In vitro Optimization of Zaltoprofen from controlled release porous Osmotic Tablets
Dr. Ravindra Babu Baggi1*, Swapna Velivela1, Nikunja B. Pati2
1Department of Pharmaceutics, Pulla Reddy Institute of Pharmacy, Hyderabad.
2School of Pharmacy and Life Science, Bhubaneswar, Centurion University, Odisha.
*Corresponding Author E-mail: baggi.ravi39@gmail.com
ABSTRACT:
The aim of the present investigation is to formulate and evaluate the controlled porosity osmotic pump tablets of zaltoprofen, with an aim to achieve zero order/near zero order release. Controlled release porosity osmotic pump tablets for zaltoprofen was prepared with osmogen by non aqueous granulation followed by semi permeable coating. The prepared tablets were evaluated with pre and post compression parameters. The effect of different parameters like effect of different concentrations of osmogens, effect of percent buildup of coat, influence of agitation intensity, effect of different pH on the drug release were also studied. Based on in vitro drug release studies the optimized formulation was selected. Finally investigated different drug release kinetics for the optimized formulation. It is clearly evident from in vitro release data; the formulated osmotic tablets drug release follows constant zero order release kinetics, until there is osmotic pressure inside the tablet which is suitable for the delivery of drugs having moderate water solubility.
KEYWORDS: Osmatic tablet, zero order, zaltoprofen, osmogens.
INTRODUCTION:
Controlled release (CR) technology[1] has rapidly emerged over the past few decades as a new field offering approaches to the delivery of drugs into systemic circulation at predetermined rate. CR formulations can achieve optional therapeutic responses, prolonged efficacy as well as decrease toxicity due to achieving predictable and reproducibility release rate of drugs for extended period of time. CR delivery systems provide desired concentration of drug at the absorption site permitting maintenance of plasma concentration within the therapeutic range and reducing dosing frequency. CR products provide significant benefits over immediate release formulations including greater effectiveness in the treatment of chronic conditions, reduced side effects, and greater patient convenience due to a simplified dosing schedule[2]. There are many Novel drug delivery systems are in the market, per oral controlled release systems hold the major part in market share due to its obvious advantages like ease of administration and better patient compliance[3]. There are many designing options available to control or modify the drug release from a dosage form. Numerous technologies have been used to control the systemic delivery of drugs[4 -5].
ODDS delivers the drug at predetermined zero order rate for a prolonged time period with constant drug delivery. ODDS provides a uniform concentration of drug at the site of absorption and thus after absorption allows maintenance of plasma concentration within therapeutic range which minimizes side effects and reduces the frequency of administration[6]. When an osmotic system comes in contact with water, water diffuses into the core through the micro porous membrane setting up an osmotic gradient and thereby controlling the release of the drug. Osmotic pressure created due to imbibitions of fluid from external environment into the dosage form regulates the delivery of drug from osmotic devices[7]. Osmotic pressure is the pressure applied to the higher concentrated solution side to prevent transport[8] of water across the semi permeable membrane. The ODDS has high in vitro-in vivo correlation. Hence osmotic drug delivery technique is most interesting and widely acceptable among all other techniques[9].
Zaltoprofen is a non steroidal anti-inflammatory analgesic which has excellent effect on postsurgery or post trauma chronic inflammation of the drug, so zaltoprofen may serve as a potent and superior analgesic for the treatment of pain. Zaltoprofen has biological half life of 2.8 hr and it absorbs throughout the intestinal tract. The drug shows linear pharmacokinetics, is suitable for oral controlled release tablets and it would be advantageous to slow down its release in GI tract not only to prolong its therapeutic action but also minimize possible side effects of zaltoprofen.
In this present study zaltoprofen used to prepare the controlled porosity osmotic pump tablet. Further optimization is to be carried out by various evaluation parameters like powder flow properties, core tablets properties, in vitro drug release, and curve fitting analysis of the various prepared formulation. The effects of pH and agitation also evaluated for the optimized formulation.
MATERIALS AND METHODS:
Zaltoprofen was used was a gift sample from Dr Reddys Laboratories Ltd., Hyderabad. Sodium chloride, microcrystalline cellulose, PVP-k30, magnesium stearate, talc, mannitol, cellulose acetate, triethyl citrate (TEC) and other chemicals were purchased SD Fine Chemicals Ltd. Mumbai, India. All other chemicals used were of analytical grade.
Preparation of Zaltoprofen Porous Osmotic Tablet [10-13]:
The preparation involves dispensing drug and other raw materials, followed by co-sifting, mixing, granulation and compression into tablets then followed by semi-permeable film coating. Zaltoprofen, microcrystalline cellulose was sifted through # 30 sieve and sodium Chloride was sifted through # 100 sieve. Zaltoprofen, microcrystalline cellulose, sodium chloride was mixed in rapid mixture granulator for 10 minutes. 5% PVP-K-30 solution was with isopropyl alcohol which was used as binding agent. Binder solution was added at a flow rate of 6ml/min to the premixed contents in the rapid mixture granulator to get a coherent wet mass. This wet mass was kneaded for 2-3 min to get wet granules. The wet granules were passed through #18 sieve and then dried in a fluid bed dryer at 30°C for 20 min. The granules were loaded into the blend and mixed for 10 min at 20rpm. Added the required quantity of magnesium stearate (sifted through #50 sieve) and blend for another 5 min at 20rpm. Compressed the tablets equivalent to make 400mg of zaltoprofen using 10mm round standard concave punch. The prepared tablets were subjected to coating process with cellulose acetate polymer using TEC as plasticizer and mannitol as pore former. The moisture content of the granules was determined by the moisture balance analyzer.
Coating with semi-permeable polymer:
Core tablets were coated by coating machine with a perforated pan. A solution of cellulose acetate in acetone at a concentration of (4%w/v), containing TEC (0.4%w/v) at 10:1 ratio of cellulose acetate: TEC was used as the coating solution. The coating solution was prepared by adding cellulose acetate in acetone and TEC with mixing and continued till the solution becomes clear. The final coating solution was solution was sprayed over the tablet bed by a spray gun till a desired weight gain. Finally the prepared osmotic pump tablets were dried at 50°C for 1 hr to remove the residual organic solvent.
Table 1: Formulation of zaltoprofen osmatic porous tablets
|
Core composition |
||||||
|
Ingredients |
Drug compartment composition, mg/core tablet |
|||||
|
F1 |
F2 |
F3 |
F4 |
F5 |
F6 |
|
|
Zaltoprofen |
200 |
200 |
200 |
200 |
200 |
200 |
|
Sodium Chloride |
0 |
50 |
100 |
150 |
175 |
200 |
|
MCC |
180 |
135 |
85 |
35 |
10 |
15 |
|
PVP k30 |
5 |
5 |
5 |
5 |
5 |
5 |
|
Magnesium stearate |
5 |
5 |
5 |
5 |
5 |
5 |
|
Talc |
5 |
5 |
5 |
5 |
5 |
5 |
|
Average weight |
400 |
400 |
400 |
400 |
400 |
430 |
(PVP k30: Polyvinylpyrrolidone-k-30, MCC: Microcrystalline Cellulose)
EVALUATION OF PREPARED FORMULATIONS:
API Excipients compatibility studies[14-16]:
API Excipients compatibility studies were performed by using FT-IR and DSC.
Pre-compression parameters[17-20]:
The prepared granules were evaluated for various flow properties tests like bulk density, tap density, compressibility index, Hausner ratio, loss on drying. Tap density, bulk density, compressibility index, Hausner ratio were determined by tap density tester and loss on drying was determined by halogen moisture analysis.
Determination of solubility of drug in different media[21]:
Solubility of zaltoprofen was determined in pH range of 1.0 8.0 at room temperature. Take known amount of API in different series of volumetric flask containing pH range of 1.2 8.0 at room temperature. Sonicated and filtered. The drug concentration of the solutions were scanned at 340nm. The solubility of API was determined to know whether drug is significantly affected by pH.
Post-compression Parameters of Tablets[22-23]:
The prepared coated tablets were evaluated for weight variation, thickness, content uniformity, friability, hardness, disintegration, assay, and in vitro dissolution studies.
In vitro Dissolution Studies[24]:
The prepared osmotic tablets were subjected to dissolution studies using Lab India USP type II dissolution test apparatus. In vitro dissolution studies were performed both for core and coated tablets. 900ml of phosphate buffer pH 6.8 was selected as a dissolution media with 50rpm. 5ml of samples were taken and replaced with same ml of fresh sample to maintain sink conditions. Temperature maintained during the complete study is 37±0.5oC with sampling points of 0.25, 0.5, 0.75 and 1 hr for core tablets and 1, 2, 4, 6, 8, 12, 18 and 24 hrs for coated tablets. Absorbance of the collected sample were measured at 340nm using UV- Visible spectrophotometer.
Drug Release Knetics[25]:
In order to determine the mode of release from the tablets, the data were fitted into zero order, first order, Higuchi, Korsmeyer-Peppas equations. The regression equations were calculated and the correlation coefficients were determined.
RESULTS AND DISCUSSIONS:
API Excipients Compatibility Studies:
API Excipients compatibility studies were performed by using FT-IR and DSC and it was found that there was no incompatibility between drug and excipients used in the formulation.
Pre-compression Parameters:
Bulk density (gm/ml), Tap density (gm/ml), % Carr's index, Hausner ratio and angle of repose are in the acceptable range according to IP and conclude that the prepared granules shows good flow properties.
Post-compression Parameters:
All formulations were found to be in the acceptable range according to IP. Thickness of the tablets was in the range of 5.5-5.6mm, hardness of 5.5-6.5 Kps and % friability was in the range of 0.1-0.5%.
In vitro Dissolution Studies:
In vitro dissolution studies were performed both for core and coated tablets with 900ml of 6.8 pH phosphate medium.
In vitro release studies were carried out for all CPOP formulation to quantify percentage cumulative release of drug. Based on the drug release profiles best formulation was selected. The Formulation no-3 (1:0.5) containing drug and NaCl in the ratio of 1:0.5 has shown 96% of drug release in 24 Hrs and the drug release pattern followed in zero order kinetics when compared to other formulations.
Table 2: Cumulative percentage of drug release of core tablets.
|
Time (hr) |
Cumulative percentage of drug release |
|||||
|
F1 |
F2 |
F3 |
F4 |
F5 |
F6 |
|
|
0 |
0 |
0 |
0 |
0 |
0 |
0 |
|
0.25 |
17.6 |
42.7 |
75.5 |
82.7 |
86 |
87.9 |
|
0.5 |
24.8 |
65.7 |
80.7 |
88.8 |
91.5 |
92.5 |
|
0.75 |
31.8 |
81.8 |
85.1 |
91.9 |
96 |
98.6 |
|
1 |
35 |
89.7 |
92.9 |
95.3 |
99.5 |
101.3 |
Figure 1: Graph showing cumulative percentage of drug release from core tablets.
Table 3: In vitro drug release of coated formulations.
|
Formulation Code (Drug: Osmogen) Time(hr) |
F1 (1:00) |
F2 (1:0.25) |
F3 (1:0.5) |
F4 (1:0.75) |
F5 (1:0.875) |
F6 (1:1) |
|
0 |
0 |
0 |
0 |
0 |
0 |
0 |
|
1 |
20 |
15 |
11 |
20 |
28 |
26 |
|
2 |
34 |
27 |
13 |
22 |
30 |
39 |
|
4 |
45 |
49 |
28 |
39 |
45 |
41 |
|
6 |
51 |
62 |
42 |
44 |
52 |
47 |
|
8 |
59 |
64 |
53 |
65 |
65 |
62 |
|
12 |
68 |
83 |
69 |
81 |
83 |
85 |
|
18 |
79 |
90 |
84 |
86 |
90 |
101 |
|
24 |
88 |
91 |
95 |
103 |
105 |
109 |
Figure 2: In vitro drug release of coated formulations.
Table 4: Influence of membrane thickness on drug release profile.
|
Influence of membrane thickness on drug release profile |
||||
|
Time(hr) |
Cumulative percentage of drug release |
|||
|
2% |
4% |
6% |
8% |
|
|
0 |
0 |
0 |
0 |
0 |
|
2 |
43 |
27 |
22 |
20 |
|
4 |
52 |
49 |
28 |
23 |
|
6 |
63 |
62 |
33 |
33 |
|
8 |
74 |
64 |
43 |
46 |
|
12 |
82 |
83 |
57 |
53 |
|
18 |
95 |
90 |
70 |
60 |
|
24 |
103 |
91 |
77 |
62 |
Figure 3: Influence of membrane thickness on drug release profile.
From table no 4, it was observed that changing the coating thickness has altered the permeability of the coating. The release rate decreases as the membrane thickness increases. The amount of water penetration is slower in tablets with a thicker coating which in turn, results in a longer time required for sufficient water to penetrate to hydrate the core. Enough osmotic pressure was not built up, so that drug can be expelled out through pores. As the membrane thickness increases, the resistance of the membrane to water diffusion increases and in turn, the liquefaction rate of the tablet core decreases, resulting in the decrease of drug release rate. It was found that the coating solution containing 4% of CA having a thickness of 0.39 mm has released the drug in maximum zero order fashion, when compared to the other membrane thickness over the core tablets.
Table 5: Dissolution profile influence of agitation intensity on drug release (rpm).
|
Cumulative percentage of drug release |
|||
|
Time (hr) |
25rpm |
50rpm |
75rpm |
|
0 |
0 |
0 |
0 |
|
1 |
2.2 |
2.6 |
3 |
|
2 |
5.3 |
5.5 |
6 |
|
4 |
8.6 |
9 |
9.3 |
|
6 |
12 |
12.9 |
14 |
|
8 |
23.5 |
24.9 |
26.9 |
|
12 |
38.6 |
40.3 |
42.7 |
|
18 |
65.6 |
68.4 |
72 |
|
24 |
88.2 |
90.9 |
93.5 |
Figure 4: Release profile of agitation intensity.
From table no 5, it is evident that the release rate is independent of the agitational intensity. The release rates obtained were quite comparable and there is no change in the release profiles obtained at different rpm. Therefore, it is clear that increase in rate of stirring did not significantly affect the release rate of the drug. It is expected that the increase in agitation speed causes more fluid velocity, which in turn forces the water to permeate through the SPM. But there is not much change in the release rate as a function of agitation intensity. Based on release profile it might be expected that the mobility of the gastro intestinal tract scarcely affect the drug release from the CPOP tablet.
Table 6: Dissolution profile on influence of pH.
|
Time (hrs) |
Cumulative percentage of drug release |
||
|
pH 1.2 |
pH 4.5 |
pH 6.8 |
|
|
0 |
0 |
0 |
0 |
|
2 |
11 |
13 |
15 |
|
4 |
20 |
19 |
18 |
|
6 |
32 |
29 |
30 |
|
8 |
41 |
39 |
44 |
|
12 |
60 |
58 |
63 |
|
18 |
80 |
77 |
79 |
|
24 |
93 |
92 |
96 |
Figure 5: Effect of pH on drug release.
From the above table (Table 6), it is evident that the release rate is independent of the pH. The release rates obtained were quite comparable and there is no change in the release profiles obtained at different pH. Therefore, it is clear that drug is independent through the GI tract and there is no much affect the release rate of the drug.
Figure 6: Different concentration of pore former.
Table 7: Influence of different concentration pore former (mannitol).
|
Time (hrs) |
Cumulative percentage of drug release |
||
|
5% |
10% |
15% |
|
|
0 |
0 |
0 |
0 |
|
2 |
27 |
43 |
45 |
|
4 |
49 |
65 |
68 |
|
6 |
61 |
78 |
76 |
|
8 |
73 |
80 |
83 |
|
12 |
84 |
86 |
91 |
|
18 |
90 |
90 |
96 |
|
24 |
96 |
101 |
102 |
From table no 7, it is evident that the release rate is dependent on pore former (Mannitol). As the concentration of pore former is increased there is increase in the drug release profile.
Table 8: Effect of different concentration of pore former and plasticizer
|
Time (hrs) |
Cumulative percentage of drug release |
|||
|
A |
B |
C |
D |
|
|
0 |
0 |
0 |
0 |
0 |
|
2 |
22 |
27 |
43 |
36 |
|
4 |
33 |
49 |
65 |
45 |
|
6 |
43 |
62 |
78 |
61 |
|
8 |
57 |
72 |
80 |
77 |
|
12 |
70 |
83 |
86 |
85 |
|
18 |
82 |
90 |
90 |
92 |
|
24 |
88 |
96 |
101 |
102 |
Figure 7: Graph showing effect of poreformer and plasticizer concentration
From the table 8, it is evident that the release rate is dependent on pore former and plasticizer. Both pore former and plasticizer inversely proportional to each other. As pore former is increased release rate increases, as plasticizer increases release rate is decreases. So there are optimized by different concentration.
Release mechanisms by mathematical models:
The rate of release of drug release was calculated using data fitting method and results obtained are as follows. The dissolution profile of optimized formulation was assessed for the release mechanism. The mathematical modeling of the profile into the drug release follows.
Table 9: Release mechanism by mathematical models.
|
Formulation |
Zero order |
First order |
Higuchi |
Korsmeyer-Peppas |
|
R2 |
R2 |
R2 |
R2 |
|
|
F1 |
0.701 |
0.953 |
0.915 |
0.944 |
|
F2 |
0.787 |
0.894 |
0.949 |
0.939 |
|
F3 |
0.938 |
0.903 |
0.974 |
0.798 |
|
F4 |
0.889 |
0.901 |
0.976 |
0.865 |
|
F5 |
0.870 |
0.911 |
0.979 |
0.973 |
|
F6 |
0.906 |
0.931 |
0.981 |
0.951 |
From the table 10, formulation F3 (drug: osmogen of 1:0.5 ratio) showed similarity factor (f2) value 58.49, denotes that the optimized formulation was similar to marketed formulation (f2 value between 50-100 denotes similarity).
Table 10: Percent similarity factor (f2) data of formulations.
|
Time (hr) |
Cumulative % drug release |
|
|
Formulation F3 |
Marketed formulation |
|
|
1 |
11 |
15 |
|
2 |
13 |
27 |
|
4 |
28 |
33 |
|
6 |
42 |
53 |
|
8 |
53 |
65 |
|
12 |
69 |
78 |
|
18 |
84 |
86 |
|
24 |
95 |
98 |
|
f2 value |
58.49 |
|
CONCLUSION:
The following conclusions could be drawn from this research work:
· Controlled porosity osmotic pump tablets for zaltoprofen could be successfully prepared with osmogens (NaCl) in different concentration and could be coated with semipermeable polymer like cellulose acetate and mannitol as a pore former and can have desired release rate.
· Formulations of core tablets have an shown increased drug release rate with an increase in osmogen concentration.
· In vitro release studies were carried out for all CPOP formulation to quantify percentage cumulative release of drug. Based on the drug release profiles best formulation was selected. The formulation 3 (1:0.5) containing drug and NaCl in the ratio of 1:0.5 has shown 80-90% of drug release in 24 Hrs and the drug release pattern followed in zero order kinetics when compared to other formulations.
· This formulation (F3) with drug: osmogen with 1:0.5 was studied for various effects like membrane thickness on release, effect of agitational intensity etc.
· The results have revealed that the release rate was more with an increase in pore former concentration.
· The release rate has not changed significantly with agitation of 25, 50 and 75rpm
· The release rate has not changed significantly with different pH 1.2,4.5,6.8
· The effect of membrane thickness on the release rate was compared in Formulation 3(1:0.5) CPOP formulation. It was found that release rate increased with decrease in membrane thickness and decreased with increase in membrane thickness.
· This optimized formula (F3) was compared with the marketed formulation. The results were better & promising with the in-house formulation in terms of controlled release of BCS class 1 drug, when compared to those with the marketed formulation.
ACKNOWLEDGMENT:
The authors wish to thank Dr Reddys Laboratories Ltd. for the supply of zaltoprofen as gift sample. The authors also like to thank Management of PRIP, for providing facilities used in the research.
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Received on 27.03.2020 Modified on 14.04.2020
Accepted on 03.05.2020 ©Asian Pharma Press All Right Reserved
Asian J. Pharm. Tech. 2020; 10(3):149-155.
DOI: 10.5958/2231-5713.2020.00026.4