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DESIGN, DEVELOPMENT AND OPTIMIZATION OF OLMESARTAN MEDOXOMIL LIQUISOLID TABLETS USING CENTRAL COMPOSITE DESIGN

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ABOUT AUTHORS:
Swati k. Nagar*1, Dr. Harsha V. Patel1, Dr.Vishnu A. Patel2, Vinod V. Siju3
1Indukaka Ipcowala College of pharmacy, New V.V.Nagar
2ARCP, Vallabh vidhyanagar
3Anand Pharmacy College, Anand.
*swati.nagar28@gmail.com

ABSTRACT-
The aim of the present study was to investigate the applicability of liquisolid technique in improving the dissolution properties and solubility of olmesartan medoxomil (OLM) in a solid dosage form. This study was designed to optimize and evaluate the effects of different formulation variables: ratio of carrier to coating material (X1) and drug concentration (X2)  on angle of repose (Y1), hardness(Y2), saturation solubility study (Y3) and cumulative percentage release at 10 min (CPR 10min)(Y4) of formulation using five  level two factor central composite design. The quadratic model generated by the design is of the form: Y = A0 + A1X1 + A2X2 + A3X1X2 + A4X12 + A5X22 + E, where Y is the measured response associated with each factor level combination. Contour and response surface plots were depicted based on the equation given by the model. The optimized formula yields observed values close to the predicted values. The liquisolid tablets were formulated with liquid vehicles, poly ethylene glycol 400 (PEG400) at five drug concentrations, 10% w/w, 15% w/w, 20% w/w, 25% w/w and 30% w/w. Avicel PH102 was used as a carrier material, Aerosil 200 as a coating material and cross carmellose sodium as a disintegrant.In-vitro drug dissolution profiles of the liquisolid formulations were studied and compared with conventional formulation (olmezest), in simulated intestinal fluid (pH 6.8). The drug release rates of LS compacts were higher as compared to directly compressed tablets, which show significant benefit of LS in increasing wetting properties and surface area of drug available for dissolution. From this study it concludes that the LS technique is a promising alternative for improvement of dissolution property.

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REFERENCE ID: PHARMATUTOR-ART-1907

INTRODUCTION-
About 40% of the drug candidates identified via combinatorial screening programs are poorly water soluble. The aqueous solubility for poorly water-soluble drugs is usually less than 100 µg/ml1.The dissolution rate is the rate-limiting factor in drug absorption for class II (low solubility and high permeability) and class IV (low solubility and low permeability) drugs as defined in the biopharmaceutical Classification System, BCS. Poorly water soluble drugs are difficult to formulate using conventional techniques2.

Among various techniques to overcome the solubility issue, several researchers reported that the formulation of liquisolid tablets is one of the most promising techniques for promoting drug dissolution3. Consequently, drug dissolution properties and oral bioavailability will be improved. The concept of ‘‘liquisolid tablets” was evolved from ‘‘powdered solution technology” that can be used to formulate ‘‘liquid medication. Theterm ‘‘liquid medication” refers to solid drugs dispersed in suitable non-volatile liquid vehicles. By simple mixing of such ‘‘liquid medication” with selected carriers and coating materials, dry-looking, non-adherent, free-flowing and readily compactible powder admixtures can be produced4 Spireas and Bolton Suggested that particles possess poroussurface with high absorption properties may be used as the carrier material such as cellulose, starch and lactose. Increasing moisture content of carriers results in decreased powder flowability5.

Coating material is required to cover the surface and so maintain the powder flowability6. Accordingly, coating material should be a very fine and highly adsorptive silica powders. The appropriate amounts of carrier and coating materials to produce acceptable flowing and compactible powders are calculated using Eqs. (1)– (3), based on the physical properties of powders termed ‘‘flowable liquid-retention potential” (?-value)7. The ratio (R) of the amount of carrier (Q) and coating (q) materials is closely related to the amount of liquid medication (W). The maximum amount of liquid loads on the carrier material, termed ‘‘load factor” (LfThe coating/carrier ratio (R) is important for determining the ‘‘optimum flowable load factor” (Lf)8 which gives acceptable flowing powders and is characterized by the ratio between (W) and(Q), as shown in Eqs. 1 and 2.

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Lf = ?CA + φCQ (1/R)          …………… (1)

Where ?CA is the flowable liquid-retention potential of the carrier and  is the φCQ flowable liquid-retention potential of the coating material.

Lf= W/Q                …………….. (2)

From Eq. (2), the amount of Q can be determined and applied to the Eq. (3) to calculate the required amount of the coating (q) material9. Then, the amounts of Q and q can be used to prepare liquisolid formulations. It had been proposed that R value of 25 (used with different carriers and coating materials) produces powder admixture with good flow and compactible properties Therefore, this ratio will be used in this research

R=Q/q                     ……………. (3)

The liquisolid tablets that containing water-insoluble drug are expected to enhance drug dissolution because of increased wetting properties of the drug particles and the large surface area available for dissolution10. The liquisolid tablets are suitable to formulate low dose water-insoluble drugs. Recently, a sustained release oral dosage form using liquisolid technology had been formulated successfully11. This proved that liquisolid technology can be developed either to improve or to reduce drug dissolution rates depending on the excipients added.

The aim of this study was to improve dissolution of a hydrophobic drug, OLM, using liquisolid tablets containing different non-volatile liquid vehicles. OLM, antihypertensive drug, is a weak acid (pKa = 4.96) which is practically insoluble in water12.

This technique of liquisolid compacts has been successfully employed to improve the in-vitro release of poorly water soluble drugs as hydrocortisone11, methylclothiazide13, hydrochlorothiazide14, prednisolone15 and the liquid drug clofibrate16.Also several water insoluble drugs, namely, nifidipine, gemfibrosil, and ibuprofen, have exhibited higher bioavailability in rats as compared to their commercial counterparts. The in-vivo evaluation of hydrochlorothiazide liquisolid tablets in beagle dogs showed that the absolute bioavailability of the drug from liquisolid tablets was 15% higher than from commercial tablets17.

EXPERIMENTAL

Materials
Olmesartan medoxomil was obtained from CTX Life science ltd. Surat. Microcrystalline cellulose (Avicel PH102, PH 101, PH 112, PH 200), cross carmellose sodium (Akhil healthcare ltd, Vadodara),Aerosil  200, Cab-o-sil M-5 ( Pramukh Swami Pharma, Ahmedabad), polyethylene glycol 400 (Chemdyes ltd. Ahmedabad),Neusilin (Priti industry, bhavnagar), fujacalin (Canberra chemicals, Mumbai), starcap 1500 (Colorcone ltd, Goa), All materials were of either pharmacological grade or analytical grade.

Selection of Non-volatile solvent
Selection of solvent was performed on the basis of solubility study18. Solubility study of drug was performed in various solvents( propylene glycol, polyethylene glycol 200, polyethylene glycol 400, polyethylene glycol 600, Cremophore® EL, Glycerol, Tween 20,Tween 80,Liquid paraffin, Span 80, Span 20,Fixed oil, Castor oil, water, methanol,) to select suitable non-volatile solvent for the preparation of liquisolid compact by “shake flask method”. Excess amount of drug was added to each of vial containing 2 ml of solvents as mention above.

The system was subjected to vortex mixing on vortexer followed by shaking on rotary shaker for 72 hrs at 37oC19. After calibration for additional 72 hrs the solution was centrifuged on centrifuge, the supernants were diluted by methanol and analysed by UV-spectrophotometer for the presence of drug. Three determinations were carried out for each sample20. It is describe in table 1.

Angle of slide measurement
The study involves an in-house lab model. The model consists of two wooden blocks jointed at one end. At the distal end of joint the upper wooden block was fixed with a polished metal surface.

Briefly 10 gms of each of material was weighed accurately until the plate containing block creates an angle with another wooden block at which the powder started to slide. The angle (ø) represented the angle of slide. It was taken as a measure for the flow characters of powders. An angle of slide corresponding to 330 considered as ideal for optimal flow properties21.

Flowable liquid retention potential determination
To the 10 gm of each of material, increasing amount of optimized solvent was added and mixed well. The corresponding Phi-value was calculated from the following equation after every addition of the non-volatile liquid.

The Phi-values were plotted graphically against the corresponding angle of slide (?).The Phi-value corresponding to an angle of slide of 330 was recorded as the flowable liquid retention potential of carrier and coating material. The Phi-values for carrier and coating material has been abbreviated as   ?CA and φCO respectively. The carrier and coating material with maximum liquid retention potential have been selected as optimum22.

Calculation for the amount of carrier and coating material
On the basis of Phi-value of optimized carrier and coating material the liquid load factor (Lf) and quantities of carrier and coating materials were calculated by using following formula.

Lf = ?CA + φCQ (1/R)                                                                  

Lf= W/Q

R=Q/q

Where,

Lf=Liquid load factor

?CA = Flowable retention potential for carrier material

φCQ = Flowable retention potential for coating material

R=Excipient ratio (Q/q)

W=Weight of liquid vehicle

Q=Weight of carrier material

q= Weight of coating material

Preparation of Liquisolid Compacts: Several liquisolid systems of OLM (denoted as F1 to F13) were prepared and compressed into tablets each containing 10 mg drug, using the single punch tablet press. A two-factor, five-level central composite design was used for constructing a polynomial models using Design Expert (Version 7.1.5; Stat-Ease Inc, Minneapolis, Minnesota). A design matrix comprising 13 experimental runs were performed, the obtained result was computed in order to construct polynomial eqution. Y = A0 + A1X1 + A2X2 + A3X1X2 + A4X12 + A5X22 + E, Where, Y is the measured response associated with each factor level combination; A0 is constant; A1, A2, are linear coefficients, A3, A4, A5, are interaction coefficients between the two factors and are computed from the observed experimental values of Y.The concentration range of independent variables under study is shown in table 2along with their low and high levels, which were selected based on the results from preliminary experimentation. The ratio of carrier to coating material (X1), Drug concentration (X2), used to prepare the 13 formulations and the respective observed responses are given in table 3, 4.

All liquisolid formulations contained microcrystalline cellulose “Avicel® PH 102” as the carrier powder and silica (Aerosil 200) as the coating material at different powder excipient ratio (R) using central composite design23. PEG 400 was used as the liquid vehicle in different amounts as 33.3mg, 40mg, 50mg, 66.6mg and 100mg to prepare the liquid medications with a different drug concentration.Finally, standard 5% crosscarmelose sodium was used as a disintegrant and 1% magnesium stearate as a lubricant and talc 2% in all systems. Liquisolid tablets were prepared as follows; OLM was dispersed in PEG 400 and the mixture ofAvicel PH102- Aerosil 200 and were added to the mixture under continuous mixing in a mortar. Finally, crosscarmellose sodium was mixed and mixture was blended for a period 10 minutes and then talc and magnesium stearate was added before compression as a lubricant.The blend was compressed into tablets, at a hardness of 4-6 kg/cm2 on a rotary tablet punching machine with batch size of 20 tablets was prepared each time24.

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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)

Saturation solubility-
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

Hardness
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.

Friability
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)
                  (Winitial)

Thickness
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.

Weight variation
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
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):
Figure
­­­7 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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CONCLUSION:
The Liquisolid technique is a promising alternative for improvement of dissolution property of water-insoluble drugs, such as OLM. The higher dissolution rate showed by Liquisolid compacts may imply enhanced oral bioavailability due to the increased wetting properties and surface of drug available for dissolution. The Liquisolid compact of OLM made in PEG 400 showed better dissolution rate than marketed tablet (olmezest) based upon solubility and molecular fraction (FM) of the drug in their liquid medication. From this technique solubility of pure drug (0.12µg/ml) increases upto the 25µg/ml.

ACKNOWLEDGEMENTS:
Authors would like to express sincere thanks to SICART lab, V.V. Nagar for providing instruments.  We also thank to CTX lifescience, Surat to provide gratis sample of expensive Olmesartan medoxomil.

Table 1- Solubility study of OLM in different non-volatile solvents.

Sr no

Solvents

Solubility (mg/ml)

1.

Propylene glycol

2.253333 ± 0.041096

2.

PEG-200

6.15 ± 0.122474

3.

PEG-400

20.52 ± 0.384014

4.

PEG-600

10.76667 ± 0.262467

5.

GLYCERIN

4.756667 ± 0.316263

6.

Cremophore® EL

3.553333 ± 0.294882

7.

Tween 20

19.1 ± 0.348807

8.

Tween 80

9.653333 ± 0.192585

9.

Span 80

2.746667 ±0.373661

10.

Span 20

15.41333 ±0.083799

11.

Liq.paraffin

0.883333 ±0.041096

12.

Castor oil

14.14333 ±0.20822

Table 2: Factors and their different levels for Central composite design for preparation liquisolid tablets.

Independent Variables

Levels

Lowest(-α)

Low(-1)

Medium(0)

High(+1)

Highest(+α)

Ratio of carrier to coating material (R) (X1)



5


10


15


20


25

Drug concentration(Cd)

(X2)

10%

15%

20%

25%

30%

Dependent Variables

Goal

Angle of Repose (Y1)

Minimize

Hardness (kg/cm2) (Y2)

Maximize

Saturation solubility study(Y3)

Maximize

Cumulative percentage release at 10 min CPR10 min (Y4)

Maximize

Table 3- Formulation of liquisolid compact-

FORMULA

DRUG(mg)

WEIGHT OF SOLVENT (mg)

DRUG CONC

(%)

[X2]

R=Q/q

[X1]

Lf=W/Q

Avicel PH 102

Q=W/Lf

(mg)

Aerosil 200

q= Q/R(mg)

CCS

10%

(mg)

TOTAL

WEIGHT

(mg)

F1






      10

66.6

15

10

0.693

96.10

9.61

18.23

208.56

F2

66.6

15

20

0.609

109.35

5.4675

19.14

218.97

F3

40

25

10

0.693

57.72

5.77

11.34

129.82

F4

40

25

20

0.609

65.68

3.28

11.89

136.084

F5

50

20

5

0.861

58.07

11.61

12.96

148.64

F6

50

20

25

0.592

84.43

3.377

14.78

169.08

F7

100

10