An Assessment of Olmesartan Medoxomil Tablet by Inclusion Complex Technique

Deepak Sarangi, Subhashree Mallick, Anjum Ara, Sanjeeb Kumar Sahoo, Rabinarayan Rana

Department of Pharmaceutics, Roland Institute of Pharmaceutical Sciences, Brahmapur, Odisha, India.

*Corresponding Author E-mail: sarangi.dipu@gmail.com

ABSTRACT:

Olmesartan Medoxomil is an AT1 subtype selected angiotensin-II receptor antagonist approved for the treatment of hypertension. It has low water solubility, so the current effort is being made to enhance the solubility of the Olmesartan by inclusion complex and to incorporate them into tablets by direct compression. Complexing agent like Beta cyclodextrin and polyvinyalpyrrolidone has been used for complexation method. FT-IR studies have shown that there is no link between drugs and complexing agents. Among all methods, the inclusion complex (OLBCD 3) containing the drug: Beta cyclodextrin in a 1: 3 ratio showed rapid drug release (87.41% within 30 minutes) and post compression parameters are within limits. All the values obtained from pre compression and post compression parameters meets the legal requirements for tablets. Stability studies of batch no OLBCD 3 shows no significant change. Therefore, it can be concluded that the structure was stable.

KEYWORDS: Solubility, Olmesartan medoxomil, Inclusion complex, Complexation, PVP.

INTRODUCTION:

Dissolution and solubilisation are the two dominant factors to consider in achieving oral therapeutic efficacy^1,2,3. Solubility and dissolution of the poorly soluble drug profile remains a major problem in the development of dosage forms. Many techniques including micronization, nanonization, chemical modification, pH adjustment, solid dispersion, self-emulsification, salt formation, co-solvency, complexation, etc. have been described to overcome the problems associated with formulation of a tablet^4,5,6.

Among these intricacies, the art of complexation is the broadly used technique with simple and less time-consuming. To enhance drug solubility, drug has to be interacting with cyclodextrin that is beneficial due to low hygroscopicity, low toxicity, high fluid, excellent adherence and compression with cyclodextrin improves drug stability in formation, leading to extended shelf life^7,8. The properties of lipophilic drug-cyclodextrin, more commonly known as inclusion complexes, which can be modified by simply adding the drug and the formulation additives, which has led to the drug's stability. Inclusion complexes are constructed by the insertion of a non-polar molecule (known as a guest) into the socket of another molecule (as host). Cyclodextrin molecules are frequently used hosts. Olmesartan Medoxomil is an AT1 subtype selected angiotensin-II receptor antagonist approved for the treatment of hypertension^9,10. The dose of Olmesartan significantly reduces blood pressure through arterial vasodilatation and reduces sodium retention, as do other angiotensin receptor blockers. The half life of Olmesartan is 13 hours and the soluble concentration in water is less than 7.75 μg/ml. Oral bioavailability of tablet detection is only 26% in healthy people due to low water solubility¹¹. In the present study, a research effort was made to increase Olmesartan’s solubility using complexation method and forming conventional tablet formulations to determine which of these ratios exhibited the best liquid solubility and dissolution profile compared to the product being marketed¹².

MATERIALS AND METHOD:

Olmesartan Medoxomil received as a gift sample from Thars Laboratory, Kochi, India. Beta Cyclodextrin, Polyvinylpyrrolidone, Lactose, Microcrystalline cellulose, Magnesium stearate and Purified talc are obtained from SD Fine Chem Ltd, Mumbai. All other materials used are analytical grade.

Compatibility Study using FTIR:

The FT-IR spectra of Olmesartan sample along with complexing agents were obtained on Shimadzu IR Affinity (Japan) having Spectra Manager II software and scanned over the range 400-4000 cm-1. Dry KBr (50 mg) was finely ground in the mortar and samples (1-2 mg) were subsequently added and gently mixed.

Preparation of inclusion complex with complexing agents:

Inclusion complex was concocted by triturating Olmesartan and β-cyclodextrin in ratios 1:1, 1:2 and 1:3 w/w with incorporation of few drops of 40% of ethanol to form a paste in a separate china dish. Then solvent was allowed to evaporate at 40⁰C to form a dry solid mass, which was further crushed to fine particles and passed through sieve no.60 and kept in a desiccators for further use. Same process is followed for Polyvinylpyrrolidone (PVP) inclusion complex.

Table 1: Formulation design of inclusion complexes

Formulation Code	Drug: ß-Cyclodextrin	Drug: PVP
OLBCD 1	1:1
OLBCD 2	1:2
OLBCD 3	1:3
OLPVP 1		1:1
OLPVP 2		1:2
OLPVP 3		1:3

Summarization of prepared inclusion complexes:

Solubility studies:

Solubility of pure drug, processed inclusion complexes were studied by adding excess amount in various solvents like water, phosphate buffer pH 6.8 and methanol separately. The mixtures were consigned to the mechanical agitation for 48 hours in isothermal shaker at 25±1⁰C followed by the filtration through Watmann's filter paper and determined by UV spectrometer at λ _max 257nm.

Drug content:

All the prepared inclusion complexes formulations equivalent to 20mg of Olmesartan were weighed accurately and dissolved in 100ml of phosphate buffer pH 6.8 in a separate volumetric flask. The solution was filtered, diluted suitably with same solvent and analyze the drug content using UV spectrophotometer at λ_max 257nm.

Preparation of Olmesartan Tablet using inclusion complex:

The tablet containing equivalents to 20mg of Olmesartan were prepared by direct compression method as per the formula given in Table 2.

Table 2: Formulation of Olmesartan Tablet with inclusion complexes

Ingredients	OLBCD 1 (mg)	OLBCD 2 (mg)	OLBCD 3 (mg)	OLPVP 1 (mg)	OLPVP 2 (mg)	OLPVP 3 (mg)
Drug: ß-Cyclodextrin (Eq. to 20mg)	80	80	80
Drug: PVP (Eq. to 20mg)				80	80	80
Lactose	26	26	26	26	26	26
Microcrystalline cellulose	2	2	2	2	2	2
Magnesium stearate	1	1	1	1	1	1
Purified talc	1	1	1	1	1	1
Total weight (mg)	110	110	110	110	110	110

Evaluation of Tablets:

Pre compression parameters such as bulk density, tapped density, Hausner's ratio, Carr's compressibility index and angle of repose were evaluated for blended powders. Further post compression parameters like weight variation, hardness, friability, disintegration and in vitro dissolution studies were evaluated for prepared tablets.

In vitro drug release:

Dissolution study of marketed tablet as well as the tablet prepared from formulations was carried in USP II apparatus by keeping 900ml of 6.8 pH Phosphate buffers as a dissolution medium. The paddles were operated at 100rpm with 37±1⁰C of maintained temperature. The sample of 5ml were withdrawn at 15, 30, 45, and 60 min and replaced with equal volume of dissolution medium. The withdrawn samples were diluted with same dissolution medium and the amount of drug dissolved was estimated by UV spectrophotometer at 257nm. Then the release data were fitted into various mathematical models like zero order, first order, Higuchi and Korsmeyer-Peppas. Regression analysis was performed by using excel software on the in vitro release data to best fit into various kinetic models according to the regression coefficient 'r'

Stability study:

The optimized formulation was subjected for three months study according to standard guidelines. The selected formulation was packed in aluminium foil and kept tightly closed in a wide mouth bottle and stored at 40⁰C / 75% RH for 3 months and evaluated periodically

RESULTS AND DISCUSSION:

Infra-red spectrum of drug and mixture of drug-polymers were determined by KBr disks method. Samples were prepared with KBr disks.

From Fig. 1, 2 and 3 characteristic peaks of Olmesartan medoxomil were present in the spectrum of drug and polymer mixture, indicating compatibility between drug and polymer. The spectrum confirmed that there was no specific change in the chemical integrity of the drug. There was no change in functional group peaks of Olmesartan medoxomil in all the IR-spectra.

Table 3: Drug content of Prepared formulations

Sl. No	Formulation Code	% Age of drug content
1	OLBCD 1	97.12
2	OLBCD 2	98.24
3	OLBCD 3	98.69
4	OLPVP 1	97.62
5	OLPVP 2	98.37
6	OLPVP 3	97.21

Table 4: Precompression Parameters

Name of parameters	OLBCD 1	OLBCD 2	OLBCD 3	OLPVP 1	OLPVP 2	OLPVP 3
Bulk density (gm/cc)	0.495	0.435	0.552	0.437	0.337	0.437
Tapped density (gm/cc)	0.612	0.692	0.659	0.699	0.599	0.649
Hausner’s Ration	1.132	1.232	1.168	1.632	1.832	1.682
Carr’s index (%)	14.95	14.65	15.12	14.85	14.95	14.75
Angle of repose (degrees)	17	17	18	17	17	17

Table 6: In vitro drug release profile

Time (minute)	OLBCD 1	OLBCD 2	OLBCD 3	OLPVP 1	OLPVP 2	OLPVP 3	Marketed Product
15	12.48	13.32	14.35	10.39	13.39	9.39	14.25
30	45.35	47.86	54.67	39.78	49.78	31.78	52.47
45	68.87	67.49	78.96	65.13	55.13	67.13	72.96
60	87.41	88.17	97.12	82.14	84.14	85.14	93.39

Percentage of drug content estimation of all formulations was conducted by using UV spectrophotometer. The absorbance’s were measured and percentage of drug content was estimated. Percentage drug content of all formulations were found in the range of 97.12%-98.69% which was within the pharmacopoeia limits and shown in Table 3.

The pre-compression of formulated powders are taken for the testing and is found to be within the limit and tabulated in Table 4.

Fig.4. In-vitro drug release according to time

CONCLUSION:

In this current study, an endeavour has been made to enhance the solubility and dissolution rate of poorly water-soluble drug Olmesartan Medoxomil by complexation. Hence compressing the prepared formulations into tablets by direct compression method and formulations procedures were simple, inexpensive and less time consuming. FT-IR studies endorsed no significant interactions between drug and excipients. Drug content estimation for all formulations complies within the standard range. In vitro release study of all formulations showed increase in percentage drug release than that of marketed drug and among the formulations, OLBCD3 showed higher percentage of drug release. Both the pre compression and post compression parameters of the prepared tablets were evaluated and the results were obtained within the standard range. The tablet prepared from OLBCD3 formulation showed 97.12 % of drug release where as the marketed tablet showed 93.39% drug release in 60 minutes. The drug release pattern showed first order kinetics model following Super case II drug release mechanism. Stability study of formulation showed no significant changes in physical properties of tablets within the stipulated period.

DECLARATION OF INTEREST:

The authors do not have any conflict of interest.

ACKNOWLEDGEMENT:

The authors are thankful to the teaching and non teaching staffs, Lab Heads of Roland Inst. of Pharmaceutical Sciences for their cooperation during the research work.

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Received on 10.04.2021 Modified on 26.04.2021

Res. J. Pharma. Dosage Forms and Tech.2021; 13(3):193-197.

DOI: 10.52711/0975-4377.2021.00034