(631f) Interactive Mixtures for Dissolution Rate Enhancement of Cefuroxime Axetil

The poor aqueous solubility of newly developed drug molecules is often associated with slower dissolution rate in biological fluids, insufficient and inconsistent biological exposure and sub-optimal efficacy in patients when delivered via the peroral route of administration. One of the methods commonly employed to enhance the dissolution rate is to increase the surface area available for dissolution. In principle, for a given dose of drug, increasing the surface area by decreasing the particle size will lead to a proportional increase in dissolution rate. However, formulations containing micronized drug particles do not always exhibit an improvement in dissolution rate; even reduced rates have been reported. This has been attributed to the agglomeration of fine, primary particles (due to electrostatic and van der Waals forces), which decreases the surface area available for dissolution.

            One approach used to take better advantage of this particle size reduction procedure is the preparation of interactive mixtures. Interactive mixtures result from the adherence of fine particles of one constituent to the considerable larger particles of the other (carrier particle). On contact with the dissolution medium, the carrier particles (water-soluble or hydrophilic) dissolve rapidly and also facilitate wetting of the drug particles, releasing the dispersed drug particles into the dissolution medium. This method is believed to maximize the fraction of the particles surface that is in contact with the dissolution medium, thus improving the dissolution rate. This approach should increase the dissolution rate of poorly-soluble drugs such as cefuroxime axetil (CFA).

EXPERIMENTAL

The current study investigates the possibility of dissolution rate enhancement of CFA (commercially available, amorphous API, < 53 µm size range) by forming an interactive mixture with coarse carrier particles of sucrose (500-1000 µm size range). Interactive mixtures with 10% w/w drug loading were prepared using a high shear centrifugal planetary mixer (Thinky USA, Inc.) which was able to deagglomerate the drug particles and cause them to adhere to the sucrose carrier particles. Physical mixtures containing the same amount of drug were also made using a laboratory-scale end-over rotation V-blender for comparison. This mixing method did not effectively break up the CFA agglomerates and the absence of interaction was assessed using optical microscopy. Mechanical stability of the mixtures was determined by sieving methods.  Dissolution studies were performed as per the USP 32/NF 27 method for cefuroxime axetil tablets using 0.07N hydrochloric acid (900 ml) as the dissolution medium with the basket apparatus. Samples were analyzed using a validated UV spectroscopic assay. Dissolution studies were performed for the CFA agglomerates as well. The intrinsic dissolution rate of the API itself was measured for reference using the stationary disk method.

RESULTS

The intrinsic dissolution rate (IDR) of amorphous CFA was found to be 0.0765±0.009 mg/cm²/min. Interactive mixtures of the model drug, CFA and sucrose carrier particles showed a significant improvement in dissolution rate as compared to physical mixtures of the same and CFA agglomerates. The amount dissolved with respect to time was modeled using the Wagner model (assuming exponential surface area changes). The rate constant determined by this method for the CFA agglomerates, physical mixture and interactive mixture with sucrose (n=3 each) were 0.0010±0.0000065 min^-1, 0.0014±0.000013 min^-1 and 0.0254±0.0012 min^-1, respectively. In addition the effective specific surface area (SSA) was calculated using the rate constant and IDR values. The SSA was found to be 331.61±15.39 cm²/g, 17.64±1.26cm²/g and 12.96±0.84 cm²/g for the interactive mixture, physical mixture and CFA agglomerates respectively. These results indicate that interactive mixing resulted in a significant increase in the fraction of the particles surface area that was available for dissolution leading to an increase in the dissolution rate. The considerably slower dissolution of CFA agglomerates and the physical mixture can be attributed to the fact that a large fraction of the particles surface was inaccessible to the dissolution medium. This problem was overcome by distributing primary particles of the API over the surface of the water-soluble carrier particles in the interactive mixture.

CONCLUSION

Agglomeration of fine particles is a particular problem for hydrophobic drugs which can limit the amount of drug that can dissolve and as a result contribute to the poor oral bioavailability of such drugs. In addition agglomeration can also to negate the particle size reduction procedure that is commonly employed to improve dissolution rate. This study demonstrated that deagglomeration of the CFA agglomerates and distribution of the primary particles of the drug over the surface of the carrier particles significantly enhanced the dissolution rate by increasing the effective surface area of the fine drug particles exposed to the dissolution medium and thus available for dissolution. It is expected that interactive mixtures can help to overcome limitations associated with the use of poorly-soluble, finely powdered drugs. This approach can be further extended to other poorly-soluble drugs in cases where it is critical to maximize the amount dissolved in the gastrointestinal tract.