketed formulation (VENTAB-XL 37.5). It can also be concluded that floating drug delivery system of Venlafaxine HCl can be successfully formulated as an approach to increase gastric residence time and thereby improving its bioavailability.

Academic research paper on topic "Development and evaluation of gastroretentive floating tablets of an antidepressant drug by thermoplastic granulation technique"

Full Length Article

Development and evaluation of gastroretentive floating tablets of an antidepressant drug by thermoplastic granulation technique

Harshal Ashok Pawar*, Rachana Dhavale 1

Dr. L. H. Hiranandani College of Pharmacy, Smt. CHM Campus, Opp. Ulhasnagar Railway Station, Ulhasnagar 421003, Maharashtra, India



Article history:

Received 22 December 2013 Accepted 25 April 2014 Available online xxx

Keywords: Venlafaxine HCl Gastroretentive Carnauba wax Buoyancy

Thermoplastic granulation

The present study was undertaken with an aim to formulate, develop and evaluate gastroretentive floating tablets of an antidepressant drug, Venlafaxine HCl (hydrochlo-ride), which release the drug in a sustained manner over a period of 24 h. Three different hydrophobic retardants namely hydrogenated cottonseed oil, carnauba wax, cetyl alcohol and a hydrophilic polymer Methocel® (hydroxy propyl methyl cellulose (HPMC)) K15M were used in different combinations at different ratios for the preparation of tablets. The tablets were prepared by Hot Melt or Thermoplastic granulation method and evaluated for tablet thickness, hardness, weight variation, friability, floating lag time and in vitro drug release. Formulation F8 with hydrophilic polymer (Methocel® K15M) and hydrophobic retardant (carnauba wax) in the ratio 1:2.6 (approx.) was considered as an optimized formulation. The optimized formulation showed satisfactory sustained drug release and remained buoyant on the surface of the medium for more than 24 h and its release profile was comparable with the marketed formulation (VENTAB-XL 37.5). It can also be concluded that floating drug delivery system of Venlafaxine HCl can be successfully formulated as an approach to increase gastric residence time and thereby improving its bioavailability.

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* Corresponding author. Tel.: +91 8097148638.

E-mail addresses: (H.A. Pawar), (R. Dhavale). 1 Tel.: +91 9981892674. Peer review under the responsibility of Beni-Suef University

2314-8535/Copyright 2014, Beni-Suef University. Production and hosting by Elsevier B.V. All rights reserved.

1. Introduction

Oral sustained drug delivery system is complicated by limited gastric residence time. Rapid gastrointestinal transit can prevent complete drug release in the absorption zone and reduce the efficacy of administered dose, since the majority of drugs are absorbed in stomach or the upper part of small intestine (Choi et al., 2008; Mahant and Nasa, 2011). Floating drug delivery offers several applications for drugs having poor bioavailability because of the narrow absorption window in the upper part of the gastrointestinal tract. It retains the dosage form at the site of absorption and thus enhances the bioavailability (Kaza et al., 2009). Venlafaxine HCl is a unique antidepressant, and is referred to as a serotonin, norepinephrine-dopamine reuptake inhibitor (Keith, 2006). Venlafaxine HCl is a highly water soluble drug (Nidadavolu, 2014). Venlafaxine HCl and its active metabolite, o-des-methyl venlafaxine (ODV) inhibit the neuronal uptake of norepinephrine, serotonin and to a lesser extent dopamine (Ric et al., 1991). Hence it lacks the adverse anticholinergic, sedative and cardiovascular effects of tricyclic antidepres-sants (Simona and Aguiar, 2004) .The steady state half-lives of Venlafaxine HCl and ODV are 5 and 11 h, respectively, necessitating the administration 2 or 3 times daily so as to maintain adequate plasma levels of drug (Troy et al., 1995). The half-life of Venlafaxine HCl is relatively short, and, therefore, patients are directed to adhere to strict medication routine, avoiding missing a dose. Even a single missed dose can result in the withdrawal symptoms (Parker and Blennerhassett, 1998). In such case the formulation releasing the drug in sustained manner will aid the patient to adhere to strict medication routine by avoiding the need to take the dosage form 2 or 3 times daily. The use of sustained release formulation is associated with less nausea and dizziness (Olver et al., 2004).

The objective of the present research work was to provide gastroretentive formulation that will provide once-daily, sustained release dosage form. The swellable hydro-philic polymer Methocel® K15M (hydroxy propyl methyl cellulose) and hydrophobic retardants like hydrogenated cottonseed oil, carnauba wax and cetyl alcohol were tried at different ratios to prepare various formulations of Ven-lafaxine HCl.

2. Materials and methods

Venlafaxine hydrochloride was obtained as a gift sample from Amoli Organics Pvt. Ltd., Vadodara, India. Carnauba Wax, cetyl alcohol and Talc were procured from SD Fine Chemicals, Mumbai. Hydrogenated cottonseed oil was obtained as gift sample from Zhaveri Pvt. Ltd., Mumbai. Methocel® K15M (hydroxy propyl methyl cellulose) was obtained as gift sample from Colorcon Asia Pvt., Ltd. Goa, India. All other excipients and chemicals used were of analytical grade. VENTAB-XL 37.5 (Batch no. DN3651) was procured from the local market.

2.1. Drug—excipients interaction study and identification

2.1.1. Fourier transform infrared spectroscopy (FTIR)

An infrared spectrum of pure drug, mixture of drug with each retardant and physical mixture of optimized formulation was recorded using SHIMADZU FTIR Spectrophotometer. The scanning range was 500—4000 cm-1 and the IR spectra of samples were obtained using KBr disc method. Any change in spectrum pattern of drug due to presence of polymers was investigated to identify any chemical interaction.

2.1.2. Differential scanning calorimetry (DSC)

The possibility of drug—excipient interaction was further investigated by differential scanning calorimetry. DSC analysis was performed using SIECKO SII EXSTAR DSC 6220 Software on 10 mg sample. Samples were heated in aluminum pan at a rate of 10 0C/min. within a 30—305 °C temperature range under a nitrogen flow of 10 ml/min. Alumina was used as a reference.

2.1.3. UV spectroscopy (determination of l (lambda)max) The stock solution (1000 mg/ml) of Venlafaxine HCl was prepared in distilled water. This solution was appropriately diluted with distilled water to obtain a concentration of 3 mg/ ml. The UV spectrum was recorded in the range of 200—400 nm on Shimadzu double beam UV—visible spectro-photometer. The same procedure was carried out in 0.1 N HCl (hydrochloric acid, pH 1.2). The spectrum and wavelength of maximum absorption were recorded.

2.2. Preparation of standard curve

The stock solution (1000 mg/ml) of Venlafaxine HCl was prepared in 0.1 N HCl. From this 30 mg/ml second stock solution was made. This was withdrawn as 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10 ml and diluted each with 0.1 N HCl (pH 1.2) to obtain concentrations of 3, 6, 9, 12, 15, 18, 21, 24, 27 and 30 mg/ml. The absorbance of these solutions were measured at 225 nm against blank i.e. 0.1 N HCl. Same procedure was followed for the preparation of standard curve of distilled water. The coefficient of correlation and equation for the line are determined.

2.3. Preparation of Venlafaxine HCl effervescent tablet

Effervescent floating tablets, each containing 37.5 mg Ven-lafaxine HCl were prepared by melt granulation method. The composition of various formulations is shown in Table 1.All the ingredients except wax were passed through sieve 40. The wax/oil were melted in porcelain dish on hot plate and drug was added to it. Then to this mixture other sieved ingredients except talc were added. The resultant mixture was allowed to solidify at room temperature and then passed through sieve 16 to form granules. The granules were lubricated by adding talc extra granularly. The lubricated granules were then compressed into a tablet using 10 mm standard flat-face punches on single punch tableting machine (Royal Artist Pvt.

Table 1 - Formulation of effervescent floating tablets of Venlafaxine HCl.

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

Venlafaxine hydrochloride 37.5 37.5 37.5 37.5 37.5 37.5 37.5 37.5 37.5 37.5 37.5 37.5

Hydrogenated cottonseed oil 80 - - 120 - - 160 - - 200 - -

Carnauba wax - 80 - - 120 - - 160 - - 200 -

Cetyl alcohol - - 80 - - 120 - - 160 - - 200

HPMC K15M 142 142 142 102 102 102 62 62 62 22 22 22

NaHCO3 50 50 50 50 50 50 50 50 50 50 50 50

Talc. 3 3 3 3 3 3 3 3 3 3 3 3

Ltd., Mumbai, India). Each tablet contains 37.5 mg of Venlafaxine HCl and total tablet weight was kept constant at 312.5 mg .The prepared tablets were evaluated for below mentioned parameters.

2.4. Pre-compression evaluation

The granules were evaluated for flow property i.e. angle of repose, bulk density, tapped density, compressibility index (Carr's index) and Hausner's ratio using standard procedures (Indian Pharmacopoeia, 1996; Lachman et al., 1990).

2.5. Post-compression evaluation

The prepared tablets were evaluated for their physical parameters like hardness, thickness, weight variation, friability and drug content (Indian Pharmacopeia, 1996; Lachman et al., 1990).

To study weight variation, twenty tablets of each formulation were weighed using an electronic balance and the test was performed. Thickness and diameter of tablets was determined using Vernier caliper. Ten tablets from each batch were used, and their average values calculated. Hardness of ten tablets of each formulation was determined using Monsanto hardness tester.

Friability of twenty tablets was determined using the Roche friabilator. This test subjects a number of tablets to the combined effect of shock and abrasion by utilizing a plastic chamber which revolves at speed of 25 rpm, dropping the tablets to a distance of 6 inches in each revolution. A sample of pre-weighed tablets was placed in Roche friabilator, which was then operated for 100 revolutions for 4 min. The tablets were then dusted and reweighed.

Ten tablets containing Venlafaxine HCl were crushed to a fine powder. A quantity equivalent to 100 mg of Venlafaxine hydrochloride was added into 100 ml volumetric flask and dissolved in 0.1 N HCl (pH 1.2). After suitable dilutions the absorbance was determined by UV spectrophotometer (Shi-madzu) at 225 nm against blank. The drug content was calculated by using calibration curve (Vasanth et al., 2012).

The in vitro buoyancy test was determined by floating lag time, as per the method described by (Rosa et al., 1994; Abdul and Lila, 2011). The tablets were placed in a 100-ml beaker containing 0.1 N HCl (pH 1.2). The time required for the tablet to rise to the surface and float was determined as floating lag time (FLT) and the time for which the tablet constantly floats on the surface of the medium (duration of floating), was measured.

The release rate of Venlafaxine HCl floating tablets was determined using USP Type II Apparatus (Paddle Type). The dissolution test was performed, using 900 ml of 0.1 N HCl, at 37 ± 0.5 °C at 50 rpm for 24 h. A 5 ml sample was withdrawn from the dissolution apparatus at specified time and the samples were replaced with fresh dissolution medium. The samples were filtered through a 0.45 mm membrane filter and sufficiently diluted. Absorbance of these solutions were measured at 225 nm using UV-visible spectrophotometer (Vasanth et al., 2012). The marketed formulation VENTAB-XL 37.5 mg was also evaluated for in vitro drug release.

The floating tablets were weighed individually (designated as W0) and placed separately in glass beaker containing 200 ml of 0.1 N HCl and incubated at 37 °C ± 1 °C. At regular 1 h time intervals until 4 h the floating tablets were removed from beaker, and the excess surface liquid was removed carefully using the tissue paper. The swollen floating tablets were then re-weighed (Wt), and % swelling index (SI) was calculated using the following formula (Lodhiya et al., 2009).

SI (%) = (Wt - W0/W0) X 100 (1)

where, Wt = weight of tablet at time t, W0 = initial weight of tablet.

2.6. Kinetic analysis of release data

The obtained dissolution data was fitted to zero order, first order, Higuchi and Korsmeyer-Peppas equations to understand the rate and mechanism of drug release from the prepared formulations. The correlation coefficients values were calculated and used to find the fitness of the data.

Zero order equation (Brahamankar and Jaiswal, 2009),

Qt = Q0 + Kct (2)

describes the systems where the drug release rate is independent of concentration of the dissolved substance, where, Qo = initial amount of drug, Qt = cumulative amount of drug release at time t, K0 = zero order release constant, t = time in h.

First order release equation (Brahamankar and Jaiswal, 2009)

Log Qt = Log Q0 + Kt/2.303 (3)

the drug release rate depends on its concentration, where, Qo = initial amount of drug, Qt = cumulative amount of drug release at time t, K = first order release constant, t = time in h. Higuchi release equation (Higuchi, 1963),

Q = KHt1/2 or Mt/Mo = Kt1/2 (4)

the Higuchi equation suggests that the drug releases by diffusion mechanism. Q = cumulative amount of drug release at time t, KH = Higuchi constant, t = time in h.

Korsmeyer—Peppas equation (Korsmeyer et al., 1983)

F = (Mt/Mœ) = Kmtn

which describes the drug release from a polymeric system, where F = fraction of drug released at time t, Mt = amount of drug released at time t, MM = total amount of drug in dosage form, Km = kinetic constant, n = diffusion or release exponent, t = time in h.

2.7. Statistical analysis

In-vitro drug release profile of Venlafaxine HCl sustained release tablets was compared with drug release profile of marketed formulation VENTAB-XL 37.5 tablets under similar experimental conditions. The data obtained from in vitro drug release was used to determine the similarity factor and dissimilarity factor between marketed product and optimized formulation. The similarity factor (f2) and dissimilarity factor f1) were calculated using the formulas (Shah et al., 2011)

[£|Rt - Tt| E Rt]

: 100, where t = 1 to n

f2 = 50 log| 1 + n X - Tt)2] 0 5 x 100 J

where n is number of time points, Rt and Tt are dissolution of reference and test products at time t respectively. In general, f1 values lower than 15 (0—15) and f2 values higher than 50 (50—100) show the similarity of the dissolution profiles.

The Independent-samples t-test was also applied to check similarity between the optimized formulation (F8) and marketed product. Differences were considered to be statistically significant at p < 0.05 (Kavita et al., 2010).

2.8. Stability study

The optimized formulation (F8) packed in silver foil and subjected to stability studies at 40 °C ± 2 0C/75 ± 5% RH. Sample was withdrawn at predetermined time intervals of 0 (initial), 30, 60 and 90 days. Tablet was evaluated for the different physicochemical parameters viz. appearance, weight variation, thickness, hardness, friability, drug content and in vitro release.

Results and discussion

3.1. Drug-excipients interaction and identification

The wavelength of maximum absorbance was obtained at 225 nm (Fig. 1). The calibration curve was found to be linear in the range of 3-30 mg/ml and straight line equation was obtained having the regression coefficient value of 0.9955 (Fig. 2).

FTIR spectrum of Venlafaxine HCl showed a characteristic stretching band of O-H at 3350.35 cm-1, aromatic C=H stretching at 1614.42 cm-1, C-O stretching at 1514.12 cm-1

Fig. 1 - UV spectrum of Venlafaxine HCl in 0.1 N HCl.

and C-N stretching at 1178.51 cm-1, C-O-C stretching at 1043.49 cm-1, C=O stretching at 1732.08 cm-1 wavenumber (Fig. 3). These characteristic stretching bands were slightly varied after pre-formulation study, revealing no chemical interaction (Figs. 4-7).

DSC thermo gram showed a sharp endothermic peak at 214.7 °C which is corresponding to melting point of the drug (Fig. 8). Pre-formulation study indicated the slight broadening and shifting of endothermic peak due to melting effect of hydrophilic polymers and hydrophobic retardants (Fig. 9) (Bagdiya et al., 2012).

3.2. Formulation development

The concentration of all the three selected hydrophobic retardants (carnauba wax, hydrogenated cottonseed oil and cetyl alcohol) was decided on trial and error basis. Sodium bicarbonate was incorporated as a gas-generating agent. The trial batches were conducted to finalize the concentration of sodium bicarbonate. Talc was used as glidant to improve the flow of the granules. FTIR study showed that all the retardants/excipients used were compatible with Venlafaxine HCl.

Nanjwade et al. reported that the use of a hydrophobic carrier along with a hydrophilic polymer effectively controls the initial rapid release of a highly water soluble drug such as Venlafaxine HCl. Hot melt granulation method (also known as

y = 0.0494X + 0.0644 R2 = 0.9955

10 20 30

Concentration(|ig /ml)

Fig. 2 - Calibration curve of Venlafaxine HCl in 0.1 N HCl.

4000 3500 3000 2500 2000 1750 1500 1250 1000 750 500

Fig. 3 - FTIR of pure Venlafaxine HCl.

4000 3500 3000 2500 2000 1750 1500 1250 1000 750 500

Fig. 4 - FTIR of combination of Venlafaxine HCl and carnauba wax.

4000 3500 3000 2500 2000 1750 1500 1250 1000 750 500

Fig. 5 - FTIR of combination of Venlafaxine HCl and hydrogenated cottonseed oil.

Fig. 6 - FTIR of combination of Venlafaxine HCl and cetyl alcohol.

Fig. 7 - FTIR of physical mixture of optimized formulation (F8).

Fig. 8 - DSC of pure Venlafaxine HCl.

thermoplastic granulation method) is especially more effective in achieving this than the direct compression method (Nanjwade et al., 2011).

From the literature survey it was evident that Methocel® K15M is a good polymer for floating drug delivery system as it is a matrix forming and low density polymer (Lakshmaiah et al., 2014). Hydrophobic melt able materials impart sufficient integrity to the tablets (Ghada and Ramadan, 2012). Lipids/waxes are considered as an alternative to polymers in the design of sustained drug delivery systems due to their advantages such as the low melt viscosity (thus avoiding the need of organic solvents for solubilization), absence of toxic impurities such as residual monomer catalysts and initiators, potential biocompatibility and biodegradability (Senthil et al., 2011).

Reza et al., has stated that the drug particles present on the surface of a matrix system were initially released into the surrounding media generating many pores and cracks which

50.0 1D0.0 150.0 200.0 250.0 300.a

Temp Cei

Fig. 9 - DSC of physical mixture of optimized formulation (F8).

facilitate further release of drug and also formation of channels within the matrix in the case of a water soluble drug like Venlafaxine HCl. HPMC tablets upon contact with the dissolution medium swell due to the disruption of hydrogen

bindings among the polymeric chains and form a thick gel layer at the tablet surface, which gets eroded over a period of time. These parameters are responsible for controlling drug release rate from HPMC tablets (Costa and Lobo, 2001).

Table 2 - Pre-compression evaluation.

Formulation Angle of Bulk density Tapped density Compressibility Hausner's

code reposea (g/ml) (g/ml) index (%) ratio

F1 28.24 ± 0.13 0.408 ± 0.13 0.434 ± 0.11 5.99 ± 0.04 1.06 ± 0.13

F2 27.08 ± 0.02 0.404 ± 0.17 0.439 ± 0.08 7.97 ± 0.17 1.08 ± 0.08

F3 30.11 ± 0.08 0.416 ± 0.05 0.449 ± 0.13 7.34 ± 0.09 1.07 ± 0.02

F4 29.25 ± 0.11 0.408 ± 0.01 0.444 ± 0.03 8.10 ± 0.08 1.08 ± 0.15

F5 28.78 ± 0.14 0.422 ± 0.12 0.464 ± 0.09 9.05 ± 0.11 1.09 ± 0.06

F6 29.54 ± 0.06 0.404 ± 0.04 0.449 ± 0.16 10.02 ± 0.06 1.11 ± 0.12

F7 27.82 ± 0.05 0.415 ± 0.06 0.444 ± 0.11 6.53 ± 0.15 1.06 ± 0.04

F8 27.16 ± 0.18 0.435 ± 0.12 0.478 ± 0.09 8.99 ± 0.02 1.09 ± 0.11

F9 30.78 ± 0.06 0.421 ± 0.08 0.484 ± 0.07 13.01 ± 0.14 1.14 ± 0.03

F10 28.45 ± 0.12 0.408 ± 0.05 0.439 ± 0.05 7.06 ± 0.07 1.07 ± 0.08

F11 29.65 ± 0.05 0.416 ± 0.14 0.454 ± 0.08 8.37 ± 0.18 1.09 ± 0.05

F12 31.24 ± 0.11 0.4123 ± 0.02 0.492 ± 0.12 16.19 ± 0.07 1.19 ± 0.12

a (q ± s.d) n = 3.

Table 3 - Post-compression evaluation.

Formulation Hardness Thickness Wt. variation Friability Drug content

code (kg/cm2 ± SD)a (mm ± SD)a (mg ± SD)b (%w/w)b (% ± SD)a

F1 3.10 ± 0.10 3.24 ± 0.005 314.65+_2.37 0.58 ± 0.06 99.2 ± 0.14

F2 5.06 ± 0.15 3.33 ± 0.026 314.10 ± 2.06 0.64 ± 0.11 98.6 ± 0.12

F3 2.11 ± 0.12 3.43 ± 0.015 315.55 ± 2.52 0.48 ± 0.02 100.5 ± 0.09

F4 3.46 ± 0.05 3.24 ± 0.011 316.00 ± 2.62 0.78 ± 0.05 98.6 ± 0.05

F5 7.23 ± 0.05 3.43 ± 0.020 315.30 ± 2.26 0.54 ± 0.02 99.8 ± 0.12

F6 2.36 ± 0.11 3.16 ± 0.015 315.40 ± 1.89 0.67 ± 0.12 98.5 ± 0.02

F7 4.38 ± 0.02 3.55 ± 0.005 316.20 ± 1.75 0.54 ± 0.07 97.8 ± 0.05

F8 8.53 ± 0.07 3.36 ± 0.015 315.33 ± 2.36 0.45 ± 0.11 101.2 ± 0.15

F9 2.63 ± 0.05 3.24 ± 0.015 314.05 ± 1.25 0.64 ± 0.05 99.4 ± 0.08

F10 3.11 ± 0.07 3.27 ± 0.005 315.1 ± 2.33 0.72 ± 0.07 97.3 ± 0.15

F11 7.13 ± 0.11 3.58 ± 0.010 313.9 ± 1.66 0.59 ± 0.13 102.1 ± 0.08

F12 2.0 ± 0.10 3.26 ± 0.020 314.4 ± 2.06 0.68 ± 0.02 99.3 ± 0.12

a n = 10. b n = 20.

Table 4 - Post-compression evaluation.

Formulation FLT (sec ± SD)a FD (h) SI (% ± SD)a

F1 28 ± 2.2 >24 91.36 ± 0.34

F2 24 ± 2.8 >24 88.8 ± 0.28

F3 26 ± 3.1 <24 90.4 ± 0.38

F4 32 ± 2.4 >24 80.8 ± 0.4

F5 28 ± 2.5 >24 83.04 ± 0.26

F6 38 ± 3.2 <24 81.44 ± 0.42

F7 62 ± 2.7 >24 44.16 ± 0.33

F8 55 ± 2.5 >24 53.92 ± 0.38

F9 69 ± 2.8 >24 47.52 ± 0.42

F10 98 ± 3.2 <24 31.8 ± 0.25

F11 72 ± 3.4 <24 30.56 ± 0.42

F12 104 ± 3.1 <24 34.4 ± 0.28

10 20 Time(hrs.)

Fig. 11 — In vitro drug release profiles of formulations F8—F12 and marketed formulation.

a n = 3, FD — floating duration, FLT — floating lag time.

The slower drug release from the tablets derived by melt granulation could be due to the formation of a more uniform, and hence, a more effective and rigid hydrophobic coating around the hydrophilic drug particles during hot melt granulation (Nanjwade et al., 2011). The decrease in drug release rate when the hydrophobic content of the matrix was increased may be due to slower penetration of the dissolution medium in matrices as a result of increased lipophilicity (Hamdani et al., 2002). Further, penetration of dissolution fluid was hindered by the hydrophobic coating around the drug particles, leading to diminished drug release over an extended period (Yonezava et al., 2001).


■ Marketed

Fig. 12 — In vitro drug release profile of optimized and marketed formulation.


3.3. Physical characteristics

The granules of twelve formulations (F1-F12) were evaluated for angle of repose, bulk density, tapped density, Carr's index and Hausner's ratio showed the pre-compressed blend has good flow property (Table 2). Formulated matrix tablets evaluated for physical parameters such as hardness, thickness, weight variation, friability, drug content and swelling index, the results are shown in Table 3. It was found that all the granules have good flow property as they showed angle of repose value was between 25 and 30°, represents good flow property. Carr's index value was found to be less than 10 showing excellent property except formulation F9 and F12 which showed 13.04 and 16.19 respectively. Hausner's ratio was found to be less

than 1.12 showing excellent flow property except formulation F9 and F12 which showed 1.14 and 1.19 respectively.

The total weight of each formulation was maintained constant; the weight variations of the tablets were within the permissible limits. According to IP specification, for tablets weighing more than 250 mg, ±5% deviation from the mean weight is acceptable. The weight of the tablet was fixed at 312.5 mg and was maintained for all the batches in order to minimize the effect of weight on the drug release because the effect of retardant/polymer concentration is the only area of interest. Tablet hardness varied as hydrophobic retardant was changed. Hardness of tablets containing hydrogenated cottonseed oil was in range 3—4.4 kg/cm2 (approx.) while that of

0 5 10 15 20 Time(hrs.)

Fig. 10 - In vitro drug release profiles of formulations F1-F7.

Table 5 - Showing f1 and f2 values.

Formulation code f1 Value f2 Value

F1 9 62

F2 14 56

F3 8 64

F4 15 54

F5 20 47

F6 13 57

F7 14 54

F8 6 68

F9 14 54

F10 39 34

F11 37 31

F12 62 21

Table 6 - Independent t-test values for comparison between F8 and marketed product.

Time points (h) t-Statistic dF Two-tailed

probability (p)

1 4.53 10 0.0011

2 2.03 10 0.0693

3 0.46 10 0.6551

4 16.84 10 0.0000

6 16.92 10 0.0000

8 5.47 10 0.0003

10 3.62 10 0.0046

12 1.707 10 0.1187

16 5.559 10 0.0002

20 1.755 10 0.1098

24 1.112 10 0.2923

tablets containing carnauba wax was in range 5-8.5 kg/cm2 (approx.) and cetyl alcohol showed hardness in range 2-2.6 kg/cm2 (approx.). Tablet thickness was also used to assess the quality of tablets. The thickness of floating tablets ranged from 3.16 to 3.58 mm. Friability test of all the formulations was found satisfactory showing enough resistance to the mechanical shock and abrasion less than 1%. Drug content in all formulations was calculated and the presence of active ingredient ranged from 97 to 102%.

Swelling study was done which indicated that there was no significant swelling. All formulations showed swelling only up to first 4 h due to the presence of hydrophilic polymer (Table 4), and then constant results were obtained.

3.4. Evaluation of buoyancy of the tablets

The in vitro buoyancy studies in 0.1 N HCl (pH 1.2), revealed buoyancy variations for all the formulations (Table 4). Sodium

bicarbonate was used as the effervescent base which generates carbon-di-oxide gas in the presence of hydrochloric acid present in dissolution medium. The gas generated is trapped and protected within the gel (formed by hydration of Methocel K15 M), thus decreasing the density of the tablet. As the density of the tablet falls below 1 (density of water), the tablet becomes buoyant. Preliminary studies were done to estimate the ideal amount of the effervescent base needed to obtain short floating lag time together with prolonged buoyancy. This revealed that sodium bicarbonate in the amount 50 mg produced tablets with lag time less than a minute in formulations F1-F6 and F8 and more than 1 but less than 2 min in formulations F7 and F9-F12. It was found that the tablets of formulations F1, F2, F4, F5 and F7-F9 floated in buffer for duration more than 24 h and tablets of formulations F3, F6 and F10-F12 floated in the buffer solution for less than 24 h. The formulations containing carnauba wax showed superiority in floating duration as well as maintained the integrity of formulations due to comparatively more hardness than other formulations. Although the specific gravity of cetyl alcohol is least (0.8187 at 50 °C), that of hydrogenated cottonseed oil is lesser (0.917 at 25 °C) and that of carnauba wax was highest (0.990-0.999 at 25 °C) among three, but due to comparatively more hardness of carnauba wax it had prolonged duration of floating along with integrity.

In vitro drug release

In vitro dissolution studies were performed in 0.1 N HCl (1.2 pH) and results depicted in Figs. 10 and 11. Formulations F7, F8 and F9 showed release for 24 h up to 99.62, 99.9 and 98.75% respectively. Marketed tablet showed 99.54% release in 24 h. Formulations F1, F2, F3, F4 and F6 showed release less than 24 h. F1, F2 and F3 formulations each had hydrophobic

(a) 120

o> 100

a> n 60

■a o) SS u. 40

E 3 20

y = 3.6388x+ 18.006 R2 = 0.9669

(c) 120

o> 3 100

ss « 80

0) IS > 0) 60

■S a) 40

3 0 20

0.0679X + 2.1495 R2 = 0.8098

y = 22.053X - 10.017 R2 = 0.9982

Square Root of Time

y = 0.6448X + 1.1237 R2 = 0.9923


Fig. 13 - Kinetic evaluation of optimized formulation (F8): (a) zero order plot, (b) first order plot, (c) Higuchi plot, (d) Korsmeyer-Peppas plot.

Table 7 - Stability studies of optimized formulation (F8).

Parameters After 30 days After 60 days After 90 days

Physical appearance No change No change No change

Weight variation 315.33 ± 2.36 315.28 ± 2.1 314.86 ± 1.94

(mg ± SD)b

Thickness (mm ± SD)a 3.36 ± 0.015 3.38 ± 0.021 3.42 ± 0.026

Hardness 8.53 ± 0.07 8.53 ± 0.11 8.64 ± 0.23

(kg/cm2 ± SD)a

Friability (% ± SD)b 0.45 ± 0.11 0.45 ± 0.08 0.45 ± 0.14

Drug content (%)a 101.2 ± 0.15 101.12 ± 0.32 100.96 ± 0.21

Buoyancy lag time 55 ± 2.5 56 ± 2.9 56 ± 3.2

(sec ± SD)c

Duration of >24 >24 >24

floating (h)

a n = 10. b n = 20. c n = 3.

retardant in concentration 80 mg which is less so, sustained effect was less. Formulations F4 and F6 also showed less sustained effect while formulation F5 showed release more than 24 h as an exception because even if concentration was 120 mg (lesser) the sustained effect was more may be due to combination of hydrophilic polymer and hydrophobic retardant (i.e. carnauba wax), which showed good effect even in less concentration. Hydrophilic polymer was used as sustaining agent, gas (carbon-di-oxide) entrapping agent and also as filler.

Formulations F10, F11 and F12 failed to show sustained effect may be due to less concentration of hydrophilic polymer and thus unable to form good matrix. All the three retardants in concentration of 160 mg, in formulations F7, F8 and F9 showed desired release for 24 h but after comparing with marketed formulation (VENTAB-XL 37.5), it was found formulation F8 was most similar to it and hence formulation F8 was considered as optimized formulation (Fig. 12). The similarity and dissimilarity factor comparison is showed in Table 5. Independent t-test (Table 6) also proved that F8 was the best formulation as the maximum time points of F8 had p > 0.05 (i.e. retaining the Null's hypothesis) compared to other formulations proving that it is most similar to marketed

product. The amount of hydrophobic retardant was found to be inversely proportional to rate of release. Cetyl alcohol showed good results, hydrogenated cottonseed oil showed better results and carnauba wax showed best results (Fig. 13).

Hardness also played an important role in release. Formulations F8 had the higher hardness value and hence showed good sustained property. Formulations made with cetyl alcohol i.e. F3, F6, F9 and F12 had least hardness and thus had less sustained effect compared to other formulations. But as an exception F9 showed release up to 24 h, thus it can be concluded that cetyl alcohol also shows good release in the concentration 160 mg. Hardness obtained with tablets of carnauba wax was higher whereas with hydrogenated cottonseed oil it was moderate and cetyl alcohol tablets showed least hardness.

3.6. Stability studies

According to ICH guidelines, three months stability studies conducted at controlled temperature 40 °C ± 2 °C and humidity 75 ± 5% RH showed negligible changes in results (Table

3.7. Kinetic analysis of release data

To understand the rate and mechanism of drug release from optimized tablet formulation, dissolution data was fitted into different release kinetic models. The model that best fitted the release data was selected based on the correlation coefficient value (r2) obtained from various kinetic models (Table 8). In vitro drug release profile from all these formulations could be best expressed by Korsmeyer-Peppas equation and Higu-chi equations as plots showed highest linearity with r2 value 0.9164-0.9961 and 0.9805-0.9982 respectively. In Kors-meyer-Peppas equation, linear plot was for optimized formulation with high correlation coefficient (r2) value 0.9923 and Higuchi value 0.9982. Also, Korsmeyer-Peppas equation's 'n' values for all formulations except F12 were above 0.5. It was concluded that the optimized formulation followed mixed mechanism of diffusion and erosion, so called anomalous/ Non-Fickian diffusion mechanism for drug release.

Table 8 - Kinetic studies of formulations F1-F12

Formulation Zero order First order Higuchi Korsmeyer- -Peppas Release mechanism

R2 R2 R2 R2 n

F1 0.9827 0.8366 0.9922 0.9902 0.614 Non-Fickian

F2 0.9923 0.8344 0.97 0.973 0.5624 Non-Fickian

F3 0.9748 0.9272 0.9968 0.9961 0.5395 Non-Fickian

F4 0.991 0.7314 0.9595 0.966 0.544 Non-Fickian

F5 0.9925 0.7918 0.9805 0.992 0.6961 Non-Fickian

F6 0.9671 0.9025 0.9851 0.9778 0.6685 Non-Fickian

F7 0.9924 0.7335 0.9736 0.9809 0.5651 Non-Fickian

F8 0.9669 0.8098 0.9982 0.9923 0.6448 Non-Fickian

F9 0.9878 0.8434 0.9822 0.9848 0.6711 Non-Fickian

F10 0.8293 0.9215 0.9352 0.9164 0.63 Non-Fickian

F11 0.9031 0.9474 0.9659 0.9638 0.849 Non-Fickian

F12 0.9573 0.8908 0.9660 0.9642 0.2616 Fickian

4. Conclusion

The effervescent-based floating drug delivery system was the promising system. The use of hydrophobic retardant and hy-drophilic polymer in combination had its own advantages of maintaining integrity and buoyancy of tablets. And also in initial burst effect was minimized. It could be concluded that for proper floating duration and in vitro release, the hydro-phobic retardant and hydrophilic polymer must be used in proper ratio. Formulation F8 showed release similar to marketed tablet and was considered optimized formulation. F8 followed zero order, Higuchi and Korsmeyer-Peppas release kinetics. The aim of preparation of gastroretentive tablets of Venlafaxine HCl was achieved.


We would like to thank Amoli Organics Pvt Ltd., Vadodra for providing the drug and Zhaveri Pvt Ltd., Mumbai for providing hydrogenated cottonseed oil. We are also thankful to HSNC Board and Principal Dr. Paraag Gide for helping us in conducting the research.


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