Crystal quality, control

Crystallization process control is desirable from a number of standpoints. The primary objective is often to meet customer requirements by achieving consistent product quality to a desired specification of crystal size, size distribution and purity. Secondly, process requirements often dictate maintenance of stable crystallizer operation, the avoidance of fines and encrustation, and the minimization of subsequent downstream processing. 

At present, defect-free silicon crystals have been achieved at only at diameters of 200 mm. Comparisons of crystal quality were made among three techniques a typical conventional Czrochralski crystal growth technique, a slow-cooled controlled reaction and the perfect silicon process. The quality levels achieved in D-defect levels of the material is... 

T. Inada and T. Fukuda, Direct Synthesis and Growth of Indium Phosphide by the Liquid Phosphorous Encapsulated Czochralski Method O. Oda, K. Katagiri, K. Shinohara, S. Katsura, Y. Takahashi, K. Kainosho, K. Kohiro, and R. Hirano, InP Crystal Growth, Substrate Preparation and Evaluation K. Tada, M. Tatsumi, M. Morioka, T. Araki, and T. Kawase, InP Substrates Production and Quality Control... 

X-ray topography is the X-ray analogue of transmission election microscopy and as such provides a map of the strain distribution in a crystal. The theory of image formation is well established and image simulation is thus a powerful means of defect identification. Despite a reputation for being a slow and exacting technique, with modem detector technology and care to match spatial resolution of detector and experiment, it can be a powerful and economical quality-control tool for the semiconductor industry. 

Badger, J. and Hendle, J. (2002). ReUable quality-control methods for protein crystal structures. Acta Crystulhgr. 0 58,284-291. 

A basic, yet crucially important, application of powder XRD is in the identification ( fingerprinting ) of crystalline phases, based on the fact that different crystal structures give rise to distinct powder XRD patterns. Qualitative characterization of materials in this manner finds applications in many scientific disciplines (both academic and industrial), including quality control, polymorph screening, and the characterization of products from rapid throughput crystallization experiments [97, 98]. 

Nitz, S., Kollmannsberger, H., Lachermeier, C., Horner, G. (1999) Odour assessment with piezoelectric quartz crystal sensor array, a suitable tool for quality control in food technology Adv. Food. Sci. 21 136-150. 

For x-ray investigations, the diffractometer method is generally used. The lattice constants indicate purity or composition of solid solutions the rapid counting-tube goniometric method can be used at the manufacturing plant for quality control. The rotating-crystal and neutron diffraction methods are sometimes used for structure elucidation. 

Dissolution of a drug substance is controlled by several physicochemical properties, including solubility, surface area, and wetting properties. For insoluble compounds, dissolution is often the rate-limiting step in the absorption process. Knowledge ofthe dissolution rate of a drug substance is therefore very useful for formulation development. The appropriate dissolution experiments can help to identify factors that contribute to bioavailability problems, and also assist in the selection of the appropriate crystal form and/or salt form. Dissolution tests are also used for other purposes such as quality control and assisting with the determination of bioequivalence (Dressman et al., 1998). 

Vibrational Spectroscopy [Infrared (mid-IR, NIR), Raman]. In contrast to X-ray powder diffraction, which probes the orderly arrangement of molecules in the crystal lattice, vibration spectroscopy probes differences in the influence of the solid state on the molecular spectroscopy. As a result, there is often a severe overlap of the majority of the spectra for different forms of the pharmaceutical. Sometimes complete resolution of the vibrational modes of a particular functional group suffices to differentiate the solid-state form and allows direct quantification. In other instances, particularly with near-infrared (NIR) spectroscopy, the overlap of spectral features results in the need to rely on more sophisticated approaches for quantification. Of the spectroscopic methods which have been shown to be useful for quantitative analysis, vibrational (mid-IR absorption, Raman scattering, and NIR) spectroscopy is perhaps the most amenable to routine, on-line, off-line, and quality-control quantitation. 

The product of the simpler synthesis was compared in detail with the product of the RR-amine process. In particular, the Research Quality Control Unit searched for the presence of different polymorphs and new impurities (e.g., the dialkylation byproduct from the first step). They compared the stabilities of both products and also compared the hardness and dissolution rates of tablets made from both products. Since the DBTA resolution, crystallization, and product isolation steps, as wll as the final dilevalol hydrochloride preparation step, were the same for both the RR-amine process and the simpler synthesis, it was anticipated that these steps should protect against the introduction of new impurities or changed physical parameters in the final crystalline product. Such proved to be the case. 

A filter can be standardized against a calibration curve and subsequently used as a single standard to determine quartz content of other filters provided appropriate quality control measures are taken, i.e. the crystal should be checked after analyzing the standard filter to determine if quartz was dislodged from filter and a previously run sample should be included as a quality control sample. 

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