Development of Extended Release Pellets of Quetiapine Fumarate by using HPMC and Eudragit RSPO

 

Tushar M. Patel1* and Mukesh C. Gohel2

1Research Scholar at Hemchandracharya North Gujarat University, Patan, Gujarat, India

L. M. College of  Pharmacy, Ahmadabad, Gujarat, India.

2 Professor and Postgraduate Director, Anand Pharmacy College, Anand, Gujarat, India

*corresponding author e-mail: tushar@lmcp.in

 

ABSTRACT:

The aim of the present investigation was to develope extended release pellets of quetiapine fumarate. The combinations of hydrophilic (hydroxypropyl methylcellulose; HPMC K100M) and hydrophobic (Eudragit RSPO) extended release excipients were utilized for the development. The amount of HPMC K100M (X1), amount of Eudragit RSPO (X2), and amount of acidifier (anhydrous citric acid) (X3) were chosen as independent variables. These variables were optimized employing a simplex lattice design. The selected dependent variables were the cumulative percentage of quetiapine fumarate dissolved at 1 (Y1), 6 (Y2), 12 (Y3) and 20 hr (Y4). The in vitro drug release study was carried out in citrate buffer (pH 4.8) for 5 hr and thereafter the study was conducted in phosphate buffer (pH 6.6) up to 20 hours. Optimization was performed for the independent variables X1, X2 and X3 using the target ranges; 9%≤Y1≤14%; 56%≤Y2≤60%; 76%≤Y3≤80%; 90%≤Y4≤100% (selected on the basis of NDA documents of the innovator).  The optimized amounts of HPMC K100M (X1), Eudragit RSPO (X2) and anhydrous citric acid (X3) were 131, 100 and 54 mg respectively. Extended release pellets of the optimized formulation showed a release profile that was close to the values of innovator drug product (Seroquel XR®). The drug was released as per first order from the optimized formulation.

 

KEYWORDS: Quetiapine fumarate, extended release, HPMC, Eudragit RSPO, pellets, simplex lattice design.

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INTRODUCTION:

Quetiapine, a novel antidepressant drug, and its active human plasma metabolite (nor-quetiapine) exhibit affinity for brain serotonin (5-HT2) and dopamine D1 and D2 receptors [1]. Quetiapine fumarate is an ideal candidate for designing modified release dosage form as it has short elimination half-life of 6-7 hr, high therapeutic index, and rapid absorption from the gastro intestinal tract [2-3]. The absorption of quetiapine fumarate is not affected by food. The FDA has approved once-daily quetiapine XR as adjunct treatment of major depressive disorder in adults on December 2009. To improve the patient compliance as well as to reduce side effects, the drug needs to be formulated in extended release dosage form. Combination of hydrophobic and hydrophilic polymer matrix systems are widely used in oral extended release drug delivery because of their flexibility to obtain a desirable drug release profile, cost-effectiveness, and broad regulatory acceptance. .

 

These extended release dosage forms are designed to deliver the drug at a 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 dosage schedule and improving comfort of the patient [4-5]. Hydrophilic polymers like hydroxypropyl methylcellulose, sodium carboxymethylcellulose, Carbopols® and polyvinyl alcohol have been extensively examined in the formulation of extended release systems either alone or in combination with other hydrophobic release controlling agents like, Eudragit RSPO, ethyl cellulose, carnauba wax, cetyl alcohol, cetostearyl alcohol, etc [6-10]. The combination of hydrophilic and hydrophobic 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]. Additionally, it is a powerful, efficient and systematic tool that reduces formulation development time as well as number of batches required for the development of pharmaceutical dosage forms [16-20]. US FDA has also endorsed the use of design of experiments in the formulation development. The objectives of the present study were to prepare quetiapine fumarate controlled release matrix pellets by using a blend of HPMC K100M and Eudragit RSPO and to determine the optimal levels (design space) of these factors using simplex lattice design.

 

MATERIAL AND METHODS:

Quetiapine fumarate was obtained as a gift sample from Amneal Pharmaceuticals India Pvt. Ltd. (Ahmedabad, India), Eudragit RSPO and HPMC K100M and obtained as gift samples from Alembic Pharmaceuticals Ltd (Vadodara, India) and Torrent Pharmaceuticals Ltd. (Ahmedabad, India) respectively. All other ingredients were procured from local market and were of analytical grade.

 

EXPERIMENTAL DESIGN:

FDA and ICH guidelines put stress on the importance of systemic formulation approach. Simplex lattice design was used to ascribe the relationship between the independent variables and the responses. Quetiapine fumarate is a weakly basic drug, Hence, an acidifier is required in extended release dosage form to decrease the microenviornmental pH. Three factors, amount of HPMC K100M (X1), Eudragit RSPO (X2), and anhydrous citric acid (X3), were used in the design and the responses were the cumulative percent of the drug dissolved at 1, 6, 12 and 20 hr. Tables 1 and 2 summarize the levels of independent variables and the target ranges for the responses respectively. Target ranges have been decided from the NDA documents of the innovator company (Astrazeneca). Contour plots were constructed using the Design Expert software (version 8.0, Stat-Ease Inc., Minneapolis, U.S.A.). A suitable polynomial model was selected based on the values of multiple correlation coefficients (R2) and adjusted multiple correlation coefficients (adjusted R2).

 

 

Table 1: Independent variables for simplex lattice Design

Independent Variables     

Low level (0)

High level (1)

HPMC K100M, mg (X1)

100

200

Eudragit RSPO, mg (X2)

75

175

Anhydrous citric acid mg  (X3)

10

110

 

 

Table 2: Dependent variables (Responses)

Dependent variables

Target range

Y1=cumulative % drug release in 1 hr

9≤Y1≤14

Y1=cumulative % drug release in 2 hr

56≤Y2≤60

Y2=cumulative % drug release in 6 hr

76≤Y3≤80

Y3=cumulative % drug release in 12 hr

90≤Y4≤100

 

Selected on the basis of NDA documents of the innovator

 

Preparation of quetiapine Fumarate Matrix Pellets:

Matrix pellets of quetiapine fumarate were prepared by extrusion-spheronization method. Quetiapine fumarate, Eudragit RSPO, HPMC K100M, anhydrous citric acid were sifted through sieve # 40 and accurately weighed. The ingredients were blended in geometric fashion. A mixture of ethanol and water in a proportion of 8:2 was gradually added to the powder blend. The dough was then passed through an extruder (aperture of 1.5 mm size). The extrudates were then processed in a spheronizer fitted with cross-hatched plate rotated at 900 rpm for 5 min. The pellets were air-dried and used for further studies. Hard gelatine capsules were filled with matrix pellets containing 230 mg of quetiapine fumarate equivalent to 200 mg free quetiapine base. 

 

In Vitro Dissolution Test:

Quetiapine fumarate release was determined using a USP type I dissolution apparatus. The capsules were added to 900 ml of 0.05M citric acid and 0.09 N sodium hydroxide (pH 4.8) buffer at 37±0.5°C. The basket speed was 200 rpm. Ten ml samples were withdrawn at defined time intervals of 1, 2 and 4 hr and the same volume of buffer was replaced. At 5 hr, the pH of the medium was adjusted to 6.6 by addition of 100 ml 0.05M dibasic sodium phosphate and 0.46N sodium hydroxide. Samples were subsequently collected at 6, 8, 12, 16 and 20 hr. The samples were analyzed by using a double beam UV-VIS spectrophotometer (UV-1700, Shimadzu Corp, Kyoto, Japan) at 246 nm [21]. Dissolution tests were repeated three times for all formulations and the percentage drug dissolved was calculated using standard calibration curve.

 

RESULTS AND DISCUSSIONS:

The pellets exhibited good mechanical strength with acceptable friability (0.5 %) and flow property (angle of repose: 25o). The pellets underwent swelling and gelling during dissolution testing.


Table 3: Drug release from simplex lattice design batches.

Run

Independent Variables

Dependent Variables

Amount of HPMC K100M (X1)

Amount of Eudragit RSPO (X2)

Amount of citric acid (X3)

Percentage drug released

1 hr (Y1)

2 hr (Y2)

6 hr (Y3)

12 hr (Y4)

1.

150

125

10

9

35

52

64

2.

100

75

110

26

75

94

100

3.

133

108

44

10

54

76

94

4.

150

75

60

14

60

87

101

5.

100

125

60

17

49

68

81

6.

200

75

10

8

31

45

56

7.

100

175

10

9

29

40

48

8.

133

108

44

11

53

76

93


Experimental Design:

The experimental results of eight runs are presented in Table 3. Replication of centre point batch (133, 108, 44) was investigated to determine the repeatability. The more an experiment is replicated, the greater is models reliability. The centre point also assists us in investigating curvature. Various models, such as linear, quadratic and cubic were fitted to the data for four responses simultaneously using Design Expert® software and adequacy. Analysis of variance (ANOVA) test was used to draw conclusions. The multiple correlation coefficient (R2) and adjusted multiple correlation co-efficient (adjusted R2) were used for selection of adequate models

 

The lack of fit analysis showed that a quadratic model was appropriate for the description of all responses.

The quadratic model generated by the design is of the form:

 

Y= A1X1+A2X2+A3X3+A4X1X2+A5X1X3+A6X2X3

 

Where, A1 to A6 are the co-efficients of respective factors and their interaction terms. The coefficient of main effect (A1, A2 and A3) represents the average result of changing one factor at a time from its low to high value. The coefficients of interaction terms (A4-A6) show how the response changes when two factors are changed simultaneously. The equations for the responses are shown below:

 

Y1 = 0.04 X1 + 0.05 X2 + 0.41X3 – 3.04 * 10-4 X1X2 - 1.71 * 10-3 X1X3 - 7.14 * 10-4 X2X(R2 = 0.975 and Adj R2 = 0.912)

 

Y2 = -0.06 X1 – 0.11 X2 + 0.29 X3 + 2.82 * 10-3 X1X2 + 3.64 * 10-3 X1X3 – 3.63 * 10-4 X2X3 (R2 = 0.990 and Adj R2 = 0.967)

 

Y3 = - 0.11 X1 – 0.21 X2 – 0.06 X3 + 4.49 * 10-3 X1X2 + 7.70 * 10-3 X1X3 + 1.10 * 10-3 X2X3 (R2 = 0.996 and Adj R2 = 0.986)

 

Y4 = -0.15 X1 – 0.32 X2 – 0.51 X3 + 6.06 * 10-3 X1X2 + 0.01 X1X3 + 4.08 * 10-3 X2X3   (R2 = 0.988 and Adj R2 = 0.957)  

 

A positive or a negative mathematical sign before a co-efficient indicate a synergistic effect or an antagonistic effect for the factor respectively. For HPMC content of 20% or more, the particles of HPMC are close enough to permit a faster establishment of the gel layer. A stable gel layer was formed around pellets during dissolution studies and it persisted during the dissolution studies. Eudragit RSPO shows time dependent swelling. The drug release at a later time point is dependent on amount of Eudragit RSPO.  Contour plots are presented to describe the relationship between the independent variables and the responses (Figures 1, 2 3 and 4). The drug release was dramatically retarded from the matrix pellets on increasing levels of polymer. Formation of tightly swollen gel layer and time dependent swelling by Eudragit RSPO are the most possible reasons for retardation in drug release.

 

Fig. 1. Contour plot of Y1 (A: HPMC, B: Eudragit RSPO, C: Anhydrous citric acid)

 

The values of coefficients indicate that the drug release at 1 hr increases with increase in the amount of citric acid (b3 = +0.41). The interaction of HPMC-Eudragit RSPO (b12 = -3.04 X 10-4) and interaction of Eudragit RSPO-citric acid (b23 = -7.14 X 10-4) were noticed. Eudragit RSPO is a water insoluble hydrophobic matrixing agent and shows time dependent swellings. At higher level of Eudragit RSPO, the drug release was retarded probably due to better bonding between insoluble particles of Eudragit RSPO and subsequent control of water uptake. The optimum amount of HPMC K100M, Eudragit RSPO and anhydrous citric acid for the optimum drug release is 100 to 180 mg, 75 to 175 mg and 10 to 66 mg respectively. The optimum combination of above three ingredients can be obtained from the regions between the contours of 9 to 14 % drug release.

 

The desired value for Y2 (drug release at 6 hour) is between 56 to 60 %. Again this time, the contours describing 56 to 60 percent drug release is focused at higher amount of citric acid as shown in the contour plot. From the equation of Y2 it can be concluded that both HPMC and Eudragit RSPO has negative effect of the drug release at Y2 (b1 = -0.11 and b2= -0.21 respectively) while the amount of citric acid has positive effect on Y2 (b3 = +0.29). This can be supported by the fact that citric acid provides acidic environment in the matrix which is suitable for solubilization quetiapine fumarate as it is weakly basic drug. The optimum amount of HPMC K100M, Eudragit RSPO and anhydrous citric acid for the optimum drug release is 100 to 161 mg, 75 to 113 mg and 48 to 110 mg respectively. The optimum combination of above three ingredients can be obtained from the regions between the contours of 56 to 60 % drug release.

 

The target drug release for Y3 is between 76 to 80 percentages. The equation of Y3 indicates that amount of Eudragit RSPO has more negative effect (b2 = -0.21) as compared to HPMC (b1 = -0.11), this may be due to hydrophobic nature of Eudragit RSPO. The amount of HPMC K100M, Eudragit RSPO and anhydrous citric acid required for the target drug release is 100 to 169 mg, 75 to 113 mg and 40 to 110 mg respectively. The optimum combination of above three ingredients can be obtained from the regions between the contours of 76 to 80 % drug release.

Fig. 2. Contour plot of Y2

 

Fig 3. Contour plot of Y3

 

Fig 4. Contour plot of Y4

The desired range of Y4 is 90 to 100%. From the equation of Y4, it can be concluded that interaction of HPMC and Eudragit RSPO has significant effect on Y4 (b12 = 6.06 X 10-3). This can be explained by the fact that at 20 hour, Eudragit RSPO has started swelling creating more space for drug release with erosion of HPMC from the matrix. The optimum amount of HPMC K100M, Eduragit RSPO and anhydrous citric acid required for the target drug release is 100 to 169 mg, 75 to 115 mg, 39 to 110 mg respectively. The optimum combination of above three ingredients can be obtained from the regions above the contours of 90 % drug release.

 

Optimization

In order to determine an acceptable formulation, the optimization process was performed for the factors X1, X2 and X3 using the following target ranges; 9%≤Y1≤14%; 56%≤Y2≤60%; 76%≤Y3≤80%; 90%≤Y4≤100% in the Design Expert software.

 

Fig 5. Overlay plot showing optimum composition of X1, X2 and X3

 

The optimized levels of each independent variable were based on the criterion of desirability. The optimized coded levels of amount of HPMC K100M (X1), Eudragit RSPO (X2) and anhydrous citric acid (X3) as obtained from overlay plot (Figure 5) were 131, 100 and 54 mg respectively with a maximum value of desirability of one. The predicted and observed responses for the optimized formulation, indicates that the release profile of the quetiapine fumarate matrix pellets was close to each other (Table 4). The complete drug release profile is shown in figure 6. 

 

The overlaid plot can be used for defining the design space. We can identify a region (square or rectangle) showing the normal operating range (NOR) in design space. FDA does not consider a change within the NOR as change for document resubmission. The area of NOR shall be used in mind while scale up experiments are performed. The drug release data of the optimized batch were fitted to kinetic models such as Hixson-Crowell, Korsemeyer-Peppas, Weibull, zero-order, first-order and Higuchi. The first order model showed a good fit (r=0.9976).


 

Tablet 4: Comparison of predicted and observed values

Variables

X1

X2

X3

Y1

Y2

Y3

Y4

Predicted and observed values

131mg

100 mg

54 mg

13.0

56.0

80.0

96.0

 

(12.4)

(59.2)

(78.5)

(98.6)

The parenthesis show observed values


 

Fig 6: Drug release profile of optimized formulation.

 

CONCLUSIONS:

In the present study, quetiapine fumarate controlled release matrix pellets were prepared using a blend of Eudragit RSPO, HPMC K100M and anhydrous citric acid. Multiple regression analysis was carried out to evolve linear, quadratic and cubic model. The composition of an acceptable batch was decided to be 131 mg HPMC K100M, 100 mg Eudragit RSPO and 54 mg anhydrous citric acid. The observed responses of the optimized formulation were very close to the predicted values. The drug was released by the mechanism of first order. The amount of HPMC had a dominant role in the initial phase of drug release, while in the later phase; effect of Eudragit RSPO predominated. These can be considered as critical formulation parameters while going for scale-up operations and regulatory submission.

 

ACKNOWLEDGEMENTS:

The authors are thankful to Amneal Pharmaceuticals India Pvt. Ltd. for providing us gift sample of quetiapine fumarate. Authors are also thankful to Alembic Pharmaceuticals Limited (Vadodara, India) and Torrent Pharmaceuticals Ltd. (Ahmedabad, India) for providing gift samples of Eudragit RSPO and HPMC K100M respectively.

 

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Received on 13.04.2014          Modified on 15.05.2014

Accepted on 23.05.2014          © RJPT All right reserved

Research J. Pharm. and Tech. 7(7): July  2014 Page 771-775