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.

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.

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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