Publications by authors named "Peter L D Wildfong"

27 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

Professor Samuel H. Yalkowsky: Scientist, Mentor, and Molecular Empath.

J Pharm Sci 2018 01 24;107(1):2-4. Epub 2017 Aug 24.

School of Pharmacy, University of Wisconsin-Madison, Madison, Wisconsin 53706.

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http://dx.doi.org/10.1016/j.xphs.2017.08.010DOI 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

Solid-state transformations of ribavirin as a result of high-shear mechanical processing.

Int J Pharm 2017 May 2;524(1-2):339-350. Epub 2017 Apr 2.

Graduate School of Pharmaceutical Sciences, Duquesne University, 600 Forbes Avenue, Pittsburgh, PA 15282, USA. Electronic address:

Ribavirin (CHNO; anti-viral agent) was crystallized as two unique, phase-pure polymorphs (R-I and R-II). Calorimetrically determined isobaric heat capacities and heat of transition data were utilized to determine the solid-state transition temperature (T), confirming enantiotropism, while R-I was determined to be kinetically stable at ambient temperature. Unprocessed samples of the low T polymorph, R-II, did not convert into R-I when held isothermally well above T for 7days. In contrast milled R-II completely transformed to R-I after 15min at the same storage conditions, indicating that defects sustained during processing reduced the energy barrier for transformation, allowing it to occur. R-II was subjected to both cryogenic milling and impact milling at ambient temperature for various durations. Cryomilling resulted in an in situ progressive reduction of crystallinity, with complete conversion to amorphous ribavirin after 2h. Limited molecular mobility attributable to the low milling temperature (T=-196°C) likely inhibited recrystallization, allowing the amorphous solid to persist. In contrast, continuous impact milling at ambient temperature resulted in complete in situ conversion from R-II to R-I after 3h. The data suggested rapid conversion to R-I from highly disordered regions during extended milling, facilitated by localized heat buildup that likely exceeded T and/or T.
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http://dx.doi.org/10.1016/j.ijpharm.2017.04.002DOI Listing
May 2017

Experimental Determination and Theoretical Calculation of the Eutectic Composition of Cefuroxime Axetil Diastereomers.

AAPS PharmSciTech 2017 Oct 22;18(7):2570-2578. Epub 2017 Feb 22.

Graduate School of Pharmaceutical Sciences, Duquesne University, 600 Forbes Avenue, Pittsburgh, Pennsylvania, 15282, USA.

Cefuroxime axetil (CFA), an ester prodrug of cefuroxime exists as a pair of diastereoemers, namely isomer A and isomer B. To enable phase diagram construction, crystallization of the diastereomers of CFA from the commercially available amorphous drug substance was carried out. Isomer A was separated with a purity approaching 100% whereas the maximum purity of isomer B was 85% as confirmed by solution state proton NMR spectroscopy. The crystalline forms of isomer A and isomer B were confirmed as forms AI and BI, respectively, based on differential scanning calorimetry (DSC) analysis and powder X-ray diffraction. DSC analysis was used to observe the melting behavior of different diastereomer mixture compositions. The binary solid-liquid phase diagram for mixture compositions ranging from 0 to 85% w/w isomer B indicated the formation of a eutectic mixture having a melting temperature of 124.7 ± 0.4°C and a composition of 75% w/w (+/-5% wt.) isomer B. The eutectic composition was calculated using an index based on the van't Hoff equation for melting point depression and was found to be 75% isomer B and 25% isomer A. As CFA is present in commercial preparations as a mixture of diastereomers, the formation of a eutectic mixture between the diastereomers may impact the solubility and stability of the commercial product. Eutectic formation can be explained on the basis of the chemical similarity of diastereomers that favor miscibility in the liquid state.
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http://dx.doi.org/10.1208/s12249-017-0739-8DOI Listing
October 2017

Improved Flux of Levodopa via Direct Deposition of Solid Microparticles on Nasal Tissue.

AAPS PharmSciTech 2017 Apr 5;18(3):904-912. Epub 2016 Jul 5.

Graduate School of Pharmaceutical Sciences, Duquesne University, 600 Forbes Avenue, Pittsburgh, Pennsylvania, 15282, USA.

Epithelial flux and permeability across bovine olfactory tissue were compared when levodopa (L-DOPA) was loaded in different physical states. Aqueous solution of L-DOPA was prepared in Krebs-Ringer buffer (KRB), at a concentration (0.75 mg/mL) verified to be less than the saturation solubility at both 25 and 37°C. Sodium metabisulfite was added to solution to minimize L-DOPA oxidation; chemical stability of aqueous L-DOPA was evaluated using HPLC-UV. Solid-state characterization of unprocessed, dry, crystalline L-DOPA powder was performed using TGA, DSC, PXRD, and optical microscopy to ensure that preparation of L-DOPA microparticles used for diffusion experiments did not elicit a phase change. Measurements of in vitro flux were made for all preparations, using freshly excised bovine olfactory mucosal membrane. Samples obtained from transport studies were analyzed by HPLC-UV. Tissue viability was measured before and after experiments using transdermal epithelial electrical resistance (TEER). The average steady-state flux (J ) of L-DOPA from solid microparticles directly deposited on nasal epithelial tissue was 6.08 ± 0.69 μg/cm/min, approximately three times greater than the J measured for L-DOPA from solution (2.13 ± 0.97 μg/cm/min). The average apparent permeability coefficient (P ) of L-DOPA was calculated to be 4.73 × 10 cm/s. These findings suggest that nasal delivery of L-DOPA by administration of solid microparticles not only benefits from improved chemical and microbiological stability by avoiding the use of aqueous formulation vehicle but also does not compromise cumulative mass transport across the olfactory membrane.
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http://dx.doi.org/10.1208/s12249-016-0581-4DOI Listing
April 2017

Physical characterization of drug:polymer dispersion behavior in polyethylene glycol 4000 solid dispersions using a suite of complementary analytical techniques.

J Pharm Sci 2014 Sep 13;103(9):2911-2923. Epub 2014 May 13.

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

Fifteen model drugs were quenched from 3:1 (w/w) mixtures with polyethylene glycol 4000 (PEG4000). The resulting solids were characterized using powder X-ray diffraction (PXRD), analysis of pair distribution function-transformed PXRD data (where appropriate), hot-stage polarized light microscopy, and differential scanning calorimetry (DSC). Drug/polymer dispersion behavior was classified using the data from each technique, independent of the others, and limitations to single-method characterization of PEG-based systems are highlighted. The data from all characterization techniques were collectively used to classify dispersion behavior, which was compared with single-technique characterization. Of the 15 combinations, only six resulted in solids whose dispersion behavior was consistently described using each standalone technique. The other nine were misclassified using at least one standalone technique, mainly because the phase behavior was ambiguously interpreted when only the data from one technique were considered. The data indicated that a suite of complementary techniques provided better classifications of the phase behavior. Of all the quenched solids, only cimetidine was fully dispersed in PEG4000, suggesting that it solidified from a completely miscible mixture of molten drug and polymer that did not phase separate upon cooling. In contrast, ibuprofen and PEG4000 completely recrystallized during preparation, whereas the remaining 13 drugs were partially dispersed in PEG4000 at this composition.
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http://dx.doi.org/10.1002/jps.24008DOI Listing
September 2014

Informatics calibration of a molecular descriptors database to predict solid dispersion potential of small molecule organic solids.

Int J Pharm 2011 Oct 3;418(2):217-26. Epub 2011 Jul 3.

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

The use of a novel, in silico method for making an intelligent polymer selection to physically stabilize small molecule organic (SMO) solid compounds formulated as amorphous molecular solid dispersions is reported. 12 compounds (75%, w/w) were individually co-solidified with polyvinyl pyrrolidone:vinyl acetate (PVPva) copolymer by melt-quenching. Co-solidified products were analyzed intact using differential scanning calorimetry (DSC) and the pair distribution function (PDF) transform of powder X-ray diffraction (PXRD) data to assess miscibility. Molecular descriptor indices were calculated for all twelve compounds using their reported crystallographic structures. Logistic regression was used to assess correlation between molecular descriptors and amorphous molecular solid dispersion potential. The final model was challenged with three compounds. Of the 12 compounds, 6 were miscible with PVPva (i.e. successful formation) and 6 were phase separated (i.e. unsuccessful formation). 2 of the 6 unsuccessful compounds exhibited detectable phase-separation using the PDF method, where DSC indicated miscibility. Logistic regression identified 7 molecular descriptors correlated to solid dispersion potential (α=0.001). The atomic mass-weighted third-order R autocorrelation index (R3m) was the only significant descriptor to provide completely accurate predictions of dispersion potential. The three compounds used to challenge the R3m model were also successfully predicted.
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http://dx.doi.org/10.1016/j.ijpharm.2011.06.003DOI Listing
October 2011

A shared assignment to integrate pharmaceutics and pharmacy practice course concepts.

Am J Pharm Educ 2011 Apr;75(3):44

Mylan School of Pharmacy, Duquesne University, USA.

Objective: To demonstrate for first-year pharmacy students the relevance of pharmaceutics course content to pharmacy practice by implementing a joint, integrated assignment in both courses and assessing its impact.

Design: Medication errors and patient safety issues relevant to ophthalmic and otic formulations were selected as the assignment topic. A homework assignment based on a mock court case involving a patient who was given an inappropriate formulation because of a pharmacist's medication error was given to students. The scenario was followed by essay and calculation questions linking physical pharmacy concepts with patient safety recommendations.

Assessment: Students' average score on the crossover assignment was 88.7%. Minute papers completed before and after the assignment showed improvement in student learning. Students' scores on examination questions related to the assignment topic were significantly higher than the previous year's students' performance on similar questions. In a survey conducted at the end of the semester, 91% of students indicated that the assignment helped them relate the covered topics to future practice, and 98% agreed that the assignment emphasized the importance of the pharmaceutics in professional practice.

Conclusion: A crossover assignment was an effective means of demonstrating the connection between specific pharmaceutics concepts and practice applications to pharmacy students.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3109798PMC
http://dx.doi.org/10.5688/ajpe75344DOI Listing
April 2011

Research funding expectations as a function of faculty teaching/administrative workload.

Res Social Adm Pharm 2011 Jun 23;7(2):192-201. Epub 2010 Jul 23.

Mylan School of Pharmacy, Duquesne University, Mellon Hall, Room 411, 600 Forbes Ave, Pittsburgh, PA 15282, USA.

Background: Persistent faculty shortages at US pharmacy schools make faculty recruitment and retention a perennial priority. The literature indicates that a key retention issue is whether the faculty member's scholarship is compromised because of a heavy teaching or service workload.

Objective: Assess US pharmacy faculty perceptions concerning their views of appropriate expectations of research grant support given their teaching/administrative workloads.

Methods: Data and opinions were collected using a multiple-choice, cross-sectional survey instrument (SurveyMonkey®; Menlo Park, CA), e-mailed to 1047 faculty members, randomly selected from all Accreditation Council of Pharmacy Education (ACPE)-accredited US pharmacy schools. Statistical analyses were performed using SPSS® (Chicago, IL) for Windows, Version 17.0.

Results: Of the researcher respondents, a majority felt that the amount of teaching expected was too much to be a competitive researcher. Teaching commitment was found more likely to increase than decrease after achieving tenure. Reported new faculty start-up funding was well below that typically found at nonpharmacy research schools.

Conclusions: This information is anticipated to help pharmacy faculty members gauge their workload and productivity relative to a national peer group, and to help pharmacy schools improve in faculty recruitment and retention. The survey findings may assist pharmacy schools in clarifying reasonable teaching and funding expectations for pre- and post-tenure faculty, which in turn may help attract more pharmaceutical scientists to academic pharmacy positions.
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http://dx.doi.org/10.1016/j.sapharm.2010.04.006DOI Listing
June 2011

Structural interpretation in composite systems using powder X-ray diffraction: applications of error propagation to the pair distribution function.

Pharm Res 2010 Dec 2;27(12):2624-32. Epub 2010 Sep 2.

Duquesne University, Graduate School of Pharmaceutical Sciences, Pittsburgh, Pennsylvania 15282, USA.

Purpose: To develop a method for drawing statistical inferences from differences between multiple experimental pair distribution function (PDF) transforms of powder X-ray diffraction (PXRD) data.

Methods: The appropriate treatment of initial PXRD error estimates using traditional error propagation algorithms was tested using Monte Carlo simulations on amorphous ketoconazole. An amorphous felodipine:polyvinyl pyrrolidone:vinyl acetate (PVPva) physical mixture was prepared to define an error threshold. Co-solidified products of felodipine:PVPva and terfenadine:PVPva were prepared using a melt-quench method and subsequently analyzed using PXRD and PDF. Differential scanning calorimetry (DSC) was used as an additional characterization method.

Results: The appropriate manipulation of initial PXRD error estimates through the PDF transform were confirmed using the Monte Carlo simulations for amorphous ketoconazole. The felodipine:PVPva physical mixture PDF analysis determined ±3σ to be an appropriate error threshold. Using the PDF and error propagation principles, the felodipine:PVPva co-solidified product was determined to be completely miscible, and the terfenadine:PVPva co-solidified product, although having appearances of an amorphous molecular solid dispersion by DSC, was determined to be phase-separated.

Conclusions: Statistically based inferences were successfully drawn from PDF transforms of PXRD patterns obtained from composite systems. The principles applied herein may be universally adapted to many different systems and provide a fundamentally sound basis for drawing structural conclusions from PDF studies.
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http://dx.doi.org/10.1007/s11095-010-0259-7DOI Listing
December 2010

Thermal conductivity measurements for small molecule organic solid materials using modulated differential scanning calorimetry (MDSC) and data corrections for sample porosity.

J Pharm Biomed Anal 2010 Mar 5;51(4):979-84. Epub 2009 Nov 5.

Fujian Health College, 366 Jinxi, Minhou County, Fuzhou, Fujian Province, 350101, China.

A method for measuring the thermal conductivity (k) of small molecule organic solid materials using modulated differential scanning calorimetry (MDSC) is demonstrated. Sample preparation required powder consolidation, unavoidably introducing air voids into compacts. Supporting equations for the technique were modified to include a porosity term (epsilon), and the theoretical quadratic relationship between k and epsilon was confirmed by experimental measurements for 18 representative materials. Zero-porosity extrapolation was used to approximate values of "true" thermal conductivity for non-porous solids (k(epsilon=0)). Zero-porosity-extrapolated values ranged from 0.1273W/(Km) to 0.3472W/(Km) for all materials, consistent with expected values of k for non-porous organic polymers.
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http://dx.doi.org/10.1016/j.jpba.2009.10.022DOI Listing
March 2010

A structural investigation into the compaction behavior of pharmaceutical composites using powder X-ray diffraction and total scattering analysis.

Pharm Res 2009 Nov 28;26(11):2429-37. Epub 2009 Aug 28.

Duquesne University, Pittsburgh, Pennsylvania, USA.

Purpose: To use advanced powder X-ray diffraction (PXRD) to characterize the structure of anhydrous theophylline following compaction, alone, and as part of a binary mixture with either alpha-lactose monohydrate or microcrystalline cellulose.

Materials And Methods: Compacts formed from (1) pure theophylline and (2) each type of binary mixture were analyzed intact using PXRD. A novel mathematical technique was used to accurately separate multi-component diffraction patterns. The pair distribution function (PDF) of isolated theophylline diffraction data was employed to assess structural differences induced by consolidation and evaluated by principal components analysis (PCA).

Results: Changes induced in PXRD patterns by increasing compaction pressure were amplified by the PDF. Simulated data suggest PDF dampening is attributable to molecular deviations from average crystalline position. Samples compacted at different pressures were identified and differentiated using PCA. Samples compacted at common pressures exhibited similar inter-atomic correlations, where excipient concentration factored in the analyses involving lactose.

Conclusions: Practical real-space structural analysis of PXRD data by PDF was accomplished for intact, compacted crystalline drug with and without excipient. PCA was used to compare multiple PDFs and successfully differentiated pattern changes consistent with compaction-induced disordering of theophylline as a single component and in the presence of another material.
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http://dx.doi.org/10.1007/s11095-009-9954-7DOI Listing
November 2009

Evaluation of chemometric algorithms in quantitative X-ray powder diffraction (XRPD) of intact multi-component consolidated samples.

J Pharm Biomed Anal 2009 Apr 13;49(3):619-26. Epub 2008 Dec 13.

Duquesne University, Mylan School of Pharmacy, Graduate School of Pharmaceutical Sciences, 600 Forbes Av., Pittsburgh, PA 15282, USA.

Quantitative X-ray powder diffraction (XRPD) data obtained from intact, consolidated samples affords the opportunity to analyze mixtures that simulate pharmaceutical drug products without the need for reversion back to powders; an analytical preparation step that destroys the contextual solid-state information intrinsic to intact consolidated samples. Traditional, standardless quantitative methods generally involve sophisticated pattern refinement procedures (e.g., Rietveld refinement) and are limited to crystalline materials. Methods that incorporate an internal standard are not optimal for compact analysis, and may often be susceptible to prediction errors associated with intensity attenuation. Chemometric-based XRPD utilizes full-pattern methods that combine analyses of both Bragg diffraction and diffuse scatter, thereby allowing for enhancement of signal-to-noise, sensitivity, and selectivity. Classical least-squares (CLS) regression, principal components regression (PCR) and partial least squares (PLS) regression are three chemometric algorithms commonly employed in spectroscopy. In the present work, quantification of a consolidated four-component system, composed of two crystalline materials and two disordered materials was analyzed intact, using two different XRPD optics geometries. Calibrations constructed for the prediction of individual constituent concentrations using the aforementioned three multi-variate algorithms were statistically compared with traditional diffraction-absorption univariate calibration. PLS regression modeling of data collected in transmission geometry provided the best statistical results for the quantification of constituent concentration. Further, this calibration was minimally affected by diffraction pattern anomalies traditionally corrected prior to phase quantification.
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http://dx.doi.org/10.1016/j.jpba.2008.12.007DOI Listing
April 2009

Informatic calibration of a materials properties database for predictive assessment of mechanically activated disordering potential for small molecule organic solids.

J Pharm Sci 2009 Aug;98(8):2696-708

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

The potential for small molecule organic crystalline materials to become disordered as a result of high shear mechanical processing was investigated. A data-driven model was generated from a database of critical materials properties, which were expected to correlate with the potential of a small molecule organic crystalline solid to become fully disordered by the application of mechanical energy. The model was compared with a previously published disordering model based on fundamental thermodynamic relationships. Samples of 23 crystalline solids were subjected to extensive comminution under controlled temperature conditions; powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC) were used to confirm disordering. Logistic regression was used to investigate the significance of each materials property with respect to the prediction of disordering potential. Seven materials properties (glass transition temperature, melting temperature, heat of fusion, crystallographic density, Young's modulus, molar volume and attachment energy) were identified as having a significant correlation with the potential for material disordering. Stepwise multivariate logistic regression was used to further assess the correlation between disordering potential and each of the seven properties. A linear probability model based on two materials properties (glass transition temperature and molar volume) was developed for the prediction of disordering potential.
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http://dx.doi.org/10.1002/jps.21647DOI Listing
August 2009

A near-infrared spectroscopic investigation of relative density and crushing strength in four-component compacts.

J Pharm Sci 2009 Mar;98(3):1095-109

Duquesne University Graduate School of Pharmaceutical Sciences, 410A Mellon Hall, 600 Forbes Avenue, Pittsburgh, Pennsylvania 15282, USA.

Near-infrared spectroscopy (NIRS) is commonly employed for the analysis of chemical and physical attributes of intact pharmaceutical compacts. Specifically, NIRS has proven useful in the nondestructive measurement of tablet hardness or crushing strength. Near-infrared (NIR) reflectance and transmittance spectra were acquired for 174 13-mm compacts, which were produced according to a four-constituent mixture design (29 points) composed of anhydrous theophylline, lactose monohydrate, microcrystalline cellulose, and soluble starch. Six compacts were produced for each design point by compacting at multiple pressures. Physical testing and regression analyses were used to model the effect of variation in relative density (and crushing strength) on NIR spectra. Chemometric analyses demonstrated that the overall spectral variance was strongly influenced by anhydrous theophylline as a result of the experimental design and the component's spectroscopic signature. The calibration for crushing strength was more linear than the relative density model, although accuracy was poorer in comparison to the density model due to imprecision of the reference measurements. Based on the consideration of reflectance and transmittance measurements, a revised rationalization for NIR sensitivity to compact hardness is presented.
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http://dx.doi.org/10.1002/jps.21473DOI Listing
March 2009

The use of net analyte signal orthogonalization in the separation of multi-component diffraction patterns obtained from X-ray powder diffraction of intact compacts.

J Pharm Biomed Anal 2008 Jun 8;47(2):238-47. Epub 2008 Jan 8.

Duquesne University, Mylan School of Pharmacy, Graduate School of Pharmaceutical Sciences, Pittsburgh, PA 15282, USA.

X-ray powder diffraction (XRPD) analysis of intact multi-component consolidated mixtures has significant potential owing to the ability to non-destructively quantify and discriminate between solid phases in composite bodies with minimal sample preparation. There are, however, limitations to the quantitative power using traditional univariate methods on diffraction data containing features from all components in the system. The ability to separate multi-component diffraction data into patterns representing single constituents allows both composition as well as physical phenomena associated with the individual components of complex systems to be probed. Intact, four-component compacts, consisting of two crystalline and two amorphous constituents were analyzed using XRPD configured in both traditional Bragg-Brentano reflectance geometry and parallel-beam transmission geometry. Two empirical, model-based methods consisting of a multiple step net analyte signal (NAS) orthogonalization are presented as ways to separate multi-component XRPD patterns into single constituent patterns. Multivariate figures of merit (FOM) were calculated for each of the isolated constituents to compare method-specific parameters such as sensitivity, selectivity, and signal-to-noise, enabling quantitative comparisons between the two modes of XRPD analysis.
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http://dx.doi.org/10.1016/j.jpba.2007.12.042DOI Listing
June 2008

1-Isopropyl-4-nitro-6-meth-oxy-1H-benzimidazole.

Acta Crystallogr Sect E Struct Rep Online 2008 Jun 25;64(Pt 7):o1336-7. Epub 2008 Jun 25.

Mylan School of Pharmacy, Duquesne University, 600 Forbes Avenue, Pittsburgh, PA 15282, USA.

There are two independent mol-ecules in the asymmetric unit of the title compound, C(11)H(13)N(3)O(3). The inter-planar angles for the two rings of the benzimidazole ring system is 2.21 (12)° in one mol-ecule and 0.72 (12)° in the other. The nitro group is twisted in the same direction relative to the least-squares plane through its attached benzene ring in both mol-ecules, with inter-planar angles of 15.22 (9) and 18.02 (8)°. In the crystal structure, mol-ecules are stacked along the a axis through π-π inter-actions (centroid-centroid distance 4.1954 Å). C-H⋯O hydrogen bonds are also present.
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http://dx.doi.org/10.1107/S160053680801859XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2961682PMC
June 2008

Demonstration of a shear-based solid-state phase transformation in a small molecular organic system: chlorpropamide.

J Pharm Sci 2007 May;96(5):1100-13

Duquesne University Mylan School of Pharmacy, 600 Forbes Avenue, Pittsburgh, Pennsylvania 15282, USA.

Elucidation of the mechanisms for mechanically activated phase transformations of API are necessary for progress in materials and process understanding. The mechanically induced solid-state transformation between the A and C enantiotropes of the anti-diabetic drug chlorpropamide (C(10)H(13)ClN(2)O(3)S) was investigated. The structure of the high temperature stable phase (form C) was solved using powder X-ray data. Transmission powder X-ray diffraction (PXRD) and Raman spectroscopy were used for in situ quantification and analysis of the phase interconversion that occurs as a function of applied pressure during compaction. Each polymorph was observed to undergo a solid-state transition, which increased with pressure to a maximum extent that corresponded with the consolidation limit of the respective bulk powder. Neither form was observed to convert under hydrostatic pressure, suggesting a shear dependence for interconversion at compaction pressures. Examination of the two crystallographic structures indicated that both forms have a common slip system and preserved molecular positions. It is suggested that the transformation of either form is allowed when resolved shear stresses initiate deformation, causing lattice distortion, which allows the simultaneous reconformation of molecules.
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http://dx.doi.org/10.1002/jps.20920DOI Listing
May 2007

Towards an understanding of the structurally based potential for mechanically activated disordering of small molecule organic crystals.

J Pharm Sci 2006 Dec;95(12):2645-56

Department of Pharmaceutical Sciences, Duquesne University, Mylan School of Pharmacy, 600 Forbes Av., Pittsburgh, Pennsylvania 15282, USA.

The potential for various small molecule organic crystals to undergo complete mechanically induced disordering is investigated. A model is proposed, which considers changes in free energy required for lattice incorporation of a critical dislocation density. Application requires knowledge of a few physical properties, namely the elastic shear modulus, Burgers vector magnitude, molar volume, melting temperature, and heat of fusion. The model was tested using seven compounds; acetaminophen, aspirin, gamma-indomethacin, salicylamide, sucrose, and two proprietary drug compounds, PFZ1 and PFZ2. Crystalline solids were subjected to high shear, controlled temperature comminution for various durations, after which the samples were examined using powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC). The results verified that acetaminophen, aspirin, and salicylamide, which were suggested by the model to be resistant to complete mechanical disordering, remained fully crystalline, even after 5 h of milling. Sucrose and gamma-indomethacin were both predicted to be susceptible to amorphization, which was confirmed by physical characterization. Single, 3-h grinding experiments were performed on two proprietary compounds, PFZ1 and PFZ2. The model indicated that each should be resistant to complete disordering, a trend held by PFZ1. Evidence of partial disordering of PFZ2 was unexpected and is discussed with respect to possible temperature effects.
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http://dx.doi.org/10.1002/jps.20672DOI Listing
December 2006

Quantitative determination of polymorphic composition in intact compacts by parallel-beam X-ray powder diffractometry II. Data correction for analysis of phase transformations as a function of pressure.

J Pharm Biomed Anal 2005 Sep;39(1-2):1-7

Duquesne University, Mylan School of Pharmacy, Department of Pharmaceutical Sciences, Pittsburgh, PA 15282, USA.

An analytical, non-destructive method using parallel-beam transmission powder X-ray diffractometry (PXRD) is presented for in situ whole compact detection and quantification of solid-state phase transformations in powder compacts. Accurate quantification of analyte in intact compacts using PXRD requires a mathematical correction prior to interpolation of calibration data to account for sample differences that result as a function of pressure; namely, compact thickness and solid fraction. Chlorpropamide is examined as a model system, selected because of its susceptibility to polymorphic transformations when consolidated using moderately low pressures. The results indicate that quantification of the transformed phase of chlorpropamide without corrections for solid fraction and thickness, underestimates the extent of transformation by 2.4%. Although the magnitude of the correction for this particular system of polymorphs is small, more significant values are expected for other compounds, particularly those with sufficient compactibility to allow the formation of low solid fraction calibration samples.
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http://dx.doi.org/10.1016/j.jpba.2005.03.003DOI Listing
September 2005

Quantitative determination of polymorphic composition in intact compacts by parallel-beam X-ray powder diffractometry.

J Pharm Biomed Anal 2002 Nov;30(4):1111-9

Department of Industrial and Physical Pharmacy, School of Pharmacy, 1336 Robert E. Heine Pharmacy Building, Purdue University, 47907-1336, West Lafayette, IN, USA.

This paper details the development of a method using parallel-beam X-ray powder diffractometry as a novel means of determining polymorphic composition in intact compacts. Two polymorphic systems, chlorpropamide and glycine, were selected. The polymorphic components were weighed, mixed, and compressed using a Carver press with 3/8-in. concave tooling. The compacts were then analyzed using parallel-beam X-ray powder diffractometry in transmission geometry. The data were processed using the profile-fitting module in the Shimadzu XRD-6000 software V 4.1 (for NT 4.0/98). The integrated intensity ratio of a selected peak for each crystal form was used for quantitation of each polymorph. Excellent linear correlation was observed for both polymorphic systems. The convex shape of the compact surface had no effect on the XRD patterns. Since parallel-beam X-ray diffractometry is not sensitive to the shape of the sample surface, it provides a simple method for quantifying polymorphs in intact compacts. Further work to extend this to formulated tablets is ongoing. The relatively larger variation in one of the peaks in the chlorpropamide study was found to be consistent with the computational analysis of the slip behavior of the stable polymorph. This method provides the first reported non-invasive X-ray diffraction pattern quantitation of crystal forms in intact compacts.
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http://dx.doi.org/10.1016/s0731-7085(02)00419-3DOI Listing
November 2002

Accelerated fluid bed drying using NIR monitoring and phenomenological modeling: method assessment and formulation suitability.

J Pharm Sci 2002 Mar;91(3):631-9

Purdue University Department of Industrial and Physical Pharmacy, 1336 RHPH Building, West Lafayette, IN 47907-1336, USA.

The theory behind a fluidized bed fast-drying method is investigated as a potential timesaving process, which can reduce overall drying time compared to single-temperature cycles. The method teaches that for formulations in which heat transfer dominates the drying mechanism, an increase in temperature during the evaporative phase of drying decreases overall process time by 50%, without changing the physical properties of the active ingredient. The method is also examined in terms of its potential for cycle shortening for a given formulation. A combined expression for the overall drying profile has been developed and committed to a macro that facilitates the identification of phenomenological trends, which identify whether or not a process will benefit by using fast drying. The relationship and macro also allows prediction of time frames associated with a given set of dryer and formulation parameters.
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http://dx.doi.org/10.1002/jps.10070DOI Listing
March 2002
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