Effect of co-solutes and process variables on crystallinity and the crystal form of freeze-dried myo-inositol.
The purpose of this study was to elucidate how co-solutes affect the crystallization of small solute molecules during freeze-drying and subsequent storage. Crystallization profiles of myo-inositol and its mixture with dextran 40k in frozen solutions and dried solids were assessed by thermal analysis (DSC), powder-X-ray diffraction, and simultaneous DSC and PXRD analysis. Higher mass ratios of dextran maintained myo-inositol in the non-crystalline mixture state, in frozen solutions, during freeze-drying process, and exposure of dried solids to higher temperatures. Co-lyophilization with a lower mass ratio of dextran resulted in solids containing a variety of myo-inositol crystal forms and crystallinity depending on the composition and thermal history of the process. Heating of some inositol-rich amorphous solids showed crystallization of myo-inositol in the metastable form and its transition to stable form before melting. Heat-treatment of inositol-rich frozen solutions resulted in high crystallinity stable-form inositol solids, leaving dextran in the amorphous state. Sufficient direct molecular interactions (e.g., hydrogen bonding) should explain the stability of dextran-rich amorphous solids. Optimizing solute composition and processes should be a potent way to control crystal form and crystallinity of components in freeze-dried formulations.
Drug Division, National Institute of Health Sciences, Kamiyoga 1-18-1, Setagaya 158-8501 Tokyo, Japan. Electronic address: izutsu@nihs.go.jp.
Ken-Ichi
KI
Izutsu
Faculty of Pharmaceutical Science, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan.
Riho
R
Kusano
Faculty of Pharmaceutical Science, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan.
Ryoko
R
Arai
Drug Division, National Institute of Health Sciences, Kamiyoga 1-18-1, Setagaya 158-8501 Tokyo, Japan.
Hiroyuki
H
Yoshida
Faculty of Pharmaceutical Science, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan.
Masataka
M
Ito
Drug Division, National Institute of Health Sciences, Kamiyoga 1-18-1, Setagaya 158-8501 Tokyo, Japan.
Hiroko
H
Shibata
Faculty of Pharmaceutical Science, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan.
Kiyohiko
K
Sugano
Drug Division, National Institute of Health Sciences, Kamiyoga 1-18-1, Setagaya 158-8501 Tokyo, Japan.
Yukihiro
Y
Goda
Faculty of Pharmaceutical Science, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan.
Katsuhide
K
Terada
D002626:Chemistry, Pharmaceutical / Q000379:methods; D003460:Crystallization / Q000379:methods; D003911:Dextrans / Q000737:chemistry; D005079:Excipients / Q000737:chemistry; D005612:Freeze Drying / Q000379:methods; D005615:Freezing; D006860:Hydrogen Bonding; D007294:Inositol / Q000737:chemistry*; D012996:Solutions / Q000737:chemistry*; D044366:Transition Temperature
D003911:Dextrans; D005079:Excipients; D012996:Solutions; D007294:Inositol
Co-lyophilization; Crystal form; Crystallinity; Crystallization; Freeze-drying; Myo-inositol; Polymorph