Spray-freeze-drying in the manufacture of pharmaceuticals

Spray-freeze-drying in the manufacture of pharmaceuticals

Abstract

Over the last decade, the development of new drug delivery methods and devices for dry powder inhalation1, needle-free intradermal powder injection2 or sustained parenteral drug delivery3 has led to an increasing demand for powder formulations incorporating an active pharmaceutical ingredient (API)4,5.

In contrast to the production and handling of powders for oral dosage forms, methods to prepare stable biopharmaceutical powders are limited due to the sensitivity of peptides and proteins to powder processing conditions4,6. Furthermore, bulk properties such as size distribution or density of the final particles are different depending on the application4,5,7. Particles for dry powder inhalation, for example, should have particles of less than 5 µm in diameter and a narrow size distribution5, whereas particles for needle-free ballistic injection must be 30-60µm with a density greater than 0.7 g/ml7 for a successful intradermal delivery. One of the most commonly used methods of drying protein formulations is freeze-drying8-11 but, because it does not involve droplet formulation, the final dry cake can only be reduced to particles by subsequent mechanical milling or grinding4. Some reported disadvantages associated with this method of powder manufacturing include the following:

Production of particles with diameters above 1 mm
Broad particle size distributions
Changes of solid state and degradation of the peptide or protein due to heat generation during inter-particle collision12,13

Protein Spray-Freeze Drying. Effect of Atomization Conditions on Particle Size and Stability

Protein Spray-Freeze Drying. Effect of Atomization Conditions on Particle Size and Stability

Henry R CostantinoLaleh FirouzabadianKen HogelandChichih WuChris BeganskiKaren G CarrasquilloMelissa CórdovaKai GriebenowStephen E ZaleMark A Tracy

Abstract

Purpose. To investigate the effect of atomization conditions on particle size and stability of spray-freeze dried protein.

Methods. Atomization variables were explored for excipient-free (no zinc added) and zinc-complexed bovine serum albumin (BSA). Particle size was measured by laser diffraction light scattering following sonication in organic solvent containing poly(lactide-co-glycolide) (PLG). Powder surface area was determined from the N2 vapor sorption isotherm. Size-exclusion chromatography (SEC) was used to assess decrease in percent protein monomer. Fourier-transform infrared (FTIR) spectroscopy was employed to estimate protein secondary structure. PLG microspheres were made using a non-aqueous, cryogenic process and release of spray-freeze dried BSA was assessed in vitro.

Results. The most significant atomization parameter affecting particle size was the mass flow ratio (mass of atomization N2 relative to that for liquid feed). Particle size was inversely related to specific surface area and the amount of protein aggregates formed. Zinc-complexation reduced the specific surface area and stabilized the protein against aggregation. FTIR data indicated perturbations in secondary structure upon spray-freeze drying for both excipient-free and zinc-complexed protein.

Conclusions. Upon sonication, spray-freeze dried protein powders exhibited friability, or susceptibility towards disintegration. For excipient-free protein, conditions where the mass flow ratio was > ∼0.3 yielded sub-micron powders with relatively large specific surface areas. Reduced particle size was also linked to a decrease in the percentage of protein monomer upon drying. This effect was ameliorated by zinc-complexation, via a mechanism involving reduction in specific surface area of the powder rather than stabilization of secondary structure. Reduction of protein particle size was beneficial in reducing the initial release (burst) of the protein encapsulated in PLG microspheres.

Keywords

particle size, PLG microspheres, protein delivery, spray-freeze drying, stability

Mechanical and tribological properties of alumina-MWCNTs composites sintered by rapid hot-pressing

Mechanical and tribological properties of alumina-MWCNTs composites sintered by rapid hot-pressing

Ondrej HanzelFrantišek Lofaj, Jaroslav Sedláček, Margita Kabátová, Monika Tatarková, Pavol Šajgalík

Abstract

Alumina – MWCNTs composites were prepared using a novel approach. This process comprises functionalization of MWCNTs and stabilization of alumina-MWCNTs dispersion with subsequent freezing, which resulted in formation of granulated powders with homogeneous distribution of MWCNTs. The granulated powders were sintered by rapid hot pressing (RHP) at 1550 °C. Relative densities, microstructural analysis, tribological properties, fracture toughness and bending strength of prepared composites were investigated to reveal the effect of MWCNTs. Compared to pure alumina, bending strength and fracture toughness of dense alumina-5 vol.% MWCNTs composites decreased about 37% and 18%, respectively. At higher MWCNT contents, strength remained almost constant and fracture toughness slightly increased. Thus, the positive effect of CNTs on fracture toughness was demonstrated despite their counteracting effect on the refinement of the microstructure.

Keywords

Al2O3 – MWCNT compositesRapid hot pressingTribological propertiesMechanical properties