Structural features of the glassy state and their impact on the solid-state properties of organic molecules in pharmaceutical systems.

This paper reviews the structure and properties of amorphous active pharmaceutical ingredients (APIs), including small molecules and proteins, in the glassy state (below the glass transition temperature, T). Amorphous materials in the neat state and formulated with excipients as miscible amorphous mixtures are included, and the role of absorbed water in affecting glass structure and stability has also been considered. We defined the term "structure" to indicate the way the various molecules in a glass interact with each other and form distinctive molecular arrangements as regions or domains of varying number of molecules, molecular packing, and density.

Perspectives on the Wetting of Solids in Pharmaceutical Systems.

Purpose: The ability of water and aqueous solutions to wet relatively nonpolar pharmaceutical solids during the processing and administration of solid dosage forms is an important part of development.

Results: Various factors, both fundamental and technological, which are important to wettability are reviewed and analyzed. Initially, the ideal thermodynamic importance of liquid surface tension and solid surface energetics, determined by the contact angle and the polarity of the solid surface, are established.

Considerations in the Development of Physically Stable High Drug Load API- Polymer Amorphous Solid Dispersions in the Glassy State.

In this Commentary, the authors expand on their earlier studies of the solid-state long-term isothermal crystallization of amorphous API from the glassy state in amorphous solid dispersions, and focus on the effects of polymer concentration, and its implications for producing high load API doses with minimum polymer concentration. After presenting an overview of the various mechanistic factors which influence the ability of polymers to inhibit API crystallization, including the chemical structure of the polymer relative to the API, the nature and strength of API-polymer noncovalent interactions, polymer molecular weight, impact on primary diffusive molecular mobility, as well as on secondary motions in the bulk and surface phases of the glass, we consider in more detail, the effects of polymer concentration. Here, we examine the factors that appear to allow relatively low polymer concentrations, i.

What Are the Important Factors That Influence API Crystallization in Miscible Amorphous API-Excipient Mixtures during Long-Term Storage in the Glassy State?

In this Perspective, the authors examine the various factors that should be considered when attempting to use miscible amorphous API-excipient mixtures (amorphous solid dispersions and coamorphous systems) to prevent the solid-state crystallization of API molecules when isothermally stored for long periods of time (a year or more) . After presenting an overview of a variety of studies designed to obtain a better understanding of possible mechanisms by which amorphous API undergo physical instability and by which excipients generally appear to inhibit API crystallization from the amorphous state, we examined 78 studies that reported acceptable physical stability of such systems, stored below under "dry" conditions for one year or more. These results were examined more closely in terms of two major contributing factors: the degree to which a reduction in diffusional molecular mobility and API-excipient molecular interactions operates to inhibit crystallization.

What We Need to Know about Solid-State Isothermal Crystallization of Organic Molecules from the Amorphous State below the Glass Transition Temperature.

In this Perspective, the authors have examined various principles associated with the isothermal crystallization of organic molecules from the amorphous state. The major objective was to better understand the underlying principles influencing long-term crystallization from the glassy state at temperatures sufficiently low enough to prevent crystallization over a period of about 2-3 years; this time frame was chosen based on the requirements for ensuring the physical stability of solid drug products. As such, after considering the general thermodynamic, dynamic (molecular mobility), and structural properties of both supercooled liquids and glasses, current understanding from the literature of overall crystallization, nucleation and growth from glasses, was reviewed.