Accessed from 128.83.63.20 by nEwp0rt1 on Fri Dec 02 22:05:18 EST 2011
`Physical Tests / Æ941æ X-Ray Powder Diffraction 427
`
`USP 35
`
`METHOD III (GRAVIMETRIC)
`
`Procedure for Chemicals—Proceed as directed in the in-
`dividual monograph preparing the chemical as directed
`under Loss on Drying Æ731æ.
`Procedure for Biologics—Proceed as directed in the in-
`dividual monograph.
`Procedure for Articles of Botanical Origin—Place about
`10 g of the drug, prepared as directed (see Methods of Anal-
`ysis under Articles of Botanical Origin Æ561æ) and accurately
`weighed, in a tared evaporating dish. Dry at 105(cid:176) for 5
`hours, and weigh. Continue the drying and weighing at 1-
`hour intervals until the difference between two successive
`weighings corresponds to not more than 0.25%.
`
`
`
`Æ941æ CHARACTERIZATION OF
`CRYSTALLINE AND PARTIALLY
`CRYSTALLINE SOLIDS BY X-RAY
`POWDER DIFFRACTION (XRPD)
`
`INTRODUCTION
`
`Every crystalline phase of a given substance produces a
`characteristic X-ray diffraction pattern. Diffraction patterns
`can be obtained from a randomly oriented crystalline pow-
`der composed of crystallites or crystal fragments of finite
`size. Essentially three types of information can be derived
`from a powder diffraction pattern: the angular position of
`diffraction lines (depending on geometry and size of the
`unit cell), the intensities of diffraction lines (depending
`mainly on atom type and arrangement, and particle orienta-
`tion within the sample), and diffraction line profiles (de-
`pending on instrumental resolution, crystallite size, strain,
`and specimen thickness).
`Experiments giving angular positions and intensities of
`lines can be used for applications such as qualitative phase
`analysis (e.g., identification of crystalline phases) and quanti-
`tative phase analysis of crystalline materials. An estimate of
`the amorphous and crystalline fractions1 can also be made.
`The X-ray powder diffraction (XRPD) method provides an
`advantage over other means of analysis in that it is usually
`nondestructive in nature (to ensure a randomly oriented
`sample, specimen preparation is usually limited to grinding).
`XRPD investigations can also be carried out under in situ
`conditions on specimens exposed to nonambient conditions
`such as low or high temperature and humidity.
`
`PRINCIPLES
`
`X-ray diffraction results from the interaction between X-
`rays and electron clouds of atoms. Depending on atomic
`1There are many other applications of the X-ray powder diffraction technique
`that can be applied to crystalline pharmaceutical substances, such as determi-
`nation of crystal structures, refinement of crystal structures, determination of
`the crystallographic purity of crystalline phases, and characterization of crys-
`tallographic texture. These applications are not described in this chapter.
`
`arrangement, interferences arise from the scattered X-rays.
`These interferences are constructive when the path differ-
`ence between two diffracted X-ray waves differs by an inte-
`gral number of wavelengths. This selective condition is de-
`scribed by the Bragg equation, also called Bragg’s law (see
`Figure 1).
`
`2dhkl sinq hkl = nl
`The wavelength, l, of the X-rays is of the same order of
`magnitude as the distance between successive crystal lattice
`planes, or d hkl (also called d-spacings). q hkl is the angle be-
`tween the incident ray and the family of lattice planes, and
`sin q hkl is inversely proportional to the distance between suc-
`cessive crystal planes or d-spacings.
`The direction and spacing of the planes with reference to
`the unit cell axes are defined by the Miller indices {hkl}.
`These indices are the reciprocals, reduced to the next-lower
`integer, of the intercepts that a plane makes with the unit
`cell axes. The unit cell dimensions are given by the spacings
`a, b, and c, and the angles between them a,
`b , and g.
`The interplanar spacing for a specified set of parallel hkl
`planes is denoted by dhkl. Each such family of planes may
`show higher orders of diffraction where the d values for the
`related families of planes nh, nk, nl are diminished by the
`factor 1/n (n being an integer: 2, 3, 4, etc.).
`Every set of planes throughout a crystal has a correspond-
`ing Bragg diffraction angle, q hkl, associated with it (for a
`specific l).
`A powder specimen is assumed to be polycrystalline so
`that at any angle q hkl there are always crystallites in an orien-
`tation allowing diffraction according to Bragg’s law.2 For a
`given X-ray wavelength, the positions of the diffraction
`peaks (also referred to as “lines”, “reflections”, or “Bragg
`reflections”) are characteristic of the crystal lattice (d-spac-
`ings), their theoretical intensities depend on the crystallo-
`graphic unit cell content (nature and positions of atoms),
`and the line profiles depend on the perfection and extent of
`the crystal lattice. Under these conditions, the diffraction
`peak has a finite intensity arising from atomic arrangement,
`type of atoms, thermal motion, and structural imperfections,
`as well as from instrument characteristics.
`The intensity is dependent upon many factors such as
`structure factor, temperature factor, crystallinity, polarization
`factor, multiplicity, and Lorentz factor.
`The main characteristics of diffraction line profiles are 2q
`position, peak height, peak area, and shape (characterized
`by, e.g., peak width, or asymmetry, analytical function, and
`empirical representation). An example of the type of powder
`patterns obtained for five different solid phases of a sub-
`stance are shown in Figure 2.
`In addition to the diffraction peaks, an X-ray diffraction
`experiment also generates a more or less uniform back-
`ground, upon which the peaks are superimposed. Besides
`specimen preparation, other factors contribute to the back-
`ground—for example, sample holder, diffuse scattering from
`air and equipment, and other instrumental parameters such
`as detector noise and general radiation from the X-ray tube.
`The peak-to-background ratio can be increased by minimiz-
`ing background and by choosing prolonged exposure times.
`2An ideal powder for diffraction experiments consists of a large number of
`small, randomly oriented spherical crystallites (coherently diffracting crystal-
`line domains). If this number is sufficiently large, there are always enough
`crystallites in any diffracting orientation to give reproducible diffraction
`patterns.
`
`Official from May 1, 2012
`Copyright (c) 2011 The United States Pharmacopeial Convention. All rights reserved.
`
`EXHIBIT E
`
`

`

`Accessed from 128.83.63.20 by nEwp0rt1 on Fri Dec 02 22:05:18 EST 2011
`428 Æ 941æ X-Ray Powder Diffraction / Physical Tests
`
`USP 35
`
`Figure 1. Diffraction of X-rays by a crystal according to Bragg’s Law.
`
`INSTRUMENT
`
`Instrument Setup
`
`X-ray diffraction experiments are usually performed using
`powder diffractometers or powder cameras.
`A powder diffractometer generally comprises five main
`parts: an X-ray source; the incident beam optics, which may
`perform monochromatization, filtering, collimation, and/or
`focusing of the beam; a goniometer; the diffraction beam
`optics, which may include monochromatization, filtering,
`collimation, and focusing or parallelizing of beam; and a
`detector. Data collection and data processing systems are
`also required and are generally included in current diffrac-
`tion measurement equipment.
`Depending on the type of analysis to be performed
`(phase identification, quantitative analysis, lattice parameters
`determination, etc.), different XRPD instrument configura-
`tions and performance levels are required. The simplest in-
`struments used to measure powder patterns are powder
`cameras. Replacement of photographic film as the detection
`method by photon detectors has led to the design of dif-
`fractometers in which the geometric arrangement of the op-
`tics is not truly focusing, but parafocusing, such as in Bragg-
`Brentano geometry. The Bragg-Brentano parafocusing con-
`figuration is currently the most widely used and is therefore
`briefly described here.
`A given instrument may provide a horizontal or vertical
`q /2q geometry or a vertical q /q geometry. For both geome-
`tries, the incident X-ray beam forms an angle q with the
`specimen surface plane, and the diffracted X-ray beam
`forms an angle 2q with the direction of the incident X-ray
`beam (an angle q with the specimen surface plane). The
`basic geometric arrangement is represented in Figure 3. The
`divergent beam of radiation from the X-ray tube (the so-
`called primary beam) passes through the parallel plate colli-
`mators and a divergence slit assembly and illuminates the
`flat surface of the specimen. All the rays diffracted by suita-
`bly oriented crystallites in the specimen at an angle 2q con-
`verge to a line at the receiving slit. A second set of parallel
`plate collimators and a scatter slit may be placed either be-
`hind or before the receiving slit. The axes of the line focus
`and of the receiving slit are at equal distances from the axis
`
`of the goniometer. The X-ray quanta are counted by a radi-
`ation detector, usually a scintillation counter, a sealed-gas
`proportional counter, or a position-sensitive solid-state de-
`tector such as an imaging plate or CCD detector. The re-
`ceiving slit assembly and the detector are coupled together
`and move tangentially to the focusing circle. For q /2q scans,
`the goniometer rotates the specimen around the same axis
`as that of the detector, but at half the rotational speed, in a
`q /2q motion. The surface of the specimen thus remains tan-
`gential to the focusing circle. The parallel plate collimator
`limits the axial divergence of the beam and hence partially
`controls the shape of the diffracted line profile.
`A diffractometer may also be used in transmission mode.
`The advantage with this technology is to lessen the effects
`due to preferred orientation. A capillary of about 0.5- to 2-
`mm thickness can also be used for small sample amounts.
`
`X-Ray Radiation
`
`In the laboratory, X-rays are obtained by bombarding a
`metal anode with electrons emitted by the thermionic effect
`and accelerated in a strong electric field (using a high-volt-
`age generator). Most of the kinetic energy of the electrons
`is converted to heat, which limits the power of the tubes
`and requires efficient anode cooling. A 20- to 30-fold in-
`crease in brilliance can be obtained by using rotating an-
`odes and by using X-ray optics. Alternatively, X-ray photons
`may be produced in a large-scale facility (synchrotron).
`The spectrum emitted by an X-ray tube operating at suffi-
`cient voltage consists of a continuous background of poly-
`chromatic radiation and additional characteristic radiation
`that depends on the type of anode. Only this characteristic
`radiation is used in X-ray diffraction experiments. The princi-
`pal radiation sources used for X-ray diffraction are vacuum
`tubes using copper, molybdenum, iron, cobalt, or chro-
`mium as anodes; copper, molybdenum, or cobalt X-rays are
`employed most commonly for organic substances (the use
`of a cobalt anode can especially be preferred to separate
`distinct X-ray lines). The choice of radiation to be used de-
`pends on the absorption characteristics of the specimen and
`possible fluorescence by atoms present in the specimen. The
`wavelengths used in powder diffraction generally corre-
`spond to the K
`a radiation from the anode. Consequently, it
`is advantageous to make the X-ray beam “monochromatic”
`by eliminating all the other components of the emission
`spectrum. This can be partly achieved using K
`b filters—that
`
`Official from May 1, 2012
`Copyright (c) 2011 The United States Pharmacopeial Convention. All rights reserved.
`
`

`

`Accessed from 128.83.63.20 by nEwp0rt1 on Fri Dec 02 22:05:18 EST 2011
`Physical Tests / Æ 941æ X-Ray Powder Diffraction 429
`
`USP 35
`
`Figure 2. X-ray powder diffraction patterns collected for five different solid phases of a substance (the intensities are normal-
`ized).
`
`
`
`is, metal filters selected as having an absorption edge be-
`tween the K
`a and K
`b wavelengths emitted by the tube.
`Such a filter is usually inserted between the X-ray tube and
`the specimen. Another more commonly used way to obtain
`a monochromatic X-ray beam is via a large monochromator
`crystal (usually referred to as a “monochromator”). This
`crystal is placed before or behind the specimen and diffracts
`the different characteristic peaks of the X-ray beam (i.e., K
`a
`and K
`b ) at different angles so that only one of them may be
`selected to enter into the detector. It is even possible to
`separate K
`a 1 and K
`a 2 radiations by using a specialized
`monochromator. Unfortunately, the gain in getting a mono-
`chromatic beam by using a filter or a monochromator is
`counteracted by a loss in intensity. Another way of separat-
`ing K
`a and K
`b wavelengths is by using curved X-ray mirrors
`that can simultaneously monochromate and focus or paral-
`lelize the X-ray beam.
`
`RADIATION PROTECTION
`
`Exposure of any part of the human body to X-rays can be
`injurious to health. It is therefore essential that whenever X-
`ray equipment is used, adequate precautions be taken to
`protect the operator and any other person in the vicinity.
`Recommended practice for radiation protection as well as
`limits for the levels of X-radiation exposure are those estab-
`lished by national legislation in each country. If there are no
`official regulations or recommendations in a country, the
`latest recommendations of the International Commission on
`Radiological Protection should be applied.
`
`SPECIMEN PREPARATION AND MOUNTING
`
`The preparation of the powdered material and the
`mounting of the specimen in a suitable holder are critical
`steps in many analytical methods, particularly for X-ray
`powder diffraction analysis, since they can greatly affect the
`quality of the data to be collected.3 The main sources of
`errors due to specimen preparation and mounting are
`briefly discussed in the following section for instruments in
`Bragg-Brentano parafocusing geometry.
`
`Specimen Preparation
`
`In general, the morphology of many crystalline particles
`tends to give a specimen that exhibits some degree of pre-
`ferred orientation in the specimen holder. This is particularly
`evident for needle-like or platelike crystals when size reduc-
`tion yields finer needles or platelets. Preferred orientation in
`the specimen influences the intensities of various reflections
`so that some are more intense and others less intense, com-
`pared to what would be expected from a completely ran-
`dom specimen. Several techniques can be employed to im-
`prove randomness in the orientation of crystallites (and
`therefore to minimize preferred orientation), but further re-
`duction of particle size is often the best and simplest ap-
`proach. The optimum number of crystallites depends on the
`3 Similarly, changes in the specimen can occur during data collection in the
`case of a nonequilibrium specimen (temperature, humidity).
`
`Official from May 1, 2012
`Copyright (c) 2011 The United States Pharmacopeial Convention. All rights reserved.
`
`

`

`Accessed from 128.83.63.20 by nEwp0rt1 on Fri Dec 02 22:05:18 EST 2011
`430 Æ 941æ X-Ray Powder Diffraction / Physical Tests
`
`USP 35
`
`this effect simultaneously with that arising from specimen
`transparency. This effect is by far the largest source of errors
`in data collected on well-aligned diffractometers.
`
`EFFECT OF SPECIMEN THICKNESS AND TRANSPARENCY
`
`When the XRPD method in reflection mode is applied, it
`is often preferable to work with specimens of “infinite thick-
`ness”. To minimize the transparency effect, it is advisable to
`use a nondiffracting substrate (zero background holder)—for
`example, a plate of single crystalline silicon cut parallel to
`the 510 lattice planes.5 One advantage of the transmission
`mode is that problems with sample height and specimen
`transparency are less important.
`The use of an appropriate internal standard allows the
`detection and correction of this effect simultaneously with
`that arising from specimen displacement.
`
`CONTROL OF THE INSTRUMENT
`PERFORMANCE
`
`The goniometer and the corresponding incident and dif-
`fracted X-ray beam optics have many mechanical parts that
`need adjustment. The degree of alignment or misalignment
`directly influences the quality of the results of an XRPD in-
`vestigation. Therefore, the different components of the dif-
`fractometer must be carefully adjusted (optical and mechan-
`ical systems, etc.) to adequately minimize systematic errors,
`while optimizing the intensities received by the detector.
`The search for maximum intensity and maximum resolution
`is always antagonistic when aligning a diffractometer.
`Hence, the best compromise must be sought while perform-
`ing the alignment procedure. There are many different con-
`figurations, and each supplier’s equipment requires specific
`alignment procedures. The overall diffractometer perfor-
`mance must be tested and monitored periodically, using
`suitable certified reference materials. Depending on the type
`of analysis, other well-defined reference materials may also
`be employed, although the use of certified reference materi-
`als is preferred.
`
`QUALITATIVE PHASE ANALYSIS
`(IDENTIFICATION OF PHASES)
`
`The identification of the phase composition of an un-
`known sample by XRPD is usually based on the visual or
`computer-assisted comparison of a portion of its X-ray pow-
`der pattern to the experimental or calculated pattern of a
`reference material. Ideally, these reference patterns are col-
`lected on well-characterized single-phase specimens. This
`approach makes it possible in most cases to identify a crys-
`talline substance by its 2q -diffraction angles or d-spacings
`and by its relative intensities. The computer-aided compari-
`son of the diffraction pattern of the unknown sample to the
`comparison data can be based on either a more or less ex-
`tended 2q range of the whole diffraction pattern or on a set
`of reduced data derived from the pattern. For example, the
`list of d-spacings and normalized intensities, Inorm, a so-called
`(d, Inorm) list extracted from the pattern, is the crystallo-
`graphic fingerprint of the material and can be compared to
`(d, Inorm) lists of single-phase samples compiled in databases.
`For most organic crystals, when using Cu K
`a radiation, it
`is appropriate to record the diffraction pattern in a 2q -range
`from as near 0(cid:176) as possible to at least 40(cid:176) . The agreement
`in the 2q -diffraction angles between specimen and reference
`is within 0.2(cid:176) for the same crystal form, while relative inten-
`sities between specimen and reference may vary considera-
`5In the case of a thin specimen with low attenuation, accurate measurements
`of line positions can be made with focusing diffractometer configurations in
`either transmission or reflection geometry. Accurate measurements of line po-
`sitions on specimens with low attenuation are preferably made using dif-
`fractometers with parallel beam optics. This helps to reduce the effects of
`specimen thickness.
`
`Figure 3. Geometric arrangement of the Bragg-Brentano
`parafocusing geometry.
`
`diffractometer geometry, the required resolution, and the
`specimen attenuation of the X-ray beam. In some cases,
`particle sizes as large as 50 m m will provide satisfactory re-
`sults in phase identification. However, excessive milling
`(crystallite sizes less than approximately 0.5 m m) may cause
`line broadening and significant changes to the sample itself,
`such as
`• specimen contamination by particles abraded from the
`milling instruments (mortar, pestle, balls, etc.),
`• reduced degree of crystallinity,
`• solid-state transition to another polymorph,
`• chemical decomposition,
`• introduction of internal stress, and
`• solid-state reactions.
`Therefore, it is advisable to compare the diffraction pat-
`tern of the nonground specimen with that corresponding to
`a specimen of smaller particle size (e.g., a milled specimen).
`If the X-ray powder diffraction pattern obtained is of ade-
`quate quality considering its intended use, then grinding
`may not be required.
`It should be noted that if a sample contains more than
`one phase and if sieving is used to isolate particles to a
`specific size, the initial composition may be altered.
`
`Specimen Mounting
`
`EFFECT OF SPECIMEN DISPLACEMENT
`
`A specimen surface that is offset by D with reference to
`the diffractometer rotation axis causes systematic errors that
`are very difficult to avoid entirely; for the reflection mode,
`this results in absolute D · cosq shifts4 in 2q positions (typi-
`cally of the order of 0.01(cid:176) in 2q at low angles
`
` for a displacement D = 15 m m) and asymmetric broaden-
`ing of the profile toward low 2q values. Use of an appropri-
`ate internal standard allows the detection and correction of
`4Note that a goniometer zero alignment shift would result in a constant shift
`on all observed 2q -line positions; in other words, the whole diffraction pat-
`tern is, in this case, translated by an offset of Z(cid:176) in 2q .
`
`Official from May 1, 2012
`Copyright (c) 2011 The United States Pharmacopeial Convention. All rights reserved.
`
`

`

`Accessed from 128.83.63.20 by nEwp0rt1 on Fri Dec 02 22:05:18 EST 2011
`Physical Tests / Æ 941æ X-Ray Powder Diffraction 431
`
`USP 35
`
`bly due to preferred orientation effects. By their very nature,
`variable hydrates and solvates are recognized to have vary-
`ing unit cell dimensions, and as such, shifting occurs in peak
`positions of the measured XRPD patterns for these materials.
`In these unique materials, variance in 2-q positions of
`greater than 0.2(cid:176) is not unexpected. As such, peak position
`variances such as 0.2(cid:176) are not applicable to these materials.
`For other types of samples (e.g., inorganic salts), it may be
`necessary to extend the 2q region scanned to well beyond
`40(cid:176) . It is generally sufficient to scan past the 10 strongest
`reflections identified in single-phase X-ray powder diffraction
`database files.
`It is sometimes difficult or even impossible to identify
`phases in the following cases:
`• noncrystallized or amorphous substances,
`• the components to be identified are present in low
`mass fractions of the analyte amounts (generally less
`than 10% m/m),
`• pronounced preferred orientation effects,
`• the phase has not been filed in the database used,
`• the formation of solid solutions,
`• the presence of disordered structures that alter the unit
`cell,
`• the specimen comprises too many phases,
`• the presence of lattice deformations,
`• the structural similarity of different phases.
`
`QUANTITATIVE PHASE ANALYSIS
`
`If the sample under investigation is a mixture of two or
`more known phases, of which not more than one is amor-
`phous, the percentage (by volume or by mass) of each crys-
`talline phase and of the amorphous phase can in many
`cases be determined. Quantitative phase analysis can be
`based on the integrated intensities, on the peak heights of
`several individual diffraction lines,6 or on the full pattern.
`These integrated intensities, peak heights, or full-pattern
`data points are compared to the corresponding values of
`reference materials. These reference materials must be single
`phase or a mixture of known phases. The difficulties en-
`countered during quantitative analysis are due to specimen
`preparation (the accuracy and precision of the results re-
`quire, in particular, homogeneity of all phases and a suitable
`particle size distribution in each phase) and to matrix
`effects.
`In favorable cases, amounts of crystalline phases as small
`as 10% may be determined in solid matrices.
`
`Polymorphic Samples
`
`For a sample composed of two polymorphic phases a and
`b, the following expression may be used to quantify the
`fraction Fa of phase a:
`Fa = 1/[1 + K
`
`(Ib/Ia )]
`
`The fraction is derived by measuring the intensity ratio be-
`tween the two phases, knowing the value of the constant K
`K
` is the ratio of the absolute intensities of the two pure
`polymorphic phases Ioa/Iob. Its value can be determined by
`measuring standard samples.
`
`.
`
`Methods Using a Standard
`
`The most commonly used methods for quantitative analy-
`sis are
`• the external standard method,
`• the internal standard method, and
`6If the crystal structures of all components are known, the Rietveld method
`can be used to quantify them with good accuracy. If the crystal structures of
`the components are not known, the Pawley method or the partial least-
`squares (PLS) method can be used.
`
`• the spiking method (also often called the standard addi-
`tion method).
`The external standard method is the most general
`method and consists of comparing the X-ray diffraction pat-
`tern of the mixture, or the respective line intensities, with
`those measured in a reference mixture or with the theoreti-
`cal intensities of a structural model, if it is fully known.
`To limit errors due to matrix effects, an internal reference
`material can be used that has a crystallite size and X-ray
`absorption coefficient comparable to those of the compo-
`nents of the sample and with a diffraction pattern that does
`not overlap at all that of the sample to be analyzed. A
`known quantity of this reference material is added to the
`sample to be analyzed and to each of the reference mix-
`tures. Under these conditions, a linear relationship between
`line intensity and concentration exists. This application,
`called the internal standard method, requires precise meas-
`urement of diffraction intensities.
`In the spiking method (or standard addition method),
`some of the pure phase a is added to the mixture contain-
`ing the unknown concentration of a. Multiple additions are
`made to prepare an intensity-versus-concentration plot in
`which the negative x-intercept is the concentration of the
`phase a in the original sample.
`
`ESTIMATE OF THE AMORPHOUS AND
`CRYSTALLINE FRACTIONS
`
`In a mixture of crystalline and amorphous phases, the
`crystalline and amorphous fractions can be estimated in sev-
`eral ways. The choice of the method used depends on the
`nature of the sample:
`• If the sample consists of crystalline fractions and an
`amorphous fraction of different chemical compositions,
`the amounts of each of the individual crystalline phases
`may be estimated using appropriate standard sub-
`stances, as described above. The amorphous fraction is
`then deduced indirectly by subtraction.
`• If the sample consists of one amorphous and one crys-
`talline fraction, either as a 1-phase or a 2-phase mix-
`ture, with the same elemental composition, the amount
`of the crystalline phase (the “degree of crystallinity”)
`can be estimated by measuring three areas of the
`diffractogram:
`A = total area of the peaks arising from diffraction
`from the crystalline fraction of the sample,
`B = total area below area A,
`C = background area (due to air scattering, fluores-
`cence, equipment, etc).
`When these areas have been measured, the degree of
`crystallinity can be roughly estimated as:
`
`% crystallinity = 100A/(A + B – C)
`
`It is noteworthy that this method does not yield an absolute
`degree of crystallinity values and hence is generally used for
`comparative purposes only. More sophisticated methods are
`also available, such as the Ruland method.
`
`SINGLE CRYSTAL STRUCTURE
`
`In general, the determination of crystal structures is per-
`formed from X-ray diffraction data obtained using single
`crystals. However, crystal structure analysis of organic crys-
`tals is a challenging task, since the lattice parameters are
`comparatively large, the symmetry is low, and the scattering
`properties are normally very low. For any given crystalline
`form of a substance, the knowledge of the crystal structure
`allows for calculating the corresponding XRPD pattern,
`thereby providing a preferred orientation-free reference
`XRPD pattern, which may be used for phase identification.
`
`Official from May 1, 2012
`Copyright (c) 2011 The United States Pharmacopeial Convention. All rights reserved.
`
`

`

`Accessed from 128.83.63.20 by nEwp0rt1 on Fri Dec 02 22:05:18 EST 2011
`
`Official from May 1, 2012
`Copyright (c) 2011 The United States Pharmacopeial Convention. All rights reserved.
`
`

`

`Accessed from 128.83.63.20 by nEwp0rt1 on Fri Dec 02 22:05:18 EST 2011
`General Information / Æ 1005æ Acoustic Emission 433
`
`USP 35
`
`General Chapters
`
`The chapters in this section are information, and aside
`from excerpts given herein from Federal Acts and regula-
`tions that may be applicable, they contain no standards,
`tests, assays, nor other mandatory specifications, with re-
`spect to any Pharmacopeial articles. The excerpts from perti-
`nent Federal Acts and regulations included in this section
`are placed here inasmuch as they are not of Pharmacopeial
`authorship. Revisions of the federal requirements that affect
`these excerpts will be included in USP Supplements as
`promptly as practical. The official requirements for Pharma-
`copeial articles are set forth in the General Notices, the indi-
`vidual monographs, and the General Tests and Assays chap-
`ters of this Pharmacopeia.
`
`Æ 1005æ ACOUSTIC EMISSION
`
`INTRODUCTION
`
`Ultrasound techniques can be categorized into two dis-
`tinct types: acoustic emission (passive mode) and ultrasound
`spectroscopy (active mode). Both of these techniques have
`many applications.
`The technique of acoustic emission is based on the detec-
`tion and analysis of sound produced by a process or system.
`This is essentially equivalent to listening to the process or
`system, although these sounds are often well above the fre-
`quencies that can be detected by the human ear. Generally,
`frequencies up to about 15 kHz are audible.
`In the case of ultrasound spectroscopy, the instrument is
`designed to generate ultrasound waves across a defined fre-
`quency range. These waves travel through the sample and
`are measured using a receiver. An analogy can be drawn
`with UV-visible or IR spectroscopy in that the detected ultra-
`sound spectrum reflects changes in velocity or sound atten-
`uation due to the interaction with a sample across a range
`of frequencies. However, as the scope of this chapter is lim-
`ited to acoustic emission, ultrasound spectroscopy will not
`be discussed further.
`Acoustic emission is well-known in the study of fracture
`mechanics and therefore is used extensively by material
`scientists. It is also widely used as a nondestructive testing
`technique and is applied routinely for the inspection of air-
`craft wings, pressure vessels, load-bearing structures, and
`components. Acoustic emission is also used in the engineer-
`ing industry for the monitoring of machine tool wear.
`In terms of pharmaceutical applications, the dependence
`of the acoustic emission measurement on physical properties
`such as particle size, mechanical strength, and cohesivity of
`
`General Information
`
`solid materials allows the technique to be used for the con-
`trol and endpoint detection of processes such as high shear
`granulation, fluid bed drying, milling, and micronization.
`
`General Principles
`
`Acoustic emissions can propagate by a number of modes.
`In solids, compressional and shear or transverse modes are
`important. Compressional modes have the highest velocity
`and thus reach the acoustic detector (or acoustic emission
`transducer) first. However, in most process applications of
`acoustic emission, there are many sources—each producing
`short bursts of energy—and, consequently, the different
`modes cannot easily be resolved. The detected signal, for
`example on the wall of a vessel, is a complex mixture of
`many overlapping waveforms resulting from many sources
`and many propagation modes.
`At interfaces, depending on the relative acoustic impe-
`dance of the two materials, much of the energy is reflected
`back towards the source. In a fluidized bed, for example,
`acoustic emissions will only be detected from particles di-
`rectly impacting the walls of the bed close to the
`transducer.
`A convenient method of studying acoustic emission from
`processes is to use the “average signal level”. A root mean
`square-to-direct current (RMS-to-DC) converter may be used
`to convert the amplitude-modulated (AM) carrier into a
`more slowly varying DC signal. This is referred to as the
`average signal level (ASL). The ASL can then be digitally
`sampled (typically at a sampling frequency of about 50 Hz)
`and stored electronically for further signal processing.
`The simplest way of studying the acoustic data is to ex-
`amine changes in the ASL. However, other information can
`be derived from examining the power spectrum of the ASL.
`The power spectrum is calculated by taking the complex
`square of the amplitude spectrum and can be obtained by
`performing a Fast Fourier Transform (FFT) on the digitized
`raw data record. Power spectra may be averaged to pro-
`duce a reliable estimate of power spectral density or to give
`a “fingerprint” of a particular process regime. Interpretation
`of the power spectrum is complicated by th