Development and Optimization
of Extended-Release Venlafaxine HCl
Matrix Tablet
Jyotir
Patel*
Department of Pharmacy, Shri Jagdish Prasad Jhabarmal Tibrewala University, Vidyanagari,
Jhunjhunu,
Rajasthan, India
*Corresponding Author E-mail:
ABSTRACT:
The purpose of this research was to prepare
a extended release drug delivery system of Venlafaxine hydrochloride by using a wax matrix system. The
effects of paraffin wax and carnauba wax on drug release profile was
investigated. A 32 full factorial design was applied to systemically
optimize the drug release profile. Amounts of carnauba wax (X1) and
paraffin wax (X2) were selected as independent variables and release
after 12 h and time required for 50% (t50) drug release were
selected as dependent variables. A mathematical model was generated for each
response parameter. Both waxes retarded release after 12 h and increases the t
50 but paraffin wax showed significant influence. The drug release
pattern for all the formulation combinations was found to be approaching Peppas kinetic model. Suitable combination of two waxes
provided fairly good regulated release profile. The response surfaces and contour
plots for each response parameter are presented for further interpretation of
the results. The optimum formulations were chosen and their predicted results
found to be in close agreement with experimental findings.
KEY WORDS: Venlafaxine HCl, paraffin wax, carnauba wax,
extended release, factorial design, response surface
INTRODUCTION:
Venlafaxine is a unique antidepressant, and is
referred to as a serotonin-norepinephrine-dopamine
reuptake inhibitor[1],[2]. It works by blocking the transporter
"reuptake" proteins for key neurotransmitters affecting mood, thereby
leaving more active neurotransmitter in the synapse. The neurotransmitters
affected are serotonin (5-hydroxytryptamine)
and norepinephrine (noradrenalin). It is widely
prescribed for the treatment of depression, depression with associated symptoms
of anxiety, generalized anxiety disorder, and social anxiety disorder. The
recommended oral dosages of Venlafaxine hydrochloride
are typically in the range of 75 to 225 mg per day. Because of its relatively
short half-life of 5h, Venlafaxine should be
administered in divided dosages throughout the day [3].
Hydrophobic wax matrix systems are being widely used in oral
controlled drug delivery because of their flexibility to obtain a desirable
drug release profile, cost-effectiveness, and broad regulatory acceptance [4]. Factorial design is an optimization technique,
where all the factors are studied in all possible combinations. This technique
is considered most efficient in estimating the influence of individual
variables (main effects) and their interaction using minimum experimentation[5],[6].
A Factorial Design for two factors at
three levels each 3 2 is considered identical to a two factor
composite design [7].
MATERIALS AND METHODS:
Venlafaxine HCl was obtained
from Cadila Healthcare Pvt. Ltd. (Ahemadabad,
India), Talc powder by Cosmo Chem. (Pune, India), and
lactose, from M/s Loba Chemie
Ltd. (Mumbai, India) were procured from commercial sources. All other chemicals
used in the study were of analytical grade.
Drug-excipient compatibility studies:
Drug-excipient compatibility studies
were done by Fourier Transform Infrared Spectroscopy. The drug with
other excipients like carnauba wax, paraffin wax and Eudragit L 100 (on a 1:1 ratio) were subjected to storage
at room temperature and elevated temperature in stability chamber at 45°/75% RH
for three month. After three month the samples were taken and IR spectrum of
samples were recorded with FTIR spectrometer (460 Plus, Jasco).
Preparation of wax matrix tablets:
The preliminary
study was done by using various waxes such as compritol,
precirol, carnauba wax, paraffin wax and stearic acid. From the preliminary study paraffin wax and
carnauba wax were selected for further study. The paraffin wax was selected for
its retardant effect and carnauba wax to provide mechanical strength to the
matrix.
The waxes were molten and then required quantity of drug (Venlafaxine
HCl) was slowly added to the molten wax. After
cooling, the mass was subjected to granulation by passing through the sieve no
16. Granules were mixed with lactose and talc and blend was compressed into
flat-faced tablets (200 mg, 8 mm diameter) using a Rimek
Mini Press-II MT tablet machine (Karnawati Eng. Ltd.,
Mehsana, India) to achieve a tablet thickness of
1.5±0.1 mm [8]-[10] .
TABLE 1: COMPOSITION OF WAX MATRIX TABLET OF VENLAFAXINE HCL
|
Ingredients
|
Quantity (mg)
|
|
Venlafaxine
|
37.5
|
|
Paraffin wax
|
18.5-56.25
|
|
Carnauba wax
|
18.5-56.25
|
|
Talc
|
5
|
|
Lactose
|
q.s.
|
[Table 1] lists the composition of different formulations prepared by using
varying amounts of paraffin wax, carnauba wax and lactose along with a fixed
quantity of talc.
Factorial Design:
TABLE 2: A 3² FULL FACTORIAL EXPERIMENTAL DESIGN LAYOUT
|
Coded Factor Level
|
|
X1
|
X2
|
|
-1
|
-1
|
|
-1
|
0
|
|
-1
|
1
|
|
0
|
-1
|
|
0
|
0
|
|
0
|
1
|
|
1
|
-1
|
|
1
|
0
|
|
1
|
1
|
*X1 indicates amount of carnauba wax
(mg); X2 amount of paraffin wax. Translation of coded levels in actual level is
as follows, For -1, actual level of X1 and X2 is
18.75; For 0, actual level of X1 and X2 is 37.5; and For 1, actual level of X1
and X2 is 56.25.
A 3² full FD was constructed where the amounts of Carnauba wax (X1)
and paraffin wax (X2) were selected as the factors. The levels of
the two factors were selected on the basis of the preliminary studies carried
out before implementing the experimental design [11],[12]. All other formulations and processing
variables were kept invariant throughout the study. [Table 2] summarizes the
experimental runs, their factor combinations, and the translation of the coded
levels to the experimental
units.
Physical evaluation:
Ten tablets from each batch were evaluated for uniformity in
tablet weight and thickness. Tablets from each batch were examined for
friability using a Roche-type friabilator (Tropical
Equipment Pvt. Ltd., Mumbai, India) and hardness using a Monsanto-type hardness
tester (Campbell, Mumbai, India) [13],[14] .
In Vitro Release Study [15] :
Drug release studies (n=3) were conducted for all the formulation
combinations using dissolution test apparatus (Veego,
DA-6D USP Standard). Distilled water (900 ml) was taken as the release medium
at 100 rpm and 37±1º employing USP II paddle method (Apparatus 2). Aliquots of
small samples were periodically withdrawn and the sample volume replaced with
an equal volume of fresh dissolution medium. The samples were analyzed
spectrophotometrically at 224 nm.
Data Analysis:
The data obtained from dissolution kinetics studies were analyzed
using PCP Disso v2.08 software developed by Poona College of Pharmacy, Pune. The computed values of kinetic constant (k) and diffusional release exponent (n) were calculated using
logarithmic transformation of the relationship proposed by Korsmeyer,
which was
(Eqn.
1),
Where, M t /M∞ is
the fraction of drug released at time t. The values of t 50% were
calculated by MS-Excel on computers.
Various computations for the current optimization study using RSM were carried
out, employing Stat Ease Design Expert Version 7 [16] .
Statistical second-order model including interaction and polynomial terms were
generated for all the response variables. The general form of the model is,
(Eqn. 2),
where β0 the intercept, is the arithmetic average
of all quantitative outcomes of nine runs, β1 to β8
are the coefficients computed from the observed experimental values of Y, and X
1 and X 2 are the coded levels of the independent variable(s).
The terms X 1 X 2 and X 2 i (i= 1, 2) are the
interaction and polynomial terms, respectively. The statistical validity of the
polynomials was established on the basis of Yates' ANOVA. Subsequently,
feasibility as well as grid search was performed to locate the composition of
optimum formulations. Also, three-dimensional response surface graphs and
contour plots were drawn in MS-Excel using the output files generated by the
State Ease Design Expert Version-7 software.
Validation of Optimization Model:
Six optimum formulations were selected by intensive search,
performed over the entire experimental domain, to validate the chosen
experimental design and polynomial equations. The criterion for selection of
optimum was primarily based on the highest possible values of the response
parameters, which are released in 12 h and t 50% . The formulations
corresponding to this optimum were prepared and evaluated for various response
properties. The resultant experimental data of response properties were
subsequently quantitatively compared with predicted values, also linear
regression plots between these, forcing the line through the origin were
attempted.
RESULTS
AND DISCUSSION:
FTIR spectrum shows no evidence of interaction between drug and
studied excipients. All the major drug peaks
(functional group) at 3669 cm -1 [CH stretch]; 1438 cm -1
[N-(CH3) 2] and 2995 cm -1 [OH] were seen in
subsequent spectra of drug and excipients kept
together. The literature documented that significant reduction in the dose
frequency can be achieved via SR drug delivery system of Venlafaxine
HCl . Design of experiment (DOE) has been
widely used in pharmaceutical field to study the effect of formulation variables
and their interaction on response variable
The nine formulations were designed, using various higher and
lower levels of carnauba wax and paraffin wax [Table 1]. All the preparations of each
formulation passed weight variation test; the weight variation in all the nine
formulations was found to be 198.5 mg to 202.8 mg, which was within pharmacopoeial limits. The hardness was found to be between
6 to 7 kg/cm2. Friability of all the
formulations was found to be less than 0.5%. In the current study, [Table 3]
shows that with the increasing amount of carnauba wax and paraffin wax, the
release after 12 h is decreased and time taken for 50% drug release increases
linearly.
[Table 3] lists various dissolution kinetic parameters computed
for all nine batches. In the current study, in all the nine cases studied, the
n varied between 0.2437 and 0.6068. Further, the magnitudes of kinetic constant
(k) ranges between 10.47 and 49.02; consequently, the value of t50%
varies in between 1 h 17 min to12 h 42 min according to wax content.
The mathematical relationship constructed for the studied response
variables are expressed as Eqns. 2 and 3. All the polynomial equations were
found to be highly statistical significant (P< 0.001) as determined by
ANOVA. Release 12 h= 71.46-6.89X 1 +0.13X 2 -11.88 X
1 X 2 -0.65 X 1 2 - 2.34 X2
2 -0.17 X1 2 X 2 -0.91X 1 X2
2 -0.25 X1 2 X2 2 (Eqn. 3)
and T50%= 5.26+1.71 X 1 +0.16 X 2 +3.66 X 1 X
2 +0.36 X1 2 +1.11X2 2 +0.11 X1 2 X2
+0.23 X 1 X2 2 +0.094 X1 2 X2
2 (Eqn. 4)
Figure 1: Response surface plots showing influence of carnauba
wax and paraffin wax on percentage release in 12 h. A) Response surface plots
showing influence of carnauba wax and paraffin wax on percentage release in 12
h for extended release formulation of Venlafaxine
HCL. B) Contour plots showing relationship between various levels of carnauba
wax and paraffin wax to attain fixed value of percentage release after 12h.
80-100% release after 12 h, 60-80% release after 12 h and 40-60% release after
12 h.
TABLE 3:
DISSOLUTION PARAMETERS FOR WAX MATRIX FORMULATIONS (N=3) PREPARED AS PER 32
FACTORIAL DESIGN
|
Trial No.
|
Release after
12 h ± SD
|
T50%
(h)
|
n
|
k
|
Model
|
|
F1
|
71.49±0.0618%
|
4.35±0.0432
|
0.4178
|
24.85
|
Peppas
|
|
F2
|
82.59±0.0632%
|
1.41±0.0481
|
0.2681
|
42.73
|
Peppas
|
|
F3
|
68.79±0.0787%
|
6.35±0.0512
|
0.5323
|
17.85
|
Peppas
|
|
F4
|
78.46±0.0496%
|
3.14±0.0649
|
0.3791
|
30.61
|
Peppas
|
|
F5
|
88.21±0.0384%
|
1.17±0.0821
|
0.2437
|
49.02
|
Peppas
|
|
F6
|
48.50±0.0651
|
12.42±0.0213
|
0.6068
|
10.47
|
Peppas
|
|
F7
|
68.30±0.0590%
|
5.46±0.0305
|
0.5097
|
18.40
|
Peppas
|
|
F8
|
77.29±0.0361%
|
2.56±0.0632
|
0.3376
|
32.93
|
Peppas
|
|
F9
|
59.50±0.2212%
|
8.34±0.0419
|
0.5723
|
14.16
|
Peppas
|
k: Kinetic Constant; n: Diffusional release exponent
Figure 2 :Response surface
plots showing influence of carnauba wax and paraffin wax on time required for
50% (t50%) drug release (A) Response surface plots showing influence of
carnauba wax and paraffin wax on time required for 50% (t50%) drug release for
extended release formulation of Venlafaxine HCl. (B) Contour plot showing relationship between various levels
of carnauba wax and paraffin wax to attain fixed value of t50%. 10-15 h
required for 50% release of drug, 5-10 h required for 50% release of drug and
0-5 h required for 50% release of drug.
Application of two-way ANOVA based factorial analysis indicates
that a high amount of carnauba wax and paraffin wax has a significant influence
on release after 12 h and time required for 50% of drug release (P<0.001). [Figure 1], shows that
release after 12 h varies in a nearly linear descending pattern with decrease
in the amount of waxes. [Figure 2] also exhibits a near linear trend of t50 %,
but in ascending order. As there is no confounding of the contour lines in
[Figure 1] and [Figure 2], both the waxes seem to contribute independently
towards drug release.
Figure 3A: In vitro
dissolution profile of extended release formulations of Venlafaxine
HCL A) The plot shows release profile of nine formulations as per 32 Factorial
Design
Figure 3B: In vitro
dissolution profile of extended release formulations of Venlafaxine
HCL B) The plot shows release profile of an optimum formulation. F1, F2, F3,
F4, F5, F6, F7, F8, F9, A1, A2, A3, A4, A5, A6.
TABLE 4: COMPARISION OF OBSERVED AND
PREDICTED RESPONSE PARAMETERS
|
Formulation Code
|
Formulation composition Carnauba/Paraffin
wax
|
Response Property
|
Experimental Value
|
Predicted Value
|
|
A1
|
18.72/41.95
|
Release 12 h
|
77.10
|
76.21
|
|
T50%
|
4.36
|
4.27
|
|
A2
|
21.43/44.56
|
Release 12 h
|
73.50
|
73.56
|
|
T50%
|
5.00
|
4.88
|
|
A3
|
31.69/34.60
|
Release 12 h
|
75.80
|
75.11
|
|
T50%
|
4.12
|
4.25
|
|
A4
|
34.70/36.50
|
Release 12 h
|
71.99
|
72.68
|
|
T50%
|
4.09
|
4.77
|
|
A5
|
47.61/27.40
|
Release 12 h
|
74.18
|
74.27
|
|
T50%
|
4.23
|
4.08
|
|
A6
|
52.25/29.60
|
Release 12 h
|
70.36
|
71.64
|
|
T50%
|
4.77
|
4.89
|
Results are average of three determinations. k – Kinetic Constant,
n- Diffusional Release Exponent
[Table 4] shows the values of observed and predicted responses
using factorial design along with the percentage predicted errors for these six
optimum formulations. The predicted error for the response variables ranged
between -1.73 and 1.43%, with the mean ± standard deviation of the percentage
error being -0.2117±1.110%. Also, the linear plots between the predicted and
observed responses demonstrated high of r 2 (ranging between 0.9701
and 0.9977), indicating excellent goodness of fit. Thus, the low magnitudes of
error, as well as the significant values of r 2 , designate a high prognostic ability of Response Surface Methodology (RSM).
For all the six optimum formulations, the value of n ranged
between 0.685 and 0.839, visibly indicating a peppas
release behavior approaching. Evidently, the values of dissolution parameters
had a propensity to range optimally between relatively controlled limits rather
than those of the original formulations designed as per 3 2
factorial designs. The release profile of optimum formulations shows
superiority in the drug release as depicted in the [Figure 3a] and [Figure 3b].
REFERENCES:
1.
Holiday
SM, Benfield P. Venlafaxine: A review of its
pharmacology and therapeutic potential in depression. Drugs 1995;49:280-94
2.
Haskins
JT, Moyer JA, Muth EA, Sigg
E. Inhibition of noradrenergic neuronal activity by the novel bicyclic compounds, Wy- 45030 and
Wy-45881. Soc Neurosci Abstr
1984;10:262.
3.
Troy
SM, Parker VD, Fruncillo RJ, Chiang ST. The
pharmacokinetics of Venlafaxine when given in a
twice-daily regimen. J Clin Pharmacol
1995;35:404-9.
4.
Goodhart
FW, McCoy RH, Ninger FC. Release of a water soluble
drug from a wax matrix timed release tablet. J Pharm Sci 1974; 63:1748-51.
5.
Foster
TP, Parrott EL. Release of highly water-soluble medicinal compounds from inert,
heterogeneous matrix. J Pharm Sci
1990; 79:938-42.
6.
Foster
TP, Parrott EL. Release of highly water-soluble medicinal compounds from inert,
heterogeneous matrix I: Physical mixture. J Pharm Sci 1990; 79:806-10.
7.
Doornbos
DA, Haan P. Optimization Techniques in formulation
and Processing. In: Swarbrick J. Boylan
JC, editors. Encyclopedia Pharmaceutical Technology. Vol. 11. New York: Marcel
Dekker Inc; 1995. p. 77-160
8.
G.M. Zentner, G.S. Rork, K.J. Himmelstein, The controlled porosity osmotic pump, J.
Control. Release 1 (1985) 269–282.
9.
G.M. Zentner, G.S. Rork, K.J. Himmelstein, Controlled porosity osmotic pump, US patent
4,968,507, Nov. 6, 1990.
10. G.M. Zentner,
G.S. Rork, K.J. Himmelstein,
Controlled porosity osmotic pump,Journal
of controlled release 1 (1985) 269–282.
11. P. Schultz, P. Kleinebudde,
A new multiparticulate delayed release system. Part
I. Dissolution properties and release mechanism, J. Control. Release 47 (1997)
181–189.
12. J.R. Cardinal, S.M. Herbig,
R.W. Korsmeyer, J. Lo, K.L. Smith, A.G. Thombre, Asymmetric membranes in delivery devices, US
patent 5,698,220, Dec. 16, 1997.
13. S.M. Herbig, J.R.
Cardinal, R.W. Korsmeyer, K.L. Smith,
Asymmetric-membrane tablet coatings for osmotic drug delivery, J. Control.
Release 35 (1995) 127–136.
14. A.G. Thombre,
J.R. Cardinal, A.R. DeNoto, S.M. Herbig,
K.L. Smith, Asymmetric membrane capsules for osmotic drug delivery I.
Development of a manufacturing process, J. Control. Release 57 (1999) 55–64.
15. L. Liu, J. Ku, G. Khang,
B. Lee, J.M. Rhee, H.B. Lee, Nifedipine controlled
delivery by sandwiched osmotic tablet system, J. Control. Release 68 (2000)
145–156.
16. www.drugbank.com
17. Raymond C Rowe, Paul J Sheskey
and Siân C Owen, Handbook of pharmaceutical excipients.