Drugs solid state

The practical applications of the various microscopical techniques have created opportunities for microscopists in industry and, in particular, within pharmaceutical research and development. Microscopy is used extensively, from the earliest stages of drug discovery into late development and even into manufacturing. Pharmaceutical microscopy can be conveniently divided into physico-chemical and biological applications. This chapter will consider exclusively the physico-chemical aspects of microscopy in the pharmaceutical industry. There are three broad areas in which microscopy can play an important role in the development of drugs solid-state analysis, particle size and morphology studies, and contaminant identification. This chapter presents an overview of how microscopy contributes to each of these three areas. The emphasis will be on practical examples taken from the literature and from the author s experience. 

Another interesting example of the use of solid state extraction cartridges is the determination of the tricyclic antidepressant drugs in blood serum (2). 

Bau, R. (1998) Crystal structure of the antiarthritic drug gold thiomalate (Myochrysine) A double-helical geometry in the solid state. Journal of the American Chemical Society, 120, 9380-9381. 

It is not only the solid state of a drug that suffers from ambiguities, but also the aqueous state. The state relevant for the intrinsic solubility is the state of the saturated solution of the neutral species. Since most aqueous drug solubilities are small, direct interactions of the drug molecules are usually rare. Hence, this state is usually very similar to the state of the drug at infinite dilution in water. Most computational methods disregard saturation effects. Usually this is a good approximation, but one should keep in mind that this approximation may result in some moderate, but systematic errors at the upper end of the solubility scale. 

The stability of suspensions, emulsions, creams, and ointments is dealt with in other chapters. The unique characteristics of solid-state decomposition processes have been described in reviews by D. C. Monkhouse [79,80] and in the monograph on drug stability by J. T. Carstensen [81]. Baitalow et al. have applied an unconventional approach to the kinetic analysis of solid-state reactions [82], The recently published monograph on solid-state chemistry of drugs also treats this topic in great detail [83],... 

Often the stability of a drug in the solid state depends on its physical state (i.e., crystalline or amorphous [8]). If freeze-drying produces an amorphous solid and the amorphous form is not stable, then freeze-drying will not provide an acceptable product. 

The degradation of proteins in the solid state occur to a lesser extent and typically via different mechanisms than those that occur in solution [109,110]. Lyophilization is currently the more common technique in the manufacture of dried therapeutic proteins however, there is increasing interest in the use of spraydrying, owing to the unique physical nature of the spray-dried powder and its potential usefulness in protein drug delivery. 

Ledwidge, M. T. Corrigan, O. I., Effects of surface active characteristics and solid state forms on the pH solubility profiles of drug-salt systems, Int. J. Pharm. 174, 187-200 (1998). 

The chemical and physical stability of a solid drug decreases with decreasing crystallinity and increasing amorphous character, corresponding to an increase in molecular mobility (i.e., diffusivity) in the solid state. This phenomenon is of particular significance to proteins, peptides, and other biological materials. Certain additives other than water may stabilize proteins in the solid state, perhaps by locking in the defects. 

For a polymorphic drug, the polymorph obtained depends on the physical conditions, such as temperature, pressure, solvent, and the rate of desupersaturation. For a solvated drug, in addition to these conditions, the thermodynamic activity of the solvating solvent may also determine the solvate obtained. However, kinetic factors may sufficiently retard the crystallization of a stable form or the solid-state transition to the stable form that an unstable form may be rendered metastable. 

SR Byrn. Solid State Chemistry of Drugs. New York Academic Press, 1982, pp 1-186. 

The development of novel pharmaceuticals species is tightly related to the mechanism of interactions between drugs and target integral membrane proteins. Solid-state NMR is highly attractive for these biological systems for two main reasons there is no limitation on molecular mass and it enables to study the membrane protein systems in their native forms. 

Ignoring the physical aspects of a given formulation can be disastrous, since the stability of the drug entity can be strongly affected by its matrix [3], A wide variety of reactions are known to take place in the solid state [4], the pathway of which can be dramatically different when compared with how the same reaction would proceed in the liquid or gaseous phase [5]. 

When the crystallography of compounds related by polymorphism is such that nuclei in the two structures are magnetically nonequivalent, it will follow that the resonances of these nuclei will not be equivalent. Since it is normally not difficult to assign organic functional groups to observed resonances, solid state NMR spectra can be used to deduce the nature of polymorphic variations, especially when the polymorphism is conformational in nature. Such information is extremely valuable at the early states of drug development when solved single crystal structures for each polymorph or solvate species may not yet be available. 

It was recognized very early that diffuse reflectance spectroscopy could be used to study the interactions of various compounds in a formulation, and the technique has been particularly useful in the characterization of solid state reactions [24]. Lach concluded that diffuse reflectance spectroscopy could also be used to verify the potency of a drug in its formulation. In addition, studies conducted under stress conditions would be useful in the study of drug-excipient interactions, drug degradation pathways, and alterations in bioavailability owing to chemisorption of the drug onto other components in the formulation [24]. 

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