Filter (NO

Incident beam


Diffracted beam


Detector (movable Geiger Counter)

Figure 9 Design plan of a typical X-ray powder diffractometer.

Geiger counter, which is connected to a chart recorder. In normal use, the counter is set to scan over a range of 20 values at a constant angular velocity. Routinely, a 20 range of 5-70° is sufficient to cover the most useful part of the powder pattern. The scanning speed of the counter is usually 20 of 2°/min and therefore, about 30 minutes are needed to obtain a trace.

An X-ray diffractometer is made up to an X-ray tube generating X-rays from, for example, Cu, Ka, or Co source and a detector. The most common arrangement in pharmaceutical powder studies is the Bragg-Brentano 0- 0 configuration. In this arrangement, the X-ray tube is moved through angle 0, and the detector is moved through angle 0. The sample is fixed between the detector and the X-ray shown in Figure 3.

The powder pattern consists of a series of peaks that have been collected at various scattering angles, which are related to d-spacing, so that the unit cell dimensions can be determined. In most cases, the measurement of the d-spacing will suffice to positively identify a crystalline material. If the sample is of amorphous nature, that is, does not show long-range order, the X-rays are not coherently scattered, and no peaks will be observed.

Although XRPD analysis is a relatively straightforward technique for the identification of solid-phase structures, there are sources of error, including the following:

• Variations in particle size. Large particle sizes can lead to nonrandom orientation, and hence particles <10 mm should be used, that is, the sample should be carefully ground. However, if the size is too small, for example, 1 mm, it leads to the broadening of the diffraction peaks. Indeed, if the crystal sizes are too small, then the sample may appear to be amorphous.

• Preferred orientation. If a powder consists of needle- or plate-shaped particles, these tend to become aligned parallel to the specimen axis, and thus certain planes have a greater chance of reflecting the X-rays. To reduce the errors caused by this source, the sample is usually rotated. Alternatively, the sample can be packed into a capillary.

• Statistical errors. The magnitude of statistical errors depends on the number of photons counted. To keep this number small, scanning should be carried out at an appropriately slow speed.

• Sample height. The sample should be at the same level as the top of the holder. If the sample height is too low, the pattern shifts down the 20 scale, and if it is too high, it moves up the 20 scale.

• Sample preparation procedures. The greatest potential source of problems is grinding, which can introduce strain, amorphism, and polymorphic changes. Even the contamination from the process of grinding (e.g., in a mortar) can significantly affect the diffraction pattern. Furthermore, the atmosphere surrounding the sample can create problems as a result of the loss or gain of moisture or carbon dioxide. This is particularly true if a heating stage is used; particularly when a compound undergoes a solid-state transition from a low-melting form to a high-melting form, this can be detected by a change in the diffraction pattern. Using the Anton Parr TTK-450 temperature attachment, the compound can be investigated between subambient temperature and several hundred degrees. In cases where desolvation occurs upon micronization, heating the sample makes the peaks shaper and stronger, indicating an increase in crystallinity. This is analogous to the annealing exotherm observed in the DSC thermogram. In a similar way, the sample can be exposed to varying degrees of humidity in situ, and the diffraction pattern determined.

• Irradiation effects. Sample exposure can result in solid-state reactions, caboniza-tion, polymorphic changes, and the like, as a result of high energy exposure of the sample.

• Size of sample. The limited amount of compound available can be problematic. However, modern diffractometers can use the so-called zero-background holders (ZBH). These are made from a single crystal of silicon that has been cut along a nondiffracting plane, and then polished to an optically flat finish. Thus, X-rays incident on this surface will be negated by Bragg extinction. In this technique, a thin layer of grease is placed on the ZBH surface, and the sample of ground compound is placed on the surface. The excess is removed such that only a monolayer is examined. The total thickness of the sample and grease should be of the order of a few microns. It is important that the sample is deagglomerated so that the monolayer condition is met. Using this technique, the diffraction pattern of approximately 10 mg of the compound can be obtained. One disadvantage of the ZBH is that weak reflections may not be readily detectable because of the small sample size used.

• Calibration. The XRPD should be properly calibrated using the standards available from reliable sources, such as the Laboratory of the Government Chemist (LGC) in the United Kingdom or the National Institute of Standards and Technology (NIST) in the United States. Analyzing one or two peaks of LaB6 (line broadening calibrator), at least weekly, should give confidence in the diffract-ometer performance and alert the user to any problems that may develop. The common external standards are: silicon, a-quartz, gold, and silicon (SRM 640b). The primary standards for internal d-spacing include silicon (SRM 640b), fluorophlogopite (SRM 675), and the secondary standards for internal d-spacing are: tungsten, silver, quartz, and diamond. The internal quantitative intensity standards are: Al2O3 (SRM 676), a- and ^-silicon nitride (SRM 656), oxides of Al, Ce, Cr, Ti, and Zn (SRM 674a), a-silicon dioxide (SRM 1878a), and cristobalite (SRM 1879a). A typical external sensitivity standard is Al2O3 (SRM 1976).

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