INTRODUCTION:

Benazepril Hydrochloride (Fig. 1) is the ACE (Angiotensin Converting Enzyme) inhibitor. ACE (Angiotensin Converting Enzyme) inhibitors are used largely in the treatment of hypertension and congestive heart failure¹. Dilation of blood vessels is the major mechanism which results in lowering of blood pressure. ACE inhibitors are also prescribed for cardiac failure, diabetic nephropathy, chronic renal failure, renal involvement in systemic sclerosis (scleroderma renal crisis), left ventricular systolic dysfunction, and acute myocardial infarction².

Fig. 1: Chemical structure of Benazepril Hydrochloride.

Efficiency, quicker onset and longer duration of action are the advantages of Benazepril Hydrochloride at the same time low bioavailability is the limitation so by incorporating this drug in mouth dissolving tablet, bioavailability can be improved³. Mouth Dissolving Tablets (MDTs) rapidly disintegrates when placed on the tongue. Orally disintegrating tablets have better patient acceptance and compliance and may offer improved biopharmaceutical properties, efficacy and increased bioavailability compared with conventional oral dosage forms⁴. Major intention behind MDT products initially was to overcome the difficulty in swallowing of conventional tablets and capsules among pediatric and geriatric populations⁵. Former applications of MDTs are significant in the management of many conditions such as allergies, cold, and flu symptoms. High porosity in the tablet matrix is the key factor for rapid disintegration of MDT. To improve the porosity, volatile substances such as subliming agents can be used in tableting process, which sublimated from the formed tablet. Also freeze-drying technique is used to form a highly porous MDT⁶. Direct compression using superdisintegrant is the conventional technique that can be used for preparation of MDT. MDTs prepared by direct compression shows better disintegration due to absence of binder and low moisture contents. Generally recommended concentration of superdisintegrants generally used is 1-10% by weight relative to total weight dosage form. Crosscarmellose sodium (Ac-Di-Sol), Sodium Starch Glycolate (SSG) and Crosspovidone (CP) are the generally used superdisintegrants⁷.

MATERIAL AND METHODS:

Chemicals and reagents:

Benazepril Hydrochloride was procured from Amneal India Pvt. Ltd., Ahmedabad. Ac-Di-Sol (Croscarmellose Sodium), Kollidon CL (Crospovidone) were procured from Wings Biotech Pvt. Ltd., Baddi. Glycolys (Sodium Starch Glycolate), Avicel PH-102 (Microcrystalline Cellulose), Pearlitol 200 SD (Mannitol) and Magnesium stearate were procured from Signet Chemicals, Mumbai.

Instrumentation:

The proposed work was carried out using instruments, Shimadzu UV-visible spectrophotometer (model UV-1800 series), FT-IR Spectroscopy (ABB FTLA 2000, INDIA), 16 station tablet punching machine (Rimex minipress-1) and USP XXIV Paddle dissolution apparatus (VDA-6DR Veego)

Drug excipient compatibility by Fourier Transform Infrared (FTIR) study:

The FT-IR for pure drug was obtained by powder diffuse reflectance on FTIR spectrometer in the wave number region of 4000-400 cm^-1. The spectrum was compared with the reference spectrum of Benazepril Hydrochloride. The physical mixture of excipient with drug was prepared by simple blending. The IR spectra for drug and physical mixture with drug were obtained using FT-IR instrument. IR spectrum were observed for detection, insertion or shifting of peaks⁸.

Formulation of Tablets:

The raw materials were passed through a no. 100 screen prior to mixing. Benazepril hydrochloride, superdisintegrant, microcrystalline cellulose and mannitol were mixed using a glass mortar and pestle. The blends were lubricated with magnesium stearate. The blends ready for compression were converted into tablets using a 16 station-punch tablet machine. Before compression final blend were evaluated for mass-volume relationship (bulk density, tapped density, Hausner’ ratio, compressibility index) and flow properties (Angle of repose). To know the actual amount of three superdisintegrant for the desirable property of fast dissolving tablets a 3² randomized full factorial design was used. In this design one factor was evaluated, each at two levels and experimental trials were performed at all six possible combinations (Table 1). The amount of Sodium starch glycolate (SSG), croscarmellose sodium and crospovidone was selected as independent variables⁹.

Evaluation of Tablets:

After compression of powder blends, the prepared tablets were evaluated for organoleptic characteristics like color, odor, taste, diameter, thickness and physical characteristics like hardness, friability, disintegration time, wetting time, dispersion time¹⁰.

Weight variation:

To perform weight variation test twenty tablets were taken and weighed individually. Individual tablet weigh was compared with average weight of twenty tablets¹¹.

Hardness:

Hardness of a tablet is defined as the force applied across the diameter of the tablet in order to break the tablet. Hardness of the tablet of each formulation was determined using Monsanto Hardness Tester¹².

Table1: Formulation of Factorial Design Batches of MDTs

Ingredients (in mg)	MDT1	MDT2	MDT3	MDT4	MDT5	MDT6
Benazepril Hydrochloride	10	10	10	10	10	10
Crospovidone	30	45	-	-	-	-
Sodium Starch Glycolate	-	-	30	45	-	-
Croscarmellose Sodium	-	-	-	-	30	45
Avicel PH 102(Microcrystalline cellulose)	50	50	50	50	50	50
Magnesium Stearate	6	6	6	6	6	6
Mannitol	154	139	154	139	154	139

Friability:

Friability of the tablets was determined using Roche friabilator. This device subjects the tablets to the combined effect of abrasions and shock in a plastic chamber revolving at 25rpm and dropping the tablets at a height of 6 inch in each revolution. Preweighed sample of tablets was placed in the friabilator and were subjected to 100 revolutions. Tablets were dedusted using a soft muslin cloth and reweighed.

The friability (F%) was determined by the formula

F%= W₀-W/W₀ x 100

Where, W₀ was initial weight of the tablets before the test and W was the weight of the tablets after test¹³.

Wetting time:

Wetting time of the tablets was measured using a piece of tissue paper (12cm X 10.75cm) folded twice, placed in a small petridish (ID = 6.5cm) containing 6ml of Sorenson’s buffer (pH 6.8). A tablet was put on the paper and the time for the complete wetting was measured¹⁴.

In vitro dispersion time:

In vitro dispersion time was measured by placing a tablet in a beaker which contains 10ml of 6.8pH phosphate buffer. Three tablets from each formulation were randomly selected and in vitro dispersion time was performed¹⁶.

Optimization of Mouth Dissolving Tablet:

The optimized Mouth Dissolving tablet was prepared with the best amount of co-processed superdisintegrant suggested by the Design expert software. The prepared tablets were evaluated for its physicochemical properties¹⁷.

In vitro dissolution study:

In vitro dissolution study for optimized tablet was carried out using USP paddle method at 50rpm in 900ml of Sorenson’s buffer (pH 6.8) as dissolution media, maintained at 37±0.5°C. 5ml of aliquot was withdrawn at the specified time intervals (1 minute), filtered through Whatmann filter paper and assayed spectrophotometrically at 240nm. An equal volume of fresh medium, pre-warmed at 37°C, was replaced into the dissolution media after each sampling to maintain constant volume throughout the study¹⁸.

RESULTS AND DISCUSSIONS:

Drug excipient compatibility by Fourier Transform Infrared (FTIR) study:

When Benazepril Hydrochloride compared with the standard, it was found that drug was pure. The FT-IR spectrum of drug sample was concordant with reference spectra. The FT-IR spectra verified the authenticity of the procured sample as the characteristic peaks of the drug were found at 3435 (O–H stretching), 2980 (N–H stretching), 2467 (C–N stretching), 1739 (Acid C=O stretching) and 1674 (C=C stretching). Drug-excipient interaction study was carried out for 4 weeks and samples were evaluated after every week for physical changes, change in absorption maxima and by FT-IR spectra. There was not any sign of physical change at the end of study. The FT-IR spectra of the physical mixture retained all the peaks of the pure drug and there was no significant shift in the peaks corresponding to the Benazepril Hydrochloride was observed on storage (Fig. 2). Both the drug and excipient were found to be compatible with each other. Hence, the selected drug and excipients were successfully incorporated in the design fast dissolving tablets¹⁹.

Fig.2: FTIR Spectra of A) Benazepril Hydrochloride B) Benazepril Hydrochloride + Crospovidone

Precompression parameters of tablet blend:

For tablets prepared using super disintegrants, the bulk density of blend varied between 0.688-0.742g/cc. The tapped density was found in the range of 0.720-0.815 g/cc. By using these two density data, Hausner’s ratio and compressibility index was calculated. The powder blends of all formulation had Hausner’s ratio of less than 1.25 indicating good flow characteristics. Blends having value of compressibility index less than 16% were considered as free flowing ones. The values for compressibility index were found in the range of 5.555-7.365. The flowability of the powder was also evidenced by the angle of repose. The angle of repose below 30⁰ indicates well to excellent flow properties of powder. Lower the friction occurring within the mass, better the flow rate. The angle of repose was found to be in the range 23.30-27.29⁰. The results for characterization of blend were shown in Table 2²⁰.

Post –compression Characterization of Mouth Dissolving Tablets:

After compression of powder, the tablets obtained were evaluated for their organoleptic (color, odor), physical (size, shape and texture) and quality control parameters (thickness, hardness, friability, disintegration time, dispersion time and wetting time). All the formulations were white in color, flat in shape with smooth surface not having any defects. The average weights of the prepared tablets were found between 242.5-249.6 mg. So it was predicted that all the tablets exhibited uniform weight with low standard deviation values within the acceptable variation. The friability of the formulations was less than 1.0%, showed the durability of the tablets; resistance to loss of weight indicates the tablet’s ability to withstand abrasion in handling, packaging and shipment. The friability of all the formulations was found to be less than 1.0%. It was clear from the study that the concentration of super disintegrants also affected the percent friability²¹. The hardness of tablets varied from 3.0-3.6 kg/cm²(Table 3)

Super disintegrants were incorporated in the formulations (MDT1- MDT6) to facilitate quicker disintegration of the tablet as soon as it contacts the saliva in the mouth. These disintegrants act by drawing water into the tablet owing to the wicking or capillary action leading to swelling and breakup of the tablet. In the formulation of fast dissolving tablets three super disintegrants (sodium starch glycolate, Ac-Di-Sol and Crospovidone) were tested in different concentrations. The disintegration process of the tablet was fully dependable on nature and concentration of super disintegrant used. The in vitro wetting time was also studied to know the time required for complete wetting of tablets when placed on tongue²². The in vitro wetting time of all the formulations varied between 11±1.76 to 22±3.54 s (Fig. 3).

Fig.3: In vitro wetting time of mouth dissolving tablet

The same sequence was observed in case of measurement of dispersion time of the tablet (Table 3). The tablets with crospovidone showed the best results for all the characterization parameters and hence it was selected as one factor of the optimization of the fast dissolving tablets²³.

Optimization of Mouth Dissolving Tablet:

For optimization of mouth dissolving tablets and to know the desirable property randomized full factorial design was used. In this design one factor was evaluated, each at two levels and experimental trials were performed at all six possible combinations. The formulations and evaluation optimized batch of tablet is shown in Table 4²⁴.

Table 4: Formulation and evaluation of optimized batch of MDT

Formulation
Ingredients	Quantity (in mg)
Benazepril Hydrochloride	10
Crosspovidone	30
Avicel PH 102(Microcrystalline cellulose)	50
Magnesium Stearate	6
Mannitol	154
Evaluation
Weight (mg)	249.6 ±1.31
Hardness (kg/cm²)	3.0 ±0.08
Friability (%)	0.42 ±0.02
Wetting time (s)	11 ±1.76
Dispersion time (s)	16 ±1.22

n=3, ±SD

In vitro dissolution study:

In vitro drug release study was performed at 37±0.5⁰C in paddle dissolution apparatus for the optimized formulation and conventional marketed tablet. The optimized formulation showed the better release than the marketed preparation for immediate release of drug (Table 5). MDT of Benazepril Hydrochloride showed 98.68% drug release at in 10 minutes while marketed tablet showed 98.46% drug release in 60 minutes²⁵.

Table 5: Comparative % drug release of MDT with marketed tablet

Time (min)	% Drug release
Time (min)	MDT1	Marketed Preparation
5	91.94±2.79	-
10	98.68±1.84	21.87±3.25
15	-	30.96±1.28
20	-	40.41±3.54
25	-	52.92±2.74
30	-	64.80±2.38
35	-	75.87±2.35
40	-	91.89±1.39
45	-	97.92±1.37
50	-	98.19±1.73
55	-	98.28±1.46
60	-	98.46±2.24

n=3, ±SD

The effect of superdisintegrant can be clearly observed in drug release analysis of mouth dissolving tablet in comparison with marketed formulation of drug.

Fig.4: Comparative in vitro drug release of MDT and Marketed tablet

Fig.4 shows comparative drug release of MDT and marketed tablet. From the graph it is predictable that MDT have quicker onset of action with significant drug release which will be helpful in patients with severe hypertension and cardiovascular diseases.

CONCLUSION:

Mouth dissolving tablets of Benazepril Hydrochloride was prepared successfully by direct compression technique using superdisintegrants. The mouth dissolving tablets of antihypertensive drug were found to be a better option in treatment of hypertension conditions by providing fast onset of action and thus leading to patient convenience and compliance. It is concluded that by incorporating Benazepril Hydrochloride in the form of mouth dissolving tablet, fast and better therapeutic action can be achieved for the treatment of hypertension.

ACKNOWLEDGEMENT:

The authors are grateful to the authorities Smriti College of Pharmaceutical Education, Indore, Madhya Pradesh for the facilities.

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

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Received on 21.04.2020 Modified on 16.07.2020

Research J. Pharm. and Tech. 2021; 14(6):3161-3166.

DOI: 10.52711/0974-360X.2021.00551

Formulation Codes	Parameters
Formulation Codes	Bulk Density (g/cc)	Tapped Density (g/cc)	Hausner’s Ratio	Compressibility Index (%)	Angle of Repose (⁰)
MDT1	0.714 ±0.010	0.765 ±0.011	1.071±0.012	6.6 ±1.123	23.30±0.867
MDT 2	0.739 ±0.012	0.796 ±0.009	1.077 ±0.023	7.16 ±1.243	25.15 ±1.232
MDT 3	0.704 ±0.019	0.745 ±0.020	1.058 ±0.031	5.555 ±1.433	24.40 ±0.934
MDT 4	0.757 ±0.006	0.815 ±0.003	1.076 ±0.011	7.111 ±1.348	26.52±1.244
MDT 5	0.688 ±0.023	0.720 ±0.013	1.046 ±0.002	4.444 ±1.298	23.50±1.423
MDT 6	0.742 ±0.034	0.801 ±0.005	1.079 ±0.022	7.365 ±1.344	27.29±1.364

Formulation codes	Parameters
Formulation codes	Weight(mg)	Hardness (kg/cm²)	Friability (%)	Wetting time (s)	Dispersion time (s)
MDT1	249.6 ±1.31	3.0 ±0.08	0.42 ±0.02	11 ±1.76	16 ±1.22
MDT 2	247.5 ±1.50	3.3±0.15	0.73 ±0.05	14 ±2.35	20 ±3.24
MDT 3	248.4 ±2.05	3.2 ±0.13	0.84±0.03	13 ±4.23	18 ±2.56
MDT 4	246.2 ±1.42	3.1±0.17	0.68±0.07	15 ±4.25	21 ±4.35
MDT 5	245.5 ±1.38	3.6 ±0.16	0.83 ±0.04	19 ±3.41	26 ±3.75
MDT 6	242.5 ±2.52	3.5± 0.19	0.35 ±0.06	22 ±3.54	30 ±2.47