Pharmaceutical materials amorphous

This article provides an overview of the properties and occurrence of amorphous pharmaceutical materials, and outlines their key applications in dosage form development. It describes their characteristics and the fundamental scientific basis for these characteristics. It also highlights the topical issues of chemical/ physical stability and polyamorphism. ... 

The common physical characteristics of amorphous pharmaceutical materials are quite different from those... 

Table 1 Examples of some amorphous pharmaceutical materials...

Although amorphous pharmaceutical materials can be readily isolated and may persist for many thousands of years,they are in fact a thermodynamically metastable state and will eventually revert to the more stable crystalline form. Fig. 4 shows a snapshot in time of the free energy-temperature relationship for a material that can be isolated as both an amorphous form and a crystalline form. This quasi-equilibrium thermodynamic view of the amorphous state shows that the amorphous form has a significantly higher free energy than the crystalline form, and illustrates why it is expected to have a much higher aqueous solubility and significantly different physical properties (e.g., density). 

The chemical and physical stability of amorphous pharmaceutical materials is controlled by the same basic factors as for crystalline materials [i.e., molecular structure (chemistry), purity (absence of catalysts, chemical reactants, or nucleating agents), molecular orientation (physical form), and molecular mobility (related to temperature)]. For any sample of a given molecular structure and purity, there will be more possible molecular orientations that occur in an amorphous sample than in a crystalline sample. Thus... 

Fig. 8 The temperature dependence of average molecular relaxation times for amorphous pharmaceutical materials. (From Ref.. )...

Hancock, B.C. Dalton, C.R. Pikal, M.J. Shamblin, S.L. A pragmatic test of a simple calorimetric method for determining the fragility of some amorphous pharmaceutical materials. Pharm. Res. 1998, 15 (5), 762-767. 

For amorphous materials, both chemical and physical instability are related to molecular mobility which increases with increasing temperature. As an empirical rule, amorphous pharmaceutical materials should be stored 50° below its glass transition temperature (Tg) to minimize potential chemical and physical instability... 

In recent years there has been increasingly more interest in determining the amorphous content of pharmaceutical materials. This is due to... 

Lack of molecular order in amorphous pharmaceutical systems may be because of difficulty in crystallizing the material in question, such as for... 

The ability of amorphous materials to form molecular-level mixtures has been used by many workers in an attempt to stabilize, and otherwise modify, the properties of difficult-to-handle pharmaceutical materials. Several reviews of the uses of such solid dispersion systems have been published. 

Different localized levels of molecular order can coexist in some pharmaceutical materials, giving rise to the occurrence of partially crystalline (and partially amorphous ) systems. In most cases, the properties of such materials (e.g., density) are intermediate to those of the 100% amorphous and 100% crystalline samples. By deliberately varying the level of crystallinity in such systems, their properties can be customized for a particular purpose. An example of this is with the tableting excipients microcrystalline cellulose and spray-dried lactose, which have had their compression characteristics optimized by manipulating their amorphous content. The properties of partially crystalline materials may be approximated in many instances by making physical mixtures of the totally amorphous and crystalline samples. This is known as the two-state model for partially crystalline systems.However, such experiments should be undertaken with caution as the mixed two-state material can sometimes have significantly different properties from the partially crystalline material that is manufactured directly (the real one-state system). ... 

Amorphous substances are an important class of pharmaceutical materials that exhibit distinct physical and chemical properties. They are ubiquitous, and may be formed both intentionally and unintentionally during normal pharmaceutical manufacturing operations. The properties of amorphous materials can be exploited to improve the performance (e.g., bioavailability and dissolution rate) of pharmaceutical dosage forms, but these properties can also give rise to unwanted effects (e.g., physical instability) that need to be understood and managed in order for the systems to perform as required. 

The basis for reactivity in the solid state lies in molecular mobility and molecular complementarity. Grinding is well known to create lattice defects and amorphous phases,and the formation of polymorphic forms of drugs as a result of these stresses is well documented in the pharmaceutical literature. Therefore, the concepts of solid-state reactivity in pharmaceutical materials can be applied to understanding the formation of cocrystals. 

For pharmaceutical materials moisture is known to affect a wide range of properties such as powder flow compactibility and stability (physical chemical and microbiological) (8 46-53). The interaction between moisture and a solid is complex and can occur in a variety of ways. For example water can be stoichiometrically incorporated into a solid s crystal structure in the form of a hydrate (pseudo-hydrate) as discussed previously in this section. In addition moisture can have non-stroichiometrical i.e., nonspecific interactions with a solid by adsorbing on the surface or being absorbed into the material and acting as a plasticizer. These non-specific interactions are more common in amorphous or semi crystalline materials and are the subject of this section. 

A further consideration is the study of the generation of amorphous material in otherwise crystalline drugs using DSC. It is now well established that many pharmaceutical materials may contain small quantities of amorphous material that may... 

Thermal analysis is an extremely important analytical tool for the pharmaceutical industry. All transitions in materials involve the flow of heat (either into the sample during an endothermic event or out of the sample during an exothermic event) and DSC is the universal detector for measuring a wide variety of transitions in pharmaceutical materials. These include measurement of amorphous structure, crystallinity (and polymorphs), drug-excipient interaction and many other applications. 

While amorphous water as such may not figure in freeze-drying technology, the opposite is true for many of the other components that make up the finished pharmaceutical preparation. In fact, the realisation of the importance of amorphism in pharmaceutical product development has led to the birth of a new scientific discipline pharmaceutical materials science. Successful freeze-drying is firmly based on the same... 

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Whereas the technique has been used to characterize the solid-state properties of pharmaceutical materials, Raman spectroscopy has also been valuable for the quantification of polymorphs within mixtures, for quantification of the amorphous state within crystalline materials, and for the identification of polymorphs within formulations. These aspects will be considered in later subsections. 

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