(81e) Use of Supercritical-CO2 Assisted Spray Drying Technology for the Production of Pharmaceutical Powders

The main goal of this work is to explore an alternative particle engineering (PE) technology for the production of pharmaceutical compounds with enhanced properties and improved performance while maintaining a high process throughput and yield. In this work, the Supercritical-CO₂ assisted spray drying (SASD) particle engineering technology was used to produce composite inhalation powders. For that purpose, a systematic Quality by Design (QbD) approach using the design of experiments (DoE) tool, followed by a statistical analysis to predict the powder in-vitro aerodynamic performance were implemented.

Introduction

In what regards to the inhalation field, the delivery of drugs to the lungs is increasing, either to treat local diseases such as asthma, cystic fibrosis, lung cancer, amongst others, or for systemic drug delivery, such as insulin for diabetes. Drug delivery to the lungs presents several advantages such as the rapid onset of drug action and improved bioavailability by avoiding first pass metabolism, which reduces the total drug load required and minimizes the potential for adverse side effects, leading to a more efficient therapy for the patients.

The new strategies of carrier-free inhaled drug delivery are possible due to advances in the particle engineering field, in which Spray-drying (SD) is one of the most well-known and enabling technologies. However, due to the environmental deterioration, the exploration and use of alternative greener technologies should be encouraged. For this reason, the production of composite particles using supercritical fluids, namely, Supercritical-CO₂ Assisted Spray Drying (SASD) was investigated, using supercritical carbon dioxide (scCO₂) as a cosolvent to assist the atomization process, minimizing the use of solvents. scCO₂ was selected due to its mild critical conditions (31.4 ºC, 7.4 MPa): it is inert, safe, non-toxic, recyclable, inexpensive and environmental friendly. The use of scCO₂ as a cosolvent minimizes the use of organic solvents, decreases the drying temperature required for the solvents evaporation, being a more eco and energy-friendly approach, does not required additional gas for the atomization step, which reduces the consumption of gases and potentially reduces the shear stress induced during the atomization step that may cause protein denaturation. Furthermore, the possibility of using lower drying temperatures is particularly suitable for processing labile drugs such as biologics (e.g. proteins). Additionally, it is a highly versatile technology, able to work with water or organic solvents, enabling the handling of both hydrophobic and hydrophilic drugs, while generating powders with enhanced aerosolization properties.

In the SASD PE technology, the feed solution composed of the solute and solvent or solvents mixture, and the scCO₂ feed are independently pumped and mixed inside a heated static mixer to promote saturation of the mixture with scCO₂, by adding scCO₂ in excess. The resulting mixture is atomized inside the drying chamber through a pressure nozzle. The formed droplets are then dried by a hot drying gas stream to evaporate the solvents, forming dried particles. The drying gas used was air. The particles were then collected by a high efficiency cyclone. The main difference between the SASD and SD technology is the atomization step. In the SD technology the atomization step has only one phase: the liquid disperses and forms droplets that are then dried due to the solvent evaporation, forming particles. In the SASD technology, the liquid is dispersed forming the primary droplets; then the scCO₂ inside the primary droplets expands and forms smaller secondary droplets that will form particles upon solvent evaporation.

The main goal of this work was to optimize the SASD technology process parameters for the production of composite particles with enhanced properties and in-vitro aerodynamic performance using the DoE tool under QbD principles. A formulation composed of trehalose and leucine dissolved in a water/ethanol system was used.

Experimental methods

Composite particles of trehalose/leucine were produced by a custom-made SASD apparatus. The feed solution was composed of 2% w/w of trehalose/leucine (C_solids) in an 80:20 weight ratio dissolved in 20% w/w ethanol-in-water.

The DoE performed was a full factorial design (8 points plus 2 central points to assess the reproducibility) and the process parameters investigated were: the static mixer pressure (P_sat: 9.0 – 11.7 MPa), the drying gas inlet temperature (T_in: 85 – 150 ºC) and the liquid feed flowrate (F_feed: 3.5 – 7.5 mL/min). The main goal was to determine the most critical parameters.

The powder properties were characterized in terms of particle morphology by SEM, particle size by laser diffraction, bulk density using a graduated beaker, residual water and ethanol content using Karl-Fischer and gas chromatography respectively, mDSC and XRPD for the solid-state characterization and the in-vitro aerodynamic performance was evaluated using an 8-stage ACI actuated by a Plastiape device at 60 L/min. The powder fine particle fraction (FPF) was measured below 5 µm and relative to the capsule emitted dose (FPF_ED(<5µm)).

The statistical analysis used to quantify the impact of the input parameters (P_sat, T_in, F_feed) on the output parameter (FPF) was performed using SIMCA v13.0.3.0 software from Umetrics.

Results & Discussion

Process yields as high as 70% (batch size of 11 grams) were obtained. Regarding the powders PS, it was observed that the powders produced at a higher T_in and F_feed presented a larger PS than the powders produced at lower temperatures and lower F_Feed. The higher temperature possibly caused particle inflation without breakage, leading to slightly larger particles while the lower F_feed possibly produced smaller droplets because the ratio F_CO₂/F_feed increased, possibly leading to a stronger secondary atomization that formed smaller droplets and then particles. The particle size span of the SASD particles is smaller than the particles produced by SD using a conventional two-fluid nozzle.

Regarding the residual water and ethanol solvent content, it was observed that the higher the drying temperatures (T_in and T_out) and the lower the F_Feed, the lower the residual water and ethanol content in the final powder. In addition, all powders presented a residual EtOH content below the ICH limits (< 5000 ppm). Globally, it is possible to observe that as expected, the powders BD is inversely proportional with the powder T_in. The powders produced at the higher drying temperatures and lower F_feed values presented a lower BD since higher temperatures promote the production of hollow particles which in combination with a low F_feed, leads to the production of particles with lower water and EtOH content, which further contributes to a lower BD. The same trends were observed in previous work conducted using the Spray drying technology where higher T_in and lower F_feed produces smaller particles.

According to the XRPD and DSC data, and similarly to what was observed when spray drying this formulation, amorphous trehalose and crystalline leucine were observed in all powders.

According to the SEM micrographs all powders seem similar, uniform and spherical with the powders spray dried at higher T_in presenting a slightly smoother surface, in agreement to what would be expected and was observed with conventional SD.

The powders were then characterized in terms of aerodynamic performance where FPF_{ED(< 5µm)} values as high as 86% were obtained. The mass median aerodynamic diameter (MMAD) values were also lower than 2.5 µm for all cases. All powders presented a high FPF (76 – 86%), which makes it harder to draw conclusions on the process parameters impact due to the very small variations. Therefore, it would not be possible to make a clear conclusion without applying statistical analysis tools.

The statistical models obtained predicted well the powder properties as well as the powder FPF. The reproducibility trials presented similar FPF values which shows the good process reproducibility. An acceptable model was obtained, being able to predict the powder FPF based on a correlation with the aerodynamic particle size (aPS) ^– determined based on the powder PS, density and shape factor– which presented a R² and Q² of 0.658 and 0.545, respectively. It was observed that the main descriptors that influence aPS and therefore the FPF are the F_feed and T_in where it was observed that the higher T_in and the lower F_Feed the higher the FPF. According to the model, the P_sat did not had a significant impact on the powder aPS and consequently on the FPF.

Conclusions

In the proof-of-concept, small and uniform particles (Dv50~1 µm) were produced which resulted in inhalation powders with FPF values as high as 86% by decreasing the F_feed and increasing the T_in. When comparing to powders produced using the SD technology under analogous conditions, similar solid state properties were observed. The SCF technology presents unique features and several advantages particularly relevant for the production of micro and nano particles for manufacture of small molecules and biopharmaceutical compounds. Further studies, outside the analyzed ranges and concerning other process/formulation parameters should be undertaken to better understand this technology and widen its potential to produce particles suitable for other delivery routes such as oral, injectable, nasal and topical amongst others.