Mechanical Activation of Secondary Processed Orally Inhaled Active Pharmaceutical Ingredients

  • Roberto Depasquale

Student thesis: Doctoral ThesisPhD


The physicochemical properties and surface chemistry of orally inhaled active pharmaceutical ingredients (API) are critical to the quality attributes of dry powder inhaler (DPI) formulations. The requirement to reduce the particle size distribution of the APIs to a respirable range, largely performed through air-jet micronisation, imparts large amounts of energy to the drug particles, which together with particle fracture and size reduction, it is accompanied by the generation of structural defects and, at the limit, the formation of amorphous regions. This is known as mechanical activation, which may cause instability in the physicochemical properties and interfacial chemistry at the particle surface as it undergoes structural relaxation. During the thermodynamically driven relaxation process, differing drug properties may lead to DPI formulations with unpredictable formulation structure and product functionality. A fundamental understanding of the structural relaxation dynamics is therefore essential in the development and commercialisation of a quality-by-design led inhalation product. This thesis investigated the structural relaxation dynamics of micronised fluticasone propionate (FP), salmeterol xinafoate (SX) and glycopyrrolate bromide (GLY). Physicochemical properties and surface interfacial chemistry, via cohesive-adhesive balance (CAB) measurements, of micronised drug are assessed as a function of environmental stressed laagering over well-defined periods of time and in situ conditioning in hydrofluoroalkane (HFA). The influence of these dynamics upon DPI performance was also examined in both binary (FP, SX, GLY) and tertiary formulations (FP-SX). The results indicated how structural relaxation of hydrophobic and hydrophilic APIs trigger off different stress relaxation pathways with different sensitivities to laagering conditions. These data suggested that the introduction of a post-micronisation conditioning step may expedite structural relaxation of hydrophobic APIs. Whilst the physical properties of hydrophobic APIs are largely unaffected by mechanical activation, surface interfacial chemistry governing inter-particulate forces between API and the lactose carrier is directly affected by environmental conditions of temperature and relative humidity during structural relaxation. The study also showed the potential use of post-micronisation conditioning to tailor the surface chemistry properties of APIs. For hydrophilic APIs, data suggested that post-micronisation conditioning is essential in enabling physical and chemical stability of inhaled formulations. Furthermore, in vitro aerosolisation studies suggested that the aerodynamic particle size distribution and fine particle mass were directly affected by post-micronisation laagering conditions. The importance of generating a well defined, understood and controlled design space throughout product development dictates the need for more robust API processing prior to DPI formulation. This work highlights how a tailored post-micronisation laagering strategy can have a significant effect on physicochemical and interfacial properties as well as product performance of binary and tertiary carrier based DPI formulations.
Date of Award17 Jun 2015
Original languageEnglish
Awarding Institution
  • University of Bath
SupervisorRobert Price (Supervisor)

Cite this