Eighty specimens of cellulosic materials were analyzed over a period of several years to study the diffraction characteristics resulting from polymorphism, crystallinity, and chemical substitution. The aim of the study was to produce and verify the quality of reference data useful for the diffraction analyses of cellulosic materials. These reference data can be used for material identification, polymorphism, and crystallinity measurements. Overall 13 new references have been characterized for publication in the Powder Diffraction File (PDF) and several others are in the process of publication.

An experimental X-ray powder diffraction pattern was produced and analyzed for imipenem monohydrate, an antimicrobial pharmaceutical agent. Although there are no experimental powder patterns in the ICDD PDF-4/Organics Database, there is one powder pattern calculated with single-crystal X-ray diffraction data from the Cambridge Structural Database. Here, we report the refined experimental powder diffraction data for imipenem monohydrate. These data for imipenem monohydrate are consistent with an orthorhombic crystal system having reduced unit-cell parameters of a = 8.2534(3) Å, b = 11.1293(4) Å, and c = 15.4609(6) Å. The resulting unit-cell volume, 1420.15(15) Å 3 , indicates four formula units per unit cell. Observed peaks are consistent with the P 2 1 2 1 2 1 space group.

The ICDD sponsored a round robin on the quantitative Rietveld phase analysis of pharmaceuticals. 11 participating laboratories from the pharmaceutical community submitted both raw data and processed quantitative results. The purpose of the round robin was to evaluate current practices in laboratories, so procedures and methods were not specified, but they were recorded. Cluster analysis tools were applied to all the data sets and their use helped identify the root causes of several types of errors in specimen preparation, data treatment, and Rietveld analysis. The authors considered this round robin to be difficult. Sample homogeneity was an issue and molecular orientation was observed in many data sets. Each material studied has structural polymorphs so the selection of starting parameters and their refinement was nontrivial. Similar to prior round robins on inorganic materials and minerals, this round robin identified operator errors as the major contributor to poor results. Four laboratories achieved excellent results on all phases in all three samples, with accuracy within relative errors of 5% to 10%.

The ability to analyze unknown solid state materials by powder diffraction depends on a comprehensive reference collection and the accuracy in determining key parameters in both the unknown and the reference. The Powder Diffraction File (PDF), was created through contributions of the global scientific community, to provide an accurate, comprehensive reference database. The latest version of the PDF for organics and pharmaceutical analyses, PDF-4/Organics Release 2009, contains 370,844, standardized, quality reviewed and edited, material entries. The primary reference data in the database is a collection of peaks, interplanar d-spacings (d’s), and their corresponding peak intensities (I’s). Comparison of d,I pairs from the experimental data with those of reference materials, was described by Hanawalt and Rinn in 1936 (1) and has been the basis for phase identification methods for decades. PDF-4/Organics Release 2009 contains 66,275,578 d,I pairs for search and comparison to an unknown. With such large numbers of d-spacings and materials how can we be confident that we have correctly idenified an unknown? In recent years, especially with powerful PC’s, total pattern analysis techniques are now used in material identification. These techniques require the use of “full or total patterns” for both the unknown and reference data. With PDF-4/Organics all reference materials can be represented as full digital patterns either though experimental measurement or by calculation, enabling the use of several types of full pattern methods (Reitveld, LeBail, pattern fitting) in phase identification and quantitation. Not as obvious is the ability to use other dependent variables in conjunction with diffraction or crystallographic data to facilitate material identification. Such variables might include elemental composition, physical properties (density, color, mp), functional groups, nomenclature, prototype structures, and chemistry classification (i.e. subfiles). PDF-4/Organics is a relational database, with a JAVA interface and embedded plotting and statistics software. The database has 48 types of searches and data can be sorted and displayed for 70 fields, in any permutation. We can now statistically examine methods and techniques that have been historically and empirically applied to phase identification and materials analysis. How much data is required for minor phase analysis, how many d-spacings are required to uniquely describe a material for patent purposes? What limits in detection are imposed by not using a standard, or expanded by use of a standard? In this presentation we will discuss some of the fundamental statistics of powder X-ray diffraction and answer basic questions on how this method works.

Sessionsdistribution of conformational states represented in the PDB.A systematic review of multiple deposits shows that a single protein is rarely represented by a single structural conformer.This result sheds light on the first link and demands the reformulation of the proteinfolding problem.A vast majority of proteins shows significant number of distinct conformational states with, sometimes large, structural divergence (up to ~24Å).The results suggest that every single protein evolved according to its own optimization principles combining different proportions of rigid (solid-like) and mobile (liquid-like) structural elements.The results suggest further that the optimization process that produced the particular combination of those elements is intricately connected with the function of individual proteins.Therefore, the structural description of the protein, besides the folding class (the architecture represented by the SCOP database), should include the natural structural divergence (width of the distribution) as two main attributes.Additionally, our analysis suggested the principles of functional evolution by use of the Dual Personality sequences (sequences with incomplete representation in the atom records that have distinctive sequence features from regularly folded and intrinsically disordered fragments).

PDF-4/Organics 2008 is ICDDs collection of standard reference X-ray powder diffraction (XRPD) patterns for organic compounds. It includes 29,653 experimental patterns and 311,887 patterns derived from single crystal data. Most of the derived patterns are based on data from the Cambridge Structural Database (CSD) through an agreement between ICDD and CCDC (Cambridge Crystallographic Data Centre). This database contains XRPD patterns for more than half of the USP (United States Pharmacopeia) APIs (active pharmaceutical ingredients) and their polymorphs. Additionally, it contains a large number of patterns for inorganic and organic excipients typically found in pharmaceutical formulation. Since the solid state of a pharmaceutical substance can affect its pharmacological action, the polymorph study is a must for any API, which can exist in more than one solid state. PDF- 4/Organics 2008 contains many substances with polymorphs and has many physical and chemical properties associated with polymorphism. These include habit, space group, cell parameters, cell volume, crystal system, density, and melting point. There is also standardized cell data as well as author-reported raw data in the database. The standardization assures data uniformity. It provides not only the swift and easy means for data comparison, but also the accuracy of data representation. The population distribution for these properties and their applications were studied, compared, and will be presented. Many phase identification processes have been widely researched and reported. These processes generally utilize techniques involving data reduction, peak finding, modeling, and refinement. Illustrations of this traditional process, for pharmaceutical materials, using PDF-4/Organics 2008 for the pattern matching between experimental data and reference patterns will be given.

An experimental X-ray powder diffraction pattern was produced and analyzed for alpha-polymorphic tegafur, also called Ftorafur (an antineoplastic agent). The indexed data matched the powder patterns in the ICDD PDF-4/Organics database calculated from the reported single-crystal X-ray diffraction data in the Cambridge Structural Database. Alpha tegafur has a triclinic crystal system, with reduced cell parameters of a=16.720(6) Å, b=9.021(5) Å, c=5.995(3) Å, α=93.66(4)°, β=93.15(8)°, γ=100.14(4)°. There are four formula units contained in one unit cell. The cell volume and space group were determined to be 886.27 Å3 and P-1, respectively.

Developments in X-ray analysis hardware and software have combined to dramatically improve the throughput, speed, and accuracy of formulation analyses. We will focus on a complimentary development, the growth and application of a comprehensive database based on the Powder Diffraction File™ (PDF®). The PDF is an edited and standardized combination of several crystallographic databases with ∼497 000 published entries. The comprehensive nature of this database, combined with phase identification and digital pattern simulations, was used to identify complex formulations with crystalline and noncrystalline ingredients. We will show how these parallel developments enhance the ability to correctly identify complex formularies.

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Release 2003 of the Powder Diffraction File (PDF) contains ∼280 000 unique entries organized in a series of tables in a relational database format. The PDF is available in two products, PDF-4/Full File and PDF-4/Organics, which allow users to access and query over 150 million filled entry fields. An editorial database is used to generate the commercial products that contain tables of experimental details and statistical evaluation criteria used by the editors to evaluate quality and determine quality marks for each entry in the PDF. This editorial database has nearly doubled the searchable entry fields. This database was mined to evaluate experimental methods in X-ray diffraction. Both experimental powder diffraction data and data calculated from predominantly single crystal X-ray structural analyses were assigned statistical quality criteria. For experimental powder data, the average delta two theta values for alld-spacings in the entry set were used. Calculated data were evaluated usingRfactor values as the primary quality criteria. A Quality Index, which measures the errors in refined unit cell parameters divided by the magnitude of the cell parameter, can be used to compare all types of data. Experimental variables were then analyzed versus these criteria. Variables include optic configuration, (i.e., Seeman–Bohlin, Guinier, Debye–Scherrer), use of internal and external standards, use of monochromators, wavelength divergence, wavelength selection, equipment radius, specimen transparency, and specimen absorption. This study significantly differs from prior round robin analyses in that the use of the database allows us to study very large population sets for every variable analyzed.

The continuous development of a modern database of solid state organic and organometallic materials combined with the development of new statistical and physical methods of analysis have combined to provide pharmaceutical scientists with an array of tools for the analysis of polymorphs both as single phase materials and in formulations. Key developments include the creation of quality indices, standardized calculation methods, and editorial analysis programs now applied to evaluate quality, calculate physical properties, and simulate digital patterns for both powder and single crystal x-ray determinations. These developments have been incorporated in the PDF-4 Organics database. A second development has been the rapid growth and incorporation of similarity indices and cluster analyses in a variety of commercial x-ray analysis programs. (1-5) A third development has been the incorporation of statistical analysis packages within the database framework to rapidly analyze large groups of data very quickly. All three of these developments take advantage of advances in personal computer technology. For example the statistical analysis package developed for Release 2008 PDF-4 Organics, performs analyses that have been known for decades, but does this on a relational database platform using JAVA point and click interfaces so that a large array of polymorph analysis methods can be applied quickly to sophisticated data sets. Rapid analysis multi-tool sets are also incorporated into several commercial cluster analysis programs. The presentation will not focus on the tools but the results that can be obtained in application of the tools. We will introduce a series of "polymorph" maps as applied to several known and some previously unexplored pharmaceutical systems. Such maps demonstrate the essence of data mining where unexpected results can be obtained from the science of extracting data from a large database. The presentation will also demonstrate various data mining approaches that have been successfully used to elucidate polymorphism in commercial pharmaceuticals.