INTRODUCTION:

Direct compression is the modern and the most efficient process used in tablet manufacturing due to its low manufacturing cost and high mechanical integrity of tablets. There are currently limited pharmaceutical tablets on commercial production that can be made by direct tabletting because most powders lack the proper characteristics of binding or bonding together into a compact entity¹. Crystallo-co-agglomeration (CCA) technique involves simultaneous crystallization and agglomeration of drug/s with/without excipient/s from good solvent and /or bridging liquid by addition of a non-solvent.

The spherical agglomerates obtained by CCA can be used as intact beads (encapsulated spansules) or directly compressible tablet intermediates having satisfactory micromeretic (flowability), mechanical (friability, crushing), compressional (compressibility, compactibility) and drug release properties². Aceclofenac (2-[[2-[2-[(2,6-dichlorophenyl)amino] phenyl]acetyl]oxy]acetic acid), a nonsteroidal anti-inflammatory drug has been recommended for the treatment osteoarthritis, rheumatoid arthritis and inﬂammatory disease of the joints. Aceclofenac proved as effective as other NSAIDs with lower indications of gastro-intestinal adverse effects and thus, resulted in a greater compliance with treatment. Aceclofenac is well absorbed after oral administration with hepatic first pass metabolism. It exhibits very slight solubility in water, poor ﬂow and compression characteristics. Because of the poor aqueous solubility, aceclofenac poses a dissolution- related absorption problem^3,4. Accordingly a number of investigations over recent years have been carried out seeking to improve its solubility/or dissolution rate. However one strategy that has not been explored to enhance dissolution is that of crystallo-co-agglomeration (CCA), a technique ﬁrst described by Kadam et al⁵.

The aim of the current study was to seek to improve the ﬂow, compaction and dissolution properties of a poorly water-soluble and compactible drug, aceclofenac, by incorporating a disintegrating agent in the drug agglomerates by crystallo-co-agglomeration technique. This study also investigated the effect of different disintegrants on the flow, packing, tableting and release properties of the agglomerates.

MATERIALS AND METHODS:

Aceclofenac was gift sample of Aristo Pharmaceuticals Pvt. Ltd, India and hydroxypropylcellulose of Nippon Soda Co., Ltd, Japan. Crospovidone and croscarmellose sodium were supplied by Torrent Pharmaceuticals Ltd, India. Sodium starch glycolate was obtained from Vijalak pharma Pvt. Ltd, India. Polyethylene glucol 6000, acetone, dichloromethane were purchased from S.D. Fine Chemicals Pvt. Ltd, India. All other chemicals/solvents used were of analytical grade.

Crystallo-co-agglomeration technique:

Aceclofenac agglomerates were prepared using a three solvent system comprising acetone: dichloromethane: water (good solvent, bridging liquid and bad solvent, respectively). In a vessel, mixture of polyethylene glycol 6000 (6.5% w/w of total solid content) and hydroxypropylcellulose (10% w/w of drug and disintegrant amount) was dissolved in distilled water (50 ml) and 1/3 of the total disintegrant was uniformly dispersed in the solution. Acetone (4 ml) at 50 ⁰C containing 1 gm aceclofenac and the other 2/3 of disintegrant was separately stirred for 20 min. The latter dispersion was added immediately to the dispersion containing dissolved polymer under constant stirring conditions (400 rpm, paddle type agitator with 4 blades) kept at room temperature. The stirring was continued for 20 min and 1 ml bridging liquid dichloromethane was added drop wise to obtain agglomerates, which were then filtered (membrane filter 0.45 µm) and dried overnight. The dried crystals were stored in screw-capped jars at room temperature before use. By changing the type of disintegrant and its concentration nine batches were prepared. As a reference, the aceclofenac agglomerates in the absence of disintegrant were prepared. Different composition of aceclofenac agglomerates is shown in Table 1.

Precompressional studies of aceclofenac agglomerates

Yield and drug-loading efficiency of agglomerates⁶:

The practical yield of agglomerates was calculated by weighing the prepared agglomerates after drying stage. For the determination of drug content, agglomerates (100 mg) were powdered and dissolved in 10 ml phosphate buffer (pH 6.8) and vortexed for 20 min. The solution was ﬁltered and after sufficient dilution with phosphate buffer (pH 6.8) analyzed spectrophotometrically at 247 nm for drug content.

Determination of the amount of disintegrant in agglomerates⁵:

Agglomerates (1 gm) were powdered and samples equivalent to approximately 100 mg of aceclofenac were weighed accurately and dispersed in acetone, such that any drug dissolved whereas the disintegrant remained dispersed. The dispersion was then ﬁltered to separate aceclofenac solution from the disintegrant. After ﬁltration the acetone solution was diluted with phosphate buffer (pH 6.8) and the samples were analyzed spectrophotometrically at 274 nm. The drug content was determined by reference to an appropriate standard curve and the amount of disintegrant was taken as the difference between total amounts of powder and the spectrophotometrically determined weight of aceclofenac.

Micromeretic properties^5,7:

Flowability assessment of agglomerates was done by angle of repose, Carr`s index and Hausner`s ratio. The angle of repose (θ) was assessed by the ﬁxed funnel method. A known amount of agglomerates was allowed to flow through a funnel fixed at a constant height (h=2.5 cm) and mean diameter (2r) of the powder pile was measured to calculate the angle of repose as q = tan^-1 h/r. The loose bulk density (LBD) and tapped bulk density (TBD) of plain aceclofenac and its agglomerates were determined using bulk density apparatus (Electro Lab, India) from 3 independent analyses. Carr`s index and Hausner`s ratio were calculated using LBD and TBD values. The Particle size distribution was studied by the sieve analysis method.

Determination of shape factor:

The agglomerates were photographed using an image analysis (scion image analyzer-Scion CG-7 RGB, USA). Area (A) and perimeter (P) obtained from tracings of enlarged photomicrographs of agglomerates were used to calculate the shape factor S = 4 π (A_actual)/P_actual². Twenty granules per batch were evaluated.

Solubility studies⁸:

An excess quantity of aceclofenac and its agglomerates was added into the 10 ml of different solutions i.e. water, acidic buffer pH 1.2 and phosphate buffer pH 6.8 in a shaking water bath (100 agitations/ min) at room temperature for 24 hrs. The solutions were then filtered through No. 41 whatman filter paper and the filtrate was suitably diluted and analyzed spectrophotometrically at 274 nm.

Measurement of packability⁹:

The packability of the samples was investigated by tapping them in to a 25-ml measuring cylinder using a tapping machine. Initially, 25 gm of substance was weighed and then was gently poured into a measuring cylinder. The volume of 25 gm samples was recorded. The poured density (minimum density) was calculated from the powder mass (25 gm) and the volume. Then the cylinder was tapped and the volume was recorded after every 100 taps until the volume did not change significantly. The packability was evaluated by measuring the tapped density according to the modified Kawakita equation (Eq. 1):

where a and b are the constants, n is the tap number, C denotes the volume reduction which can be calculated according to the Eq. 2,

Where V₀ and V_n are the powder bed volumes at initial and n^th tapped state, respectively. The data were also analyzed by Kuno equation (Eq. 3):

ln (ρf-ρn) = -kn + ln (ρf-ρo)

Where ρf, ρn and ρ0 are the apparent densities at equilibrium, nth tapped and initial state, respectively and k is the constant. The packability was assessed by comparing the constants a, 1/b and k in Eqs.2 and 4, respectively. The constant a represents the proportion of consolidation at the closest packing attained and constant 1/b describes cohesive properties of powders or the apparent packing velocity obtained by tapping. The constant k in Kuno’s equation represents the rate of packing process.

Fourier Transform Infrared Spectroscopy (FTIR) studies:

The pure drug, physical mixtures and best formulation (F9) were subjected for FTIR analysis. The samples were prepared on KBr-press (Startech Lab, India). The samples were scanned over a range of 4000-400 cm^-1 using Fourier transformer infrared spectrophotometer (8600, Shimadzu Corporation, Japan). Spectra were analyzed for drug polymer interactions.

Differential scanning calorimetry (DSC) studies:

The pure drug and best formulation (F9) were subjected to differential scanning calorimeter equipped with an intracooler (Mettler, Switzerland). Indium/Zinc standards were used to calibrate the DSC temperature and enthalpy scale. The sample were sealed in aluminium pans and heated at a constant rate 20°C/min over a temperature range of 20-250°C. An inert atmosphere was maintained by purging nitrogen gas at a flow rate of 50 ml/min.

X-ray diffraction of powder (XRDP):

The X-ray powder diffraction patterns were recorded on an X-ray diffractometer (PW 1729, Philips, Netherland). The samples were irradiated with monochromatized CuK-α radiation (1.542A°) and analysed between 10-50° 2θ. The voltage and current used were 30kV and 30mA, respectively. The range and the chart speed were 1x10⁴ CPS and 5mm/2θ respectively.

Scanning electron micrographs (SEM) analysis:

The shape and surface topography of agglomerated crystals and conventional crystals were observed through a scanning electron microscope (JEOL USA Inc., Peabody, MA). Dried samples were fixed on aluminum stubs using double-sided copper tape and coated with gold palladium in the presence of argon gas using a Hummer I sputter coater (Anatech Ltd., Denver, NC), under vacuum (0.1 mm Hg).

Preparation of tablets and their physico-chemical evaluations¹⁰:

The aceclofenac-disintegrant agglomerates (100±10 mg) were compacted using 4 mm flat punches on a 10 station rotary compression machine. The thickness and diameter of the tablets were measured using digital vernier calipers. The crushing strength and friability of the tablets were determined using Monsanto hardness tester and Roche friabilator respectively. Weight variation test was carried out by weighing 20 tablets individually and then calculating the average weight.

In vitro disintegration time¹¹:

The disintegration time for all formulations was carried out using tablet disintegration test apparatus. Six tablets were placed individually in each tube of disintegration test apparatus and discs were placed. The water was maintained at a temperature of 37° ± 2°C and time taken for the entire tablet to disintegrate completely was noted.

In vitro drug release studies:

The tablets were subjected to in vitro dissolution studies using an 8 station USP (Type-II) dissolution apparatus (Electro Lab, TDT-O8L, Mumbai). The dissolution studies were carried out in 900 ml of phosphate buffer pH 6.8 and hydrochloric acid buffer pH 1.2 at 37 ± 0.5^oC. The speed of the paddle was set at 50 rpm. Sampling was done every 2 minutes interval. For each sample, 5 ml of sample was withdrawn from the dissolution medium and replaced with equal volume of fresh medium. The samples withdrawn were analyzed in the UV spectrophotometer at 274 nm.

RESULTS AND DISCUSSION:

Crystallo-co-agglomeration mechanism:

Aceclofenac was crystallised using a three solvent system comprising acetone: dichloromethane: water. Water containing PEG-6000, HPC and 1/3 disintegrant (aqueous dispersion) was used as the crystallization medium. In this process, the crystallization of the drug was performed by addition of acetone dispersion containing the drug and 2/3 disintegrant to the aqueous dispersion with constant stirring and DCM was added drop wise to obtain quasi-emulsified droplets of drug solution. The crystallization of the drug then proceeded from the outer surface of the droplet due to both decreasing temperature and counter diffusion of both solvents through the interface of emulsion droplets. The batch processing time of 20 min is necessary to produce agglomerates with good sphericity and flowability. The end-point of the process was apparent when the dispersion (comprised primarily of suspended disintegrant) became transparent continuous phase containing spherical agglomerates. The spherically agglomerates crystals are formed by coalescence of dispersed crystals.

Table 1: Composition of the aceclofenac-disintegrant agglomerates

Ingredients	F1	F2	F3	F4	F5	F6	F7	F8	F9	F10
Aceclofenac (gm)	1	1	1	1	1	1	1	1	1	1
Sodium starch glycolate (mg)	-	250	-	-	300	-	-	350	-	-
Crospovidone (mg)	-	-	250	-	-	300	-	-	350	-
Croscarmellose sodium (mg)	-	-	-	250	-	-	300	-	-	350
HPC (%w/w of drug and disintegrant amount)	10	10	10	10	10	10	10	10	10	10
PEG-6000 (%w/w of total solid content)	6.5	6.5	6.5	6.5	6.5	6.5	6.5	6.5	6.5	6.5

Table 2: Disintegrant content of the aceclofenac-disintegrant agglomerates

Formulation codes	Ratio of disintegrant/drug incorporated in to crystallization medium (%)	Ratio of disintegrant/drug measured in agglomerates (%)
Formulation codes		SSG	CP	CCS
F2-F4	25	12.46	13.26	12.93
F5-F7	30	16.44	16.07	15.26
F8-F10	35	19.67	18.43	17.76

Table 3: Precompressional parameters of aceclofenac-disintegrant agglomerates

Formulation code	Yield (%w/w)	Drug loading (% w/w)	Geometric mean diameter (µm)	Shape factor
Pure drug	---	---	22.49	---
F1	82.25 ± 0.18	95.2 ± 0.14	508.23	1.06
F2	80.91 ± 0.11	96.8 ± 0.16	465.41	0.84
F3	80.33 ± 0.09	97.0 ± 0.11	451.2	1.032
F4	79.2 ± 0.11	97.5 ± 0.16	502.32	1.04
F5	78.17 ± 0.14	99.2 ± 0.11	485.41	1.05
F6	79.15 ± 0.12	98.8 ± 0.2	472.12	0.96
F7	79.2± 0.16	98.6 ± 0.25	508.33	1.07
F8	78.57 ± 0.21	98.1 ± 0.14	501.15	1.07
F9	80.25 ± 0.24	99.2 ± 0.16	493.31	0.81
F10	77.49 ± 0.14	98.7 ± 0.15	513.14	1.08

In this study, PEG 6000, which is more hydrophilic, was used to increase aqeous solubility of the drug along with improving the micromeritic properties.

Precompressional studies of aceclofenac agglomerates:

The results of various precompressional evaluations of agglomerates are given in Table 2 and 3. The practical yield was found satisfactory and ranged from 77.4 to 82.2%. The drug loading of the agglomerates was uniform among the different spherical crystals prepared and range from 95.2 to 99.2% w/w indicating negligible loss of drug during the process. As both phases (acetone and aqueous) contain the disintegrant, then it is likely that it is distributed both inside the agglomerates (intagranularly) and outside the agglomerates (extragranularly), attached to the surface. The maximum amount of disintegrant incorporated in to agglomerates was sodiumstarch glycolate (19.67% in F8). The geometric mean diameters of the agglomerates (451-513 µm) were approximately 23 times larger than those of the untreated aceclofenac (22.49 ± 10.4 µm). The data indicate that the original single crystals of drug were uniformly agglomerated by the spherical crystallization process employed. The presence of HPC on the particle surface increases particle-particle interaction, causing faster squeezing out of DCM to the surface, resulting in increased particle size.

Micromeretic properties:

The prepared agglomerates showed improved flowability when compared to pure drug as observed from the values of angle of repose (24.1-28.5⁰), Hausner’s ratio (1.0–1.22) and Carr’s index (8.86–11.6%). Among different agglomerates prepared, formulation F9 showed maximum flowability as evident by low values of angle of repose (23.04⁰), Hausner’s ratio (1.0) and Carr’s index (8.86). Pure drug exhibited poor flowability and compressibility as indicated by high value of angle of repose (46.57 ± 0.625⁰), Hausner’s ratio (1.45 ± 0.04) and Carr’s index (29.63 ± 0.29%). This is because of irregular shape and small size of the crystalline powder, which put hurdles in the uniform flow of powder from the funnel. The bulk and tapped densities of the spherical agglomerates were lower than corresponding values of the original sample. The reduction in bulk density of agglomerates indicates a greater porosity. The improved flowability of spherical agglomerates is due to increase in the sphericity of agglomerates, since the agglomerates displayed shape factor values close to 1. Results are shown in Table 4.

Solubility and packability studies

The results of solubility and pakability studies are shown in Table 5. The results of solubility studies indicate that pure aceclofenac possess a very low solubility in water (0.093 mg/ml) and hydrochloric acid buffer pH 1.2 (0.021 mg/ml).the drug solubility in agglomerates increased significantly, demonstrating that the incorporation of PEG 6000 enhances the drug solubility by improving wettability. Maximum solubility was observed in F9 (1.28 and 0.238 mg/ml in water and hydrochloric acid buffer pH 1.2 respectively).

Table 4: Micromeretic properties of aceclofenac-disntegrant agglomerates

Formulation code	Bulk Density^a (g/cm³)	Tapped Density^a (g/cm³)	Angle of repose^a (θ)	Hausner`s ratio^a	Carr`s index^a
Pure drug	0.38 ± 0.02	0.52 ± 0.03	46.57 ± 0.62	1.45 ± 0.04	29.63 ± 0.29
F1	0.25 ± 0.07	0.3 ± 0.12	28.55 ± 0.17	1.2 ± 0.02	10.34 ± 0.03
F2	0.26 ± 0.05	0.26 ± 0.16	27.3 ± 0.23	1.01 ± 0.02	11.69 ± 0.21
F3	0.22 ± 0.12	0.22 ± 0.08	25.04 ± 0.2	1.04 ± 0.02	9.6 ± 0.39
F4	0.22 ± 0.08	0.25 ± 0.1	26.5 ± 0.13	1.14 ± 0.11	10.66 ± 0.41
F5	0.24 ± 0.04	0.25 ± 0.2	26.1 ± 0.13	1.05 ± 0.01	10.06 ± 0.34
F6	0.26 ± 0.11	0.26 ± 0.12	24.1 ± 0.11	1.02 ± 0.01	9.04 ± 0.23
F7	0.23 ± 0.09	0.25 ± 0.16	25.2 ± 0.16	1.12 ± 0.03	9.72 ± 0.11
F8	0.23 ± 0.1	0.23 ± 0.09	25.2 ± 0.23	1.03 ± 0.02	9.69 ± 0.21
F9	0.25 ± 0.08	0.2 ± 0.05	23.04 ± 0.26	1.10 ± 0.02	8.86 ± 0.39
F10	0.22 ± 0.12	0.25 ± 0.08	24.5 ± 0.13	1.14 ± 0.05	9.06 ± 0.41

^aMean ± SD, n = 3.

Table 5: Solubility and pakability studies of aceclofenac-disintegrant agglomerates

Formulation code	*Solubility (mg/ml)**			Packability parameters
Formulation code	Phosphate buffer pH 6.8	Water pH 7.0	Hydrochloric acid buffer pH 1.2	a^a	1/b^a	k^b
Pure drug	11.4 ± 0.15	0.09 ± 0.18	0.021 ± 0.13	0.385	11.750	0.0027
F1	22.25 ± 0.18	0.21 ± 0.14	0.056 ± 0.11	0.094	57.532	0.0047
F2	37.31± 0.12	0.59 ± 0.15	0.10 ± 0.1	0.107	52.13	0.005
F3	41.85 ± 0.14	0.63 ± 0.12	0.12 ± 0.09	0.105	51.72	0.0051
F4	39.2 ± 0.11	0.60 ± 0.16	0.104 ± 0.05	0.108	54.16	0.0056
F5	47.17 ± 0.14	0.82 ± 0.11	0.155 ± 0.04	0.105	52.65	0.0054
F6	52.15 ± 0.12	0.90 ± 0.20	0.162 ± 0.08	0.105	51.89	0.0051
F7	49.2 ± 0.16	0.88 ± 0.25	0.157 ± 0.06	0.106	54.18	0.0057
F8	58.57 ± 0.21	1.02 ± 0.14	0.22 ± 0.10	0.107	53.16	0.0058
F9	64.25 ± 0.24	1.28 ± 0.16	0.238 ± 0.14	0.106	52.13	0.057
F10	57.49 ± 0.14	1.17 ± 0.15	0.227 ± 0.06	0.107	52.52	0.0058

^*Mean ± SD, n = 3; ^a Parameters in Eq. 1; ^b Parameters in Eq. 3

Fig. 1: Comparative FTIR spectrum of pure drug, Formulation F9 and its physical mixture

The low values of the Carr index and parameter a of the Kawakita equation for the agglomerates indicated that the agglomerates have better packability. In other words they are well packed before tapping since tapping does not improve the packing significantly. The large 1/b-value of agglomerates indicated that the apparent packing velocity obtained by tapping for the agglomerates was slower or the cohesiveness of the agglomerates was larger than that for the untreated particles, since the agglomerates were packed more closely, even without any tapping, as a consequence of their better flowability and packability. The larger k (derived from Eq. 4) obtained for the agglomerates confirmed these findings.

FTIR, DSC and PXRD studies:

The possible interaction between the drug and the carrier was studied by IR spectroscopy and DSC. The principal IR peaks of the pure aceclofenac, physical mixture and spherical agglomerates are shown in Table 6 and Fig. 1. There was no considerable change in the positions of characteristic absorption bands and bonds of various functional groups present in the drug. This observation clearly suggests that the drug remains in its normal form with no prominent change in its characteristics even in its physical mixture and formulation. The results of IR spectra indicated the absence of any well defined interaction between drug and the carrier in the presence of acetone, dichloromethane and water.

Fig. 2: Comparative DSC thermograms of pure aceclofenac and Formulation F9

The DSC pattern of pure aceclofenac and its agglomerates are shown in Fig. 2. In the DSC studies pure aceclofenac showed a sharp endotherm at 152.51⁰C corresponding to its melting point. There was no appreciable change in the melting endotherm of spherical agglomerates compared to that of pure drug (F7 agglomerates = 153.27 ⁰C). The DSC results (Fig. 5) also revealed little amorphization of aceclofenac when prepared in the form of agglomerates with HPC. This is evident by a decrease, although little, in the enthalpy changes of agglomerates when compared with that of pure drug (pure aceclofenac = -391.59 mJ/mg; F7 agglomerates = -388.45 mJ/mg).

The results of PXRD pattern of aceclofenac and its agglomerates are shown in Fig. 3. The PXRD scan of plain aceclofenac showed intense peaks of crystallinity, whereas the PXRD pattern of the agglomerates exhibited halo pattern with less intense and denser peaks compared to plain aceclofenac indicating the decrease in crystallinity or partial amorphization of the drug in its agglomerated form.the results also indicated that polymorphic changes had not been detected after recrystallization, since all PXRD peaks of the spherical agglomerates were consistent with the pattern of original drug crystals.

Fig. 3: Comparative PXRD patterns of (a) pure drug, (b) Formulation F9 and (c) physical mixture of F9

Fig. 4: SEM of (a) Pure aceclofenac crystals, (b) Shape and (c) Surface of aceclofenac-crospovidone agglomerates (F9), (d) Shape and (e) Surface of agglomerates without disintegrant (F1)

Table 6: FTIR of pure aceclofenac, physical mixture and agglomerates of formulation F9

Major peaks (wave number, cm^-1)	Aceclofenac pure drug	F9 physical mixture (aceclofenac + CP)	Formulation F9
O-H and N-H stretching (Hydrogen bonded).	3340 and 3282	3340 and 3280	3340 and 3280
Aromatic C-H stretching.	3065	3060	3060
C-H stretching of CH₂ groups (asymmetric and symmetric).	2970 and 2937	2970 and 2937	2970 and 2937
C=O of COOH.	1768	1770	1770
C=O of side chain.	1728	1725	1725
C=C ring stretching.	1589, 1504 and 1490	1589, 1504 and 1490	1589, 1504 and 1490
C-H bending of CH₂ groups (asymmetric and symmetric).	1440 and 1344	1438 and 1344	1438 and 1342
O-H bending.	1247	1247	1247
C-O-C	1151	1149	1151
Substituted phenyl rings	858 and 760	860 and 755	858 and 750
C-Cl	663	663	659

Table 7: Physico-chemical evaluation of aceclofenac tablets

Formulation Code	Thickness^a (mm)	Diameter^a (mm),	Hardness test^a (Kg/cm²)	Friability^b (%)	Weight variation^c (%)	Disintegration time^d (sec)
F1	3.23 ± 0.04	7.13 ± 0.01	3.0 ± 0.12	0.38 ± 0.01	1.35 ± 0.12	75.43 ± 0.51
F2	4.25 ± 0.12	7.18 ± 0.05	3.2 ± 0.14	0.39 ± 0.04	2.32 ± 0.17	25.03 ± 0.64
F3	4.33 ± 0.04	7.14 ± 0.02	4.1 ± 0.15	0.36 ± 0.14	1.67 ± 0.24	22.95 ± 0.22
F4	4.35 ± 0.17	7.18 ± 0.03	3.9 ± 0.14	0.38 ± 0.02	1.53 ± 0.15	26.71 ± 0.5
F5	4.28 ± 0.05	7.18 ± 0.05	3.4 ± 0.13	0.42 ± 0.18	2.1 ± 0.15	24.34 ± 0.11
F6	4.35 ± 0.03	7.11 ± 0.03	4.1 ± 0.12	039 ± 0.24	1.32 ± 0.13	20.59 ± 0.31
F7	4.33 ± 0.03	7.14 ± 0.03	3.8 ± 0.14	0.45 ± 0.10	1.7 ± 0.15	24.12 ± 0.9
F8	4.25 ± 0.12	7.18 ± 0.05	3.4 ± 0.14	0.36 ± 0.04	2.31 ± 0.12	22.58 ± 0.21
F9	4.33 ± 0.04	7.14 ± 0.02	4.2 ± 0.15	0.28 ± 0.14	1.6 ± 0.2	18.03 ± 0.5
F10	4.35 ± 0.17	7.18 ± 0.04	3.9 ± 0.14	0.34 ± 0.02	1.36 ± 0.13	22.42 ± 0.6

^aMean ± SD, n = 3; ^bMean ± SD, n = 10; ^cMean ± SD, n = 20, ^dMean ± SD, n = 6.

Morphology of agglomerates (SEM):

An examination of the SEMs, confirm that the aceclofenac pure drug (Fig. 4a) was markedly smaller in particle size than the prepared agglomerates and was plate-like in appearance with no evidence of porosity. Aceclofenac-crospovidone agglomerates (Fig. 4b) illustrate aceclofenac particles crystallized from acetone-water system containing HPC, PEG-6000 and disintegrants. SEMs obtained at higher magnifications (Fig. 4c) revealed that agglomerates were spherical aggregates of plate-shaped crystals with clear evidence of porosity. It was also apparent that the presence of disintegrating agent in crystallization medium produced agglomerates with a high surface roughness. Aceclofenac agglomerates prepared by CCA technique but without disintegrant were also found to be spherical (Fig. 4d). The higher magnifications of aceclofenac agglomerates without disintegrating agent (Fig. 4e) indicate uniform surface with no evidence of porosity. The Fig. 4b and 4d clearly indicate that the use of disintegrant in the crystallization media had no major effect on the overall shape of aceclofenac crystals.

Physico-chemical evaluations of tablets:

The results of physicochemical evaluations of tablets are given in Table 7. The thickness and diameter of all tablets was found in range of 3.23-4.35 mm and 7.11- 7.18 mm respectively. Hardness of tablets was between 3.0-4.1 kg/cm² for all the formulations. This ensures the good handling characteristics of all the formulations. Friability was found in between 0.28-0.45% in all the formulation ensuring that the tablets were mechanically stable. The weight variation was found to be in the range of 1.32-2.3% which is within the acceptable limits.

Fast disintegration of tablets is a prerequisite for improving the dissolution of drug. This could be attributed to an increase in the surface area of the practically water insoluble drug exposed to the dissolution medium after disintegration of tablet. Therefore it was expected that any changes in disintegration time would alter the dissolution profiles of aceclofenac. This rapid disintegration assists swallowing and also plays a role in drug absorption in buccal cavity. The disintegration time for all the formulations ranged 18-26 sec. The agglomerates without any disintegrant showed disintegration time of 75 sec. The formulation F9 containing crospovidone as disintegrant showed least disintegration time of 18 sec among all the formulations. The faster disintegration of crospovidone tablets when compared tablets with other disintegrants may be attributed to its rapid capillary activity and pronounced hydration with little tendency to gel formation.

In vitro drug release studies:

The dissolution proﬁles of drug and its agglomerates are shown in Fig. 5 and 6. In vitro release profile of all formulations (F1-F10) in phosphate buffer pH 6.8 was ranging from 99.13-99.96%. The formulation F1 containing untreated aceclofenac showed 99.41% release in 28 min. The dissolution profiles of tablet were influenced by nature and concentration of superdisintegrants, which could be attributed to deposition of polymer onto the drug surface. The best formulations in case of each superdisintegrant with respect to drug release were F8 in case of SSG (99.88% in 14 min), F9 for CP (99.13% in 8 min) and F10 for CCS (99.85% in 10 min). Marketed formulation (zerodol) showed in vitro drug release of 85.36% in 10 min.

Fig. 5: In vitro release profile of aceclofenac agglomerates in phosphate buffer pH 6.8

Fig. 6: In vitro release profile of aceclofenac agglomerates in hydrochloric acid buffer pH 1.2

In vitro drug release of marketed formulation (zerodol) in hydrochloric acid buffer pH 1.2 was 5.09% for 30 min. The incomplete release could be due to poor solubility of aceclofenac in hydrochloric acid buffer pH 1.2. Hence the drug solubility in pH 1.2 was improved by adopting CCA technique. In vitro release profile of all formulations (F1-F10) in hydrochloric acid buffer pH 1.2 was carried out and the results ranged from 92.863-99.084%. The formulation F1 containing untreated aceclofenac showed 80.62% release in 30 min. The dissolution profiles of tablet were influenced by nature of superdisintegrants. The best formulations in case of each superdisintegrant with respect to drug release were F8 in case of SSG (96.8% in 14 min), F9 for CP (99.04% in 10 min) and F10 for CCS (98.37% in 12 min).

The aceclofenac agglomerates prepared with HPC and PEG 6000 exhibited better dissolution rate when compared with plain aceclofenac. Mainly two attributes to enhance drug dissolution rate from F-9 agglomerates can be considered; viz., surface treatment with HPC, PEG 6000 and formation of partially amorphous aceclofenac during crystallization process. Among the formulations prepared, F9 (with 350 mg CP) showed highest drug release of 99.13 and 99.04% drug in 8 and 10 min respectively in pH 6.8 and 1.2 buffers.

CONCLUSION:

Aceclofenac-disintegrant agglomerates prepared by crystallo-co-agglomeration technique have shown improved ﬂowability, solubility, packability and compactibility resulting in successful direct tableting without capping. The main factor in the improvement of the ﬂowability and packability was a signiﬁcant reduction in interparticle friction, due to the spherical shape of the tableted particles. The dissolution rate of aceclofenac from the aceclofenac-disintegrant agglomerates was enhanced signiﬁcantly with increasing the amount of disintegrant.

ACKNOWLEDGEMENT:

The authors greatly acknowledge Aristo Pharmaceuticals Ltd., Mumbai; Torrent Pharmaceuticals Ltd., Ahmedabad; Nippon soda, Japan for the gift samples of Aceclofenac, CP and HPC respectively.

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Received on 02.06.2011 Accepted on 20.06.2011

Asian J. Pharm. Tech. 1(2): April-June 2011; Page 40-48