INTRODUCTION:

Since 1906, starch form maize and potato has been used in pharmaceutical industry as disintegrant in tablet formulations [1,2]. It can also be used as a binder, filler and diluents. The wide range of application of starch in this field is due to its physiochemical properties and inertness making it compatible in many oral drug formulations [3]. Disintegrant acts by causing the tablet to break into small pieces in the presence of water thus leading to rapid release of drug which results in higher surface area for drug dissolution and absorption [1,4]. Fast disintegrating tablet (FDT) is one of the popular novel drug delivery system that emphasizes the characteristic of disintegrant. The tablet would disperse and dissolved in the mouth without the need of excess water [5].

This formulation is design to ease the administration of drug and increase medicine compliance among patients that are having difficulty to swallow especially among pediatrics and geriatrics.

Losartan Potassium is an angiotensin II receptor antagonist with anti hypertensive activity. It belongs to class 1 of Biopharmaceutical Classification System (BCS). It is readily absorbed from the GI tract following oral administration but the bioavailability is about 33% due to substantial first-pass metabolism. C_max occurs at about 1hr after an oral dose and has short terminal elimination half-life is about 1.5 to 2hrs respectively, thereby requiring two to three times daily dosing in large number of patients, which often leads to non-compliance [6].

A hypothesis that legume starch has the ability to be disintegrant has been proven through a comparison study on a pea starch with few other conventional natural starches. Based on the study, 5% of pea starch concentration is enough to produce a short time disintegrating tablet and they concluded it can be used as an alternative natural disintegrant apart from maize and potato starch [7].

Chickpea (Cicerarietinum) is belongs to the family Fabaceae which is the same family as pea starch. A comparison study on properties of pea starch and chickpea starch has also been made and they found that chickpea starch has good granule swelling compared to pea starch which is a very important characteristic of a disintegrant [8]. One of the mechanisms of disintegrant is through the swelling of the granule of the starch which allows the tablet to break into fragments. The chickpea starch is digestible by enzyme in the gastrointestinal system making it edible and safe to be consumed [8]. It also has high starch yield when compared to other pulse seed such as pea, lenthil and faba bean with concentration of starch of 50.4% of its total carbohydrates content [9]. Chickpea is also considering to be an economic source of staple food in some part of the world and thus making it a cheap alternative natural disintegrant when compare to other semi-synthetic disintegrant such as crospovidone, sodium glycolate and alginic acid which is more expensive.

In this research, Losartan potassium is used as model drug which is an antihypertensive drug. This study was intended to evaluate the influence of natural starch from Cicerarietinum as disintegrant in Losartan Potassium Fast Disintegrating Tablet can offer advantages over conventional formulation in terms of convenience, side-effect profiles, efficacy, and/or a fast onset of action.

MATERIALS AND METHODS:

Materials:

Crospovidone, Chickpea starch, Losartan potassium (pure), lactose, Microcrystalline cellulose (MCC), povidone, magnesium Stearate, sodium hydroxide (NaOH), potassium dihydrogen phosphate (KH₂PO₄)

Methods:

Preformulation studies of powder extracted from chickpea starch:

Starch powder extracted from chickpea (Cicer arietinum) was evaluated for flow properties including bulk density (𝝆 bulk), tapped density (𝝆tapped), compressibility index [1] and Hausner ratio.

Bulk density (𝝆 bulk):

Bulk density was determined by pouring gently about 35 grams of chickpea starch powder through glass funnel into a 100 ml clean dry graduated measuring cylinder. The volumes occupied by the powder were recorded. Bulk density was calculated

Bulk density (g/cm3) =

Tapped density (𝝆tapped):

Tapped density of the chickpea starch powder was determined by using tapped density tester. The cylinder was tapped for 100 times. Volume occupied after tapping were recorded. Tapped density was calculated

Tapped density (g/cm3) =

Compressibility index and Hausner ratio:

The bulk density and tapped density were then further calculated for compressibility index and Hausner ratio to evaluate the flow property of the chickpea starch powder.

Compressibility Index = 100 x

Hausner ratio =

Formulation of fast disintegrating tablet of Losartan potassium:

Fast disintegrating tablets (FDT) of Losartan potassium were prepared by direct compression method using two different disintegrants of various concentration of crospovidone (super disintegrant) and chickpea starch powder as shown in Table 01 and Table 02. All the ingredients of the fast disintegrating tablet of Losartan potassium were weighed and passed through 500 micron sieve. The ingredients were then blended in small pouch to obtain uniform mixing. After sufficient mixing of the drug and other components, magnesium Stearate was finally added and mixed lightly. The blended materials were then compressed using 10 rotating tableting machine of 8 mm diameter punches. The tablets were individually compressed to an average weight of 150 mg. 10 tablets of each formulations were prepared.

Table 01: Formulation design of fast disintegrating tablet of Losartan potassium with crospovidone as disintegrant.

Ingredients (mg)	Formulation code
Ingredients (mg)	LCP01	LCP02	LCP03
Losartan	50	50	50
Crospovidone	22.5	15	7.5
Povidone	15	15	15
Microcrystalline Cellulose	61	68.5	76
Lactose	-	-	-
Magnesium stearate	1.5	1.5	1.5
Total weight	150	150	150

Drug-Excipient compatibility studies:

To study the compatibility of Losartan potassium with other components of the fast disintegrating tablets including the disintegrants, Fourier transform infrared spectroscopy (FTIR) and Differential scanning calorimetry (DSC) studies were done.

Fourier-Transform Infrared (FTIR) studies:

Pure Losartan potassium and physical mixture of losartan potassium and disintegrants were subjected for FTIR analysis using Fourier Transformer Infrared Spectrophotometer (8400S, Shimadzu, Japan). The samples were prepared on KBr-press and scanned over wave number range of 4000 to 400 cm^-1 and the obtained spectra were analysed for functional groups of drug and interactions with disintegrants.

Differential Scanning Calorimetry (DSC):

DSC studies were performed on pure Losartan potassium, crospovidone; chickpea starch powder, lactose and optimized formulations of Losartan-crospovidone and Losartan-chickpea starch. Accurately weighted samples (3-10 mg) were sealed in flat bottomed aluminium pans and heated in the differential scanning calorimeter (Mettler-Toledo DSC machine). A temperature range of 10^oC to 270^oC was used and the heating range was 10^oC/min.

Evaluation of physiochemical characteristics of Losartan potassium fast disintegrating tablets:

Hardness:

The hardness of the tablet was determined by placing each tablet diagonally between two plungers of tablet hardness tester. Required pressure was applied until the tablet broke down into two parts completely. The reading on the scale was noted down in kg/cm². For adequate mechanical stability, 2-4 kg/cm² hardness was set.

Weight variation:

Weight variation test was done as per standard procedure. Ten tablets from each formulation were weighed using an electronic balance and the average weight was calculated. The results are shown in Table 03.

Thickness:

The thickness of four tablets were randomly selected tablet from each formulation was determined in mm using a vernier calliper. The average values were calculated. The results are presented in Table 03.

Friability:

The friability of tablets using 20 tablets of the best formulations were measured using a Roche Friabilator. Tablets were pre-weighed and rotated at 25 rpm for 4 minutes (100 revolutions). Tablets were then taken out and reweighed. The percentage of friability was calculated based on the loss in weight as given in the equation below. The weight loss should not be more than 1% to pass the test.

Disintegration time:

The disintegration time for fast disintegrating tablet was measured using the conventional test for tablets as described in the pharmacopoeia. Tablets were placed in disintegration tubes and time required for complete disintegration, that is without leaving any residues on the screen is recorded as disintegration time.

Determination of maximum wavelength [2]:

Standard stock solution:

50mg of pure Losartan potassium was dissolved in phosphate buffer pH 6.8 to 100ml (500μg/ml primary stock solution) and 1 ml of it was diluted to 50 ml with the same medium to obtain a sample of concentration 10μg/ml. The absorbance was observed and the maximum wavelength was found to be λ=206 nm.

Procedure for calibration curve:

In to a series of 10ml volumetric flask, dilution of stock solution (10μg/ml) was done. 5 different concentration of solutions (2, 4, 6, 8, and 10µg/ mL) were produced from the serial dilution. The absorbance was measured at λ=206 nm using pH 6.8 phosphate buffer as blank. Calibration curve was then plotted for concentration of Losartan potassium vs. measured absorbance was measured at 206 nm using Elico-SL159 UV/Vis spectrophotometer as shown in Figure 01.

Dissolution studies:

Dissolution studies were done to study percentage of drug release on each formulation. 2 tablets of each formulation was used. The studies were done using USP paddle method (Apparatus 2). The vessels were filled with 900ml of 6.8 pH phosphate buffer as medium. The paddles were rotated at 75 rpm at 37±5 0 C. Sample (5ml) of the solution was periodically withdrawn from the dissolution apparatus at 5, 10, 20, 30, 45 and 60 minutes. The samples were replaced with fresh dissolution medium of same quantity. Absorbance of these solutions was measured at 206 nm using Elico-SL159 UV/Vis spectrophotometer. The percentage of drug release was calculated using an equation obtained from a standard curve and results are presented in Figure 01, Figure 02 and Figure 03.

RESULTS AND DISCUSSION:

This study was undertaken with the aim of characterizing Starch powder extracted from Chickpea (Cicerarietinum) and to study the effect of chickpea starch as disintegrating agent on release of Losartan potassium fast disintegrating tablets. Losartan potassium fast disintegrating tablets were prepared using direct compression method with addition of various concentration of two different type of disintegrant which are chickpea starch and crospovidone. Crospovidone is a super disintegrant which act as a guide to know whether chickpea starch exhibiting the same disintegration property.

Preformulation studies of powder extracted from chickpea starch

Losartan potassium was characterized for flow properties by measuring the bulk density, tapped density, compressibility index and Hausner ratio. The results are shown in Table 03. According to USP scale of flowability, the starch powder extracted from chickpea falls under very, very poor flow character. [3] This matter can be resolves by using lubricant. In this study, the flowability of the starch powder was improved by using Magnesium stearate.

Table 03: Results of preformulation studies of powder extracted from chickpea starch

Preformulation Studies	Result
Bulk density (g/cm³)	0.4621
Tapped density (g/cm³)	0.7407
Compressibility index	1.6029
Hausner ratio	60.2900

Drug-Excipient compatibility studies:

Fourier-Transform Infrared (FTIR) studies

Figure 01 shows the FTIR spectra of pure Losartan potassium, physical mixture of Losartan potassium + crospovidone, physical mixture of Losartan potassium + chickpea starch. FTIR spectra of all combinations containing physical mixture of drug and the disintegrants showed characteristics peaks approximately the same as that of the pure drug. The spectrum of pure Losartan potassium shows some characteristics peaks at 715.61cm^-1& 669.32cm^-1 due to C-Cl bond, 1460.16cm^-1due to N=N stretching, 1629.9cm^-1& 1637.62cm^-1 due to C=C bond, 2929.97cm^-1& 2870.17cm^-1due to C-H bond and 3379.40cm^-1& 3213.51cm^-1 due to O-H bond. It was observed that there was no appearance of new peaks and no major shifts in peak of the spectrums. This indicate there was no interaction between the drug and disintegrants used.

Figure 01: FTIR spectrums of Losartan potassium (A), Losartan potassium + chickpea starch (B) , Losartan potassium + crospovidone (C) and combination of all spectrums (D)

Differential Scanning Calorimetry (DSC)

DSC was performed to characterize thermal changes in the melting point of Losartan potassium with other excipients presents in different formulation.Based on the thermograms obtained from the DSC studies as shown in Figure 02 and Figure 03 there were a sharp endothermic peak at 67.40 ̊ C for Losartan potassium, a broad endothermic peak at 87.59 ̊ C for Crospovidone, a broad endothermic peak at 78.37 ̊ C for Chickpea starch, and a sharp endothermic peak at 146.41 ̊ C for lactose. The melting point of the drug, disintegrants and diluents of the optimized formulation did not display a major change and thus, this indicates that there is no apparent possible interaction.

Figure 02: DSC thermograms of pure Losartan potassium (A), crospovidone (B), chickpea starch (C), and lactose (D)

Figure 03: DSC thermograms of optimized formulation of Losartan potassium-crospovidone (A) and optimized formulation of Losartan potassium-chickpea starch (B)

Evaluation of physiochemical characteristics of losartan potassium fast disintegrating tablets:

Table 04 indicate the results of physiochemical characteristics of Losartan potassium fast disintegrating tablet of different formulations (weight variation and thickness). The weight variations of all the formulations were in the range of 149.3 mg to 150.9 mg. They PASS the test as they did not exceed the limit given by USP (± 7.5). The thickness of the tablets was in the range of 2.3 mm to 3.0 mm. The hardness of the tablets was determined to be in the range of 3 to 5 kg/cm².Friability test was also done using 20 tablets each of the best optimized formulations which are LCP01 and LCS05. The result is shown in Table 05. The tablets pass the test as the percentage of loss is less than 1%.

Table 04: The results of weight variation test and thickness of tablets test of different formulations.

Formulation code	Weight Variation(mg)	Thickness (mm)
LCP01	150.7±1.39	2.9±0.05
LCP02	150.4±1.00	2.8±0.09
LCP03	150.6±0.66	2.8±0.10
LCS01	150.6±1.18	2.6±0.12
LCS02	150.5±0.37	2.5±0.02
LCS03	150.9±0.86	2.6±0.02
LCS04	150.9±0.45	2.6±0.03
LCS05	150.6±0.29	2.3±0.02
LCS06	149.3±1.02	3.0±0.05

Table 05: Results of friability test of formulation LCP01 and LCS05.

LCP01

LCS05

Initial weight = 3.0872 g

Final weight = 3.0836 g

% Loss = 0.1%

Initial weight = 3.0357 g

Final weight = 3.0214

% Loss = 0.5%

Disintegration time:

Figure 04 and Figure 05 shows disintegration time of formulation LCP and LCS. All formulations disintegrated less than 15 minutes. This indicates that they fulfilled the official requirement of USP. Disintegration time of LCP01 is 53 seconds which give the shortest time of disintegration which make it the best formulation. This also may due to the highest concentration content of crospovidone. LCS05 give the best reading of disintegration time for LCS formulations which is 185 seconds (3 minutes and 5 seconds). This is due to the use lactose as diluent instead of microcrystalline cellulose (MCC).Lactose and MCC are hydrophilic substance However, MCC have less hydrophilic nature than lactose. This is why lactose can disintegrate faster than MCC.

Fig 04: Disintegration time of formulation code LCP01, LCP02 and LCP03

Fig 05: Disintegration time of formulation code LCS01, LCS02, LCS03, LCS04, LCS05 and LCP06.

Calibration curve:

A calibration curve was plotted using absorbance values obtained from 5 different concentration of solutions (2, 4, 6,8, and 10 µg/mL) produced from serial dilution as shown in Figure 06. The equation of the standard curve: y = 0.0739x – 0.018 was used for the estimation of Losartan potassium concentration in dissolution samples.

Figure 06: Calibration curve of Losartan potassium in pH 6.8 phosphate buffer.

Dissolution studies:

The dissolution studies profile of losartan potassium fast disintegrating tablets containing different concentration of disintegrants in different formulations are shown in Figure 07, Figure 08 and Figure 09. In LCP formulations, dissolution of LCP01 formulation had been quicker than the other formulations and showed a better release of 97% at the end of 5th minutes ensuring fast disintegrating of the drug. This is due to high concentration of crospovidone. In LCS formulations, the dissolution of drug from LCS05 formulation had been quicker than the other formulations and showed a better release of 87% at the end of 20th minutes. This is due to the use of lactose which act as a better diluent for Losartan potassium as compared to microcrystalline cellulose. Furthermore, the dissolution rate profile of marketed formulation of Losartan potassium tablet shows complete drug release within 10 minutes. The comparison graphs between the marketed preparation and the best formulation of LCP and LCS shows that LCP give better dissolution profile as compared to other formulation.

Figure 07: A comparative study of In-vitro drug release of fast disintegrating tablet and using crospovidone as disintegrant for formulation LCP01, LCP02 and LCP03

Figure 08: A comparative study of In-vitro drug relase of fast disintegrating tablet and using chickpea starch powder for formulation LCS01, LCS02, LCS03, LCS04, LCS05 and LCS06

Figure 09: A comparative study of In-vitro drug release of fast disintegrating tablet LCP01, LCS05 and Marketed Tablet.

CONCLUSION

In terms of dissolution test, the dissolution profile of LCS is comparable with the release profile of LCP; the chickpea starch has almost potential disintegration action as the super disintegrant which is the crospovidone. The drug release of LCS is within the acceptance limit (according to USP monograph). The chickpea formulation is compatible with Losartan potassium and exhibits no interactions with each other and other excipient used in this study. Only 17.5% of chickpea starch concentration was used in the optimized formulations Chickpea starch can be used as an alternative natural disintegrant. For future studies, the chickpea starch can be refined and the powder flow can be improved. This may lead to better disintegration properties. Not only that, chickpea is cheap and easily available. Using chickpea starch as disintegrant may help to lower the budget of drug producing where in the future may help those who cannot afford to buy expensive medicine.

REFERENCES:

1. John C Carter,The role of disintegrants in solid oral dosage manufacturing, Carter Pharmaceutical Consulting, Inc., 2002-2006.

2. Ramu. G, Mohan. G.K , Jayaveera K.N, Suresh N, Prakash C, Ramesh B. Evaluation of Abelmoschus starch as tablet disintegrant, India Journal of Natural Products and Resources, 2010; 1(3):342-347.

3. Isah AB, Olorunsola EO, Zaman Y. Physiochemical properties of Borassus Aethiopum starch, Asian Journal of Pharmaceutical and clinical research, 2012; 5(3):132-134.

4. Nitalikar MM, SakarkarDM, Formulation development and characterization of fast disintegrating tablets of Nimesulide, Stamford Journal of Pharmaceutical Sciences, 2011; 4(2):25-28.

5. Indhumathi D, Prabha KS, Formulation and evaluation of oral dissolving tablet of Fluoxetine using super disintegrants, International Journal of Pharma and Bio Sciences, 2011; 2(1):833-847.

6. Sean CS. The Complete Drug Reference, 34th Edition, London, England, UK: Pharmaceutical Press; 2011.

7. Housler O, Rein H, Kerstin Laures, Lubricant sensitivity of starch based disintegrants, 9th World Meeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical Technology atLissabon: april-2014.

8. Polesi L.F, SarmentoS.B.S, Anjos, C.B.P.Composition and characterization of pea and chickpea starches.Brazil: Brazilian Journal of Food Technology, 2011; 14(1): 74-81.

9. Frimpong A, A study of chickpea (Cicerarietinum L.) seed starch concentration, composition and enzymatic hydrolysis properties. Saskatchewan: Adams Frimpong; 2010

Received on 10.10.2018 Modified on 27.11.2018

Research J. Pharm. and Tech 2019; 12(2):637-643.

DOI: 10.5958/0974-360X.2019.00113.6