The effect of different grades polymer blends on release profiles of diclofenac sodium from hydrophilic matrices

Article history: Received on: 21/07/2015 Revised on: 12/08/2015 Accepted on: 30/08/2015 Available online: 28/10/2015 An attempt was made to design matrix tablet of diclofenac sodium by using various grades of hydroxypropyl methyl cellulose (HPMC E50, E15 and E300LV). The effect of hydrophilic polymers was studied on release characteristics of the diclofenac matrix tablet. Dicalcium phosphate and magnesium stearate were used as an excipients. Tablets were prepared by direct compression method. The in vitro dissolution test carried out for 12 hrs using USP dissolution apparatus II at 50 rpm in 900ml phosphate buffer pH 6.8. Statistically significant difference was found among the drug release profile from different matrices. The tablet evaluation parameters of hardness, friability, thickness, content uniformity were founded within the limit. At a fixed polymer level, drug release from the higher viscosity grades E50 was slower as compared to the lower viscosity grades (E300LV and E15). Tablet prepared with HPMC E50 is more release retardant. As the drug to polymer ratio increased drug release decreased. The dissolution study revealed that maximum retardation of the drug was obtained by highest viscosity grade HPMC at higher concentrations. The release of the model drug from these HPMC matrix tablets was prolonged.


INTRODUCTION
Diclofenac sodium is a non-steroidal anti-inflammatory agent, which is commonly used for rheumatoid arthritis as longterm therapy.The biological half-life of diclofenac sodium is about 1-2 hrs; therefore to maintain a therapeutic drug blood level, it requires multiple dose.After long-term and frequent administration of diclofenac sodium, it gives adverse side effects like gastrointestinal disturbances, peptic ulceration, and perforation (Scholer et al., 1986;Lin et al., 1991).Diclofenac sodium is one of the most useful NSAIDs agents.It is a practically insoluble in an acidic solution (pKa 4.0), but get dissolved in intestinal fluid and water (Bravo et al., 2004).The conventional tablets make the drug immediately available for absorption in the upper GI tract resulting local GI toxicity varying from minorgastric discomfort to ulceration and bleeding of the mucosa (Carson et al., 1990 andSivakumar et al., 2010).It is well documented that the GI toxicity is not only caused by the inhibition of the prostaglandin synthesis, but it is probably also .

MATERIALS AND METHODS
Diclofenac sodium was received as a gift sample from the Wockhardt research center, Aurangabad.Hydroxypropylmethylcellulose E50, E15, E300LV purchased from Merck Pvt.Limited, Mumbai.All the other excipients and chemicals were of analytical grade and procured from S D Fine Chemical, Mumbai.

Method of tablet preparation at different ratio
All the material containing diclofenac sodium, filler (ditab), lubricant (magnesium stearate), and flow promoter (aerosil) passed through sieve # 60, triturated and mixed in mortar and pestle.This mixture was then compressed in the 12 station compression machine (Karnavati, India), by using 9mm punch.The all formulations batches and their codes mentioned in table1.(IP, 1996;Liberman and Lachman , 1991)

Bulk density
Bulk density was determined by placing the drug excipients blend into a graduated cylinder and measuring the volume and weight by using the following formula.

Tapped density
Tapped density was determined by USP method II tablet blend was filled with 100 ml graduated cylinder of tap density tester which was operated for a fixed number of taps until the powder bed volume has reached a minimum, thus was calculated by the following formula.

Angle of repose
Tablet blend was poured from funnel, to form the heap of powder.Height (h) & diameter (D) of powder were measured.The repose angle θ was calculated by the following formula.

Carr's index
It is an indirect method of measuring powder flow from bulk densities was developed by Carr.The compressibility of the granulations was determined by the following formula (Tetsuo et al., 2005) (I.P., 1990;Liberman and Lachman, 1991;Tetsuo et al., 2005)

Weight variation
Twenty tablets were randomly selected from each batch individually weigh, the average weight and standard deviation of 20 tablets was calculated.

Thickness
Thickness and diameter of tablets were determined by using calibrated Vernier caliper.20 tablets from each batch were selected randomly, and their average thickness was measured.

Hardness
The Hardness was measured by using the Pfizer hardness tester, for each batch three tablets were tested.

Friability
For each formulation, the friability of 20 tablets was determined using the Roche friabilator (Lab Hosp).This test subjects a number of tablets to the combined effect of shock, abrasion by utilizing a plastic chamber which revolves at a speed of 25rpm, dropping the tablets to a distance of 6 inches in each revolution.A sample of reweighed 20 tablets was placed in Roche friabilator, which was then operated for 100 revolutions for 4 minutes.The tablets were then dusted and reweighed.

Drug content uniformity
Five tablets were weighed individually, and these tablets were crushed in a mortar.Drug equivalent to 10 mg of powder was taken, to this 10 ml of distilled water was added.The absorbance was measured at 276 nm after suitable dilution using double beam UV visible spectrophotometer.The drug content was determined.
In vitro drug dissolution studies (Ming-Thau et al., 1992 andSamanta et al., 2010) In vitro drug release study for the prepared matrix tablets was conducted for a period of 12 hrs using a six-station USP type II (paddle) apparatus at 37 o C and 50 rpm speed.The dissolution studies were carried out for 12 hrs in the distilled water.0.1N HCl and phosphate buffer pH 6.8, Sampling were done after every 1hr interval; samples of 10ml were withdrawn from dissolution medium and replaced with fresh medium to maintain the volume constant.The release rates from these hydrophilic polymeric matrices were conducted in a medium of by changing the pH by starting with a tablet in HCl solution (pH 1.2) for 2 hrs.Then, the tablets were immersed in a phosphate buffer (pH 6.8) for 8 hrs.The sample solutions were analyzed for diclofenac sodium by UVabsorbance at 276nm using a spectrophotometer.The cumulative percentage of drug release was calculated.

Drug polymer interaction study
Compatibility of excipients with diclofenac sodium was studied by Fourier Transform Infrared Spectroscopy (Shimadzu).

Bulk density =
The FT-IR spectra of all the combinations containing drug and polymer shows same or slightly shift in peak values which revealed that all polymers used are compatible with drug, as shown in fig. 1.

Evaluation of powder characteristic of SR tablets
The powders prepared for compression of tablets were evaluated for their flow properties.The powder characteristic indicates good flowability with an angle of repose value ranging from 25-30 i.e. (<30).The angle of repose of all formulations was found to be the range of 23.10 ± 0.750 to 28.38 ± 0.12.The bulk density of all the formulations showed acceptable range.The bulk density of these powders was found to be in the range of0.424 ± 0.06 to 0.630 ± 0.02gm/cm 3 for all formulations.The measured tapped density was in the range of 0.440 ± 0.06 to 0.870 ± 0.05gm/cm 3 for all formulations.Carr's index of powder was found the range of 09.00±0.02 to 20.00± 0.02 for all formulations.These values indicate that the prepared powder exhibited good flow properties.The result mentioned in the table 2.

Characterization of SR tablets
The weights of the tablets of all formulations found with low standard deviation values, representing uniformity of weight.The difference in weight was within the range of 5% complying with Pharmacopeial specification (Indian Pharmacopoeia).The weight variation deviation of different formulations was found to be between 3.102 to 4.584.The hardness for different formulations was found to be between 4.8±0.22 to 6.6± 0.16 kg/cm 2 .It was indicated satisfactory mechanical strength.The diameter and thickness of all the formulations were found in the range of 9.10 ± 0.03 to 9.18 ± 0.05 mm and 3.23 ± 0.04 to 3.43±0.02mm respectively.The friability of all formulations was found to be between 0.46 ± 0.04 to 0.65 ± 0.06%.The tablets compressed were stable and having better physical characteristics.The percentage drug content for different tablet formulation varied from 95.32 ± 0.03 to 99.32 ± 0.03 was found to be within limits which indicate uniform drug distribution in all formulations, the limit (85% to 115%) of % drug content allowed by I.P., the result of tablet characterization is mentioned in the table 3.

CONCLUSION
From the preformulation and precompression studies, it was concluded that diclofenac sodium suitable drug candidate for the formulation of hydrophilic matrix tablets and the formulated tablets showed compliance for various physiochemical parameters.According to the in vitro drug release studies, the decrease in the release rate was observed with an increase in the viscosity of the polymer.As the drug to polymer ratio increased, more drug gets retarded from tablets.The tablet formed with HPMC E50 controlled drug release more than HPMC E15 and HPMC E300LV.The order of drug release retardation was HPMC E50>HPMC E15>HPMC E300LV.
t = Tapped density; M = Weight of powder taken; V b = Tapped volume.
angle of repose; h = height of the cone; r = radius of the cone

Table 2 :
Comparative study of powdered characteristics for formulation