International Journal for Pharmaceutical Research Scholars (IJPRS) · 2019-11-12 · cyclohexanol hydrochloride and has the 1 *Address for Correspondence: Department of Pharmaceutic

International Journal for Pharmaceutical Research Scholars (IJPRS) ISSN No: 2277-7873

RESEARCH ARTICLE V-1, I-2, 2012

© Copyright reserved by IJPRS 437

Development and In Vitro Characterization of Sustained Release Pellets of

Venlafaxine Hydrochloride Remya PN1, Damodharan N1, Dineshkumar S*1, Sowjanya V2

1Srm College of Pharmacy, Srm University, Kanchipuram District, Tamilnadu, India. Manuscript No: IJPRS/V1/I2/00095, Received On: 18/05/2012, Accepted On: 28/05/2012

ABSTRACT The present study was undertaken with development and in-vitro characterization of sustained release pellets of venlafaxine hydrochloride by wruster process technique .which release the drug in sustained manner over a period of 20 hours. The different viscosity grades of polymers are HPMC-E6, Ethyl cellulose 7cps, MCC-101 were preparation of granules or pellets by wurster coating .The granules were prepared and evaluated for Angle of repose, bulk density, tapped density, cars index, moisture content, stability studies and dissolution studies were carried out. Formulation f1 and f2 can be considered as an optimized formulation for disperse the drug freely in GIT tract of venlafaxine HCl for getting more bioavailability.

KEYWORDS Venlafaxine HCl, Pellets, Ethyl cellulose, Wruster process technique, Dissolution studies, Bioavailability.

INTRODUCTION The purpose of the present research was to develop a pharmaceutically equivalent, stable, cost effective and quality improved formulation of venlafaxine HCl pellets to present it in the form of sustained release capsules and these were compared with that of the marketed dosage form. In this study various prototype formulation trails were taken and evaluated with respect to the various quality controls such as dissolution, assay, acid resistance and moisture content. The formula was finalized by comparing the in vitro dissolution profile with that of the innovator. Venlafaxine hydrochloride, structurally a novel antidepressant. It is designated (R/S)-1-[2-(dimethylamino) -1-(4-methoxy phenyl) ethyl] cyclohexanol hydrochloride or (±)-1-[α- [(dimethylamino) methyl]-p- methoxy benzyl] cyclohexanol hydrochloride and has the

empirical formula of C17H27NO2 HCl.7

Venlafaxine, an antidepressant agent structurally unrelated to other antidepressants, is used to treat melancholia, generalized anxiety disorder (GAD), panic disorder, post-traumatic stress disorder, and hot flashes in breast cancer survivors. The Melting Point of Venlafaxine was found to be 215-217oC and its solubility as 572 mg/ml in water.

Preclinical studies have shown that venlafaxine and its active metabolite, O-desmethyl venlafaxine (ODV), are potent inhibitors of neuronal serotonin and nor epinephrine reuptake and weak inhibitors of dopamine reuptake. Venlafaxine and ODV have no significant affinity for muscarinic cholinergic, H1 -histaminergic, or α1 -adrenergic receptors in vitro. It is by oral administration and peak plasma concentration is may be achieved about 6 hrs of Extended release capsules and bioavailability

*Address for Correspondence: S. Dineshkumar Department of Pharmaceutics, Srm college of pharmacy, Srm university, Kanchipuram District, Tamilnadu, India. E-Mail Id: [email protected]

Development and In Vitro Characterization of Sustained Release Pellets of Venlafaxine Hydrochloride


was 45% following oral administration. Venlafaxine was metabolized mainly by hepatic metabolism. The primary route of excretion is by renal elimination.

MATERIALS AND METHODS Materials

Table 1: The following Materials used for the study

Methodology Venlafaxine hydrochloride sustained release pellets were prepared by wurster coating method using different excipients and polymers to release the drug slowly through an extend period of time.

Procedure The compatibility studies were carried out at 40oC/75% RH for 0,2 and 4 weeks and control samples were to be kept at 2-8oC. With respect to physical and chemical aspects, they were tested.

Procedure for the Preparation of Venlafaxine Hydrochloride Sustained Release Pellets Step 1: Dispensing Weigh the raw materials according to the manufacturing work order into double lined poly bags and affix dispensing labels with all details. Step 2: Pulverization and Blending 1. Pulverize the Venlafaxine HCl powder thoroughly and collect in double lined Poly bags.

2. Sieve through #30 mesh by using sifter

Step 3: Preparation of Binder Solution HPMC is dissolved in water under stirring and mix the blend with the binder.

Step 4: Extrusion-Spheronization The blend is taken into extrusion-spheronization to form appropriate uniform size pellets.

Step 5: Preparation of Sustained Release Coating Solution 1. Take Ethyl cellulose and Diethyl phthalate

in a Glass container under stirring continuously.

Materials Manufactured by

Venlafaxine HCl Cadila Pharmaceuticals Limited.

Avicel Microcrystalline Cellulose

FMC Biopolymer Limited.

Hydroxy Propyl Methyl Cellulose

Clorocon Asia Private Limited.

Opadry White Colorcon Asia Private Limited.

Diethyl Phthalate Tirumalai Chemicals Limited.

Ethyl Cellulose Aqualon

Table 2: Finalized formula F1 to F6

Sr. No. Ingredients F1 F2 F3 F4 F5 F6 1. Venlafaxine HCl 84.8 84.8 84.8 84.8 84.8 84.8 2. MCC 101 141.21 141.21 141.21 141.21 141.21 141.21 3. Hpmc-E6 1.14 1.14 1.14 1.14 1.14 1.14 4. Opadry White - 2.27 2.27 4.543 4.543 4.543 5. Ethyl Cellulose-7Cps 9.65 9.65 11.36 34.754 27.80 30.58 6. Hpmc-E6 1.71 1.71 - - - -

7. Diethylphthalate - - - 9.73 7.785 8.807

8. Iso Propyl Alcohol q.s q.s q.s q.s q.s q.s



2. Filter the solution through nylon mesh to get a uniform solution.

Step 6: Sustain Release Coating Load the pellets into Fluidized bed coater and spray the SR coating coating solution by using Fluidized bed coater Maintain the required conditions in Coater.

Step 7: Drying and Sifting for SR Coated Pellets 1. Initially dry the pellets under the current of

air for 30 min by using heaters and maintain temperature from 28ºC-32ºC. Dry the pellets till the moisture content of pellets reduce to 1.5%.

2. Sift the SR coated pellets from sieve #12 mesh, collect #12 mesh passing. sifting the #12 mesh passing through #16 mesh retained pellets and labeled as 12/16 fraction pellets.

Totally 6 Formulation trails were done using the same procedure. During all the stages of the manufacturing process, temperature and humidity was maintained at 25 ± 50C and 50 ±

RESULTS & DISCUSSION

10% RH. To optimize the formulation, the capsules were assay by U.V Spectroscopic method and drug release study.

The formula of Trial 5 was optimized and selected for evaluation studies. By using the same formula as that of Trial 5 batch that was taken for the stability study purpose.

Step 8: Filling: Filling of the pellets into capsules by manually.

Loading of Venlafaxine Hydrochloride Sustained Release Pellets in Capsules

Procedure 1. Size‘1’ capsules were selected for capsule

formulation 2. The pellets were loaded in hard gelatin

capsules No-1 by manual filling because it is a lab scale batch.

3. The pellets were transferred into capsules by spreading it into equal quantities equivalent to 250 mg Venlafaxine HCl .As per the above procedure, drug loading was carried out for 6 trails.

Table 3: Preformulation: API characterization

Sr. No. Test Specification Result 1 Description White or almost crystalline powder. A white powder 2 Solubility Freely soluble in Water Complies

3 Identification by IR

The IR Spectrum of the sample should in concordant with that of the IR spectrum obtained with working

Standard.

Complies

4 Bulk density

Tapped density Carr’s Index (%)

------

0.256g/ml 0.4919g/ml

47.778% 5 Melting range Between 215-217oC Complies 6 Assay % (Non aqueous ) 99.0% to 101.0%w/w 100.1%w/w 7 Heavy metals Not less than 20ppm Less than 20ppm

8

Related substances a) Impurity-F

b) Unspecified individual impurities

c)Total impurities

Not more than 0.10% Not more than 0.10% Not more than 0.20%

Below detection limit Below detection limit Below detection limit



Table 4: Evaluation of Sustained Release Pellets

Sr. No

Formulations

Angle of Repose

(º)

Bulk Density (gm/cc)

Tapped Density (gm/cc)

Compressibility Index (%)

Moisture Content

(%)

Assay%(w/w)

1 F1 28.8 0.65 0.79 17.7 2.43 89.9%

2 F2 25.6 0.69 0.81 14m.8 2.44 92.7%

3 F3 27.1 0.67 0.78 14.1 1.92 94.3%

4 F4 28.6 0.70 0.88 20.5 2.63 102%

5 F5 26.5 0.68 0.82 17.0 2.34 88.9%

6 F6 24.4 0.66 0.77 14.2 2.35 96.5%

Table 5: Dissolution Profile Comparison of Innovator and other formulations

Sr. No Dissolution Time (hrs) F1 F2 F3 F4 F5 F6 Innovator

1. 2 98.5 82.6 72.5 6.6 11.8 29.8 26.5

2. 4 99.0 95.7 88.5 16.0 36.1 57.7 51.3

3. 8 98.8 99.1 97.2 33.3 62.3 81.3 83.0

4. 12 98.7 99.8 98.8 46.4 74.8 92.3 92.7

5. 20 98.5 99.3 99.8 62.3 86.6 96.0 98.0

Figure 1: Comparative dissolution profile for F1 to F6 with innovator



Kinetics of Drug Release Comparison of Different Orders of Venlafaxine Hydrochloride Release The release profile of Venlafaxine HCl from formulation 6 was processed into graphs for comparison of different orders of drug release and, to understand the linear relationship, i.e., Kinetic principles. The data were processed for regression analysis using MS-Excel statistical functions. In vitro release data time points between 2 to 20 hour were considered and treated as shown in Table 5.

Kinetic models of optimized batch Zero-order kinetics

Figure 2: Zero-order kinetics of F6 Formulation

First-order kinetics:

Figure 3: First-order kinetics of F6 Formulation

Higuchi Kinetics

Figure 4: Higuchi plot of F6 Formulation

Korsmeyer-Peppas Kinetics:

Figure 5: Korsmeyer-Peppas of F6 Formulation

The value of compressibility index above 25%, 15-25%, less than 15% indicates poor flowability, optimum flowability and high flowability respectively. As Venlafaxine Hydrochloride value is more than 40% it exhibits very poor flow.

Different Kinetic models were applied to the innovator product & optimized formulation F6. It was observed that formulation F6 followed the First Order Reaction and Korsmeyer-Peppas Model kinetics and it complies with innovator’s product.



CONCLUSION The conclusions arrived in this thesis indicated that the sustained release pellets of venlafaxine hydrochloride, developed in this investigation was found to be equivalent to innovator’s US market product, effexor based on in vitro release studies.

Thus the objectives envisaged in this thesis were arrived. Further studies are needed to investigate this formulation for its performance in vivo and its equivalence with the marketed product, Effexor. Thus objectives of the present thesis are achieved.

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International Journal for Pharmaceutical Research Scholars (IJPRS) · 2019-11-12 · cyclohexanol hydrochloride and has the 1 *Address for Correspondence: Department of Pharmaceutic

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