Publications by authors named "Kevin DeBoyace"

7 Publications

  • Page 1 of 1

Crystal structure of -butyl 4-[4-(4-fluoro-phen-yl)-2-methyl-but-3-yn-2-yl]piperazine-1-carboxyl-ate.

Acta Crystallogr E Crystallogr Commun 2021 Apr 5;77(Pt 4):360-365. Epub 2021 Mar 5.

Graduate School of Pharmaceutical Sciences, Duquesne University, 600 Forbes Ave, Pittsburgh, PA 15282, USA.

The title sterically congested piperazine derivative, CHFNO, was prepared using a modified Bruylants approach. A search of the Cambridge Structural Database identified 51 compounds possessing an butyl piperazine substructure. Of these only 14 were asymmetrically substituted on the piperazine ring and none with a synthetically useful second nitro-gen. Given the novel chemistry generating a pharmacologically useful core, determination of the crystal structure for this compound was necessary. The piperazine ring is present in a chair conformation with di-equatorial substitution. Of the two N atoms, one is hybridized while the other is hybridized. Inter-molecular inter-actions resulting from the crystal packing patterns were investigated using Hirshfeld surface analysis and fingerprint analysis. Directional weak hydrogen-bond-like inter-actions (C-H⋯O) and C-H⋯π inter-actions with the dispersion inter-actions as the major source of attraction are present in the crystal packing.
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http://dx.doi.org/10.1107/S2056989021002346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025862PMC
April 2021

Predicting Density of Amorphous Solid Materials Using Molecular Dynamics Simulation.

AAPS PharmSciTech 2020 Feb 26;21(3):96. Epub 2020 Feb 26.

Graduate School of Pharmaceutical Sciences, School of Pharmacy, Duquesne University, 600 Forbes Avenue, 422C Mellon Hall, Pittsburgh, Pennsylvania, 15282, USA.

The true density of an amorphous solid is an important parameter for studying and modeling materials behavior. Experimental measurements of density using helium pycnometry are standard but may be prevented if the material is prone to rapid recrystallization, or preparation of gram quantities of reproducible pure component amorphous materials proves impossible. The density of an amorphous solid can be approximated by assuming it to be 95% of its respective crystallographic density; however, this can be inaccurate or impossible if the crystal structure is unknown. Molecular dynamic simulations were used to predict the density of 20 amorphous solid materials. The calculated density values for 10 amorphous solids were compared with densities that were experimentally determined using helium pycnometry. In these cases, the amorphous densities calculated using molecular dynamics had an average percent error of - 0.7% relative to the measured values, with a maximum error of - 3.48%. In contrast, comparisons of amorphous density approximated from crystallographic structures with pycnometrically measured values resulted in an average percent error of + 3.7%, with a maximum error of + 9.42%. These data suggest that the density of an amorphous solid can be accurately predicted using molecular dynamic simulations and allowed reliable calculation of density for the remaining 10 materials for which pycnometry could not be done.
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http://dx.doi.org/10.1208/s12249-020-1632-4DOI Listing
February 2020

Differential scanning calorimetry isothermal hold times can impact interpretations of drug-polymer dispersability in amorphous solid dispersions.

J Pharm Biomed Anal 2018 Feb 2;150:43-50. Epub 2017 Dec 2.

Duquesne University Graduate School of Pharmaceutical Sciences, 600 Forbes Ave, Pittsburgh, PA 15282, United States. Electronic address:

Differential scanning calorimetry (DSC) is a commonly employed analytical technique for the analysis and characterization of amorphous solid dispersions. However, steps typical of standard temperature programs can alter the material in situ. Data for two active pharmaceutical ingredients are detailed, wherein isothermal hold times, traditionally employed to remove thermal history and/or residual solvent, were observed to impact the observed dispersability of the compounds in polyvinylpyrrolidone vinyl-acetate copolymer (PVPva). Re-crystallized tolbutamide was observed to re-dissolve in PVPva, while terfenadine was observed to crystallize during the isothermal hold period. Exposing co-solidified drug-polymer mixtures to temperature changes and experimental hold times can potentially confound correct categorization of dispersability, particularly when DSC is used as the lone characterization technique. This work illustrates the importance of using a combination of techniques to improve the certainty of conclusions made with respect to the true, initial physical state of a co-solidified mixture.
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http://dx.doi.org/10.1016/j.jpba.2017.12.001DOI Listing
February 2018

Modeling and Prediction of Drug Dispersability in Polyvinylpyrrolidone-Vinyl Acetate Copolymer Using a Molecular Descriptor.

J Pharm Sci 2018 01 12;107(1):334-343. Epub 2017 Oct 12.

Duquesne University Graduate School of Pharmaceutical Sciences, 600 Forbes Ave, Pittsburgh, Pennsylvania 15282. Electronic address:

The expansion of a novel in silico model for the prediction of the dispersability of 18 model compounds with polyvinylpyrrolidone-vinyl acetate copolymer is described. The molecular descriptor R3m (atomic mass weighted 3rd-order autocorrelation index) is shown to be predictive of the formation of amorphous solid dispersions at 2 drug loadings (15% and 75% w/w) using 2 preparation methods (melt quenching and solvent evaporation using a rotary evaporator). Cosolidified samples were characterized using a suite of analytical techniques, which included differential scanning calorimetry, powder X-ray diffraction, pair distribution function analysis, polarized light microscopy, and hot stage microscopy. Logistic regression was applied, where appropriate, to model the success and failure of compound dispersability in polyvinylpyrrolidone-vinyl acetate copolymer. R3m had combined prediction accuracy greater than 90% for tested samples. The usefulness of this descriptor appears to be associated with the presence of heavy atoms in the molecular structure of the active pharmaceutical ingredient, and their location with respect to the geometric center of the molecule. Given the higher electronegativity and atomic volume of these types of atoms, it is hypothesized that they may impact the molecular mobility of the active pharmaceutical ingredient, or increase the likelihood of forming nonbonding interactions with the carrier polymer.
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http://dx.doi.org/10.1016/j.xphs.2017.10.003DOI Listing
January 2018

The Application of Modeling and Prediction to the Formation and Stability of Amorphous Solid Dispersions.

J Pharm Sci 2018 01 5;107(1):57-74. Epub 2017 Apr 5.

Department of Pharmaceutical Sciences, Duquesne University, 600 Forbes Av, Pittsburgh, Pennsylvania 15282. Electronic address:

Amorphous solid dispersion (ASD) formulation development is frequently difficult owing to the inherent physical instability of the amorphous form, and limited understanding of the physical and chemical interactions that translate to initial dispersion formation and long-term physical stability. Formulation development for ASDs has been historically accomplished through trial and error or experience with extant systems; however, rational selection of appropriate excipients is preferred to reduce time to market and decrease costs associated with development. Current efforts to develop thermodynamic and computational models attempt to rationally direct formulation and show promise. This review compiles and evaluates important methods used to predict ASD formation and physical stability. Recent literature in which these methods are applied is also reviewed, and limitations of each method are discussed.
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http://dx.doi.org/10.1016/j.xphs.2017.03.029DOI Listing
January 2018

Raman spectroscopy for the process analysis of the manufacturing of a suspension metered dose inhaler.

J Pharm Biomed Anal 2011 Apr 14;54(5):1013-9. Epub 2010 Dec 14.

Merck Respiratory Product Development, 556 Morris Avenue, S7-A2-2123, Summit, NJ 07901, United States.

The purpose of this research was to demonstrate the utility of Raman spectroscopy for process analysis of a suspension metered dose inhaler manufacturing process. Chemometric models were constructed for the quantification of ethanol and active pharmaceutical ingredient such that both could be monitored in real-time during the compounding and filling operations via tank measurements and recirculation line flow-cell measurements. Different spectral preprocessing techniques were used to delineate the effects of mixing speed and temperature changes from actual concentration effects. Raman spectroscopy offers advantages in time savings and quality of information over the standard methods of analysis for respiratory formulations, such as a drug content assay via HPLC and ethanol testing via GC. The successful implementation of this work will allow formulation scientists to quantitatively assess both the formulation (e.g., the concentration of active pharmaceutical ingredient (API) and ethanol), as well as the manufacturing process (e.g., determination of mixing endpoints) in real-time.
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http://dx.doi.org/10.1016/j.jpba.2010.12.007DOI Listing
April 2011

Tunable thermoassociation of binary guanosine gels.

J Phys Chem B 2008 Jan 9;112(4):1130-4. Epub 2008 Jan 9.

Department of Chemistry and Chemical Biology, 118 Cogswell Building, Rensselaer Polytechnic Institute, Troy, New York 12180.

It is well-known that aqueous solutions of individual guanosine compounds can form gels through reversible self-assembly. Typically, gelation is favored at low temperature and acidic pH. We have discovered that binary mixtures of 5'-guanosine monophosphate (GMP) and guanosine (Guo) can form stable gels at neutral pH over a temperature range that can be tuned by varying the relative proportions of the hydrophobic Guo and the hydrophilic GMP in the mixture. Gelation was studied over the temperature range of 5-40 degrees C or 60 degrees C at pH 7.2 using visual detection, circular dichroism (CD) spectroscopy, and CD thermal melt experiments. Solutions with high GMP/Guo ratios behaved similar to solutions of GMP alone while solutions with low GMP/Guo formed firm gels across the entire temperature range. Most interesting were solutions between these two extremes, which were found to exhibit thermoassociative behavior; these solutions are liquid at refrigerator temperature and undergo sharp transitions to a gel only at higher temperatures. Increasing the GMP/Guo ratio and increasing the total concentration of guanosine compounds shifted the onset of gelation to higher temperatures (ranging from 20 to 40 degrees C), narrowed the temperature range of the gel phase, and sharpened the reversible phase transitions. The combination of self-assembly, reversibility, and tunability over biologically relevant temperature ranges and pH offers exciting possibilities for these simple and inexpensive materials in medical, biological, analytical, and nanotechnological applications.
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http://dx.doi.org/10.1021/jp709613pDOI Listing
January 2008
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