Single-Stream Spray Drying Process to Generate Uniform and Functional Powder Particles

  • Abdul Khaliq Elzhry Elyafi

Student thesis: Doctoral ThesisDoctor of Philosophy


Particle properties, especially size and shape, are considered critical attributes for many pharmaceutical materials as they affect the manufacturability of solid dosage forms and their critical quality attributes such as dose uniformity, dissolution rate and bioavailability. Regulatory guidelines e.g. ICH Q6A highlighted the need for controlling particle properties through setting acceptance criteria for particle size of drug substances. However, generating pharmaceutical ingredients with uniform and adjustable particle properties is faced with several challenges, most importantly a difficulty to control particle crystallisation. Thus, the interest in developing new technologies for engineering particles with controllable size and morphology has increased dramatically in the last two decades. Spray drying is at the forefront of industrial techniques used to produce complex microparticles at the desired scale. Nevertheless, this method generates polydisperse droplets with potential for their coalescence. Therefore, the particles may exhibit variation in size/morphology within the same batch, and semi-dried ones could agglomerate or deposit in the chamber.

This work aims to develop a novel spray drying-based technology for generating monodisperse pharmaceutical particles with controllable attributes (size and shape). This is expected to improve powders’ processability during solid dosage manufacturing and reduce variation in quality attributes of final products. A custom-built lab-scale spray dryer for generating monodisperse particles, referred to as a single-stream spray dryer, is presented. It combines a monodisperse droplet generator (MDG) with a drying chamber and ancillary equipment to design particles with highly uniform size and shape. A stroboscopic imaging system was utilised as a process analytical technology tool to optimise the jet velocity and MDG vibration frequency necessary for generating monodisperse droplets. The performance of the new spray dryer was explored using model ingredients D-Mannitol, Metformin HCl and Felodipine. Monodisperse spray-dried (Mono-SD) powders were fabricated and compared with untreated and conventionally spray-dried (SD) ones. The impact of particle size/shape, powder mono-/polydispersity and excipient dilution on the homogeneity and content uniformity of binary blends containing a low-dose drug was also investigated. Several characterisation techniques were utilised, including Morphologi 4 and laser diffraction to study particle size and shape parameters, microscopy for morphology, shear cell for powder flow testing and differential scanning calorimetry along with x-ray powder diffraction for studying materials’ crystallinity.

The generated Mono-SD particles exhibited spherical shapes with a very narrow size distribution. By contrast, conventional SD particles showed uncontrolled shape and size with agglomerates. As a result, Mono-SD powders showed significantly better bulk powder properties (e.g. flowability and packing density) even with particle sizes less than 50 μm. The repose angle for all Mono-SD powders was less than 16º, whereas it was above 42º for all other untreated/SD powders. This clearly indicates that Mono-SD powders exhibit superior flow compared to untreated/SD powders. Moreover, this high flowability of Mono-SD translated into significantly better blend homogeneity and content uniformity for binary mixtures containing Felodipine at low doses (< 10% w/w) compared to untreated and conventionally SD powders. On the other hand, no significant impact on material compressibility could be observed for Metformin HCl and D-mannitol Mono-SD powders. In fact, conventional SD powder for D-mannitol had significantly better compaction, potentially due to higher bonding generated between polydisperse particles during compression. The findings suggest that the novel single-stream spray dryer has a great promise for creating particles with the desired size and shape. In terms of functionality, the impact of Mono-SD properties on flowability and dose uniformity is overwhelmingly positive, while for compaction polydisperse particles were more useful due to their apparent higher bonding capacity.
Date of AwardSept 2021
Original languageEnglish
SupervisorAli Al-Khattawi (Supervisor) & Afzal-Ur-Rahman Mohammed (Supervisor)


  • spray drying
  • monodisperse particles
  • flowability
  • content uniformity
  • solid dosage forms

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