Development of Venlafaxine Hydrochloride Controlled Release Pellets Prepared Employing the Blend of Ethyl Cellulose and Polyethylene Oxide

 

D. V. Madat¹, M. C. Gohel² and A.Ramkishan³

¹ D. D. University, Nadiad, Gujarat.

²Ahmadabad University, Ahmadabad, Gujarat.

³ Deputy Drugs Controller (II), I/C, CDSCO Zonal Office, Ahmadabad, Gujarat

*Corresponding Author E-mail: dhavalmadat@gmail.com

 

The objective of the present investigation was to develop controlled release matrix pellets of venlafaxine HCl using the concept of design of experiments. Extrusion-spheronization technique was adopted for the preparation of the matrix pellets of venlafaxine HCl employing ethyl cellulose (EC) and polyethylene oxide (PEO) as insoluble and soluble matrixing agents respectively. Hydroalcoholic fluid was used as a binder to facilitate pellet formation. The pellets were assessed for flow property and friability. Media change method was used to study the in vitro dissolution pattern of venlafaxine HCl. Model fitting was carried out to identify the most valid kinetics of drug release. The use of hydroalcoholic medium, in place of water, facilitated processing without sticking. The pellets exhibited good flow and low friability. The drug was released at a controlled rate from the formulated product. Multiple regression analysis was used to evolve mathematical models for drug release at 2, 6 and 12 hr. Response surface plots were drawn to visualize the impact of independent variables on drug release. The drug release at 2, 6 and 12 hr was influenced by the amount of EC and PEO. The kinetics of drug release was best explained by Weibull model. The drug was released by non-fickian diffusion. The use of systematic formulation study is advantageous for the development of CR pellets of venlafaxine HCl. The optimum batch consisted of 37.5 mg venlafaxine HCl, 30% EC and 20% PEO. 

 

 

INTRODUCTION:

Venlafaxine hydrochloride is structurally a novel antidepressant. It imparts antidepressant effect by inhibiting the neuronal uptake of norepinephrine, serotonin and to a lesser extent, dopamine.^[1] The short biological half-life (5±2 hr) and the fast clearance make venlafaxine HCl, a suitable candidate for the development of controlled release formulation. Furthermore, the drug is required to be taken for a long period by the patients. The use of controlled release formulation is associated with less nausea and dizziness at the initiation of therapy.^[2] Hence, to improve the patient compliance as well as to reduce the side effects, the drug needs to be formulated in controlled release (CR) dosage form.

 

Hydrophilic polymer matrix systems are widely used in oral controlled drug delivery because of their flexibility to obtain a desirable drug release profile, cost-effectiveness, and broad regulatory acceptance.^[3] These dosage forms are designed to deliver the drug at a controlled and predetermined rate, thus maintaining a therapeutically effective concentration of the drug in the systemic circulation for a long period of time and therefore reducing the frequency of dosing and improving patient compliance.^[4,5] Hydrophilic polymers like hydroxypropyl methylcellulose, sodium carboxymethylcellulose, Carbopols^® and polyvinyl alcohol have been extensively examined in the formulation of controlled release systems either alone or in combination with other release controlling agents like, ethyl cellulose.^[6-10] The hydrophilic polymers can also be used to formulate matrix pellets so as to get the required release pattern.

 

The use of statistical optimization techniques have been documented for the formulation of many pharmaceutical solid dosage forms.^[11-15] The use of design of experiments have been endorsed by the US FDA and also by the ICH Q8 and Q9 guidelines.

The objectives of the present study were to prepare venlafaxine hydrochloride controlled release matrix pellets by using a blend of ethyl cellulose and PEO and to determine the optimal levels of these factors using response surface methodology.

 

Hence, in the present investigation, the influence of content of PEO on venlafaxine hydrochloride release was statistically evaluated using 3² full factorial design.

 

MATERIALS AND METHODS:

Venlafaxine hydrochloride, ethyl cellulose (EC), PEO and magnesium stearate were obtained as gift samples from Torrent Pharmaceuticals Ltd. (Ahmedabad, India). All other ingredients were of analytical grade.

 

Full Factorial Design:

FDA and ICH guidelines put stress on the importance of systematic formulation approach. A 3² full factorial design was used in the development of dosage form of venlafaxine hydrochloride. The amount of ethyl cellulose (X₁) and PEO (X₂) were selected as critical material attributes. The percentage drug release at 2 (Y₁), 6 (Y₂), and 12 (Y₃) hr were chosen as dependent variables. The experimental design layout of the formulations is outlined in Table 1 and Table 2.  A statistical model, incorporating interactive and polynomial terms, was used to evaluate the responses (Equation 1).

 

Y = b₀ + b₁X₁ + b₂X₂ + b₁₁X₁² + b₂₂X₂² + b₁₂X₁X₂                 (1)

 

Where Y is the dependent variable, b₀ is the arithmetic mean response of the nine runs, and b_i is the estimated coefficient for the factor X_i. The main effects (X₁ and X₂) represents the average result of changing one factor at a time from its low to high value. The interaction term (X₁X₂) shows how the response changes when two factors are changed simultaneously.

 

Table 1: Levels of independent variables

Independent Variables	Low level (-1)	Medium level (0)	High level (+1)
Amount of ethyl cellulose, % (X1)	30	40	50
Amount of PEO, % (X2)	20	30	40

 

Preparation of Venlafaxine Hydrochloride Matrix Pellets:

Matrix pellets of venlafaxine hydrochloride were prepared by extrusion-spheronization method. The quantity of venlafaxine hydrochloride was 37.5 mg per dose. Ethyl cellulose, PEO and magnesium stearate were sifted through sieve # 60 and accurately weighed. The ingredients were blended in geometric fashion. A mixture of ethanol:water in proportion of 8.5:2 was gradually added to the powder blend. The dough was then passed through an axial type extruder (apertures of 1 mm size). The extrudates were cut with the help of a blade and then processed in a spheronizer fitted with cross-hatched plate rotated at 900 rpm for 5 min. the spherical pellets were air dried and used for further studies. Hard gelatin capsules were filled with matrix pellets containing 37.5 mg of the drug. The prepared pellets were evaluated in terms of friability by using the friability tester and flow property by measuring angle of repose respectively.

 

In Vitro Dissolution Test:

Venlafaxine hydrochloride release was determined using a dissolution apparatus USP XXV. The capsules were added to 0.1N HCl solution (adjusted to pH 1.2) at 37±0.1°C. The paddle speed was 100 rpm. Five ml samples were withdrawn at defined time intervals, and the same volume of the dissolution fluid was replaced. After 2 hr, the dissolution medium was replaced with phosphate buffer pH 6.8 and the dissolution study was continued. Samples were subsequently collected at every hr. The samples were analyzed by using a double beam UV-VIS spectrophotometer (UV-1700, Shimadzu Corp, Kyoto, Japan) at 226.0 nm. Dissolution tests were repeated three times for all formulations and the percentage drug dissolved was calculated using standard calibration curve. The results are depicted in Table 2.

 

Table 2: Formulation and dissolution characteristics of formulated batches

15%≤Y₁≤30%; 50%≤Y₂≤65%; 80%≤Y₃≤95%

 

Statistical Analysis:

The statistical analysis of the formulated batches was performed by carrying out multiple regression analysis in Microsoft Excel^®. To demonstrate the influence of each factor on responses graphically, the response surface plots were generated using Sigma Plot software (Sigma Plot Software 8.0, Jandel Scientific Software, San Rafael, CA). The value of P < 0 .05 was considered to be significant. Diffusion exponent (n) was computed employing an in-house developed software in FORETRAN.

 

RESULTS AND DISCUSSION:

The pellets exhibited acceptable friability (0.45%) and flow property (25.68±0.23°). They underwent swelling and gelling during dissolution testing. During the dissolution studies, a gel layer was formed around pellets and it persisted for 12 hr. The results of percentage drug release at 2 (Y₁), 6 (Y₂), and 12 hr (Y₃) showed variation (Table 2). Hence, further data analysis was done. Table 3 shows regression coefficient and correlation coefficient. The results of multiple regression analysis revealed that the amount of PEO had statistically significant influence on all the three dependent variables (P < 0.05, Table 3). Ethyl cellulose was found to influence Y₂ and Y₃. Figures 1 to 3 show the influence of ethyl cellulose and PEO on the drug release at 2, 6 and 12 hr. At low (-1), medium (0) and high (1) values of the amount of PEO, the percentage drug released in 2 hr (Y₁) decreased noticeably as the level of ethyl cellulose changed from low to high.

 

At a higher level of PEO, mobility of drug particles in the swollen matrices is decreased. Hence, the drug release rate is decreased. Both the independent factors (X₁ and X₂) showed significant effect on Y₂ (P < 0.05). The drug release was more influenced by the amount of PEO for Y₂. Diffusion/erosion properties of the gel layer were more sensitive to the strength of the gel layer.

 

Figure 1: Response surface plot showing the effect of independent variables on drug release at 2 hr.

 

Figure 2: Response surface plot showing the effect of independent variables on drug release at 6 hr

 

Figure 3: Response surface plot showing the effect of independent variables on drug release at 12 hr

 

Multiple regression analysis for percentage drug release at 12 hr (Y₃) showed significant contribution of both the factors (P < 0.05). Dramatic effect on drug release was seen when high concentration of ethyl cellulose and PEO were used. It is apparent that above certain threshold values for both the independent variables, the effect of the variables becomes nonlinear.

 

Figure 4, 5 and 6 reveal that at low, medium and high values of any one independent variable, the percentage drug release decreased noticeably as the level of the other independent variable was changed from low to high. At high levels of X₁ and X₂, lower Y₁ was observed. It is therefore concluded that percentage drug release at 2 hr can be modulated by changing the factors X₁ and X₂. The responses Y₂ and Y₃ showed similar trend. The high solubility of venlafaxine HCl presented challenge in modulating drug release in 2 and 6 hr. (Figure 4-6)

 

Figure 4: Effect of X₁ and X₂ on Y₁

 

Table 3: Summary of regression output of significant factors for the measured responses

Dependent variables	Regression coefficients
	b0	b1	b2	b11	b22	b1b2	r
Y1	11.444 (0.0019)	-0.5167 (0.4559)	-2.816 (0.001)	-3.317 (0.0120)	0.1833 (0.8722)	0.0833 (0.9416)	0.9546
Y2	47.756 (7.3×10-5)	-3.9833 (0.0178)	-7.9833 (0.0024)	0.9166 (0.5737)	0.3167 (0.8418)	0.525 (0.6453)	0.9870
Y3	83.3444 (1.08×10-5)	-10.1833 (0.000957)	-4.0333 (0.0138)	-1.1167 (0.4672)	0.1333 (0.9273)	0.925 (0.4024)	0.9926

Note: values in parenthesis show respective p-values

 

Figure 5: Effect of X₁ and X₂ on Y₂

 

Figure 6: Effect of X₁ and X₂ on Y₃

 

The drug diffusion through most types of polymeric systems is often best described by Fickian or Non-Fickian diffusion. The relaxation of the polymer chains may also influence the drug release mechanism. This process is described as non-Fickian or anomalous diffusion. Weibull model showed a superior fit to the data.

 

The results shown in table 3 reveal that the value of diffusion exponent increases with increase in concentration of PEO (P=0.04). The target ranges for acceptable formulation were 15%≤Y₁≤30%; 50%≤Y₂≤65%; 80%≤Y₃≤95%. The batch P-1 showed the closest dissolution profile to the target values.

 

CONCLUSION:

The present investigation described the influence of concentration of ethyl cellulose and PEO on venlafaxine hydrochloride release. The results of multiple regression analysis indicated that both the factors can be considered as critical material attributes influencing the drug release at 2, 6 and 12 hr (P < 0.05). Weibull model best described the drug release. The mechanism of drug release was found to be anomalous type. The content of PEO had a dominant role in the initial phase of drug release, while in the later phase content of ethyl cellulose had predominant effect on drug release. The present study demonstrate that controlled release of venlafaxine HCl can be obtained by using a blend of soluble (PEO) and insoluble (EC) matrixing agents. The present study can help industrialist to identify reliable operating range in the contour plot so that regulatory resubmissions are reduced in the event if minor changes are made in the operating range.

 

ACKNOWLEDGEMENTS:

The authors are thankful to Torrent Pharmaceuticals Ltd. (Ahmadabad, India) for providing gift samples of venlafaxine hydrochloride, ethyl cellulose, PEO and magnesium stearate.

 

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Received on 20.08.2012       Modified on 01.09.2012

Accepted on 09.09.2012      © RJPT All right reserved