Mechanical Relaxation of Process-Induced Structural Disorder of α-Lactose Monohydrate Upon Particle Comminution

  • Harsimran Bansal

Student thesis: Doctoral ThesisPhD


The physical and chemical properties of orally inhaled powders in capsule-based dry powder inhalers (DPI) are crucial in maintaining a stable and functioning product during its shelf-life. The process history of a material has been known to directly influence formulation structure, performance, thermodynamic stability and shelf-life of a DPI product. It is also well-known that size-reduction processes, such as air-jet micronisation, activate an otherwise stable crystalline form of a material due to the high energy attrition the materials are subjected to. Process-induced structural defects upon particle comminution, which appear almost exclusively at the surface of a processed material, inevitably lead to an unstable, activated state. This energetic state will undergo mechanical relaxation post-micronisation. Relaxation is a thermodynamically driven and a time-dependant process where a material is driven to revert to a more stable form. Certain materials, including micronised lactose monohydrate, may succumb to degradation in the presence of a partial water vapour pressure, and can be rendered unusable during this period of relaxation. It is, therefore, crucial to understand the underlying processes dictating relaxation to achieve better control and a quality-led design of an orally inhaled drug product.This study focused on characterising the inherent disorder associated with micronised α-lactose monohydrate, and identifying methods and mechanisms by which material stability can be restored. An array of physical and chemical characterisation techniques were used to assess the material properties of micronised lactose before and upon conditioning using well-defined conditions of relative humidity and liquefied propellants.These studies indicated that air-jet micronisation can introduce profound changes to the distribution of crystal-bound water within micronised lactose monohydrate. The laagering effects of freshly micronised lactose monohydrate under ambient conditions were also investigated, and suggested an apparent but insignificant amount of dissipation of the energy associated with the mechanical activation process.Studies using controlled environmental conditioning to stabilise micronised lactose monohydrate showed no significant changes in the material’s physical properties. However, results showed an unprecedented thermal behaviour in the material. Drastic changes in the distribution of freely-bound water and in the material’s lattice were observed. In another study, a novel technique assessing the degradation of freshly micronised and conditioned lactose was undertaken over a six-month period under stressed stability conditions. A volatile degradation molecule was suppressed upon conditioning, suggesting a more stable form of micronised lactose monohydrate may have formed. A study was also undertaken to understand the effect of intense ball milling for size-reduction of primary crystals of lactose monohydrate. With a lower energy input during comminution, ball milling did not induce similar thermal changes observed for micronised lactose whilst its physical character was comparable.In establishing that freely available water under ambient conditions is a major issue for controlling metastable pharmaceutical powders, investigations into the stability and conditioning of commercially available capsule-based DPI products was commenced using water activity measurements. A novel method developed to assess the influence of water activity and equilibrium relative humidity in the headspace surrounding hermetically sealed capsule-based products, suggested that pre-equilibration appears to play a defining role in the successful shelf-life of capsule-based inhaler products.Finally, a study on the stability of a tiotropium formulation was investigated at elevated temperatures across a wide range of relative humidities with time. Results indicated that a relationship between the formulation and the material properties of the capsule may readily degrade the formulation and severely affect shelf-life and product performance.
Date of Award21 Mar 2018
Original languageEnglish
Awarding Institution
  • University of Bath
SponsorsDFE Pharma
SupervisorRobert Price (Supervisor) & Nikoletta Fotaki (Advisor)


  • Mechanical Relaxation
  • Process Induced Structural Disorder
  • α-Lactose Monohydrate
  • Lactose Monohydrate
  • Particle Comminution
  • Comminution
  • water activity
  • physical properties
  • stability
  • Conditioning
  • Micronised Lactose
  • fine particle fraction
  • micronized
  • Inhalation
  • Cohesive interface
  • material characteristics
  • Characterisation
  • FPF
  • MMAD
  • FPM
  • mass median aerodynamic diameter
  • aerodynamic diameter
  • APSD
  • DSC
  • Degradation
  • Furfural
  • humidity and temperature influence
  • Water absorption
  • Water content
  • CAB
  • cohesive adhesive balance

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