The influence of crystallisation on the mechanical and interfacial properties of active pharmaceutical ingredients

  • Harshal Kubavat

Student thesis: Doctoral ThesisPhD


Crystallisation of organic molecules is a fundamental process routinely used for
purification and isolation of active pharmaceutical ingredients (APIs). In the
formulation of traditional dry powder inhaler (DPI) products, harvested primary
crystalline APIs are secondarily processed and subsequently blended with
excipients to form an ordered mixture. In DPI formulations containing drug
particles and coarse carrier material, the delicate balance of cohesive and
adhesive forces between the drug(s) and carrier enable delivery of respirable
APIs to the targeted regions of the lungs. The destructive and relative
uncontrolled nature of secondary-processing techniques such as milling, leads
to the generation of respirable formulations of varying performance, resulting in
varying clinical efficacy. The relationship between the primary crystallisation of
APIs and the physical, chemical, mechanical properties of the primary crystals
and the relationship to the secondary processing of these materials remain
poorly understood. This body of work aimed to address the paucity of data
within this area, within the context of DPI formulations.

A nanoindentation approach using atomic force microscopy (AFM) developed to
determine the elastic modulus of crystalline pharmaceutical samples provided
the Young’s modulus of a range of pharmaceutical materials. Differences were
observed indicating lactose monohydrate to have the highest stiffness (high
Young’s modulus) and formoterol fumerate dihydrate having the lowest of the
materials tested (0.93 GPa). Utilising AFM cohesive-adhesive force
measurements against a reference Highly Ordered Pyrolytic Graphite (HOPG)
substrate, fluticasone propionate was seen to have the greatest cohesive
tendency of 1.13 times greater to itself over HOPG. In contrast, budesonide had
the most adhesive tendency towards HOPG, with a cohesive-adhesive balance
(CAB) value of 0.65, indicating that the differences in DPI performance of these
materials may be as a result of differences in their interfacial properties which
could be a influenced by prior processing history.

Crystallisation of fluticasone propionate (FP) was conducted using four different
solvent/anti-solvent combinations to investigate the influence of different endsolvents on the Young’s modulus of the resultant crystals, their micronisation behaviour and in vitro performance in carrier based DPI formulations. The Young’s modulus of FP crystals produced varied significantly and these differences were reflected in the number of passes required in the microniser to reduce the particle size of the primary crystals to less than 5 µm. Furthermore, the resultant micronised materials were determined to have different cohesive-adhesive balance values, supporting differences in their respective DPI formulation performance attributes, both in binary formulation and in combination with a second drug, salmeterol xinafoate.

The impact of changes in crystal habit on the mechanical properties of
budesonide crystals was investigated alongside the resultant effect on
interactive forces of the micronised material and the performance in a DPI
formulation. The Young’s modulus determined by AFM nanoindentation on the
{002} face of each habit confirmed a Young’s modulus four times greater for
one of the habits and supported the particle size data of the resultant
micronised materials from each primary crystal samples. Cohesive-adhesive
balance measurements of the micronised budesonide samples with respect to
lactose monohydrate supported in vitro aerosolisation performance studies,
whereby the fine particle dose and fine particle fraction of the emitted dose of
the sample with lower adhesive tendency towards the lactose carrier particle
was greater.

The relative mechanical and processing differences between anhydrous and
monohydrate forms of ipratropium bromide (IB) was evaluated using
supercritical fluid technology and temperature drop crystallisation techniques,
respectively. The aerosolisation efficiency of these materials from DPI
formulations determined the effect of crystal form on the functionality of the
two samples. Repeated force-distance measurements revealed no significant
differences between the anhydrous and monohydrate form of IB and revealed
both forms to have an average elastic modulus of approximately 4 GPa. No
differences were seen in the secondary processing of these materials relating
the milling behaviour, interfacial properties or aerosolisation performance in
vitro, demonstrating the suitability of supercritical fluid technology in
producing an anhydrous form of ipratropium bromide for inclusion in a carrier based DPI formulation.
Date of Award1 Jun 2011
Original languageEnglish
Awarding Institution
  • University of Bath
SupervisorRobert Price (Supervisor)


  • nanoindentation micronisation
  • Young's modulus dry powder inhaler
  • crystallization

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