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INTRODUCTION

Compression of timed-release microspheres/ microcapsules into tablets is an alternate to encapsulation in hard gelatin capsules (HGC).  The design of such dosage form should reduce some of the disadvantages of HGC, namely; the tampering potential with contents and the higher cost associated with filling.  The new dosage form should be designed to disintegrate rapidly in the stomach, and upon disintegration should release its contents of, preferably, undamaged pellets. The aim of this work is to attempt to compress pellets containing ketoprofen with the aid of a suitable mix of excipients in order to reduce/keep the damage to individual microspheres to minimal.  The excipients will be used in the form of powders, granules or placebo pellets prepared by extrusion – spheronization technology.

 Materials & Methods

 Ketoprofen capsules 200 SR (Al-Amriah pharm, Egypt.), Microcrystalline cellulose [(MCC), Avicel PH101, ], lactose ( ), calcium carbonate, starch, coloring pigment, ethanol,

 Wet Granulation

Equal mixes of excipients comprising starch, MCC, calcium carbonate, or lactose in addition to a coloring pigment were mixed in a Turbula mixer for 5 min. Then different volumes of either water or ethanol as a wetting solvent were added while mixing in a mortar until wet masses were formed.  The wet masses were then fed to a oscillating granulator equipped with sieve size 1mm, and the produced granules were then dried at 45^oC.

 Extrusion – Spheronization

Equal mixes of excipients were mixed, wetted with water, placed in an extruder (Caleva 25), and spheronized at 1000 rpm in Caleva-250 for 5 min.  The produced pellets were then dried and separated into fractions by sieving analysis.

Results & Discussion

The density of the materials used in this study was determined by solvent displacement method (Table 1), and the results indicate that those materials have similar densities except for calcium carbonate. This may imply that possible problems of segregation between the mixes of excipients may be minimal because of the similar densities.

 Table 1. The apparent true density of the different excipients used as determined by solvent displacement method.

N.B.  A=Avicel; L=Lactose; C=CaCO₃; S=Starch.

The effect of granulating liquid on the flowability of prepared granules is summarized in Table 2. The results indicate that the flowability according to the tested parameters were all acceptable. And in some combinations, the type of solvent used will have significant effect on the flowability of granules. This may be attributed to the strength of binding bridges between excipients molecules as formed by the wetting liquid.

Table 2.  Summary of the flowability parameters of granules prepared with either water or ethanol as a granulating liquid.

N.B.  A=Avicel; L=Lactose; C=CaCO₃; S=Starch.

The effect of granules type on their compression and mechanical properties is presented in Table 3.  It can be seen that the mechanical strength varies according to each combination of excipients used.  The friability was always below 1%.  Disintegration also was very rapid, with maximum value of not more than 2 min were required.  These results also indicate that the selected wetting solvent for granulation will also affect the mechanical properties of any prepared tablets.

Direct Compression

Weights of 400 mg of powders, granules or pellets were compressed using hand operated IR press with a flat-face 12 mm punch and die set. 

 Evaluation of Flowability of Granules and Pellets

The dry powders, and produced granules and pellets were evaluated for their flowability using tapping density method followed by estimation of Hausner & Carr’s index) and angle of repose determination.  Also, true density measurement using solvent displacement method was conducted (using ethanol as the non-solvent).

 Direct compression of Microspheres

Ketoprofen microspheres were emptied from their gelatin shell and mixed with a combination of excipients granules comprising MCC + starch and MCC + Ca carbonate. The percentage of active drug particles was 40%.  The compression force used was 2 tons for 15 sec. The tablets were evaluated for their mechanical properties and release profiles at least 24 hr following preparation.

 Evaluation of Produced Tablets

The produced tablets were evaluated for the following properties:

Hardness, using a hardness tester followed by mathematical estimation of tensile strength (Ts).

 Friability, using a friability tester, in this method 5 tablets were subjected to this test for 4 minutes.

 Disintegration, by using a disintegration tester employing 0.1 N HCl as the disintegration medium.

 Dissolution: by using a dissolution tester and employing purified water as the dissolution medium.  The samples were analyzed spectrophotometrically at 264 nm.

Table 3 : Summary of the mechanical properties of tablets prepared with of different mixes of granules moistened with water of alcohol.

N.B: A=Avicel; L=Lactose; C=CaCO₃; S=Starch.

The two combinations of A+S & A+C granules (60%) were selected to be compressed with active ketoprofen pellets (40%).  The dissolution profiles in purified water from such tablets are shown in Figure 1.  Based on statistical analysis using t-test, ANOVA and similarity function (f₂), a significant degree of damage has occurred to the active drug pellets during compression.  The degree of damage was lower when A+S combination was used.  Which may also indicate that when calcium carbonate was used, and because of its higher density, it could have resulted in added pressure against the active drug molecules.  These results collectively show that the need for high levels of excipients will be necessary in order to prepare pellets in the form of tablets with the optimum requirement.

References

1. Bahsir, A.A., (2004), J. Pharm. Pharmacol.

2. El-Mahdi, I.M., Banigesh, A.I., (2003), Int. J. Pharm.

3. Al-Zagallai, A.A., (2004), Int. J. Pharm.