(T0930-09-58) Crystallization Kinetics of Amorphous Lactose: The Difference between α and β Anomers

Purpose: Lactose is often used as a carrier for active pharmaceutical ingredients in dry powder inhaler formulations. Two anomers α and β (in approximately 30/70 ratio) are present in anhydrous inhalation grade lactose. Lactose micronization via a jet mill is commonly performed to achieve a particle size similar to the API in dry powder inhalers for lung delivery. This micronization process has the potential to make the lactose partially amorphous. Annealing the lactose via humidity induced crystallization may be required for which the optimal relative humidity and crystallization kinetics of α and β anomers are important to understand.

Methods: In this study, a powder X-ray diffractometer equipped with a RH chamber was used to monitor the crystallization process of α and β anomers.

Results: In a 20% amorphous content lactose sample, β anomer gradually crystallized into its anhydrous form at 38% RH within 5 hours. The crystallinity increased slightly after raising the RH to 53% for the next 5 hours. α anomer shows completely different crystallization kinetics within the same sample. The crystallinity of α anomer remained the same in the first 5 hours under 38% RH and only began to crystallize after the RH was raised to 53%, eventually reaching a plateau within 4 hours at 53%RH (see Figure 1). The similar phenomenon was observed in fully amorphous lactose made by cryo-milling (Figure 2). After exposing to 38% RH at 25 °C for 6 hours, β anomer starts to crystallize into β anhydrous form while α anomer still remains amorphous. The β anhydrous form keeps growing in the next 4 hours at 38% RH. But no significant crystalline peak can be observed from α anomer. After RH is raised to 53 %, both α and β anomers achieved complete crystallization within 1 hour.

Conclusion: The different crystallization processes between α and β anomers are hypothesized to be related to the RH dependence of glass transition temperature (T_g). The T_g of α and β lactose is lowered by water vapor sorption as water is the plasticizer. T_g of α lactose drops to 25 °C near 40%RH. Thus, the nucleation and growth of α lactose are both very slow at 38%RH and 25 °C as α lactose is still in glassy state. While the T_g of β lactose is hypothesized to be lower than 25 °C at the same 38 %RH condition. At the same condition, β lactose is in the supercooled liquid state where crystallization is fast. The findings in this work can be used to direct annealing conditions to ensure complete crystallization of both α and β anomers as needed for drug product performance.

Figure 1. Powder X-ray patterns of a 20% amorphous lactose sample under 38 %RH and 53 %RH at 25 °C. The figure on the left shows the gradual crystallization of β anomer associated with characteristic 2θ reflection at 10.5°. The figure on the right shows no progression of crystallization of α anomer associated with characteristic 2θ reflection at 12.5° under 38 %RH and significant crystallization at 53 %RH.

Figure 2. Powder X-ray patterns of fully amorphous lactose made by cryo-milling. The figure on the left shows the gradual crystallization of β anomer and no crystallization of α anomer under 38 %RH. Both anomers achieved complete crystallization after exposing to 53 %HR. The figure on the right shows simultaneous crystallization of both α and β anomers under 53 %RH.