Effective inhibition of mannitol crystallization in frozen solutions by sodium chloride.
OBJECTIVE
The purpose of this work was to study the possibility of preventing mannitol crystallization in frozen solutions by using pharmaceutically acceptable additives.


METHODS
Differential scanning calorimetry (DSC) and low-temperature X-ray diffractometry (LTXRD) were used to characterize the effect of additives on mannitol crystallization.


RESULTS
DSC screening revealed that salts (sodium chloride, sodium citrate, and sodium acetate) inhibited mannitol crystallization in frozen solutions more effectively than selected surfactants, alpha-cyclodextrin, polymers, and alditols. This finding prompted further studies of the crystallization in the mannitol-NaCl-water system. Isothermal DSC results indicated that mannitol crystallization in frozen solutions was significantly retarded in the presence of NaCl and that NaCl did not crystallize until mannitol crystallization completed. Low-temperature X-ray diffractometry data showed that when a 10% w/v mannitol solution without additive was cooled at 1 degrees C/min, the crystalline phases emerging after ice crystallization were those of a mannitol hydrate as well as the anhydrous polymorphs. In the presence of NaCl (5% w/v), mannitol crystallization was suppressed during both cooling and warming and occurred only after annealing and rewarming. In the latter case however, mannitol did not crystallize as the hydrate, but as the anhydrous delta polymorph. At a lower NaCl concentration of 1% w/v, the inhibitory effect of NaCl on mannitol crystallization was evident even during annealing at temperatures close to the Tg' (-40 degrees C). A preliminary lyophilization cycle with polyvinyl pyrrolidone and NaCl as additives rendered mannitol amorphous.


CONCLUSIONS
The effectiveness of additives in inhibiting mannitol crystallization in frozen solutions follows the general order: salts > alditols > polyvinyl pyrrolidone > alpha-cyclodextrin > polysorbate 80 approximately polyethylene glycol approximately poloxamer. The judicious use of additives can retain mannitol amorphous during all the stages of the freeze-drying cycle.
College of Pharmacy, 308 Harvard Street S.E., University of Minnesota, Minnesota 55455, USA.
Chitra
C
Telang
Lian
L
Yu
Raj
R
Suryanarayanan
D002152:Calorimetry, Differential Scanning; D003460:Crystallization; D005079:Excipients / Q000737:chemistry*; D005612:Freeze Drying / Q000379:methods; D008353:Mannitol / Q000737:chemistry*; D019999:Pharmaceutical Solutions / Q000737:chemistry; D012965:Sodium Chloride / Q000737:chemistry*; D013678:Technology, Pharmaceutical
D005079:Excipients; D019999:Pharmaceutical Solutions; D008353:Mannitol; D012965:Sodium Chloride