PRELIMINARY STUDY OF INSULIN DRY POWDER FORMULATION: CRITICAL PROCESS PARAMETERS ON SPRAY-FREEZE-DRYING AND CRITICAL MATERIAL ATTRIBUTE OF TREHALOSE AND INULIN AS STABILIZER

Objective: The aim of this study was to obtain recommendations about critical process parameters (CPP) and optimal ratio of trehalose and inulin as critical material attribute (CMA) on insulin dry powder formulation with spray-freeze-drying (SFD) method. Methods: Inulin dry powder was formulated with the SFD method, which consisted of an atomization process and freeze-drying (FD). SFD processes were optimized in order to obtain dry powder and CPP was analyzed. All seven variations of formulas proceeded with physicochemical characterization to obtain the optimal formula. Results: In the early optimization, there was a slight time lag between the atomization process and FD; as a result, some of the powder coagulated and crystallized. Another critical parameter was that the FD process should not be interrupted for at least 50 h of FD. Dry powder proceeded with physicochemical characterization, a formula without inulin showed semicrystalline properties, while six formulas had amorphous properties due to its combination. All formulas had a spherulite shape and rough surface. Five formulas with the combination of trehalose and inulin obtained dry powders with a diameter range of 30-43 μm, moisture content below 3.5% and high encapsulation efficiency (EE). Formula with the ratio of 1:1 (F4) showed optimal properties with moisture content and EE of 2.62% and 99.68%, respectively. Conclusion: This study concluded that there were two critical process parameters in the SFD method. There should be no time lag in SFD process and FD time which should not be interrupted. The optimal ratio for trehalose and inulin was shown by F4 with ratio of 1:1.

Degradation of lactoferrin caused by droplet atomization process via two-fluid nozzle: The detrimental effect of air–water interfaces

ABSTRACTBiological macromolecules, especially therapeutic proteins, are delicate and highly sensitive to degradation from stresses encountered during the manufacture of dosage forms. Thin-film freeze-drying (TFFD) and spray freeze-drying (SFD) are two processes used to convert liquid forms of protein into dry powders. In the production of inhalable dry powders that contain proteins, these potential stressors fall into three categories based on their occurrence during the primary steps of the process: (1) droplet formation (e.g., the mechanism of droplet formation, including spray atomization), (2) freezing, and (3) frozen water removal (e.g., sublimation). This study compares the droplet formation mechanism used in TFFD and SFD by investigating the effects of spraying on the stability of proteins, using lactoferrin as a model. This study considers various perspectives on the degradation (e.g., conformation) of lactoferrin after subjecting the protein solution to the atomization process using a pneumatic two-fluid nozzle (employed in SFD) or a low-shear drop application through the nozzle. The surface activity of lactoferrin was examined to explore the interfacial adsorption tendency, diffusion, and denaturation process. Subsequently, this study also investigates the secondary and tertiary structure of lactoferrin, the quantification of monomers, oligomers, and ultimately, aggregates. The spraying process affected the tertiary structure more negatively than the tightly woven secondary structure, resulting in a 1.5 nm red shift in peak position corresponding to the Tryptophan (Trp) residues. This conformational change can either (a) be reversed at low concentrations via relaxation or (b) proceed to form irreversible aggregates at higher concentrations. Interestingly, when the sample was allowed to progress into micron-sized aggregates, such a dramatic change was not detected using methods such as size-exclusion chromatography, polyacrylamide gel electrophoresis, and dynamic light scattering at 173°. A more complete understanding of the heterogeneous protein sample was achieved only through a combination of 173° and 13° backward and forward scattering, a combination of derived count rate measurements, and micro-flow imaging (MFI). Finally, compared to the low-shear dripping used in the TFFD process, lactoferrin underwent a relatively fast conformational change upon exposure to the high air-water interface of the two-fluid atomization nozzle used in the SFD process as compared to the low shear dripping used in the TFFD process. The interfacial induced denaturation that occurred during spraying was governed primarily by the size of the atomized droplets, regardless of the duration of exposure to air.

An Atomization Model of Air Spraying Using the Volume-of-Fluid Method and Large Eddy Simulation

When painting complex surfaces, such as large-curvature surfaces, poor coating quality is often obtained, which may be caused by lack of an appropriate atomization model, insufficient understanding of atomization mechanisms and laws, and improper painting parameters. This paper presents a numerical model of paint atomization of air spraying using the volume-of-fluid method and large eddy simulation. The interface capture and the turbulent flow were mainly considered in the model: the former was tracked by the volume-of-fluid method and the latter was predicted by the large eddy simulation. After the computational domain being meshed by the staggered-grid method, the governing equations were discretized by the finite volume method and were solved by the SIMPLE (Semi-Implicit Method for Pressure-Linked Equations) Consistent algorithm. The results of numerical simulations show that the characteristics of atomization flow field, such as velocity variation, pressure distribution, and paint volume fraction are in agreement with the regularities of atomization. Moreover, the primary and secondary atomization phenomena can be clearly observed: as soon as the paint issues from the nozzle, the paint flow begins to distort and the paint fragments continuously eject from the main paint flow and then these paint fragments distort and disintegrate into smaller elements. A comparison with the experimental data from the literature proves that the model of the whole atomization process of air spray is effective. The model is suitable for simulating the whole atomization process and easy to obtain initial conditions, which can be applied to set the appropriate painting parameters and study paint atomization mechanisms and laws in depth.

Atomization Control to Improve Soft Actuation Through Vaporization

Soft actuation through droplet evaporation has significantly improved the actuation speed of methods that utilize liquid vaporization. Instead of boiling bulk liquid, this method implements atomization to disperse small droplets into a heater. Due to the large surface area of the droplets, the liquid evaporates much faster even at small temperature changes. However, further analysis is required to maximize the performance of this complex multi-physics method. This study was conducted to provide further insight into the atomizer and how it affects actuation. Numerical simulations were used to inspect the vibration modes and determine how frequency and voltage affect the atomization process. These results were used to experimentally control the atomizer, and the droplet growth on the heater surface was analyzed to study the evaporation process. A cuboid structure was inflated with the actuator to demonstrate its performance. The results show that simply maximizing the atomization rate creates large droplets on the surface of the heater, which slows down the vaporization process. Thus, an optimal atomization rate should be determined for ideal performance.