RH‐Temperature Stability Diagram of the Dihydrate, β‐Anhydrate, and α‐Anhydrate Forms of Crystalline Trehalose

Abstract

Trehalose crystals exhibit polymorphic, deliquescent, and hydrate‐forming traits and can exist in dihydrate, β‐anhydrate, or α‐anhydrate (isomorphic desolvate) forms. The objective of this study was to identify the relative humidity (RH) and temperature boundaries for phase changes of these different trehalose crystal forms. The deliquescence points (RH0s) of the anhydrate and dihydrate trehalose crystals were determined from 20 to 50 °C using a combination of water activity and dynamic vapor sorption measurement techniques. Increasing temperatures from 20 to 50 °C resulted in decreases in RH0 from 95.5% to 90.9% RH for the dihydrate and 69.9% to 62.0% RH for the β‐anhydrate. The effects of temperature on the anhydrate–hydrate RH boundaries were also determined, using a combination of equilibration in controlled water activity solutions, powder X‐ray diffraction, and Fourier‐transform infrared spectroscopy techniques. Increasing temperatures resulted in increases in the anhydrate–hydrate RH boundaries. The irreversible β‐anhydrate to dihydrate boundary increased from 44.9% to 57.8% RH, and the reversible α‐anhydrate to dihydrate boundary increased from 10% to 25% RH, as temperature increased from 20 to 50 °C. This is the first report of an RH–temperautre stability map for crystalline trehalose. Practical Application The manuscript addresses the issue of the physical stability and phase transformations of crystalline trehalose stored in different temperature and relative humidity environments. Unwanted hydrate formation or dehydration of crystal hydrates can lead to other undesirable water–solid interactions and/or physical modifications that have the potential to influence product quality and delivery traits. Therefore, this study identified relative humidity and temperature stability boundaries of the different trehalose crystal forms, using a variety of established and novel techniques to create a relative humidity–temperature stability map of crystalline trehalose from 20 to 50 °C.

Selection of Cryoprotectant in Lyophilization of Progesterone-Loaded Stearic Acid Solid Lipid Nanoparticles

“…From its thermogram it can be observed that trehalose has an endothermic peak at approximately 115 • C which corresponds to the melt of the α-anhydrate, and another at 190 • C corresponding to the melt of the β-anhydrate. These observations for trehalose are all in agreement with the recent literature [21]. A scan of progesterone-loaded stearic acid SLNs shows a shift to a slightly lower temperature of the stearic acid melt with a shoulder that is not evident in the stearic acid melt and that shows no evidence of a progesterone melt.…”

Relative humidity–temperature transition boundaries for anhydrous β‐caffeine and caffeine hydrate crystalline forms

“…Previous phase diagrams of hydrate‐forming deliquescent anhydrous compounds (Allan et al., 2019; Allan & Mauer, 2017b) used compounds that exhibited deliquescence boundaries for both the anhydrate and hydrate crystal forms in environmental conditions of relevance for food and ingredient storage. Unlike these other compounds (glucose, trehalose, and citric acid with solubilities of > 400 g/L) (Lafontaine, Sanselme, Cartigny, Cardinael, & Coquerel, 2013; Lammert, Schmidt, & Day, 1998), caffeine has a lower aqueous solubility (22.8 g/L at 25 °C, Table 1, Edwards et al., 1997).…”

“…Therefore, the kinetics of vapor‐mediated equilibration may be too slow for accurate anhydrate–hydrate boundary determination for long‐term caffeine polymorphic form stability. In previous studies by Allan and Mauer, RH–temperature phase and stability diagrams of hydrate‐forming deliquescent crystalline ingredients (glucose, citric acid, sodium sulfate, trehalose, and lactose) were produced by solution‐mediated equilibration (a w ) using a series of ethanol–water solutions (Allan, Chamberlain, & Mauer, 2019; Allan, Grush, & Mauer, 2020; Allan & Mauer, 2017a; Allan & Mauer 2017b). Solution‐mediated equilibration is advantageous for two reasons: (1) faster equilibration rates, and (2) the equilibrium a w at which both the anhydrate and hydrate are stable, which is the anhydrate–hydrate boundary, can be precisely measured.…”

“…The objective of this study was to document the β‐caffeine ↔ caffeine hydrate RH–temperature boundary across the range of temperatures accessible to current instrumentation (20 to 45 °C) and also to measure the deliquescence boundary of caffeine. The methodologies previously used to identify anhydrate–hydrate boundaries for sodium sulfate, glucose, citric acid, trehalose, and lactose (Allan et al., 2019; Allan et al., 2020; Allan & Mauer, 2017b) were implemented to identify the β‐caffeine ↔ caffeine hydrate RH–temperature boundary. The identified RH–temperature anhydrate–hydrate phase boundaries of caffeine will be useful for determining ideal RH–temperature storage conditions and a w criteria for maintaining the desired form of caffeine.…”

Harnessing Birefringence for Real-Time Classification of Molecular Crystals Using Dynamic Polarized Light Microscopy, Microfluidics, and Machine Learning

“…Therefore, the ability to monitor, formulate, and analyze fundamental governing kinetics using online process monitoring instruments become crucial for devising control or storage strategies to obtain or maintain the desired crystal form. 17,72,73 As a showcase for monitoring and quantifying phase transformations from metastable to stable phases of molecular crystals, we conducted SMPT of β-glycine to α-glycine and azithromycin sesquihydrate to azithromycin dihydrate. SMPT occurs in three steps; first, the metastable phase dissolves, second, nucleation of the stable phase occurs, and last, growth of a stable phase takes place.…”