INTRODUCTION:

Sustained release formulations describe the slow release of a drug substance from a dosage form to maintain therapeutic response for extended period (8-12 h) of time. In long term therapy for the treatment of chronic disease conditions, conventional formulations are required to be administered in multiple doses and therefore have several disadvantages.

Sustained release formulations are preferred for such therapy because they maintain uniform drug levels; reduce dose and side effects, show better patient compliance, and increase the safety margin for high potency drugs. Introduction of matrix tablets as sustained release has given a new breakthrough for Novel Drug Delivery System (NDDS) in the field of pharmaceutical technology. The hydrophilic polymer matrix is widely used for formulating a sustained release dosage form. Drug release retardant materials are the key performers in the matrix systems. Natural polymers are economical, readily available, non-toxic and capable of chemical modifications, potentially biodegradable and biocompatible. Losartan Potassium (LP) is a potent, highly specific Angiotensin II Type 1 (AT1) receptor antagonist with antihypertensive activity. It is readily absorbed from the gastrointestinal tract with oral bioavailability of about 33% and a plasma elimination half- life ranging from 1.5 to 2.5 h. Administration of LP in a sustained release dosage form with an extended release over 8 -12hrs, would be more desirable as these characteristics would allow a rapid onset followed by protracted anti-hypertensive effects by maintaining the plasma concentrations of the drug well above the therapeutic concentration, thus minimizing the need for frequent administration and dose related side effects [1].

MATERIALS AND METHODS:

Materials:

Losartan potassium is obtained as gift sample from ApogenPharmaPvt Ltd., Bapatla. Guar gum, Xanthan, Gum karaya, Gum kondagogu, Olibanum were purchased from Girijan Cooperative Corporation LTD, Tirupathi. MCC was received from Fisher scientific. Magnesium stearate and Talc were procured from SD Fine chemicals Ltd. All the chemicals and reagents used in this investigation were of analytical grade.

Methods:

Chemical modification of selected gum:

1. Carboxymethylation of Guar Gum:

Carboxymetylation of Guar gum was performed by following the procedure as suggested by S. Kamel, N. Ali et.,,al., [2].

2. Carboxymethylation in solid phase (solvent free method):

Carboxymetylation in soild phase was performed by following the procedure as suggested by K.J.Edger, C.M.Buchananet.,al.,[3].

3. Cross linked Guar gum:

Crosslinking of Guar gum was performed by following the procedure as suggested byMr. S.N.Nemade, Ms. Sweetiet.,al.,[4].

4. Cross linked Guar gum-Films:

Crosslinking of Guar gum was performed by following the procedure was as suggested by Mr. S.N.Nemade, Ms. Sweetiet.,al.,,[4].

Rheological studies on polymers [5, 6]:

Preparation of sample solution:

One gram of Guar gum was dissolved in 100ml of water (1%w/v) and allowed to stand for overnight, and then the viscosity of sample dispersions was analysed by using cup and bob type Brookfield viscometer. The same process was repeated for all the remaining polymers used in this investigation.

Determination of viscosity:

A digital Brookfield viscometer (Cup and Bob type) was used for this study. It measures the torque required to rotate an immersed spindle in a fluid. The instrument features a rotating spindle with multiple speed transmission and interchangeable spindles that measures a variety of viscosity ranges. Different sample dispersions (1% w/v) of gum mucilage were prepared in 100ml beaker and about 8ml of sample solutions were taken in a small sample adaptor. Now the spindle groove (SC4 - 18) was immersed in the fluid and the speed of rotation was varied from 0.25 to 1.50 in order to determine it shear stress. Shear rate, shear stress, viscosity of different samples were noted against the corresponding speed of rotation.

Preformulation studies on Losartan Potassium:

Fourier Transform Infrared Spectrophotometer (FTIR):

Losartan Potassium - selected excipients and mixtures were subjected to IR spectral study in order to detect the interactions between the drug and selected inactive ingredients. The drug excipients mixtures were prepared by blending the drug and excipients in 1; 1 ratio. The resulting blend was transferred into a vial and sealed properly. Such sealed vials were kept in a stability chamber and maintained at 40 ± 0.2⁰C, 75 ± 0.5% RH. The vials were stored for a period of 1 month. The samples were withdrawn and subjected to IR studies by KBR pellet technique.

The physicochemical compatibility between Losartan Potassium and excipients (Guar gum, CMGG, CMGG-I_2,BG-C, BG-F) used in this work were carried out by subjecting to IR spectral studies by using Perkin Fourier Transform Infrared spectrophotometer, (Shelton USA). The samples were scanned with in the wave length region between 3923cm^-1 to 665cm^-1. The spectra obtained for Losartan Potassium and physical mixtures Losartan Potassium blended with the selected components were compared.

Preparation of Losartan Potassium sustained release tablets by wet granulation method:

Accurately weighed quantities of the drug, polymer (selected gums) and modified gums were mixed in a polybag and then taken into a glass mortar and then wetted with isopropyl alcohol (IPA) as granulating fluid. The cohesive mass was then passed through mesh no. #40. The granules obtained were dried in a hot air oven and maintained at a temperature not more than 50⁰ C for about 45min. The granules were then passed through sieve no.# 24 to separate fines. Based on the drug content, granules were weighed and required quantities of MCC, talc and magnesium stearate were added and compressed into tablets with 16 station rotary tableting machine (Cadmach machinery, Ahmedabad, India) using 9mm round punches to the required hardness.

Evaluation of modified release tablets:

1) Pre-compression parameters:

Losartan Potassium granules formulated with selected and modified gums were evaluated for various pre-compression parameters like bulk density, tapped density, carr’s index and Hausner’s ratio as per the standard procedure reported in literature [7, 8].

2) Post-compressionparameters:

The formulated tablets were characterized for hardness, friability, weight variation, drug content and swelling index.

a) Thickness: of tablets was measured by using verniercaliper.

b) Hardness and Friability: was measured by using Monstanto hardness tester (Cadmach, Ahmedabad, India) and the Roche friabilator (Electro lab, Mumbai, India).

c) Weight variation:

Twenty tablets were collected and were weighed collectively and individually. From the collective weight, average weight was calculated. The per cent weight variation was calculated by using the following formulae.

% weight variation = [Average weight – Individual weight] / Average weight × 100

d) Drug content determination:

Five tablets were collected, powdered and powder containing the equivalent to 100mg of drug was dissolved in 100ml of buffer (water). Then the solution was filtered, suitably diluted and analysed for Losartan Potassium by measuring the absorbance spectrophotometrically at 254nm.

e) Swelling index:

The swelling capacity of a polymer is determined by the amount of liquid material that can be absorbed. Formulated tablets were weighed individually (W₁) and transferred into different beakers containing 100ml of water. After every 2hrs time interval the tablets were removed from the beaker carefully and excess surface water was removed with the help of blotting paper. The swollen tablets were then reweighed (W₂) and the % of swelling capacity were determined by using the following formulae. The swelling index was observed for a period of 24hrs.

Swelling index (%) = [Final weight (W₂) – Initial weight (W₁)] / Initial weight (W₁)×100.

3) In vitro dissolution studies of formulated tablets [9]:

In vitro dissolution studies for losartan potassium sustained release tablets were performed in water by using USP type II dissolution test apparatus with paddle stirrer, the stirring speed employed was 100rpm and the temperature was maintained at 37 ± 0.5⁰C. Samples were withdrawn at different time intervals and replaced with fresh dissolution medium, solutions were filtered and determined for losartan potassium content by UV- Spectrophotometer at 254nm.

4) Kinetic studies [10 - 12]:

The in-vitro release data was subjected to zero order, first order, Higuchis, Korsemeyer- Peppas and Hixson crowell mathematical model in order to establish the drug release mechanism and kinetics of drug release from the modified release tablets.

5) Similarity factor analysis (f₂):

To determine the similarity factor, in-vitro release profile of all the formulated tablets was compared with the theoretical release profile. If f₂> 50, it is considered that the products share similar drug release behaviors’. The data was analyzed by using the following formulae.

f₂= 50 log{1+(1/n)ƹ(R_i– T_i)2] – 0.5 × 100

Where n = number of time points, R_i and T_i are dissolution of reference and test products at time.

RESULTS AND DISCUSSION:

The rheological study on selected gums and modified gums was carried out by employing Brookfield viscometer. Based on the rheograms (figure no: 1 to 3), it was observed that the aqueous dispersions of Guar gum and Xanthan gum exhibited plastic flow and the remaining gum dispersions (Gum karaya, Gum kondagogu, Gum Olinanum CMGG, CMGG-I, BG-C and BG-F) exhibited pseudo plastic flow within the applied shear rate (table no: 1).All the tablets formulated with wet granulation technique using natural and modified gums found to be satisfactory (table no: 2).The micromeritic properties of Losartan Potassium granules formulated with selected, modified exhibited good flow characteristics (table no: 3).The drug and the gum blends were subjected to IR- spectra studies to notice the drug excipient interactions (if any). The principle peaks observed with the losartan potassium were also noticed with the blends and hence these results clearly demonstrated that the losartan is compatible with selected, modified gums and the blends can be used to develop losartan potassium sustained release tablets (figure no: 4 to 15). All the formulated tablets (F1 to F9) were evaluated for thickness, hardness, friability, weight variation and drug content. The formulated tablets satisfied all the quality control requirements and found to be within limits (table no: 4).

All the formulated tablets (F1 to F9) were subjected to In vitro drug release studies and the results were shown in (figure no: 16, 17). The drug release from the formulations with selected gums (F1 to F5) followed zero order release kinetics where the remaining formulations with modified gums (F6 to F9) followed 1^st order release kinetics.The value of “n” as estimated for selected gums by linear regression of log Q_t / Q_∞vs log t of formulations (F1, F4, F5) was 0.57, 0.98, 0.73 indicated that drug release from tablets followed Anomalous (non-fickian) diffusion, whereas the remaining formulations (F2, F3) was 1.02, 1.01 indicated that the drug release from the tablets followed case ii type of mechanism (table no: 5). The value of “n” as estimated for modified gums by linear regression of log Q_t / Q_∞vs log t of formulation (F6) was 0.61 indicated that drug release from tablets followed Anomalous (non-fickian) diffusion, whereas the remaining formulations (F7, F8,F9) was 0.45, 0.177, 0.22 indicated that the drug release from the tablets followed Anomalous (Fickian) diffusion (table no: 5). The release data observed from all the formulated tablets (F1 to F9) were compared with the theoretical release profiles and patented losartan potassium sustained release tablets (Formulation and In-vitro evaluation of sustained release matrix tablets of Losartan Potassium, PHARMANEST- International journal of Advances in pharmaceutical sciences, Jan- Feb- 2011, Vol-2, 1). From the observed results the formulations F1and F6 has similarity factor greater than 50 and satisfied all the requirements (table no: 5).

CONCLUSION:

The formulations prepared with 100% W/W Guar gum satisfied all the Quality control requirements and provided required release of Losartan Potassium for sustained release formulations.

ABBREVATIONS:

CMGG- Carboxy methylated Guar gum, CMGG-I – Carboxy methylated Guar gum –Iodine, BG-C – Borax Guar gum crosslinked, BG-F – Borax Guar gum films.

Table no 1.Rheological properties observed from selected and modified gums:

Polymer	Viscosity (cp)	Shear Stress (D/cm²)	Shear Rate (1/Sec)	Correlation coefficient (r) value
Polymer	Viscosity (cp)	Shear Stress (D/cm²)	Shear Rate (1/Sec)	Newtonian	Bingham law	Power Law
Guar gum	1469	4.32 7.36 13.54 22.80 27.28	0.33 0.66 0.99 1.35 1.65	0.9808	0.861	0.9806
Xanthan gum	1292	4.71 7.56 11.72 17.46 23.28	0.33 0.66 0.99 1.35 1.65	0.979	0.901	0.971
Gum Karaya	1262	6.14 9.62 14.06 15.32 15.72	0.33 0.66 0.99 1.35 1.65	0.901	0.910	0.968
Gum kondagogu	1182	5.82 8.89 12.91 14.61 14.81	0.33 0.66 0.99 1.35 1.65	0.916	0.915	0.973
Olibanum gum	1398	5.19 9.30 16.07 18.85 18.96	0.33 0.66 0.99 1.35 1.65	0.913	0.877	0.971
CMGG	1296	5.03 8.79 13.70 17.06 18.65	0.33 0.66 0.99 1.35 1.65	0.977	0.935	0.994
CMGG- I	1238	5.19 8.71 11.92 16.35 18.09	0.33 0.66 0.99 1.35 1.65	0.992	0.972	0.996
BG- C	1714	8.20 10.65 16.65 23.68 28.03	0.33 0.66 0.99 1.35 1.65	0.983	0.921	0.987

Table no 2. Composition of Losartan Potassium formulated with selected and modified gums:

	Quantity mg per tablet
Ingredients	F1	F2	F3	F4	F5	F6	F7	F8	F9
Losartan potassium	100	100	100	100	100	100	100	100	100
Guar gum	100	-	-	-	-	-	-	-	-
Xanthan	-	100	-	-	-	-	-	-	-
Gum karaya	-	-	100	-	-	-	-	-	-
Gum kondagogu	-	-	-	100	-	-	-	-	-
Olibanum	-	-	-	-	100	-	-	-	-
CMGG	-	-	-	-	-	100	-	-	-
CMGG-I	-	-	-	-	-	-	100	-	-
BG-C	-	-	-	-	-	-	-	100	-
BG-F	-	-	-	-	-	-	-	-	100
MCC	-	-	-	-	-	100	100	100	100
Magnesium stearate	5	5	5	5	5	5	5	5	5
Talc	5	5	5	5	5	5	5	5	5
Total weight	210	210	210	210	210	310	310	310	310

Table no 3. Micromeritic properties observed from Losartan potassium granules formulated with selected and modified gums:

Gum	Bulk density (gm /ml)	Tapped density (gm /ml)	Carr’s index (%)	Hausner’s ratio (%)
Guar gum	0.750 ± 0.14	0.900 ± 0.44	16.6 ± 1.08	1.21 ± 0.05
Xanthan	0.666 ± 0.25	0.800 ± 0.32	16.6 ± 1.03	1.20 ± 0.02
Karaya	0.454 ± 0.36	0.526 ± 0.46	13.6 ± 1.07	1.15 ± 0.06
Kondagogu	0.500 ± 0.41	0.588 ± 0.26	15.0 ± 1.02	1.17 ± 0.04
Olibanum	0.434 ± 0.21	0.500 ± 0.55	13.0 ± 1.07	1.15 ± 0.07
CMGG	0.434 ± 0.36	0.526 ± 0.46	17.3 ± 1.02	1.21 ± 0.05
CMGG-I	0.434 ± 0.42	0.500 ± 0.35	13.0 ± 1.05	1.15 ± 0.01
BG-C	0.476 ± 0.31	0.555 ± 0.39	14.2 ± 1.03	1.16 ± 0.04
BG-F	0.454 ± 0.14	0.526 ± 0.31	13.6 ± 1.05	1.15 ± 0.022

Table no 4. Physical characters observed from losartan potassium tablets formulated with selected and modified gums:

Formulation code	Hardness (kg/cm²)	Thickness (mm)	Average weight (mg)	Friability (%)	Drug content (%)	Swelling Index (%)
F1	4 ± 0.12	3.27 ± 0.03	213.6 ±0.14	0.497± 0.02	99.2 ± 0.24	565.35
F2	4 ± 0.08	3.35 ± 0.08	212.5± 0.23	0.493± 0.04	96.6 ± 0.16	73.4
F3	3.5 ±0.23	3.41 ± 0.04	212.5± 0.23	0.605 ±0.08	95.5 ± 0.12	---------
F4	3.5 ±0.17	3.46 ± 0.07	211.6± 0.01	0.609± 0.01	95.5 ± 0.45	----------
F5	3.8 ±0.12	3.34 ± 0.06	213.5± 0.01	0.491± 0.12	96.2 ± 0.32	46.01
F6	3.7 ± 0.14	4.11 ± 0.01	312.8 ±0.26	0.740 ±0.1	95.8 ± 0.6	75.85
F7	3.5 ± 0.32	4.17 ± 0.03	312.3 ±0.15	0.745± 0.09	95.1 ± 0.3	60.9
F8	4 ± 0.14	4.09 ± 0.05	312.6 ±0.09	0.330 ±0.32	97.2 ±0.8	200.5
F9	4 ± 0.19	4.13 ± 0.09	312.6 ±0.09	0.275± 0.19	98.4 ± 0.5	212.5

Table no 5. Release kinetics observed from losartan Potassium formulated with selected and modified gums:

	Correlation coefficient (r) value
Formulation code	Zero order	First order	Higuchic’s	Peppa’s	T₅₀	F₂	Diffusion Exponent n value
F1	0.956	0.854	0.9837	.9866	5.4	79.4	0.5773
F2	0.952	0.911	0.8783	0.8978	2.2	31.6	1.0156
F3	0.945	0.905	0.8701	0.8903	2.1	29.8	1.0238
F4	0.942	0.907	0.8718	0.8941	2.2	27.9	0.988
F5	0.950	0.935	0.9773	0.9763	4.4	46.8	0.733
F6	0.893	0.9073	0.9919	0.9922	3.2	51.5	0.612
F7	0.751	0.9609	0.9613	0.9784	2.0	34.0	0.458
F8	0.313	0.9620	0.9051	0.9835	0.3	22.6	0.177
F9	0.507	0.9644	0.9198	0.9952	0.2	18.1	0.222

Fig no 3.Rheograms of CMGG, CMGG-I and BG-C:

Fig no 4.FT- IR spectra of Losartan potassium:

Fig no 5.FT-IR spectra of guar gum:

Fig no 6.FT-IR spectra of CMGG:

Fig no.7.FT-IR spectra of CMGG-I:

Fig no 9. FT-IR spectra of BG-F

Fig no 10. FT-IR spectra of BG-C:

Fig no 11.FT-IR spectra of Losartan potassium + Guar gum:

Fig no 12. FT-IR spectra of Losartan potassium + CMGG:

Fig no 13.FT-IR spectra of Losartan Potassium + CMGG-I:

Fig no 14.FT-IR spectra of Losartan Potassium + BG-C:

Fig no 15.FT-IR spectra of Losartan Potassium + BG-F:

Fig no 16.In vitro release profiles observed from losartan potassium tablets formulated with selected Gums:

Fig no 17.In vitro release profiles observed from Losartan potassium tablets formulated with chemically modified Gums:

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Received on 30.06.2018 Modified on 01.08.2018

Res. J. Pharma. Dosage Forms and Tech.2018; 10(3):149-156.

DOI: 10.5958/0975-4377.2018.00023.X