Analysis of pharmaceutical solids

X-ray powder patterns can be obtained using either a camera or a powder diffractometer. Currently, diffractometers find widespread use in the analysis of pharmaceutical solids. The technique is usually nondestructive in nature. The theory and operation of powder diffractometers is outside the purview of this chapter, but these topics have received excellent coverage elsewhere [1,2]. Instead, the discussion will be restricted to the applications of x-ray powder diffractometry (XPD) in the analysis of pharmaceutical solids. The U.S. Pharmacopeia (USP) provides a brief but comprehensive introduction to x-ray diffractometry [3],... 

Roggo, Y., Edmond, A., Chalus, P., and Ulmschneider, M. (2005a), Infrared imaging for qualitative analysis of pharmaceutical solid forms and trouble shooting, Anal. Chim. Acta, 535, 79-87. 

Strachan CJ, Rades T, Gordon KC, et al. Raman spectroscopy for quantitative analysis of pharmaceutical solids. J Pharm Pharmacol 2007 59(2) 179-192. 

NMR and IR for the analysis of pharmaceutical solids polymorphs of fosinopril sodium. J Pharm Biomed Anal 11 1063-1069, 1994. 

Kasprzyk-Hordern B, Dinsdale RM, Guwy AJ (2008) Multiresidue methods for the analysis of pharmaceuticals, personal care products and illicit drugs in surface water and wastewater by solid-phase extraction and ultra performance liquid chromatography-electrospray tandem mass spectrometry. Anal Bioanal Chem 391(4) 1293-1308... 

The topics of polymorphism and pseudopolymorphism dominate the majority of publications that deal with utilizing infrared spectroscopy for the physical characterization of pharmaceutical solids. Typically, in each of the publications, IR spectroscopy is only one technique used to characterize the various physical forms. It is important to realize that a multidisciplinary approach must be taken for the complete physical characterization of a pharmaceutical solid. Besides polymorphism, mid- and near-IR have been utilized for identity testing at the bulk and formulated product level, contaminant analysis, and drug-excipient interactions. A number of these applications will be highlighted within the next few sections. 

The errors that are solely attributed to sampling, specifically in the instance of heterogeneous solids, usually give rise to the most important source of uncertainty in carrying out analysis of pharmaceutical substances. 

Fractal analysis has been found to be a useful tool for not only characterizing the irregularities in surfaces but also for correlating these with the physical description and flow properties of pharmaceutical solids... 

McCauley, J.A. Brittain, H.G. Thermal Methods of Analysis. Physical Characterization of Pharmaceutical Solids, Brittain, H.G., Ed. Marcel Dekker, Inc. New York, NY, 1995 223-251. 

Solid-state nuclear magnetic resonance (SSNMR) spectroscopy is a powerful technique used in the analysis of solids, and is currently finding more and more applications, particularly in the analysis of pharmaceutical formulations. It is a non-destructive, non-invasive technique that can be employed to simultaneously examine the physical and chemical states of both the active pharmaceutical ingredient (API) and the excipients present as they exist within the formulation. It is also highly selective, as nuclei of the API often have different chemical shifts than do common excipients. 

There are two broad applications of X-rays in the characterization of materials (i) X-ray spectrometry and (ii) X-ray diffractometry. The former technique is used for chemical analysis and has found only limited use in the characterization of pharmaceuticals. On the other hand, X-ray diffractometry, by providing a means for the study of the structure of crystalline materials, is extensively used to characterize pharmaceutical solids. There are two principal applications of X-ray diffractometry. X-ray crystallography is concerned with the structure determination of crystalline phases. Single crystals are usually used for this purpose. On the other hand, in X-ray powder diffractometry, the sample is usually in the form of a powder. X-ray powder diffractometry is recognized as a powerful technique for the identification of crystalline phases. The technique can also be used for the quantitative analyses of solids. This article will be restricted to the principles and applications of X-ray powder diffractometry (XRD) in the characterization of pharmaceutical solids. 

The most common variables affecting Heckel analysis are the rate and duration of compression, the degree of lubrication, and even the size and shape of the dies and punches (86) hence these variables should be taken into consideration during analysis. Although the use of the Heckel relationship to study the compression behavior of pharmaceutical powders/granules has been criticized (81), it still remains one of the most commonly used methods in the field of formulation research and development of pharmaceutical solids. 

Abstract The problem of validation criteria for developing ion-selective membrane electrodes for the analysis of pharmaceuticals arises from the connection between the reliability of ion-selective membrane electrodes construction and the reliability of the analytical information. Liquid membrane selective electrodes are more suitable for validation than the solid variety. The influence of the stability of... 

RS Plumb, RD Gray, AJ Harker, SJ Taylor. Use of reduced sorbent bed and disk membrane solid-phase extraction for the analysis of pharmaceutical compounds in biological fluids, with applications in the 96-well format. J Chromatogr B 687 457 161, 1996. 

The pharmaceutical analysis of finished solid oral dosage forms is discussed in Chapter 6 from the standpoint of what makes this type of delivery form unique and successful (i.e., the physical properties and the state of the drug substance... 

Plumb, R.S. Gray, R.D.M. Jones. C.M. "Use of Reduced Sorbent Bed and Disk Membrane Solid-Phase Extraction for the Analysis of Pharmaceutical Compounds in Biological Fluids, with Application in the 96-Well Format, J. Chromatogr. B 694, 123-133 (1997). 

The ultimate development in the field of sample preparation is to eliminate it completely, that is, to make a chemical measurement directly without any sample pretreatment. This has been achieved with the application of chemometric near-infrared methods to direct analysis of pharmaceutical tablets and other pharmaceutical solids (74-77). Chemometrics is the use of mathematical and statistical correlation techniques to process instrumental data. Using these techniques, relatively raw analytical data can be converted to specific quantitative information. These methods have been most often used to treat near-infrared (NIR) data, but they can be applied to any instrumental measurement. Multiple linear regression or principal-component analysis is applied to direct absorbance spectra or to the mathematical derivatives of the spectra to define a calibration curve. These methods are considered secondary methods and must be calibrated using data from a primary method such as HPLC, and the calibration material must be manufactured using an equivalent process to the subject test material. However, once the calibration is done, it does not need to be repeated before each analysis. 

Nuclear magnetic resonance (NMR) spectroscopy has become a fundamental technique for pharmaceutical analysis (1-8). Typically, when one thinks of NMR spectroscopy, solution-phase studies, such as structure elucidation, immediately come to mind (1). Within a drug discovery setting, structure elucidation is the one of the primary uses of NMR. It is ironic to think that although approximately 80% of all pharmaceutical products are solid-state formulations, solid-state NMR is relatively new to pharmaceutical analysis. Based on the myriad of uses of NMR spectroscopy as applied to pharmaceutical analysis, this chapter focuses on the use of solid-state NMR for the analysis of pharmaceuticals. 

UV-Vis spectroscopy in solution is probably one of the most frequently applied spectroscopic methods in the quantitative analysis of pharmaceuticals (see other chapters of this book). In solid-state analysis, this situation is quite the opposite since most solids are too opaque to permit the use of this technique in the conventional transmission mode. UV-Vis spectroscopy on solids can only be realized via diffuse-reflection techniques connected with mathematical corrections (e.g. Kubelka-Munk function) and lacking the high reproducibility of UV-Vis spectroscopy in solution owing to particle dispersion effects. The number of published papers on the application of UV-Vis spectroscopy to solid pharmaceuticals is very small and these papers include topics such as photo-stabihty of dyes and active ingredients in tablets, drug-excipient interactions in dmg products, quantitative measurements on discolouration in dmg products, and others. For further reading we refer to Brittain [26] and the literature cited therein. 

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