Amorphous form drug substance physical stability

As the active substance in a solid solution is in an amorphous state and therefore in a more energetic form, and as its surface area is much greater both in solid solutions and in solid dispersions, the question of its physical and chemical stability arises. The main criterion for physical stability is the extent of recrystallization, which can reduce the bioavailability of the active substance. Surprisingly, a survey of publications in which recrystallization and chemical stability have been investigated reveals only relatively few cases of instability. Table 80 contains a list of publications with stability data for solid solutions of drugs in povidone with a... 

All the active substances investigated so far were converted to the amorphous form by trituration with crospovidone, and this always remained stable in the few trials that have been conducted so far (Table 140). Stability results are available for a much larger number of drugs in coevaporates with crospovidone (Table 141). As all the drugs tested in coevaporates were found to have very good physical stability of their amorphous state, the same can be assumed for triturations. This correlates with similar results obtained with povidone (see Section 2.4.3.2). 

Some new drug substances exist in different crystalline forms that differ in their physical properties. Polymorphism may also include solvation or hydration products (also known as pseudopol5rmorphs) and amorphous forms. Differences in these forms could, in some cases, affect the quality or performance of the new drug products. In such cases, the bioavailabUity stability can be altered requiring choice of specific stable solid dosage forms. 

It is also important to note that each of these dispersions can be exploited to enhance the delivery of the drug substance. For example, the majority of dissolution enhanced products are prepared in the amorphous state to leverage the higher solubility of the material and increase release rates from the drug product. Furthermore, the homogeneous nature of the dispersion provides a kinetic barrier for recrystallization of the amorphous form that contributes to improved physical stability. However, in the case of controlled release and directly shaped products where the systems may be prepared to have specific structural and mechanical attributes, the use of solid dispersions wherein both the drug and polymer exist as crystalline materials within the system may be beneficial. 

Additional preformulation and physicochemical characterization of the candidate compound are performed and stress stability studies may be initiated. Ideally, the optimal solid-state (polymorphic) and chemical (salt) form of the molecule are identified as part of clinical candidate selection. Selection of the most stable and bio-available chemical and physical forms will expedite subsequent development. The methods for testing the drug substance are refined and additional methods may be developed, including tests for physical, chemical, and chiral purity. Analytical characterization becomes extremely critical where significant formulation intervention is required such as amorphous formulations for BCS 2/4 compounds, inhalation products, or highly concentrated formulations for monoclonal antibodies. 

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