INTRODUCTION:

Oral route of drug administration is perhaps the most appealing route for the delivery of drugs. Of the various dosage forms administered orally, the tablet is one of the most preferred dosage forms because of its ease of manufacturing, convenience in administration, accurate dosing, stability compared with oral liquids, and because it is more tamperproof than capsules. The bioavailability of drug is dependent on in vivo disintegration, dissolution, and various physiological factors. In recent years, scientists have focused their attention on the formulation of quickly disintegrating tablets. The task of developing rapidly disintegrating tablets is accomplished by using a suitable diluents and superdisintegrant. The compressed tablet is the most popular dosage form in use today. About two-thirds of all prescriptions are dispensed as solid dosage forms, and half of these are compressed tablets. A tablet can be formulated to deliver an accurate dosage to a specific site¹.

Despite increasing interest in controlled-release drug delivery systems, the most common tablets are those intended to be swallowed whole and to disintegrant and release their medicaments rapidly in the gastrointestinal tract (GIT).

The proper choice of disintegrant and its consistency of performance are of critical importance to the formulation development of such tablets².Bioavailability of a drug depends on absorption of the drug, which is affected by solubility of the drug in GI fluid and permeability of the drug across GI membrane. The drugs solubility mainly depends on physical – chemical characteristics of the drug. However, the rate of drug dissolution is greatly influenced by disintegration of the tablet.

Disintegrant is a term applied to various agents are added to tablet formulation for the purpose of causing the compressed tablet to break apart when placed in an aqueous environment and this process of desegregation of constituent particles before the drug dissolution occurs, is known as disintegration process and excipients which induce this process are known as disintegrant. Superdisintegrant which are effective at low concentration and have greater disintegrating efficiency and they are more effective intra-granularly^{3, 4}.

Co-processing is defined as combining 2 or more established excipient by an appropriate process. Co-processing of excipient could lead to formation of excipient with superior properties compared with the simple physical mixture of their components or with individual components. A large number of co-processed diluents are commercially available. The representative examples are Ludipress, Cellactose, and Starlac^{4, 5}.

Aceclofenac is an orally administered non-steroidal anti-inflammatory drug used in painful condition and was developed in Spain. Aceclofenac has pronounced analgesic action, also used in rheumatoid arthritis and osteoarthritis. Aceclofenac provides symptomatic relief in a variety of pain. It is a newer derivative of Diclofenac and has less gastrointestinal complications. Aceclofenac is comparatively more efficacious and safer in treatment of osteoarthritis as compared to Diclofenac Sodium^6-8.

In present study, prepare co-processed super disintegrating agent consisting of crosspovidone and sodium starch glycolate and was evaluated for various parameters like flow property, compressibility and swelling ratio. Finally, Aceclofenac tablet consisting of co-processed crosspovidone and sodium starch glycolate was prepared and evaluated for various quality control parameters like Hardness, Friability, Disintegration time, and Dissolution rate study. Stability study of optimized batch was performed.

MATERIALS AND METHODS:

Materials:

Aceclofenac was received as a gift sample from Torrent Pharmaceutical Ltd., Ahmedabad, Gujarat, India. Sodium Starch Glycolate (SSG) was gifted from Colorcon Asia Pvt. Ltd. (Mumbai). Crospovidone, Lactose, Di-basic calcium phosphate (DCP), microcrystalline cellulose (MCC), Sucrose and Magnesium stearate (Mg – stearate) were purchased from S D Fine, India. All other reagents and chemicals used were of analytical grade.

Preparation and Evaluation of Co-processed Superdisintegrant:

The co-processed superdisintegrant was prepared as follows. A blend of crospovidone (7.5 g) and SSG (7.5 g) was added to 65 ml of isopropyl alcohol. The contents of the beaker (250 ml capacity) were stirred on a magnetic stirrer. The temperature was maintained between 65 - 70ºC, and stirring was continued till most of isopropyl alcohol evaporated. The wet coherent mass was granulated through 60-mesh sieve. The wet granules were dried in a tray dryer at 60ºC for 20 minutes. The dried granules were sifted on 60-mesh sieve and stored in airtight container till further use⁹.

Swelling Ratio:

The study was carried out in 100ml stopper graduated cylinder. The initial bulk volume of 1g dried co processed material (SSG + Crosspovidone) was noted and then water added in sufficient quantity to yield 100 ml uniform dispersion. The sediment volume of the swollen mass was noted after 24 hr storage at room temperature. The swelling ratio was calculated by taking the ratio of the swollen volume to the initial bulk volume. Swelling ratio was carried out in distilled water. It was carried out in triplicate¹⁰.

Bulk and Tapped density:

A pre-weighed, pre-sieved quantity of dried mucilage was poured into a graduated cylinder and the volume recorded. The cylinder was then tapped until powder bed volume reached a minimum value and the tapped volume recorded. The bulk and tapped densities were calculated¹¹.

Bulk Density =

Weight of powder / Bulk volume of powder …………..(1)

Tapped Density =

Weight of powder / Tapped volume of powder…………(2)

Carr’s index and Hausner ratio:

Carr’s Index and Hausner ratio was calculated by the following formula.

Carr’s Index =

100 (Tapped density – Bulk density) / Tapped density.…(3)

Hausner Ratio = Tapped density / Bulk density …………(4)

Angle of repose:

A glass funnel was secured with its tip positioned at a fixed height (H) above a graph paper placed on a horizontal surface. The sample was poured through the funnel until the apex of the conical pile touched the tip of the funnel. The angle of repose was calculated using the formula tan α = H/R, where α is the angle of repose and R is the radius of the conical pile¹¹.

Formulation of Aceclofenac Tablet:

Aceclofenac tablets were prepared by direct compression using co-processed crosspovidone and sodium starch glycolate by using flat faced punches and die on a single punch tablet machine (Model Rimek II, Karnavati Eng. Ahemadabad). Combined granules of lactose and MCC were used as a diluent ². The average weight of tablet was kept 200 mg. Various formulations are shown in Table 1.

Evaluation of Aceclofenac Tablet:

Hardness and Friability test:

Hardness was measured by Monsanto Hardness Tester. Friability was evaluated as the percentage weight loss of 20 tablets tumbled in a friabilator (USP XXIII, Model EF2, Electrolab, Mumbai, India) for 4 min at 25 rpm. The tablets were de-dusted, and the loss in weight caused by fracture or abrasion was recorded as percentage friability¹².

Disintegration Time (DT):

The time required for disintegration of six tablets per batch was carried out in USP disintegration test apparatus (Model ED2L, Electrolab, Mumbai, India) containing 900 ml distilled water at 37+0.5⁰ C. The mean DT was calculated¹².

Dissolution Rate Study:

The drug release study was carried out using USP XXIII Paddle Type Dissolution Test Apparatus (Model TDL 08, Electrolab, Mumbai, India) at 37+0.5⁰ C and at 50 rpm using 900ml in distilled water and phosphate buffer (pH 6.8) as dissolution medium (n=5). Five milliliters sample solution was withdrawn at predetermined time intervals, filtered through a 0.45 micron membrane filter, diluted suitably, and analyzed spectrophotometrically at 276nm using a Shimazdu-1700 UV-Visible double beam spectrophotometer. Equal amounts of fresh dissolution medium were replaced immediately after withdrawal of a test sample. The percentage drug dissolved at different time intervals was calculated using regression equation generated from the standard curve¹³.

Stability Study:

To study the effect of storage on hardness and disintegration time, stability study of optimized formulation (Batch I) was carried out at 40⁰c in a humidity oven (Rivotek STD Model, Rivotek, Mumbai, India) having 75% RH. Samples were withdrawn after three-month interval and evaluated for change in hardness and DT.

RESULT AND DISCUSSION:

Physicochemical parameters data of co-processed material are shown in Table 2. Flow properties of the powder can be judged from the angle of repose. The powder flow depends on 3 general areas: (1) the physical properties of the particle (e.g., shape, size, compressibility): (2) the bulk powder properties (e.g., size distribution, compaction); and (3) the processing environment (e.g., storage, humidity)¹⁴. A chapter on powder flow has been recently introduced in USP 29–NF 24¹². It was observed that co-processed material is free flowing in nature and had good compressibility which shows that material is suitable for direct compression. It was observed from the swelling ratio that co-processed material has more swelling then the single component crosspovidone and sodium starch glycolate.

To obtain a rapid disintegration a disintegrant force must develop inside the tablet that is capable of weakening and breaking inter-particle bonds. This is generated by the replacement of solid/air with solid/liquid interfaces. The displacement of air by water or aqueous liquids is a wetting process that may lead to hydration of the involved particles and produce disintegration. Particles with different properties will produce greater disruptive shear forces and smaller disintegration times. This means that disintegration could be a function of a given surface of contact between particles with different hydration properties ¹⁴.

Formulation scientists generally use superdisintegrant for developing rapidly disintegrating tablets or for improving dissolution of active pharmaceutical ingredients from solid dosage forms. The superdisintegrant are used from as low as 4% to as high as 66% in fast dissolving formulations or for improving dissolution of active pharmaceutical ingredients¹⁵.

It was observed that all batches had hardness in between 2.5 to 4 kg/cm²and friability is in between 0.6 to 0.8 % which are within the limit. It was observed from disintegration time data that as the amount of superdisintegrant increases there was decreases in disintegration time. There was a no major difference in DT between crosspovidone and SSG (Batches A to F). This may be because of that SSG and crospovidone both are worked as standard superdisintegrant. It was observed that when incorporation of co-processed superdisintegrant in to formulation, there was a major change in DT (Batches G to I). This may be due to co-processed form of SSG and crospovidone works better than the single component. There was a marginal difference among the DT in all three batches. It was concluded that co-processed superdisintegrant reduce the DT (Table-3).

Figure 1, 2, and 3 shows dissolution profile of all formulated batches. It was observed that from all batches batch A to I more than 90% drug release within 60min. It was also observed that in first 10 min drug release was found to be 33 to 57% from different batches, while from co-processed disintegrating agent containing batches shows 55-60% drug release. It was also observed that from batches G to I containing co-processed superdisintegrant had almost 80% of drug were release within 15min as compared to others. It is evident that there is a noticeable improvement in dissolution rate of Aceclofenac by using co-processed superdisintegrant. The dissolution enhancement may be attributed to increased hydrophilicity. From results of DT and drug release, it was concluded that Batch I shows better results and was considered as an optimized batch^{16 –
18}.

Figure 1. In – vitro Drug Release of Aceclofenac Containing Various % of Crospovidone.

Figure 2. In – vitro Drug Release of Aceclofenac Containing Various % of SSG.

Figure 3. In – vitro Drug Release of Aceclofenac Containing Various % of Co-processed Superdisintegrant.

Table 1. Formulation of Aceclofenac Tablet containing SSG, Crospovidone and Co-processed superdisintegrant.

Materials (mg)	Batch Code
Materials (mg)	A	B	C	D	E	F	G	H	I
Aceclofenac	100	100	100	100	100	100	100	100	100
Lactose + MCC (Granules)	82	78	74	82	78	74	82	78	74
Crospovidone	8	12	16	---	---	---	---	---	---
Sodium Starch Glycolate	---	---	---	8	12	16	---	---	---
Co-processed (Crosspovidon + SSG)	---	---	---	---	---	---	8	12	16
Magnesium Stearate	10	10	10	10	10	10	10	10	10
Total	200	200	200	200	200	200	200	200	200

--- indicates no addition of excipient

Table 2. Physicochemical Parameters of Co-processed Crosspovidone and SSG.

Physicochemical Parameters	Results
Angle of Repose	Free-Flowing Powder
Bulk Density (gm/ml) Mean ± S.D. (n=3)	0.26 ± 0.04
Tapped Density (gm/ml) Mean ± S.D. (n=3)	0.65 ± 0.03
Carr’s Index (%) Mean ± S.D. (n=3)	60 ± 2.25
Hausner’s Ratio Mean ± S.D. (n=3)	2.5 ± 0.45
Swelling Ratio Mean ± S.D. (n=3)	5.0 ± 0.50

Optimized batch (Batch I) containing co-processed superdisintegrant was kept for stability study at 40⁰c in humidity oven having 75% RH. Samples were withdrawn after three-month interval and evaluated for change in hardness and DT. It was observed that there were marginal increases in DT (20.0 ± 0.5 to 21.0 ± 0.5 sec) and decreases in hardness (4.0 ± 0.5 to 3.5 ± 0.5 Kg/cm²). It was concluded that tablets are stable after stability study.

Table 3. Results of Quality Control Parameters of Aceclofenac Tablets.

Batches	Hardness (kg/cm²) Mean ± S.D. (n=6)	Friability (%) Mean ± S.D. (n=6)	Disintegration Time (Sec) Mean ± S.D. (n=6)
A	4.0 ± 0.50	0.60 ± 0.01	159.0 ± 5.0
B	3.0 ± 0.35	0.70 ± 0.08	45.0 ± 2.5
C	2.5 ± 0.25	0.75 ± 0.12	30.0 ± 2.0
D	3.5 ± 0.25	0.70 ± 0.08	187.0 ± 6.0
E	2.5 ± 0.15	0.70 ± 0.08	50.0 ± 2.5
F	2.5 ± 0.25	0.80 ± 0.10	32.0 ±2.0
G	2.5 ± 0.15	0.80 ± 0.10	35.0 ± 2.0
H	2.5 ± 0.15	0.80 ± 0.12	25.0 ± 1.0
I	4.0 ± 0.50	0.60 ± 0.08	20.0 ± 0.5

Co-processed superdisintegrant offer new avenues and opportunities for formulation scientists as an additional option for improving the solubility of sparingly soluble drugs. The superdisintegrant in this study were kept away from aqueous fluid, which might have changed their characteristics. The areas where further work can be done include using a fluid bed dryer or microwave dryer for drying granules and a spray dryer for preparation of co-processed excipient, optimizing different ratios of crospovidone and SSG, and using other combinations of superdisintegrant.

CONCLUSION:

Co-processed superdisintegrant consisting of crospovidone and SSG exhibited good flow and compression characteristics. Aceclofenac tablets containing co-processed superdisintegrant exhibited quick disintegration and improved drug dissolution. The co-processed superdisintegrant proved to be superior to the plain crospovidone and SSG. Furthermore, the co-processed superdisintegrant displayed superiority in terms of hardness, disintegration time, and drug dissolution. The advantages of the proposed method are easy adaptability in industry and the possibility of bypassing the existing patents in the areas of quick disintegration and dissolution.

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Received on 04.07.2010 Modified on 23.07.2010

Research J. Pharm. and Tech. 4(2): February 2011; Page 290-293