Atomic pair distribution function: a revolution in the characterization of nanostructured pharmaceuticals
2015; Future Medicine; Volume: 10; Issue: 16 Linguagem: Inglês
10.2217/nnm.15.116
ISSN1748-6963
Autores Tópico(s)Drug Solubulity and Delivery Systems
ResumoNanomedicineVol. 10, No. 16 EditorialFree AccessAtomic pair distribution function: a revolution in the characterization of nanostructured pharmaceuticalsSimon JL BillingeSimon JL Billinge*Author for correspondence: E-mail Address: sb2896@columbia.edu Department of Applied Physics & Applied Mathematics, Columbia University, New York, NY 10027, USA Condensed Matter Physics & Materials Science Department, Brookhaven National Laboratory, Upton, NY 11973, USAPublished Online:21 Aug 2015https://doi.org/10.2217/nnm.15.116AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail Keywords: atomic pair distribution functiondrugfingerprintingformulationnanoparticlesPDFpharmaceuticalphase quantificationtotal scatteringx-ray diffractionGiven our druthers, we would never work with drugs in the amorphous (a-) or nanocrystalline (n-) solid forms. Like naughty, unruly children, they can't be relied on and tend not to do as they are told: not traits that are desirable in the drug marketplace. But what if these were the only solid forms that a promising active pharmaceutical ingredient (API) could be brought to market? Or like the children, what if this form gave you exciting new possibilities, for example, for targeted drug delivery? Then it would be great to find foolproof ways of characterizing and controlling their undesirable excesses. Increasingly, we are pushed in this direction. Only a small percentage of drugs currently at market are amorphous. However, with 70–90% of the molecules in the drug development pipeline being classified as poorly soluble [1] in the biopharmaceutics classification scheme [2]. The increased solubility of the nanocrystalline [3] and amorphous [4,5] states is starting to look very attractive to formulation scientists.To make substantial progress on these issues, it is critical to have tools that allow us to detect and characterize the structure of APIs in the a- and n-forms. This is a major challenge because the industry standard workhorse for structural characterization, conventional x-ray diffraction (XRD), loses its power when the crystallite size becomes nanometer in scale. The diffraction pattern gets broad and noisy, the so-called 'amorphous halo', and carries little information. However, recently, the development of the total scattering pair distribution function (TSPDF) method applied to small molecule systems has shown great promise for fingerprinting, quantification and even modeling of nanocrystalline and amorphous APIs.The TSPDF method was developed for studying nanostructure in crystals [6] and was later applied to inorganic nanoparticles [7]. It grew out of a rich 70-year history of applying a similar approach to study the scattering from inorganic glasses and amorphous materials [8]. Coupled with modern developments in sources, instrumentation and computing, it is becoming a powerful method for studying structure at the nanoscale. It is based on a Fourier analysis of the x-ray, neutron and electron scattering data collected over the entire reciprocal space (from which it gets its 'total scattering' name) from an orientationally disordered sample [7]. More recently, it has been applied successfully to small molecule systems [9,10]. Earlier attempts to use similar Fourier methods on conventional XRD data [11] suffer from the lack of information in the conventional XRD pattern, and uncertainties in data processing and interpretation due to the narrow range of the data [12].The total scattering pair distribution function methodThe experimental TSPDF is straightforwardly obtained as the Fourier transform of the properly corrected powder diffraction pattern for the material [7]. It turns out, from the nature of the scattering equations, that this 1D function is a histogram that gives the probability of finding two atoms in the material separated by the distance r. As such it not only represents a good fingerprint of a material structure, but it is also a very intuitive function, allowing rapid investigation of structures, and changes in structure. For example, the PDF from an organic molecule will have a sharp peak at 1.4 Å, a second neighbor distance at around 2.5 Å and so on. Peaks in the function continue to higher-r values as long as there are well-defined interatomic distances present in the structure up to the size of the crystallite. By seeing where the peaks disappear one can determine immediately, without complicated modeling, an average crystallite size, which is less than or equal to the particle size in the material (it will be less if there is significant structural disorder). It is straightforward to calculate TSPDFs from structural models [13] allowing a quantitative assessment of material structure. Most importantly in the context of amorphous and nanocrystalline APIs, unlike crystallography, it doesn't assume a long-range ordered crystalline structure; it may still be used for clumps of packed molecules as small as 1 nm, indeed for studying the molecule itself.Applications of TSPDF in characterization of a- and n-APIsFingerprinting is a critical part of pharmaceutical development and manufacturing. It is desired simply to determine whether a particular form of an API is present in the sample. This is an important safety, quality control and intellectual property (IP) protection issue. It is also important in studies of drug stability, since pharmaceuticals may change their solid form with time.Fingerprinting crystalline API's in the sample is done using conventional XRD, but this doesn't work for a- and n-drug forms. However, it was shown that, in favorable cases, a nanocrystalline drug form could be successfully fingerprinted using TSPDF [9]. In particular, a sample of melt-quenched carbamezapine that appeared amorphous in a conventional XRD measurement could be shown to be 4.5-nm diameter nanoparticles of the β-form of the drug [9].Once their presence is known, it is highly desirable to quantify the amount of different constituents in a multiphase sample, for example, a pill formulation. This is especially difficult when one or more of the constituents is in the a- or n-forms, but TSPDF shows promise also in this direction [14] where recrystallization of sulfamerazine from the amorphous state was followed.A frequent question is whether it is possible to detect dilute quantities of an API in a formulation or, for example, in suspension in a solvent. It is difficult to detect small amounts of material, and a de facto lower limit of a few percent was considered a good rule of thumb for being able to detect dilute species [7]. However, using the latest data reduction techniques and very intense x-ray beams, it was recently demonstrated that nanoparticles of an API could be detected at the level of 0.25 wt% in aqueous solvent [15], a surprising level of sensitivity, especially given the weak scattering from the organic, but a very exciting development.Beyond fingerprinting and phase quantification it would be wonderful to be able to extract quantitative structural parameters from a- and n-drugs by structural modeling. This has been done in inorganic materials for some time [7] but challenges exist when transferring this to molecular systems, for example, differentiating intra- and intermolecular atomic-pairs and moving atoms in mutually rigid parts of a molecule as rigid bodies. Progress has been made in both areas [16] [prill d et al. solution and refinement of organic crystal structures by fitting to the atomic pair distribution function (pdf), 2015]. There is still much work to do in making these methods easy to use and robust, but the initial signs are promising. For example, in [16] it was possible actually to solve the (already known) structure of a rigid molecule, quinacridone, using only PDF data.Experimental determination of TSPDFsThe first reported TSPDFs from pharmaceuticals were obtained using intense synchrotron radiation [9]. The high fluxes of high energy x-rays available at such sources make them very attractive for TSPDF studies [12]. Access to synchrotron sources is surprisingly easy and affordable for both academics and industrial users and should not be overlooked as a possibility, often with mail-in programs becoming available meaning that researchers don't even have to travel to the beamline for data to be collected. However, data suitable for PDF analysis may also be obtained from laboratory x-ray sources [12], but PDFs of sufficient quality for reliable fingerprinting (and further analysis) do require short wavelength x-rays as obtained from silver or molybdenum x-ray tubes.In another interesting development, it was recently shown that PDFs of a quality sufficient for semiquantitative analysis of nanostructure in materials could be obtained from rather standard configuration transmission electron microscopes [17]. When working with molecular materials, beam damage is an issue. However, it was recently shown that with careful data collection protocols, these approaches may be extended to pharmaceuticals and small molecule systems [18].Finally, we note that anything that you can do with PDFs, such as fingerprinting, quantification and structural analysis, can now be done in a spatially resolved manner with resolutions down to the micron scale, with the marriage of computed tomography and PDF [19]. This very recent development has not been applied in the pharmaceutical area, but would allow the quantification of nanoparticle structure and morphology of an n-API component, to be mapped out spatially, for example, in a pill compress. The experiments are nondestructive and map nanostructure inside solid objects since the short-wavelength x-rays penetrate into the bulk.Future perspectiveMotivated by the desire to characterize a- and n- pharmaceuticals, a great deal of development has recently gone into TSPDF methods and we now have exceptionally powerful tools available for studying drugs and formulations at the nanoscale. But these tools have applications well beyond amorphous drugs, as they can be used to study the structure of any nanoparticle, ex situ or in situ. As the nanobio community becomes more aware of these methods, we expect to see many exciting applications to studies that were hardly dreamed of at the beginning of this journey.Financial & competing interests disclosureThe author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.References1 Thayer AM. Finding solutions. Chem. Eng. News 88(22), 13–18 (2010).Crossref, Google Scholar2 Amidon GL, Lennerns H, Shah HVP, Crison JR. A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharmaceut. 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Commun. 4, 2536 (2013).Crossref, Medline, Google ScholarFiguresReferencesRelatedDetailsCited ByDescribing the Influence of Ball-milling on the Amorphization of Flubendazole Using the PDF and RMC Methods with X-ray Powder Diffraction DataJournal of Pharmaceutical Sciences, Vol. 111, No. 11Quantifying the Local Structure of Nanocrystals, Glasses, and Interfaces Using TEM-Based Diffraction22 November 2021 | Chemistry of Materials, Vol. 33, No. 23Structure determination of organic compounds by a fit to the pair distribution function from scratch without prior indexing9 May 2021 | Journal of Applied Crystallography, Vol. 54, No. 3Amorphous dispersions of flubendazole in hydroxypropyl methylcellulose: Formulation stability assisted by pair distribution function analysisInternational Journal of Pharmaceutics, Vol. 600There's no place like real-space: elucidating size-dependent atomic structure of nanomaterials using pair distribution function analysis1 January 2020 | Nanoscale Advances, Vol. 2, No. 6Applications of Powder X-Ray Diffraction in Small Molecule Pharmaceuticals: Achievements and AspirationsJournal of Pharmaceutical Sciences, Vol. 107, No. 12Physical Stabilization of Pharmaceutical Glasses Based on Hydrogen Bond Reorganization under Sub- Tg Temperature2 December 2016 | Molecular Pharmaceutics, Vol. 14, No. 1Total scattering atomic pair distribution function: new methodology for nanostructure determination16 May 2016 | Journal of Experimental Nanoscience, Vol. 11, No. 12Recent advances in the characterization of amorphous pharmaceuticals by X-ray diffractometryAdvanced Drug Delivery Reviews, Vol. 100 Vol. 10, No. 16 STAY CONNECTED Metrics History Published online 21 August 2015 Published in print August 2015 Information© Future Medicine LtdKeywordsatomic pair distribution functiondrugfingerprintingformulationnanoparticlesPDFpharmaceuticalphase quantificationtotal scatteringx-ray diffractionFinancial & competing interests disclosureThe author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.PDF download
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