Solid state stability amorphous solids

The solid state stability of indinavir sulfate has been evaluated under a variety of storage conditions and containers. For materials stored in open dishes or in double polyethylene liners within fiber containers, changes in crystallinity i.e., conversion of the crystalline etlranolate to amorphous material or to a hydrate crystal form) have been detected using XRPD or KF methods [7]. Changes in chemical purity i.e., formation of degradation products) have been detected using GC and HPLC methods... 

Matsuda, Y. and S. Kawaguchi. 1986. Physicochemical characterization of oxyphenbutazone and solid-state stability of its amorphous form under various temperature and humidity condEtlrota. 

Furlanetto et al. (26) attempted to predict and compare the solid-state stability of cefazolin sodium and cephaloridine sterile powders using data obtained at 37°C, 45°C, and 60°C. They analyzed samples for up to 6 months and found cephaloridine to be more stable than cefazolin sodium, in contrast to the relative stability of the compounds as indicated by their respective compendial storage instructions. They attributed greater stability of the cephaloridine samples to greater crystallinity compared to the cefazolin sodium samples which appeared to be mostly amorphous. Rather than comparing different samples of the same drug, this study determined the relative stability of two different drugs and compared the results to expectations based on previous information. 

Oguchi and coworkers examined the decarboxylation behavior of -aminosalicylic acid (PAS) as a freeze-dried solid under thermal stress conditions (80°C) in the presence of the excipients pullulan (a linear polysaccharide which can not form inclusion complexes with PAS) and a-cyclodextrin (39). The solid-state stability was shown to correlate with the fraction of amorphous PAS. Increasing relative amounts of pullulan resulted in higher fractions of amorphous PAS. Rapid freezing (liquid nitrogen) was shown to result in a greater relative amount of amorphous drug, as expected. 

Rigsbee, D.R. Pikal, M.J. Solid state stability of insulin comparison of crystalline and amorphous forms. Proceedings of the American Association of Pharmaceutical Scientists Annual Meeting, Orlando, FL, U.S.A., 1993. 

An example highlighting the impact of crystallinity on stability is that of meropenem (MERREM ), a trihydrate of a carbapenem antibiotic. Meropenem batches of different hydration states were examined for solid-state stability at 40 °C over a 1 month period [59]. An increase in amorphous content was shown to lead to a higher extent of and more rapid degradation in the solid state. However, the crystalline trihydrate exhibited a nearly 300-fold improvement in stability compared with a sample which was 80% amorphous. Similar observations have also been made on cephalosporin antibiotics as reported by Pikal and co-workers [58]. 

One of the issues relating to the stability of the amorphous state, particularly in vivo, is its solution-mediated transformation characteristic. Solution-mediated transformation of amorphous to crystalline state is the conversion of metastable solids such as amorphous solids to the crystalline state when the solids are exposed to a solvent, in this case water. The transformation to the thermodynamically stable crystalUne state occurs at a higher rate in the presence of solvents than in the dry state because of higher molecular mobility in the presence of solvents. 

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. 

When determining the solubility and dissolution rate of amorphous or partially crystalline solids, the metastability of these phases with respect to the highly crystalline solid must be considered. While the low diffusivity of the molecules in the solid state can kinetically stabilize these metastable forms, contact with the solution, for example during measurements of solubility and dissolution rate, or with the vapor, if the solid has an appreciable vapor pressure, may provide a mechanism for mass transfer and crystallization. Less crystalline material dissolves or sublimes whereas more crystalline material crystallizes out. The equilibrium solubility measured will therefore approach that of the highly crystalline solid. The initial dissolution rate of the metastable form tends to reflect its higher... 

The chemical and physical stability of a solid drug decreases with decreasing crystallinity and increasing amorphous character, corresponding to an increase in molecular mobility (i.e., diffusivity) in the solid state. This phenomenon is of particular significance to proteins, peptides, and other biological materials. Certain additives other than water may stabilize proteins in the solid state, perhaps by locking in the defects. 

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. 

Amorphous form provide the most rapid dissolution and the most often increased solubility by supersaturation however, practical usefulness is limited by stability issues, including transformation of the solid state form. 

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 physical form of the salt must be taken into account and several issues must be considered (Serajuddin and Pudipeddi, 2002). Forexample, amorphous material might result. Even if crystalline, the salt form might prove to be polymorphic. On crystallization or recrystallization, formation of a hydrate or a solvate might occur, and the effect of temperature and humidity on this form should be investigated. Both the physical and chemical stability of the different candidate salt forms in the solid state will ultimately deLne the optimal form of the drug. 

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