Formulation and Evaluation of Oro-dispersible tablets of an Antihypertensive drug using Superdisintegrants

Syed Shariff Miyan*, Vazir Ashfaq Ahamed, Prof. Mohammed Khaleel and Mohammed Yakhoob H.

M.M.U. College of Pharmacy, Ramanagara-562 159, Karnataka, INDIA

ABSTRACT:

The purpose of present investigation was to develop fast dissolving tablets of an oral antihypertensive drug Ramipril. Solid dispersion of Ramipril with PEG-6000 was prepared by solvent evaporation technique and oro-dispersible tablets were prepared by direct compression technique. Sodium starch glycolate, Crosspovidone and Crosscarmellose sodium were used as superdisintegrants and Camphor as subliming agent. The prepared tablets were exposed to vacuum drying to produce highly porous tablets. The blends were evaluated for pre-compressive parameters and the prepared tablets were analyzed for post-compressive parameters such as; weight variation, hardness, and friability, drug content, wetting time, disintegration time, in-vitro dissolution studies, short term accelerated stability study and drug-excipient compatibility studies.

All formulation showed weight variation and drug content within the acceptable limits. The results revealed that sublimation of camphor from the tablets resulted in highly porous tablets with dispersion time less than 30 seconds and rapid in-vitro dissolution. The optimized formulation (F6) showed desired disintegration time and good release profile with maximum drug being released at different time intervals.

It was concluded that oro-dispersible tablets of Ramipril with improved drug dissolution can be prepared by solid dispersions of the drug with PEG-6000 and a combination of superdisintegrants was proved more optimized compare to single superdisintegrant. Camphor can be used to produce highly porous tablets for the ease of quicker disintegration and dissolution. The present work helped in understanding the effect of formulation variables especially combination of superdisintegrants on the drug release profile, potentials for rapid dispersion, quicker absorption, improved bioavailability, effective therapy and improved patient compliance.

KEYWORDS: Oro-dispersible tablets, Ramipril, PEG-6000, Solid dispersion, Subliming agent, Superdisintegrants.

INTRODUCTION:

The tablet is the most widely used dosage form because of its convenience in terms of self-administration, compactness, and ease in manufacturing. However, geriatric, bedridden and pediatric patients felt difficulty in swallowing conventional tablets. To overcome this drawback, innovative drug delivery systems known as fast dissolving tablets have developed. A tablet which can rapidly disintegrate in saliva (rapidly disintegrating tablet) is an attractive dosage form and patient-oriented pharmaceutical preparation. The concept of rapid disintegrating drug delivery system emerged from the desire to provide patients with conventional mean of taking their medication. Dysphagia (difficulty in swallowing) is a common problem of all age groups, especially elderly and pediatrics, because of the physiological changes associated with these groups of patients².

Other categories that experience problems using conventional oral dosage forms includes the nauseated, mentally ill, and non co-operative patients, those with motion sickness, sudden episodes of allergic or asthma attack where an ultra-rapid onset of action is required³. Mouth dissolving tablet improved compliance in patients. The potential advantages such tablets include, administration without water, anywhere, anytime lead to their suitability to geriatric and pediatric patients. They are also suitable for the mentally ill, the bedridden and patients who do not have easy access to water. The benefits, in terms of patient compliance, rapid onset of action, increased bioavailability, and the tablets that can rapidly dissolve or disintegrate in the oral cavity have attracted a greater deal of attention⁴.

Therefore an effort to increase dissolution of drug is often needed. Methods available to improve dissolution include salt formation, micronization and addition of solvent or surface active agents. Solid dispersion is one of such methods and it involves a dispersion of one or more active ingredients in an inner carrier or matrix in solid state prepared by melting, dissolution in solvent or melting-solvent method etc. Solid dispersion technology has been successfully been used for improving the solubility of the poorly soluble drugs and hence bioavailability of such drugs^5-8.

Superdisintegrants such as Sodium starch Glycolate (SSG), Crosspovidone (CP) and crosscarmellose sodium (CCS) were extensively used to fabricate mouth dissolving tablets. Subliming agents such as Menthol, Camphor, mannitol, Urea etc, were included in the blend as subliming agent and tablets were first prepared and later exposed to vacuum to produce highly porous tablets which may either dissolve in the buccal cavity or get dispersed in the mouth for quicker, better and total release of the medicament for absorption^9-11

Ramipril^15-17 is a 2-azabicyclo [3.3.0] octane3carboxylic acid derivative. It is a white, crystalline substance soluble in polar organic solvents and buffered aqueous solutions. Ramipril melts between 105°C to 112°C. Ramipril Capsules USP is indicated for the treatment of hypertension. It may be used alone or in combination with diuretics such as thiazide. The recommended initial dose for patients not receiving a diuretic is 2.5 mg once a day.

Ramipril is a long-acting angiotensin-converting enzyme inhibitor. It is a prodrug that is transformed in the liver to its active metabolite ramiprilat. Both ramipril and ramiprilat inhibit ACE in human subjects and animals. Angiotensin converting enzyme is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to decrease aldosterone secretion.

Following oral administration of Ramipril, peak plasma concentrations (Cmax) of Ramipril are reached within one hour. The extent of absorption is at least 50% to 60% and is not significantly influenced by the presence of food in the gastrointestinal tract, although the rate of absorption is reduced.

The primary objective of fast dissolving tablets is to disintegrate or dissolve rapidly in oral cavity within short period of 15-60 seconds, without need of water and should have pleasant after feel in the mouth. The important parameters to formulate a fast dissolving tablet are choice of superdisintegrants and optimization of concentration of superdisintegrants used.

The present work aims to investigate the potential of the solid dispersion and vacuum drying technique for development of oro-dispersible tablets of Ramipril using, sodium starch Glycolate, Crosspovidone and crosscarmellose sodium as superdisintegrants.

MATERIALS AND METHOD:

Materials: Ramipril was obtained as a gift sample from Lupin Pharmaceuticals Limited, India. Crosscarmellose, Crosspovidone and sodium starch Glycolate were obtained as gift samples from micro labs, India. Other materials such as; PEG-6000, Talc-IP, Magnesium stearate-IP and Camphor were of AR Grade and were purchased from S.D.Fine Lab., Mumbai.

Preparation of Solid Dispersion: SD of Ramipril: PEG 6000 at 1:2 weight ratios was prepared by the solvent evaporation method. Ramipril was dissolved in 1 part of ethanol, and the polymer was dissolved in 2 part of purified water. The solutions were mixed with the help of magnetic stirring for 30 minutes. Then, the solvent was evaporated under reduced pressure and dried at 40⁰C until constant weight. The dried material was powdered, sieved through no # 40 mesh and then stored in a dessicator at room temperature for further study.

Preparation of fast disintegrating tablets of Ramipril

The ingredients (as shown in Table 1) were passed through a screen (40 mesh) prior to mixing. Powdered solid dispersion containing amount equivalent to 2.5 mg Ramipril, was mixed with the appropriate concentrations of superdisintegrants and filler then co-grounded in a mortar for 15 minutes. Talc and magnesium stearate were added and mixed for 10 minutes in a polybag. The mixed blend of drug and excipient was compressed into tablets using a 12mm flat punch tablet machine (Kambert, Ahmadabad, India) to produce tablets weighing ~250mg. Sublimation of camphor from the tablets was performed under vacuum at 50°C for 8 hours.

Table 1; Showing composition of Oro-dispersible tablets of Ramipril

Ingredients (mg)	F1	F2	F3	F4	F5	F6
Solid dispersion containing 2.5 mg of Ramipril	7.5	7.5	7.5	7.5	7.5	7.5
Crosscarmellose sodium (CCS)	12.5	---	----	12.5	----	12.5
Crospovidone (CP)	----	12.5	----	12.5	12.5	----
Sodium starch glycolate (SSG)	----	----	12.5	----	12.5	12.5
Camphor	12.5	12.5	12.5	12.5	12.5	12.5
Saccharin sodium	2.5	2.5	2.5	2.5	2.5	2.5
Talc	1.0	1.0	1.0	1.0	1.0	1.0
Magnesium stearate	2.0	2.0	2.0	2.0	2.0	2.0
Lactose	212	212	212	199.5	199.5	199.5
Total weight of the tablet (mg)	250	250	250	250	250	250

Table 3; showing pre-compressive parameters of the blend, n=3

Formulation code	Angle of repose	Loose bulk density (g/ml)	Tapped bulk density (g/ml)	Hausner’s factor	Carr’s Index (%)
F1 F2 F3 F4 F5 F6	29.36±0.02 28.46±0.01 27.43±0.01 28.37±0.06 29.90±0.03 28.96±0.04	0.2456±0.02 0.2326±0.006 0.242±0.003 0.242±0.004 0.2382±0.004 0.2480±0.003	0.291±0.004 0.283±0.004 0.283±0.004 0.284±0.006 0.278±0.004 0.283±0.005	1.186±0.02 1.190± 0.22 1.202± 0.14 1.224± 0.04 1.240± 0.14 1.154± 0.02	17.89±1.04 18.34±0.83 16.80±1.23 18.30±0.80 19.57±1.10 18.25±1.06

Tan θ = h / r or θ= tan^-1 [ h / r ]

EVALUATION OF ORO-DISPERSIBLE RAMIPRIL TABLETS:

I) Evaluation for pre-compressive parameters:¹²

1) Bulk Density: Blends were poured gently through a glass funnel into a graduated cylinder at exactly to 10 ml mark. Excess blend was removed using a spatula and the weight of the cylinder with blend required for filling the cylinder volume was calculated. The cylinder was then tapped over hard wooden slab from a height of 2.0cm until the time when there was no more decrease in the volume. Both loose bulk density and tapped bulk density, and thereby Hausner’s factor and Carr’s compressibility indices were calculated by using following equations;

a) Loose bulk Density:.

Loose bulk Density =

b) Tapped bulk Density:

Tapped bulk Density =

2) Hausner’s factor:

Hausner’s factor =

3) Carr’s Compressibility Index:

Percent Carr’s Index =

4) Angle of Repose: For determination of angle of repose (ө), the blends were poured through a funnel, which was fixed at a position such that its lower tip was at a height of exactly 2.0 cm above the surface. The blends were poured till the time when upper tip of the pile surface touched the lower tip of the funnel. The tan^-1 of the (height of the pile/radius of its base) gave the angle of repose. The results of pre-compressive parameters are given in Table 3.

II) Evaluation for post -compressive parameters:^13,14

(a) Thickness and diameter:, thickness and diameter of each tablet was measured using a calibrated dial caliper.

(b) Weight variation test: Twenty tablets were taken and their weight was determined individually and collectively on a digital weighing balance. The average weight of each tablet was determined from the sum of weight of twenty tablets. Mean and standard deviation (S.d) of weight was calculated from each batch.

(c) Hardness test: Hardness was determined by taking six tablets from each formulation, using a Monsanto Hardness Tester. A mean of S.d values were calculated for each batch.

(d) Friability test: Six pre-weighed tablets were rotated at 25 rpm for 4 minutes using a Roche Friabilator. The tablets were de-dusted and re-weighed using digital weighing balance and the percentage weight loss was calculated by using the equation;

F = × 100

(e) Wetting time and water absorption ratio:

A piece of whatman filter paper folded twice was kept in a Petri dish (internal diameter 4 cm) containing 6 ml of purified water. A tablet having a small amount of Rosaline dye powder on the upper surface was placed on the tissue paper. When the upper surface of the tablet acquires a red colour, the time was recorded as wetting time. The same procedure without using Rosaline dye was followed to determine the water absorption ratio R, was determined according to the following equation. Above experiments were performed in triplicate.

R = [(W_a – W_b) / W_b] × 100

Where, W_a and W_b were the weights of the tablet after and before the tests.

(f) Disintegration time: ^[1]

Disintegration time was measured in 900 ml simulated gastric fluid (without enzymes) maintained at 37±0.5^o C by USP 24 method (without disc). The disintegration time of 6 individual tablets were recorded and the average was taken.

(g) Drug content estimation: ^[18]

● Standard solution: 25 mg of pure Ramipril was dissolved in little quantity of Methanol in a volumetric flask and then the volume was made to 25ml mark with Methanol and sonicated for 5 minutes. The above solution will give 1mg/ml solution of Ramipril which was further diluted with Methanol (1ml was diluted to 100ml) to produce a stock solution containing 10 µg/ml of Ramipril. The above stock solution of Ramipril was further diluted with Methanol to produce a series of concentrations ranging between 0.6 to 16µg/ml. Absorbance was measured spectrophotometrically at 226nm against Methanol as blank.

● Sample solution: 20 tablets from each batch were randomly selected and were weighed accurately and then finely powdered. To a powder equivalent to 25mg of Ramipril about 50ml of Methanol was added and dissolved with the aid of shaker for 15 minutes; sufficient quantity of Methanol was added to produce 250 ml in a volumetric flask, mixed well and filtered.

To 1ml of the above filtrate was further diluted to 100ml using Methanol and mixed well. The absorbance of the resulting solution (1µg/ml) was measured at the 226nm using blank in the reference cell. The total content of drug in the solution was calculated with the help of standard graph. The above experiment was done in triplicate.

(h) In vitro dissolution study

The release of drug from ODT was determined using USP dissolution testing apparatus type II (paddle method; ELECTROLABS, INDIA). The dissolution test was performed using 900 ml of simulated gastric fluid (without enzyme) at 37 ± 0.5°C and 50 rpm. A sample (10 ml) of the solution was withdrawn from the dissolution apparatus at different time intervals and the samples were replaced with fresh dissolution medium. The samples were filtered through a 0.45μ membrane filter and appropriately diluted to produce suitable concentration with simulated gastric fluid. Absorbance of these solutions was measured at 226nm using a Shimadzu UV-1700 double beam spectrophotometer. Cumulative percentage drug release was calculated using an equation obtained from a standard calibration curve (see figure 1). The results of post-compressive parameters are shown in table 4. The cumulative percent drug release from the tablets is shown in figure 2 and table 5.

(Figure;1 standard calibration curve of drug in methanol)

(i)Accelerated stability studies ^[19,20,21]

Short term accelerated stability study was performed on the prepared ODT formulation to investigate stability of formulation and it also gives evidence of the drug - excipients interaction in terms of physical and chemical changes (see table 2). The stability study involved storing the prepared formulation in below mentioned conditions for a period of 2 months and the tablets were evaluated at different time intervals for any physical and chemical changes.

The procedure was divided into two parts;

Part I:

Achieving of 60% RH:

26.66 gm of sodium hydroxide was weighed and dissolved in 100 ml of distilled water to get 26.66% sodium hydroxide solution. The solution was placed in the desiccator over which a wire mesh was placed, over which the dosage form was placed and the desiccator was sealed. The desiccator was placed in the oven maintained at 25⁰C to create the relative Humidity of 60%.

(Table 4 showing post-compressive parameters of oro-dispersible tablets of ramipril, n=3)

	Before vacuum drying	After vacuum drying to sublimate camphor
Formulation code	Average Weight (mg	Hardness (kg/cm^2)	Friability (%)	Disintegration Time (sec)	Wetting Time (sec)	Water absorption ratio	Drug content (%)
F1 F2 F3 F4 F5 F6	249.20±0.008 251.18±0.122 250.10±0.029 252.00±0.028 251.77±0.121 250.88±0.030	3.2±0.04 3.1±0.14 3.2±0.02 3.3±0.08 3.2±0.40 3.6±0.22	0.61±0.04 0.65±0.08 0.65±0.05 0.88±0.24 0.78±0.33 0.87±0.15	38±2.00 40±2.04 29±0.08 27±2.04 23±0.04 22±0.28	28±0.09 31±0.06 26±0.55 27±0.33 24±0.07 22±0.56	122±0.13 116±0.11 102±0.22 122±0.14 118±0.16 132±0.20	98.66±0.14 99.24±0.68 98.22±0.22 98.16±0.66 99.04±0.55 98.79±0.27

Achieving of 75% RH:

Saturated solution of sodium chloride was prepared and placed in the desiccator over a wire mesh, above which the dosage form was placed and the desiccator was sealed. The desiccator was kept in oven maintained at 40⁰C to create the relative humidity of 75%.

Part II

The sealed formulation were placed in amber colored bottles, tightly plugged with cotton and capped. They were then stored at 25⁰C /60% RH and 40⁰C / 75% RH for two months and evaluated for their physical appearance and drug content.

Table 2: Conditions for stability studies according to ICH guidelines

Type of study	Storage condition		Minimum time
	Temperature	Relative humidity (%)
Long term	25^0C±2^0C	60% ±5% RH	12 Months
Intermediate	30^0± 2^0C	65%± 5% RH	6 Months
Accelerated	40^0± 2^0C	75%± 5% RH	6 Months

(J) Drug: Excipient Compatibility study:

To establish drug-excipients compatibility, binary powder mixtures were prepared in 1:1 ratios with excipients. The binary mixtures were ground in a mortar, screened and the mixtures were filled individually in amber colored vials and sealed.

1. After specific time period the mixture were subjected to assay and all binary mixtures showed desired drug concentration ranges.

2. The IR spectra were recorded using FT IR Spectrophotometer (Shimadzu 8400S, Japan) Potassium bromide pressed pallet method was followed.

RESULT AND DISCUSSION:

In the present investigation the solubility of Ramipril was enhanced by treating with PEG-6000 (solvent evaporation method) and the ODTs of Ramipril were prepared by direct compression method. Before compression, the measurement of qualitative and quantitative assessment of internal cohesive and frictional forces under low levels of external loading applied in mixing and tabelting was convinced through angle of repose. The values for angle of repose were found in the range of 27.43 to 29.90°. Carr’s index of the prepared blends falls in the range of 16.80 to 19.57% and this is also supported by Hausner’s factor values which were in the range of 1.154 to 1.240. Hence the prepared blends possessed good flow properties and can be used for manufacturing of tablets (see table 3).

All the tablets were prepared under similar experimental conditions. All the formulations exhibited white color, odorless, flat shaped with almost smooth surfaces (but formed fine pores on all surfaces when subjected to vacuum drying). The average weight of the ODTs prepared by direct compression method was 249.2 to 252.0mg (before sublimation of camphor) and average weight after sublimation was found between 237.2 to 240.0mg which clearly indicated that the loss of camphor from each tablets may be around 12 to 12.1 mg per tablet (4.82%). Hardness of prepared ODT tablets was between 3.1 to 3.6 kg/cm². The percent friability of formulations was found to be 0.61 to 0.88 (less than 1.0%) and thus hardness and friability of all formulations were within acceptable limits. The disintegration time is very important and it is desired to be less than 1 minute. The quick disintegration may assist swallowing and drug absorption in buccal cavity, thus greater bioavailability of the drug. Disintegration time of prepared ODTs was found in the range of 22 to 40 seconds and the order was:

F1 (CCS)<F2 (CP)<F3 (SSG)< F4 (CCS+CP) <F5(CP+SSG) <F6 (CCS+SSG)

The above finding indicated that, a combination of crosscarmellose sodium (CCS) and sodium starch glycolate (SSG) in appropriate concentrations showed least time for disintegration.

Wetting time is the indicator from the ease of the tablet disintegration in buccal cavity. It was observed that wetting time of tablets was in the range of 22 to 31 seconds. It was found that the nature and combination of the superdisintegrants(s) present affected the wetting of the tablets. The formulation containing combination of CCS with SSG (F6) took less time while tablets containing CP alone (F2) took more time to get wet.

Assay for the prepared formulations was performed in triplicate to determine drug content uniformity and it was found between 98.16 to 99.24% (see table 4).

In vitro dissolution study was performed by using simulated gastric fluid (without enzymes) as dissolution medium using USP dissolution apparatus type 2 at a paddle speed of 50rpm. At the end of 60 minutes the cumulative percentage drug release from various ODT was found to be 78.22, 76.44, 78.28, 80.82, 83.77 and 90.44% from F1, F2, F3, F4, F5 and F6 respectively. This clearly indicated that the superdisintegrants present alone released lower amount of drug compare to the tablets containing double disintegrants (see table 5 and figure 2). The formulation F6 which contained double superdisintegrants released maximum drug when compared to other formulations. With reference to type and combination of superdisintegrants present, the order of release was as follows;

F6 > F5 > F4 > F1 > F2 > F3

The results of short term stability studies indicated that there were no major changes in the physical properties such as colour, odour, and texture and disintegration time. Drug content was found under acceptable limits for all ODT formulation (see table 6).

Drug-excipient interaction study was performed using FT IR spectrophotometer (Shimadzu 8400S, Japan) the kneaded mixture of drug and excipients was prepared and scanned; no excipient was interacted with the drug. The FT IR spectra of pure drug and optimized formulation (F6) are shown in figure 3, and 4.

Table:5, In-vitro cumulative % release of drug from oro-dispersible tablets of Ramipril, n=3

Time in minutes	Cumulative % drug release from prepared tablets
	Formulation code
	F1	F2	F3	F4	F5	F6
0	0.0	0.0	0.0	0.0	0.0	0.0
5	6.882(±1.88)	5.172(±1.25)	6.065(±0.22)	7.544(±1.23)	9.123(±0.50)	8.222(±0.622)
10	10.884(±1.66)	8.405(±0.67)	12.529(±1.24)	14.660(±1.37)	15.660(±1.25)	15.662(±0.204)
15	16.228(±1.44)	12.215(±1.24)	21.022(±1.58)	22.177(±1.44)	22.440(±1.43)	25.222(±1.28)
20	24.228(±1.44)	19.012(±1.60)	30.234(±1.16)	28.402(±1.06)	28.660(±1.15)	33.442(±0.90)
25	32.666(±1.08)	27.413(±1.24)	36.462(±0.54)	36.225(±1.33)	38.662(±1.17)	41.780(±1.12)
30	38.245(±1.44)	35.654(±1.67)	40.706(±2.67)	43.343(±2.10)	43.128(±0.54)	48.542(±1.66)
35	47.246(±1.46)	43.655(±1.28)	50.233(±1.64)	49.566(±1.37)	53.015(±1.24)	57.442(±0.80)
40	55.442(±0.98)	53.224(±0.61)	58.660(±1.36)	56.290(±1.35)	60.773(±1.24)	62.884(±0.12)
45	64.222(±0.22)	60.126(±0.66)	63.956(±1.28)	65.666(±1.1)	67.212(±0.08)	71.462(±1.80)
50	70.662(±0.44)	71.346(±0.98)	70.222(±1.29)	73.284(±0.80)	73.192(±0.55)	80.220(±0.12)
55	74.11(±0.55)	72.22(±1.16)	72.35(±0.98)	78.48(±0.64)	80.44(±0.26)	85.28(±0.90)
60	78.42(±1.26)	76.44(±1.66)	75.28(±0.64)	81.82(±1.10)	83.77(±0.90)	90.44(±1.66)

Table:6, Results of short term accelerated stability study p=physical appearance(color, odour and texture), H=hardness, %= percent drug content

TIME IN DAYS	F1			F2			F3			F4			F5			F6
	P	H	%	P	H	%	P	H	%	P	H	%	P	H	%	P	H	%
0 DAYS	+++	3.2	98.60	+++	3.1	99.24	+++	3.2	98.22	+++	3.3	98.16	+++	3.2	99.04	+++	3.6	98.79
30 DAYS	+++	3.1	98.57	+++	3.1	98.26	+++	3.2	98.11	+++	3.2	98.12	+++	3.2	99.00	+++	3.5	98.70
60 DAYS	+++	3.1	98.56	+++	3.0	98.25	+++	3.2	98.15	+++	3.2	98.13	+++	3.2	99.01	+++	3.5	98.73

(Figure:2 showing dissolution profile of fabricated oro-dispersible tablets of Ramipril)

(Figure:3, FT IR spectra of pure drug Ramipril)

(Figure 4, FT IR spectra of optimized formulation, F6)

CONCLUSION:

In the present investigation it can be concluded that the oro-dispersible tablets of Ramipril (F6 was the optimized formulation) can be successfully prepared by using solid dispersions of the drug in PEG 6000 and then blending with suitable proportions of two superdisintegrants such as; crosscarmellose sodium (CCS) and sodium starch glycolate (SSG). After direct compression, sublimation of camphor provides highly porous tablets which can disintegrate quickly to achieve complete and effective dissolution. In vivo studies are required to correlate in vitro release data and to access the taste of prepared oro-dispersible tablets.

AKNOWLEDGEMENTS:

The author wish to thank Prof. Mohammed Khaleel, Principal, M. M. U. College of Pharmacy for providing facilities to carry out this research work

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Received on 10.06.2011

Accepted on 01.08.2011

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Research Journal of Pharmaceutical Dosage Forms and Technology. 3(6): Nov.- Dec., 2011, 269-275