Importance Of Assessing Mannitol Crystallinity In Lyophilized Drug Products

Mannitol is a versatile excipient used in freeze-dried injectables in the pharmaceutical industry. Depending on the freezing and/or annealing conditions employed, mannitol is retained either as amorphous or crystalline. Crystalline mannitol is more prevalent in drug product formulations than amorphous mannitol. When crystalline, it provides an opportunity to conduct lyophilization cycles at aggressive conditions due to its high eutectic melting point (about - 1.5°C). The resultant freeze-dried solids are pharmaceutically elegant in appearance with cake uniformity. Reconstitution of the dried solids is generally rapid and complete.

During lyophilization, mannitol either crystallizes spontaneously during the freezing step or an annealing step is included to encourage its crystallization. However, if mannitol remains amorphous or if crystallization is incomplete, it may crystallize during storage which may have serious consequences to the drug product stability due to changes in the residual moisture level associated with the conversion of amorphous to crystalline mannitol.