Amorphous pharmaceutical materials properties

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. ... 

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 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. 

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. 

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. 

Another physical property that can affect the appearance, bioavailability, and chemical stability of pharmaceuticals is degree of crystallinity. Amorphous materials tend to be more hygroscopic than their crystalline counterparts. Also, there is a substantial body of evidence that indicates that the amorphous forms of drugs are less stable than their crystalline counterparts [62]. It has been reported, for example,... 

A great many of the materials that are used as pharmaceutical excipients occur naturally in the amorphous or partially amorphous state (e.g., gelatin and starch). Many others have been found to possess improved handling and mechanical properties when processed in such a manner as to render them at least partially amorphous. Examples of this include the grades of microcrystalline cellulose and lactose monohydrate used as pharmaceutical tableting diluents. ° ... 

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