Design and Evaluation of an Extended Release Drug Delivery System of Propafenone Hydrochloride.
Sushil J. Pawar*, Santosh Y. Nandedkar, Rajendra D. Wagh, Tanvir Shaikh and Vaibhav Jagtap
A.R. Ajmera College of Pharmacy, Dhule -424005 MS
Corresponding author: pawarsushil88@gmail.com
ABSTRACT:
The objective of present study is that to invent the formulation of Propafenone Hydrochloride as an extended release drug delivery system and to develop extended release formulation of Propafenone Hydrochloride mini tablets in capsule form by wet granulation technique using drug release retarding agents. Propafenone Hydrochloride is an antiarrhythmic agent, with a short half-life having usual dosage regimen of 425mg, twice daily. The drug is suitable for to prepare extended release tablet but in case of single unit dosage form intake of food affect activity of Propafenone Hydrochloride i.e. (Increased in high plasma level concentration and bioavailability). So, comparatively multiple unit dosage form i.e. mini tablets of Propafenone Hydrochloride administration food did not change plasma level concentration and bioavailability. The formulation design was implemented using Hydroxypropylmethylcellulose (Methocel E3 LV) as release retarding agent. The matrix component was varied using 0.5%, 1%, 2.5%, 3%, and 4.5%w/w of the total weight of the formulation. The final lubricated blends were evaluated for physico-chemical evaluation. The mini tablets were evaluated and filled into the capsule and then evaluated for in vitro release studies and drug contents. Release profile of the optimized formulations signified that, it gives satisfactory results.
KEYWORDS: Propafenone Hydrochloride, HPMC E3 LV, Extended release, Mini tablets, Capsule.
INTRODUCTION:
Extended release tablets and capsules are commonly taken only once or twice daily, compared with counterpart conventional forms that may have to take three or four times daily to achieve the same therapeutic effect. Typically, extended release products provide an immediate release of drug that promptly produces the desired therapeutic effect, followed by gradual release of additional amounts of drug to maintain this effect over a predetermined period.1
Multi-particulate drug delivery systems are mainly oral dosage forms consisting of a multiplicity of small discrete units, each exhibiting some desired characteristics. In these systems, the dosage of the drug substances is divided on a plurality of subunit, typically consisting of thousands of spherical particles or number of mini tablets with diameter of 0.05-2.00mm. Thus multiparticulate dosage forms are pharmaceutical formulations in which the active substance is present as a number of small independent subunits.
To deliver the recommended total dose, these subunits are filled into a sachet or encapsulated or compressed into a tablet. Multiparticulates are discrete particles that make up a multiple unit system. They provide many advantages over single-unit systems because of their small size.2
Fig. 1. Mini-tablets delivered as a tablet (a) or a capsule (b).3
Multiparticulates are less dependent on gastric emptyting, resulting in less inter and intra-subject variability in gastrointestinal transit time. They are also better distributed and less likely to cause local irritation. Recently much emphasis is being laid on the development of multiparticulate dosage forms in preference to single unit systems because of their potential benefits such as increased bioavailability, reduced risk of systemic toxicity, reduced risk of local irritation and predictable gastric emptying.2
Propafenone Hydrochloride is a Class 1C antiarrhythmic drug with local anesthetics effects and a direct stabilizing action on myocardial membranes.4 Propafenone hydrochloride is nearly complete absorbed more than 90% after oral administration with peak plasma levels occurring approximately in 3.5 hr. Systemic bioavailability ranges from 5 to 50%, due to significant first-pass metabolism. This wide range in systemic bioavailability is related to two factors: presence of food (food increases bioavailability) and dosage (bioavailability is 3.4% for a 150-mg tablet compared to 10.6% for a 300-mg tablet). After administration in most individuals propafenone is more than 95% protein bound within the concentration range of 0.5 to 2 mg/ml. Propafenone is easily metabolized by CYP3A4 and CYP1A2 and eliminated through urine. Propafenone has biological half-life of 2-10 hours.5-7 Propafenone hydrochloride is suitable for to prepare extended release tablet but in single dosage food increased peak blood level and bioavailability, during multiple dose administration of propafenone to healthy volunteer’s food did not change bioavailability.8
The purpose of the present study was to prepare and evaluate orally extended release multiparticulate drug delivery system of Propafenone hydrochloride, by using Hydroxypropylmethylcellulose (Methocel E3 LV) polymers by using wet granulation technique. The final lubricated blends were evaluated for physico-chemical evaluation. The mini tablets were evaluated and filled into the capsule and then evaluated for in vitro release studies and drug contents. Drug- polymer interactions were in the solid state studied by infrared spectrophotometry (IR).
MATERIAL AND METHODS:
Material:
Propafenone Hydrochloride was received as a gift sample from Watson Pharma Pvt Ltd, Mumbai. Lactose monohydrate, Polyvinylpyrrolidone K29/32, Hydroxypropylmethylcellulose (E3LV, K4MCR, and K100LVCR), Carbopol 971P, Precirol AT05, Sodium lauryl sulfate, Colloidal Silicon Dioxide, Magnesium Stearate. All this excipients were received from Signet Chemicals, Mumbai.
Methods:
Formulation and Preparation of Propafenone ER Capsule Containing Mini tablets:
Dispensing: Dispensed all the materials accurately using a calibrated weighing balance.
Sifting and Mixing: Sifted Propafenone HCl, lactose monohydrate and Aerosil 200 through mesh # 30 ASTM and mixed for 5 minutes at slow speed of Impeller in rapid mixer granulator
Preparation of binder solution: Dissolved Methocel E3 LV or PVP K30 and sodium lauryl sulphate (for B.No. F11-13) in purified water under stirring.
Granulation of Propafenone HCl: The dry mixed contents were granulated using binder solution of in Rapid mixer granulator at slow Impeller speed.
Drying: Dried the granules from Step 5 at 600C till the desired LOD is achieved (Limit : Less than 2.0% w/w at 105°C for 15 minutes).
Sifting and Blending: The dried granules were passed through mesh # 30 ASTM sieve. Sifted Aerosil through mesh # 30 ASTM and blended with granules for 10 minutes in blender. Magnesium Stearate sifted through mesh # 60 ASTM and lubricated the blend for 5 minutes in blender.
Compression: Compressed the blend into mini tablets.
Capsulation: Capsulation for 425mg strength: 34 such minitablets filled in size “00” capsules.
Evaluation of Pre-compression Parameters of Mini Tablets:
The final lubricated blends were evaluated for Loss on drying (LOD), Bulk density (BD), Tapped density (TD), Compressibility index, Hausner’s Ratio and Partical size determination (PSD). The results shown in Table 2 and 3.9
Table 1: Composition of Different Formulations
|
Ingredients (mg) |
F1 |
F2 |
F3 |
F4 |
F5 |
F6 |
F7 |
F8 |
F9 |
F10 |
F11 |
F12 |
F13 |
|
Propafenone HCl |
12.5 |
12.5 |
12.5 |
12.5 |
12.5 |
12.5 |
12.5 |
12.5 |
12.5 |
12.5 |
12.5 |
12.5 |
12.5 |
|
Lactose Monohydrate |
2.94 |
2.44 |
2.44 |
2.44 |
2.44 |
2.52 |
2.70 |
2.62 |
2.38 |
2.44 |
2.86 |
2.82 |
2.78 |
|
Methocel E3LV |
0.16 |
-- |
-- |
-- |
-- |
0.08 |
0.40 |
0.48 |
0.72 |
0.16 |
0.16 |
0.16 |
0.16 |
|
Methocel K4M |
-- |
0.16 |
-- |
-- |
-- |
-- |
-- |
-- |
-- |
-- |
-- |
-- |
-- |
|
Methocel K100LV |
-- |
-- |
0.16 |
-- |
-- |
-- |
-- |
-- |
-- |
-- |
-- |
-- |
-- |
|
Carbopol-971P |
-- |
-- |
-- |
0.16 |
-- |
-- |
-- |
-- |
-- |
-- |
-- |
-- |
-- |
|
Precirol AT O5 |
-- |
-- |
-- |
-- |
0.16 |
-- |
-- |
-- |
-- |
-- |
-- |
-- |
-- |
|
Povidone K29/32 |
-- |
0.50 |
0.50 |
0.50 |
0.50 |
-- |
-- |
-- |
-- |
0.5 |
-- |
-- |
-- |
|
Sodium Lauryl Sulfate |
-- |
-- |
-- |
-- |
-- |
-- |
-- |
-- |
-- |
-- |
0.08 |
0.12 |
0.16 |
|
Purified water |
q.s |
-- |
-- |
-- |
-- |
q.s |
q.s |
q.s |
q.s |
q.s |
q.s |
q.s |
q.s |
|
Isopropyl alcohol |
-- |
q.s |
q.s |
q.s |
q.s |
-- |
-- |
-- |
-- |
-- |
-- |
-- |
-- |
|
Aerosil |
0.20 |
0.20 |
0.20 |
0.20 |
0.20 |
0.20 |
0.20 |
0.20 |
0.20 |
0.20 |
0.20 |
0.20 |
0.20 |
|
Magnesium stearate |
0.20 |
0.20 |
0.20 |
0.20 |
0.20 |
0.20 |
0.20 |
0.20 |
0.20 |
0.20 |
0.20 |
0.20 |
0.20 |
|
Total wt of Minitablet |
16 |
16 |
16 |
16 |
16 |
16 |
16 |
16 |
16 |
16 |
16 |
16 |
16 |
Table 2: Evaluation of Pre-compression Parameters of Mini Tablets
|
Batch No. |
F1 |
F2 |
F3 |
F4 |
F5 |
F6 |
F7 |
F8 |
F9 |
F10 |
F11 |
F12 |
F13 |
|
% LOD |
0.84 |
0.91 |
0.85 |
0.92 |
0.98 |
0.87 |
0.89 |
0.96 |
0.89 |
0.93 |
0.97 |
0.86 |
0.96 |
|
Bulk Density(g/ml) |
0.416 |
0.399 |
0.398 |
0.49 |
0.45 |
0.413 |
0.419 |
0.422 |
0.402 |
0.403 |
0.415 |
0.413 |
0.41 |
|
Tapped Density(g/ml) |
0.562 |
0.554 |
0.546 |
0.670 |
0.596 |
0.559 |
0.549 |
0.583 |
0.548 |
0.541 |
0.588 |
0.585 |
0.583 |
|
Carr’s Index (%) |
26 |
28 |
27.11 |
26.92 |
24.33 |
25.87 |
23.68 |
27.62 |
26.64 |
29.51 |
29.51 |
29.41 |
29.21 |
|
Hausner Ratio |
1.351 |
1.389 |
1.372 |
1.368 |
1.325 |
1.341 |
1.310 |
1.381 |
1.363 |
1.342 |
1.421 |
1.417 |
1.412 |
Table 3: Evaluation of Pre-compression Parameters of Mini Tablets
|
% Retention |
F1 |
F2 |
F3 |
F4 |
F5 |
F6 |
F7 |
F8 |
F9 |
F10 |
F11 |
F12 |
F13 |
|
20# |
0.40 |
0.00 |
0.00 |
0.70 |
9.36 |
0.38 |
0.00 |
0.00 |
0.00 |
0.56 |
0.21 |
0.20 |
0.19 |
|
40# |
14.55 |
17.78 |
7.24 |
19.74 |
15.54 |
14.57 |
9.17 |
17.40 |
7.46 |
17.83 |
29.25 |
29.05 |
28.90 |
|
60# |
27.88 |
23.73 |
14.94 |
15.75 |
22.47 |
27.90 |
12.45 |
27.33 |
13.47 |
13.65 |
34.10 |
33.99 |
33.88 |
|
80# |
19.19 |
12.51 |
8.79 |
5.48 |
12.36 |
19.21 |
4.98 |
14.35 |
4.09 |
12.53 |
16.99 |
17.59 |
18.94 |
|
100# |
19.39 |
7.65 |
6.53 |
22.03 |
3.37 |
19.37 |
12.22 |
13.64 |
13.23 |
11.41 |
9.38 |
9.49 |
9.62 |
|
Fines |
18.59 |
38.93 |
62.49 |
36.29 |
36.89 |
18.57 |
61.18 |
27.28 |
61.75 |
44.02 |
9.27 |
9.68 |
9.73 |
Figure 1: FTIR Spectroscopy of pure drug
Figure 2: FTIR Spectroscopy for API-All Excipients
Evaluation of Compression Parameters of Mini Tablets:
All prepared matrix tablets were evaluated for its uniformity of weight, diameter, hardness, and thickness according to official methods. The results shown in Table 4.10
In-Vitro Dissolution Study:
In-vitro drug release studies were carried out using USP dissolution apparatus type II paddle (Electrolab, Mumbai, India) at 50 rpm. The dissolution medium filled up to 900 ml volume consists of 0.08N HCl followed by pH 6.8 Phosphate buffer, maintained at 37± 0.50C. The drug release at time intervals 1 and 2 (0.08N HCl) then 3, 4, 5 and 6 (pH 6.8 Phosphate buffer) was measured using an UV spectrophotometer (Shimadzu) at 305 nm. The results shown in Table 5.11
Similarity and Dissimilarity Factor:
Similarity factor was analyzed by using formula f2 = 50×log {[1+ (1/n) Σ t=1n (Rt-Tt) 2] -0.5 ×100}. Dissimilarity factor was analyzed by using formula f1= {[Σ t=1n |Rt-Tt|] / [Σ t=1n Rt]} ×100 where, n is the number of dissolution sample times, Rt and Tt are the individual or mean percent dissolved at each time point, t, for the reference and test dissolution profiles, respectively. The results shown in Table 6.12
Drug Content:
Mix the contents of 20 capsules and crush to uniform powder. Transfer powder equivalent to about 250 mg of Propafenone Hydrochloride to a 250 mL volumetric flask. Add 150 mL of diluent Sonicate for 20 minutes with intermittent swirling. Allow solution to cool to room temperature and diluent to the volume with diluent and mix well. Measure the absorbance of the resulting solution and the maximum at about 305nm and calculate the drug content. The results shown in Table 7.13
Stability Studies:
The optimized formulation was subjected to stability study at 25°C/60% RH, 40°C/75% RH for 90 days. The samples were withdrawn at intervals of thirty days and checked for physical changes, hardness, drug content and percentage drug release.14
Evaluation of Compression Parameters of Mini Tablets
Table 3:Compress the Lubricated blend in to mini tablets using following parameters
|
1 |
Machine |
Rotary Tablet Press |
|
2 |
Die |
3.0 mm, circular |
|
3 |
Upper Punch |
3.0 mm, circular, plain. |
|
4 |
Lower Punch |
3.0 mm, circular, plain. |
|
5 |
Description |
White, circular, biconvex tablet, plain on both sides. |
|
6 |
Group Weight of 20 minitablets |
320 mg ± 16mg (304- 336mg) |
|
7 |
Weight Variation (%w/w)* |
± 7.5% of group weight of 10 tablets (148 – 172mg) |
|
8 |
Hardness (kp) |
2.0 kp (0.5 kp – 4.0kp) |
|
9 |
Thickness (mm) |
2.10 ± 0.30 (1.80 – 2.40mm) |
|
10 |
Friability (406.25 minitablets = 6.5g) |
Not more than 1.00%w/w |
Compression Details (Environmental Condition: NMT 25°C and NMT 60% RH); Compression into minitablets for 425mg strength
Table 4: Evaluation of Compression Parameters of Mini Tablets
|
Batch No. |
F1 |
F2 |
F3 |
F4 |
F5 |
F6 |
F7 |
F8 |
F9 |
F10 |
F11 |
F12 |
F13 |
|
Diameter (mm) |
2.09 |
2.19 |
2.22 |
2.26 |
2.16 |
1.98 |
2.13 |
2.21 |
2.25 |
2.17 |
2.11 |
2.15 |
2.14 |
|
Thickness (mm) |
1.99 |
2.05 |
2.62 |
2.19 |
2.08 |
2.13 |
2.15 |
2.12 |
2.21 |
2.26 |
2.10 |
2.16 |
2.19 |
|
Hardness (kp) |
1.80 |
1.92 |
2.02 |
2.13 |
1.98 |
1.89 |
2.17 |
2.05 |
2.09 |
2.10 |
2.01 |
2.11 |
2.02 |
|
Avg weight of 10 Mini tabs (mg) |
15.8 |
15.9 |
16.1 |
16.1 |
16.9 |
17.1 |
15.9 |
16.0 |
17.2 |
15.8 |
16.1 |
16.2 |
16.5 |
In vitro Release Study:
Table 5: Dissolution Profile of Innovator and Batches F1-F13
|
Time (hr) |
Innovator |
F1 |
F2 |
F3 |
F4 |
F5 |
F6 |
F7 |
F8 |
F9 |
F10 |
F11 |
F12 |
F13 |
|
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
|
1 |
14 |
24 |
9 |
10 |
9 |
9 |
29 |
10 |
12 |
15 |
14 |
14 |
15 |
14 |
|
2 |
25 |
41 |
15 |
19 |
15 |
15 |
48 |
20 |
20 |
23 |
24 |
32 |
32 |
33 |
|
3 |
81 |
88 |
33 |
24 |
17 |
25 |
91 |
52 |
58 |
67 |
63 |
78 |
77 |
74 |
|
4 |
99 |
98 |
51 |
37 |
28 |
45 |
100 |
71 |
78 |
86 |
84 |
94 |
93 |
86 |
|
5 |
102 |
101 |
75 |
58 |
47 |
57 |
101 |
90 |
92 |
97 |
96 |
97 |
98 |
91 |
|
6 |
103 |
103 |
91 |
79 |
70 |
68 |
103 |
94 |
98 |
101 |
99 |
100 |
99 |
96 |
Table 6: Similarity (f2) and Dissimilarity (f1) Factors
|
Factor |
F1 |
F2 |
F3 |
F4 |
F5 |
F6 |
F7 |
F8 |
F9 |
F10 |
F11 |
F12 |
F13 |
|
f1 |
7.31 |
36.55 |
46.46 |
56.13 |
48.35 |
11.32 |
20.87 |
15.56 |
8.25 |
10.32 |
2.12 |
2.36 |
7.07 |
|
f2 |
54.06 |
25.24 |
19.83 |
16.29 |
20.09 |
46.67 |
37.50 |
43.13 |
54.27 |
49.86 |
67.21 |
65.80 |
52.93 |
Table 7: Drug Content of Batches F1-F13
|
Drug Content |
F1 |
F2 |
F3 |
F4 |
F5 |
F6 |
F7 |
F8 |
F9 |
F10 |
F11 |
F12 |
F13 |
|
% |
99.84 |
98.96 |
99.37 |
97.99 |
98.88 |
99.56 |
99.85 |
98.96 |
98.79 |
99.92 |
100.09 |
100.03 |
100.17 |
Figure 3: Dissolution Profile of Batches F1 – F6
Figure 4: Dissolution Profile of Batches F7 – F13
From the above dissolution data compilation (Figure 3 and 4) following conclusion is made, F1 batch using HPMC as release retarding agent as compare to F2-F5 bathes close to innovater dissolution profile. However, further optimization trials to be carried out for finalizing the concentration of Methocel E3LV as the rate-controlling polymer in the formulation. Based on the drug release profile observed for the batches (F6-F10) in comparison with the innovator profile, batch (F1) using only 1% Methocel E3LV as binder and release retarding agent gave a profile closest to that of the innovator profile. The drug release profile of the batch (F10) using combination of 1% Methocel E3LV and 3.125% Povidone as binder was slightly slower at 3rdhr and 4thhr as compared to the batch containing only 1% Methocel E3LV as binder. Addition of Sodium Lauryl Sulphate helped in improving the granulation process. However, significant change in the drug release profile of batches F11-F13 observed by changing concentration of Sodium Lauryl Sulphate from 0.5% to 1% in the formulation. So select the concentration 0.5% of SLS having better drug release profile compare to other concentration. From the dissolution data, it shows that the optimized batch F11 is close to innovator dissolution profile. The similarity (f2) and dissimilarity (f1) factors of batch F11 (f1-2.12 and f2-67.21) were observed within a limit (f1 less than 10 and f2 more than 50).
CONCLUSION:
The drug Propafenone hydrochloride can be formulated in extended release mini tablets in capsule formulation using optimum amount of hydroxypropylmethylcellulose by wet granulation technique. The capsules were found to be effective in extend the drug release up to 6 hrs. Among all the formulations, F11 shows the release profile closer to that of Rythmol SR. From the value of f1 and f2 factor also concludes that the formulation which developed in the study was found similar with innovater product and the value of f1 and f2 was good within a standard limit. The stability studies were carried out according to ICH Q1A guideline which indicates that the selected formulation was stable. FT-IR studies revealed that there was no interaction between Propafenone hydrochloride and other excipients used in the capsules. The results suggest that the developed extended release capsules of Propafenone hydrochloride could perform better than conventional dosage forms, matched with the Rythmol SR, leading to improve efficacy and better patient compliance. Thus, the aim of this study was achieved.
ACKNOWLEDGEMENTS:
The authors are thankful to Watson Pharma Pvt. Ltd for providing the drug Propafenone hydrochloride and all excipients.
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Received on 31.07.2011 Modified on 20.08.2011
Accepted on 04.09.2011 © RJPT All right reserved
Research J. Pharm. and Tech. 4(11): Nov. 2011; Page 1725-1729