Evolution of phases and habit during the crystallization of freeze-dried lactose/salt mixtures in humid air

Phase compositions, transient phases, and morphology of the crystallization of freeze-dried lactose/salt mixtures in humid air were estimated by in situ X-ray diffraction analysis complemented by ex situ scanning electron microscopy, powder diffraction, and analysis of the solid state α/β anomeric ratios by gas-liquid chromatography. The salts studied are calcium chloride (CaCl₂), magnesium chloride (MgCl₂), potassium chloride (KCl), and sodium chloride (NaCl) with lactose/salt molar ratios of 2:1, 4:1, and 9:1 mol/mol. Following an induction period during which water is sorbed, crystallization is rapid and the predominant phases observed using the in situ method in freeze-dried lactose/magnesium chloride (MgCl₂), sodium chloride (NaCl), and potassium chloride (KCl) are mixtures of α-lactose monohydrate and β-lactose. In general, the α/β ratio of the solid state as measured by gas-liquid chromatography was similar to the crystalline phase composition as measured by X-ray diffraction. A transient phase appears in lactose/KCl (4:1 and 9:1 mol/mol), lactose/MgCl₂ (9:1 mol/mol), and lactose/NaCl (9:1 mol/mol), namely, α/β mixed phase. Another transient effect observed with nearly all the lactose-salt mixtures was the observation of a subtle shift in the lattice parameters of α-lactose from a = 8.006 Å, b = 21.562 Å and c = 4.800 Å for short crystallization times to a = 7.982 Å, b = 21.562 Å, and c = 4.824 Å for longer times. The transient effects, namely, the observation of the α/β mixed phase and the distortion in α-lactose monohydrate lattice parameters, are explained in terms of stresses induced during the rapid onset of crystallization.