INTRODUCTION:

Recent advances in novel drug delivery systems (NDDS) aim to enhance safety and efficacy of drug molecule by formulating a convenient dosage form for administration and to achieve better patient compliance. One such approach is fast dissolving tablets ^{1, 2}. Lisinopril is a drug of the angiotensin converting enzyme (ACE) inhibitor class that is primarily used in treatment of hypertension, congestive heart failure, heart attacks and also in preventing renal and retinal complications of diabetes. The present study involved the comparison between various synthetic superdisintegrants in combination.

Materials and methods:

Lisinopril were obtained as a gift sample from Modern Lab., Indore (M.P). Croscarmellose sodium, crospovidone, sodium starch glycolate, mannitol, magnesium stearate were purchased from S.D. Fine Chemicals, India.

Preformulation Studies:

Angle of repose:

Angle of repose (θ) was determined using funnel method. The blend was poured through a funnel that can be raised vertically until a maximum cone height (h) was obtained. The radius of the heap (r) was measured and angle of repose was calculated³.

θ= tan -1 (h/r)

Bulk density:

The term bulk density (b*) refers to a measure used to describe a packing of particles. It is (gm/ml) and was determine using a balance and measuring cylinder. Initially the weight of the measuring cylinder was tarred. Then, drugs were poured into the measuring cylinder using a funnel and weighed (M). Then volume of the powder (Vb) was taken. Bulk density of the granules was calculated using following formula⁴.

b* = M/Vb

Tapped density:

Blend was tapped for a fixed number of taps. The minimum volume (Vt) occupied in the cylinder and the weight (M) of the blend was measured. The tapped density (Electrolab) (t*) was calculated using following formula⁵.

t* = M/ Vt

Hausner’s ratio:

Hausner’s ratio is an index of ease of powder flow; it is calculated by following formula⁶.

Hausner ratio = Tapped density/Bulk density

Carr’s Index (CI) ¹¹:

Tapped and bulk density measurements can be used to estimate the Carr’s index of a material. Carr’s index was determined by,

C.I (%) = Tapped density – bulk density /Tapped density*100

Formulation of Fast Dissolving Tablets:

Fast dissolving tablets of Lisinopril were prepared by direct compression method. The drug and excipients were passed through sieve (#80) to ensure better mixing, synthetic superdisintegrants Croscarmellose sodium, crospovidone, sodium starch glycolate were used in different proportions of 10:5 and 5:10 respectively. The powders were compressed into tablets on ten-station rotary punch-tableting machine using 6 mm flat punch set.

Evaluation of Fast Dissolving Tablets:

Quality control tests for FDTs of all formulations were performed, and the average values were calculated. All the tablets were evaluated for different parameters as weight variation, hardness, friability, wetting time, water absorption ratio, disintegration time and in vitro dissolution study.

Weight Variation:

Twenty tablets were selected randomly from each batch and weighed individually on electronic balance (Shimadzu). The individual weighed is then compared with average weight for the weight variations.

Hardness:

The strength of tablet is expressed as tensile strength (kg/cm²). The tablet crushing load, which is the force required to break a tablet into pieces by compression. It was measured using a tablet hardness tester (Monsanto hardness tester). Three tablets from each formulation batch were tested randomly and the average readings were noted⁷.

Friability:

Friability of the tablets was determined using Roche Friabilator. This device consists of a plastic chamber that is set to revolve around 25 rpm for 4 min dropping the tablets at a distance of 6 inches with each revolution. Pre weighed sample of 20 tablets was placed in the friabilator and were subjected to 100 revolutions. Tablets were dusted using a soft muslin cloth and reweighed. The friability (F %) is given by the formula⁸

F (%) = (1 – W₀ / W) × 100

Where, W is weight of the tablets before the test

W₀ is the weight of the tablets after test.

Wetting time:

Five circular tissue papers of 10 cm diameter were placed in a Petri dish with a 10cm diameter. 10 ml of water at 37±0.50 containing eosin, a water-soluble dye, was added to the petridish. A tablet was carefully placed on the surface of tissue paper. The time required for water to reach the upper surface of the tablets was noted as the wetting time. Six tablets from each formulation batch were tested randomly and the average reading noted⁹.

Water absorption ratio:

A piece of tissue paper folded twice was placed in a small petridish containing 6 ml of water. A tablet was put on the paper and the time required for complete wetting was measured. The wetted tablet was then weighed. Water absorption ratio R, was determined using following equation,

R = Wa – W b/ Wb × 100

Where Wa = weight of tablet after absorption

Wb = weight of tablet before absorption

In vitro disintegration time:

Disintegration time was measured using a disintegration apparatus. Tablets were added to 10 ml of Sorenson’s buffer solution of pH 6.8 at 37 ± 0.5°C. Time required for disintegration of the tablets was noted.

In vitro drug release:

In vitro drug release of Lisinopril fast dissolving tablets was determined using USP Dissolution Apparatus II. The dissolution test was performed using 900 ml of Phosphate buffer (6.8) at 37 ± 0.50. The speed of rotation of paddle was set at 50 rpm. 5 ml samples were withdrawn at time points of 5, 10, 15, 20, 25, and 30 min and same volume was replaced with fresh media. Absorbance of solution was checked by UV spectrophotometer at a wavelength of 206 nm¹⁰.

Figure 1. Cumulative % drug release of Lisinopril FDT in phosphate buffer PH 6.8 using synthetic superdisintegrants in combination

Figure 2. Log % drug retained for Lisinopril FDT in phosphate buffer PH 6.8 using synthetic superdisintegrants in combination

Table 1. Formulation of Lisinopril FDT using combination of synthetic superdisintegrants:

Ingredient	CP-CCS 1L1	CP-CCS 2L2	CP-SSG 1L3	CP-SSG 2L4	CCS-SSG 1L5	CCS-SSG 2L6
Lisinopril	30	30	30	30	30	30
MCC	20	20	20	20	20	20
CPV	20	10	20	10	-	-
CCS	10	20	-	-	20	10
SSG	-	-	10	20	10	20
Mannitol	116	116	116	116	116	116
Mg.st	2	2	2	2	2	2
Talc	2	2	2	2	2	2
Total	200	200	200	200	200	200

Table 2. Evaluation of Lisinopril FDT using combination of synthetic superdisintegrants:

Formulation	L1	L2	L3	L4	L5	L6
Hardness	3.1±0.0082	2.8±0.057	2.9±0.066	2.8±0.05	2.8±0.052	2.7±0.055
DT	145±0.502	152±0.235	167±0.787	172±1.003	176±0.047	179 ±0.996
Friability	0.013 ± 0.0004	0.014 ±0.0001	0.014 ±0.0001	0.015 ±0.0006	0.016 ±0.0003	0.017 ±0.0004
Wetting time	21±0.656	26±0.661	25±0.771	29±0.694	27±0.521	31±0.539
Dispersion time	25±0.773	29±0.702	28±0.683	31±0.541	32±0.64	35±0.586
Water abs ratio	78±1.352	64±0.646	72±1.125	60±0.623	54±0.7346	49±0.669

Table 3. Preformulation studies of Lisinopril FDT using combination of synthetic superdisintegrants:

Formulation	L1	L2	L3	L4	L5	L6
Bulk density	0.52±0.005	0.53±0.0053	0.52±0.0052	0.53±0.0055	0.54±0.005	0.54±0.005
Tapped density	0.54±0.005	0.55±0.0053	0.55±0.0054	0.56±0.0059	0.56±0.0058	0.58±0.006
Hausner’s ratio	1.03±0.195	1.03±0.196	1.05±0.001	1.05±0.001	1.03±0.0005	1.07±0.0005
Carr’s index	3.70±0.007	3.63±0.006	5.45±0.007	5.35±0.0065	3.57±0.1	6.89±0.16
Angle of Repose	31±0.55	32±0.57	31±0.554	33±0.58	32.5±0.59	33±0.586

Table 4. Cumulative % drug release of Lisinopril FDT in phosphate buffer PH 6.8 using synthetic superdisintegrants in combination:

TIME IN MINUTES	L1	L2	L3	L4	L5	L6
2	32.09	38.12	21.98	41.78	16.98	12.89
4	47.19	49.98	21.99	41.78	22.79	12.9
6	55.21	51.23	47.32	49.23	37.77	25.76
8	72.37	54.23	59.65	51.13	43.95	44.34
10	85.85	78.12	79.65	61.87	55.49	47.76
15	90.98	89.98	92.23	98.99	67.87	56.87
20	99.89	99.99	99.97	98.99	99.97	97.98
25	99.89	--	---	--	--	99.98

Table 5. Log % drug retained for Lisinopril FDT in phosphate buffer PH 6.8 using synthetic superdisintegrants in combination:

TIME IN MINUTES	L1	L2	L3	L4	L5	L6
2	1.83193373	1.79155031	1.8922059	1.7650722	1.91918273	1.940068
4	1.72271617	1.69914369	1.8921503	1.7650722	1.88767355	1.9400182
6	1.65118106	1.68815276	1.7216458	1.70560716	1.7939998	1.870638
8	1.44138088	1.66058091	1.6058435	1.68904234	1.74857562	1.7455432
10	1.15075644	1.34004732	1.3085644	1.58126681	1.64845759	1.7180032
15	0.95520654	1.00086772	0.890421	0.00432137	1.50691073	1.6347795
20	-0.95860731	-2	-1.522879	0.00432137	-1.5228787	0.3053514
25	-0.95860731	--	--	--	--	--

RESULTS AND DISCUSSION:

The formulation and results for evaluation of different batches of Lisinopril FDT’s prepared by direct compression method are shown in Table 1 and 2. The most important parameter that needs to be optimized in the development of Fast Dissolving tablets is the disintegration time of tablets. In the present study tablets in all the batches disintegrated in the range of 140 –180 secs fulfilling the official requirements for Fast Dissolving tablets. It was observed that the formulations (L1 – L6) containing combinations of synthetic superdisintegrants used in different ratios of 10:5 and 5:10 respectively were prepared. The formulations contained crospovidone (CP), croscarmellose (CCS) and sodium starch glycolate (SSG) in combined form as CP and CCS in combination of 10:5 and 5:10 ratios, CP and SSG in combination of 10:5 and 5:10 ratios and CCS and SSG in combination of 10:5 and 5:10 ratios respectively. The tablet formulations containing 10:5 ratios viz. 20 mg of CP and 10 mg of CCS (L1), 20 mg of CP and 10 mg of SSG (L3), 20 mg of SSG and 10 mg of CCS (L6) showed DT as 145, 167 and 179 secs and formulations containing 5:10 ratios viz. 10 mg of CP and 20 mg of CCS (L2), 10 mg of SSG and 20 mg of CP (L4), 10 mg of SSG and 20 mg of CCS (L5), showed DT as 152, 172, 176 secs respectively. The wetting time is important to check minimum volume of water required for wetting of the tablet. The wetting time for formulations L1 –L6 showed in the range of 21 to 31 secs respectively. It has been reported that wetting is closely related to the inner structure of the tablets and the hydrophillicity excipients. The superdisintegrants show its disintegrant effect by swelling action. Thus the result indicates that these tablets would disintegrate almost instantaneously when they will come in contact with even slight amount of saliva in the mouth. The Preformulation studies were carried out and all the parameters passed the requirements for all formulations as shown in Table 3. The cumulative percentage drug release of the tablets from the prepared batches was found to be 99.99% due to the effect of two superdisintegrants in combination as shown in Table 4 and 5 respectively. It was observed that nearly all the batches showed drug release close to 100% in phosphate buffer pH 6.8. The in-vitro drug release for the formulations L1 –L6 was found to be in the range of 98.99 -99.99% respectively. The FTIR studies were carried out for the pure drug Lisinopril, superdisintegrants and the optimized formulation L1 and the spectra’s showed no interaction. FT-IR spectra of pure drug Lisinopril (Figure-3.a) revealed the presence of characteristic peak of N-H stretching around 3557.85cm^-1, O-H stretching around 3300 cm^-1, aromatic C-H stretching around 3200cm^-1, sp³ C-H stretching at 2957cm^-1, C=O stretching around 1700 cm^-1 and C-O stretching around 1045 cm^-1.The FT-IR spectra of croscarmellose sodium revealed the presence of characteristic broad and strong peak for OH stretching around 3413.19 cm^-1, stretching peak around 2891.42 cm^-1corresponds to the stretching vibration of CH₃ group, a strong band around 1600cm^-1corresponds to the carbonyl stretching and C-O stretching around 1166cm^-1.(Figure-3.b). FT-IR spectra of crospovidone revealed the presence of characteristic peak for CH₃ group at 2991.72cm^-1, C=O stretching peak at 1615cm^-1. Peaks in the region of 1400 cm^-1 indicate the stretching vibration of C-C. Peak at 843.89 cm^-1 indicates presence of methylene out of plane bending (Figure–3.c). FT-IR spectra sodium starch glycolate revealed the presence of characteristic peaks of OH around 3472cm^-1, stretching peak around 2969.54cm^-1corresponds to CH₃, peaks around 1663cm^-1correspond to stretching of C=O and C-O stretching around 1163cm^-1.(Figure -3.d). FT-IR spectra of the optimized formulation (L1) revealed the presence of characteristic peaks of N-H stretching, O-H stretching, aromatic C-H stretching, sp³ C-H stretching, C=O stretching and C-O stretching (Figure -3.e ). The formulation L1 consists of crospovidone 20 mg and croscarmellose 10 mg which improved the DT to an extent as both the superdisintegrants are ranked to be better in terms of swelling and disintegrating the tablets.

CONCLUSION:

Fast Dissolving tablets of Lisinopril were prepared by direct compression method using crospovidone (CP), croscarmellose (CCS) and sodium starch glycolate (SSG) in combined form as CP and CCS in combination of 10:5 and 5:10 ratios, CP and SSG in combination of 10:5 and 5:10 ratios and CCS and SSG in combination of 10:5 and 5:10 ratios respectively. From the observed parameters it was concluded that the formulation (L1) satisfied all the official requirements. The tablets had acceptable hardness of average 3.1 kg/ cm², 0.013 % friability, In-vitro disintegration time 145 secs and in-vitro drug release of 99.98%. Hence it can be concluded that using a combination of synthetic superdisintegrants would be quite effective in providing faster onset of action without the need of water for swallowing.

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Received on 16.06.2012 Accepted on 16.07.2012

Asian J. Pharm. Tech. 2(3): July-Sept. 2012; Page 94-98