Amorphous pharmaceutical solids: preparation, characterization and stabilization
Introduction
An amorphous solid (glass) can be defined with reference to a crystalline solid: similar to a crystalline solid, an amorphous solid may have short-range molecular order (i.e., in relationship to neighboring molecules); but unlike a crystalline solid, an amorphous solid has no long-range order of molecular packing or well-defined molecular conformation if the constituent molecules are conformationally flexible. Amorphous solids exist in many industrially important products, such as polymers, ceramics, metals, optical materials (glasses and fibers), foods, and pharmaceuticals. In the case of pharmaceutical materials, the importance of amorphous solids stems from:
- 1.
Useful properties. Amorphous solids have higher solubility, higher dissolution rate, and sometimes better compression characteristics than corresponding crystals.
- 2.
Instability. Amorphous solids are generally less stable physically and chemically than corresponding crystals.
- 3.
Common occurrence. Amorphous solids can be produced by standard pharmaceutical processes and are the common form of certain materials (e.g., proteins, peptides, some sugars and polymers).
Although the amorphous solid has always been an essential part of pharmaceutical research, the current interest [1], [2], [3] has been elevated by two developments: (1) a growing attention to pharmaceutical solids in general, especially polymorphs and solvates [4], [5], [6] and (2) a revived interest in the science of glasses and the glass transition [7], [8], [9]. Studies of crystalline and amorphous solids are often so intertwined that it is natural to treat the two solids as “polymorphs” of each other. This view is harmonious with one definition of polymorphism (i.e., any solids that share the same liquid state) [10], and with the “energy landscape” model of solids [11], which regards crystalline and amorphous states as connected minima on a multi-dimensional potential energy surface corresponding to different molecular packing, conformations, etc.
Since the study of amorphous solids has a long and rich history, it is appropriate to ask how pharmaceutical systems differ from other systems (polymers, ceramics, semi-conductors, optical glasses, etc.). From a functional standpoint, the overriding issues for pharmaceutical systems are the physicochemical stability and bioavailability of the active ingredient, rather than such properties as mechanical strength and conductivity. From a structural standpoint, pharmaceutical systems often feature extensive hydrogen bonding, complex molecular geometry, and conformational flexibility. Such features make the problem of structural elucidation fundamentally different from, for example, that of inorganic glasses. The capacity to absorb water (hygroscopicity) and the ensuing consequences are of great concern to pharmaceutical systems. Furthermore, the stabilization of labile substances (e.g., proteins and peptides) is a distinctively pharmaceutical topic [12], [13], [14], with one objective being the prevention of structural damage during freezing and drying through the use of additives.
The topics discussed here — preparation, characterization, and stabilization of amorphous pharmaceutical solids — define a broad and active field, for which several excellent reviews have been published [1], [2], [3]. The aim of this review, therefore, is not to be comprehensive. In fact, topics well covered previously will be de-emphasized. Little will be said, for example, about common experimental techniques, although the information derived from them is freely discussed. This should not be interpreted as a priority judgement and the reader should consult other reviews for relevant topics.
Section snippets
Preparation
For both thermodynamic and kinetic reasons, the preparation of amorphous solids is straightforward for some materials (good glass formers), but difficult for others (poor glass formers). Thermodynamically, the glass forming ability originates from a crystalline state that is not substantially more stable than the amorphous state, which may be the case for molecules that pack poorly or contain many internal degrees of freedom. Kinetically, a slow crystallization rate allows a material to become
Characterization
The strategy for characterizing amorphous solids differs from that for crystalline solids. Molecular-level structural elucidation, as is feasible for crystalline solids by diffraction and spectroscopic methods, is less applicable to amorphous solids, and greater emphasis is placed on structural mobility and changes. It is customary to characterize an amorphous material both below and above the glass transition temperature, i.e., both as the frozen solid and as the supercooled viscous liquid.
Stabilization
Research aimed at stabilizing amorphous solids is multi-faceted, including: (i) the stabilization of labile biomolecules (e.g., proteins and peptides) through additives, (ii) the prevention of crystallization of excipients that must remain amorphous for their intended functions, (iii) the specification of appropriate storage temperatures to achieve acceptable shelf life, and (iv) the prevention of chemical degradation and microbial growth through anti-oxidant, pH buffer, preservatives, etc. Our
Concluding remarks
Amorphous solids exist widely in and impart special properties to pharmaceutical products. This review has examined concepts and approaches that are relevant to the preparation, characterization and stabilization of amorphous pharmaceutical solids. What can we extrapolate from the present state of affairs? The recognition of broad patterns of structural relaxation dynamics justifies searches for similar patterns shown by rate processes of greater complexity and importance: crystallization and
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