Design of freeze-dried formulations for the enhancement of drug release

Student thesis: Doctoral ThesisDoctor of Philosophy


A commonly used approach for the improvement of dissolution and disintegration is to render a poorly soluble drug into its amorphous or disordered form. However, such amorphous materials are physically unstable and are difficult to formulate into oral dosage forms due to their sensitivity to the physical and thermal processes that are involved in production. The first aim of work presented here was to produce the amorphous form of a drug in-situ within a capsule. The second aim was to develop a predominantly amorphous freeze-dried buccal tablet for the rapid delivery of emergency medicine. Nifedipine and naloxone were used as the test compounds to achieve aims 1 and 2 respectively. Nifedipine and polyvinylpyrrolidone K10 (PVP) were dissolved in tert-butanol at 37 oC to provide a range of drug to polymer ratios. These solutions were dispensed into gelatin capsules, freeze-dried, sealed and packaged in amber vials under nitrogen. The nifedipine content was maintained at 10 mg per capsule, but the PVP concentration was increased from 0 to 90% w/w. Differential scanning calorimetry, infra-red spectroscopy, polarization light microscopy and USP in vitro dissolution were used to optimise and characterise drug-polymer interactions in the freeze-dried formulations. The optimised in-situ freeze-dried capsule formulation (10% w/w nifedipine in PVP) formed a predominantly amorphous and porous formulation, with 3 months shelf life at 40 oC, stabilised by drug-polymer hydrogen bond intermolecular interactions. Drug released in vitro dissolution by optimized formulation reached 80% in < 6 min, approximately half the time required by the marketed nifedipine formulation. Excipients and naloxone HCl were dissolved in aqueous solution and dispensed into aluminium blisters to be freeze-dried. The optimised tablet composition (mannitol 24% w/v, gelatin 65% w/v, sodium bicarbonate 11% w/v and naloxone 800 μg) formed stable predominantly amorphous tablets. Sodium bicarbonate was found to be essential in preventing mannitol from recrystallizing in freeze concentrates, while high gelatin to mannitol ratio ensured the stability of amorphous mannitol during and after freeze-drying. A novel disintegration assay was developed to represent conditions in the buccal cavity: i.e. temperature 33-37 oC, dissolution volumes (0.1-0.7mL), mucin containing disintegration medium. The amorphous tablet has shown to disintegrate in less than 10 s. The disintegration assay was discriminatory for quality control purposes and has potential for future development as an assay to predict in vivo performance. In conclusion, rapidly dissolving tablets have been developed which are suitable for proof-of-concept clinical trial in humans to determine the pharmacokinetics of naloxone delivered via the buccal route.
Date of Award2016
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorPaul Royall (Supervisor) & Sukhi Bansal (Supervisor)

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