Pore networks and polymer rearrangement on a drug-eluting stent as revealed by correlated confocal Raman and atomic force microscopy.

Drug release from and coating morphology on a CYPHER sirolimus-eluting coronary stent (SES) during in vitro elution were studied by correlated confocal Raman and atomic force microscopy (CRM and AFM, respectively). Chemical surface and subsurface maps of the SES were generated in the same region of interest by CRM and were correlated with surface topography measured by AFM at different elution times. For the first time, a direct correlation between drug-rich regions and the coating morphology was made on a drug-eluting medical device, linking drug release with pore formation, pore throats, and pore networks.

Forced degradation studies of rapamycin: identification of autoxidation products.

The immunosuppressant drug rapamycin, also known as Sirolimus, underwent autoxidation under mild conditions to give numerous monomeric and oligomeric compounds, which were generally characterized by size-exclusion chromatography and NP-HPLC with UV and MS detection. Some of the more predominant products, epoxides and ketones, were isolated and identified. Two epoxides and 10S-epimer of rapamycin were described for the first time.

Mass balance in rapamycin autoxidation.

The immunosuppressant drug rapamycin is a complex polyene-containing natural product which undergoes autoxidation. The resulting product mixtures contained numerous monomeric and oligomeric compounds, which represented challenges for addressing mass balance in forced degradation studies and in analysis of aged developmental drug-eluting stents. A combination of SEC with ultraviolet and refractive index detection and RP-HPLC was used to account for drug loss and product formation.

Investigation of mass-balance issue in e-beam sterilized paclitaxel eluting coronary stents by SPME/GC-MS.

Paclitaxel eluting coronary stents were sterilized by e-beam in a closed system, to investigate sterilization related mass-balance issues and evaluate potential volatile paclitaxel degradation products. A solid-phase microextraction (SPME) method utilizing a polydimethyl-siloxane/divinyl-benzene (PDMS/DVB) fiber was optimized for extracting the volatiles from the head-space of the sterilized stents. GC-MS was used for separation, identification, and quantitation of the components.

Thrombogenic collagen-mimetic peptides: Self-assembly of triple helix-based fibrils driven by hydrophobic interactions.

Collagens are integral structural proteins in animal tissues and play key functional roles in cellular modulation. We sought to discover collagen model peptides (CMPs) that would form triple helices and self-assemble into supramolecular fibrils exhibiting collagen-like biological activity without preorganizing the peptide chains by covalent linkages. This challenging objective was accomplished by placing aromatic groups on the ends of a representative 30-mer CMP, (GPO)(10), as with l-phenylalanine and l-pentafluorophenylalanine in 32-mer 1a.

Multivariate analysis applied to the study of spatial distributions found in drug-eluting stent coatings by confocal Raman microscopy.

Multivariate data analysis was applied to confocal Raman measurements on stents coated with the polymers and drug used in the CYPHER Sirolimus-eluting Coronary Stents. Partial least-squares (PLS) regression was used to establish three independent calibration curves for the coating constituents: sirolimus, poly(n-butyl methacrylate) [PBMA], and poly(ethylene-co-vinyl acetate) [PEVA]. The PLS calibrations were based on average spectra generated from each spatial location profiled.

An investigation of adhesion in drug-eluting stent layers.

An atomic force microscopy (AFM) method was developed to quantify the adhesion forces between and cohesive forces within the layers of a drug-eluting stent (DES). Surface pairs representing both the individual components and the complete chemistry of each layer within the DES were prepared. As a model, the CYPHER Sirolimus-eluting Coronary Stent was studied.

Determination of relative response factors of impurities in paclitaxel with high performance liquid chromatography equipped with ultraviolet and charged aerosol detectors.

A case study was conducted to determine the relative response factors (RRFs) of paclitaxel-related impurities by high performance liquid chromatography (HPLC) equipped with an ultraviolet (UV) detector and charged aerosol detector (CAD) in tandem. The peak response using CAD was independent of analyte structure in an isocratic analysis for this application. After a sample containing known and unknown impurities was analyzed with HPLC-UV-CAD, an empirical approach was developed to calculate the RRFs for all impurities.

Methodology for the preparation of 2-argininylbenzothiazole.

An efficient process to produce kilogram quantities of a key argininylbenzo[d]thiazole intermediate was developed for the preparation of the tryptase inhibitor RWJ-56423. A variety of activated arginine esters and benzo[d]thiazole nucleophiles were evaluated as coupling partners. Our work led to the selection and optimization of an argininyl imidazolide ester and benzothiazol-2-yl MgCl nucleophile.

A new procedure for preparation of carboxylic acid hydrazides.

The standard method for preparing carboxylic acid hydrazides is hydrazinolysis of esters in alcoholic solutions. However, when applied to alpha,beta-unsaturated esters, the main product typically is the pyrazolidinone resulting from an undesired Michael-type cyclization. Other alternative methodologies reported for direct preparation of hydrazides from acids are inefficient.

Determination of the absolute configuration of a key tricyclic component of a novel vasopressin receptor antagonist by use of vibrational circular dichroism.

We present the results of a study using vibrational circular dichroism (VCD) for (+)-1, which furnished an unambiguous determination of its absolute configuration as S. The most abundant conformation of (+)-1 in CDCl(3) solution was also established.

Reductive Amination of Aldehydes and Ketones with Sodium Triacetoxyborohydride. Studies on Direct and Indirect Reductive Amination Procedures(1).

Sodium triacetoxyborohydride is presented as a general reducing agent for the reductive amination of aldehydes and ketones. Procedures for using this mild and selective reagent have been developed for a wide variety of substrates. The scope of the reaction includes aliphatic acyclic and cyclic ketones, aliphatic and aromatic aldehydes, and primary and secondary amines including a variety of weakly basic and nonbasic amines.