Impact of excipient choice on the aerodynamic performance of inhalable spray-freeze-dried powders.

Spray-freeze-drying (SFD) is a process in which a solution is dispersed into a freezing medium and dried by sublimation, resulting in lyophilized powders with spherical particles. This study aims at screening and evaluating the impact of the excipient choice and spray solution characteristics in SFD on the physico-chemical characteristics of lyospheres and rate their suitability for producing pulmonary applicable powders using a novel SFD method. A monodisperse droplet-stream was injected into a vortex of cold gas for the production of inhalable, uniform spherical lyophilisates with a narrow particle size distribution. Model solutions containing graded contents (0.3%, 1.0%, and 3.0% w/v) of common bulk-forming excipients like mannitol, lactose, poylvinylpyrrolidone (PVP), maltodextrin or hydroyxpropyl methylcellulose (HPMC) and their blends were dispersed using a single 20 µm pinhole diaphragm. Powders were analyzed regarding their geometric particle size, apparent density, mechanical stability and aerodynamic performance. The diameter of the frozen droplets partially correlated with the Ohnesorge number of the spray solutions. The lyosphere powders had median geometric particle diameters ranging from 20 µm to 81 µm. Some powders showed signs of particle shrinkage during the drying step and diameters were reduced down to 30% of their initial size. The apparent particle densities ranged from 0.009 g/cm3 to 0.087 g/cm3. The mechanical stability of the lyospheres depended on the constituents and concentration of the initial spray solution. Mannitol/maltodextrin formulations yielded large porous particles with promising performance in the Next-Generation-Impactor, emitted fractions between 92 and 98% (w/w) and fine-particle-fractions of over 55% (w/w). According to our first steps towards formulations for free-flowing inhalable spray freeze-dried powders the impact of excipient choice on the SFD process is significant and based on the current findings we consider mannitol or mannitol/maltodextrin as best performing formulations.

Jet-vortex spray freeze drying for the production of inhalable lyophilisate powders.

Spray-freeze-dried powders were suggested for nasal, epidermal (needle-free injection) or pulmonary application of proteins, peptides or nucleic acids. In spray-freeze-drying processes an aqueous solution is atomized into a refrigerant medium and subsequently dried by sublimation. Droplet-stream generators produce a fast stream of monodisperse droplets, where droplets are subject to collisions and therefore the initial monodispersity is lost and droplets increase in diameter, which reduces their suitability for pulmonary application. In jet-vortex-freezing, a droplet-stream is injected into a vortex of cold process gas to prevent droplet collisions. Both the injection position of the droplet-stream and the velocity of the cold gas vortex have an impact on the size distributions of the resulting powders. A model solution containing mannitol (1.5%m/V) and maltodextrin (1.5%m/V) was sprayed at 5 droplet-stream positions at distances between 1mm and 30mm from the gas jet nozzle and 5 gas velocities (0.8-6.8m/s) at a process temperature of -100°C. Mean geometric diameters of the highly porous particles (bulk density: 0.012±0.007g/cm3) ranged between 55±4 and 98±4µm. Evaluation of the aerodynamic properties by Next-Generation-Impactor (NGI) analysis showed that all powders had high emitted doses (98±1%) and fine-particle fractions ranged between 4±1% and 21±2%. It was shown that jet-vortex freezing is a suitable method for the reproducible production of lyophilized powders with excellent dispersibility in air, which has a high potential for nasal and pulmonary drug delivery.

Aerodynamic Droplet Stream Expansion for the Production of Spray Freeze-Dried Powders.

In spray freeze-srying (SFD), a solution is sprayed into a refrigerant medium, frozen, and subsequently sublimation dried, which allows the production of flowable lyophilized powders. SFD allows commonly freeze-dried active pharmaceutical ingredients (e.g., proteins and peptides) to be delivered using new applications such as needle-free injection and nasal or pulmonary drug delivery. In this study, a droplet stream was injected into a vortex of cold gas in order to reduce the risk of droplet collisions and therefore droplet growth before congelation, which adversely affects the particle size distribution. Droplets with initial diameters of about 40-50 µm were frozen quickly in a swirl tube at temperatures around -75°C and volumetric gas flow rates between 17 and 34 L/min. Preliminary studies that were focused on the evaluation of spray cone footprints were performed prior to SFD. A 23 factorial design with a model solution of mannitol (1.5% m/V) and maltodextrin (1.5% m/V) was used to create flowable, low density (0.01-0.03 g/cm3) spherical lyophilisate powders. Mean particle diameter sizes of the highly porous particles ranged between 49.8 ± 6.6 and 88.3 ± 5.5 µm. Under optimal conditions, the mean particle size was reduced from 160 to 50 µm (decrease of volume by 96%) compared to non-expanded streams, whereas the SPAN value did not change significantly. This method is suitable for the production of lyophilized powders with small particle sizes and narrow particle size distributions, which is highly interesting for needle-free injection or nasal delivery of proteins and peptides.

Collisions and coalescence in droplet streams for the production of freeze-dried powders.

Streams of mono-disperse micro-droplets with diameters ranging from about 20 µm to 100 µm were produced from diluted aqueous solutions containing carbohydrates and proteins using a pinhole type piezoelectric generator with either a 20 µm or a 50 µm single-orifice diaphragm. Image sequences indicating droplet size, velocity, inter-droplet spacing at various distances from the nozzles as well as collision events and coalescence were recorded using a high-speed camera and analysed quantitatively. The size-dependent gradual deceleration of the droplets is superimposed by small scale random movements, which equally affect both large and small droplets and lead to early contacts and coalescence. The loss of mono-dispersity can be reduced by quick cooling since both the nucleation rate and the freezing rate of micro-droplets are extremely dependent upon the temperature of their gaseous environment.

Pharmaceutical spray freeze drying.

Pharmaceutical spray-freeze drying (SFD) includes a heterogeneous set of technologies with primary applications in apparent solubility enhancement, pulmonary drug delivery, intradermal ballistic administration and delivery of vaccines to the nasal mucosa. The methods comprise of three steps: droplet generation, freezing and sublimation drying, which can be matched to the requirements given by the dosage form and route of administration. The objectives, various methods and physicochemical and pharmacological outcomes have been reviewed with a scope including related fields of science and technology.