Abstract
Purpose. To study the crystallization, polymorphism, and phase behavior of D-mannitol in binary mixtures with NaCl to better understand their interactions in frozen aqueous solutions.
Methods. Differential scanning calorimetry, hot-stage microscopy, Raman microscopy, and variable-temperature X-ray diffractometry were used to characterize D-mannitol-NaCl mixtures.
Results. NaCl and D-mannitol exhibited significant melt miscibility (up to 7.5% w/w or 0.20 mole fraction of NaCl) and a eutectic phase diagram (eutectic composition 7.5% w/w NaCl; eutectic temperature 150°C for the α and β polymorphs of D-mannitol and 139°C for the δ). The presence of NaCl did not prevent mannitol from crystallizing but, depending on sample size, affected the polymorph crystallized: below 10 mg, δ was obtained; above 100 mg, α was obtained. Pure mannitol crystallized under the same conditions first as the δ polymorph and then as the α polymorph, with the latter nucleating on the former. KCl showed similar eutectic points and melt miscibility with D-mannitol as NaCl. LiCl yielded lower eutectic melting points, inhibited the crystallization of D-mannitol during cooling, and enabled the observation of its glass transition.
Conclusions. Despite their structural dissimilarity, significant melt miscibility exists between D-mannitol and NaCl. Their phase diagram has been determined and features polymorph-dependent eutectic points. NaCl influences the polymorphic behavior of mannitol, and the effect is linked to the crystallization of mannitol in two polymorphic stages.
Similar content being viewed by others
REFERENCES
C. Telang, L. Yu, and R. Suryanarayanan. Effective inhibition of mannitol crystallization in frozen solutions by sodium chloride. Pharm. Res. 20:660-667 (2003).
E. Y. Shalaev and F. Franks. Solid-liquid diagrams in pharmaceutical lyophilization: Crystallization of solutes. In H. Levine (ed.), Progress in Amorphous Food and Pharmaceutical Systems, Royal Society of Chemistry, 2002, pp. 200-215.
M. J. Pikal. Freeze drying. In J. Swarbrick and J. C. Boylan (eds.), Encyclopedia of Pharmaceutical Technology, Marcel Dekker, New York, 1993, pp. 275-303.
A. Martini, K. Silvia, M. Crivellente, and R. Artico. Use of subambient differential scanning calorimetry to monitor the frozen state behavior of blends of excipients for freeze-drying. PDA J. Pharm. Sci. Tech. 51:62-67 (1997).
A. I. Kim, M. J. Akers, and S. L. Nail. the physical state of mannitol after freeze-drying: effects of mannitol concentration, freezing rate, and a noncrystallizing cosolute. J. Pharm. Sci. 87:931-935 (1998).
F. H. Cocks and W. E. Brower. Phase diagram relations in cryobiology. Cryobiology 11:340-358 (1974).
F. W. Gayle, F. H. Cocks, and M. L. Shepard. The water-sodium chloride-sucrose phase diagram and applications in cryobiology. J. Appl. Chem. Biotechnol. 27:599-607 (1977).
M. G. Fakes, M. V. Dali, T. A. Haby, K. R. Morris, S. A. Varia, and A. T. M. Serajuddin. Moisture sorption behavior of selected bulking agents used in lyophilized products. PDA J. Pharm. Sci. Tech. 54:144-149 (2000).
H. R. Costantino, J. D. Andya, P. A. Nguyen, N. Dasovich, T. D. Sweeney, S. J. Shire, C. C. Hsu, and Y.-F. Maa. Effect of mannitol crystallization on the stability and aerosol performance of a spray-dried pharmaceutical protein, recombinant humanized anti-ige monoclonal antibody. J. Pharm. Sci. 87:1406-1411 (1998).
K. Izutsu, S. Yoshioka, and T. Terao. Decreased protein-stabilizing effects of cryoprotectants due to crystallization. Pharm. Res. 10:1232-1237 (1993).
K. Izutsu, S. Yoshioka, and T. Terao. Effect of mannitol crystallinity on the stabilization of enzymes during freeze-drying. Chem. Pharm. Bull. 42:5-8 (1994).
R. K. Cavatur and R. Suryanarayanan. Characterization of frozen aqueous solutions by low temperature X-ray powder diffractometry. Pharm. Res. 15:194-199 (1998).
K. Ito. Freeze drying of pharmaceuticals. Eutectic temperature and collapse temperature of solute matrix upon freeze drying of three-component systems. Chem. Pharm. Bull. 19:1095-1102 (1971).
M. Siniti, S. Jabrane, and J. M. Letoffe. Study of the respective binary phase diagrams of sorbitol with mannitol, maltitol and water. Thermochim. Acta 325:171-180 (1999).
H. Bauer, T. Herkert, M. Bartels, K.-A. Kovar, E. Schwarz, and P. C. Schmidt. Investigations on polymorphism of mannitol/sorbitol mixtures after spray-drying using differential scanning calorimetry, X-ray diffraction and near-infrared spectroscopy. Pharmazeutische Industrie 62:231-235 (2000).
L. Yu, D. S. Mishra, and D. R. Rigsbee. Determination of the glass properties of D-mannitol using sorbitol as an impurity. J. Pharm. Sci. 87:774-777 (1998).
Powder Diffraction File. (PDF-2), International Centre for Diffraction Data, Newtown Square, PA (1996).
A. Burger, J. O. Henck, S. Hetz, J. M. Rollinger, A. A. Weissnicht, and H. Stottner. Energy/temperature diagram and compression behavior of the polymorphs of D-mannitol. J. Pharm. Sci 89:457-468 (2000).
B. Debord, C. Lefebvre, A. M. Guyot-Hermann, J. Hubert, R. Bouche, and J. C. Guyot. Study of different crystalline forms of mannitol: comparative behavior under compression. Drug. Dev. Ind. Pharm. 13:1533-1546 (1987).
L. Yu. Nucleation of one polymorph by another. J. Am. Chem. Soc. 125:6380-6381 (2003).
R. C. Weast (ed.). CRC Handbook of Chemistry and Physics, 50th ed., The Chemical Rubber Co., Cleveland, OH (1970).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Telang, C., Suryanarayanan, R. & Yu, L. Crystallization of D-Mannitol in Binary Mixtures with NaCl: Phase Diagram and Polymorphism. Pharm Res 20, 1939–1945 (2003). https://doi.org/10.1023/B:PHAM.0000008040.14958.bc
Issue Date:
DOI: https://doi.org/10.1023/B:PHAM.0000008040.14958.bc