Amorphous and glassy states of molecular and pharmaceutical compounds Applications and uses

Awareness of the importance of amorphous materials in the pharmaceutical field is relatively recent. This disordered state of matter can be generated inadvertently during the manufacture of crystalline forms, following milling, atomization, compaction, granulation and other operations. However, its formation may be intentional, opening up new formulation possibilities to increase the solubility and bioavailability of poorly soluble active molecules, or to protect fragile biomolecules. The physical properties of amorphous and glassy states are highly specific and differ from those of the crystalline state. In view of strict regulatory requirements, knowledge of these states has become indispensable for mastering the formulation of solid drug forms. A general and fairly detailed presentation of their properties was given in the article [PHA 2 030] . In the present article, we focus on the practical use of amorphous compounds in the pharmaceutical field, emphasizing not only the physical origin of the benefits that can be derived from them, but also ways of circumventing the disadvantages specific to this solid state, which is by nature unstable.

Advantages of the amorphous form

The use of the amorphous form of solid Active Pharmaceutical Ingredients (APIs) – and in particular those with low solubility in aqueous biological fluids – is one of the most effective approaches for significantly increasing their solubility and bioavailability. Unlike the action of solubilizing agents, which merely push back the solubility limit of the crystalline form and may also modify membrane permeability, "dissolution" of an amorphous form leads to profound supersaturation relative to this limit and therefore to very high concentrations, even for the pure compound.

In the case of formulations based on very fragile biomolecules (proteins, vaccines), it is possible to increase their physical and chemical stability by intimately mixing the biomolecules with cryoprotectants (sugars, amino acids, polyols, etc.), provided these are in amorphous form. They can ensure structural immobilization of fragile molecules if their own molecular mobility is correctly adapted.

Difficulties of the amorphous form

The main pitfalls in using amorphous materials are their formation and physical stability. The conditions that enable us to obtain a glassy (i.e. solid amorphous) compound, and maintain it in this state for as long as possible during storage, are those that prevent crystallization. It is therefore essential to understand and control this complex mechanism (nucleation-growth) as well as possible, and also to be able to judge the applicability...