Robert Kevin Perrone

The synthesis and characterization of BMS-204352 (MaxiPost) and related 3-fluorooxindoles as openers of maxi-K potassium channels

3-Aryl-3-fluorooxindoles can be efficiently synthesized in two steps by the addition of an aryl Grignard to an isatin, followed by treatment with DAST. Oxindole 1 (BMS-204352; MaxiPost) can be isolated using chiral HPLC or prepared by employing chiral resolution. Cloned maxi-K channels are opened by 1, which demonstrates a brain/plasma ratio >9 in rats.

Pharmaceutical relationships of three solid state forms of stavudine

Three solid state forms of stavudine designated forms I, II and III have been identified and characterized. Forms I and II are anhydrous polymorphs whereas form III is hydrated and is pseudopolymorphic with forms I and II. Physico-chemical and thermodynamic properties of the three solid state forms have been characterized. Solid-state stability and potential for interconversion of the forms to aid in the selection of preferred form for development and commercialization has been studied. Conditions of recrystallization governing the formation of thermodynamically most stable polymorphic form I devoid of other forms was identified.

From bench to humans: formulation development of a poorly water soluble drug to mitigate food effect.

This study presents a formulation approach that was shown to mitigate the dramatic food effect observed for a BCS Class II drug. In vitro (dissolution), in vivo (dog), and in silico (GastroPlus®) models were developed to understand the food effect and design strategies to mitigate it. The results showed that such models can be used successfully to mimic the clinically observed food effect. GastroPlus® modeling showed that food effect was primarily due to the extensive solubilization of the drug into the dietary lipid content of the meal. Several formulations were screened for dissolution rate using the biorelevant dissolution tests. Surfactant type and binder amount were found to play a significant role in the dissolution rate of the tablet prototypes that were manufactured using a high-shear wet granulation process. The performance of the lead prototypes (exhibiting best in vitro dissolution performance) was tested in dogs and human subjects. A new formulation approach, where vitamin E TPGS was included in the tablet formulation, was found to mitigate the food effect in humans.

Synthesis and anti-MRSA Activity of Novel Cephalosporin Derivatives

Abstract Cephalosporin derivatives containing a unique combination of lipophilic C-7 sidechains and polar C-3 thiopyridinium groups were synthesized and found to exhibit potent anti-MRSA activity in vitro and in vivo. The optimum C-7 sidechains utilized were 2,5-dichlorophenylthioacetamido and 2,6-dichloropyrid-4-ylthioacetamido. The C-3 thiopyridinium rings were substituted at nitrogen with amino acid and pyruvic acid groups that were designed to confer aqueous solubility as required for IV formulation. This paper describes the characteristics of these novel cephalosporins and highlights synthetic methods developed to allow their practical, large-scale syntheses.

Determination of polymeric impurities in asunaprevir drug substance and product using size exclusion effect of reversed-phase columns

Graphical abstract Figure. No caption available. HighlightsA simple RPLC method was developed for a polymeric impurity in drug substance and product.Overcome several challenges of polymer quantitation such as band broadening, peak coeluting and low sensitivity.The method demonstrated adequate accuracy, precision, sensitivity and robustness. ABSTRACT This paper describes the development of a simple reversed‐phase HPLC method that can quantitate trace amounts of a polymeric degradants (BMT‐041910) in asunaprevir drug substance and formulated drug product with quantitation limits of ˜0.05% w/w. The method has overcome several challenges of polymer quantitation such as band broadening, peak coeluting and low sensitivity. The hydrophobic function group (BOC) of BMT‐041910 is removed to increase its aqueous solubility by a simple sample treatment procedure (des‐BOC). The des‐BOC polymer (BMT‐052076) is excluded from stationary phase pores and eluted as a single peak before solvent front, and then its peak area response can be used to determine BMT‐041910 amount. The HPLC conditions were optimized using a 250 × 4.6 mm Waters XSelect CSH column maintained at 30 °C with a mobile phase of water‐acetonitrile‐trifluoroacetic acid (20:80:0.1 v/v/v). The feasibility of other HPLC approaches including size exclusion chromatography and normal phase chromatography were also investigated and found to be less suitable for this particular application. Validation data for this method in terms of precision, linearity, accuracy and sensitivity are also presented.