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Current Drug Therapy, 2020, 15, 00-00 1

RESEARCH ARTICLE

Formulation Development and Characterization of Controlled Release

Core-in-Cup Matrix Tablets of Venlafaxine HCl

Balaji Maddiboyina1, Vikas Jhawat2,*, Gandhi Sivaraman3, Omprakash Sunnapu4, Ramya Krishna
Nakkala1, Mudavath Hanuma Naik1 and Monika Gulia2

1
Department of Pharmaceutical Sciences, Vishwa Bharathi College of Pharmaceutical Sciences, Guntur, A.P, India;
2
Department of Pharmacy, School of Medical & Allied Sciences, GD Goenka University, Gurugram, Haryana, India;
3
Department of Chemistry, Gandhigram Rural Institute Deemed University, Dindigul, Tamilnadu, India; 4Department of
Pharmaceutical Sciences, Anna University, Dindigul, Tamilnadu, India

Abstract: Background: Venlafaxine HCl is a selective serotonin reuptake inhibitor, which is given in
the treatment of depression. The delivery of the drug at a controlled rate can be of great importance for
a prolonged effect.
Objective: The objective was to prepare and optimize the controlled release core in a cup matrix tablet
of venlafaxine HCl using the combination of hydrophilic and hydrophobic polymers to prolong the
effect with rate controlled drug release.
Methods: The controlled release core in cup matrix tablets of venlafaxine HCl was prepared using
HPMC K5, K4, K15, HCO, IPA, aerosol, magnesium stearate, hydrogenated castor oil and micro crys-
talline cellulose PVOK-900 using wet granulation technique. Total ten formulations with varying con-
ARTICLE HISTORY centrations of polymers were prepared and evaluated for different physicochemical parameters such
FTIR analysis for drug identification. In-vitro drug dissolution study was performed to evaluate the
Received: October 28 2019 amount of drug release in 24 hrs, drug release kinetics study was performed to fit the data in zero order,
Revised: February 12 2020 first order, Hixson-crowell and Higuchi equation to determine the mechanism of drug release and stabil-
Accepted: March 01 2020
ity studies for 3 months as observed.
DOI:
10.2174/1574885515666200331104440
Results: The results of hardness, thickness, weight variation, friability and drug content study were in
an acceptable range for all formulations. Based on the in vitro dissolution profile, formulation F-9was
considered to be the optimized, extending the release of 98.32% of drug up to 24 hrs. The data fitting
study showed that the optimized formulation followed the zero order release rate kinetics and when
compared with the innovator product (flavix XR), showed better drug release profile.
Conclusion: The core-in-cup technology has the potential to control the release rate of freely water
soluble drugs for single administration per day by optimization with the combined use of hydrophilic
and hydrophobic polymers.
Keywords: Venlafaxine HCl, polymers, controlled release, core and cup, HPMC, wet granulation, matrix tablets.

1. INTRODUCTION of the drug. Thus the drug in the formulation must be chemi-
cally, physically and microbiologically stable. Side-effects of
The treatment of acute diseases or chronic illness has
the drug and drug interactions should be avoided or mini-
been achieved by the delivery of drugs to patients for many
years. These drug delivery systems include tablets, injectables, mized by the use of suitable drug delivery systems. The de-
suspensions, creams, ointments, liquids and aerosols. Today livery systems also need to improve the convenience of drug
these conventional drug delivery systems are widely used. administration [1]. Dosage forms can be designed to modify
The term drug delivery can be defined as techniques that are the release of the drug over a given time or after the dosage
used to get the therapeutic agents inside the human body. form reaches the required location. Drug release only occurs
Another role of the delivery systems is to allow safe application sometime after the administration or for a prolonged period
of time or to a specific target in the body. Modifications in
drug release are often desirable to increase the stability,
*Address correspondence to this author at the Department of Pharmaceutical safety and efficacy of the drug to improve the therapeutic
Science, School of Medical and Allied Science, GD Goenka University,
outcome of the drug treatment and/or to increase patient
Gurugram, Haryana, India; Tel: 9729216101;
E-mail: Jhawat231287@gmail.com compliance and convenience of administration [2].

1574-8855/20 $65.00+.00 ©2020 Bentham Science Publishers

2 Current Drug Therapy, 2020, Vol. 15, No. 0 Maddiboyina et al.

A novel core-in-cup approach can be utilised for Formulation Development:

characterising controlled release, buccoadhesive controlled
release system, osmotically controlled, mucoadhesive drug 3.1. Formulation Of Core Tablets
delivery system and also for chronotherapeutic drug delivery
The ingredients of the formulation were weighed accu-
system. The core-in-cup is an innovative oral pulsatile drug
delivery system containing a dry coated tablet in a core-in- rately as per the formula. Binder solution was prepared in a
cup manner, in which the core tablet is surrounded with an combination of IPA: Water (9:1) using PVPK-90D as the
inactive material on the bottom and circumference wall [3]. binding agent. Uniform sized granules were prepared by
This system is comprised of following 3 different components: slowly adding the binder solution to the powder mix and
passing through sieve no. 30. The core tablets containing the
• Active material core tablet active drug were prepared using an automatic compression
• Impermeable outer shell machine having flat punches to form disc-shaped core tablets
(Table 1 and Table 2).
• Top cover layer-barrier of a soluble polymer.
The drug is released after a certain time delay after the 3.2. Formulation of Cup
erosion of the top cover layer begins. This time delay in drug The core tablets having active material were placed in the
release can be modified by the quantity of material used
centre of round flat faced punch placed within the die cavity
along with its physiochemical characteristics and the drug’s
to form the cup by lowering the punch moved down slightly.
solubility [4]. The release time delay increases with the in-
Weighed quantity of the powder mix to form the outer cup
crease in the thickness of the top layer.
was added in the die of the rotary and finally compressed
In the present study, we tried to formulate and optimize (Fig. 1).
the controlled release core-in-cup matrix tablet of Ven-
lafaxine HCl for a prolonged effect. Venlafaxine hydrochlo- In the second run, the hydrophobic material was used to
ride is an antidepressant for oral administration, well ab- form a barrier on the circumference and the base of the core
sorbed (around 92%) with 45% absolute bioavailability and tablet, which finally gave the core-in-cup tablet of
extensively metabolized in the liver via CYP2D6 [5-7]. It venlafaxine HCl (8 mm round flat punch).
acts by a dual mechanism such as serotonin reuptake inhibi-
tion and the central nervous system [8-9]. 3.3. Evaluation Parameters
3.3.1. Pre Compression Parameters for Pure Drug
2. MATERIALS AND METHODS
3.3.1.1. Bulk Density (BD)
Venlafaxine HCl was obtained as a gift sample provided
by Dr. Reddy’s Laboratories, Hyderabad. HPMC K 5CPS, Bulk density = Weight of powder / Bulk volume
HPMC K 4 M, HPMC K 15 M, Microcrystalline cellulose, PVP
K-90D and other chemicals used were of analytical grade 3.3.1.2. Tapped Density (TD)
and were obtained from Apex pharmaceuticals, Chennai. Tapped Density = Weight of powder / Tapped volume
2.1. Preformulation Studies 3.3.1.3. Carr’s Index
2.1.1. Infrared Absorption Spectrum Carr’s Index is used to evaluate the bulk density and
The infrared absorption spectrum of Venlafaxine was tapped density of a powder and the rate at which it is packed
recorded with a KBr disc over the wave No. 4000 to 400 cm-1. down. The Carr’s Index is represented per the as below
equation:
2.1.2. Preparation of Standard Calibration Curve
Carr’s Index (%) = [(TD-BD) x100]/TD
The standard stock solution of Venlafaxine HCl was pre-
pared by dissolving 50 mg of pure drug in 50ml of distilled 3.3.1.4. Hausner’s Ratio
water, which gave the concentration of 1mg/ml. Then, 2.5ml The Hausner’s ratio is a number that is correlated to the
of this solution was further diluted with 25ml distilled water,
flow ability of a powder or granular material and its standard
which gave the concentration of 100 µg /ml. Further dilu-
values are given in Table 3.
tions were made to obtain the concentration range of 20-100
µg/ml. The absorbance was measured at 225.5nm to prepare Hausner’s Ratio = TD / BD
the calibration curve.

3. COMPATIBILITY STUDIES OF DRUG AND Table 1. Compression Parameters.

POLYMERS
The mixture of drug and individual excipient of all ex- Parameters Core Cup
cipients and drugs was taken in the formulation ratio in a
Lower punch 5.5mm round 8mm round
flint vial and stored at 400C/ 75% RH, (Accelerated condi-
tion) and 600c (stress condition). Any change in the physical Upper punch 5.5mm round 8mm round
characteristics of samples was observed with respect to the
control sample stored at 40oC for 0, 10, 20 and 30 days [4, 10]. Dies 5.5mm round 8mm round
Formulation Development and Characterization of Controlled Release Current Drug Therapy, 2020, Vol. 15, No. 0 3

Table 2. Composition Table.

F1 F2 F3 F4 F5 F6 F7 F8 F9 F10

Core mg/ mg/ mg/ mg/ mg/ mg/ mg/ mg/ mg/ mg/
tablet tablet tablet tablet tablet tablet tablet tablet tablet tablet

Venlafaxine HCl 75 75 75 75 75 75 75 75 75 75

HPMC 5 CPS 5 10 - - - - - - - -

HPMC K 4 M - - 5 10 - - - - - -

HPMC K 15 M - - - - 10 15 3.75 5 5 3.75

HCO 9.375 9.375 9.375 9.375 9.375 9.375 7.5 9.375 9.375 7.5

Avicel PH 102 26.06 21.06 26.06 21.06 21.06 16.06 29.185 26.06 26.06 29.185

PVP K-90D 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5

Yellow iron oxide 0.375 0.375 0.375 0.375 0.375 0.375 0.375 0.375 0.375 0.375

Aerosil 0.937 0.937 0.937 0.937 0.937 0.937 0.937 0.937 0.937 0.937

Mg. Stearate 0.75 0.75 0.75 0.75 0.75 0.75 0.75 0.75 0.75 0.75

Core tablet weight 125 125 125 125 125 125 125 125 125 125

Cup

HCO 181.88 181.88 181.88 181.88 181.88 181.88 181.88 121.25 181.88 121.25

Avicel PH 102 60.625 60.625 60.625 60.625 60.625 60.625 60.625 121.25 60.625 121.25

PVP K-90D 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5

Total tablet weight 375 375 375 375 375 375 375 375 375 375

Fig. (1). Diagrammatic representation of core in cup formulation. (A higher resolution / colour version of this figure is available in the elec-
tronic copy of the article).

3.4. Post-Compressional Studies test was performed according to the official method. The
3.4.1. Thickness average weight was noted and the standard deviation was
calculated.
Before the compression of the cup, the thickness of the
core tablets was measured. Finally, the thickness of core-in- 3.4.3. Hardness Test
cup tablets was determined in millimetre (mm).
The hardness of five core tablets was measured using a
3.4.2. Weight Variation Test Schleuniger tablet tester before the compression of the cup
Twenty tablets of each formulation were weighed and after the compression of core-in-cup tablets. The results
separately using a Sartorius electronic balance and the are reported in kilopascals (Kp).
4 Current Drug Therapy, 2020, Vol. 15, No. 0 Maddiboyina et al.

Table 3. Effect of Carr’s Index and Hausner’s Ratio on flow property.

Flow Character Carr’s Index (%) Hausner’s Ratio

Excellent ≤10 1.00-1.11

Good 11-15 1.12-1.18

Fair 16-20 1.19-1.25

Passable 21-25 1.26-1.34

Poor 26-31 1.35-1.45

Very poor 32-27 1.46-1.59

Very very poor 38 >1.6

3.4.4. Friability Test formulation for 3 months. The samples were withdrawn at
30, 60 and 90 days for physical and in vitro evaluation of
For each pulse dose tablet formulation, the friability of 6
drug release [14-15].
tablets was determined using the Roche friabilator (17). Fri-
ability can be determined by the following equation: 4. RESULTS AND DISCUSSION
4.1. Pre-formulation Studies
In pre-formulation studies, characterization of API (iden-
tification test by FTIR,) was performed and it was found that
3.4.5. In vitro Dissolution Studies all are within the range specified in the pharmacopoeia (Fig.
Dissolution apparatus (USP type II paddle, Electrolab, 2) and the calibration curve was plotted from the data ob-
India) was used to study in vitro drug release of venlafaxine tained in Table 4.
HCl using water as the dissolution media for 24hrs [11]. Op-
erating parameters included the stirring speed of 50 rpm, the 4.2. Pre-compression Parameters
temperature was maintained at 37 ±0.50C and the total vol- Bulk density and tapped density for the formulations
ume of media used was 900ml of purified water. The disso- were in the range of 0.313- 0.577gm/ml and 0.440-
lution samples of 10ml were withdrawn at sampling inter- 0.833gm/ml. Compressibility index and Hauser’s ratios were
vals1, 2, 4, 8, 10, 12, 24 hours and checked for the amount of in the range of 16.72-34.98% and 1.09-1.53. From the above
drug released. trial batches, formulation trials F3, F4, F6, and F8 showed
passable flow properties, where as trials F1, F2, F5, and F7
3.4.6. Similarity Factor (f2) showed poor flow properties and trials F9, F10 showed good
This is used for the performance difference between the flow properties. The results obtained confirm that the
two same dosage compounds. If the value is more than 50, it batches which exhibit good flow properties have good pack-
is similar (f2), and if less than 50, it is dissimilar (f1). ing characteristics (Table 5).

3.4.7. Release Kinetics 4.3. Post-compression Parameters

The in vitro drug release data was fitted with various Thickness of tablets was found to be almost uniform in
kinetic equations such as zero order (% release vs time), first all the six formulations. They were found to be in the ranges
order (log% unreleased vs time), Hixson - crowell release of 4.18-4.54mm. All the tablets passed weight variation test
equation (3 √ Q O - 3√Q t)and Higuchi matrix (% release vs as the % weight variation, which was within the Pharma-
square root of time) to understand the mechanism and kinet- copeia limits of ± 5% of the weight. The average weight of
ics of drug release. Regression coefficient (r2) values were all tablet formulations was within the ranges of 375-377mg.
calculated for the linear curves obtained by regression analy- The weights of all the tablets were found to be almost uniform.
sis of the above plots. In order to define a model which will
represent a better fit for the formulation, drug release data The measured hardness of tablets of each batch of all
were further analysed by Peppas equation, Mt/M∞=ktn, formulations was ranged between 5.08-6.62Kg/cm2, which is
where Mt is the amount of drug released at time t and M∞ is falling within the hardness specification as per I.P. The fri-
the amount released at time ∞, the Mt/M∞ is the fraction of ability of tablets was found to be within the ranges between
drug released at time t, k is the kinetic constant and n is the 0.001 to 0.102%, which are generally considered and accept-
diffusion exponent, a measure of the primary mechanism of able as per I.P. The data indicates that the percentage friabil-
drug release [12, 13]. ity was less than 1% in all the formulations, ensuring no
physical damage will take place during handling and
3.4.8. Stability Studies shipping of tablets. The results indicate that the percentage
The stability studies were carried out as per ICH guide- of drug content was within the ranges of 99.08 to 100.2 %
lines at refrigerator and workbench for the following selected of venlafaxine HCl which was within the acceptable limits
Formulation Development and Characterization of Controlled Release Current Drug Therapy, 2020, Vol. 15, No. 0 5

Fig. (2). a) FT-IR Spectrum of Venlafaxine HCl b) Calibration Curve of Venlafaxine HCl. (A higher resolution / colour version of this figure
is available in the electronic copy of the article).

Table 4. Calibration Curve of Venlafaxine HCl.

Concentration (µg/ml) Absorbance at 225.5nm Equation of line and regression

0 0

2 0.163

4 0.316 y = 0.0746x+0.0086

6 0.457 R2 = 0.9994

8 0.598

10 0.755
6 Current Drug Therapy, 2020, Vol. 15, No. 0 Maddiboyina et al.

Table 5. Pre-compression evaluation Parameters.

Formulations Bulk Density (gm/cc) Tapped Density (gm/cc) Carr’s Index (%) Hausner’s Ratio

F1 0.577 0.769 24.96 1.33

F2 0.526 0.714 26.33 1.35

F3 0.389 0.445 18.13 1.20

F4 0.330 0.465 21.05 1.09

F5 0.545 0.714 23.66 1.31

F6 0.379 0.440 20.08 1.14

F7 0.500 0.769 34.98 1.53

F8 0.313 0.440 18.33 1.19

F9 0.555 0.833 16.72 1.50

F10 0.490 0.65 17.0 1.22

Table 6. Post-compression evaluation Parameters.

Batch no Thickness (mm) ± S.D Average Weight (mg) ± S.D Hardness (Kp) ± S.D Friability (%) ± S.D Assay (%)

Core Core-in-cup Core Core-in-cup

F1 4.42+ 0.012 5.32 + 0.07 375 + 1.922 6.23 + 0.08 10.0 + 2.02 0.033 + 0.007 99.30

F2 4.39 + 0.021 5.14 + 0.12 376 + 0.655 6.41+ 0.05 10.9 + 1.56 0.006 + 0.023 99.08

F3 4.23 + 0.014 5.01 + 0.03 377 + 1.01 6.23 + 0.21 11.0 + 0.98 0.083 + 0.015 99.53

F4 4.32 + 0.011 5.05 + 0.09 375 + 1.577 6.02 + 0.01 11.1 + 1.20 0.024 + 0.025 99.85

F5 4.35 + 0.017 5.11 + 0.02 377 + 1.09 6.62 + 0.31 11.7 + 2.30 0.118 + 0.022 99.76

F6 4.18 + 0.001 5.12 + 0.01 375 + 0.56 6.04 + 0.42 10.5 + 1.78 0.058 + 0.029 99.45

F7 4.54 + 0.012 5.01 + 0.01 376 + 1.01 6.20 + 0.24 11.5 + 1.94 0.001 + 0.034 99.67

F8 4.24 + 0.015 5.04 + 0.03 376 + 1.55 6.41 + 0.15 10.1 + 1.93 0.078 + 0.044 99.75

F9 4.31 + 0.008 5.16 + 0.05 375 + 1.23 5.08 + 0.08 11.8 + 0.99 0.009 + 0.015 100.2

F10 4.36 + 0.005 5.09 + 0.06 377 + 0.577 6.11 + 0.33 12.0 + 0.52 0.102 + 0.035 99.85

Table 7. Dissolution Profiles of Core in Cup Tablets of Venlafaxine HCl Trial Batches.

Time (hrs) F1 F2 F3 F4 F5 F6 F7 F8 F9 F10

1 19.82 18.832 17.83 16.32 23.24 22.60 21.83 22.62 21.24 32.60

2 39.50 33.592 31.59 30.92 50.64 52.68 48.59 43.02 36.97 47.02

4 45.34 44.324 61.34 50.32 63.24 67.20 61.32 57.80 52.44 59.51

8 69.24 67.24 83.24 61.24 89.08 75.56 73.24 78.65 73.40 74.54

10 93.13 91.13 92.12 87.28 94.12 87.72 87.13 86.42 87.44 83.44

12 100 100 98.91 96.16 97.36 91.68 94.92 98.86 93.40 96.91

24 - - 99.72 99.18 99.32 99.08 99.44 99.32 98.32 99.53

Formulation Development and Characterization of Controlled Release Current Drug Therapy, 2020, Vol. 15, No. 0 7

Fig. (3). Dissolution profiles of F1-F10. (A higher resolution / colour version of this figure is available in the electronic copy of the article).

as per the I.P. Finally F9 formulation was considered as op- 4.4. In vitro Dissolution Studies
timized formulation batch because all the parameters were
The data obtained from the in vitro dissolution study is
found to be within limits when compared with all formula-
given in Table 7 and shown in Fig. (3).
tions (Table 6).
We selected F-9 as best formulation as it showed zero
Table 8. Comparative Dissolution profiles of optimized batch order release kinetics in 24hr than all other formulations
(F-9) with Flavix XR. (Table 8, Fig. 4).

4.5. Similarity Factor (f2)

TIME(hrs) Flavix XR F9
Similarity factor (f2) between the marketed and opti-
1 21.50 21.24 mized formulation was found to be 79.027 (Fig. 5).
2 35.94 36.97 4.6. Release Kinetics
4 54.10 52.44 Drug release kinetics data obtained from the above mod-
8 71.88 73.40 els will reveal that the optimized batch (F-9) follows Zero
Order (Table 9).
10 75.62 87.44
4.7. Stability Studies
12 93.18 93.40
There was no significant change in the physical and
24 98.98 98.32
chemical properties of the tablets of formulation F-9 after

Fig. (4). Comparative Dissolution profiles of optimized batch (F-9) with Flavix XR. (A higher resolution / colour version of this figure is
available in the electronic copy of the article).
8 Current Drug Therapy, 2020, Vol. 15, No. 0 Maddiboyina et al.

Fig. (5). Similarity factor between the optimized and marketed formulation. (A higher resolution / colour version of this figure is available in
the electronic copy of the article).

Table 9. Drug release Kinetics.

Formulation Code Drug Release Kinetics (R2) Release Exponential ( n)

Zero Order First Order Higuchi Plot Peppas Plot

F1 0.9573 0.0516 0.9714 0.0223 0.2396

F2 0.9731 0.0533 0.97 0.0262 0.2578

F3 0.6771 0.9332 0.8948 0.6329 1.0496

F4 0.7566 0.9448 0.9255 1.0421 0.65

F5 0.6229 0.9479 0.8742 0.5477 0.973

F6 0.6512 0.9879 0.8906 0.5356 0.952

F7 0.6875 0.9813 0.9123 0.5554 0.9668

F8 0.6935 0.8687 0.9163 0.5692 0.9795

F9 0.9989 0.567 0.9329 0.5939 0.9926

F10 0.6969 0.9543 0.9242 0.5005 0.9085

Table 10. Stability studies of optimized batch and innovator.

Formulation Code Parameters Initial 1 Month 2 Months 3 Months Limits as per Specifications

Innovator 400C/75% RH % Release 98.98 98.98 98.85 98.77 Not less than 85%
0
F-9 40 C/75% RH % Release 99.85 99.73 99.63 99.48 Not less than 85%

3 months. Parameters quantified at various time intervals are from the dosage matrix into the in-vitro dissolution fluid.
shown in Table 10. Tablets of each formulation were subjected to various
evaluation parameters like thickness, hardness, friability,
CONCLUSION weight variation and drug content of the formulations, which
were found to be satisfactory. Among all formulations pre-
In the present study, an attempt was made to design and pared and evaluated, F9 showed within limits, zero order
evaluate the controlled release core-in-cup tablets of ven- release kinetics and matched similar release patterns with
lafaxine HCl (anti-depressant) by the wet granulation tech- that of innovator release at each hour release. Thus, formula-
nique. The release of the drug from a matrix tablet contain- tion F9 was taken as an optimized formulation. The tablets
ing hydrophilic polymers generally involves factors of diffu- equivalent to 75 mg of drug were formulated by the core-in-
sion. The core-in-cup formulation has a hydrophilic polymer cup method in which core tablet is 125 mg and the coating
HPMC K15M. Diffusion is related to the transport of drug material with different polymers at different concentrations.
Formulation Development and Characterization of Controlled Release Current Drug Therapy, 2020, Vol. 15, No. 0 9

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Declared none.