Formulation and Evaluation of Sustained Release Tablets of Venlafaxine Hydrochloride for the treatment of Depressive disorders

 

Dilip M. Kumbhar*¹, Vijay D. Havaldar, Kailas K. Mali, Remeth J. Dias, Vishwajeet S. Ghorpade, Rahul B. Londhe

YSPM’s, YTC, Faculty of Pharmacy, Wadhe, Satara, 415011 India

 

ABSTRACT:

The purpose of present investigation was to formulate the sustained release tablets of Venlafaxine HCl (VHL) by direct compression method using natural polymer, xanthan gum and semi synthetic polymers such as hydroxypropyl methylcellulose (HPMC) K4M, HPMC K15M, HPMC K100M and Carbopol alone or in combination. The drug and all the excipients were evaluated to study compatibility and flow properties. The prepared tablets were evaluated for tablet dimensions, weight variation test, friability, drug content and in vitro drug release study. The FTIR study of drug with all excipients showed that there was no any interaction between the drug and excipients. The precompression study of powder blend showed good flow properties. All the tablets showed dimensions and hardness within prescribed limit. Friability and weight variation test was found to be satisfactory.  Drug content was found to be in the range of 94.24 to 101.02% and all the formulations sustained release of drug. Formulation containing equal concentrations of carbopol and xanthan gum showed 90.02% drug release in 12 h. From above results, it can be concluded that tablets of VHL prepared with carbopol and xanthan gum by direct compression method have sustained release of drug that may be useful in the treatment of depressive disorders. 

 

 

 

INTRODUCTION:

Oral route is the most commonly adopted and convenient route for drug delivery because of flexibility in the formulation, patient compliance and physician’s convenience for dose adjustment. Most of the conventional dosage formulations are immediate-release systems where there is no control over drug release and often results in multiple dosing that lead to fluctuations in plasma drug concentration.

 

Moreover, to achieve effective concentration at the targeted site of action, intermittent drug intake becomes necessary and often sub or supra therapeutic drug concentrations results in unpredicted side effects. Sustained release dosage formulations (SRDF) are gaining popularity where the initial release of drug is sufficient to provide a therapeutic dose soon after administration and then sustained release is obtained over an extended period so that it can avoid above mentioned disadvantages of immediate release system.⁽¹⁾ Depressive disorders may occur to the patient of any age that reduce patients functioning and often are recurring. It is the leading cause of disability worldwide in terms of total years lost due to disability.⁽²⁾ The World Mental Health Survey conducted in seventeen countries found that on an average about 1 in 20 people reported having an episode of depression in the 2014.⁽³⁾ Almost one million lives are lost yearly due to suicide, which translates to 3000 suicide deaths every day. Every person who is suffering from this disorder may try to commits a suicide and end his or her life.⁽⁴⁾ Venlafaxine hydrochloride (VHL), chemically 1-[2- (Dimethylamino) -l- (p-methoxyphenyl) ethyl] cyclohexano hydrochloride is a oral antidepressant drug, used for the treatment of Major Depressive Disorder (MDD) and Social Anxiety Disorder (SAD) also known as Social Phobia. It is a serotonin-nor-epinephrine-dopamine reuptake inhibitor. It has mean elimination half life of 5 h and the usual dose is 75 mg daily with maximum of 375 mg.⁽⁵⁾  VHL is a highly water soluble drug (Class I) with the biological half life of 5 h thus requires two to three time daily dosing to maintain plasma drug concentration. Therefore, in order to maintain therapeutic level of drug in the body it is necessary to prepare sustained release tablets of venlafaxine hydrochloride ⁽⁶⁾. In case of sustained release formulations natural and semi synthetic polymers shows good promising retardation properties. Natural polymers are inexpensive and easily available more while semi synthetic polymers are cheap compared to the synthetic polymers and very helpful to formulate the sustained release formulations.⁽⁷⁾ In present investigation an attempt was made to prepare and evaluate sustained release tablets of venlafaxine hydrochloride which will improve the patient compliance.

 

MATERIALS AND METHODS:

MATERIALS:

VHL was obtained as gift sample from Sterling Pharma Pune, India, and carbopol 934, xanthan gum were purchased from Fine Chem Industry, Mumbai.  All other reagents used were of analytical grade.

 

METHODS:

Preparation of sustained release tablets:

The sustained release tablets of VHL were prepared by direct compression method using xanthan gum, hydroxypropyl methylcellulose (HPMC) K4M, HPMC K15M, HPMC K100M and carbopol from 10 to 40%.  On the basis of flow characteristics and compressibility index, direct compression method was preferred for the preparation of sustained release tablets. All the ingredients including drug and excipients were accurately weighed (Table 8) and mixed with the release retarding polymers and other excipients in ascending order of their weight. The powder mixture was blended for 20 min for uniform distribution of drug in the formulation. Finally, 200 mg of the powder mixture was weighed accurately and fed into the die of single punch machine and compressed. ⁽⁸⁾

 

Table 1. Formulation table of VHL SR tablets

*All quantities are in mg, DCP- dicalcium phosphate; MCC- microcrystalline cellulose; HPMC – hydroxypropylmethyl cellulose

 

 

 

 

Drug-polymer interaction study:

Infrared spectrum of VHL and other polymer was determined on Fourier transform infrared spectrophotometer (MIRacle10, Shimadzu, Japan). Small quantity of sample was taken and directly put on IR platform. Then the spectra were scanned over wavelength region of 4000 to 400 cm-1 at resolution of 4 cm^-1.⁽⁹⁾

 

Pre-compression evaluation:

Angle of repose:

The angle of repose for the powder mixtures of each formulation was determined by funnel method. The powder mixture was allowed to flow through funnel orifice on a plain paper kept on the horizontal surface. This forms a pile of angle of powder mixture on the paper. Substituting the values of the base radius ‘r’ and pile height ‘h ’in the following equation calculated the angle of repose.

 

tanq = h/r

 

Where,

h is height of pile; r is radius

 

Bulk density and tapped density:

The 20 gm of powder was allowed to flow in a graduated cylinder of a mechanical tapping device. Initial volume occupied by the powder (Vu) was noted. The measuring cylinder was tapped until no further change in the volume was observed (100 taps). The initial volume after tapping was noted (Vp) The term bulk density refers to measure used to describe a packaging of particles or granules. It is weight / volume ratio of the substance expressed in gm/cubic cm.

D_f = M/Vu

 

Where,

D_f = bulk density,

M = Weight of sample in grams,

Vu = final volume of powder in cm³

 

The tapped density was obtained by dividing the weight of sample in grams by final tapped volume in cm³ and it was calculated as:

D_O =M/Vp

 

Where,

Do = tapped density

M = weight of sample in grams

Vp = final tapped volume of powder in cm³

 

Compressibility index:

It is an expression of the packaging tendency of powders. The percentage compressibility of a powder is direct measure of the potential powder arch or bridge strength and stability. Carr’s index of each formulation was calculated according to equation given below:

 

% Compressibility =

Where,

D_f = Taped density

D₀ = Bulk density

 

Hausners ratio:

It is an indirect index of ease of powder flow. It was calculated by following formula-

 

Hausner’s Ratio = d_t / d_b

Where,

d_t is tapped density,

d_b is bulk density.

Post-Compression Evaluation:

Thickness of tablets was evaluated by using Micrometer screw gauze. Hardness of tablets was determined by using Monsanto hardness tester. Friability was determined by using friability test apparatus (Roche friabilator).Twenty tablets were accurately weighed and placed inside the chamber of friabilator. The apparatus was rotated for 100 revolutions. After rotations, the tablets were weighed and the loss in weight was determined. The loss in weight should not be more than 1%.⁽¹⁰⁾

 

Determination of Drug Content:

Twenty tablets from each formulation were accurately weighed and powdered. Powder equivalent to 30 mg of drug was weighed and transferred into a 100 ml volumetric flask and volume was made up to 100 ml using methanolic HCl (0.1 N). From above solution, 5 ml of solution was pipetted out and diluted it up to 100 ml with water and absorbance was taken on UV Visible spectrophotometer (UV 1800, Shimadzu, Japan) at 225 nm and finally drug content was determined.

 

In vitro Drug Release study:

In vitro dissolution test was carried out by using USP Type II dissolution apparatus (Dissolution Tester TDT-06L, Electrolab, India) in triplicate for all formulations. The dissolution media used was 900 ml 0.1 N HCl (pH 1.2) for 2 h and phosphate buffer pH 6.8 thereafter at 37± 0.5⁰C. The speed of rotation was maintained to 50 rpm. At a predetermined time intervals, aliquots of samples were withdrawn and diluted. The samples were analyzed for drug release by measuring the absorbance at 225 nm using spectrophotometric method.⁽¹¹⁾ Drug release data was fitted to model dependent and independent kinetics. ⁽¹²⁾

 

RESULT AND DISCUSSION:

Drug-polymer interaction study

The FTIR spectrum of VHL showed O-H stretching at 3768cm^-1, N-H stretching at 3323cm^-1, C-H stretching in aromatic ring at 3014cm^-1, C-H stretching of alkenes at 2933 cm^-1. All these peaks were observed in physical mixture of drug and polymers and also in optimised formulation. It indicates that the there was no any unusual interaction between drug and polymers used in formulation.

 

 

Figure 1. Overlay IR Spectra of drug, physical mixtures and optimised formulation

 

 

Pre-Compression Evaluation:

Angle of Repose:

Angle of repose was found to be in the range of 25.8 to  30.4⁰, indicating good flow properties (Table 2).

 

Bulk Density:

The bulk density was found to be in the range of 0.49-0.52 gm/ml (Table 2).This indicated good packing capacity of powder blend.

 

Tapped Density:

The tapped density was found to be in the range of 0.53-0.59 gm/ml (Table 2). It may have influence on compressibility and tablet dissolution.

 

Carr’s Index:

Carr’s index was found in the range of 5.55-13.5 %, indicating good flow properties (Table 2).

 

Hausner’s Ratio:

Hausners ratio was found in the range of 1.05-1.15 indicating acceptable flow property (Table 2).

 

 

Table 2. Precompression properties of VHL SR tablets

Batch	Bulk Density (gm/ml)	Tapped Density (gm/ml)	Carr’s Index (%)	Hausner’s Ratio	Angle of Repose
F1	0.50±0.04	0.55±0.02	9.09±2.1	1.10±0.04	26.86±0.8
F2	0.49±0.02	0.54±0.06	9.25±1.9	1.10±0.02	28.21±0.8
F3	0.50±0.02	0.56±0.04	10.71±1.9	1.12±0.02	29.02±0.5
F4	0.50±0.02	0.53±0.02	5.66±2.1	1.06±0.02	27.47±0.9
F5	0.51±0.06	0.57±0.06	10.52±2.5	1.11±0.04	29.6±0.7
F6	0.52±0.04	0.58±0.02	10.34±2.1	1.11±0.04	30.4±0.5
F7	0.50±0.04	0.57±0.04	12.28±1.9	1.14±0.06	27.47±0.5
F8	0.52±0.06	0.56±0.06	7.14±2.5	1.07±0.06	29.96±0.4
F9	0.51±0.04	0.55±0.06	7.27±2.5	1.07±0.06	25.81±0.7
F10	0.51±0.04	0.59±0.06	13.55±2.5	1.15±0.06	26.81±0.7
F11	0.51±0.04	0.57±0.06	10.52±2.5	1.11±0.06	24.21±0.7
F12	0.51±0.04	0.54±0.06	5.55±2.5	1.05±0.06	25.81±0.7

Values are expressed as mean±SD; n=3

 

Post-compression evaluation:

The thickness of the tablets was found to be in the range of 3.02 – 3.09 mm (Table 2). Uniform thicknesses were obtained due to uniform die fill, thus indicating good flow property, uniform pressure and uniform punch movement.  Hardness of the tablets was found to be in the range 5.10-6.09 kg/cm² (Table 3). Tablet hardness has influence on tablet density and porosity results in different release pattern of drug. This ensures that tablet could withstand to pressure, shocks during handling,

 

transportation and manufacturing process. Friability of tablets was observed in acceptable range 0.26-0.42% (Table 3). This ensures that tablet could withstand to pressure, shocks during handling, transportation and manufacturing process.

Drug content:

All the formulations showed drug content within the range of 94.28 to 99.42% (Table 3).

 

Table 3. Post compression evaluation of VLH SR tablets

All values are expressed as mean±SD

 

 

 

In vitro Drug Release study:

In vitro drug release of all the formulations was found to be in the range of 88.17% to 97.56%. In vitro drug release studies revealed that the release of drug from different formulations varies with the characteristic and composition of matrix forming polymers (figure 2). The effect of polymer level on release was studied by varying the levels of HPMC in the VHL SR tablets. The in vitro cumulative drug release profile of formulation F1 (HPMC K4M 15%) showed controlled release of drug up to 6h. It indicates that the low concentration of HPMC K4M fails to control the drug release and also, showed the burst release of drug. As the proportion of HPMC was increased, there was a progressive decline in the release rate because of formation of thick gel structure that delayed the drug release from the matrices, where hydration of HPMC resulted in extensive swelling and increase in the diffusion path length. ⁽¹³⁾ In order to decrease burst release of drug and controlled release over period of 12h, different viscosity grades of HPMC were tried to prepare the matrix tablets with varying concentration of polymer. The formulation F6 containing high viscosity grade of HPMC controlled the release of VHL upto 8h with maximum drug release 89.11%. It indicates that different grades of HPMC were unable to control drug release up to 12h. The formulations with carbopol alone showed good sustained drug release as compared with the HPMC formulations. The batches F7 and F8 showed the drug release 94.43% and 92.44% respectively over period of 9h. In case of carbopol-934P, the carboxyl groups highly dissociate repulsion between the negatively charged carboxyl groups causing uncoiling and expansion of molecules and thus result in gel formation. The gel thus formed consists of closely packed swollen particles. Carbopol-934P is a cross-linked polymer with high molecular weight (~2×106 Da) and viscosity, and when it comes in contact with water, it would swell and hold water inside its microgel network⁽¹⁴⁾.  Batches prepared with carbopol and xanthan gum retarded drug release over period of 12h. This may be due to formation of gelatinous barrier by polymers and thus forms networks of cross links around the tablet after absorption of dissolution medium ⁽¹⁵).  Drug release of these batches was found to be in the range of 88.17 to 96.24%.  The drug release kinetics is given in table 4.  The values of release exponent were found to be in the range of 0.55 to 0.90. The formulations F1 to F3 followed Higuchi kinetics, F4 to F9 followed Korsemeyer-Peppas kinetics while F10 to F12 followed zero order kinetics. The model independent parameter, mean dissolution time was found to be in the range of 2.13 – 4.29h for formulation F1 to F8. It indicates alone single polymer was unable to control drug release of VHL for 12h. Also, dissolution efficiency for these formulations was found to be in the range of 52.7-62.8. It is clearly indicated that the combination of carbopol and xanthan gum are very useful in the formulation of VHL SR tablets for sustaining the drug release.

 

Figure 2. In vitro release profiles of VHL SR tablets

 

Table 4. Drug release kinetics of VHL SR tablets

 

 

 

CONCLUSION:

The sustained release tablet of VHL was prepared by using direct compression method. From the result, it is clear that single polymer was unable to control release of drug over period of 12h. The combinations of carbopol with xanthan gum formulations have capacity to control drug release for long period. Among the various sustained release formulations studied, formulation F11 was optimized formulation  prepared with carbopol (15%) and xanthan gum (15%) showed the best result in terms of the desired sustained release profile over a period of 12 h (90.02% ± 1.5). Therefore, the present investigation of sustained release tablets of VHL formulated with carbopol and xanthan gum is considered to be potentially useful for treatment of major depressive disorder which improves the patient compliance and convenience.

 

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Received on 27.09.2016       Accepted on 27.10.2016     

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