Processing as a source of moisture

Crowley and Martini [48] reported on several studies evaluating the impact of unit process operations on hydrates. AU showed some level of dehydration liberating freed crystalline water to participate in moisture-mediated reactions. The authors speculated that such energetic processing conditions are likely to have a similar affect on hydrated excipients with a potential deleterious effect on moismre-sensitive APIs. They commented that classical excipient compatibility studies were ill-equipped to predict such moismre-mediated interactions and that compression, attrition and other energy-intensive unit operations were rarely mentioned as requiring investigations. 

High-energy processes (milling, lyophilisation, granulating, drying) can introduce certain amounts of amorphicity into otherwise highly crystalline material [20]. As has been previously indicated, enhanced levels of amorphicity lead to increased local levels of moismre, and increased chemical reactivity in these areas. Hancock and Zografi [49] reported on the impact of a roller-compaction process on the water vapour sorption of a sample of aspirin. They speculated that 

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