Amorphous and glassy states of molecular and pharmaceutical compounds: general properties

Most drugs (65%) are marketed in solid form, whether as tablets, capsules or powders (for inhalation, oral suspension or reconstitution). Solids can be crystalline or amorphous. Crystalline solids are characterized by a periodic structural organization of the molecules. They are generally very stable forms, with specific physical properties. For these reasons, they have long been the only forms developed. Amorphous solids, on the other hand, lack long-range molecular order and, although rigid, are structurally analogous to liquids. While their chemical properties are the same, these two physical forms of the same pharmaceutical compound differ considerably in their physico-chemical properties. This difference has a crucial impact on biopharmaceutical characteristics, notably dissolution in water, as well as stability during storage. Awareness of the importance of amorphous materials in the pharmaceutical field is fairly recent, and is the subject of growing interest. The number of publications, corresponding to the "amorphous" and "drug" fields in Scopus, has risen from around 80 in 1995 to 800 in 2014. The creation of an amorphous pharmaceutical material can have a negative impact, but also offer new development opportunities. Biomolecules, for example, are almost inevitably formulated in glassy matrices.

During the formulation of crystalline materials (active substances or excipients), the formation of amorphous solids can occur accidentally, which must be avoided for several reasons:

• their lower physical and chemical stability;

• their high sensitivity to the history they undergo during formation and storage, resulting in irregular product quality;

• their own difficulty of analytical characterization;

• faster solid-state chemical kinetics;

• amplified surface effects generating problems in terms of oxidation by air, hygroscopicity, adsorption on an excipient, and when making mixtures.

In order to assess the level of control required in manufacturing and storage, it is therefore all the more important to understand how a given crystalline material can be amorphized, and to be able to quantify the degree of amorphization and its possible impact.

Amorphous pharmaceutical solids can also have much better biopharmaceutical properties, and so be the subject of intentional preparation. There are two situations where this is particularly useful:

• stabilization of fragile molecules: for protein- and vaccine-based formulations, improved physical and chemical stability is achieved by intimately mixing proteins with...