PRIMER

Powder diffraction
James A. Kaduk   1,2 ✉, Simon J. L. Billinge   3,4, Robert E. Dinnebier5, Nathan Henderson   6,
Ian Madsen7, Radovan Černý8, Matteo Leoni   9, Luca Lutterotti10, Seema Thakral11
and Daniel Chateigner   12
Abstract | Powder diffraction is a non-​destructive technique, which is experimentally simple in
principle. Because the physics behind diffraction is well understood, an exceptionally large
amount of information can be obtained from a single measurement. The positions and relative
intensities of the peaks yield a fingerprint that can be used for qualitative phase analysis.
Quantitative phase analysis can be obtained by detailed analysis of the intensities. Unit cells can
be derived from the peak positions. Crystal structures can be solved using powder diffraction
data and refined by the Rietveld method. The peak profiles contain information about crystallite
size, strain and nanostructure. Non-​idealities in the intensities give information on texture.
Abandoning the crystallographic model provides information about local structure, by pair
distribution function analysis. For powder diffraction, everything is a sample; the technique is
commonly applied to characterize minerals, ceramics, metals and alloys, catalysts, polymers,
pharmaceuticals, organic compounds, environmental and forensic samples, among others. The
major features of contemporary laboratory powder diffractometers are described. Methods for
obtaining suitable powder specimens are summarized. Major applications of qualitative and
quantitative phase analysis, structure solution, size/strain/nanostructure analysis using peak
profiles, texture analysis and pair distribution function analysis are introduced.

Unit cell
The unit cell is the
parallelepiped built on
the vectors, a, b and c, of a
crystallographic basis of the
direct lattice. Its volume is
given by the scalar triple
product, V = (a, b, c), and
corresponds to the square
root of the determinant of
the metric tensor.
Short-​range atomic order
The regular and predictable
arrangement of atoms over a
short distance, usually with one
or two atom spacings. However,
this regularity does not persist
over a long distance, and is
aperiodic. Examples of
materials with short-​range
order include amorphous
materials such as wax,
glass and liquids
✉e-​mail: kaduk@
polycrystallography.com
https://doi.org/10.1038/
s43586-021-00074-7
Crystallography, based on the diffraction of X-​rays,
neutrons or electrons, is imperative for determining
the atomic structure of crystalline materials. From the
earliest days of crystallography, it was realized that
structures could be obtained from powders that do
not contain single crystals1. Over time, the impact of
powder diffraction on materials sciences has increased
as people push towards studying complex materials,
nanomaterials, applications of polycrystalline mate-
rial and investigations in situ and in operating devices
(operando studies)2,3. The mathematical difficulties of
extracting structural information from powders, which
are expected to be orientationally averaged samples,
where diffraction information is compressed from
3D to 1D, are being overcome with improved compu-
tation and analytical methods. Furthermore, material
properties often depend on defects in the material, par-
ticle morphology and the internal strain state — all of
which can be studied using powder diffraction. Powder
diffraction can also be used to study larger-​scale features
(correctly called microstructure) such as compositional
inhomogeneity, the distribution of phases in a sample
and grain properties, including size, shape, distribu-
tion of size parameters, orientation function and the
nature and distribution of grain boundaries4. Finally,
new intense sources of X-​rays, neutrons and electrons
are making spatially resolved and time-​resolved studies
possible, offering more analysis opportunities for the
powder method.
When a single crystal is illuminated with a beam
of monochromatic X-​rays, discrete diffracted beams
are obtained. When viewed on a 2D detector, these
diffracted beams appear as spots. The positions of the
Bragg peaks yield information about the 3D lattice of
the structure, which is described by the unit cell. The
intensities of the Bragg peaks depend on the long-​range
average arrangement of atoms on this lattice. In powder
diffraction, in addition to peak positions and intensities,
the width and shape of the peaks yield information about
the size, shape and strain state of the crystallites in the
polycrystalline array or powder. Information about short-​
range atomic order is not contained in the Bragg peaks,
but in a structured diffuse background. Total scattering
measurements such as atomic pair distribution function
analysis recover the Bragg peaks and diffuse scattering,
and extract important structural information about local
atomic packing and disordered molecular structures
beyond any long-​range order. Total scattering experiments
may be used to investigate atomic arrangements in the
absence of any long-​range order, for example in small
clusters of atoms, metallic or quantum dot nanoparticles
and amorphous materials3,5.

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Author addresses
1
Department of Physics, North Central College, Naperville, IL, USA.
2
Department of Chemistry, Illinois Institute of Technology, Chicago, IL, USA.
3
Deprtment of Applied Physics and Applied Mathematics, Columbia University,
New York, NY, USA.
4
Condensed Matter Physics and Materials Science Department, Brookhaven National
Laboratory, Upton, NY, USA.
5
Max Planck Institute for Solid State Research, Stuttgart, Germany.
6
Bruker AXS Inc., Madison, WI, USA.
7
CSIRO Mineral Resources, Clayton South, Victoria, Australia.
8
Laboratory of Crystallography, University of Geneva, Geneva, Switzerland.
9
Department of Civil, Environmental, and Mechanical Engineering, University of Trento,
Trento, Italy.
10
Department of Industrial Engineering, University of Trento, Trento, Italy.
11
Department of Pharmaceutical Sciences & Research, University of Minnesota,
Minneapolis, MN, USA.
12
Université de Caen Normandie, CRISMAT-​ENSICAEN, IUT Caen, Caen, France.
Powder diffraction measurements normally make
the starting assumption that the sample is isotropic,
meaning that there is a crystallite, or powder particle,
in the beam with every possible orientation, sampled
with equal probability. Systems intermediate between
single crystals and isotropic powders are less tractable
mathematically but may still be studied by diffraction,
although it is more difficult. The experiment involves
hitting a region of the sample with a monochromatic
incident beam of X-​rays and measuring the intensity
as a function of the angle between the incident beam
and the detector. As such, the scattering intensities exit
the sample in cones of uniform intensity called Debye–
Scherrer cones (Fig. 1a). The 3D information of a single
crystal diffraction pattern is compressed into the 1D
powder pattern. Overlap of powder diffraction peaks
means that information may be lost, limiting the con-
tent of a powder pattern compared with single crystal
diffraction.
Different aspects of materials that can be derived
from a powder diffraction pattern are shown schemat-
ically in Fig. 2. In crystalline materials the most prom-
inent features in the pattern are sharp Bragg peaks5.
Bragg peak positions in a detector during a diffraction
experiment are determined by the Bragg equation6:
Pair distribution function
A representation of the nλ = 2d sin θ (1)
probability of finding two
atoms in a material separated
by some distance r. It is often where n is the order of diffraction, λ is the wavelength of
present with respect to the the probe, d is the spacing between a well-​defined set
probabilities in a random of crystal planes and the diffraction angle is 2θ. Sharp
distribution of atoms, so some Bragg peaks appear at discrete 2θ angles, where this equa-
probabilities are positive and
others are negative.
tion is satisfied for each set of crystallographic planes in
the crystal lattice (Fig. 1b). Each Bragg spot is therefore
Long-​range order labelled with three integers, (hkl), the Miller index labels
The property of crystal associated with the respective crystallographic planes.
structures in which atoms are
In practice, there are many experimental aspects that
arranged with translational
periodicity over extents of at can be optimized to obtain good data, as discussed in the
least three unit cells. This is the Experimentation section. However, this ease of meas-
property that gives rise to urement, coupled with modern sensitive 2D detectors,
Bragg peaks. opens up powerful opportunities for probing materials in
Diffraction angle
special environments (in situ) such as high-​temperature
The angle between the incident furnaces, high-​pressure cells and high magnetic fields,
and diffracted X-​ray beams as well as following synthesis reactions in solvent flow
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cells, in samples spinning in a levitator and in oper-
ating devices (in operando) such as cycling fuel cells
and batteries. Intense synchrotron-​based X-​ray sources
yield small beams that can be rastered across a speci-
men to spatially resolve information with micrometre-​
scale reso­lution, and similarly in electron microscopes
with resolutions of tens of nanometres7,8. This approach
can even be combined with computed tomography to
obtain 3D spatially resolved measurements of polycrys-
talline samples9–11. Typical data sets take seconds to hours
to collect, but with modern instrumentation the data
collection rates can reach up to 100 diffraction patterns
per second (hundreds of hertz), allowing time-​resolved
studies of materials in real working devices12. The ease of
collection also makes powder diffraction ideal for stro-
boscopic pump probe measurements that allow studies
of materials with femtosecond time resolutions after
some excitation pulse13.
Structural information in the powder pattern is
generally extracted using modelling methods based
on regression. Structural models are proposed, the
powder pattern is computed from the model and com-
pared with the measured one, and the parameters in the
model are then updated using a regression algorithm
that minimizes the misfit between the calculated and
the measured data.
The information content in a powder diffraction
pattern is considerable, and powder X-​ray diffraction is
becoming more widely used in a wide range of scientific
disciplines from archaeology to drug development. One
of the powder diffractionist’s mottos is that everything
is a sample; the technique is commonly applied to char-
acterize minerals, ceramics, metals and alloys, cata-
lysts, polymers, pharmaceuticals, organic compounds,
environmental and forensic samples, and many other
types of solid. Powder diffraction is more than crystal
structure solution; it allows investigation of real mate-
rials in real environments, to give information about
defects, texture, nanostructure, strain, phase compo-
sition, kinetics, phase transformations, size and shape
distributions and heterogeneity. Where crystallography
yields the average structure, powder diffraction gives
us a materials science view of materials. This Primer
gives a high-​level view of various aspects of powder
diffraction.
This Primer describes basic aspects of laboratory
instrumentation, and specimen preparation techniques
and issues. Major applications of qualitative and quan-
titative phase analysis, structure solution, size/strain/
nanostructure analysis using peak profiles, texture
analysis and pair distribution function analysis are
introduced. Structure refinement using the Rietveld
method14 is not covered, and should be the subject of
a future Primer. Specific examples of applications to
pharmaceuticals and organic pigments are presented.
Methods for structure validation and assessing accuracy
are introduced, as well as databases and data deposition.
Although the applications of powder diffraction are vast,
there are limitations. Powder diffraction is at the thresh-
old of big data, and we can expect increasing use of pow-
der data in materials design. Many more details on all of
these topics are found in ref.3.
 Primer

Goniometer
Experimentation illuminates a flat sample, which is prepared by packing
An instrument for the accurate The major features of contemporary laboratory powder a powder into a cavity in a sample holder and is then
and precise measurement of diffractometers are described. As this is powder diffrac- diffracted towards the detector. Multiple transmission
angles. A goniometer is the tion, methods for obtaining suitable powder specimens geometries are possible, but frequently a parallel beam or
heart of a powder
diffractometer, capable of
are summarized. spot/point beam is created with the use of X-​ray mirrors
measuring angles to or physical collimation. The sample is presented to the
0.001–0.0001°. Instrumentation X-​ray beam as a flat plate or capillary and X-​rays are
Here, the most common laboratory configurations are scattered as they transmit through the sample. There
Collimators highlighted, primarily Bragg–Brentano (reflection; are many choices for optics — for example, divergence
Devices that narrow and/or
Fig. 3a,c) and, to a lesser extent, Debye–Scherrer (trans- slits and axial Soller slits15 — that can be optimized
shape a beam of X-​rays. In a
powder diffractometer, they mission; Fig. 3b,d) geometries. An exhaustive discussion for specific material types and experiments. Generally
can take the form of a slit, tube of diffractometer components can be found elsewhere15. speaking, larger slits and collimators will bias towards
or set of parallel plates. In both the Bragg–Brentano and Debye–Scherrer higher intensity data whereas narrower ones will yield
Fluorescent X-​rays
configurations, the X-​ray source is mounted to the inci- higher resolution diffraction peaks. The intensity gain
Secondary X-​rays emitted dence side of the instrument and the X-​ray detector is from larger optics is the result of a larger beam of
when an atom is bombarded attached on the opposite side of the sample to measure X-​rays and higher sampling volume, resulting in higher
by high-​energy X-​rays that diffracted X-​rays. A goniometer is used for precise con- counts but wider peaks from instrumental broadening.
knock an electron from a core
trol over incident and diffracted angles relative to the Conversely, the use of smaller optics will minimize the
orbital. The fluorescent X-​rays
are emitted when an electron
sample. The sample itself is positioned in the centre instrument contribution to the observed peak shape,
in a higher-​energy orbital fills of the instrument. Bragg–Brentano systems (Fig. 3a,c) resulting in sharper, less intense peaks.
the hole. use physical slits to define a diverging X-​ray beam that The use of copper radiation is prevalent in laboratory-
b
​ ased systems, although other X-​ray sources (for exam-
a hkl ple, cobalt, chromium, molybdenum or silver) can be
Refle
cted chosen for specific applications to provide higher sam-
beam
ple penetration and reduced peak overlap or to focus on
Primary beam
particular characteristic distances. For example, inter-
stratified clay minerals possess large d-​spacings that
can be intentionally pushed to higher 2θ angles with a
longer wavelength, such as cobalt. Cobalt radiation is
hkl
hkl sometimes used to avoid the fluorescent background
Refl
ecte
d be from illuminating iron-​containing specimens with
am copper radiation16. Molybdenum or silver radiation
4θ Primary beam can be used to generate approximate pair distribution
functions from laboratory data rather than synchrotron
data. With regard to detectors, semiconductor-​based
technologies are increasingly common and include
hkl high-​speed linear detectors as well as multimode detec-
b tors, which can collect data in 0D/1D/2D modes, with
large fields of view that can be binned into 0D/1D/2D
applications. Linear detectors — also referred to as
position-​sensitive detectors or 1D detectors — provide
increased data collection speeds relative to previously
used point detectors, such as scintillation counters.
These position-​sensitive detectors typically contain
100–1,000 or more channels, resulting in 100–1,000×
M increases in data collection speed. Many of these detec-
θ
tors can also use energy filtering to suppress or eliminate
θ the background from fluorescent X-​rays from the sample,
d improving signal-​to-​background ratios. Some detectors
are even capable of rejecting Kβ X-​rays — higher-​energy
P Q X-​rays produced from a 3p–1s transition — yielding a
2θ pseudo-​monochromatic Kα (2p–1s transition) pat-
N
tern. However, the Kα pattern consists of two closely
spaced wavelengths, Kα1 and Kα2, in a 2:1 intensity ratio.
Fig. 1 | Diffraction principles. a | Comparison between scattered beams originating 2D detectors are typically coupled with point beam
from a single crystal and a powder. For the latter, some Debye–Scherrer cones are geometries and capture large portions of Debye rings
drawn in reciprocal space. b | Geometry used for simplified derivation of Bragg’s law.
for applications such as microdiffraction, residual stress
d, distance between planes containing these lattice points (d-​spacing); hkl, Miller index
labels associated with the respective crystallographic planes; M and N, lattice points; and texture analysis.
P and Q, points on the incident and diffracted beam vectors, respectively, drawn from More detailed information regarding X-​ray powder
M perpendicular to these vectors; θ, diffraction angle. Part a reprinted with permission diffraction physics, optics and instrumentation is avail-
from ref.173, Royal Society of Chemistry. Part b reprinted with permission from ref.173, able in refs17–23. In summary, the peak width is influ-
Royal Society of Chemistry. enced by the size of the incident and diffracted beam

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Information content of a powder pattern
Background
Sample Scattering from
sample holder,
air, etc.
Compton
scattering
Diffuse scattering
• Local structure
• Amorphous fraction
• Lattice dynamics
Fig. 2 | Schematic of the information content of a powder pattern. Reprinted with
permission from ref.173, Royal Society of Chemistry.
Preferred orientation
Preferred orientation arises
when there is a stronger
tendency for the crystallites
in a powder or a texture to be
oriented more in one way, or
one set of ways, than all others.
4 | Article citation ID:
Reflections
Position Intensity Profile (full width
at half maximum,
peak shape)
Instrument Sample
function broadening
Lattice parameters, Crystal structure Real structure
space group • Atomic positions • Micro-strain
• Macro-strain • Temperature factor • Domain size
• Qualitative phase • Occupancy
analysis • Texture
• Quantitative phase
analysis
slits, or the width of the channels of the strip detector.
Meanwhile, the asymmetry of the peaks is affected by
Soller slits that control the axial divergence of the beam
in the direction perpendicular to the diffraction plane.
Modern instruments provide enough flexibility to
optimize a particular measurement.
Specimen preparation
Specimen preparation methods24 are as varied as the
materials that can be characterized by this technique. For
example, large rocks are commonly crushed into a fine
powder that should be representative of the entire sam-
ple for the purpose of quantification. Alternatively, small
volumes of high-​potency pharmaceutical compounds
might need to be analysed in a contained environment.
Here, an overview of common techniques is provided, as
well as some general comments on sources of error and
recommendations for minimizing these effects.
The ideal diffraction specimen should be a fine,
smooth powder that is homogeneous and has randomly
distributed crystallite orientations. For Bragg–Brentano
geometries, it should be presented to the X-​ray beam
as a flat surface aligned with the centre of the goniom-
eter without any height offset, tilting or roughness. For
transmission geometries, the ideal specimen is a thin
sheet or filled capillary: if too thick, the specimen might
not be fully penetrated by the X-​ray beam, inadvertently
becoming a beam stop. Large forms, such as solid metal
pieces or geological cores, can be analysed with powder
diffraction, but do not represent ideal specimens. These
will frequently demonstrate altered peak intensities
or locations due to texture, orientation, residual stress or
large grains; however, these types of sample are not
addressed further in this section.
The sample must be reduced to a fine, smooth pow-
der with a particle size no larger than 40 μm, and ide-
ally <5 μm. This is typically achieved by hand grinding
in a mortar and pestle or with the aid of mechanical
grinding aids such as shaker or micronizing mills. The
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crystallinity of softer materials, for example pharmaceu-
ticals or small organic molecules, can be decreased by
aggressive grinding, so a gentle hand should be used to
avoid loss of crystallinity or structural changes resulting
from friction and heat. Harder samples, such as felsic
rocks, should be processed with appropriately hard
grinding media, such as agate or corundum. For sam-
ples with multiple phases, this is also an opportunity to
ensure homogeneous distribution of each component.
Visual cues that a good powder has been achieved are
a soft, flour-​like texture with an even colour and an
absence of visible speckles or granularity. Rough, coarse
or grainy samples should be avoided as they can lead to
inaccurate peak shapes and intensities, as well as poor
statistics from a limited number of crystallites. For the
purposes of phase identification, particle sizes of <40 μm
(~325-​mesh sieve) are typically sufficient to ensure ade-
quate data quality. For more challenging applications,
such as accurate quantification of mixtures, smaller par-
ticle sizes of 1–5  μm are more appropriate24–26. This min-
imizes the effects of microabsorption, where materials of
contrasting densities can produce inaccurate peak inten-
sities due to large, dense grains shadowing other phases.
On the other hand, use of a McCrone micronizing mill,
the most commonly used tool for achieving such small
particle sizes, often results in micro-​strain broadening24,
so if the purpose of the experiment is to analyse the
strain in the sample, alternate methods might be used.
Once a smooth powder is achieved, many materials
can be prepared simply by packing into a cavity holder,
flattening to a smooth surface and removing any excess
powder. This approach is referred to as top-​loading or
front-​loading (Fig. 4a). The specimen should be flush
with the surface of the holder, as the peak positions
are sensitive to height discrepancies. Positive displace­
ment — when the specimen is too high — will lead to
reflections with higher observed 2θ positions, and nega-
tive displacement — when the specimen is too low — will
shift peaks to lower angles.
One of the more common sources of error is
preferred orientation, which arises in materials that have
specific cleavage or growth directions, or otherwise
demonstrate anisotropic morphologies, such as fibres
or platelets. This can lead to non-​random crystal orien-
tations, which in turn lead to inaccurate peak intensities.
Diffraction planes that are overly represented will gain
intensity, and reflections from orthogonal directions
will demonstrate lower intensities than expected from a
fully randomized powder. Incorrect peak intensities can
lead to challenges in phase identification as well as diffi-
culties in extracting information for structural analysis.
To reduce the preferred orientation, a minimal amount
of force should be used when employing a top-​loading
approach.
For highly orienting materials, a side-​loading or
back-​loading technique can be selected. In this approach,
the powder is added from the side or the back of the
holder, using a piece of frosted glass or sandpaper to stop
the specimen from falling out. The logic here is to apply
minimal amounts of external force to the top surface of
the specimen, which will then be presented to the X-​ray
beam. These approaches can be more time-​consuming

than top-​loading but can yield more accurate peak
intensities with practice and a steady hand.
A limited or restrictive amount of sample (<100 mg)
is another frequently encountered challenge, especially
in fields such as forensics, art conservation, nanomate-
rials and pharmaceutical research and development. In
these cases, there may not be sufficient material to fill a
standard holder. Historically, specimens such as these
were prepared on flat surfaces such as glass slides or alu-
minium plates, which can lead to strong artefacts, such
as non-​flat background from amorphous glass signal or
sharp diffraction peaks from aluminium. Higher-​quality
data can be obtained by dusting a small amount of sam-
ple onto a low or zero-​background holder (Fig. 4b). These
are frequently fitted with a bespoke silicon wafer that
precludes strong diffraction lines. These wafers can
also be used for slurries, gels or pastes where crystalline
material is suspended in a liquid or amorphous medium.
Materials that are air-​s ensitive, hygroscopic or
susceptible to rapid oxidation can be prepared using
specialty preparation techniques for controlled environ-
ments. This can be as complex as using a dedicated dif-
fractometer stage, or as simple as a speciality specimen
holder. A commercially available air-​sensitive holder is
shown in Fig. 4c. The polymer base can be prepared in a
glovebox under a controlled atmosphere and then sealed
using the domed cap and inset O-​ring. Similar strategies
can be employed with thin sheets of X-​ray transparent
polymer and adhesive or clips. The holder should be
characterized both with and without a prepared sample
to provide information about scatter and contribution to
observed background.
Transmission experiments are likely not appropriate
for every sample in a laboratory setting, but are generally
the default at synchrotrons. These experiments require
Bragg–Brentano diffractometer
a b
X-ray tube Detector
Divergence slit
Sample
c d
X-ray tube Air scatter screen
Detector
Divergence slit
Fig. 3 | Diffractometer geometries. a | Schematic of Bragg–Brentano diffractometer. b | Schematic of Debye–Scherrer
diffractometer. c | Photograph of Bragg–Brentano diffractometer. d | Photograph of Debye–Scherrer diffractometer. Some
key parts labelled. Part c, image courtesy of Bruker AXS LLC. Part d, image courtesy of Bruker AXS LLC.
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Primer
consideration of factors including transmission effi-
ciency, sample density, sample thickness and background
contributions from the films or capillaries. Additionally,
transmission samples can be more time-​consuming
to prepare. For example, it often takes several minutes to
compact a fine powder into a thin (0.3–0.7 mm in diam-
eter) capillary. However, there are potential advantages
to using a transmission geometry, with improvements
in data quality, such as higher accuracies in peak inten-
sities from randomization with capillary spinning, and
a reduction in peak broadening due to sample transpar-
ency, particularly for organic materials. Pair distribution
function experiments are frequently conducted with
hard radiation (molybdenum or silver) in a transmission
geometry or at a synchrotron beamline.
Transmission specimens can be prepared by suspend-
ing the sample between two thin sheets of X-​ray trans-
parent polymer, frequently a polyimide (such as Kapton)
or biaxially oriented polyethylene terephthalate (BoPET;
such as Mylar). Alternatively, the powder can be packed
into a thin-​walled capillary, commonly borosilicate glass
or quartz, and then flame-​sealed or sealed with adhesive.
The sample should be finely powdered and gradually
added to the capillary to prevent clogging and uneven
packing. For highly absorbing materials, dilution of the
sample might be required, using lighter materials such
as amorphous silica beads. Absorption can be estimated
using the web tools supported by the Advanced Photon
Source at Argonne National Laboratory.
Regardless of the preparation technique, the exper-
iment should always be driven by the specific research
question. Higher-​end applications, such as quantifi-
cation of trace phases or ab initio structure determi-
nation, demand immaculate diffraction specimens
and higher-​quality data. Such experiments depend on
Debye–Scherrer diffractometer
Detector
X-ray tube Goebel mirror
Sample
X-ray tube Detector
Capillary sample
Goebel mirror
5
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a d

1,500

Counts
0
10 12 14 16 18 20 22 24 26 28 30 32 34
c 2θ (°)

–1.0 mm
–0.7 mm
–0.3 mm
No displacement
+0.3 mm
+0.7 mm
+1.0 mm

Fig. 4 | Specimen preparation. a | Empty poly(methyl methacrylate) specimen holder (left) and one filled with powder (right).
b | Silicon zero-​background holder (left) and one coated with powder (right). c | Empty controlled-​environment sample
holder commercially available from Bruker (left) and one filled with powder (right). d | Effects of specimen displacement on
peak positions for Bragg–Brentano geometry. Vertical lines correspond to the Powder Diffraction File (entry 04-011-1756)
of Ca2(SO4)2(H2O) bassanite, synthetic phase. Wavelength: 1.54 Å. Shifts of the specimen surface lower than the ideal value
move peaks to lower angles, and shifts higher than the ideal move peaks to higher angles. θ, diffraction angle.

Rietveld refinement
A method of analysing powder
diffraction data in which the
crystal structure is refined
by fitting the entire profile
of the diffraction pattern to
a calculated profile using a
least-​squares approach.
There is no intermediate step
of extracting structure factors,
and so patterns containing
many overlapping Bragg
peaks can be analysed.
accurate intensities of well-​resolved peaks. Rapid, less
refined preparation might suffice for more routine tasks
such as general phase identification or quick checks for
quality control of a manufacturing process.
Results
In this section, major applications of qualitative and
quantitative phase analysis, structure solution, size/
strain/nanostructure analysis using peak profiles, tex-
ture analysis and pair distribution function analysis are
introduced.
Representative powder patterns are shown in Fig. 5.
On a 2D detector placed perpendicular to the incident
beam, the patterns appear as circles due to the intersec-
tion of the Debye–Scherrer cones with the planar detec-
tor (Fig. 5a). In an ideal powder, the intensity around the
rings is uniform, apart from well understood details such
as polarization effects, and can be azimuthally averaged
to get the 1D powder diffraction pattern, similar to that
shown in Fig. 2. If the powder is non-​ideal, the ring
intensity is no longer uniform, as illustrated in Fig. 5b,
where large grains in the sample result in sharp, discrete
peaks that deviate from the average intensity of the ring.
In such cases, the experiment could be repeated with
more attention paid to sample preparation, but it may
be possible to minimize problems during data analysis,
for example, to obtain meaningful average intensities, by
removing pixels that are statistically far from the average
from the integration procedure.
The rings can also become non-​uniform when a
well-​averaged powder with many crystallites in the beam
has a preferred orientation (sometimes called powder tex-
ture); the orientations of the crystallites are not random
(Fig. 5c). This can happen, for example, for a powder film
with faceted grains sitting on a substrate. Where possi-
ble, care should be taken to prepare samples by careful
grinding and sieving, and taking steps to mitigate texture
effects. However, for materials in situ in a device, the goal
is to measure the powder as it is during application and
not remove or modify the sample. Non-​uniformities in
the intensities around the Debye–Scherrer rings contain
important information about the nature of the powder.
Modern powder diffraction methods are being developed
to make use of this information explicitly to quantify and
understand information about textures and grain size
distributions, and how they change under processing3.
Structure models
The process of using crystallographic models to refine
crystal structures using powder diffraction data is often
called Rietveld refinement, after the pioneering approach
of Hugo Rietveld14. There have been enormous devel-
opments over the years and the latest codes model the
shapes of Bragg peaks using physical, rather than ad
hoc, functions. These full pattern fitting methods allow
extraction of detailed information about the nano­
structure and strain state of materials. Crystalline and
non-​crystalline local atomic structure can be modelled
in real space using the pair distribution function method,
which applies similar least-​squares regression approaches
either using highly constrained small-​box models5 or
direct simulations of pair distribution functions and total
scattering diffraction patterns from large boxes of many
atoms27. Whether the data are modelled in real or recip-
rocal space, the scattering from non-​periodic structures
— not based on Bragg scattering or periodic boundary

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Chebyshev background
conditions — can be calculated using the Debye scat-
function tering equation28, allowing approaches for modelling
A background function using structure on the nanoscale29. These approaches are all
Chebyshev polynomials Tn(x), referred to as structure refinement, rather than struc-
often shifted Chebyshev
ture solution methods, because a good starting model for
polynomials of the first kind.
The polynomials are defined the structure is needed for the modelling to succeed. In
by recursion relations: T0(x) = 1, favourable circumstances it is also possible to derive an
T1(x) = x, T2(x) = 2x2 – 1, and Tn + 1 ab initio structure solution from powder data, which is
(x) = 2xTn(x) – Tn - 1(x). The value
useful in cases where it is not possible to obtain a single
of x is often not 2θ but some
value within the range of the
crystal of an unknown material30. In extremely favoura-
diffraction pattern, such as ble circumstances, the structure solution has even been
{[2(2θ – 2θmin)] / (2θmax – 2θmin)} – 1. demonstrated from pair distribution function data of
small, non-​crystalline, atomic clusters31,32.
Hanawalt search
A search/match phase
identification method that uses Qualitative phase analysis
the three strongest, most Both the positions and intensities of peaks in a powder
intense peaks for the search pattern are determined by characteristics of the unit cell.
phase and the eight strongest
The positions are governed by the size, shape and sym-
peaks for the match phase.
metry of the unit cell, and the intensities by the nature
and arrangement of atoms. Consequently, the powder
diffraction pattern is a characteristic fingerprint of a
phase, and is exceptionally useful for phase identifica-
tion. Identification requires comparison of an exper-
imental pattern with a database of reference patterns.
The most comprehensive such database is the Powder
Diffraction File33, although other databases exist34.
The phase identification process is often referred to as
search/match. The history of the Powder Diffraction File
and search/match algorithms are summarized in ref.35.
First, the experimental data are searched against an
index — a structured subset of a database. This enables
identification of phases with a powder pattern similar to
the experimental data. The full Powder Diffraction File
entry is matched, using all peaks in the identification,
and the quality of the match is evaluated with a figure
of merit. Then, the phase is identified, generally com-
putationally and ideally using some human judgement.
Following identification, the identified phase pattern
is subtracted from the experimental pattern, and the
process repeated to identify additional phases. Search/
match is generally carried out using commercial software
such as JADE Pro, Diffrac EVA36–38, HighScore39, Match!,
Crystallographica Search-​Match or Siroquant, although
a few free programs are available40. The SIeve+ module is
also incorporated into the Powder Diffraction File.
Most phase identification is carried out using this
peak-​based or full pattern approach. A complementary
a b c spar minerals such as sanidine (entry 00-019-0227),
Fig. 5 | 2D powder diffraction patterns. a | Debye–Scherrer rings from an ideal fine-​
grained sample of a protein. b | Perspective view of Debye–Scherrer rings from a grainy
sample of BiBO3 at high pressure in a diamond anvil cell. c | 2D powder diffraction pattern
from a specimen with a crystallographic texture (preferred orientation of crystallites).
Diffraction rings are smooth, but not uniform. Part a, image courtesy of Robert Von Dreele.
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approach uses the Boolean logic capabilities of the
Powder Diffraction File — a large relational database —
either natively or as filters in the pattern-​b ased
approaches35. Such data mining techniques can involve
searching for analogues according to similarity of for-
mulas or unit cells. When the compound of interest is
not available in the Powder Diffraction File database,
a search of the primary literature, including patents, is
necessary. Only when these approaches fail is an ab initio
structure solution attempted.
Examples. A spalled-​off segment of a red flagstone was
ground in a mortar and pestle, and sieved to pass a
325-​mesh sieve (45 μm maximum particle size). The
sample was prepared as a capillary specimen 0.7 mm
in diameter and the powder diffraction pattern col-
lected with a PANalytical Empyrean diffractometer
using molybdenum Kα radiation. After background
subtraction, JADE Pro identified quartz (JADE data-
base entry 98-000-0369), muscovite-2M1 (Powder
Diffraction File entry 01-082-0576) and albite (JADE
database entry 98-000-3287) (Fig. 6a). The 98 entries
(quartz and albite) are from JADE’s internal database,
and Powder Diffraction File equivalents were iden-
tified using the mineral names and unit cells. These
three phases were used to begin a Rietveld refinement
in GSAS-​I I 25. GSAS-​I I is the second generation of
the General Structure Analysis System, and is one of the
most commonly used computer programs for Rietveld
analysis.
An initial refinement of a three-​t erm shifted
Chebyshev background function and scale factors for
all three phases indicated that there were peaks not
accounted for by these three phases (Fig.  6b) . The
d-​spacings and intensities of these peaks were manu-
ally selected from the plot, and manually entered into
the SIeve+ module of the Powder Diffraction File-4+
2021 database. A Hanawalt search41 was performed,
using the Mineral-​Related subfile of the database, and
both clinochlore-1MIIb (Powder Diffraction File entry
04-013-2805) and haematite (entry 00-033-0664) were
identified. The scale factors of these two phases
were added to the refinement, as well as one additional
background coefficient and a peak to model the scatter-
ing from the glass capillary. Close examination of the
difference plot indicated an additional peak at d = 3.24 Å.
A search of the Mineral-​Related subfile for a phase hav-
ing a strong peak at this value identified several feld-
so this sixth phase was added to the refinement. The
lattice parameters and isotropic micro-​strain broaden-
ing coefficients for the four major phases as well as a
second-​order spherical harmonic preferred orientation
model for the muscovite were included.
The refinement yielded a fit acceptable for this qual-
itative phase analysis (Fig. 6d) with the following con-
centrations: 39.6(1) wt% quartz, 41.8(4) wt% muscovite,
9.4(2) wt% albite, 8.3(2) wt% clinochlore, 1.8(1) wt%
haematite and 0.0(1) wt% sanidine. The numbers in
parentheses are the estimated standard deviations in the
least-​significant digits. The stone appears red because of
the small concentration of haematite.
7
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a b
400 400

300

300 200
SQRT (counts)

√ Intensity
100
200
0

–100
100
50

Δ/σ
0
√0 –50
5 10 15 20 25 30 35 5 10 20 30 40 50
2θ (°) 2θ (°)

[98-000-0369] Quartz [98-000-3287] Albite Obs Calc Bkg Diff

[01-082-0576] Muscovite Experimental data Albite low Muscovite Quartz

c 15 d
400
300
200
Intensity (counts)

10

√ Intensity
100
0
–100
5 –200
–300
50
Δ/σ

0
3
×10 –50
5 10 15 20 25 30 35 40 45 50 55 60 65 70 5 10 20 30 40 50
2θ (°) 2θ (°)

[00-022-1560] Ascorbic acid (vitamin C) Obs Calc Bkg Diff

[98-000-0131] Brushite Albite low Clinochlore Dolomite Haematite
Experimental data Muscovite Quartz Sanidine

e f 15,000
80
10,000

60 5,000
√ Intensity
SQRT (counts)

0
40
–5,000

–10,000
20
20
Δ/σ

0
√0
5 10 15 20 25 30 35 40 45 50 55 60 65 70 5 10 20 30 40 50
2θ (°) 2θ (°)
[02-062-0118] -Mannitol [02-072-5617] Thiamine nitrate Obs Calc Bkg Diff
[02-070-4954] Nicotinamide Experimental data 0-056-1719 Brushite CEKJOR DMANTL
LASCAC10 Monetite NICOAM02

A tablet of Nature’s Bounty B-​Complex vitamin was
ground in a mortar and pestle. The powder was prepared
as a flat plate specimen and the diffraction pattern meas-
ured with a Bruker D2 Phaser diffractometer using cop-
per Kα radiation. A default One-​Click Analysis using
JADE Pro identified ascorbic acid (vitamin C) (Powder
Diffraction File entry 00-022-1560) and brushite, dical-
cium phosphate (entry 98-000-0131) (Fig. 6c). All search/
match programs provide features to assist in identifying
minor phases. In this case, the largest unidentified peak at

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◀ Fig. 6 | Red flagstone and Nature’s Bounty B-Complex phase analysis. a | Powder
diffraction pattern of a red flagstone (note square root (SQRT) scale on y axes), with
sticks indicating patterns of the identified phases quartz, muscovite-2M1 and albite.
b | Rietveld plot from the three-​phase refinement using data from red flagstone. Dark
blue crosses represent observed data points (Obs), and light blue line is calculated pattern
(Calc). Blue-​green curve is the error plot. Rows of tick marks indicate calculated reflection
positions for each phase. c | Rietveld plot for red flagstone after three additional phases
(clinochlore, haematite and sanidine — identified by manual location of peaks in the first
difference plot and entering them into the SIeve+ module of the Powder Diffraction File).
d | Powder diffraction pattern of a Nature’s Bounty B-​Complex vitamin tablet, showing
automated identification of ascorbic acid and brushite. e | Powder pattern of the
B-​complex vitamin tablet, with identification of additional phases d-​mannitol,
nicotinamide and thiamine nitrate. f | Rietveld plot for the B-​complex vitamin, with the
five previous phases as well as monetite included. Δ, observed – calculated; θ, diffraction
angle; σ, standard deviation of observed intensity; Bkg, background; Diff, difference.
d = 3.38 Å was selected, and among the results was mone­
tite, calcium hydrogen phosphate (entry 04-009-3755),
which is a common excipient.
A three-​phase Rietveld refinement indicated the
presence of additional peaks (Fig. 6e). Ten peaks were
picked off the difference plot, and entered into SIeve+
in the Powder Diffraction File-4 Organics 2021 database.
Three phases — d-​mannitol (Powder Diffraction File
entry 02-062-0118), nicotinamide (entry 02-070-4954)
and thiamine nitrate (entry 02-072-5617) — were iden-
tified and added to the Rietveld refinement, resulting in
improved fit (Fig. 6f). The strongest unidentified feature
in the difference plot was at d = 4.125 Å. Search of the
Powder Diffraction File-4+ Organics 2021 for phar-
maceutical compounds having a strong peak at this
location yielded, among others, β-​cristobalite (entry
01-077-8673), which seemed chemically implausible.
Another possibility was α-​lactose (entry 02-086-7407),
but this would have required other unobserved strong
peaks. β-​Cristobalite was added to the refinement,
for the purpose of modelling the largest unidentified
peak. The refinement yielded the following concen-
trations: ascorbic acid = 53.6(7)%, brushite = 19.0(4)%,
monetite = 6.0(3)%, d-​mannitol = 17.8(12)%, nico-
tinamide = 1.2(2)%, thiamine nitrate = 2.0(3)% and
β-​cristobalite = 0.4(1)%. These concentrations are the
relative concentrations of the crystalline components,
as the sample contains multiple amorphous excipients.
To obtain absolute quantification, the sample needs to be
blended with a crystalline internal standard.
Quantitative phase analysis
X-​ray powder diffraction is commonly used to identify
crystalline phases in a sample. For samples containing
a mixture of phases, once the phases are identified, a
quantitative determination of their concentrations is
often required. Alternatively, non-​diffraction methods,
such as gravimetric analysis following density, chemi-
cal extraction or magnetic separation, may be used to
estimate phase abundance. However, these techniques
generally rely on specific phase properties and, therefore,
do not have broad applicability. By contrast, quantita-
tive phase analysis by diffraction is the only analytical
technique that is truly phase-​sensitive. As the contri-
bution of each phase to the observed diffraction pat-
tern is derived directly from its crystal structure, with
an intensity proportional to its concentration in the
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specimen, diffraction has a near universal applicability
for quantitative phase analysis.
Quantitative phase analysis is well established
and, ideally, should be relatively straightforward to
apply. Details of these methods can be found in ref.42.
Commonly used approaches can be divided into two
distinct groups: single peak methods and whole pattern
methods. The first approach, using single peak methods,
relies on measurement of the intensity of a peak, or a
small group of peaks over a limited 2θ range, for each
phase. Calibration using known standards then relates
the measured intensity to phase abundance in specimens
of interest. The second approach, using whole pattern
methods, relies on the measurement of diffraction
data over a wide range of 2θ, including all peaks in the
scan range43. Calibration constants are then derived by
measurement or calculation.
The presence of amorphous or non-​crystalline con-
tent requires extension of the basic methods42, nota-
bly the use of internal standards and/or Partial Or No
Known Crystal Structure techniques. Once established,
these techniques can produce quantitative phase analysis
with similar lower limits of detection and accuracy as for
crystalline phases44.
There are numerous factors, mainly experimental,
which limit the accuracy that can be attained with quan-
titative phase analysis. Many of these relate to the way
the specimen is prepared and presented to the diffraction
instrument. Therefore, it is critically important to ver-
ify diffraction-​based quantitative phase analysis against
independent methods. The most useful is calculation of
the expected bulk composition using the individual phase
concentrations and compositions, and comparing it with
the measured composition, determined using inductively
coupled plasma or another bulk technique. If this is not
possible, the quantitative phase analysis values should be
regarded only as semi-​quantitative. Such values may still
be very useful for deriving trends among samples.
Structures
In this discussion, ρ(r) is the electron density at a vec-
tor r in the unit cell, I(S) is the diffracted intensity at
a scattering vector S (for Bragg scattering, S represents a
reciprocal lattice point, and is equivalently the difference
between the diffracted and incident vectors), fn is the
atomic scattering factor for atom n and hkl are the Miller
indices of the scattering vector S. From a general Fourier
transformation relation (Fig. 7) between the density ρ(r)
of scatterers in the direct space and diffracted intensity
I(S) in reciprocal space:
I (S) = ∫ ρ(r)exp 2π i(r ⋅ S) ⋅ ρ
V
(2)
*(r)exp − 2π i(r ⋅ S)d3r
and introducing the model for one scattering event —
the Thompson model for X-​rays — the atomic scattering
factor f, periodicity and structure factor Fhkl:
Fhkl = Σn fn exp 2π i(rn ⋅ S)
(3)
= Σn fn exp 2π i(hxn + kyn + lzn )
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Multiple pattern technique
The process of measuring
multiple powder patterns from
a specimen as a function of a
variable such as temperature
or degree of orientation, with
the objective of obtaining a
more accurate set of observed
structure factor amplitudes Fhkl
than could be obtained from a
single pattern.
10 | Article citation ID:
Diffraction — Fourier transformation
X-rays
Electron density
BaSO4
Crystal Direct space
structure
Calculation — inverse Fourier transformation phase problem
Fig. 7 | Relationship between electron density and diffraction pattern. Schematic showing that electron density
in the crystal (real space, left) and diffraction pattern (reciprocal space, right) are Fourier transforms of each other.
2θ, diffraction angle.
where index n is running over all atoms in one unit cell,
to the relation:
Ihkl = K ⋅ LP(θhkl ) ⋅ A ⋅ y ⋅ m ⋅ Fhkl 2
where K is a scale factor, LP(θhkl) is the Lorentz polari-
zation factor, A is the absorption factor, y is a dynamical
correction and m is the multiplicity of the reflection hkl
in a powder peak. The diffracted intensity is concen-
trated to the nodes hkl in the reciprocal space. This rela-
tion allows the positions rn of the atoms — equivalent to
the peaks in the ρ(r) map — in the crystal to be found
by inverse Fourier transformation. However, as detec-
tors measure only the intensity of the scattered wave
and not the phase of the wave, the phases of structure
factors are missing. Instead, the phases must be found
either by sophisticated phasing methods, for example
the Patterson function45, direct methods46, maximum
entropy or charge flipping47, or in the case of single
crystal diffraction directly measured using compli-
cated experimental set-​ups involving coherent X-​ray
sources. In the case of powder diffraction, the situation
is complicated by the overlap of individual reflections
into one peak of a powder pattern, with multiplicity m
(Fig. 7). Additionally, the density of peaks increases with
increasing scattering angle, meaning that measuring the
amplitudes of structure factors can be challenging. This
complication is called the powder problem48.
One way to overcome the powder problem is the
intensity extraction method. This approach increases
peak separation in a powder diffraction pattern by
improving the diffractometer resolution or by a
multiple pattern technique . Several procedures were
developed to improve the extraction of integrated
intensities, which may be divided into two groups: those
that require no additional data to be collected (includ-
ing the Patterson function and triplet relation-​based
or maximum entropy-​related approaches49) and those
that use multiple data sets (such as texture and thermal
dilatation-​based49,50 approaches). If reliable intensities
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Powder pattern
BaSO4
4,000
3,000
2,000
1,000
0
15 20 25 30 35 40 45 50 55 60 65 70 75
2θ (°)
Reciprocal space
can be extracted from a powder pattern, the structure
solution continues in the same manner as single crystal
data. Another way to overcome the powder problem
(4) involves the profile fitting method where, instead of
trying to separate overlapping peaks, the whole pow-
der pattern is modelled and the model improved to
find one with the highest likelihood of being correct.
These methods are referred to as global optimization
or direct space methods. There is no need to extract
the integrated intensities, and the approach works
with patterns containing broad, overlapped peaks.
Generally, pattern modelling methods differ in the
algorithm that globally optimizes the structural model
to make the calculated powder pattern fit the observed
one. The agreement between a calculated pattern and
an observed pattern is quantified by the diffraction
cost function, usually an agreement factor as defined
in Rietveld refinement. The simplest algorithms, such
as reversed Monte Carlo in simulated annealing and
parallel tempering mode or evolution algorithms, are
used for obtaining a structure model49,51. These meth-
ods are readily coupled with other information aimed
to identify the correct crystal structure, for example
knowledge of the unit cell chemistry, bonding between
the atoms — either molecules or coordination poly­
hedra — bond valence sums or crystal energy calculated
using electrostatic potentials.
More extensive analysis of the structure solution
overview52,53, pattern indexing52,54, intensity extraction
method55 and profile fitting method for molecular
structures56,57 and for inorganic structures58,59 can be
found in the cited references. Consideration should be
given to indexing, the process of determining the lat-
tice constants from the positions of the peaks in a pow-
der pattern, as this can be a bottleneck in the structure
solution process. If the unit cell and space group cannot
be determined, it is difficult to make further progress.
Success in indexing depends strongly on the accuracy
of the peak positions, so using an internal standard to
compensate for specimen and instrumental aberrations

Anisotropic broadening
Broadening of diffraction
peaks, which varies as a
function of the direction in the
crystal lattice corresponding
to the peaks.
NATURE REVIEWS | MeThoDS PRImeRS | Article citation ID:
can be highly useful. Traditional approaches to index-
ing include zone indexing (ITO)60, index heuristics
(TREOR and N-​TREOR)61,62 and successive dichotomy
(DICVOL)63; however, indexing methods continue to
be developed54. These programs are embedded in most
instrument software packages and Rietveld codes, as well
as other free software40.
Profiles
The Fourier relationship between an object and its dif-
fraction pattern means that the shape of the diffraction
peaks encodes information (albeit in a complex way)
about the nanostructure of the sample under study.
Independent of the actual probe, be it X-​rays or neutrons,
the smallest objects that coherently contribute to the dif-
fracted signal of a powder are called coherently scattering
domains, or crystallites. Aspects such as the shape and
size of these domains and their distributions — the size
effects — as well as any deviation of the lattice from an
ideal 3D periodic arrangement — the micro-​strain —
can, in principle, be extracted from the diffraction pattern
via line profile analysis. The operation is not straightfor-
ward owing to the non-​ideal nature of diffractometers,
which contribute to the final shape of the profile, and
the intrinsically complex way the various pieces of
information combine into the final peak shape64–68.
The peak shapes relative to the instrument factors,
radiation source and optics and the sample are folded
into the measured profile64. It is customary to refine
the instrumental contribution to the pattern of a suit-
able line profile standard, for example NIST SRM 660
or 640 series, with possible support of advanced mod-
els to describe the experimental geometry, such as the
fundamental parameters approach69. This convolu-
tion is determinant in understanding the possibilities
of improving the resolution of a measured diffraction
pattern, particularly for separating the contribution of
partly overlapping peaks. The instrumental contribu-
tion can be reduced by using narrower slits or instru-
ments with an intrinsically narrower source emission
profile, for example a synchrotron. As a rule of thumb,
crystallite size effects lead to peak-​independent shape
and breadth, whereas micro-​strain results in progres-
sive broadening of the peaks with distance from the
reciprocal lattice centre. These trends are captured by
the traditional Scherrer equation70 and Williamson–Hall
method71 via extraction of the peak breadth from the
data. The methods are qualitative/semi-​quantitative as
the extraction process passes through a fitting step in
which arbitrary bell-​shaped functions are used, whereas
the final analysis is based on the unrealistic assumptions
of uniform size and shape of the domains. These limi-
tations can be reduced by fitting the whole pattern on
the basis of physical models of nanostructure and dif-
fraction experiment. This can be done either in meas-
urement space via the Debye scattering equation and
whole powder pattern modelling67 or in real space using
the pair distribution function approach72. By combining
the whole powder pattern modelling and fundamental
parameter approach formalism, physically sound peak
profiles, which include instrumental and specimen
effects, can be synthesized and applied beyond the scope
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of nanostructure analysis. For example, this could be
used for improved intensity extraction via Le Bail or
Pawley fitting, or for better profile modelling in the
Rietveld method. This can be especially valuable when
anisotropic broadening, for example due to anisotropic
shapes, is present.
Additionally, some lattice defects may be present
that deeply affect the local symmetry of the lattice, such
as stacking faults. In these cases, the whole pattern is
affected by stacking faults, as the coherence leading to
diffraction modifies, and extra intensity appears between
Bragg spots, known as diffuse effects73. One approach
used to address this is by generating explicit faulting
sequences and corresponding diffraction patterns using
the Debye scattering equation or Rietveld approach. An
alternative technique uses a hidden Markov model and
a recursive version of the matrix method64,74, which was
successful, for example, in modelling zeolites or clays
heavily affected by such defects.
Texture and Combined Analysis
Real materials often require texture analysis to charac-
terize and optimize the anisotropy of physical properties
in response to application requirements75. Diffraction
techniques are well suited to measure crystallographic
orientations, or texture, quantitatively described by
the orientation distribution function (ODF)75–78. The
ODF, given as f(g) for all g orientations of the crystals, can
be obtained by measurement of a sufficient number of
pole figures (Ph(y))75,76, which are linked to f(g) through
the fundamental equation of quantitative texture
analysis (QTA)76–78:
1
Ph(y ) =
2π
∫h//y f ( g )dφ∼ (5)
φ is the orientation angle of the crystal. Ph(y) is related
to the intensity of the h reflection for sample orienta-
tion y, and there are two different ways to measure
this quantity by diffraction. The classical method is to
position the detector at the Bragg angle for reflection
h and acquire the intensity variation at several sample
orientations75,76. This method is used mainly with tradi-
tional texture diffractometers and samples with only one
phase with high symmetries, such as cubic, hexagonal
or tetragonal structures. The measured intensity vari-
ations, the pole figures, are used in the inversion of the
QTA fundamental equation. In the case of low symme-
tries and/or more crystallographic phases in the sample,
too many individual pole figure measurements would
be required. Instead, it is more efficient, for a smaller
number of sample orientations, to measure the diffrac-
tion patterns each containing the full profiles of several
reflections or full diffraction images79. A pattern match-
ing algorithm such as the Rietveld method80 can then
be used, either to extract the overlapped intensities or
to directly fit an analytical ODF function to the pattern
profiles81 to bypass completely the inversion of the fun-
damental equation of QTA. The second measurement
method is used more often with modern diffractometers
equipped with large detectors that do not collect directly
independent pole figures.
11
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The inversion of the fundamental equation to obtain
f(g) is operated through various refinement proce-
dures75–78,82,83. Once refined, f(g) enables the calculation
of orientation-​dependent properties including the elas-
ticity tensor, piezoelectric coefficients and electrical and
thermal conductivity of the textured material, provided
the single crystal properties are known, using tensor
averaging and homogenization procedures84 such as
Voigt85, Reuss86, Hill87 and geometric mean88 methods.
These properties can then be used for various purposes,
for example correcting diffraction diagrams and spec-
troscopic data for textural effects, modelling anisotropic
macroscopic properties of the real textured material,
residual stresses, elastic wave velocities, magnetizations
and more.
When measured data consist of several full patterns
or diffraction images, Combined Analysis79,82,89,90 can
be used to obtain more information than just the tex-
ture. Fitting of the measured data is achieved using an
extended Rietveld method that calculates the patterns
or images using a complex sample model including all
phases, their crystal structure, nanostructure and crys-
tallographic texture and even residual stresses91. All
of these quantities are transformed into refinable para­
meters that are optimized by an algorithm that minimizes
the difference between the measured and calculated
intensity profiles. Combined Analysis provides a more
advanced view of the material’s characteristics after hav-
ing reached expertise on individual aspects of powder
X-​ray diffraction.
Applications
Total scattering analysis
Many modern materials of interest are nanostructured.
These include discrete nanoparticles, but also nano­
porous materials, and bulk materials that have nano­
scale textures. Often, the material properties are heavily
influenced, or even determined, by the nanostructure.
It is therefore important to characterize this nanostruc-
ture in detail. Images of nanostructure from electron
microscopy and scanning tunnelling microscopy, for
example, are important. However, quantitative meas-
ures of the atomic arrangements and morphologies
are highly complementary and can be obtained from
powder diffraction measurements. The information
about nanostructure is contained not in sharp Bragg
peaks but in broad diffuse scattering signals5. When
the structural coherence extends to tens or hundreds of
nanometres, conventional powder diffraction methods
may be used. In this case, the nanostructuring results in
highly broadened Bragg peaks. However, for structural
domains of size <10 nm, different approaches called
total scattering are needed to extract the structural
information. These involve careful measurements of
the Bragg and diffuse signals continuously over a wide
range of reciprocal space. The resulting 1D pattern of
intensities is often Fourier transformed from reciprocal
space to real space to obtain the atomic pair distribution
function, which gives a representation of the probabil-
ity of finding two atoms in the material separated by
some distance r (ref.5). It captures short-​range order
in the material whether the material is crystalline or
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not. This method is widely used for studying the struc-
ture of nanoparticles of different shapes and sizes92–94,
molecular systems95 and amorphous materials96,97, and
finding domains of local symmetry breaking in other-
wise crystalline materials, for example in ferroelectric
materials98–100 and various quantum materials101–103.
A schematic for obtaining pair distribution functions
from modern synchrotron sources using 2D detec-
tors is shown in Fig. 8a–c. It is also possible to get pair
distribution functions from neutron diffraction data
obtained from spallation neutrons, and from reactor
sources, although typically with lower resolution. Pair
distribution functions can also be obtained from labo-
ratory X-​ray instruments with molybdenum or silver
tubes, and from electron microscopes5.
Mathematically, the relationship between the
measured powder intensities and the pair distribution
function, G(r), is given by:
2 Qmax
G (r ) =
π
∫Q min
Q[S (Q ) − 1] sin(Qr )dQ (6)
where Q is the magnitude of the scattering vector S.
Many powder diffractionists are used to seeing powder
patterns plotted versus d-​spacing and the relationship
is Q = 2π/d = 4πsinθ/λ. The measured total scattering
intensity is contained in the scattering function S(Q),
which is a properly corrected and normalized powder
intensity. Details may be found in ref.4. In Fig. 8d, the 1D
powder intensity (in blue) and the atomic form factor
squared (in red) are shown, which is part of the normal-
ization process. It is straightforward to calculate the pair
distribution function of a structure, and it is therefore
possible to fit structural models to the pair distribution
function to explain the local structure using regression
methods similar to Rietveld refinement104–106. Similarly,
there are also big box modelling approaches where sto-
chastic regression methods such as simulated annealing
are used to fit large-​scale atomic models to the data, for
example reverse Monte Carlo modelling107.
Total scattering and pair distribution function
approaches are now widely used for many applications.
The measurements are quick and use strongly pene-
trating radiation, and so are ideal for following materi-
als as they change with time in some kind of in situ or
operando environment in the beam; for example, fol-
lowing chemical reactions that form nanoparticles108,109,
watching nanoparticle catalysts coarsen as a function of
cycling in an operating fuel cell110, watching local struc-
tural changes in a battery electrode as it discharges111,112,
studying nano-​sized pharmaceuticals in suspension113,114
and studying the local magnetic structure of magnetic
materials115,116. One example is discussed in detail, but
additional examples can be found in the literature and
in review papers27,117–119.
There are many examples of total scattering and
pair distribution function methods being applied to
study bulk crystalline materials that uncovered novel
and important physics about the material in the form
of local symmetry broken textures. To illustrate this,
the organic–inorganic halide perovskite, methylam-
monium lead iodide (MAPI)120,121, is used here as an
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example. MAPI is a material that shows great promise
for low-​cost, high-​efficiency photovoltaics122. At ambient
temperatures it has a cubic perovskite structure, shown
in Fig. 8e–g with lead at the centre of corner-​shared PbI6
octahedra ions and methylammonium ions (CH3NH3)
lying on the perovskite A-​sites. Pair distribution func-
tion data collected from the cubic phase of the material
clearly showed that the local structure is much better
explained by a locally non-​centrosymmetric tetragonal
model, although even in the pair distribution function
data the cubic model gave a better fit in the high-​r region
of the pair distribution function123 (Fig. 8h). This kind of
observation — that a lower symmetry crystal structure
fits the low-​r region of the pair distribution function but

a e f

b
g
100
RTA [0.5, 0.5, 0.5]
75
1

ΔE (meV)
50
2 25
0
–25
–50
–75 –50 –25 0 25 50 75
Distortion amplitude
c
φ h 6
8 Pm3m Pm3m
Rω = 13.3% Rω = 5.98%
Sample 6 4

Monochromatic 4
high-energy 2
2 I4mcm I4mcm
X-ray beam Rω = 6.63% Rω = 9.85%
2D detector
G (Å–2)

0 0

d –2
2.4 –2
I4cm I4cm
–4 Rω = 4.45% Rω = 10.1%
1.8 –4
I(Q) (a.u.)

–6
1.2
–8 –6
2 4 6 8 20 30 40 50
0.6
r (Å) r (Å)
0
2 4 8 12 16 20 24 28 Experimental data
Ϙ (Å–1) Model fit
Difference between model
Observed pair distribution function and experimental data
Theoretical random distribution of atoms

Fig. 8 | Total scattering analysis. a | Schematic crystal structure. b | Zoomed view of crystal structure, illustrating two
interatomic distances (1, 2) characteristic of local structure about the central atom. c | Schematic collection of pair
distribution function data using high-​energy X-​rays and 2D detector; φ is an azimuth angle with respect to an arbitrary
radius vector. d | Pair distribution function of 20-​nm CdSe nanoparticles. e | Cubic non-​equilibrium (average) structure of
methylammonium lead iodide. f | Actual local structure of methylammonium lead iodide, derived from pair distribution
function data. g | Dual-​minimum potential energy curve for lead ion from density functional theory calculation, which
results in local tetragonal distortion in methylammonium lead iodide. h | Pair distribution function observation that the
local structure of methylammonium lead iodide is better fit by a non-​centrosymmetrical I4cm symmetry model whereas
the high-​r region of the pair distribution function is better fit by the average cubic structure model. Red curves (scale ×3)
plotted below data and fit are fit residuals, where larger fluctuations indicate worse agreement. G, pair distribution
function; I, intensity; Q, 4π(sinθ/λ); r, interatomic distance; R, distance from the average Pb site. Parts e–h reprinted
with permission from ref.123, American Chemical Society.

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Polymorphs
Two or more different
crystal structures of a single
chemical substance. In the
pharmaceutical world, the term
is often incorrectly extended to
include hydrates and solvates,
which should instead be called
pseudopolymorphs.
Co-​crystals
Solids that are crystalline
single-​phase materials
composed of two or more
different molecular or ionic
compounds, generally in a
stoichiometric ratio, which
are neither solvates nor
simple salts.
14 | Article citation ID:
a higher symmetry one is better in high-​r regions — is
not uncommon in pair distribution function studies and
reflects the complexity of real materials, where domains,
often fluctuating dynamically, of broken local symme-
try can appear as a higher symmetry structure crystal-
lographically because the local broken symmetries are
averaged out.
Pair distribution function is revealing large numbers
of materials with this interesting feature. In the case of
MAPI, the system looks locally, and instantaneously,
more similar to the structure in Fig. 8f, even though the
average crystal structure results in the structure shown
in Fig. 8e. The difference is revealed by the total scatter-
ing/pair distribution function analysis and is not visible
in a more traditional crystallographic analysis.
Recently, the number of experimental facilities and
the amount of software dedicated to total scattering
and pair distribution function analysis have grown
immensely. The approach looks set to grow more in the
future, especially with the advent of novel artificial intel-
ligence, machine learning and data mining approaches
for analysing and interpreting data124–126. The coupling of
these methods to spatially resolved studies127, down to a
10-​nm spatial resolution in the electron microscope, fur-
ther increases the power and application of the methods
for solving a wider array of scientific and technological
problems.
Pharmaceuticals
X-​ray powder diffraction is one of the most important
and relevant techniques used by pharmaceutical scien-
tists during drug substance and drug product devel-
opment. Owing to its phase specificity, powder X-​ray
diffraction is usually considered the gold standard for
the identification and characterization of pharmaceutical
solid materials128.
A vast majority of active pharmaceutical ingre-
dients (APIs) exist in the solid state under ambient
conditions. The different polymorphs of an API can
exhibit differences in their physicochemical properties,
thereby influencing the stability and performance of
the dosage form. The selection of a suitable solid form
of APIs, accompanied by knowledge of their physical
properties, can significantly reduce time, efforts and
budget of drug product development. As different solid
forms of a compound exhibit different diffraction pat-
terns (Fig. 9), powder X-​ray diffraction is practically
feasible as an analytical tool, for example during the
high-​throughput screening of possible polymorphs
and salts/co-​crystals129,130. Although there are numerous
other methods available to characterize polymorphs in
pharmaceuticals, the demonstration of non-​equivalent
structure by single crystal or powder diffraction is the
authoritative technique to confirm form purity131. As a
result, many patents on drug solid-​state forms contain
powder X-​ray diffraction profiles or data on Bragg peak
positions and intensities of the identified forms128.
A large fraction of new drug candidates in the pipe-
line suffer from the problem of low aqueous solubility
and, hence, poor bioavailability upon oral administra-
tion. The salt and co-​crystal formation offer unique
advantages to modulate solid-​state and solution-​state
(2021) 1:77 www.nature.com/nrmp
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behaviour for ionizable and non-​ionizable drugs to
improve solubility. An improvement in apparent solu-
bility — a combination of dissolution and solubility —
through salt or co-​c rystal formation may lead to
improved bioavailability132. The crystalline nature of
all co-​crystals and most of the salts means they can be
analysed using powder diffraction (Fig. 9b,c).
Another promising approach to enhance the appar-
ent solubility and, consequently, the oral bioavailability
of the new drug candidates is drug amorphization, sta-
bilized using a polymer matrix. Powder X-​ray diffraction
is routinely used to confirm the absence of crystalline
phases, exhibited by the lack of Bragg diffraction peaks
in the diffraction pattern133. Kinetics of drug crystalli-
zation from an initially amorphous drug–polymer dis-
persion can be followed by powder diffraction, which
provides useful insight into the physical stability of the
amorphous solid dispersion (Fig. 9d). Subtle differences
in diffraction patterns of amorphous powders have
been associated with the method of amorphization
and with water content in polymer, such as polyvinyl
pyrrolidone. In recent years, the coupling of X-​ray total
scattering with the pair distribution function has ena-
bled insights into the local structure of amorphous and
nanocrystalline materials134.
Stresses experienced during processing and inter-
actions with other formulation components that may
result in phase transformation such as amorphous to
crystalline and vice versa, polymorphic transitions, salt/
co-​crystal formation or dissociation135 may all impact
the final drug product. The stability and in vivo behav-
iour of the resulting drug product is influenced by the
extent of conversion and the properties of the trans-
formed phase. Powder X-​ray diffraction can detect, and
in some cases quantify, the extent of form conversion,
and so is amenable to drug-​excipient mixtures as the
API’s unique diffraction profile remains unaffected by
other constituents in the formulation136, in contrast to
the other common methods such as thermal analysis or
water sorption. Developments in online time-​resolved
diffraction measurements and the accompanying, more
complicated, sample environments enabled in situ mon-
itoring of processing-​induced phase transformations,
such as in the frozen solution, during thermal treat-
ment or compression137. Use of microdiffraction with a
2D detector enables mapping of the spatial heterogene-
ity of API within the final drug product, for example
compressed tablets or lyophilized cakes138 (Fig. 9e).
To summarize, powder X-​ray diffraction has evolved
beyond simple identification and quantification of an
API, into a characterization technique integral to ena-
bling development of robust drug products with desired
quality attributes139,140.
Organic pigments
An important and challenging class of compounds is
industrial organic pigments141. Pigments are generally
insoluble, unlike dyes which are soluble colourants, and
it is therefore difficult to grow them as single crystals. An
analytical technique tailored to solids is highly useful,
and powder diffraction is an appropriate technique to
characterize materials that are difficult to obtain as single
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crystals. A complication in pigment analysis is that the and molecular conformation can affect the electronic
particle and crystallite sizes are often very small, and that structure of a molecule, and thus its colour.
the peaks are broad. The structure of the nanocrystalline α-​phase of
Pigment analysis involves qualitative and quantita- Pigment Red 170 was solved via the crystal struc-
tive phase analysis, crystallite size determination, pair ture of an isostructural methyl derivative with better
distribution function analysis, and crystal structure crystallinity142,143.
determination and refinement, as for other classes
of compounds. The properties of a pigment depend Inorganic systems
strongly on its crystal structure, and most pigments Powder diffraction is traditionally thought of as a tool
are polymorphic, so pigment powder crystallography for analysis of inorganic compounds, but is increasingly
can be of practical importance. Hydrogen bonding used to characterize organic compounds, as noted in the

a
API physical form Preclinical formulation Clinical formulation Drug product Drug product
• Characterization Enabling techniques • API physical manufacturing quality
• Polymorph/salt • Polymorphs stability • Processing-induced • Identification
screening (part b) • Salt/co-crystal (part c) • API-excipient phase transforma- and
• Crystal structure • Solid dispersion (part d) compatibility tions: milling, qualification of
• Particle size reduction • Salt/co-crystal granulation, API
dissociation compression (part e), • Storage
drying, hot melt stability
extrusion

b d
30 0.6
INDMET03
Fraction crystallized
0.5
25
Intensity (counts)

0.4
20
0.3
15 INDMET02
0.2
10 0.1

INDMET 0
5 0 100 200 300 400 500 600 700 800
3 Time (min)
×10
10 15 20 25 30 35
2θ (°) IMC — 10% PVPK12 85 °C IMC — 10% PVPK30 85 °C
IMC — 10% PVPK12 90 °C IMC — 10% PVPK30 90 °C
c
14

12 e
Intensity (counts)

10

8
50
6
Crystalline fraction

40
4
pressure (MPa)

100
Compression
(%w/w)

30
2
50
20
×102 25
10 15 20 25 30 10
2θ (°) 10
0
0 1 2 3 4 5 6 7 8
IMC IMC-CBZ IMC-SAC
IMC-CAF IMC-NA Distance (mm)

Fig. 9 | Representative case studies of application of powder X-ray diffraction in characterization of pharmaceutical
materials, with indomethacin as the model drug. a | Key stages of the drug substance and drug product development
process, wherein powder X-​ray diffraction plays a critical role. b | X-​ray diffraction patterns of three polymorphic forms of
indomethacin (IMC) (γ-​IMC (INDMET) the stable form under ambient conditions). c | Overlay of calculated patterns of γ-​IMC
and IMC co-​crystals (light blue) with caffeine (IMC-​CAF, medium blue), carbamezapine (IMC-​CBZ, red), nicotinamide
(IMC-​NA, dark blue) and saccharine (IMC-​SAC, grey-​blue). d | Fraction of IMC crystallized determined from X-​ray
diffraction patterns from IMC-​polymer solid dispersion stored at elevated temperature. e | Spatial heterogeneity in the
fraction of IMC crystallized in tablets of amorphous IMC compacted under different compression pressures. At lower
compression pressure, higher fraction of IMC crystallized near radial surface than tablet core. API, active pharmaceutical
ingredient; θ, diffraction angle. Part d adapted with permission from ref.140, American Chemical Society. Part e reprinted
with permission from ref.138, American Chemical Society.

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a
3
Al2O3
CaF2
ZnO
2
Absolute error in concentration (wt%)

b 1.0
1

Concentration error (wt%)

0.5
0

–1 0.0

–2 –0.5 Al2O3
CaF2
ZnO
–3 –1.0
0 20 40 60 80 100 0 20 40 60 80 100
Concentration (wt%) Expected concentration (wt%)

c 3
d
6
Concentration error (wt% absolute)

2
√Intensity (counts)

1
5

–1
4

–2

–3
3
10 5 10 15 20 25 30 35 40 45 50 55 60 65
Concentration (wt%) 2θ (°)
Synchotron Bassanite C2S
Experimental data Montmorillonite
X-ray Calcite C3A Model fit Orthodase
Reground X-ray Gypsum Difference between Muscovite
C4AF
model and experimental data Kaolinite
C3S Quartz

Fig. 10 | International Union of Crystallography Commission on Powder Diffraction Reynolds Cup round robin
example results. a | Absolute concentration errors obtained for corundum, zincite and fluorite in samples 1a–1h of the
International Union of Crystallography Commission on Powder Diffraction round robin on quantitative phase analysis.
b | Absolute concentration errors obtained 10 years later, with more careful analysis. c | Absolute concentration errors
obtained for cement phases. d | Raw data (blue dots) and quantitative refinement (heavy red line) for a complex mineral
blend used in the tenth Reynolds Cup round robin. Calculated contributions to diffraction pattern shown for each phase
(various colour traces). 2θ, diffraction angle. Part c data from ref.150.

above sections. Applications to minerals144, cements145,
ceramics146, mining147 and other industries have been
reviewed recently.
Reproducibility and data deposition
Accuracy
In this section, the accuracy of quantitative phase analy­
ses is discussed, followed by a consideration of the
accuracy of crystal structures in the next section.
As the concentrations in an unknown sample are, by
definition, unknown, the standard approach to quanti-
fying accuracy is to measure samples of known concen-
trations, to qualify the method. The International Union
of Crystallography Commission on Powder Diffraction
ran a round robin on quantitative phase analysis148,149.
As is typical in such round robins, both the accuracy
and precision were lower than desired. The accuracy of
a single participant is summarized in Fig. 10. Revisiting

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 Primer

the same samples a few years later yielded better accu- available containing the normal values for structural
racy (Fig. 10b). The improvement resulted from use of parameters, for example interatomic distances, angles
optimized structure models in Rietveld refinements, and torsions, so it is possible to compare a structure
replicate analyses and experience. with these normal values. Such comparisons are done
The accuracy of quantitative phase analysis of Port­ differently for different classes of compounds.
land cements has been discussed in a series of papers150–152. The repository of organic and organometallic crys-
Typical accuracies are illustrated in Fig. 10c. The Reynolds tal structures is the Cambridge Structural Database
Cup is an annual mineral quantitative phase analysis (CSD)154 found at the Cambridge Crystallographic Data
competition, where participants are given three vials of Centre. An analysis of any desired structural parame-
blind mixtures to analyse, identify all of the components ter may be conducted using the tools in ConQuest and
and quantify. The actual values are provided after the Mercury155, or the pre-​created databases of intramolecu-
competition, allowing participants to evaluate the accu- lar (Mogul)156 and intermolecular (Gold)157 interactions
racies of their methods. The participant who gets closest supplied with the CSD.
to the correct answer is the winner. Generally, the win- Structure analysis tools for inorganic structures
ning teams provide insights into their processes, help- are less well developed. Inorganic crystal structures are
ing the community to continue improving in accuracy. archived in the Powder Diffraction File-4+ at the Inter­
The website contains many quantitative phase analysis national Centre for Diffraction Data, the Linus Pauling
recommendations from previous winners. File and/or Pearson’s Crystal Data33,158 and the Inorganic
Diffraction data for a sample used in the tenth Crystal Structure Database159. Knowledge of inorga­
Reynolds Cup (2020) are shown in Fig. 10d. This sam- nic bond distances is conveniently summarized in the
ple was prepared by the organizers from pure mineral bond valence formalism160 and tables of ionic radii161.
specimens to represent a hydrothermally altered shale Pearson’s Crystal Data contains information about the
and was blended to a known composition. Data were distribution of interatomic distances between any pair
collected using a Bruker D8 ENDEAVOR diffractome- of atom types, and similar histograms of interatomic
ter with cobalt radiation and LYNXEYE XE-​T detector. distances derived from the Inorganic Crystal Structure
Phases were identified using the International Centre Database are contained in the Build/Connectivity menu
for Diffraction Data Powder Diffraction File-4+ data- of the Diamond visualization software162.
base and quantified via the Rietveld method (with The current state of the art for automated structure
zinc oxide as the internal standard) using DIFFRAC. validation is implemented in the checkCIF web utility163.
TOPAS. Actual and refined compositions are given in At last count, this utility runs more than 460 checks of a
Table 1 and represent the sixth overall global submis- crystal structure, and generates various levels of alerts.
sion for this sample. This demonstrates a few key points: These are not necessarily errors but are unusual features
achievable accuracies can be below 1 wt%, the preferred that should be considered by the user. Although the tools
orientation can lead to larger error bars and trace phases are developed mainly for single crystal studies, meaning
below 1 wt% can be challenging to identify in complex some of the tests are not relevant for powder structures,
mixtures.
With ordinary care, achieving 2 wt% absolute accu-
Table 1 | Known and calculated weight percentages
racy can be expected in a quantitative phase analysis. for the mineral mixture referenced in Fig. 10
With extra care and optimization for a particular system,
accuracy of ~0.5 wt% absolute is achievable. To obtain Phase Composition
accuracies of ~0.1 wt% absolute, extreme care must be Actual Refined Difference
taken, including controlling of all process variables (such (wt%) (wt%)
as ambient temperature, relative humidity, temperature Quartz 15.3 16.2 0.9
of the cooling water in the X-​ray tube, power loads in K-​feldspar 8.6 8.1 0.5
the building and details of data processing, among other
Plagioclase 10.9 10.0 0.9
factors).
Calcite 10.6 12.5 1.9
Structure validation Pyrite 3.9 3.6 0.3
Assessing the accuracy of a crystal structure determina- Rutile 3.0 3.2 0.2
tion is generally referred to as structure validation. The
Anatase 1.3 1.1 0.2
various ways of assessing structure accuracy are sum-
marized in detail in ref.153. These include statistical and Amphibole 0.1 – 0.1
graphical measures of the quality of a Rietveld refine- Chloritoid 0.3 – 0.3
ment, which are helpful for assessing better or poorer Zircon 0.1 – 0.1
refinements under similar conditions, but are more diffi-
cult to interpret on an absolute basis or in comparing dif- Kaolinite 21.6 17.7 3.9
ferent instruments. More important is what is sometimes Muscovite 4.9 8.2 3.3
called chemical reasonableness. Montmorillonite 9.8 10.5 0.7
As the true value of a structural parameter is typically
Pyrophyllite 9.6 8.9 0.7
not known, another approach must be used to assess
Accuracies are generally within 1 wt%, with larger error bars
accuracy. With the number of reported crystal structures associated with highly orienting species (such as clays and
approaching two million, there is good information phyllosilicates).

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Density functional theory
An approach to quantum
mechanical calculations,
especially in the solid state,
in which the properties of
many-​electron systems are
described by functionals, which
are functions of another
function. In density functional
theory methods, the functions
model the electron density.
18 | Article citation ID: (2021) 1:77 www.nature.com/nrmp
powder crystallography is still crystallography and many
of the tests are still relevant.
If two different techniques converge on the same
answer, there is increased confidence in the accuracy of
the result. Dispersion-​corrected density functional cal-
culations have been shown to be essentially equivalent to
single crystal structures164. Somewhat larger tolerances
have to be used with structures derived from powder
data165, but the agreement of a Rietveld-​refined and a
density functional theory-​optimized structure is good
evidence that the experimental structure is correct and
accurate. A comparison of single crystal and powder,
including synchrotron, results obtained on the same
sample of cobalt acetate tetrahydrate has been made166.
In general, powder structures can be as accurate as sin-
gle crystal ones and accurate enough to answer most
chemical questions, but suffer in precision; ultimately,
the overlap of powder reflections limits the accuracy and
precision that can be obtained.
Data deposition
The Cambridge Crystallographic Data Centre and
FIZ Karlsruhe run the CIF deposition and validation
service. This service accepts depositions of crystal
structure data in CIF format from X-​ray, neutron and
electron diffraction studies, including both single crys-
tal and powder structures. Data depositions are of two
main types: accompanying the publication in a scientific
journal and publishing directly in a database as a CSD
Communication. This second type is especially useful
for data that will not be published but that the author
wishes to make available to the general scientific com-
munity. The International Centre for Diffraction Data
encourages the submission of powder diffraction data for
inclusion in the Powder Diffraction File.
Limitations and optimizations
Laboratory diffractometers are almost infinitely custom-
izable167, and if a suitable instrument cannot be found
at a national user facility, one can almost certainly be
developed or configured.
The fundamental limitation is that the three dimen-
sions of diffraction data are condensed into a 1D dif-
fraction pattern. The overlap of peaks eventually limits
the amount of information that can be extracted from a
powder pattern. This limitation is especially pronounced
in profile analysis, where the major information on
nanostructure lies in the peak tails, which are the first
features to overlap. This also occurs in structure solution,
where atomic resolution data are helpful, but prevented
by the overlap of many weak peaks at high angles.
Powder diffraction is unusual among analytical
techniques, because the user interacts much more inti-
mately with the data when using the Rietveld method,
pair distribution functional analysis and other full pat-
tern techniques than is typical when using other diffrac-
tion methods. Ultimately, these analyses fit a model to
the data, and so the information obtained depends on
whether the model is appropriate. In the Rietveld method,
one forces a crystalline model to the data, and if nature
is more complicated than an ideal crystalline model, the
conclusions can be biased. The crystalline assumption is
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abandoned in pair distribution function analysis, so more
information can be obtained about the local structure,
at the cost of sacrificing some long-​range information.
The two techniques can be applied to the same diffraction
data, so the information extracted does depend on the
data processing.
In quantitative phase analysis, powder diffraction
is generally considered to be a bulk technique, with
detection and quantification limits of the order of
0.1–0.5 wt%, although these have been lowered to
~500 ppm using synchrotron radiation168. On the other
hand, it is ideally suited for the analysis of mixtures,
including closely related phases such as polymorphs and
hydrates, and is non-​destructive.
Optimization of a powder diffraction experiment
involves using the correct configuration for the purpose,
perhaps including the wavelength, but often the user
only has the available instrumentation to hand. Most
systematic errors are avoidable or, once minimized, can
be included in the computational model. Experimental
planning usually involves choosing the step size and
counting time. The ideal situation would involve at least
four or five points across the top of the full width at
half maximum of the sharpest peaks in the pattern, to
have enough information to define the profile shapes.
Collecting data in finer steps than this does not generally
yield more information. There should be 10,000 counts
(not counts per second) in the strongest peak of the pat-
tern, which can be rationalized by the observation that it
seems to provide a good balance between statistical and
model errors in a full pattern refinement. Perfect data
collection would acquire data to a high enough angle to
measure all of the peaks. It is a common mistake, espe-
cially when studying organic compounds, to not meas-
ure to a high enough angle. Weak peaks contain as much
information as the strong, low-​angle ones. Ultimately,
the time available may limit data collection, but as it may
not be known at the beginning how the data will be used,
it is always wise to collect the best data possible in terms
of signal/noise, resolution and angular range.
Concerning QTA, the intrinsic limitation is the prior
knowledge of the correct crystal structures present
in the sample. As peak intensities are used to reconstruct
the ODF, any modification of such intensities, either
integrated or at the maximum, biases ODF refinements
and further macroscopic properties calculated from it.
Such modifications can be structure related, such as
element substitutions, or sample related, for example
volume–absorption variations under goniometry as in
thin films or stacks. Part of such limitations is removed
when using Combined Analysis.
Outlook
Although the future of crystallography as a science, as
opposed to a technique, has been stated to be pessimis-
tic169, the future of powder diffraction is bright. Most
functional materials are not the single crystals previously
thought to be necessary for structure determination but
occur as polycrystalline or partly crystalline aggregates.
Given the physics that gives rise to the diffraction pat-
tern, powder diffraction will remain the best tool to use
for qualitative phase analysis.
 Primer

Electron crystallography
Crystallography carried out
using electrons rather than
X-​rays or neutrons as the
probe. Generally performed
in a transmission electron
microscope.
Most materials are not used as single crystals, so if they
need to be characterized structurally under operating
conditions, powder diffraction is the most suitable option.
X-​rays and neutrons are more penetrating than most other
analytical probes, and facilitate materials characterization
in containment vessels. It is essential to understand the
structures of catalysts, batteries, metal parts, chemical syn-
theses, polymers, ceramics and other systems under oper-
ating conditions. When developing structure/property
correlations, it is essential to use the right structure.
Currently, the majority of powder diffraction studies
carried out at synchrotron and neutron sources are done
in non-​ambient conditions, showing that such studies are
indeed a growth area. These experiments often generate
large amounts of data, so it can be anticipated that there will
be an increase in the use of parametric refinements and
other advanced data processing techniques.
Single crystals and ideal powders are relatively easy
to treat mathematically. It becomes more challenging to
characterize samples or systems that fall between these
extremes. Examples are textured polymer or metal-
lic systems, as well as granular samples. 2D detectors
greatly facilitate the study of such systems, as the texture
can be characterized directly or the granularity can be
integrated out. 2D detectors are critical for carrying out
multigrain crystallography170, in which single crystal pat-
terns can be obtained from individual grains and merged
or not, as required for the experiment. Such detectors
are improving rapidly in resolution and signal/noise, so
it can be expected that they will be more frequently used
in analytical laboratories.
Current databases archive crystal structures well,
as well as powder patterns, which can be accurately
reduced to d / I pairs (a stick pattern with position, d,
and intensity, I). Diffraction patterns that cannot be
reduced to peak positions and intensities represent a
challenge and opportunity for the future. Such systems
include polymers, clay minerals and aperiodic (incom-
mensurate/modulated/composite) structures. The
Powder Diffraction File has begun to archive raw data
in its entries. Development of improved ways of using
such data for qualitative and quantitative phase analy-
sis is still needed. Some progress has been made with
Partial or No Known Crystal Structure methods171,172.
A continuing challenge is to define the background in
such patterns accurately. Powder diffraction is the ideal
technique to use to characterize nanoparticles. Pair dis-
tribution function analysis has developed greatly173, but
still faces challenges.
The 2021 release of the Powder Diffraction File-4+
database contains 444,133 entries. This may be at the
small end of big data, but it is a significant size. Today,
these data are used in fairly traditional ways, but it is
anticipated that advanced data processing techniques
may be used in the near future. Cluster analysis is already
being used in the editorial process, and an increase in
these advanced statistical techniques is expected. Today,
diffraction data are sometimes used as a proxy for
structural similarity. New tools are anticipated to assess
structural similarity, both in the Powder Diffraction
File and in the structural databases. Such tools might
include atomic connectivity and local structure envi-
ronments, but also tools to look at larger-​scale features
such as framework and pore topology. These databases
contain large amounts of structural and property data.
They may have an increased use in materials design ini-
tiatives. Such data mining analysis techniques will likely
require more computer resources in terms of memory,
CPU power, storage and time than typically available in
an analytical laboratory, and may require cloud-​based
applications.
Users of the Powder Diffraction File have increas-
ingly less experience, especially crystallographic, as
crystallography and, especially, powder diffraction are
less frequently part of the undergraduate and graduate
curricula. In industry, when an experienced user retires,
often a completely inexperienced scientist takes over.
Currently, the solution and refinement of crystal
structures using powder data is a significant activity.
Ideally, crystallites and grains in a powder sample should
be in the range of 2–5 μm. The average size of crystals
used for structure determination approaches this size at
synchrotrons and even in some laboratory instruments.
Free-​electron lasers should permit structure determi-
nations from even smaller crystals, although the crystal
may be destroyed in the process. Recent developments
in electron crystallography should enable much more
routine use of this technique for solving crystal struc-
tures so long as the crystals survive electron exposure.
Cryo electron microscopy is widely used to solve the
structures of biological macromolecules, and can be
expected to be used in smaller organic and inorganic
systems. Further, the use of powder crystallography
for solving structures is likely to decline, but its use for
refining structures by the Rietveld method should per-
sist. Even though crystal structures may be solved from
very small single crystals present in a powder, character-
ization of functional materials, especially in situ and/or
in operando, will continue to be a mainstay of powder
diffraction.
Published online xx xx xxxx

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Acknowledgements
S.J.L.B.’s research is supported by the US Department of
Energy, Office of Science, Office of Basic Energy Sciences
(DOE-​BES) under contract no. DE-​SC0012704.
Author contributions
Introduction (S.J.L.B. and R.E.D.); Experimentation (N.H.);
Results (I.M., J.A.K., R.Č., M.L., L.L. and D.C.); Applications
(S.J.L.B., S.T. and J.A.K.); Reproducibility and data deposition
(J.A.K. and N.H.); Limitations and optimizations (J.A.K.);
Outlook (J.A.K.); Overview of the Primer (J.A.K.).
Competing interests
The authors declare no competing interests.
Peer review information
Nature Reviews Methods Primers thanks C. Malliakas and
the other, anonymous, reviewer(s) for their contribution to the
peer review of this work.
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Related links
Advanced Photon Source: https://11bm.xray.aps.anl.gov/
absorb/absorb.php
Cambridge Crystallographic Data Centre: www.ccdc.cam.
ac.uk
checkCiF: https://checkcif.iucr.org
CiF deposition and validation service: https://ccdc.cam.ac.
uk/deposit
Combined Analysis: http://www.ecole.ensicaen.fr/~chateign/
formation/
Crystallographica Search-​match: https://crystallographica-​
search-​match.software.informer.com/3.1/
inorganic Crystal Structure Database (iCSD): https://icsd.
products.fiz-​karlsruhe.de
international Centre for Diffraction Data: https://icdd.com
JADe Pro: https://www.jadeworld.com/jade-​platform/
developer-​centre/download-​jade
match!: https://www.crystalimpact.com/match/
Pauling File: https://paulingfile.com
Pearson’s Crystal Data: https://crystalimpact.com/pcd
Powder Diffraction File: https://icdd.com/pdfsearch/
reynolds Cup: https://www.clays.org/reynolds/
Siroquant: https://www.siroquant.com/
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