Development and Evaluation of Quick and Slow Release Carvedilol formulation

 

ABSTRACT:

The prospects of natural polymers are brighter as synthetic polymers have certain disadvantages such as high cost, toxicity, environmental pollution during synthesis, non renewable sources, side effects and less patient compliance. The purpose of the present research was to develop a quick and slow biphasic delivery system for Carvedilol. A compressed coated tablet made of a sustained release core tablet and an immediate release coat tablet was prepared by direct compression. Both the core and the coat contained Carvedilol. The sustained release effect was achieved with a polymer HPMC K4M and PEO WSR 205 to modulate the release of the drug. The in vitro drug release profile from these tablets showed the desired biphasic release behavior. The powder blends were evaluated for angle of repose, bulk density, compressibility index and drug content. The tablets were subjected to thickness, diameter, weight variation test, drug content, hardness, friability, disintegration and in vitro drug release studies. The powder blend showed satisfactory flow properties, compressibility and drug content. All the tablet formulations showed acceptable pharmaco-technical properties and complied with in-house specifications for tested parameters. The Carvedilol contained in the fast releasing component was released within 3 minutes, whereas the drug in the core tablet was released at different times (≈16 or >24 hrs), depending on the composition of the matrix tablet. Based on the release kinetic parameters calculated, it can be concluded that the batches F6 and  F7 shows best similarity with theoretical profile and were suitable for providing a constant and controlled release (zero order) for a once a day administration. The mechanism of drug release from all batches was Fickian diffusion or anomalous behavior.

 

 

INTRODUCTION:

Conventional drug therapy requires periodic doses of therapeutic agents. These agents are formulated to produce maximum stability, activity and bioavailability¹. For most drugs, conventional methods of drug administration are effective, but some drugs are unstable or toxic and have narrow therapeutic ranges ^2-4. In such cases, a method of continuous administration of therapeutic agent is desirable to maintain fixed plasma level.

 

To overcome these problems, sustained release systems were introduced three decades ago. Sustained release, sustained action, prolonged release, controlled release, extended action, timed release, depot and repository dosage forms are the terms used to identify drug delivery systems that are designed to achieve a prolonged therapeutic effect by continuously releasing medication over an extended period of time after administration of a single dose. The term controlled release has become associated with those systems from which therapeutic agents may be automatically delivered at predefined rate over long period of time⁵.

 

Sustained release dosage forms cover a wide range of prolonged action preparations that provide continuous release of their active ingredients for a specific period of time. By prescribing sustained release systems, it is possible to achieve several desirable therapeutic Potential advantages⁶.

The drug candidate selected under the study is Carvedilol, a non-selective beta blocker agent used for the treatment of mild or moderate heart failure of ischemic or cardiomyopathic origin. Its biological half life is 6 to 10 hrss and its usual dose is 3.125, 6.25, 12.5 and 25mg two to thrsee times a day. Because of the high frequency of administration and short biological half life, Carvedilol is an ideal drug in designing controlled release formulation Hence in the present work, an attempt has been made to formulate compressed coated tablet of Carvedilol contain immediate release part and controlled release matrix tablet by using different polymers like hydroxyl propyl methyl cellulose (HPMC), Polyox (PEO) either alone or in combination ^7,8.

 

The prepared compressed coated tablets were evaluated for hardness, friability, weight variation, and uniformity of drug content, In vitro dissolution studies, drug-polymer interaction studies, data analysis, release kinetics study and short term stability.

 

MATERIAL AND METHODS:

Materials

Carvedilol was obtained as a gift sample from Torrent Research Centre, Ahmadabad, Gujarat. HPMC K4M and Polyox WSR 205 were obtained from Dow chemical, Germany. All other chemicals were used of analytical grade and purchased from SD Fine chemicals.

 

Table.1 Theoretical profile for compressed coated Carvedilol tablet

Hrs	Drug release (mg)	% Drug release
1	2.50	2.50
2	3.48	13.91
3	4.46	17.83
4	5.44	21.74
6	7.39	29.57
8	9.35	37.40
10	11.31	45.23
12	13.26	53.06
16	17.18	68.72
20	21.09	84.37
24	25.01	100.03

 

Table 2. 3² Full Factorial Design Layouts

Batch Code	X1	X2
F1	-1	-1
F2	-1	0
F3	-1	1
F4	0	-1
F5	0	0
F6	0	1
F7	1	-1
F8	1	0
F9	1	1

X1=% wt of HPMC K4M

X2=%wt of PEO WSR 205

(Coded value -1, 0, 1 means respectively 10%, 15% 20%)

 

Calculation of theoretical profile

Theoretical profile for compressed coated Carvedilol tablet are predicted and given in Table 1. According to IRD (immediate release dose) calculation, 2.5 mg drug should release at first hrs for the next each hrs ((25-2.5=22.5)/23 =0.98 mg of drug should release. So, total % release for each hrs is calculated by adding 0.98 mg to each hrs shown in Table 1.

 

Preparation of compressed coated tablet

The compressed coated tablet with dual component system was prepared by compressing a smaller tablet, forming a central core containing sustained release part and an outer covering containing immediate release part to produce a compressed coated tablet.

 

Slow Release Component (Core Tablet)

The core tablets were prepared from mixtures of active ingredient Carvedilol and matrix-controlling agent (HPMC K4M and PEO WSR 205) along with excipient by direct compression. In the first step, active and inactive ingredients weighed accurately and were screened through a 60-mesh sieve. Required materials except lubricant were then combined and passed through 60-mesh sieve, following the addition of given amount of lubricant and again mixing, the powder was passed through 60-mesh sieve. Then desired amount of blend was compressed into tablets using rotary tablet compression machine (Rimek mini press tablet machine) equipped with 5.5 mm concave punch. Before compression, the surfaces of the die and punch were lubricated with magnesium stearate. The tablets, weighing 50 mg, were prepared by direct compression with 5.5 mm punches.

 

Fast Release Component (Immediate release Layer)

The powder used to enrobe the core was formulated to obtain a quick release of the drug. The composition of this component was the same for all formulations: it contained drug (Carvedilol), microcrystalline cellulose, starch and sodium starch glycollate with lubricant and glidant.

 

Optimization of tablet of Carvedilol using 3² full factorial design

It is desirable to develop an acceptable pharmaceutical formulation in shortest possible time using minimum number of man, hrs and raw materials. Traditionally pharmaceutical formulations after developed by changing one variable at a time by trial and error method which is time consuming in nature and requires a lot of imaginative efforts. Moreover, it may be difficult to develop an ideal formulation using this classical technique since the joint effects of independent variables are not considered. Therefore, it is very essential to understand the complexity of pharmaceutical formulations using established statistical tools such as factorial design. In addition to the art of formulation, the technique of factorial design is an effective method of indicating the relative significance of a number of variables and their interactions and coded values and composition of matrix tablets are shows into Table 2, 3   and 4.

 

Evaluation of precompression characteristics ^{9, 10}

Powder prepared for direct compression method was evaluated for bulk density, tapped density, angle of repose, compressibility index and drug content. The results are given in Table 5.

 

Table 3.Composition of matrix tablet of Carvedilol (inner core)

Batch codes	Weight of drug (mg)	Weight of PEO WSR 205 (mg)	Weight of HPMC K4M (mg)	Weight of magnesium stearate (mg)	Weight of talc (mg)	Weight of MCC (mg)
F1	20	5	5	1	1	18
F2	20	5	7.5	1	1	15.5
F3	20	5	10	1	1	13
F4	20	7.5	5	1	1	15.5
F5	20	7.5	7.5	1	1	13
F6	20	7.5	10	1	1	10.5
F7	20	10	5	1	1	13
F8	20	10	7.5	1	1	10.5
F9	20	10	10	1	1	8

 

Table 4.Composition of immediate release tablet (coat layer)

 

Evaluation of tablet ^11,12

Tablet prepared was evaluated for thickness, weight variation, hardness and friability as per IP’ 2007 and results are shown in Table 6.

 

Drug content estimation

Standard Solution:

100 mg of pure drug was weighed accurately and dissolved in 100 ml of methanol. From prepared solution a range of 1 to 10 μg/ml concentrations were prepared.

 

Sample solution:

20 tablets were weighed accurately and finely powdered. Equivalent to 100 mg of Carvedilol was dissolved in 100 ml of methanol. To 1ml of this prepared solution add sufficient amount of methanol to produced stock solution. The absorbance of the resulting solution was measured at the 286 nm using blank in the reference cell. The total content of Carvedilol (C24H26N2O4) in the solution was calculated using the absorbance of a standard solution. The above test was done in triplicate and results are given in Table 6.

 

In vitro drug release study ¹³

In-vitro drug release studies of the prepared matrix tablets were conducted for a period of 24 hrs using USP XXIV type 1 apparatus Basket at 37 ± 0.5 ⁰C and 100 rpm speed. The dissolution studies were carried out in duplicate for 24 hrs (initial 2 hrs with 0.1N hydrochloric acid and rest 22 hrs in pH 6.8 citrophosphate buffer with 1% SLS of ) under sink conditions. At every 1-hrss interval samples of 10 ml were withdrawn from the dissolution medium and replaced with fresh medium to maintain the sink conditions. After filtration the samples were analyzed by an UV spectrophotometer at 286 nm using dissolution medium in reference cell. The total content of Carvedilol (C₂₄H₂₆N₂O₄) in the sample was calculated using the appropriate calibration curve constructed from reference standards. In vitro drug release of different batches of Carvedilol compressed coated tablet are shown in Figure 1.

 

Release kinetic

The dissolution data obtained was fitted to various kinetic models like Zero Order, First Order, Higuchi, Hixson Crowell, K - Peppas the result are given in Table 7. Model independent methods, like similarity factor, difference factor, MDT, t50%, and t80%, were also used to compare dissolution behavior of different formulations are given in Table 8.

 

RESULT AND DISCUSSION:

Evaluation of precompression characteristics

Powder prepared by direct compression method was evaluated by measurement of bulk density, tapped density angle of repose, compressibility index and drug content. The results are shown in table 4. The results of angle of repose (<30) indicate good flow properties and the values for prepared formulations ranges from 24⁰ to 27⁰. Generally compressibility index values up to 16%, result in good to excellent flow properties and values for all formulation ranges from 14 to 16 %. Drug content for all the formulations was in the ranges from 97 to 101%.

 

Evaluation of tablets

The tablet formulations were subject to various evaluation tests, such as thickness, diameter, and uniformity of weight, drug content, hardness, friability, disintegration and In vitro dissolution. The results for all the formulations are shown in Table 5. The thickness of all the formulations was varies with drug: polymer ratio, it ranges from 5.70 to 5.87 mm. All the formulation showed uniform thickness. The weight variation test was carried out as per IP’2007 and the average percentage deviation of all the formulation was found to be within the limit. The content uniformity test was also carried out as per official method and it was found that different batches shows good content uniformity. It was found that all batches shows percent drug content more than 99 %. The tablet hardness of all the formulations was determined and it was found in the range 5 to 6 kg/cm². This test was carried out as per USP XXIV and it was found that all formulation shows disintegration of outer layer within 3 mins in Table 5.

 

In vitro drug release study

Dissolution test was carried out in 0.1N HCl for initial 2 hrs followed by 22 hrs dissolution in pH 6.8 citro phosphate buffer with 1% SLS. During initial phase of dissolution immediate release layer i.e outer layer disintegrates releasing initial dose of 5 mg for immediate action followed by slow release of drug from core to maintain therapeutic concentration. The In vitro drug release of different batches of Carvedilol compressed coated tablet are shown in the Figure 1.

 

Fig.1 In vitro drug release of different batches of Carvedilol compressed coated tablet

 

Table 5.Various evaluation parameter of powder blend for sustained release part

Formulation	Angle of repose	Bulk density	Tapped density	% Compressibility	% Drug content
F1	24.82 ± 1.38	0.36 ± 0.04	0.42 ± 0.02	14.28	98.27 ± 0.998
F2	24.73 ± 1.47	0.34 ± 0.03	0.37 ± 0.04	12.82	97.48 ± 0.973
F3	25.29 ± 1.42	0.33 ± 0.03	0.39 ± 0.02	15.38	100.42 ± 0.999
F4	24.42 ± 1.02	0.37 ± 0.04	0.43 ± 0.04	13.95	101.27 ± 0.977
F5	25.82 ± 1.68	0.37 ± 0.03	0.44 ± 0.04	15.90	101.73 ± 0.987
F6	25.54 ± 1.04	0.36 ± 0.04	0.42 ± 0.04	14.28	99.67 ± 0.927
F7	25.02 ± 1.28	0.35 ± 0.04	0.41 ± 0.02	14.63	99.39 ± 0.889
F8	25.82 ± 1.24	0.35 ± 0.03	0.42 ± 0.03	16.67	97.28 ± 0.899
F9	26.94 ± 1.05	0.36 ± 0.02	0.42 ± 0.03	14.28	98.63 ± 0.917

 

Table 6.Various parameter of tablet formulation

Formulation code	Thickness (mm)	Hardness (kg/cm2)	Weight variation (% deviation)	Friability (%)	Drug content (%)	Disintegration time (min)
F1	2.66±0.02	5.3 ± 0.15	2.98 ± 0.93	0.72 ± 0.09	97.92 ± 2.83	2.12±0.08
F2	2.67±0.01	5.2 ± 0.14	3.45 ± 0.84	0.74 ± 0.07	98.92 ± 1.93	2.10±0.06
F3	2.64±0.02	5.0 ± 0.12	2.88 ± 0.78	0.76 ± 0.06	101.73 ± 2.49	2.15±0.08
F4	2.65±0.03	5.3 ± 0.12	3.35 ± 0.86	0.79 ± 0.05	99.28 ± 2.94	2.05±0.09
F5	2.68±0.02	4.8 ± 0.11	2.56 ± 0.88	0.69 ± 0.08	97.92 ± 2.74	2.10±0.05
F6	2.66±0.02	4.5 ± 0.15	2.76 ± 0.69	0.76 ± 0.04	99.15 ± 3.04	2.08±0.06
F7	2.66±0.01	4.9 ± 0.09	3.05 ± 0.79	0.72 ± 0.03	96.92 ± 1.99	2.18±0.07
F8	2.68±0.03	4.7 ± 0.11	3.34 ± 0.77	0.68 ± 0.05	97.21 ± 2.56	2.16±0.08
F9	2.64±0.01	4.5 ± 0.12	3.45 ± 0.57	0.75 ± 0.04	99.25 ± 2.78	2. 19±0.07

 

Table 7. Kinetic study of dissolution data of all batches

Coefficient of Determination ( R2 )
Batch no.	Higuchi	Zero order	First order	Hixson crowell	K-peppas
F1	0.9612	0.8602	0.7328	0.8153	0.701
F2	0.9726	0.9746	0.9026	0.8100	0.557
F3	0.9586	0.9806	0.9255	0.7796	0.537
F4	0.9755	0.9727	0.9023	0.8626	0.533
F5	0.9553	0.9821	0.9399	0.9196	0.508
F6	0.9322	0.9881	0.9618	0.7497	0.509
F7	0.9149	0.9836	0.9824	0.8922	0.459
F8	0.8878	0.9678	0.9922	0.8639	0.421
F9	0.8675	0.9607	0.9908	0.8831	0.460

 

Dissolution pattern of batches varies with varying in the percentage of polymer. HPMC K4M gives initial burst release, while PEO WSR 205 retards initial drug release hence varying ratio of polymer were used to get optimized dissolution profile which shows good correlation with theoretical profile and follows zero order kinetic. Dissolution was also affected by factors like hardness, nature of excipient and amount of diluents.

 

Release kinetic

The dissolution data obtained was fitted to various kinetic models like Zero Order, First Order, Higuchi, Hixson crowell, K - peppas (Tables 7). Model independent methods, like similarity factor, difference factor, MDT, t50%, and t80%, were also used to compare dissolution behavior of different formulations (Table 8). Formulation F7, F8 and F9 exhibited diffusion coefficient value less than 0.5 indicating the drug release mechanism is by Fickian diffusion. For other formulation n value was found to be more than 0.5 indicating the drug release mechanism is by Non- Fickian transport (Erosion mechanism). From the drug release profile, it was evident that formulations F7 and F8 are suitable Sustained release dosage form of Carvedilol as they released approximately 100% of the drug at the end of 24 hrss.

 

Table 8.Comparison of dissolution profile of formulations by model independent method.

 

 

3² full factorial design optimization

In 3² full factorial design, two variables i.e % weight of polymer HPMC K4M and % weight of PEO WSR 205 were studied at three levels: high, medium and low levels. According to experimental design nine experiments were conducted. The Mean Dissolution Medium (MDT) ,t50, and t80 were selected as dependent variables for 3² full factorial design ^14,15.

 

Mean dissolution time

The Mean Dissolution Time of different batches of 32 full factorial design was found to be between ranges 5.75 to 12.39 hrs. Data were analyzed statistically by one-way analysis of variance (ANOVA) using Microsoft Excel 2007 and by the student’s t-test (level of significance for p<0.05).

The polynomial equation was generated by multiple linear regressions. The equation derived is as under:

 

Y = 10.18 +1.89 X1 +1.10X2+ 0.05X1X2-0.34X1²-0.69X2²

 

The data clearly indicate that the mean dissolution time values are strongly dependent on the selected independent variables. The fitted equation (for full model) relating the response (% entrapment efficiency) to the transformed factor is shown by factorial equation. The polynomial equations can be used to draw conclusions after considering the magnitude of coefficient and the mathematical sign it carries (i.e. positive or negative). The high values of correlation coefficient for mean dissolution time indicate a good fit. The equations may be used to obtain estimates of the response as a small error of variance was noticed in the replicates. The coefficients b1 and b2 were found to be significant at P<0.05. While the significance level of coefficient b12, b11 and b22 were found to be insignificant at P<0.05 so it may be concluded that these term do not significantly contribute to the prediction of MDT. The results of regression analysis reveal that on increasing the values for X1 and X2 increase in MDT is observed, because coefficient b1 and b2 bears a positive sign.

 

t 50

The t50 of different batches of 3² full factorial design was found to be between ranges 6.23 to 13.99 hrs. The polynomial equation was generated by multiple linear regressions. The equation derived is as under:

 

Y = 10.01+2.33 X1+1.17X2+1.17X1X2 -0.15X1² -0.14X2 ²

 

The data clearly indicate that the t50 values are strongly dependent on the selected independent variables. The fitted equation (for full model) relating the response (% entrapment efficiency) to the transformed factor is shown by factorial equation. The polynomial equations can be used to draw conclusions after considering the magnitude of coefficient and the mathematical sign it carries (i.e. positive or negative). The high values of correlation coefficient for mean dissolution time indicate a good fit. The equations may be used to obtain estimates of the response as a small error of variance was noticed in the replicates.. The coefficients b1 and b2 were found to be significant at P<0.05. While the significance level of coefficient b12, b11 and b22 were found to be insignificant at P<0.05 so it may be concluded that these term do not significantly contribute to the prediction of t50. The results of regression analysis reveal that on increasing the values for X1 and X2 increase in t50 is observed, because coefficient b1 and b2 bears a positive

 

t 80

The t80 of different batches of 32 full factorial design was found to be between ranges 13.23 to 23.45 hrs. The polynomial equation was generated by multiple linear regressions. The equation derived is as under:

 

Y = 17.53+3.20X1+1.44X2+ 0.79 X1X2 -0.06X1² -0.17X2²

 

The data clearly indicate that the t50 values are strongly dependent on the selected independent variables. The fitted equation (for full model) relating the response (% entrapment efficiency) to the transformed factor is shown by factorial equation. The polynomial equations can be used to draw conclusions after considering the magnitude of coefficient and the mathematical sign it carries (i.e. positive or negative). The high values of correlation coefficient for mean dissolution time indicate a good fit. The equations may be used to obtain estimates of the response as a small error of variance was noticed in the replicates. The coefficients b1 and b2 were found to be significant at P<0.05. While the significance level of coefficient b12, b11 and b22 were found to be insignificant at P<0.05 so it may be concluded that these term do not significantly contribute to the prediction of t50. The results of regression analysis reveal that on increasing the values for X1 and X2 increase in t50 is observed, because coefficient b1 and b2 bears a positive.

 

Selection of optimized batch was done on the basis of similarity factor and zero order kinetic drug release. From the values of similarity factor it was found that batch F6 and batch F7 shows maximum similarity with theoretical profile i.e. 73.55 and 72.07 respectively then the other batches. From the values of the release kinetic data, batch F6 and batch F7 shows the maximum value of coefficient of determination (r2) then other batches i.e. 0.9881 and 0.9836. So, batch F6 is selected as the optimized batch on the basis of similarity with theoretical profile and zero order drug release kinetic.

 

ACKNOWLEDGEMENT:

It is great pleasure for me to acknowledge all those who have contributed towards the conception, origin and nurturing of this project. I would like to verbalize my deep sense of reverence to Maliba Pharmacy College and Arihant school of Pharmacy and BRI, for providing me necessary facilities and help in carrying out my dissertation work. I am truthfully thankful to Torrent Research Centre for providing me the gift samples of Carvedilol and Dow Chemicals, Germany for Polyox WSR205 and HPMC K4M respectively.

 

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Received on 29.06.2012       Modified on 14.07.2012

Accepted on 29.07.2012      © RJPT All right reserved