Trainable QSAR Model of Plasma Protein Binding and its

Application for Predicting Volume of Distribution

Graham A. McGibbon, Karim Kassam, Brent G. Pautler

Advanced Chemistry Development, Inc., (ACD/Labs)

Toronto, Canada

A Platform for Consolidating and Reconciling

Information from GC/MS and LC/MS Analyses

of Mixtures or Materials

INTRODUCTION Real world materials are often complicated mixtures where the molecular constituents can

potentially impact performance or safety, for better or worse, but with toxicity often of

particular concern. Common examples include drug container closure systems, medical

devices, bioprocess components, nanomaterials and more natural materials like foods,

beverages and biological extracts.

Comprehensive characterization of such materials to detect a broad diversity of compounds

requires sensitive global non-targeted screening on replicate samples and controls, by

GC/MS and LC/MS. More challenging nowadays than data generation is managing and

consolidating it.

A platform that includes capabilities for vendor neutral multi-technique data capture,

analysis and knowledge management for those materials is described here.

METHODS ACD/Spectrus v2015 software platform offers web services, automation components, GUIs,

and a knowledgebase supported by either PostgreSQLTM or OracleTM. A browser

independent web interface exists for some applications but isn’t specifically described

further here. Data capture and processing for GC/MS and LC/MS data files from a variety of

vendors was done using inherent import filters and processing algorithms that have been

previously described at ASMS and published [1] but are continually enhanced.

The data were imported and analyzed using capabilities inherent in the platform. The

processing included deconvolution and peak detection algorithms. For GC/MS analyses,

spectra were extracted and queried against commercial databases of EI mass spectra with

the top match(es) being returned for each. For each putative compound spectrum

extracted, its retention time and matching spectra were stored in the knowledgebase. For

LC/MS analyses, a previously reported [1] non-targeted screening algorithm was applied

and the extracted features (m/z, tR) were searched against a home-built reference library,

which could easily be populated in the database architecture, or against masses of

compounds reported in a large public database collection. Extracting and comparing

features or spectra from LC/MSn to data in the database is possible but not considered in

the present work.

RESULTS - Nanomaterial Use Case Gold nanomaterials are used in biodiagnostic, imaging, therapeutic, and drug delivery

applications since they exhibit unique optical, photothermal, and surface chemical

properties that depend on their tailored preparation and (bio)functionalization.[2] Hence,

multiple analytical and physical characterization techniques are often employed on the

same material to ensure that information for any potential applications of novel materials

are explored and captured. The software platform illustrated in Figure 1 has the capability to

store a variety of data, metadata and images associated with each sample or material. The

flexible interface allows viewing and querying, see also Figure 2, the retained research

knowledge as new applications are explored for well or partially characterized materials.

Advanced Chemistry Development, Inc. Tel: (416) 368-3435 Fax: (416) 368-5596 Toll Free: 1-800-304-3988 Email: info@acdlabs.com www.acdlabs.com

NOVEL ASPECT An informatics platform for vendor neutral GC and LC data capture, analysis, reconciliation and storage with structures and documents

Figure 1. Platform used for ASTM D6042 antioxidant mixture LC/UV and LC/MS data

capture, analysis, reconciliation and storage with structures. Clockwise from upper left are

platform interfaces: vendor neutral multi-technique data processing; querying metadata

and/or data; one possible database view form, a structure query, or drawing and reporting.

Figure 2. Platform storing (left) mass and UV spectra from Au nanoclusters capped with

glutathione, applicable as a photosensitizer; and (right) mass and NMR spectra from aqueous

polyoxymetalate clusters, considered for organic chemistry catalysis, water decontaminating

or nanocomputer storage devices (qubits) uses, the latter due to unusual magnetic properties.

RESULTS - Food or Drug Polymer/Plastic Use Cases Additives in plastic containers and materials used in food or pharmaceutical packaging and

processing like container closure systems, tubing or filters [4] contribute certain properties

and aid manufacturing but inherently or upon further treatment, like sterilization, might leach

from the products, altering performance or posing health risks. Figure 3 shows knowledge

captured in an informatics platform as a means for assessing extractables and leachables.

RESULTS - Mixture Use Case Separation and identification of stabilizers used in polypropylene manufacturing is required to

correlate performance properties with polymer composition. ASTM D6042 antioxidant test

method provides a means to determine erucamide slip, Vitamin E, Irgafos 168, Irganox 3114,

Irganox 1010, and Irganox 1076 levels in polypropylene samples.[3] This test method is also

applicable for the determination of other antioxidants, such as Ultranox 626, Ethanox 330,

Santanox R, and BHT. The platform was used for LC/UV and LC/MS data capture, analysis,

and storage with chemical structures for 5 ppm and 50 ppm antioxidant mixtures.

The GC/MS analysis of a plastic sandwich bag, shows that the platform enables processing

with searches based on spectral similarity (Figure 4 left), or selected m/z and intensity values

(not shown) and algorithms that identify and structures with peaks (Figure 4 right).

DISCUSSION The platform has been used to capture a variety of analytical data, including LC/UV, LC/MS,

GC/MS, and NMR spectra from instruments of different types and vendors for some

mixtures and materials, including plastic samples. This study focused on the challenge of

data management and consolidation rather than data extraction, which in some cases could

have been automated. The platform stored GC/MS and LC/MS data elements and the

extracted and interpreted results, including associated structures. It is possible to reconcile

compounds that would be detected in both GC and LC and consolidate results for a

particular material according.

For data review the GUI for the database could be configured to view individual or

consolidated information, including choice of layout showing individual or sets of structures,

spectra and tabulated summaries. Content created in older software technologies designed

by this organization can and have been migrated to the platform described here.

The platform supports the design of custom views, dialogs and scripts that enable sample

submission projects, as well as user-assisted automation or full automation of data capture,

processing, reporting and storage for mass spectrometry workflows. Especially qualitative

investigations of mixtures and materials such as screening and structure verification.

Differently than most instrument software systems, it was possible to consolidate and create

reports showing data and results from both LC and GC even if from different companies and

if obtained during different injection sequence sets , or samples, or materials. Reports in

common formats, such as .pdf, .docx, .xlsx can be viewed and even edited in the interface.

CONCLUSION An informatics platform for materials and mixtures ‘live data’, metadata and information is

shown. Live spectra and chromatograms can have interpretations, including chemical

structures, and the capability to search any of those elements facilitates and makes the

platform highly suitable for a variety of automated or manual compound identification

workflows and for analytical knowledge management.

REFERENCES and ACKNOWLEDGEMENTS 1. Croley T et al. J. Sep. Sci. 36, 2013, 971–979. Combining targeted and nontargeted data

analysis for liquid chromatography/high-resolution mass spectrometric analyses.

2. Jain PK, Huang X, El-Sayed IH, El-Sayed MA, Acc. Chem. Res. 41, 2008,1578-86. Noble metals

on the nanoscale: optical and photothermal properties and some applications in imaging,

sensing, biology, and medicine.

3. Standard Test Method for Determination of Phenolic Antioxidants and Erucamide Slip Additives

in Polypropylene Homopolymer Formulations Using Liquid Chromatography (LC).

http://www.astm.org/Standards/D6042.htm

4. Jenke D, 2009 (Wiley) Compatibility of Pharmaceutical Solutions and Contact Materials: Safety

Assessments of Extractables and Leachables for

Pharmaceutical Products.

The authors gratefully acknowledge W.H. Casey, O. Pisani,

K.G. Stamplecoskie, and G. Vas for the extremely kind

provision of examples data.

Figure 3. (Left) Custom platform display of several chromatograms and structures from

extract standards (includes siloxanes, alkyl esters, trichloroanisol). (Right) Display including

a multi-technique report as both linked files and embedded .pdf document.

Meet ACD/Labs at Booth #83

Figure 4. Displays of plastic bag analysis results and query of platform database.

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