Latin American Journal of Pharmacy (formerly Acta Farmacéutica Bonaerense) Lat. Am. J. Pharm. 37 (7): 1414-23 (2018)
Received: May 1, 2018 Revised version: May 25, 2018 Accepted: May 26, 2018
Formulation Development and Optimization of Captopril Containing Tablets through Box-Behnken Design
Muhammad F. AKHTAR1, Muhammad HANIF1*, Abdul MAJEED1 & Shahid SHAH2
2
1 Faculty of Pharmacy, Bahauddin Zakariya University Multan, Pakistan Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Government College University Faisalabad, Pakistan
SUMMARY. Captopril immediate release tablets were optimized through Box-Behnken design (BBD) by taking starch (X1), sodium starch glycolate (X2) and polyvinylpyrrolidone (X3) as independent variables and disintegration time (Y1), % drug release at 10 and 20 min (Y2 and Y3) as dependent variables. Bulk density, tapped density, angle of repose, compressibility index (CI), Hausner’s ratio (HR), weight variation, tablet density (ρt), relative density (ρ), porosity (ɛ), tensile strength (T), hardness, friability, disintegration time and % drug release were calculated. Disintegration time ranged from 7 ± 0.26 to 20 ± 1.01 min. % Drug release at 10 min was found between 40.84 ± 0.59 and 53.28 ± 0.69% and %drug release at 20 min was found 70.08±0.56 to 91.45 ± 0.67%. Starch and sodium starch glycolate showed positive effect on disintegration time but negative effect on % drug release at 10 and 20 min. Polyvinylpyrrolidone showed positive effect on disintegration time, % drug release at 10 and 20 min. First order release kinetics was followed and non-fickian diffusion was observed. Cumulative % drug release of F12 was found 91.45% and considered as the optimized formulation due to its ideal behavior. The developed formulations were considered suitable for the development of enteric coated tablets by applying semipermeable membrane. RESUMEN. Las tabletas de liberación inmediata de captopril se optimizaron mediante el diseño Box-Behnken (BBD) tomando almidón (X1), almidón glicolato sódico (X2) y polivinilpirrolidona (X3) como variables independientes y tiempo de desintegración (Y1), liberación del fármaco a los 10 y 20 min (Y2 e Y3) como variables dependientes. Se calcularon la densidad aparente, densidad intervenida, ángulo de reposo, índice de compresibilidad (CI), índice de Hausner (HR), variación del peso, densidad de la tableta (ρt), densidad relativa (ρ), porosidad (ɛ), resistencia a la tracción (T), dureza, friabilidad, el tiempo de desintegración y el % de liberación del fármaco. El tiempo de desintegración varió de 7±0.26 a 20±1.01 min. El % de liberación de fármaco a los 10 min se encontró entre 40.84 ± 0.59 y 53.28 ± 0.69% y el % de liberación del fármaco a los 20 min se encontró 70.08±0.56 a 91.45 ± 0.67%. El almidón y el glicolato sódico de almidón mostraron un efecto positivo sobre el tiempo de desintegración pero un efecto negativo sobre el % de liberación del fármaco a los 10 y 20 min. La polivinilpirrolidona mostró un efecto positivo en el tiempo de desintegración, el % de liberación del fármaco a los 10 y 20 min. Se siguió la cinética de liberación de primer orden y se observó difusión no fickiana. El % acumulativo de liberación de F12 en el fármaco fue 91.45% y se consideró como la formulación optimizada debido a su comportamiento ideal. Las formulaciones desarrolladas se consideraron adecuadas para el desarrollo de comprimidos con recubrimiento entérico mediante la aplicación de una membrana semipermeable.
INTRODUCTION Statistical designs are influential, effective and valid tool in the designing of different types of dosage forms. By using the statistical tools, the processing time and research methodology can be improved. In the present study, BBD was used for the evaluation of independent, rotatable and quadratic relationships between variables and responses. The pharmaceutical scientists have an urge to adopt such techniques which are not only simple in implication but also cost effective. BBD has an extra advantage of minimum planned formulations1. *
The oral route is the most convenient route for delivering therapeutic agents to systemic circulation. Ease of administration, patient compliance and flexibility in formulation are some advantages of oral drug delivery systems. Among oral prescriptions, tablet dosage form is mostly used due to its extra advantage of taste masking, disintegration, immediate drug release and ease in compression 2 . Tablets can be compressed by wet granulation, dry granulation and direct compression. Direct compression is more economical and simple in terms of good manufacturing
KEY WORDS: Box-Behnken design, diffusion, in vitro models, physical characterization, tableting.
Author to whom correspondence should be addressed. E-mail:
[email protected],
[email protected]
1414
ISSN 0326 2383 (printed ed.) ISSN 2362-3853 (on line ed.)
Latin American Journal of Pharmacy - 37 (7): 1414-23 (2018)
practice, reduced cycle time and lower microbial level than those prepared by the wet and dry granulation methods. A simple formulation composition could be an active ingredient, a diluent and a lubricant 3 . Clinical investigations suggested captopril a highly efficacious remedy for hypertension and congestive heart failure. It has been effective where conventional antihypertensive therapies fail or have an untoward number of side effects 4. Furthermore, it possesses good bioavailability (7075%) including short half-life (∼2 h) 5. The objective of the research work was to develop captopril immediate release tablets. BBD was used to develop and to optimize developed formulations having three independent and three dependent variables. Independent variables were starch, sodium starch glycolate, PVP and the dependent variables were disintegration time, % drug release at 10 and 20 min. Applied precompressional parameters were bulk density, tapped density, angle of repose, CI and HR. Tablets were developed by direct compression method and characterized by their weight variation, thickness, diameter, tablet density, relative density, porosity, T, hardness, friability, disintegration time, % drug release at 5, 10, 15, and 20 min. The effects of independent variables on dependent variables were studied and used as a tool to optimize developed formulations. Variables
Independent Variables
–1
X2 Sodium starch glycolate (%)
2
X1 Starch (%)
X3 PVP 40,000 (%)
Dependent Variables
MATERIALS AND METHODS Materials Captopril was gifted by Mediceena Pharma (Pvt.) Ltd. Pakistan. Starch (BDH, England), polyvinylpyrrolidone 40,000 (Merck, Germany), magnesium stearate (Fluka, Germany), lactose (Merck, Darmstadt, Germany), and sodium starch glycolate (Sigma-Aldrich, USA) were of analytical grade. Double distilled water was used during whole study period. Experimental Design BBD is a response surface design, especially made to require only three levels, coded as –1, 0 and +1 as mentioned in Table 1. Code
Value
–1
[(Ymax + Ymin)/2] – [(Ymax – Ymin)/2α]
+1
[(Ymax + Ymin)/2] + [(Ymax – Ymin)/2α]
0
[(Ymax + Ymin)/2]
Table 1. Coded values of different concentration of variables.
BBD was used for making polynomial model 6 for optimization of tablets keeping 3 independent and 3 dependent variables (Table 2) using design expert (version 7.1 State-ease Inc., Minneapolis, MN). Independent variables were starch, sodium starch glycolate and PVP and the dependent variables were disintegration time, % drug release at 10 and 20 min. Eq. [1] is representing BBD 7. Level
0
+1
2.5
3
17
22.5
2
3.5
28
In the range
5
In the range
Y1 Disintegration time (min.)
In the range
7–20
Y2 Drug release at 10 min. (%)
Y3 Drug Release at 20 min. (%)
Constraints
40.84–53.28
Table 2. Variables and Constraints in BBD.
70.08–91.45
[1]
where 𝑌 𝑖 is the measured response of the dependent variables, b 0 is the intercept, b 1 to b 33 are the regression coefficients computed from the observed experimental values of 𝑌. 𝑋 1 , 𝑋 2 and
𝑋 3 are the coded values of the independent variables. 𝑋 𝑎 𝑋 𝑏 (𝑎, 𝑏 = 1, 2, 3, 4) and 𝑋 2 𝑖 (𝑖 = 1, 2, 3, 4) represent the interaction and quadratic terms, respectively. 1415
AKHTAR M.F., HANIF M., MAJEED A. & SHAH S.
Physical evaluation of formulations at precompression stage The glass funnel was fixed in place, 5 cm above the bench surface. After the cone from 10g of sample was built, height of the granules forming the cone (h) and the radius (r) of the base was measured. The angle of repose (θ) was calculated by using Eq.[2]. [2]
Results were only considered valid when a symmetrical cone of powder was formed. Bulk and tapped densities were calculated using the methods outlined in USP. The bulk and tapped densities were further used to calculate CI and HR to provide a measure of the flow properties and compressibility of powders. Eqs. [3] and [4] were used to calculate CI and HR.
[3] [4]
where ρ tap is the tapped density and ρ bulk is the bulk density. Preparation of captopril tablets For the preparation of core tablets; binder, filler, disintegrant, lubricant and experimental drug were accurately weighed then well mixed with Sigma Mixer (Erweka AR 400 Apparatebau–GMBH Germany) for 15 min and compressed into tablets using Single Punch Tablet Press (Minipress MII, Pharma Test, GMBH Hainburg/Germany). Weight of tablets was fixed at 500mg by taking different concentration of excipients as listed in Table 3.
Formulation
Drug (mg)
Starch (mg)
Sodium starch glycolate (mg)
PVP (mg)
Lactose (mg)
Magnesium stearate (mg)
Total weight (mg)
F2
116
85
15
17.5
261.5
5
500
15
10
F1 F3 F4 F5 F6 F7 F8 F9
F10 F11 F12
116
140
116
112.5
116
140
116
112.5
12.5 10
25
10
17.5
140
12.5
25
116
112.5
10
116
85
116
112.5
116
85
116
116 116
140 85
15
12.5
25 25 10
15
17.5
10
17.5
12.5
10
216.5 231.5 241.5
5
196.5
10
251.5 236.5 196.5 261.5 256.5
500
5
10
221.5
500
5
206.5
Table 3. Composition of Captopril immediate release tablets.
Physicochemical evaluation of the developed formulations Variation of the weight was determined by weighing randomly selected 20 tablets of each formulation by using an analytical balance (Ohaus, USA). Twenty tablets were randomly selected; their thickness and diameter were determined by Vernier Caliper. For the calculation of crushing load, hardness of tablets was determined by Hardness Tester (Erweka, GMBH Heusenstamm, Germany). Mean and standard deviation of each formulation was calculated by using Microsoft Excel 2007. Friability of core tablets was carried out on a Friabilator (Pharma Test D–63512 Hain1416
10
500 500
10
500 500
10
500
15
500
15
500
15
500
15
500
burg/Germany) according to B.P. specifications. T was calculated using Eq. [5]. [5]
where F (N) is the crushing load, d (cm) and h (cm) are the diameter and thickness of the tablet, respectively. Densities and relative densities of tablets were calculated by using Eqs. [6] and [7], respectively 8. The porosity of the tablet was calculated from the Eq. [8] 8. [6]
Latin American Journal of Pharmacy - 37 (7): 1414-23 (2018)
[7] [8]
Responses of BBD Three responses; disintegration time (Y1), %drug release at 10 min (Y2) and %drug release at 20 min (Y3) were used to evaluate the effects of independent variables on dependent variables. Randomly selected 6 tablets of each formulation were used for disintegration test by using Basket rack USP disintegration tester (Eerweka Apparatebau GMBH, Germany). Purified Water at 37 °C was used as medium and time was noted till no any palpable mass present on the wires. Cumulative %drug release was measured through dissolution studies. Preparation of standard curve in 0.01N HCl Captopril (12.89 mg) accurately weighed was dissolved in 100 mL 0.01 N HCl. From this stock solution, different dilutions were prepared in the concentration range of 8.06, 16.11, 32.23, and 64.45 μg/ml and the absorbance was taken at 205 nm. Standard curve was prepared (Fig. 1).
Figure 1. Calibration curve of captopril.
Dissolution studies Six tablets of each formulation were placed gently in USP dissolution apparatus II (Pharmatest; PT–Dt 7, Germany) having 900 mL of 0.01N HCl as dissolution media at 37 ± 0.5 °C and 50 rpm. Approximately 5 mL aliquot of each medium was withdrawn after 5, 10, 15, and 20 min, filtered by 0.45 μm syringe filter and drug concentrations were measured by UV-Visible spectrophotometer (PerkinElmer, Waltham, MA) at 205 nm 9. The quantity of aliquot withdrawn was replaced with the same quantity of dissolution medium to maintain the sink condition. Model dependent approaches Model dependent approaches were used for the in vitro kinetic evaluations of immediate release formu-
lation. Different kinetic models applied were zero order, first order, Higuchi and Korsmeyer-Peppas models. Equations used for zero order, first order, Higuchi and Korsmeyer–Peppas models (Eqs. [9-12]) are given below 10. [9]
[10]
[11]
[12]
where Ft is fraction of drug release in time t, Ko is rate constant for zero order release, F is fraction of drug release in time t, K1 is first order release rate constant, K2 is Higuchi constant, Mt is amount of drug release at time t, M∞ is amount of drug release at infinity and n is diffusion constant.
FTIR spectroscopic analysis The FTIR spectra were recorded over the wavelength range 4,000-400 cm-1 using FTIR spectrometer (Platinum-ATR, ALPHA, Bruker). Average of ten spectra is reported.
RESULTS AND DISCUSSION For the assessment and comparison of release of drug from immediate release formulations, twelve formulations were designed. Formulations were compressed and evaluated for their physicochemical properties. The optimized formulation with highest value of regression coefficient was selected by applying model dependent parameters.
Physical evaluation of formulations at precompression stage Bulk density and tapped density were found to be 0.581 ± 0.112 to 0.714 ± 0.071 g/cm 3 and 0.781 ± 0.073 to 1.042 ± 0.028 g/cm 3 , respectively. Similar results were observed by Zaman et al. 2. Angle of repose was found to be 32.725 to 43.069º. As a manufacturing rule, values of angle of repose in the range of 20º to 40º are acceptable 15 . F2, F3, F4, F7, F8, F9, F11 and F12 showed acceptable values of angle of repose. CI was found to be 14.286 to 33.333. According to Ma and Hadzija 11, values of CI between 15 and 25% indicate a compressible blend. F2, F3, F4, F8, F9 and F12 CI values predicted a compressible blend of developed formulations at precompression stage. HR was found to be 1.167 to 1.500. F8 HR indicated a good flow of powder
1417
AKHTAR M.F., HANIF M., MAJEED A. & SHAH S.
mixture. F2, F3, F4, F9 and F12 HR values indicated a passable flow of powder mixture. F1, F5, F6, F7 and F10 HR indicated a poor flow of powder mixture. F11 HR indicated a very poor flow of powder mixture. Formulation
Bulk Density (g/cm3)
Tapped Density (g/cm3)
0.625 ± 0.092
0.833 ± 0.098
F1
0.610 ± 0.023
F3
0.625 ± 0.083
F2 F4 F5 F6 F7 F8 F9
F10 F11 F12
0.641 ± 0.016 0.610 ± 0.054 0.581 ± 0.063 0.581 ± 0.059 0.714 ± 0.071 0.595 ± 0.033 0.581 ± 0.112 0.694 ± 0.089 0.625 ± 0.073
Physicochemical evaluation of the developed formulations Average weight was found to be 494 ± 0.672 to 517 ± 0.919 mg. Weight variation of ± 5% was found in all formulations (Table 4) which were within the pharmacopoeial limits. CI (%)
Angle of repose
Average weight (mg)
Hardness (Kg/cm2)
Friability (%)
1.333
25
39.433
494 ± 0.672
8 ± 0.36
0.63
1.3
23.077
HR
0.833 ± 0.134
1.367 26.829
0.833 ± 0.087
1.333
0.833 ± 0.076
25
0.833 ± 0.104
1.367 26.829
0.806 ± 0.048
1.387 27.907
0.806 ± 0.067 0.833 ± 0.055 0.781 ± 0.073 0.806 ± 0.047 1.042 ± 0.028 0.833 ± 0.039
1.387 27.907 1.167 14.286 1.313
23.81
1.5
33.333
1.387 27.907 1.333
25
42.668 35.646 37.569 43.069 40.013 39.988 37.98 40.01 41.9
36.053 32.725
498 ± 1.524
10 ± 0.12
508 ± 0.825
12 ± 0.09
506 ± 1.673
10 ± 0.47
510 ± 0.878
9 ± 0.53
511 ± 0.737 513 ± 1.783
9 ± 0.28
13 ± 0.39
517 ± 0.919
13 ± 0.68
512 ± 1.345
9 ± 0.72
515 ± 1.186 497 ± 1.089 509 ± 1.238
11 ± 0.59 12 ± 0.77 8 ± 0.81
0.71 0.57 0.74 0.65 0.55 0.57 0.53 0.79 0.67 0.72 0.61
Table 4. Values of bulk density, tapped density, HR, CI, Angle of repose, Average weight, Hardness and Friability (n = 6).
Similar results were found by Ahmad et al. 12 and Zade et al. 13 for fast dissolving tablets of Tizanidine. Shoaib et al. used hydroxypropyl methylcellulose as a polymer in the matrix tablets of Ibuprofen and found similar weight variation results having average weight of the tablet more than 800 mg 14. Friability was observed in the range of 0.53-0.79% that is in acceptable limits. The formulations having better hardness showed suitable friability results (Table 4). Granular compaction and compression force in direct compression affected the friability values. Liquid within the granules, lump and porosity are involved in more friable granules. Hardness values were also calculated and found to be 8 ± 0.36 – 13 ± 0.68 Kg/cm2 as shown in Table 4. Starch Formulation
Thickness (cm)
ρt (g/cm3)
4.26 ± 0.06
F1
11.45 ± 0.05
4.32 ± 0.02
F3
11.41 ± 0.03
4.44 ± 0.07
F2 F4 F5
1418
Diameter (cm)
11.39 ± 0.02 11.53 ± 0.07 11.49 ± 0.03
4.27 ± 0.05 4.35 ± 0.04
has inverse proportion to hardness of formulations. Similar findings were reported by Oishi et al. 15 while studying comparison of different brands of gatifloxacin available in Pakistani market. T was found to be 0.010 to 0.017 Pascal (Table 5). Hanif et al. 16 also found similar results. Thickness is directly proportional to the weight of tablets. Thickness range was found to be 4.21±0.01 to 4.44±0.07 cm in all formulations. Diameter was found to be 11.39 ± 0.02 to 11.53 ± 0.07 cm. Tablet density and relative density were found to be 0.633 to 0.664 g/cm3 and 0.760 to 0.825 g/cm3, respectively. Porosity was found to be 0.175 to 0.388. Hanif et al. also found similar results (Table 5) 16. ρ
Porosity
T(Pa)
0.638
0.766
0.234
0.01
0.636
0.764
0.236
0.633 0.653 0.637
0.76
0.783 0.764
0.24
0.013
0.217
0.015
0.236
0.012
0.011
%Drug release %Drug release at 5 min at 15 min
15.44 ± 0.54
60.7 ± 0.38
18.55 ± 0.12
72.91 ± 0.66
16.66 ± 0.34
65.48 ± 0.75
16.35 ± 0.26 15.69 ± 0.42
64.29 ± 0.59 61.68 ± 0.42
Latin American Journal of Pharmacy - 37 (7): 1414-23 (2018)
F6
11.47 ± 0.05
4.37 ± 0.05
0.649
0.805
0.195
0.016
16.08 ± 0.08
63.2 ± 0.81
F8
11.41 ± 0.04
4.21 ± 0.01
0.664
0.797
0.203
0.017
18.74 ± 0.37
73.65 ± 0.72
15.01 ± 0.49
58.99 ± 0.36
F7 F9
F10 F11 F12
11.46 ± 0.04 11.51 ± 0.06 11.5 ± 0.03
11.42 ± 0.02 11.43 ± 0.02
4.39 ± 0.03 4.43 ± 0.12 4.38 ± 0.08 4.41 ± 0.05 4.33 ± 0.03
0.647
0.802
0.645
0.825
0.643
0.797
0.637
0.612
0.651
0.781
0.198 0.175 0.203 0.388 0.219
0.011 0.013 0.011 0.015 0.01
15.05 ± 0.06 16.88 ± 0.35 17.02 ± 0.68 19.58 ± 0.73
59.2 ± 0.69
66.34 ± 0.28 66.88 ± 0.54 76.96 ± 0.68
Table 5. Values of diameter, thickness, tablet density, relative density, porosity, T, % drug release at 5 and 15 min (n = 6).
Responses of BBD The effects of independent variables on depen-
dent variables were studied and response surface methodological plots were developed (Figs. 2 and 3).
Figure 2. Three dimensional response surface methodological graph showing effects of starch, sodium starch glycolate and PVP 40,000 on disintegration time (Y1).
Figure 3. Three dimensional response surface methodological graph showing effects of starch, sodium starch glycolate and
PVP 40,000 on % drug release at 10 and 20 min (Y2 and Y3).
Y1 ranged from 7 ± 0.26 to 20 ± 1.01 min (Table Formulation
F1 F2 F3 F4
X1 (%)
28 17
22.5 22.5
Independent Variables
6) which was also within the acceptance criteria.
X2 (%)
X3 (%)
3
3.5
3
2
2.5 2
Y1 (min)
Dependent Variables Y2 (%)
Y3 (%)
2
17 ± 1.13
42.02 ± 0.27
72.11 ± 0.12
5
11 ± 0.48
44.5 ± 0.39
76.39 ± 0.26
10 ± 0.36 08 ± 0.53
50.47 ± 0.34 45.33 ± 0.48
86.63 ± 0.09 77.81 ± 0.23
1419
AKHTAR M.F., HANIF M., MAJEED A. & SHAH S.
F5
28
2
3.5
15 ± 0.89
28
2.5
5
18 ± 0.69
F9
22.5
2
F11
17
F6
22.5
F8
17
F7 F10
3
2.5
28
F12
17
5 5 2
3
3.5
2
3.5
2.5
73.28 ± 0.36
40.98 ± 0.72
70.34 ± 0.53
13 ± 0.73
43.76 ± 0.63
12 ± 0.87
50.99 ± 0.81
07 ± 0.26 20 ± 1.01
2
42.7 ± 0.57
11 ± 0.33 09 ± 0.45
75.09 ± 0.48 87.52 ± 0.64
45.92 ± 0.45 40.84 ± 0.59 46.31 ± 0.61 53.28 ± 0.69
78.83 ± 0.59 70.08 ± 0.56
79.46 ± 0.0.08 91.45 ± 0.67
Table 6. Observed Responses in BBD for Captopril Tablets (n = 6).
Y2 was found between 40.84 ± 0.59 to 53.28 ± 0.69% (Table 6) and Y3 was found between 70.08 ± 0.56 to 91.45 ± 0.67% (Fig. 4).
Figure 4. Drug release at 20 min. of captopril immediate release tablets (n = 6).
All responses were fitted to the quadratic models using BBD. BBD was also applied by Ali et al. 17. Data of Y1, Y2 and Y3 was observed and the best fitted model was quadratic and regression equations (Eqs. [13-15]) were generated. In regression equations, positive sign favors the optimization while negative sign indicates an inverse relationship between independent and dependent variables. The amount of starch (X1), sodium starch glycolate (X2) and polyvinylpyrrolidone (X3) have different effects on Y1, Y2 and Y3. [13] [14]
Starch and sodium starch glycolate showed positive effect on disintegration time but negative effect on % drug release at 10 and 20 min. Polyvinylpyrrolidone showed positive effect on disintegration time, % drug release at 10 and 20 min. The interaction of X1 and X2 showed positive effect on Y1, Y2 and Y3. The interaction of X1 and X3 showed negative effect on Y2 and Y3 but positive effect on Y1 while interaction of X2 and X3 showed positive effect on Y1 but negative effect on Y2 and Y3. Optimized formulation F12 was selected on the basis of better release pattern of drug at 5, 10, 15, and 20 min. Rapolu et al. 6 studied the effect of different polymer concentrations on reFormulation
F1
0.812
F3
0.968
F2
1420
Zero order
R2
0.983
K0
First order
R2
K1
3.8
0.951
0.057
4.025
0.989
0.063
4.565
0.995
0.076
[15]
lease profile of gastroretentive floating drug delivery system of Metronidazole by using BBD.
Dissolution studies Model dependent approaches Dissolution profiles were compared by different kinetic models; among them zero order had the minimum values of r2 i.e. 0.812 to 0.983 but first order kinetics had the maximum r2 values i.e. 0.951 to 0.999 and nonfickian diffusion was observed as value of n was greater than 0.45 in Korsmeyer-Peppas model. Model dependent in vitro kinetics like zero order, first order, Higuchi and Korsmeyer-Peppas are listed in Table 7. R2
Higuchi
0.88
0.967 0.958
KH
Korsmeyer Peppas R2
KKP
n
14.5
0.958
4.469
0.551
15.358
0.995
4.73
0.815
17.418
0.987
5.366
0.941
Latin American Journal of Pharmacy - 37 (7): 1414-23 (2018)
F4
0.975
F6
0.936
F5 F7 F8
0.064
0.983
15.644
0.991
4.817
0.798
3.957
0.967
0.061
0.935
15.098
0.971
4.651
0.612
3.862
0.948
3.706
0.98
0.959
F11
0.899
F12
0.997
0.912
F9
F10
4.1
0.857 0.971
4.612 4.154 3.693 4.187 4.819
0.953 0.978 0.985 0.993 0.961 0.974 0.999
0.059 0.055 0.078 0.066 0.055 0.067 0.084
0.923 0.914 0.987 0.979 0.908 0.929 0.989
14.734 14.142 17.596 15.849 14.092 15.978 18.386
0.964 0.969 0.988 0.989 0.978 0.985 0.993
4.541 4.354
Effect of starch and sodium starch glycolate on the formulation of tablets Starch is one of the most commonly used tablet disintegrants at concentrations of 3-25% w/w. Starch can also act as an antiadherent and lubricant in tableting and capsule filling 22. Sodium starch glycolate is commonly used as a disintegrant in tablets prepared by either direct-compression or wet-granulation processes. The usual concentration employed in a formulation is between 2 and 8%. It was observed that lesser the disintegrant, more the disintegration time but low %drug release. It
0.71
5.419
0.843
4.343
0.68
4.881 4.925 5.662
Table 7. In vitro model-dependent kinetic studies of captopril immediate release tablets.
Furthermore, in vitro kinetic studies are considered the best source of comparison 18. When drug release is not dependent on its concentration, it is referred as zero order release mechanism but when it depends on concentration of drug, it is called as first order release mechanism. Higuchi’s model shows time dependent diffusion process from tablet matrix and is based on Fick’s law of diffusion. KorsmeyerPeppas model is used for the confirmation of diffusion mechanism. % Drug release at 5 and 15 min were found to be 15.01 ± 0.49 to 19.58 ± 0.73% and 58.99 ± 0.36 to 76.96 ± 0.68%, respectively (Table 5 ). Model dependent approaches in formulations were applied successfully and multiple point dissolution studies showed the satisfactory results of F2, F8 and F12 in 0.01 N HCL. According to USP, not less than 80% of the amount of drug in captopril tablets should be dissolved in 20 min 9. Yu et al. 19 also reported similar findings of ciprofloxacin 500 mg tablets while reporting the comparative study of different brands. Dissolution studies showed the excellent release of F12 due to presence of less quantity of starch which acted as disintegrator. Hadgraft reported the diffusion controlled release of sustained release formulations. Similar studies were also reported by Shah et al. 20 and Hanif et al. 21.
0.557
0.918 0.763 0.942
may be due to the fact that more binder or less disintegrant causes the delay of disintegration 22.
Effect of polyvinylpyrrolidone on the formulation of tablets In tableting, povidone solutions are used as binders in wet-granulation processes. Povidone is also added to powder blends in the dry form and granulated in situ by the addition of water, alcohol or hydroalcoholic solutions. 0.5 to 5% is usually used. It was observed that lesser the binder, less the disintegration time but more % drug release. It may be due to the fact that less binder or more disintegrant causes the early disintegration 22. FTIR spectroscopic analysis FTIR spectra of starch, sodium starch glycolate, PVP 40,000, captopril, unloaded tablets and captopril loaded tablets are shown in Fig. 5.
Figure 5. FTIR spectra of starch (A), sodium starch glycolate (B), PVP 40,000 (C), captopril (D), unloaded tablets (E) and captopril loaded tablets (F).
1421
AKHTAR M.F., HANIF M., MAJEED A. & SHAH S.
The FT-IR spectrum of Starch showed a broad band at 3,365 cm−1 assigned to −OH and band at 2,916 cm−1 assigned to C-H band stretching. Peaks at around 1,158, 1,081 and 1,014 cm−1 are characteristic of a C-O vibrational stretching band. The significant characteristic peak at 1,465 cm−1 was attributed to the CH2 binding 23. With regard to sodium starch glycolate spectrum, a broad band in the region spanning 3600-2900 reflected the OH stretching group of this compound molecule. At 1653-1026 cm-1, overlapping bands reflect asymmetric and symmetrical stretching of C-O-C group 24. The main feature of the spectrum of PVP, whose monomer contains an amide carbonyl, is a strong band at 1649 cm−1. According to the literature, the shape of the amide carbonyl stretch absorption is one of the broadest of the carbonyl family and is positioned between 1695 cm−1 and 1615 cm−1. Other bands on this spectrum are centered at 1421 cm−1 which result from vibration of the tertiary nitrogen, and at 2954 cm−1 and 3412 cm−1, assigned to environmental CH and OH, respectively 25. At 2565 cm–1 a band indicating the presence of –SH group of captopril. The carbonyl vibration band – COOH and amide band were demonstrated in the 1743 and 1583 cm–1 region, respectively 26.
CONCLUSION BBD was used to optimize formulation of captopril immediate release tablets. The designated independent variables were starch, sodium starch glycolate, PVP while the dependent variables were disintegration time, %drug release at 10 and 20 min. Performed precompressional studies were bulk density, tapped density, angle of repose, CI and HR while the postcompressional studies were weight variation, thickness, diameter, tablet density, relative density, porosity, T, hardness, friability, disintegration time, % drug release at 5, 10, 15, and 20 min. Dissolution studies were performed by using 0.01N HCL. Disintegration time ranged from 7 ± 0.26 to 20 ± 1.01 min. which was within the acceptance criteria. % Drug release at 10min was found between 40.84 ± 0.59 to 53.28 ± 0.69% and % drug release at 20 min was found 70.08 ± 0.56 to 91.45 ± 0.67%. Starch and sodium starch glycolate showed positive effect on disintegration time but negative effect on %drug release at 10 and 20min. Polyvinylpyrrolidone showed positive effect on disintegration time, %drug release at 10 and 20 min. F2, F3, F4, F8, F9, F12 precompressional and F2, F8, F12 postcompressional studies were found within the pharmacopoeial limits. First order release kinetics was followed and non-fickian diffusion was observed as value of n was greater than 0.45 in Korsmeyer-Peppas model. Cu1422
mulative %drug release of F12 was found 91.45% and considered as the optimized formulation due to its ideal behavior in pre and post compressional studies. The developed tablets were found suitable for immediate release of captopril. REFERENCES
1.
2. 3. 4.
5.
6. 7. 8. 9. 10.
11. 12.
13. 14.
15.
16.
17.
18.
19.
20.
Adnan, S., K. Shehzadi, M. Farooq, N.M. Ranjha, M. Hanif & Z. Masood (2016) Lat. Am. J. Pharm. 35: 1018-25. Zaman, M., R.M. Sarfraz, S. Adnan, A. Mahmood, M. Hanif & J. Qureshi (2015) Trop. J. Pharm. Res. 14: 1557-63. Asif, U., A.K. Sherwani, N. Akhtar, M.H. Shoaib, M. Hanif & M.I.Qadir (2016) Adv. Polym. Tech. 35(2): 21536. Kadin, H. (1982) Captopril , in Analytical Profile of Drug Substances: 11: pp. 79-137. Mandal, A.S., S. Chatterjee, S. Kundu, N. Biswas, A. Guha & S. Paul (2011) Int. J. Pharm. 421: 145-50. Rapolu, K., K. Sanka, P.K. Vemula, V. Aatipamula, A.B. Mohd & P.V. Diwan (2013) Drug. Dev. Ind. Pharm. 39: 1928-35. Sharma, D., D. Maheshwari, G. Philip, R. Rana, S. Bhatia & M. Singh (2014) BioMed. Res. Int. 2014 (156010): 1-14 Sun, C.C. (2004) J. Pharm. Sci. 93: 646-53. Keller, P.R. (2009) Captopril Tablets , in USP32-NF27 (R.L.William, ed.) The United States Pharmacopeial Convention, Rockville, p.1781. Abbas, G., M. Hanif & M.A.Khan (2017) Des. Monomers. Polym. 20: 1-9. Ma, J.K. & B. Hadzija (2012) Basic physical pharmacy. Jones & Bartlett Publishers, Burlington, USA. Zade, P., P. Kawtikwar & D.Sakarkar (2009) Int. J. Pharm. Tech. Res. 1: 34-42. Ahmad, K., M. Iqbal Ch, K. Jallat, G. M. Khan, M. Hanif & K. Amjad (2015) Lat. Am. J. Pharm. 34: 277-82. Shoaib, M.H., J.Tazeen, H.A. Merchant & R.I. Yousuf (2006) Pak. J. Pharm. Sci. 19: 119-24. Oishi, T.S., M.A. Haque, I. Dewan & S.A. Islam (2011) Int. J. Pharm. Sci.Res. 2: 3129. Hanif, M., M., Harris, I., Rabia, M. Nadeem & H. Liaqat (2014) Pak. J. Pharm. Sci. 27: 785-92. Mujtaba, A., M. Ali & K. Kohli (2014) Chem. Eng. Res. Des. 92: 156-65. Hussain, A., M.Hanif, M.H. Shoaib, R.I. Yousuf, T. Ali & I.N. Muhammad (2013) Lat. Am. J. Pharm. 32: 484-9. Yu, X., G.L. Zipp & G.R. Davidson III (1994) Pharm. Res. 11: 522-7. Shah, V.P., Y. Tsong, P. Sathe & J.P. Liu
Latin American Journal of Pharmacy - 37 (7): 1414-23 (2018)
(1998) Pharm. Res. 15: 889-96. 21. Hanif, M., U. Zia, A. Rasul, S. Shah, N. Nazer & V. Chaurasiya (2014) Lat. Am. J. Pharm. 33: 920-7. 22. Rowe, R.C., P.J.Sheskey, S.C. Owen & American Pharmacists Association (2009) “Handbook of pharmaceutical excipients”, 6th edition APhA/Pharmaceutical Press, Chicago, London, pp. 581,663,685. 23. Bardajee, G. R. & Z. Hooshyar (2013) J. Polym. Res. 20: 298.
24. Chaud, M.V., A.C. Lima, M.M. Vila, M.O. Paganelli, F.C. Paula & L.N. Pedreiro (2013) Trop. J. Pharm. Res. 12: 163-8. 25. Slistan-Grijalva, A., R. Herrera-Urbina, J. Rivas-Silva, M. Avalos-Borja, F.Castillón-Barraza & A. Posada-Amarillas (2008) Mater. Res. Bull. 43: 90-6. 26. Stulzer, H., P. Rodrigues, T. Cardoso, J. Matos & M. Silva (2008) J. Therm. Anal. Calorim. 91: 323-8.
1423
