]
Journal of Sciences
01(01)2011
FORMULATION AND EVALUATION OF DIVALPROEX SODIUM ENTERIC COATED TABLETS 1*
1
1
Jawed Akhtar , Prashant Rana , Bharat Jawaher , * School of Pharmaceutical Sciences, Jaipur National University, Jagatpura, Jaipur-302025, Rajasthan, India * Corresponding author, E-mail:
[email protected] 1
(Received on: 10 Nov, 2011)
(Accepted on: 26 Dec, 2011) ABSTRACT Divalproex sodium Chemically it is designated as sodium hydrogen bis(2-propylpentanoate) is a stable co-ordination compound comprised of sodium valproate and valproic acid in a 1:1 molar relationship and formed during the partial neutralization of valproic acid with 0.5 equivalent of sodium hydroxide. Divalproex sodium is an anticonvulsant drug. Increase level of gama-amino butyric acid in brain & reducing the suizure action. Immediete release tablet of divalproex sodium, Before enteric coating is formulated by optimization of two binding agent (PVP K30 and PVP K90) The Enteric coating were optimized by using two different enteric coating polymer(HPMCP 50 and Eudragit L100). The results of the in vitro release studies showed that the optimized formulation (F11) delayed the release of drug for 1 h in acidic medium. The prepared tablets were evaluated in terms of their precompression parameters, physical characteristics. Keywords: Divalproex Sodium, Enteric coated, enteric coating polymer Development and Evaluation
21
Jawed Akhtar et al.
www.journalserieces.com
]
Journal of Sciences
INTRODUCTION: The tablet coating is one of the oldest pharmaceutical process still in existence. It offers many benefits namelyimproving the aesthetic quality of the dosage form, masking unpleasant odour or taste, easing ingestion, improving product stability and modified the release characteristic of the drug. An enteric coating is a barrier applied to oral medication that controls the location in the digestive system where it is absorbed. Enteric refers to the small intestine, therefore enteric coating prevent release of medication before it reaches the small intestine. Enteric/delayed release coatings consist of pH sensitive polymers, which means the coating remains intact in the acidic environment of the stomach and then solubilizes in the more alkaline environment of the small intestine. Enteric protection for solid oral dosage forms is required to prevent gastric mucosal irritation, to protect a drug which is unstable in gastric fluids or to delay release for local delivery in the intestine. Most enteric coating work by presenting a surface that is stable at the highly acidic pH found in the stomach, but break down rapidly at a less acidic (relatively more basic ) pH. The purpose of this study was to prepare and formulate the Enteric coated Divalproex sodium tablet.
22
MATERIAL AND METHODS: CHEMICALS AND MATERIALS Divalproex sodium is obtained from Sun Pharma Ltd. Vadodara (gujarat). Microcrystalline cellulose IP, Crosspovidone IP and Sodium starch glycolate IP (Nipasol Sodium) were obtained from Neelraj Agencies. Colloidal silicon dioxide, Magnessium stearate, Directly compressible lactose, Talc were purchased from S.D. Fine-chem Ltd, Ahmedabad. Polyvinyl pyrolidone K30 (PVP K30) and Polyvinyl pyrolidone K90 (PVP K90) were obtained from Ranbaxy Fine Chemicals Ltd. Castor Oil.All other ingredients, reagents and solvents are of analytical grade. All the chemicals used in the study were of pharmacopoeia quality (IP). METHODS While developing a pharmaceutical dosage form, it is very much important to determine the physico-chemical properties of the drug molecule & the other derived properties of the drug powder. This first phase of the studies is known as pre-formulation studies which provide lots of information about the formulation development. Preparation of enteric coated tablet of Divalproex Sodium. Trial batches were first taken by direct compression. In this method accurately weighed Divalproex sodium sieve no (20#) passed and other excipients sieve no (40#) passed mixed thoroughly and lubricated with Magnessium stearate Sieve no (60#) passed. And directly compressed under single punch compression machine. Trial batches (Trial F1 to F3) by direct compression are shown in Table 1. Due to failing of batch by direct compression further gone by wet granulation. Granulation was done by using two Jawed Akhtar et al.
01(01)2011
different binder solution PVP K30 (Trial F4, F5, F6, F7) and PVP K90 (Trial F8, F9, F10, F11) in sufficient Isopropyl alcohol and water. Trial batches taken by two different binder solutions shown in Table. The granules (40mesh) 0 were dried in Tray dryer at 45 C. Drying of the granules was stopped when the sample taken from the oven reached a loss on drying (LOD) value of 1.0 to 1.5 %, as measured by a moisture balance at 80°C. The dried granules were sized through 40/60 mesh, lubricated with magnesium stearate (2-3 %w/w) and purified talc (6-7%w/w), aerosil (3-4 %w/w) and then compressed on a single punch tablet machine (Cadmach Machinery Ltd., Ahmedabad, India). The tablets were off white, round and flat. The hardness of the tablets was kept constant. Formulations were prepared and coded them from F1 to F11. The detail of composition of each formulation is given in Table 1,2 and 3. Due to hygroscopic nature of Divalproex sodium Seal coating HPMC low viscosity grade, PEG, ethyl cellulose, sodium methyl paraben. Concentration of seal coatwas optimized via trial and error method. Core tablet are seal coated with 2 %, 2.5 % and 3 % seal coating polymer and evaluated for tablet coating property is done.Finally Enteric coating of seal coated tablet was performed using two different polymer.Eudragit L 100 and HPMC P 50 was used in enteric coating by tril and error method. Effect of this two polymer was compared. Seal coated were enteric coated up to 7%, 8% and 9% and evaluated for tablet coating property. EVALUATION OF DIVALPROEX SODIUM GRANULES Flow low properties of granules (before compression) were 4 characterized in terms of angle of repose , tapped density, 5 6 bulk density , Carr’s index and Hausner ratio. Results are shown in Table 5. Angle of repose: The angle of repose of granules was determined by the funnel method. The accurately weighed granules were taken in a funnel. The height of the funnel was adjustedin such away that the tip of the funnel just touched the apex of the heap of the granules. The granules were allowed to flow through the funnel freely onto the surface. The diameter of the powder cone was measured & angle of 4 repose was calculated using the following equation : tanθ = h/r where, h & r are the height & radius of the powdercone. Bulk density: Both loose bulk density (LBD) & tapped bulk density(TBD) were determined. A quantity of 2 g of powder from each formula, previously lightly shaken to break any agglomerates formed, was introduced into a 10 ml measuring cylinder. After the initial volume was observed, the cylinder was allowed to fall under its own weight onto a hard surface from the height of 2.5 cm at 2 second intervals. The tapping was continued until no further change in the volume was noted. LBD & TBD were 5 calculated using the following formulas : LBD = weight of the powder / volume of the packing
www.journalserieces.com
]
Journal of Sciences
TBD = weight of the powder / tapped volume of the packing Compressibility Index: The compressibility index of the granules was determined 6 by Carr’s compressibility Index : Carr’s index (%) = [(TBD – LBD) * 100] / TBD. Where, LBD= Weight of powder / Volume of packing TBD= Weight of powder / Tapped Volume of packing 7 EVALUATION OF TABLETS: Thickness: The thickness of the tablet was determined using a thickness gauge (Mitutoyo). Six tablets from each batch were used & average values were calculated (Table 6). Weight variation test: To study weight variation,20 tablets of each formulation were weighed using an electronic balance & test was performed according to the official method.(Table 6) Hardness & friability: For each formulation the hardness of 6 tablets were determined using monsanto hardness testers. The friability of 20 tablets was determined using Roche friabilator. The limit for friability is NMT 1%.(Table 6) In Vitro Release Studies: 8 The in vitro dissolution studies for all the formulations were carried out in two steeps, using USP apparatus type II at 100 rpm. The dissolution medium consisted of Hydrochloric acid buffer solution pH - 1.2 (900 ml), and 0 Phosphate buffer pH – 7.5 (900ml), maintained at 37 C ± 0 0.5 C. The drug release at different time intervals was measured by UV-1700 UV-visible spectrophotometer at 210 nm (Hydrochloric acid buffer solution pH - 1.2) and at 210 nm (Phosphate buffer pH – 7.4). Dissolution profiles of formulation code from F6 to F11 are shown in Table 7 and comparative dissolution profile of F7 and F11 are shown in Figure 1. Figure1: Comparative Dissolution of F7 and F11
01(01)2011
RESULTS AND DISCUSSION Uncoated tablet of Divalproex sodium were prepared by both direct compression (F1, F2, F3) and wet granulation (F4 TO F11) method. Composition of direct compression is shown in Table 1. In Direct compression method directly compressible lactose and Microcrystaline cellulose are used as diluents separately and in different ratio. Blend prepared by direct compression method fail in content uniformity and tablet prepared (Trial F1, F2, F3)show lower Assay. In wet granulation method first two different concentrations (3% and 4%) of PVP K30 was used with water. But by use of PVP K30 proper granulation was not found due to less viscosity of binder. Then Proper granulation was found by using PVP K 90(Trial no.F8,F9,F10,F11 Composition shown in Table 2) which gives higher viscous binder solution as compared to PVP K30(Trial no.F4,F5,F6,F7 Composition shown in Table 3). Formulation prepared by using PVP K30 as a binder shown problem of sticking during compression due to devoid of intact granules and also dissolution problem had obtained. Sticking and dissolution problem was solved by using PVP K90 as binding agent which gives viscous binder solution which gives intact granules as compared to PVP K30. The prepared tablets of all the formulations were evaluated for precompression parameters like angle of repose, bulk and tapped density and compressibility index and physical characters like tablet hardness, friability, weight variation buoyancy lag time, total assay, in-vitro drug release. Precompression Parameters of Divalproex Sodium Granules The formulations showed good flow property and
Table1: Composition of different enteric coating formulation of Divalproex sodium by direct compression Ingredients (mg/tab)
23
F1
F2
F3
Divalproex Na
269.04
269.04
269.04
Starch
-
-
25.00
Lactose-DCL
48.21
50.00
25.00
MCC 101
94.00
90.00
90.00
SSG
5.00
5.00
5.00
Mg.Stearate
4.05
6.05
6.05
400
400
400
Total
Jawed Akhtar et al.
www.journalserieces.com
]
Journal of Sciences
01(01)2011
Table 2: Composition of different enteric coating formulation of Divalproex sodium by Wet granulation by using PVP K30 as a binder Ingredients(mg)
F4
F5
F6
F7
Divalproex Na
250
250
250
Starch
49.21
48.88
-
250 -
MCC 101
-
-
80.69
69.43
Aerosil
-
5.39
40.33
40.33
SSG
12.00
12.00
-
-
PVP K30
10.50
14.00
19.50
19.00
Water
-
-
qs.
qs.
IPA
qs.
qs.
qs.
qs.
Aerosil
11.00
13.30
10
10
Crosspovidone
-
-
15.50
15.50
MCC 102
105.00
95.82
19.83
19.83
Talc
-
-
27
29.22
Mg.Stearate
4.75
7.32
10.17
12.18
Total
451.72
456.72
478.27
478.67
Table 3: Composition of different enteric coating formulation of Divalproex sodium by Wet granulation by using PVP K90 as a binder Ingredients(mg) Divalproex Na MCC 101 Aerosil Crosspovidone PVP K90 Water IPA Aerosil Crosspovidone MCC 102 Talc Mg. Stearate Total
F8 250 75.00 40.33 6.67 9.00 qs. qs. 11.00 15.50 19.83 20 8.00 455.33
F9 250 75.00 40.33 6.67 8.00 Qs qs. 13.30 15.50 19.83 20 8.00 456.63
compressibility index (Table 5). Angle of repose ranged from 23.13 to 31.23 for formulation prepared by wet granulation, Hausner ratio ranged from 0.056 to 0.146 and the compressibility index ranged from 17.32 to 28.78. The LBD and TBD of the prepared granules ranged from 0.451 to 0.531 and 0.501 to 0.532 respectively. The results of angle of repose indicates good flow property of the granules and the value of compressibility index further showed support for the flow property. Post Compression Parameters of Divalproex Sodium Tablets The shape of the tablets of all formulations remained off white, smooth, flat faced circular with no visible cracks. The weight variation test as the % weight variation was within results
24
F10 250 80.69 40.33 7.17 qs. qs. 10 15.50 19.83 27 7.5 458.02
F11 269.04 80.00 40.33 7.17 qs. qs. 10 15.50 19.83 27 7.5 458.02
thickness and diameter of tablets was measured by vernier calipers and was ranged between 3.2 ± 0.02 to 3.5± 0.01 mm, 10.80 to 11.02 mm respectively. The hardness of the tablets was measured by Monsanto tester (Indian Equipment Corporation (IEC) Mumbai, India) and was in 2 between 5.5 to 6.0 kg/cm . The friability was measured by Friabilator and was found to be 0.32 to 0.87%, which is an indication of satisfactory mechanical resistance of the tablets. The drug content estimations showed values in the range of 95 to 99.2% which reflects good uniformity in drug content among different formulations except formulation prepared by direct compression. All the tablets passed the Pharmacopoeial limits of ±5% of the weight. The
Table 4: Optimization of Enteric coating polymer Ingredients Eudragit L100 HPMC P 50 Triethyl citrate Talc Ferric oxide yellow IPA:DCM
Jawed Akhtar et al.
F6 50 5 25 0.2
F7 50 5 25 0.2
F8 60 6 30 0.24
F9 50 5 25 0.2
F10 60 6 30 0.24
F11 70 7 35 0.28
40:60
50:50
60:40
60:40
60:40
60:40
www.journalserieces.com
]
Journal of Sciences
01(01)2011
Table 5: Results of Pre compression flow property of granules of Divalproex Sodium Formulation Code
% LOD
Bulk Density (gm/cm3)
Tapped Density (gm/cm3)
Angle of Repose
Carr’s Index
Hausner’s Ratio
F3
1.2
0.452
0.500
45.32
9.600
1.40
F4
1.3
0.470
0.523
40.21
10.13
1.41
F5
1.1
0.485
0.536
36.86
9.5
1.20
F6
1.4
0.468
0.538
37.26
13.01
1.34
F7
1.2
0.467
0.526
37.53
11.21
1.32
F8
1.5
0.475
0.534
30.21
11.04
1.12
F9
1.4
0.465
0.538
31.22
13.56
1.15
F10
1.3
0.457
0.540
30.20
14.37
1.18
F11
1.4
0.450
0.537
31.28
14.20
1.19
Table 6: Results of Post compression flow property of Divalproex Sodium Enteric coated Tablet Formulation code
Hardness (kg/cm2)
Thickness (mm)
Friability (%)
Weight variation
F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11
16 17 15 17 15 16 17 14 15 17 16
3.50 3.54 3.50 3.49 3.52 3.49 3.47 3.48 3.50 3.49 3.50
0.76 0.57 0.79 0.77 0.67 0.78 0.52 0.46 0.52 0.51 0.39
440±5.00 440±6.76 439±5.56 495±5.77 495±4.88 525±4.54 525±5.58 500±5.56 500±5.57 500±5.58 500±4.99
Table 7: Assay and Dissolution profile of Enteric coated tablet for optimization and comparative evaluation of enteric coating polymer. Formulation code
F6
Media 0.1 N Hcl Phosphate buffer pH 7.4
F7
F8
F9
F10
F11
Time (min) 0
%drug release 0
%drug release 0
%drug release 0
%drug release 0
%drug release 0
60
13.4
4.2
11.8
3.6
2.4
70
20.2
21.6
22.8
20.4
30.2
80
36.1
38.6
34.2
43.8
42.8
90
40.8
45.7
45.6
50.9
56.9
100
45.6
56.4
55.8
58.3
64.1
120 Assay
25
60.8
68.3
69.2
68.7
70.2
85.92
90.62
92.62
95.88
99.2
Enteric Coating Parameter of Divalproex Sodium Tablets Eudragit L100 were used in trial no. F6, F7 and F8, While HPMC P50 were used in Trial No F9, F10 and F11 as enteric coating polymer. Trial No F6, F7 and F8 were formulated using 40:60, 50:50 and 60:40 Isopropyl alcohol: Dichloro methen (IPA:DCM) respectively. Both F6 and F7 were fail in coating becaue coating solution dry rapidly upon spraying from coating machine gun so, proper enteric coating were not performed on tablet. IPA:DCM in 60:40 ratio in trial no F8 were optimized because it form proper spray from coating machine gun and coating were performed
Jawed Akhtar et al.
satisfactory aspects on tablet. (Results are shown in Table 4). Trial no F7 and F9 contains only 50 gm of enteric coating polymer fail in Dissolution test as per USP because it release more than 10 % of drug in acid medium. Dissolution profile of F8 and F11 containing 60 and 70 gm of enteric coating polymer shows that as polymer amount increase dissolution profile retard also acid resistant was increased. But in comparison of both this trials F11 gives better dissolution profile and acid resistance than trial F008 containing Eudragit L100. So enteric coating formula of trial
www.journalserieces.com
]
Journal of Sciences
F11 is taken as an optimized formulation of coating polymer and solvent. Stability studies Dissolution study and percentage drug content of selected formulation F11 was carried out after subjecting the formulation for stability study(50°C / 80% RH). From the data, the formulation is found to be stable under the condition mentioned before since there was no significant change in the percentage amount of drug content(Table 8). CONCLUSION: After the result of preliminary batches of Divalproex Na Uncoated tablet, It was concluded that wet granulation method is preferred method over the direct compression because of the content uniformity and variation in assay of tablet in all batches of direct compression. It was also concluded that PVP K90 is preferred binder as compared to PVP K30. Because PVP K90 gives more viscous binding solution as compared to PVP K30. And Divalproex Sodium require intact granulation to solve sticking problem during compression.
01(01)2011
After the result of optimization of percentage coating on core tablet of drug using seal coating solution, 2.5 % seal coating of core tablet was taken as optimize percentage coating of seal coat as compared to 2 % and 3 % because of 2 % seal coated tablet are partially coated and 3 % show same effect to that of 2.5 % seal coated tablet. Enteric coating was performed by two different polymer, it indicates that HPMCP 50 was more effective as enteric coating polymer at same concentration than Eudragit L100.From the result of optimization of enteric coating as the enteric coating percentage increased in formulation, acid resistance also increase. And increased percentage of coating also effect the dissolution profile and disintegration time of enteric coated tablet. As coating weight increase dissolution retarded and disintegration time of tablet was also increased in buffer medium. 8 % enteric coating on seal coated tablet was taken as optimize percentage of coating. Trial No F11 is taken as optimized formulation of Divalproex Sodium enteric coated tablet.
Table 8: Result of stability studies Parameters
Initial
After 1 month
Description
Light grey in color round shaped tablet
Light grey in color round shaped tablet
99.2 %
98.8 %
Assay Hardness of Tablet
(Kp)
Thickness (mm) Media Dissolution Profile 0.1 N Hcl Phosphate buffer pH 7.4
15- 17
15-17
3.50- 3.57
3.50- 3.57
Time (min) 0 60 70 80
% Drug Release
Time (min)
% Drug Release
0.0 1.59±2.23 30.2±4.89 42.8±4.98
0 60 70 80
0.0 2.04 ±1.50 28.4 ±3.20 43.6 ±4.80
90
56.9±5.87
90
55.2 ±4.79
100
64.1±5.75
100
62.9 ±5.89
120
70.2±5.20
120
73.8 ±6.23
ACKNOWLEDGEMENTS: The authors thank Zydus Cadila Healthcare Ltd., Ahmedabad, India for providing Divalproex Sodium as gift sample for this work. They also thank the management of Jaipur National University for providing required facilities to carry out this research work.
26
Jawed Akhtar et al.
www.journalserieces.com
] 1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
27 13.
Journal of Sciences
5. REFERENCES: Damodaran N, Manimaran V, Sravanthi B. Formulation Development and evaluation of Enteric coated Doxacycline Tablet. Indian journal of pharmacy & pharmaceutical Science 2010; 2(1): 119. Singh C, Kumar R, Agarwal K, Nema RK. Development and Evaluation of Enteric Coated Tablet Containing Diclofenac Sodium. International Journal of Pharmaceutical Sciences and Nanotechnology2009; 2(1):443-445. Rupesg SK, Archna DK, Kesho PG, Bakade BV, Channawar MA, Chandevar AV. Formulation and Development Of Enteric coated dosage Form Using Ketorolac Tromethamine. International journal of pharma research and development 1999; 2(8): 126135. Cooper J, Gunn C. Powder flow and compaction, Tutorial Pharmacy, New Delhi, India:CBS Publisher and Distributors; 1986; 211.233. Shah D, Shah Y, Rampradhan M. Development and evaluation of controlled release diltiazem micro particles using cross linked poly (vinyl alcohol). Drug Dev Ind Pharm 1997; 23:567-574. Aulton ME, Wells TI. “Pharmaceutics: The science of Dosage form design”, London,England: Churchill Livingstone; 1988 Pue MA. Pharmacokinetics of pantoprazole following oral administration to healthy mail subject. Eur J Clin Pharmacol 1993; 575-578. Somade S, Singh K, Comparative evaluation of wet granulation and direct compression methods for preparation of controlled release Ranitidine HCl tablets. Ind. J. Pharm Sci. 2002; 64(3): 285. Crotts G, sheth A. Development of an enteric coating formulation and process for tablets primarily composed of a highly water soluble Organic acid. European journal of pharmaceutics and Biopharmaceutics2000; 71-76. Nair A, Gupta R, Jacob S. Formulation and evaluation of enteric coated tablets of proton pump inhibitor. Journal of Basic and Clinacal pharmacy 2010:1(4); 215-221. US patent application Pub no-US0037880, Extended release formulation of divalproex sodium. 2004 Feb 26 United state pharmacopoeia. USP30 NF.Pharmacopoeia Forum publication Vol No.31(1) Page no-1977 British Pharmacopoeia, Stationary office Publication London, 2009, Volume 2.
Jawed Akhtar et al.
01(01)2011
Corresponding author Email:
[email protected], Contact: +91-9887423586
www.journalserieces.com
