Samuel J. Tremont

Palladium-mediated 2,6-dialkylation of N-benzilidine imines: Preparation of 2,6-dialkylbenzaldehydes

Abstract Treatment of di-μ-trifluoroacetatobis[o-(N-phenylbenzimidoyl)]dipalladium with two equivalents of primary alkyl iodides and subsequent hydrolysis provides an efficient route to 2,6-disubstituted benzaldehydes.

Supercritical fluid extraction-liquid chromatography method development for a polymeric controlled-release drug formulation

We have recently been involved in the development of a method for assaying the active component in a controlled-release drug formulation, which is composed of a drug substance covalently bonded to polymer matrix. The drug substance in the formulation is the active enantiomer of misoprostol, a synthetic analog of natural prostaglandins and the active ingredient in Cytotec. Our method development consisted of a systematic evaluation of dynamic, off-line supercritical fluid extraction (SFE) as sample preparation for the formulation assay. Extracts were analyzed with normal phase and reversed-phase HPLC methods. The reversed-phase system utilized postcolumn reaction to provide selective detection of the extracted prostaglandin sample components. Several SFE parameters were investigated to optimize the recovery of the drug substance from the formulation, including sample quantity, extraction cell volume, extraction duration, supercritical carbon dioxide modifier, temperature, pressure, and collection solvent. The SFE experiments were completed with a commercially available multicell extractor. Preliminary validation studies utilized a formulation made with radiolabeled drug to determine the recovery achieved under the optimized SFE conditions and assessed the precision of replicate determinations. Analysis was completed under the optimized conditions to quantitate levels of the active component and related compounds in lots of the experimental polymeric formulation and to determine the total weight per cent extracted.

Polymer Delivery of the Mucosal Protective Prostaglandin Misoprostol

Misoprostol is currently marketed throughout the world for the prevention of non-steroidal anti-inflammatory drug-induced gastric/duodenal damage. Although safe and effective, intestinal side-effects, namely diarrhoea and cramping, can limit its use. We have developed and studied polybutadiene-based polymeric delivery systems for misoprostol to address side-effect problems. These systems were designed to slowly release drug in the stomach (pH 1–3) but not in the intestine (pH > 5). A covalent silicon ether bond from the polymer to the C-11 hydroxy group of misoprostol is the key element for selective gastric release. Initial polymer/misoprostol studies showed that (1) increasing the steric hinderance around the silyl ether reduced the in-vitro release rate of prostaglandin, (2) diarrhoea was absent following intrajejunal and intracolonic administration of these materials, (3) reducing the gastric release rate of drug from the polymer reduced intestinal side-effects without affecting antilesion activity, and (4) polymer delivery reduced the systemic availability of prostaglandin. Consequently, a polymer system (SC-53450) carrying the active isomer of misoprostol (SC-30249) was studied relative to misoprostol/hydroxypropyl methylcellulose (HPMC) in both rats and dogs. This material has a spectrum of mucosal protective activity in rats similar to misoprostol/HPMC, being protective against indomethacin-induced gastric, cysteamine/indomethacin-induced duodenal and indomethacin-induced lower small bowel damage. In contrast to misoprostol/HPMC, SC-53450 was not diarrhoeagenic in the rat when administered intragastrically.