Thiazolide Prodrug Esters and Derived Peptides: Synthesis and Activity.

Amino acid ester prodrugs of the thiazolides, introduced to improve the pharmacokinetic parameters of the parent drugs, proved to be stable as their salts but were unstable at pH > 5. Although some of the instability was due to simple hydrolysis, we have found that the main end products of the degradation were peptides formed by rearrangement. These peptides were stable solids: they maintained significant antiviral activity, and in general, they showed improved pharmacokinetics (better solubility and reduced clearance) compared to the parent thiazolides. We describe the preparation and evaluation of these peptides.

Statistical analysis of tablet breakability methods.

PURPOSE: Using a model tablet, the influence of breakability methodology on mass uniformity of half- and quarter-tablets as well as the comparison of different data acquisition and evaluation approaches were investigated. Moreover, different breakability evaluation criteria were compared based upon distribution as well as distribution-free models. METHODS: A cross-scored tablet, i.e. having two break-marks, was broken by different methods by different persons, and the masses determined for the whole (unbroken) tablets, the half-tablets and quarter-tablets. RESULTS: Beside the possible interaction between the methodology and the person breaking the tablets, the major factor significantly influencing the mass uniformity of broken tablets is the breakability methodology. The best results, i.e. smallest loss and smallest variability, are obtained when the breaking force applied by the thumbs is directed towards the score side of the tablet, i.e. by "opening" the score. Using our model tablet, significant differences between the different evaluation criteria are observed, with the USP/NF approach being best in line with the detailed analysis of all broken tablets. CONCLUSIONS: Assuming that for this model tablet the variance is a linear function of the break-line length, the standard deviation of quarter-tablets is theoretically calculated to be 0.87 times the standard deviation of the half-tablets. As the absolute standard deviation, expressed in mass units, will thus remain approximately identical, the relative standard deviation will nearly double as the mean mass of the quarter-tablets will be half of the mean mass of the half-tablets. This was experimentally confirmed.