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RESEARCH ARTICLE

Application of 3² Factorial Design in the Formulation of Fast Release Olmesartan Medoxomil Liquisolid Tablets

Shrinivas K. Mohite¹, Shantanu B. Kuchekar²*

¹Department of Pharmaceutical Chemistry, Rajarambapu College of Pharmacy, Kasegaon 415404, Maharshtra, India.

²Department of Pharmaceutics, Rajarambapu College of Pharmacy, Kasegaon 415404, Maharshtra, India.

*Corresponding Author E-mail: shantanubk@yahoo.com

ABSTRACT:

Fast dissolving tablets are gaining more importance in the market day by day and are available in the market for treating many disease conditions. Olmesartan medoxomil (OLM) is the novel antihypertensive drug having specific angiotensin II type 1 antagonist activity and used in the management of acute and chronic hypertension. Rapid onset of action is desirable to provide fast relief in the treatment of heart failure. Hence, it is necessary to enhance dissolution rate of OLM to obtain faster on set of action, minimize the variability in absorption, and improve its overall oral bioavailability. Liquisolid technique was used to enhance the aqueous solubility and dissolution rate to obtain faster on set of action, minimize the variability in absorption, and improve its oral bioavailability. The aim of the present study was to formulate OLM liquisolid tablets. A 3²factorial design was applied to investigate the combine effect of Neusilin US2 (carrier material) and Aerosil 200 (coating material). The angles of repose and % drug release were selected as dependent variables. Liquisolid systems of OLM were evaluated for pre and post compression parameters. In vitro drug release studies showed highest drug release at initial bursting of tablet at 2 min. The results of a 3² full factorial design revealed that the amount of Neusilin US2 and Aerosil 200 significantly affect the dependent variables, angle of repose and % drug release. Higuchi model was found to be the best fit model for the optimized batch. Thus Neuslin US2 should be in high concentration and Aerosil 200 should be in low concentration i.e high R value which gives the enhanced solubility and hence fast dissolution i.e. onset of action is obtained.

KEY WORDS: Olmesartan medoxomil, Liquisolid, factorial design.

INTRODUCTION:

Fast dissolving tablets are gaining more importance in the market day by day. Such tablets are available in the market for treating many disease conditions. There are disorders like hypertension, migraine, dysphasia, nausea and vomiting, Parkinson’s disease, schizophrenia etc. which needs fast release of drug to get an onset of action^[1-4]. The patient with above conditions show convenience with fast dissolving tablets over conventional tablets because of ease of administration, swallowing, pleasant taste and availability in several flavors ^[5].

Received on 30.05.2015 Modified on 11.06.2015

Research J. Pharm. and Tech. 8(7): July, 2015; Page 849-856

DOI: 10.5958/0974-360X.2015.00139.0

Olmesartan medoxomil (OLM) is an anti-hypertensive prodrug ester that is hydrolyzed to olmesartan during absorption from the gastrointestinal tract. It is a selective ATl subtype angiotensin II receptor antagonist and blocks the vasoconstrictor effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in vascular smooth muscle. OLM is indicated for the treatment of hypertension^[6]. The drug is rapidly absorbed following oral administration, with a bioavailability approximately 26%. Peak plasma concentrations of OLM occur 1 to 2 h after an oral dose and are highly bound to plasma proteins (99%)^[7].Rapid onset of action is desirable to provide fast relief in the treatment of heart failure. Hence, it is necessary to enhance dissolution rate of OLM to obtain faster on set of action, minimize the variability in absorption, and improve its overall oral bioavailability^[8]. Therefore, a technique named “Liquisolid technology”, has been applied to prepare fast/rapid-release solid dosage forms. Liquisolid systems are designed to contain liquid medications in powdered form. The concept of powdered solutions convert a liquid drug or poorly water-soluble solid drug dissolved in a suitable non -volatile solvent into a dry, non-adherent, free flowing and readily compressible powder by its simple admixture with selected carrier and coating materials and this method does not involve drying or evaporation^[9].Hence, the objective of the present work was to formulate the immediate release liquisolid compacts of OLM.

MATERIALS AND METHODS:

Materials:

OLM was procured from Emcure Pharamaceuticals Ltd. Pune. Polethylene glycol grades (PEG 200, 400, 600) and lactose were procured from Research lab Fine Chem Industries, Mumbai; Microcrystalline cellulose (Flocel PH102, Flocel PH 101, Flocel PH 112) were obtained from Gujarat Microwax Pvt Ltd, Neusilin US2, Fujicalinwere obtained from Gangwal Chemicals Pvt Ltd., Maharashtra, Aerosil 200, Ca-bo-sil were obtained from Akhil Healthcare (P) Ltd, Primojel was obtained from Shreeji Pharma International.

Methods:

Use of the Mathematical Model for the Design of Liquisolid Tablets:

The mathematical model for liquisolid formulations was used to calculate the suitable quantities of the carrier and coating materials required to produce liquisolid systems of acceptable flowability and compressibility was based on new essential powders properties (constant for each powder material in the liquid vehicle) called the flowable liquid retention potential (Φ-value) and compressible liquid retention potential (Ψ-number) of the carrier and coating materials as was discussed by Spireas et al. ^[10-13]

According to the new theories, the carrier and coating materials can hold only certain amounts of liquid while maintaining acceptable flow and compression properties. This depends on the ratio of the carrier to coating materials (R) of the powder system used, where:

R = Q/q (Eq 1)

As R is the ratio of the weights of carrier (Q) and coating (q) materials in the formulation. The liquid load factor (Lf) is the ratio of the weight of liquid medication (W) and the weight of the carrier powder (Q) in the system, which should be possessed by anacceptably flow and compressible liquisolid system.

Lf = W /Q (Eq2)

An acceptably flowable and compressible liquisolid system can be prepared only if a maximum liquid load on the carrier material is not exceeded Lf.

The Φ values of the powder excipients are used for calculating the required ingredient quantities. Thus, the Rand Lf of the formulations are related as follows:^[14]

Lf = Φ + Φ (1/R) (Eq3)

Where, Φ and Φ are the Φ - values of the carrier and coating powder materials, respectively.

Hence, the essential weights of the excipients used can be calculated from Eq.(3). Φ and Φ are constant for each excipient. Thus according to R, Lf can be calculated. Then from the used liquid vehicle amounts, different weights of the liquid drug solution (W) will be used. Therefore, knowing both Lf and W, the proper quantities of carrier (Q) and coating (q)powder materials can be calculated from Eqs. (1) and (2).

3² factorial design:

In this design 2 factors were evaluated, each at 3 levels as shown in Table 1, and experimental trials were performed at all 9 possible combinations as shown in Table 2 and 3^[15]. The two independent variables were selected as X1 and X2. A statistical model incorporating interactive and polynomial terms was utilized to evaluate the response.

Y = b0+ b1X1+ b2X2+ b12X1X2+ b11X12+ b22X22 (2)

where, Y is the dependent variable, b0 is the arithmetic mean response of the 9 runs, and b1 is the estimated coefficient for the factor X1.

The main effects (X1and X2) represent the average result of changing one factor at a time from its low to high value. The interaction terms (X1 X2) show how the response changes when 2 factors are changed simultaneously. The factors and there amounts were selected based on preliminary study.

Table 1: Levels of variables in coded and actual form

Levels (coded)	Variables
Levels (coded)	X₁ – Neusilin US (mg) (actual)	X₂- Aerosil 200 (mg) (actual)
-1	142	8
0	This value is set by software
+1	152	12

Table 2: Factorial batches of Liquisolid formulations of OLM in coded form and actual form

Factorial Batch code	Coded		Actual
Factorial Batch code	X₁ – Neusilin US2 (mg)	X₂- Aerosil 200 (mg)	X₁ – Neusilin US (mg)	X₂- Aerosil 200 (mg)
OLF1	+1	+1	152	12
OLF2	0	0	147	8
OLF3	0	0	147	10
OLF4	-1	-1	142	10
OLF5	+1	-1	152	8
OLF6	-1	+1	142	8
OLF7	0	0	147	12
OLF8	+1	+1	152	10
OLF9	-1	-1	142	12

Table 3: Composition of OLM Liquisolid Formulations F1 to F12

Factorial Batches	Drug (mg)	Drug conc.	R	Lf	PEG 400 (mg)	Neusilin US2 (mg)	Aerosil 200 (mg)	Primojel (mg)	Lactose (mg)	Total (mg)
OLF1	20	10%	20	1.184	180	152	12	21.17	60	445.17
OLF2	20	10%	20	1.224	180	147	8	21.17	60	436.17
OLF3	20	10%	20	1.224	180	147	10	21.17	60	438.17
OLF4	20	10%	20	1.268	180	142	10	21.17	60	433.17
OLF5	20	10%	20	1.184	180	152	8	21.17	60	441.17
OLF6	20	10%	20	1.268	180	142	8	21.17	60	431.17
OLF7	20	10%	20	1.224	180	147	12	21.17	60	440.17
OLF8	20	10%	20	1.184	180	152	10	21.17	60	443.17
OLF9	20	10%	20	1.268	180	142	12	21.17	60	435.17

R: Carrier: coating ratio, Lf: Liquid load factor

Preparation of Liquisolid tablets of OLM:

Liquisolid tablets of OLM were prepared and compressed into tablets each containing 10 mg drug, using the single punch tablet press. All liquisolid formulations contained Neusilin US2 as the carrier powder and Aerosil 200 as the coating material at different powder excipient ratio (R). PEG 400 was used as the liquid vehicle and different drug concentrations were prepared as 10% and 20%. Liquisolid tablets were prepared as follows; OLM was dispersed in PEG 400 and the mixture of Neusilin US2- Aerosil 200 and were added to the mixture under continuous mixing in a mortar. Finally, Primojel as superdisintegrant and Lactose as filler were mixed and mixture was blended for a period 10 minutes. The blend was compressed into tablets using the single punch tablet press.

Evaluation of Liquisolid granules:

Angle of repose^[16]:

Accurately weighed blend samples were passed separately in a glass funnel of 25ml capacity with diameter 0.5cm. Funnel was adjusted in such a way that the stem of the funnel lies 2.5cm above the horizontal surface. The sample was allowed to flow from the funnel, so the height of the pile h just touched the tip of the funnel. The diameter of the pile was determined by drawing a boundary along the circumference of the pile and taking the average of three diameters.

Angle of repose was calculated by formula:

θ = tan –1 (h/r)

Hausners ratio (HR):

HR was obtained by using formula;

HR = Tapped density/Bulk density

Carr’s index^[17]:

Carr’s index (CI) which is calculated as follows:

CI (%) = Tapped density – Bulk density x 100

Tapped density

Evaluation of Liquisolid Tablet^{[18, 19]}:

Thickness:

The thickness was measured using vernier caliper. Average values were calculated.

Hardness:

The hardness of the tablets was determined using Monsanto hardness tester. It is expressed in kg/cm².

Friability test:

The test was performed using Roche friabilator (Electrolab)

Disintegration test^[20]:

The disintegration time of the tablets was measured in distilled water (37 ± 2°C) using disintegration test apparatus (Electrolab, India) with disk.

In vitro drug release^[20]:

The in vitro drug release of OLM from the optimized liquisolid tablets was performed using USP dissolution a Type II apparatus (Labindia DS 8000). Liquisolid tablets were put into each of 900 mL phosphate buffer pH 6.8, at 37±0.5°C with a 50 rpm rotating speed. Samples (10 ml) were withdrawn at regular time intervals (2, 4, 6, 8, 10, 15, 20 and 25min) and filtered. An equal volume of the dissolution medium was added to maintain the volume constant. The drug content of the samples was assayed using UV visible spectrophotometric method.

Drug release kinetics study^[21-23]:

The dissolution profile of optimized batch was fitted to various models such as zero order, first order, Higuchi, Korsemeyer and Peppas to ascertain the kinetic of drug release.

RESULTS AND DISCUSSION:

Use of the Mathematical Model for Design of Liquisolid System:

From the preliminary experiments, it was found to be that PEG 400 was selected as a nonvolatile solvent for the preparation of liquisolid system of OLM. The liquisolid hypothesis discussed by Spireas et al., declared that the drug dissolved in the nonvolatile liquid vehicle. Upon incorporation of drug dispersion into the porous and closely matted fiber carrier material both absorption and adsorption took place. So the liquid medication is first absorbed into the interior of the carrier particles, then the liquid gets adsorbed onto both internal and external surfaces of the carrier. Thus Neusilin US2 was found to be the suitable carrier material for liquisolid system of OLM. Subsequently, the coating material (Aerosil 200) that had strong adsorptive power and high surface area formed the required flowable liquisolid system ^{[10,
11, 24, 25]}.

The ingredient quantities required to achieve acceptable flowability was calculated using the Φ-values of powder excipients. Thus, from different suggested R-value, the corresponding Lf was calculated using equations 1-3.

Evaluation of Liquisolid granules:

From Table 4, Angle of repose was found to be in the range of 26 – 33.5° which indicated good flow for all the batches, Carr’s index was found to be less than 20 which indicated good flowability for all the batches and Hausner’s ratio were found to be in between 1.09 to 1.18 showed good flow ability.

Table 4: Angle of repose, Hausner’s ratio and Carr’s index of Formulations OLF1 to OLF9

Batches	Angle of repose	Hausner’s ratio	Carr’s index
OLF1	30	1.17	14.24
OLF2	32	1.18	13.43
OLF3	33	1.15	14.87
OLF4	31.5	1.14	13.65
OLF5	26	1.09	11.64
OLF6	31	1.13	13.33
OLF7	34	1.16	14.76
OLF8	28	1.15	15.41
OLF9	33.5	1.14	15.77

Evaluation of Liquisolid Tablet:

As shown in Table 5, Thickness and hardness of liquisolid tablet was found to be in the range of 4.68 to 4.85 kg/cm² and 5.06 to 5.15 mm respectively. Friability of tablets was found to be below 1% which is acceptable. Disintegration time of liquisolid tablets were in the range of 1-2 minutes.

Table 5: Evaluation of post compression parameters of Formulations OLF1 to OLF9

Batches	Thickness (mm)	Hardness (kg/cm²)	Friability (%)	Disintegration Time (min)
OLF1	4.85	5.15	0.15	1.14
OLF2	4.72	5.10	0.20	1.12
OLF3	4.75	5.11	0.16	1.11
OLF4	4.71	5.07	0.25	1.19
OLF5	4.81	5.12	0.18	1.01
OLF6	4.68	5.06	0.27	1.23
OLF7	4.78	5.13	0.17	1.25
OLF8	4.83	5.14	0.14	1.15
OLF9	4.73	5.09	0.26	1.17

In vitro drug release:

Table 6: In vitro drug release of Formulations OLF1 to OLF9

Time (min)	OLF1	OLF2	OLF3	OLF4	OLF5	OLF6	OLF7	OLF8	OLF9
0	0	0	0	0	0	0	0	0	0
2	53.12	54.51	53.38	52.18	56.45	52.92	52.22	54.72	51.66
4	66.42	62.85	60.64	58.37	68.76	59.44	59.46	67.64	69.32
6	72.35	69.75	66.42	64.58	82.48	65.59	65.12	74.28	83.10
8	77.15	78.18	75.62	73.29	89.53	74.48	74.26	79.47	89.92
10	85.67	84.29	82.73	81.67	98.75	83.32	80.53	87.81	92.57
15	94.11	91.71	88.25	87.45	101.90	88.56	87.24	94.35	95.61
20	98.37	95.31	96.41	93.89	-	94.69	95.38	98.32	97.21
25	101.12	99.53	98.28	97.38	-	98.45	97.55	98.74	98.86

Figure 1: Dissolution profile of Formulations OLF1 to OLF4

Figure 2: Dissolution profile of Formulations OLF5 to OLF9

CONCLUSION:

A 3² factorial design was applied to optimize the two factors Neusilin US2 (X1) and Aerosil 200 (X2) that were chosen from the first PB screening design. Angle of repose and % drug release were selected as dependent variables. Response surface plots and counter plots were obtained. These graphs depicted that as the concentration of Neuslin US2 increases the angle of repose of liquisolid granules decreases i.e. flowability increases and as concentration of Aerosil 200 increases there is increase in the angle of repose of liquisolid granules. Also as the concentration of Neuslin US2 increases the % drug release of liquisolid tablets increases and as concentration of Aerosil 200 increases there is decrease in the % drug release of liquisolid tablets. For obtaining the good flowability and better % drug release of liquisolid system for fast drug release pattern, Neuslin US2 (X1) should be in high concentration and Aerosil 200 (X2) should be in low concentration i.e high R value which gives the enhanced solubility and hence fast dissolution i.e. onset of action is obtained.

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Figure 7: Zero order kinetics of OLF5	Figure 8: First order kinetics of OLF5

Figure 9: Koresmeyer Peppas model kinetics of OLF5	Figure 10: Higuchi model kinetics of OLF5


Figure 3: Response surface plot showing effect of formulation variables on Angle of repose	Figure 4: Contour plot showing effect of formulation variables on Angle of repose


Figure 5: Response surface plot showing effect of formulation variables on % drug release at t_2min	Figure 6: Contour plot showing effect of formulation variables on % drug release at t_2min