Untitled

Abstract

The rate of hydrolysis of methylprednisolone sodium succinate in the freeze dried solid state at 40 degrees C was determined in the presence of two common bulking agents--mannitol and lactose--at two different ratios of drug to excipient. Residual moisture levels were less than 1% in all samples tested, with no significant difference in residual moisture among different formulations. Rate of hydrolysis was significantly higher in mannitol-containing formulations versus lactose-containing formulations, and the rate of hydrolysis increases with increasing ratio of mannitol to drug. Thermal analysis and x-ray diffraction data are consistent with a composition-dependent rate of crystallization of mannitol in the formulation and its subsequent effect on distribution of water in the freeze-dried matrix. Increased water in the microenvironment of the drug decreases the glass transition temperature of the amorphous phase, resulting in an increased rate of reaction. The physical state of lactose remained constant throughout the duration of the study, and the rate of hydrolysis was not significantly different from the control formulation containing no excipient. Thermal analysis and x-ray diffraction data are consistent with formation of a liquid crystal phase in freeze-concentrated solutions of methylprednisolone sodium succinate containing no excipient.

The Influence of Water on the Stability of Lyophilized Formulations with Inositol and Mannitol as Excipients

“…5 fluenced by water mobility rather than the amount of total water. [2][3][4] Although other parameters that could affect the formulation stability should also be considered including the molecular mobility of the drug itself, this report is focusing on the association of water with the formulations and water mobility in the two formulations, both of which could have considerable influence on drug stability, as well as how variations in water contents result in changes to stability superiority.…”

“…For example, conversion between crystalline and amorphous forms can greatly affect the stability and solubility of drugs in lyophilized formulations. [1][2][3] Residual moisture may have a significant influence on the stability and quality of formulations because water can act not only as a chemical reactant but also as a plasticizer to facilitate the crystallization of amorphous materials.…”

“…[2][3][4] When water acts as a plasticizer, it increases the mobility of the system, leading to enhanced reactivity. NMR is a powerful method for determining mobility in solids.…”

Characterization of Physical State of Mannitol after Freeze-Drying: Effect of Acetylsalicylic Acid as a Second Crystalline Cosolute.

“…These results are similar to those obtained by Haikala et al 4) The DSC scans of AAS reference and the freeze-dried sample showed the same pattern. The first endotherm (137- 17) considered that these changes can have an effect on distribution of water within the freeze-dried matrix. However, further work is needed in order to have a better understanding of the pharmaceutical significance of these changes within freeze-dried solids.…”

Influence of Ethanol on Physical State of Freeze-Dried Mannitol

“…In general, freeze-dried formulations contain multiple components such as the active pharmaceutical ingredient, bulking agents, lyoprotectants, cryoprotectants, and buffers. The characteristics of freezing and freeze-drying, as well as the physical properties of the freeze-dried solid, have been studied extensively (1)(2)(3)(4). Such investigations yield data that are useful in determining the most desirable formulations and freeze-drying conditions.…”