Optimization of supercritical CO2-assisted spray drying technology for the production of inhalable composite particles using quality-by-design principles
Graphical abstract
Introduction
Although oral administration still constitutes the main delivery route for pharmaceutical drugs, the inhalation route has become more interesting and attractive due to the increased number of people suffering from respiratory diseases [1,2]. The local delivery of a drug or combination of drugs to the lungs is desirable either to treat local diseases such as COPD and asthma [3,4] or other diseases such as diabetes or Parkinson [4] using the pulmonary route for systemic drug delivery. Pulmonary drug delivery has become more attractive due to the unique features of the lungs, presenting several advantages when comparing to the oral administration route [[3], [4], [5]]. For a higher deposition in the deep lung, the particles size should be between ∼0.5 to 5 μm [6]. The aerodynamic particle size can be estimated using Eq. (1) where the particle size, shape and density play an important role. In the current work, composite particles were produced for dry powder inhaler actuation. This formulation strategy comprises a single solid phase which presents several unique advantages (better physical/chemical stability amongst other factors [3,7,8]) and challenges (flowability and aerosolization of particles [3]). Despite the limited number of FDA approved excipients for inhalation [5], a promising trehalose and leucine system was selected. Trehalose is a non-reducing sugar with a high glass transition temperature (Tg) value ∼120 °C [[9], [10], [11], [12], [13]], and therefore it is stable and suitable to both incorporate small molecules as well as peptides and proteins. On the other side, leucine is a known amino acid which confers improved aerodynamic performance since it tends to form a crystalline hydrophobic shell at the particle surface when spray dried which minimizes the particles cohesion [14,15].
In the present times where the environmental concerns are a hot topic [16]. supercritical fluids (SCF) are being presented as an alternative greener technology to conventional processes with numerous advantages [17,18]. Carbon Dioxide Assisted Nebulization with a Bubble Dryer® (CAN-BD) and Supercritical Fluid-Assisted Atomization (SAA) were initially developed to improve the atomization process [19]. These technologies present a clear advantage relatively to other SCF techniques because of their versatility in using water or organic solvents as solvent, enabling the processing of hydrophilic and lipophilic compounds [16,19,20]. In the current work, the Supercritical CO2-Assisted Spray Drying (SASD) technology [17] is being used where the SCF assists the atomization step [16,19], enabling a reduction in the solvents used while still obtaining small particle sizes, decreasing the drying temperature required to evaporate the solvents, making this technology more energy-friendly and more suitable for thermosensitive molecules such as proteins and peptides.
With respect to its applicability to pulmonary delivery applications, an intense research was carried out by Reverchon and co-workers [[21], [22], [23], [24]] as well as other research groups that followed [17,25,26]. Zhu and co-workers [26,27], proposed a supercritical fluid assisted atomization method that incorporates a hydrodynamic cavitation mixer that promoted mass transfer inside the saturator between the scCO2 and the liquid solution. This resulted in the production of smaller particles with a higher homogeneity; in addition, it is suitable for the production of proteins in aqueous solutions [[26], [27], [28], [29]]. In 2011, Adami et al. [20] added a vacuum system to the apparatus to promote a boiling point depression and decrease the operating temperatures. Problems associated with coalescence, degradation and denaturation were also removed [30] prompting other groups to explore this approach to preventing protein and peptides denaturation [31]. As can be observed in Fig. 1, the SASD apparatus is defined by a wide range of process parameters. Depending on the final target product profile, the process and formulation parameters can be manipulated, achieving a fine control over the final product properties such as particle size distribution (PSD), bulk density, morphology, residual water and solvents content. Some of the process parameters to take in consideration are: the feed flowrate, the scCO2 flowrate and temperature; the saturator/static mixer temperature and pressure, length and internal structure (necessary to promote a good mixing between the scCO2 and the liquid solution); the pressure nozzle type (channel diameter); the drying temperatures, namely the inlet temperature and outlet/precipitator temperature; the drying gas flowrate and, in case of operating in a closed cycle, the condenser temperature. The formulation parameters to take in consideration regarding the SASD process are the feed solution composition (API, excipient(s), solvent(s)), the solids concentration and the solvents mixture.
In this SASD process, a single feed solution 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 (phase equilibrium of the mixture in the static mixer is complex and has a significant impact in the particle [19]). The scCO2 used for the SASD technique has the main function of assisting the atomization process. It is hypothesized that the atomization process consists in two steps. In the first step, the saturator mixture (Feed + scCO2) exits the pressure nozzle/injector that disperses the mixture into the drying chamber/precipitator, where, due to the turbulence, primary droplets are formed – first atomization step. The secondary atomization step occurs due to the CO2 expansion from the primary droplets, breaking them and forming smaller secondary droplets. This phenomenon enables the production of small particles between 0.1 and 3 μm [20]. Therefore, the atomization stage in SASD technology comprises two steps: a 1st and 2nd atomization [22,32]. In addition, to increase the complexity of the atomization process, the Joule-Thomson effect that occurs due to the rapid expansion of CO2 gas also takes place leading to a local expansion cooling effect [33,34]. Afterwards, the particle formation occurs by solvent(s) evaporation from the droplets due to the intimate contact with the hot drying gas stream. The mechanisms of droplet drying kinetics are well known and described elsewhere [35,36]. Additionally, the powder collection may occur using a cyclone or filter bag sleeves (herein, a high efficiency cyclone was used as the particle collection system).
The main goal of this work is to assess if the Supercritical CO2-Assisted Spray Drying (SASD) technology is suitable for the production of inhalable composite particles with appropriate properties and in-vitro aerodynamic performance while maintaining a high process throughput and yield when comparing to other standard particle engineering technologies such as spray drying (SD). 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 fine particle fraction (FPF) were implemented using trehalose/leucine dissolved in a water/ethanol system as the formulation system and by manipulating the saturator pressure, the inlet drying gas temperature and the feed solution flowrate.
Section snippets
Materials
Trehalose dihydrate (Tre) and L-Leucine (Leu) were purchased from Merck KGaA (Darmstadt, Germany) and ethanol (EtOH) 96% (v/v) from PanReac (Barcelona, Spain). Deionized water was prepared by reverse osmosis (MilliQ, Millipore, Molsheim, France). All compounds were used as received. Industrial carbon dioxide (purity >99.93%) from Air Liquide was used.
Formulation and design of experiments
The schematic representation of the SASD apparatus used in these experiments is presented in Fig. 1. The formulation was fixed for all trials: it
Results and discussion
A DoE approach using a full-factorial design as represented in Fig. 2 was used in order to assess the impact of the static mixer pressure (Psat), inlet drying gas temperature (Tin) and feed flowrate (Ffeed) on the powder properties and performance. The SASD apparatus schematically presented in Fig. 1 was used for this study. The powders produced were characterized in terms of morphology, physicochemical properties and in-vitro aerodynamic performance. A statistical data analysis was performed
Conclusions
The SASD technology enabled the successful production of inhalation powders with process yield up to 70% and FPF values as high as 86% being therefore a competitive technology for the production of inhalable particles. The produced powders presented amorphous trehalose and crystalline leucine as expected. It was observed that the powder properties were well predicted by the process parameters through statistical models. Psat had no impact in any of the analyzed powder attributes within the
Acknowledgments
Ana Aguiar-Ricardo, Teresa Casimiro and Cláudia Moura acknowledge the Associate Laboratory for Green Chemistry LAQV-REQUIMTE which is financed by national funds from FCT/MCTES (UID/QUI/50006/2013) and co-financed by the ERDF under the PT2020 Partnership Agreement (POCI-01-0145-FEDER - 007265), IF Investigator position IF/00915/2014 (TC) and the Doctoral grant BDE/51908/2012 financed by Fundação para a Ciência e Tecnologia (FCT) and Hovione Farmaciencia SA.
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