Bulk characterization of pharmaceutical powders by low-pressure compression II: effect of method settings and particle size.

The aim of the present study was to investigate the effect of punch and die diameter, sample size, compression speed, and particle size on two low-pressure compression-derived parameters; the compressed density and the Walker w parameter. The excellent repeatability of the low-pressure compression method allowed small effects of variations in punch and die diameter and sample size to be demonstrated on a high significance level. Changing the compression speed, however, did not cause a significant effect in the compressed density, whereas a decrease in w was seen. The effect of particle size was studied by compressing and tapping different grades of calcium carbonate, lactose, and microcrystalline cellulose. The low-pressure compression-derived parameters were compared to tapped densities and to Compressibility Indexes obtained by tapping volumetry. Even though the relationship between particle size and the low-pressure compression-derived parameters appeared to be more complicated, a similar trend was observed. It was concluded that the low-pressure compression method provides a useful alternative to the more sample-consuming methods providing flow-related information.

Bulk characterization of pharmaceutical powders by low-pressure compression.

Low-pressure compression of pharmaceutical powders using small amounts of sample (50 mg) was evaluated as an alternative to traditional bulk powder characterization by tapping volumetry. Material parameters were extrapolated directly from the compression data and by fitting with the Walker, the Kawakita, and the Log-Exp compression models. The compression-derived material parameters were compared to the poured and tapped density and the Compressibility Index determined by tapping. The repeatability of the compression-derived parameters was generally high, supporting their potential for characterization purposes. Significant correlation was demonstrated between several of the compression and tapping-derived parameters. The discriminative power of the low-pressure compression test was discussed using the compressed density at 0.2 MPa, correlated with the tapped density, and the relative Walker coefficient, correlated with the Compressibility Index, as examples. The compressed density at 0.2 MPa and the relative Walker coefficient demonstrated excellent discriminative power, superior to the discriminative power of the correlated tapping derived parameters. The low-pressure compression test was concluded to provide a cost-effective and sensitive alternative to traditional tapping volumetry.

Prodrugs of purine and pyrimidine analogues for the intestinal di/tri-peptide transporter PepT1: affinity for hPepT1 in Caco-2 cells, drug release in aqueous media and in vitro metabolism.

A general drug delivery approach for increasing oral bioavailability of purine and pyrimidine analogues such as acyclovir may be to link these compounds reversibly to stabilized dipeptide pro-moieties with affinity for the human intestinal di/tri-peptide transporter, hPepT1. In the present study, novel L-Glu-Sar and D-Glu-Ala ester prodrugs of acyclovir and 1-(2-hydroxyethyl)-linked thymine were synthesized and their affinities for hPepT1 in Caco-2 cells were determined. Furthermore, the degradation of the prodrugs was investigated in various aqueous and biological media and compared to the corresponding hydrolysis of the prodrug valaciclovir. Affinity studies showed that the L-Glu-Sar prodrugs had high affinity for hPepT1 (K(i) approximately 0.2-0.3 mM), whereas the D-Glu-Ala prodrugs had poor affinity (K(i) approximately 50 mM). The pH-rate profiles of the prodrugs D-Glu[1-(2-hydroxyethyl)thymine]-Ala and L-Glu[acyclovir]-Sar showed specific base catalyzed degradation at pH above 4.5 and 5.5, respectively. This implicates that the degradation rates at pH approximately 7.4 (t(1/2) approximately 3.5 and 5.5 h) are approximately 25 times faster than at upper small intestinal pH approximately 6.0. In 10% porcine intestinal homogenate and 80% human plasma the half-lives of the L-Glu-Sar prodrugs were approximately between 45 and 90 min indicating a limited enzyme catalyzed degradation. In contrast, valaciclovir underwent extensive enzyme catalyzed hydrolysis in 10% porcine intestinal homogenate (t(1/2) approximately 1 min). In conclusion, L-Glu-Sar may potentially function as pro-moiety for purine and pyrimidine analogues, where release of parent compound primarily is controlled by a specific base catalyzed hydrolysis. Acyclovir is quantitatively released at the relevant pH 7.4, whereas the 1-(2-hydroxyethyl)-linked thymine is released instead of the parent compound thymine.