Mannitol, stress effect

For a two-level factorial design, only two excipients can be selected for each factor. However, for the filler-binder, a combination of brittle and plastic materials is preferred for optimum compaction properties. Therefore, different combinations such as lactose with MCC or mannitol with starch can count as a single factor. Experimental responses can be powder blend flowability, compactibility, blend uniformity, uniformity of dose unit, dissolution, disintegration, and stability under stressed storage conditions. The major advantage of using a DOE to screen prototype formulations is that it allows evaluation of all potential factors simultaneously, systematically, and efficiently. It helps the scientist understand the effect of each formulation factor on each response, as well as potential interaction between factors. It also helps the scientist identify the critical factors based on statistical analysis. DOE results can define a prototype formulation that will meet the predefined requirements for product performance stability and manufacturing. 

Although most of the focus on solute effects on macromolecular systems has involved proteins, there is evidence that some of the patterns of solute accumulation reflect the dangers that high salt concentrations pose for the covalent structure of DNA. Using cultured mammalian kidney cells Kiiltz and Chakravarty (2001) showed that hyperosmotic stress could cause double strand breaks (dsb) in DNA. Hyperosmolality due to elevated [NaCl] in the culture medium caused the most dsb. Potassium chloride and mannitol led to less damage and, interestingly, no damage to DNA was found in cells exposed to elevated levels of urea. 

Four cases of acute renal insufficiency have been described in men aged 20-42 years who received mannitol 1172 (sd 439) g over 58 (sd 28) hours (7). The onset of acute renal insufficiency was detected 48 (sd 22) hours after the start of infusion. All the patients had dilutional hyponatremia (average 120 mmol/1) and serum hyper-osmolarity (osmolar gap 70 mosm/kg water). In the three anuric cases, in which hemodialysis was performed, there was immediate recovery of diuresis. This emphasizes the risk of renal insufficiency with mannitol and stresses the importance of early hemodialysis. Mannitol is dialysable and once its suppressive effect on renal perfusion is eliminated functional recovery is prompt. 

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