The rate of crystal nucleation has been measured in four glass-forming molecular liquids: D-sorbitol, D-arabitol, D-xylitol, and glycerol. These polyalcohols have similar rates of crystal growth when compared at the same temperature relative to T (the glass transition temperature), peaking near 1.4 T, while the nucleation rates J are vastly different. In D-sorbitol and D-arabitol, J reaches a maximum of ∼10 m s near 1.1 T, whereas J < 10 m s in D-xylitol and <1 m s in glycerol based on no nucleation in large samples after long waits. This confirms the fundamentally different mechanisms for nucleation and growth. Near T, both nucleation and growth slow down with a similar temperature dependence, suggesting a similar kinetic barrier for the two processes. This temperature dependence is significantly weaker than that of viscosity η, approximately following η. This indicates that viscosity is a poor representative of the kinetic barrier for nucleation, and a better choice is the crystal growth rate. Under the latter assumption, the classical nucleation theory (CNT) describes our data reasonably well, yielding σ = 0.013 J/m for D-sorbitol and 0.026 J/m for D-arabitol, where σ is the critical nucleus/liquid interfacial free energy. There is no strong indication that the CNT fails as the length scale for corporative rearrangement exceeds the size of the critical nucleus, as recently suggested for lithium disilicate.

As a result of its higher molecular mobility, the surface of an amorphous drug can grow crystals much more rapidly than the bulk, causing poor stability and slow dissolution of drug products. We show that a nanocoating of chitosan (a pharmaceutically acceptable polymer) can be deposited on the surface of amorphous indomethacin by electrostatic deposition, leading to significant improvement of physical stability, wetting by aqueous media, dissolution rate, powder flow, and tabletability. The coating condition was chosen so that the positively charged polymer deposits on the negatively charged drug. Chitosan coating is superior to gelatin coating with respect to stability against crystallization and agglomeration of coated particles.

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Recent work has shown that diffusion and crystal growth can be much faster on the surface of molecular glasses than in the interior and that the enhancement effect varies with molecular size and intermolecular hydrogen bonds (HBs). In a related phenomenon, some molecules form highly stable glasses when vapor-deposited, while others (notably those forming extensive HBs) do not. Here we examine all available data on these phenomena for quantitative structure-property relations. For the systems that form no HBs, the surface diffusion coefficient D s decreases with increasing molecular size d (d = Ω 1/3 , where Ω is the molecular volume); when evaluated at the glass transition temperature T g , D s decreases ∼5 orders of magnitude for 1 nm of increase in d. Assuming that center-of-mass diffusion is limited by the deepest part of the molecule in the surface-mobility gradient, these data indicate a mobility gradient in reasonable agreement with the Elastically Collective Nonlinear Langevin Equation theory prediction for polystyrene as disjointed Kuhn monomers. For systems of similar d, the D s value decreases with the extent of intermolecular HB, x (HB), defined as the fraction of vaporization enthalpy due to HB. For both groups together (hydrogenbonded and otherwise), the D s data collapse when plotted against d/[1 − x(HB)]; this argues that the HB effect on D s can be described as a narrowing of the surface mobility layer by a factor [1 − x(HB)] relative to the van der Waals systems. Essentially the same picture holds for the surface crystal growth rate u s. The kinetic stability of a vapor-deposited glass decreases with x(HB) but is not better organized by the combined variable d/[1 − x(HB)]. These results indicate that surface crystal growth depends strongly on surface diffusion, whereas the formation of stable glasses by vapor deposition may depend on other factors.

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