INTRODUCTION:

Oral drug delivery is a simple method for administering solid dosage forms due to its relative stability, less bulk, dosage accuracy, and ease of production.^1,2 It offers numerous advantages over other forms. The bio availability of a drug depends on its solubility and less bioavailability can detract from the efficacy of drug efficacy. Many new chemical entities are poorly water-soluble, making oral administration difficult.^3,4

Solid dispersions are solid products consisting of hydrophobic drug with hydrophilic matrix. The drug is dispersed as crystalline particles or amorphous particles. ⁵Polymers are used to form matrix, and the selection of this is based on factors like physico-chemical and pharmacokinetic limitations.⁶

Amorphous solid dispersions are classified based on molecular interaction between drug and carrier at molecular level in solid solutions, solid suspensions, or both. The effect of drug load on release of drug from solid dispersions is different, with some of the studies showing rapid release of drug at lesser loads of drug.⁷

Olmesartan medoxomil is FDA-approved AT- II receptor blocker for treatment of hypertension. It is water insoluble and methanol soluble drug, with a 26% bioavailable and 99% bound to proteins. It undergoes metabolism in the liver and has a half life of 13-hours. Its advantages include daily dosing, no ADR’s, well-tolerated, less side effects, and economic.⁸The current research aims to enhance solubility and rate of dissolution by preparing solid dispersions for fast-dissolving tablets.

MATERIALS AND METHODS:

Materials:

Olmesartanmedoxomil was gifted by Apotex Pharma Ltd., Bangalore, Soluplus, Croscarmellose sodium, Crospovidone, Sodium Starch Glycolate, and Microcrystalline Cellulose (Avicel pH 101) are purchased from commercial sources, and potassium dihydrogen phosphate and sodium hydroxide were procured commercially.

Methods:

Olmesartan medoxomil Estimation:

Various methods are reported for Olmesartan medoxomil estimation by spectrophotometry. The study presents a simple, sensitive, and accurate method for estimating Olmesartan medoxomil using spectrophotometry, measuring absorbance values at a λmax of 257nm.

Saturated Solubility Studies:

The solubility of Olmesartan medoxomil was studied using different dissolution media. The drug was weighed, transferred into separate flasks, and kept in a incubator shaker for 24 hours. After 24 hours, the flasks were filtered and diluted with same media. The absorbance was checked at 257nm employing same medium as blank solution. This process involved transferring 500mg of drug and 50ml of different media.

Solid Dispersions Preparation:

The study focused on formulation of solid dispersions of Olmesartan employing Soluplus as carrier, maintaining a constant drug concentration while using various carrier concentrations for formulation by different techniques.

Physical Mixing:

The known weight of drug (Olmesartan medoxomil) and Soluplus are separately weighed and sieved via sieve number 80. The materials collected are transferred to clean and dry mortar made up of with glass. Olmesartan and carrier are triturated combinely for 5 minutes and passed through 100 sieve. The mixture obtained is collected and stored in an hermatically sealed amber colored bottle for further studies

Solvent Evaporation:

A known quantity of drug and Soluplus are weighed and transfered into china dish, a small volume of methanol was added and slightly heated until olmesartan and polymer were dissolved. Then it is evaporated at temperature not exceeding 60⁰C. The resulting mixture was dried, sieved through 100 No sieve. The mixture obtained is collected and stored in an hermatically sealed amber colored bottle for further studies.

Kneading:

A specific quantity of Soluplus was mixed with a specific amount of drug in a china dish, then vigorously triturated at room temperature. If necessary, the mixture obtained was grinded and sieved. The resulting mixture was dried, sieved through 100 No sieve. The mixture obtained is collected and stored in an hermatically sealed amber colored bottle for further studies.Solid dispersions composition was given in Table-1.

Table 1: Olmesartan Medoxomil Solid Dispersions Composition

S. No	Composition	Ratio
	Physical Mixing Method	*Drug: Polymer
1	OP1	1:1
2	OP2	1:2
3	OP3	1:3
Solvent Evaporation Method
4	OS1	1:1
5	OS2	1:2
6	OS3	1:3
Kneading Method
7	OK1	1:1
8	OK2	1:2
9	OK3	1:3

*One part : 40mg

Solid Dispersions Evaluation:

Physical Properties:

Solid dispersions prepared were evaluated for Particle size, Carr”s index and Angle of repose,⁹ according to the official compendium standards. Physical parameters of different solid dispersions are given in Table 2.

Drug Content Uniformity:

Olmesartan medoxomil solid dispersions were taken at and placed into volumetric flask of 100ml capacity, 90 ml of methanol is added to it and this was shaken for 30 minutes and then it was filtered. 10ml of the filtrate was transferred into a volumetric flask of 100ml capacity and it was made up to volume by the addition of pH 6.8 phosphate buffer. From the above 10ml of the filtrate was subjected to centrifugation. The filtrate was further diluted and the absorbance was checked at 257nm. The drug content uniformity test was repeated for six times (N = 6) for all batches dispersions. Drug content values for different dispersions are given in Table-2.

Table 2: Olmesartan medoxomil Solid Dispersions Physical Parameters

S. No	Solid Dispersions code	Angle of Repose (⁰)	Carr’s Index (%)	Particle Size (microns)	Drug Content (mg)
1	OPD	31.9	19.2	165±2	39.43±0.2
2	OP1	25.1	15.1	162±4	39.41±0.3
3	OP2	25.3	15.5	161±3	39.68±0.2
4	OP3	24.8	14.6	164±2	39.46±0.2
5	OS1	24.3	14.9	163±2	39.29±0.2
6	OS2	25.5	15.6	165±4	39.64±0.3
7	OS3	25.2	15.4	160±4	39.48±0.2
8	OK1	25.7	14.5	164±2	39.70±0.2
9	OK2	24.7	15.2	161±2	39.51±0.2
10	OK3	24.9	14.9	166±4	39.57±0.2

In vitro Dissolution Studies:

Solid dispersions dissolution studies were performed using USP TypeII apparatus using pH 6.8 phosphate buffer 900 ml as dissolution medium. At different time intervals like5, 10, 15, 30, 45 and 60 minutes the samples were taken and placed same volume in order to exist sink conditions during the study. Samples are diluted with pH 6.8 Phosphate buffer and amount of drug dissolved is estimated at 257 nm by double beam UV spectrophotometer. Cumulative percent of drug released is calculated. Dissolution studies were repeated six times on each formulation. In Vitro dissolution parameters were calculated from the data. Table 3 provides In Vitro dissolution parameters for various solid dispersions. Dissolution profiles for different dispersions are given in figure-1.

Table 3: Olmesartan medoxomil Solid Dispersions In Vitro Dissolution Parameters

S. No	Solid Dispersions Code	T_{50 (min)}	T_{90 (min)}	DE₃₀%	First Order
S. No	Solid Dispersions Code	T_{50 (min)}	T_{90 (min)}	DE₃₀%	K (min^-1)	R²
1	OPD	˃60	˃60	8.30	0.016	0.994
2	OP1	˃60	˃60	15.00	0.034	0.982
3	OP2	˃60	˃60	21.60	0.041	0.966
4	OP3	˃60	˃60	25.00	0.045	0.989
5	OS1	˃60	˃60	26.60	0.046	0.979
6	OS2	˃60	˃60	33.30	0.059	0.956
7	OS3	3.97	˃60	65.00	0.062	0.973
8	OK1	˃60	˃60	10.00	0.021	0.976
9	OK2	˃60	˃60	28.30	0.053	0.986
10	OK3	3.86	˃60	68.40	0.067	0.991

(a)

(b)

(c)

Figure-1: Dissolution Profiles for Olmesartan medoxomil Solid Dispersions prepared by Physical Mixing, Solvent Evpoartion and Kneading Methods

Characterization Studies:

Selected solid dispersions were optimized through dissolution studies performed and further characterized by FTIR and DSC studies. ^[10]FTIR Spectra and DSC thermograms shown in figures 2 and 3.

FTIR Studies:

(a)

(b)

Figure 2: FTIR Spectra of (a) Pure Drug (b) Optimised Solid Dispersion (OK3)

Table 4: Composition of Various Olmesartan medoxomil Fast Dissolving Tablets

Formulation Code	INGREDIENTS							Total Weight of Tablet (mg)
Formulation Code	OK3 (mg)	SSG (mg)	CCS (mg)	CP (mg)	MCC pH101 (mg)	Magnesium Stearate (mg)	Talc (mg)	Total Weight of Tablet (mg)
OPF	160	----	-----	-----	87.5	1.25	1.25	250mg
OF1	160	5	----	----	82.5	1.25	1.25	250mg
OF2	160	10	----	----	77.5	1.25	1.25	250mg
OF3	160	20	----	----	67.5	1.25	1.25	250mg
OF4	160	----	5	----	82.5	1.25	1.25	250mg
OF5	160	----	10	----	77.5	1.25	1.25	250mg
OF6	160	----	20	----	67.5	1.25	1.25	250mg
OF7	160	----	----	5	82.5	1.25	1.25	250mg
OF8	160	----	----	10	77.5	1.25	1.25	250mg
OF9	160	----	----	20	67.5	1.25	1.25	250mg

Table 5: Evaluation of Olmesartan medoxomil Fast Dissolving Tablets

S. No	Formulation Code	Weight uniformity (mg) (N=20)	Hardness (kg/cm²) (N=3)	Friability (%) loss (N==10)	Drug Content (mg/tablet) (N=10)	Disintegration time (min) (N=6)
1	OPF	248±5	3.5±0.2	0.17	39.23±0.3	3.56
2	F1	248 ± 3	3.5 ± 0.3	0.16	39.10 ± 0.2	2.95
3	F2	248 ± 4	3.5 ± 0.4	0.17	39.10 ± 0.2	2.66
4	F3	250 ± 4	3.5 ± 0.3	0.16	39.64 ± 0.2	2.41
5	F4	248 ± 2	3.5 ± 0.2	0.16	39.90 ± 0.3	1.66
6	F5	250 ± 2	3.5 ± 0.3	0.18	39.74 ± 0.3	1.42
7	F6	249 ± 1	3.5 ± 0.3	0.17	39.82 ± 0.4	1.13
8	F7	250 ± 3	3.5 ± 0.3	0.16	39.10 ± 0.2	2.38
9	F8	251 ± 3	3.5 ± 0.4	0.17	39.10 ± 0.2	2.21
10	F9	251 ± 4	3.5 ± 0.3	0.16	39.64 ± 0.2	2.09

*N= Number of Tablets

In Vitro Dissolution Studies:

The investigation used USP Apparatus Type II to conduct a dissolution test using 900ml of pH 6.8Phosphate buffer as the medium. Samples were drawn during the investigation at different time periods, and the same volume was replaced to maintain sink conditions during the study. The cumulative amount drug dissolved is estimated using UV spectrophotometer at 257nm and calculated the cumulative percentage of drug dissolved. Dissolution studies are conducted for six times on each formulation. ^[12]In vitro dissolution parameters are calculated from data for different tablet formulations. Dissolution profiles of all tablets are given in Figure- 4.

(a)

(b)

(c)

Figure 4: Olmesartan medoxomil Fast Dissolving Tablets Dissolution Profiles

Table 6: In Vitro Dissolution Parameters for Olmesartan medoxomil fast dissolving Tablets

S. No	Formulation Code	T_50(min)	T_90(min)	DE₃₀%	First Order
S. No	Formulation Code	T_50(min)	T_90(min)	DE₃₀%	K (min^-1)	R²
1	OPD	˃30	˃30	8.30	0.016	0.994
2	OPF	˃30	˃30	25.00	0.959	0.972
3	OMF	3.64	20.95	78.30	0.964	0.981
3	OF1	4.21	˃30	60.20	0.987	0.963
4	OF2	4.15	˃30	65.00	0.997	0.941
5	OF3	4.07	˃30	68.00	0.995	0.`980
6	OF4	3.79	˃30	71.60	0.983	0.931
7	OF5	3.69	˃30	73.30	0.989	0.979
8	OF6	3.05	10.42	86.66	0.987	0.996
9	OF7	4.16	˃30	65.20	0.995	0.964
10	OF8	3.99	˃30	66.50	0.998	0.956
11	OF9	3.87	˃30	69.00	0.988	0.932

DISCUSSION OF RESULTS:

The spectrophotometric method for estimating Olmesartan medoxomil in 6.8 Phosphate buffer was linear and reproducible, following Beer's law in the2-10 µg/ml concentration range. Reproducibility of method was tested on six. This method is suitable for the estimation of Olmesartan in dissolution medium.

Olmesartan medoxomil is classified as BCS class II in the biopharmaceutical classification, has low solubility in aqueous fluids. To study its solubility, saturated solubility studies were conducted, revealing its maximum solubility in 6.8 pH phosphate buffer. Hence it is used as dissolution medium for further investigation. Solid dispersions of olmesatan was prepared using physical mixing method, solvent evaporation method, and kneading method using the polymer Soluplus.¹³

Various solid dispersions composition are shown in table 1. The prepared dispersions were evaluated for Carr's index and angle of repose with values ranging from 14.5-15.6% and 24.30-25.70 respectively. The particle sizes ranged from 160-166 µm, and the drug content ranged from 39.29-39.70 mg. All solid dispersions were stable and exhibited good flow properties, meeting specified limits for particle size, Carr’s index, angle of repose and uniformity of content. The physical parameters for all solid dispersions are provided in the table no:2.

In vitro dissolution studies was conducted for various solid dispersions using pH 6.8 Phosphate buffer. Kneading method is found most effective for rapid drug release in solid dispersions like OK3, with a drug and polymer ratio of 1:3. The R² values ranged from 0.956 to 0.994, indicating linearity with a first order rate constant. The order of increasing solubility and dissolution rate was kneading > solvent evaporation > physical mixing. OK3 prepared by the kneading method showed complete solubility enhancement, making it ideal for compression into fast dissolving tablets. In vitro dissolution parameters were provided in table -3 and dissolution profiles are given in figure no:1.

The optimized solid dispersion was chosen from dissolution studies and further investigated for drug-carrier interaction through IR, DSC studies. FTIR spectrum for olmesartan medoxomil, optimized formulation showed same peaks, indicating no drug excipient interactions. DSC analysis was performed pure drug, optimized solid dispersion (OK3) prepared using kneading method. Thermogram of pure drug and optimized dispersion (OK3) exhibit onset of peak at 178. 7⁰c indicating no interaction between the olmesartan and soluplus. IR Spectra, DSC thermograms are presented in figure no:3.

The study selected solid dispersions with a rapid dissolution profile for formulation in to fast dissolving tablets, using super disintegrants like SSG, CCS, and CP. The drug concentration remained constant, while super disintegrant concentration varied for different batches. Direct compression technique was suitable for compression of optimized solid dispersions into tablets. All tablets are compressed under similar conditions to reduce variables during preparation.¹⁴ Different tablet formulations composition was given in table 4.

The study evaluated tablet formulations for physical parameters, revealing that all the formulations were stable and met specified limits according I.P. for drug content ,weight uniformity, dispersion time and friability. Hardness of the tablets ranged from 3-3.5 kg/cm2, with weight uniformity ranging from 248 to 251 mg. Friability loss was negligible, and drug content was uniform for all the tablets with not more than 2.5% variation. Disintegration time was less than 1.13-3.56 min, demonstrating a rapid disintegrating nature. In vitro dissolution showed that all formulations released drug fastly when compared to pure drug. Formulation F6 with CCS showed the fastest release of drug when compared to other tablets and marketed formulations. Drug release in the presence of different superdisintegrants was in the order CCS > CP > SSG.^[15] The first order R² values were linear, with first order rate constants ranging from 0.931 - 0.996. Formulation F6 prepared using CCS was suitable for fast dissolving tablets. The In Vitro dissolution Parameters for different fast dissolving tablets were given in table- 6. Dissolution profiles were shown in figure 4.

CONCLUSION:

The present work found that soluplus is a effective carrier for improving the solubility and dissolution of BCS class II drug olmesartan. Kneading method was found to increase dissolution rate rapidly. Tablets prepared using kneading method dispersions and various superdisintegrants release drug at a faster rate. Cross caramellose sodium being the most effective for faster drug release when compared to others.

ACKNOWLEDGMENT:

The authors express greatfullness to Apotex Pharmaceuticals ltd, for their gift samples and Chebrolu Hanumaiah Institute of Pharmaceutical Sciences, Guntur management for providing necessary facilities for doing the work.

ABBREVIATIONS:

CCS-Croscarmellose Soidium, CP-Crospovidone, DE-Dissolution Efficiency, DSC-Differential Scanning Calorimetry, FDT-Fast dissolving Tablet, FTIR-Fourier Transform Infra Red, IP-Indian Pharmacopoeia, MCC-Micro Crystalline Cellulose, OM-Olmesartan Medoxomil, SSG-Sodium Starch Glycolate.

CONFLICT OF INTEREST:

The authors have no conflict of interest.

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Received on 20.07.2023 Modified on 14.11.2023

Research J. Pharm. and Tech 2024; 17(4):1789-1794.

DOI: 10.52711/0974-360X.2024.00284

S. No

Solid Dispersions code

Carr’s Index (%)

Particle Size (microns)

Drug Content (mg)