Effect of a wet granulation manufacturing process on the stability of a pharmaceutical drug product

  • Mark Halus

Student thesis: Doctoral ThesisDoctor of Philosophy

Abstract

This thesis deals with the application of thermal analysis techniques to understand the root cause of low assay results observed during stability testing of a commercial drug product containing ethinyl estradiol and goes on to suggest improvements that could be made to the commercial manufacturing process to mitigate the stability issues. The potential for formation of different forms of ethinyl estradiol was assessed and subsequent stability of each of the forms established over a range of relative humidities at room temperature. The anhydrous crystalline and amorphous forms, along with the readily formed chloroform solvate and the less readily formed ethanol solvate of ethinyl estradiol, were subjected to %RH in the range of 11% to 85%. It was demonstrated that the amorphous form and both chloroform and ethanol solvates would revert back to the anhydrous crystalline form within 7 days at ≥54%RH, however, below this %RH there was significant degradation of the active ingredient in the amorphous state, 6.4%-9.5% (n=3) when stored at 33%RH for 87 weeks. There was 11.5%-13.5% (n=3) degradation of the chloroform solvate under the same conditions compared to 1.4% (n=3) degradation of the ethanol solvate. These observations were unexpected as it was hypothesised that the drug substance would be less stable under the more stressful higher humidity conditions.


The observations that the chloroform solvate form can be converted to the anhydrous form at high %RH or that ethanol as granulating solvent reduces the risk of degradation is important as it offers a route to improve the stability of the commercial drug product. These observations also raise a question over the applicability of the ICH recommended storage conditions. Although drug product stability is routinely tested at 60%RH or higher, as per ICH requirements for countries which span Zone I (temperate) and Zone II (subtropical) conditions, drug products could reasonably be expected to experience lower %RH when stored in real world conditions.

Thesis embargoed until 31 December 2026.
Date of AwardDec 2021
Original languageEnglish
Awarding Institution
  • Queen's University Belfast
SponsorsTEVA NI Ltd. Old Belfast Road, Millbrook, Larne, BT40 2SH
SupervisorVictoria Kett (Supervisor) & Helen McCarthy (Supervisor)

Keywords

  • Thermal analysis
  • HPLC
  • ICH stability
  • solvate
  • amorphous

Cite this

'