PubMed · 1397526
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W H Goldmann. 1992. Talin-lipid interaction.. https://doi.org/10.1042/bst020121s
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Hemoglobin has been previously shown to unfold during freeze drying when lyophilized from formulations that undergo freeze-concentration induced phase separation (Heller et al. 1997. Biotechnol Prog 13:590-596). In this report, we show that such damage may be avoided using kinetic strategies to arrest the phase separation. By rapidly cooling samples during liquid nitrogen spray-freeze drying, the time that the formulation spends in temperature regimes (ca. -3 to -23 degrees C) in which phase separation is both thermodynamically favorable and kinetically realizable is minimized. Increased protein damage with decreasing cooling rates and/or longer annealing periods at -7 degrees C is observed by FTIR spectroscopy. Phase separation and concomitant protein damage may also be avoided by addition of mannitol at concentrations sufficient to cause crystallization. Mannitol crystals segregate the freeze concentrated solution into microscopic domains that block propagation and nucleation of phase separating events. Addition of noncrystallizing sugars, such as sucrose and trehalose, or nonionic surfactants, such as Tween 80 and Triton X-100, has little protective effect against phase separation induced damage during freezing drying.
The glass transitional behaviour of HPMC powder and film samples has been studied using modulated temperature differential scanning calorimetry (MTDSC) in order to explore the ability of the technique to detect transitions which involve small changes in heat capacity. HPMC E4M Prem samples were studied in both powder and film form using a TA Instruments MDSC 2920 using a range of pans, modulation amplitudes and underlying heating rates. Moisture contents were measured using a TA Instruments TGA 2950. Studies on HPMC powder demonstrated the greater clarity with which the glass transition, seen at approximately 162 degrees C, may be seen using MTDSC compared to conventional DSC. The practical difficulties associated with casting suitable HPMC films are discussed, with similar results for Tg being found for hermetically sealed pans and pin-holed pans. Increasing the modulation amplitude from 0.212 to 0.5 degrees C improved the signal to noise ratio and increased the magnitude of the measured Tg. Increasing the underlying heating rate from 2 to 5 degrees C/min also improved the signal. The study has outlined several features which need to be considered in association with the measurement of HPMC glass transitions using MTDSC; these include the method of sample preparation, the choice of pans, the modulation amplitude and the underlying heating rate.
Many pharmaceuticals, either by accident or design, may exist in a total or partially amorphous state. Consequently, it is essential to have an understanding of the physico-chemical principles underpinning the behaviour of such systems. In this discussion, the nature of the glassy state will be described, with particular emphasis on the molecular processes associated with glass transitional behaviour and the use of thermal methods for characterising the glass transition temperature, Tg. The practicalities of such measurements, the significance of the accompanying relaxation endotherm and plasticization effects are considered. The advantages and difficulties associated with the use of amorphous drugs will be outlined, with discussion given regarding the problems associated with physical and chemical stability. Finally, the principles of freeze drying will be described, including discussion of the relevance of glass transitional behaviour to product stability.