DESIGN, DEVELOPMENT AND OPTIMIZATION OF OLMESARTAN MEDOXOMIL LIQUISOLID TABLETS USING CENTRAL COMPOSITE DESIGN
Evaluation of powder parameters
Angle of repose
The angle of repose of the powder blend was determined by using funnel method. The diameter of the powder cone was measured and angle of repose was calculated by using the equation25
Tan θ = h/r …………….. (4)
Where h and r are the height of pile and radius of the base of pile respectively.
Determination of bulk density
It is the ratio of total mass of powder and the bulk volume of powder. It was measured by pouring the weighed powder in to graduate measuring cylinder and the volume was recorded.
Pb= M/Vb …………….(5)
Determination of Tapped density
It is the ratio of total mass of powder and the tapped volume of powder. The measuring cylinder containing a known mass of blend was tapped for a fixed time. The minimum volume (Vt) occupied in the cylinder and the weight (M) of the blend was measured. The tapped density (Pt) was calculated using the following formula26
Pt =M/Vt …………… (6)
Carr’s compressibility index
An important measure that can be obtained from bulk density determinations is the percent compressibility C, grading of the powders for their flow properties.
I= Pt-Pb/Pb× 100 ……………. (7)
“Hausner” s ratio
It is calculated from the ratio of bulk density and tapped density.
Hr= Pt/Pb ……………… (8)
The saturation solubility of powders were determined in distilled water by adding excess amount of powders individually in a volumetric flask containing 25 ml distilled water. The flasks were shaken on rotary shaker for 72 hrs at 370 C. After equilibrium for additional 72 h, the solution were centrifuged on centrifuge, the supernants were diluted by methanol and analysed by UV- spectrophotometer.
Evaluation of Liquisolid Compact tablets
The hardness of the tablets was determined using Monsanto Hardness tester. It is expressed in Kg/cm2. Tablets were randomly picked from each formulation and the mean and standard deviation values were calculated27.
The friability of tablets was determined by using Roche’s Friabilator. It is expressed in percentage (%). Twenty tablets were initially weighed (Winitial) and transferred into friabilator. The friabilator was operated at 25 rpm for 4 minutes28. The tablets were weighed again (Wfinal). The percentage friability was then calculated by
(Winitial) – (Wfinal)
F = ---------------------× 100 ………………… (9)
Tablets were selected at random from individual formulations and thickness was measured by using Vernier caliper scale, which permits accurate measurement. Tablet thickness should be controlled within a ± 0.5% variation of standard value.
Twentytablets are randomly selected and weighed individually. The average weights of these tablets are determined. The weight variations of individual tablets were determined with respect to average weight and % weight variation29.
Disintegration time was measured using USP disintegration test apparatus. Randomly six tablets were selected from each batch for disintegration test. Disintegration test was performed in 900ml distilled water at 37±0.5 °C temperature and at the rate of 30±2 cycles/min.
Drug Content Uniformity
The OLM content in different liquisolid tablet formulations was determined by accurately weighing 20 tablets of each formula individually. Each tablet was then crushed and a quantity of powder equivalent to 10 mg of OLM was dissolved in 100 mL methanol. 1 mL of this solution was diluted to 10 mL with methanol and measured spectrophotometrically at λmax of 257nm30.
In Vitro Drug Release
The USP paddle apparatus II (Electrolab TDT-06P, Mumbai, India) was used for all the in vitro dissolution studies. Nine hundred milliliters of pH 6.8 was used as the dissolution media, at 50 rpm and 37 ± 0.5 °C. Appropriate aliquots were withdrawn at suitable time intervals (5, 10, 15, 20, 25, 30, 45, 60 min) and filtered through whatman filter paper No. 41 and diluted to 10 mL with PH 6.8. Sink conditions were maintained throughout the study. The samples were then analyzed at λmax of 257 nm by a UV/visible spectrophotometer. The study was carried out in triplicate.
RESULTS AND DISCUSSION-
Selection of nonvolatile solvent
In the liquisolid compact non-volatile liquid solvent is optimized for the high drug solubility in solvent. The solubility in various non-volatile solvent is given in table 1. The table shows that solubility of drug in PEG 400 is higher in comparison with other solvent. For this reason, PEG 400was selected to be the suitable solvent for preparing liquisolid compact.
Angle of slide measurement and flowable liquid retention potential determination
Angle of slide for carrier and coating materials was used to determine flowable liquid retention potentials, which are needed for calculation of the liquid load factor (Lf).
For the carrier material 5 gm of the powder was taken for determine angle of slide. But in case of the coating material i.e.cab-o-sil M5 and aerosol 200 having low density, So it was not convenient to take 10gm of material for measurement. Figure 1, 2 illustrate the relation between angle of slide and the corresponding Phi-value. It is shows that Phi-value corresponding to an angle of slide of 330 was higher for Avicel PH 102 and Aerosil 200 as carrier and coating material respectively.
Evaluation of powder parameters
Powder flow property is crucial in handling and processing operation such a as flow from hopper, mixing and compression. Angle of repose, Carr’s index, hausner’s ratio are parameter included in flowability. The powder has a good flowability, when the Hausner’s ratio is lower than 1.2 while if the ratio is more than 1.2 this indicates that the flowability is poor.
In the case of angle of repose greater than 400 have unsatisfactory flow properties, whereas minimum angle close to 250 corresponed to very good flow properties.
Table 5 revealed that all the tested batches of liquisolid compact had a good flow property. The range was 34.42 to 35.56 for liquisolid compact. From these entire batches LS 1 to LS 13 shows good angle of repose.
Hausner’s ratio and carr’s index were calculated from the density value. In case of carr’s index below 20 giving good result. So in the all batches result shows good flowability. Hausner;s ratio between 1.048±0.027 to 1.183±0.046 shows excellent flow ability of the powder blend. Drug solubility in water is (0.12µg/ml). in formulation LS 1 to LS 13 increases the solubility as compare to pure drug.
Angle of Repose of liquisolid powders (Y1) -
Figure 3 showed the response surface plot, which displayed the effect of X1 and X2 on the angle of repose Y1. From the figure, , increasing X1 up to 20 along with increasing X2 to 20% results in deccreasing the angle of repose of the formulation to the 32.40. On the other hand, increasing the X1 to 25 mg and decreasing X2 up to 20% results in decreasing the angle of repose to the maximum 35.560.Contour plot represented in figure 4 gave an idea about the exact percent of X1 and X2 at which the angle of repose becomes at minimum level.
Hardness of liquisolid tablets (Y2):
Figure 5 showed the response surface plot, which displayed the effect of X1, and X2 on the hardness Y2. From the figure, increasing X1 up to 25 along with decreasing X2 up to 20% results in decreasing the hardness Y2 of the formulation to be 3.6. On the other hand, using the medium level of X1 15 along with decreasing X2 up to 10% results in increasing the hardness Y2 to 4.4.
Contour plot in figure 6gives an idea about the exact percent of X1, and X2 at which the hardness Y2 becomes at optimum level.
Saturation solubility of liquisolid powder (Y3):
Figure7 showed the response surface plot, which displayed the effect of X1, and X2 on the saturation solubility study Y3. From the figure, increasing X1 up to 20along with increasing X2 up to 25% results in decreasing the solubility Y3 of the powder to be 22.99(µg/ml). On the other hand, using the low level of X1 5 along with medium level X2 up to 20% results in increasing the Y3 to 25.76,
Contour plot in figure 8gives an idea about the exact percent of X1, and X2 at which the hardness Y3 becomes at optimum level.
Cumulative percentage release study(CPR10min) (Y4):
Figure 9 showed the response surface plot, which displayed the effect of X1, and X2 on the in vitro release study Y3. From the figure 9it can be observed that increasing X1 up to 25along with decreasing X2 up to 20% results in a formulation having in vitro release 21.27. On the other hand, medium X1up to 15 along with increasing X2 up to 30% results in a formulation having in vitro release 26.85.
Contour plot in figure 10gives an idea about the exact percent of X1, and X2 at which the CPR10min Y4.
Selection of optimize batch-
Optimized batch was selected using Design Expert® 7.0 software, an overlay plot was generated to select optimized/check point batch with desired responses. The result of angle of repose, hardness, saturation solubility study and CPR10min values was compared with that of computed values from the regression equtions. The overlay plot of optimized batch is given inTable6, 7 andfigure 11.The predicted batch shows significant reproducibility within the percentage deviation. From the result shows that the predictive value close to the experimental value so design is significant.
Evaluation of Prepared Tablets
Thickness of tablets was found uniform between 2.20±0.01 to 4.12±0.12 mm. This indicates that the materials behaved uniformly throughout the compression process. Since the powder material was free flowing, tablets were obtained of uniform weight due to uniform die fill, with acceptable weight variations as per pharmacopoeial specifications. The hardness values shows in table 8 and it was in range from 3.6±0.02, 3.8±0.02 and 4.4±0.3. There were no cracked, split or broken tablets. Therefore, they were expected to withstand fracturing and attrition during normal handling, packaging and transporting processes. Hardness of tablets was found to be sufficient to withstand mechanical shock. Friability of tablets was found below 1% indicating a good mechanical resistance of tablets. All the parameters were found within the specified limit.
The disintegration time for the prepared liquisolid compact was shown in table 8. It was found that, the mean of the disintegration times for all investigated tablets were less than 15 minutes, which met the pharmacopoeial requirements for uncoated tablets. Disintegration time was found to be in the range of 2.20±0.06 to 4.23±0.04 min. Faster disintegration time indicate rapid release rates.
Fahmy and Kaseem claimed that usually the process involved adsorption of liquid formulation onto carrier gives uniform drug distribution,therefore, promote good content uniformity observed between liquisolid and conventional tabletsin study. Uniform drug content was observed for all the formulation from 96.24±0.2 to 102.01±0.04.
In vitro drug release
All the liquisolid compacts showed higher and faster drug release than conventional tablet. The enhanced dissolution rates of liquisolid compacts compared to conventional tablet may be attributed to the fact that the drug is already in solution in PEG 400, while at the same time it is carried by the powder particles (Avicel PH 102 and Aerosil 200). Thus, its release is accelerated due to its markedly increased wettability and surface availability to the dissolution medium. The wettability of the compacts by the dissolution media is one of the proposed mechanisms for explaining the enhanced dissolution rate from the liquisolid compacts. PEG 400 facilitates wetting of drug particles by decreasing interfacial tension between dissolution medium and tablet surface.
The dissolution profiles of the selected liquisolid tablet formulations together with the dissolution profile of conventional, directly compressed tablets (DCT) are presented in fig12-14. It was apparent that formula LS 1 has the highest dissolution pattern in both the rate and the extent of drug dissolved. The percentage of OLM dissolved from LS 1reached 100.11% after only 60 min, while the MKT had a maximum OLM content (65%) dissolved after 60 min.
Fig12-14 shows the dissolution profile from the LS compact LS-1, LS-13 and marketed tablet (MKT) of OLM. Liquisolid compacts displayed distinct in-vitro release characteristics than directly compressed counterparts. The percent drug release at the end of 60th min was, 95.89 % for LS-1, 98.2 % for LS-13 79% and 51.2 % for MKT. The 10th min percent drug release of LS compacts and conventional tablets is shown in fig12-14. It was confirms that LS-1 had highest drug release 34.56 %compared to 8.2 % for conventional tablets (MKT). Since the Liquisolid compacts contain a solution of the drug in PEG 400, the drug surface available for dissolution is tremendously increased. In essence, after disintegration, the LS primary particles suspended in the dissolving medium contain the drug in a state of molecular dispersion, whereas the directly compressed tablets are merely exposing micronized drug particles. Therefore, in the case of LS compacts, the surface area of drug available for dissolution is related to its specific molecular surface which, by any means, is much greater than that of the OLM particles delivered by the directly compressed tablets.
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