Stability of α-lactose monohydrate: The discovery of dehydration triggered solid-state epimerization

• Published in: International journal of pharmaceutics Vol. 604; p. 120715
• Main Authors: Alzoubi, Thamer, Martin, Gary P., Barlow, David J., Royall, Paul G.
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 15.07.2021
• Subjects: Differential scanning calorimetry; Epimerisation; Hot stage microscopy; Lactose; NMR; Hot stage microscopy; Differential scanning calorimetry; NMR; Lactose; Epimerisation
• ISSN: 0378-5173; 1873-3476
• DOI: 10.1016/j.ijpharm.2021.120715

[Display omitted] Lactose is present as an excipient in nearly half of all solid medicines. Despite the assumption of chemical stability, in aqueous solution, the chiral composition of lactose is prone to change. It is not known whether such epimerisation could also occur as solid crystalline α-lactose undergoes thermal desorption of its hydrated water. Thus, the aim of this study was to investigate the anomeric composition of lactose powders after heating in a differential scanning calorimeter. During thermal analysis, the heating cycles were interrupted to allow anomer-composition analysis by NMR. The onset for monohydrate desorption occurred at 143.8 ± 0.3 °C. Post water-loss, at 160 °C for example, α-lactose suffered partial conversion (11.6 ± 0.9%) to the β-anomer. When held at 160 °C for 60 min this increased to 29.7 ± 0.8% β-anomer (p < 0.05). This process of epimerisation was found to be close to zero-order with a rate constant of 0.28% per min−1. Optical microscopy indicated that the solid-state was maintained throughout thermal desorption and up to the onset of melting at 214.2 ± 0.9 °C. Only epimerisation was observed, with no additional chemical degradation detected by NMR. Similar results were observed when heating α-lactose to 190 °C, which resulted in a conversion of 29.1 ± 0.7% to β-lactose. Thus, the exothermic peak observed after monohydrate loss, which has often been attributed to re-crystallisation, comprises a contribution from epimerisation. No epimerisation or hydrate loss was observed for β-lactose powders when heated. In summary, it has been shown unequivocally for the first time that hydrate desorption (dehydration) leads to solid-state epimerisation in α-lactose powders.