Stability amorphous solids

While crystalline solids offer the advantages of chemical and thermodynamic stability, amorphous solids are occasionally preferred because they undergo dissolution at a faster rate. Rapid dissolution is desirable in the case of solids, which must be dissolved prior to paren-... 

Stabilized Amorphous Solid Dispersions with Small Molecule Excipients... 

Often the stability of a drug in the solid state depends on its physical state (i.e., crystalline or amorphous [8]). If freeze-drying produces an amorphous solid and the amorphous form is not stable, then freeze-drying will not provide an acceptable product. 

In addition to the additives used in a formulation to help stabilize the protein to freezing, the residual moisture content of the lyophilized powder needs to be considered. Not only is moisture capable of affecting the physicochemical stability of the protein itself, equally important is the ability of moisture to affect the Tg of the formulation. Water acts as a plasticizer and depresses the Tg of amorphous solids [124,137,138]. During primary drying, as water is gradually removed from the product, the Tg increases accordingly. The duration and temperature of the secondary drying step of the lyophilization process determines how much moisture remains bound to the powder. Usually lower residual moisture in the finished biopharmaceutical product leads to enhanced stability. Typically, moisture content in lyophilized formulations should not exceed 2% [139]. The optimal moisture level for maximum stability of a particular product must be demonstrated on a case-by-case basis. 

The presence of a solvent, especially water, and/or other additives or impurities, often in nonstoichiometric proportions, may modify the physical properties of a solid, often through impurity defects, through changes in crystal habit (shape) or by lowering the glass transition temperature of an amorphous solid. The effects of water on the solid-state stability of proteins and peptides and the removal of water by lyophilization to produce materials of certain crystallinity are of great practical importance although still imperfectly understood. 

The amorphous phase is not usually a desirable state for the API because the formation process is more random and difficult to control than a crystallization. A second dispersed liquid phase is usually formed just prior to freezing and may coalesce or disperse under the influence of hydrodynamic forces in the crystallizer, making the process sensitive to micro-mixing effects on scale up. Amorphous solids also have significantly lower thermodynamic stability than related crystalline material and may subsequently crystallize during formulation and storage. Because of the non-uniformity of the amorphous solid it can more easily incorporate molecules other than the API, making purification less effective. 

The most thermodynamically stable polymorph is usually desired for the API product to maximize its formulated stability. Selecting the thermodynamically stable form does however, have the disadvantage of minimizing the solubility and bioavailability. Although less desirable and common it is feasible to use an amorphous solid form of the API if it can be demonstrated that it is stable in the formulation. 

M. J. Pikal, D. R. Rigsbee, The Stability of Insulin in Crystalline and Amorphous Solids Observation of Greater Stability for the Amorphous Form , Pharm. Res. 1997, 14, 1379-1387. 

Duddu S, Weller K. Importance of glass transition temperature in accelerated stability testing of amorphous solids case study using a lyophilized aspirin formulation. J Pharm Sci 1996 85 345-347. 

In addition to characterizing frozen systems intended to be freeze dried, it is important to characterize the freeze-dried product. This includes determination of the physical state of the dried product that is, crystalline, partially crystalline, or amorphous. It may also include identification of the polymorph of a crystallizing component which exhibits polymorphism and determination of whether the crystal form observed is affected by changes in formulation and processing conditions. For amorphous systems, the glass transition temperature of the amorphous solid, as well as the extent to which Ts changes with residual moisture, may be a critical attribute of the product with regard to both physical and chemical stability. 

Before proceeding further, it is appropriate to discuss some aspects of molecular mobility of amorphous solids as it affects stability. The temperature dependence of molecular motion in amorphous systems is described by the empirical Vogel-Tammann-Fulcher (VTF) equation ... 

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