(256f) Continuous Production and Isolation of Directly Compressible Drug Nanoparticles: Using Spray Coating

Introduction

The increasing prevalence of new chemical entities displaying poor solubility is one of the major hurdles faced by the pharmaceutical industry. This leads to a poor concentration gradient, reduced rate of passive diffusion and in vivo failure. Many techniques have been employed for the enhancement of solubility or dissolution rate, such as cocrystal formation [1], salt production [2, 3], lipid-based formulations [4], and the production of API nanoparticles (nano-medicines) [5]. Approximately 80 nano-medicines have been approved by the FDA, highlighting their versatility in overcoming this poor solubility [6]. Reduction of particle size to the nano-range allows for an increased surface area, leading to rapid dissolution, a more pronounced concentration gradient and rapid passive diffusion. Methods of production can be split into two categories: top-down and bottom-up. Top-down methods rely on mechanical attrition to break large bulk particles into nanoparticles, using methods such as high-pressure homogenization [24, 25]. These methods generally require a high energy input. Bottom-up approaches however, are solvent-based approaches which employs various means to precipitate/crystallize APIs. Such methods include antisolvent precipitation, spray-drying, and supercritical drying. The major hurdle regarding nanoparticle production revolves around the isolation of these small particles, which often leads to poor yields.

Verma et. al [15] reported a supercritical CO₂-based method, similar to the supercritical CO₂-assisted spray drying (SASD) technique for nanoparticle production, referred to as CO₂-assisted dynamic bed coating process. This method used micron-sized carrier particles (e.g. MCC), that were charged in the drying chamber at the start of the experiment sitting on the steel mesh. These excipient particles moved due to high momentum of CO₂ gas creating a dynamic bed, allowing for contact with the spray of droplets, thereby facilitating the isolation of drug nanoparticles. All drug nanoparticles showed average size below 500 nm and displayed good rheological properties coupled with an enhancement in dissolution rate of up to 6-fold [15]. However, this reported method operated in batch mode, limiting its applicability at large scales. To address this limitation, the work presented herein seeks to employ celecoxib as a model drug in a new method for the continuous production and isolation of API nanoparticles, coated onto MCC particles. This was be achieved using a multi-nozzle spray dryer with the capacity for 12 nozzles for nanoparticle production. In this study, only 3 nozzles were employed.

Method

The atomization and drying of the API solution (i.e. celecoxib dissolved in methanol) in this process occurred similar to that of the SASD process described elsewhere [7, 8]. The API solution was fed to the inner pipe of a heated coaxial nozzle at a set flow rate, while the CO₂ was fed through the larger outer pipe under a set pressure. The two fluids met in the coaxial nozzle and were atomized together, forming droplets where the solvent was evaporated to produce fine (nano)particles. A solution flow rate of 0.4 ml/min was used for the 10 % loading (10% w/w of drug to excipient feed into drying chamber) runs (run 1, 2 and 3), but as three nozzles were used in this study, this corresponds to a flow rate of 0.13 ml/min per nozzle. For the 20% loading run (run 4), a flow rate of 0.8 ml/min was set, corresponding to 0.26 ml/min per nozzle. Unlike the SASD methods, this process also includes the input of excipient particles from the top of the drying chamber. MCC particles were slowly dropped from the top of the drying chamber. As the MCC descends through the chamber, it meets the atomized streams of API solution, upon which drying and coating occurs. The final coated particles can exit at the bottom of the chamber. A schematic of the equipment used can be seen in figure 1. This highlights the 12 total nozzles on the apparatus, the excipient inlet and product outlet. The temperature of the nozzles was maintained at 50 °C for all experimental runs, whilst solution concentration and amount of MCC were set at 40mg/ml and 36 g respectively.

Particle Size

Particle size was evaluated by means of SEM micrographs, an example of which can be seen in figure 3 for run 1 (10% theoretical loading). While all orientations led to nanoparticle production, orientation 3 displayed the lowest particle size of 263 nm, while orientation 1 displayed the largest particle size of 426 nm. As the nozzles in orientation 3 are all located at the top half of the chamber, it is believed that the droplets had a longer residence time, leading to more complete solvent removal prior to coating onto MCC particles. Unlike this, orientation 1 may have led to more particle/droplet agglomeration leading to this increase in particle size.

Yield

The yields obtained as detailed in table 1, are all above 40%. The best yield was obtained using orientation 2 whilst the worst yield was obtained at orientation 3. Orientation 3 employs nozzles located at the top of the drying chamber. While this may provide more time for the drying of the API solution, it may promote coating of API particles onto MCC particles, in a zone where MCC particles have not descended and dispersed adequately in the drying chamber. Opposing to this, orientation 2 employs nozzles located both in the top half and bottom half of the drying chamber. This may be allowing for more dispersion of the descending MCC particles, leading to an enhanced yield. It is also plausible that the smaller nanoparticles obtained whilst employing orientation 3 coat the MCC particle with reduced efficiency leading to a reduction in yield.

Solid State

X-Ray powder diffraction (PXRD) analysis and differential scanning calorimetry (DSC) was carried out to elucidate the solid-state nature of the precipitated API nanoparticles, coated onto MCC. PXRD data seen in figure 2 displays the diffractogram obtained for MCC, raw celecoxib (form III), and samples obtained from 10 % and 20 % theoretical loading. While the PXRD for the produced samples closely resembles that of MCC, minor crystalline peaks can still be observed and are highlighted with red dots. These peaks accurately correspond to the peaks characteristic of the stable form III for celecoxib, however these peaks are more evident in the 20 % loading sample. This is due to the 3-5% detection limit of the PXRD diffractometer employed (PANalytical Empyrean diffractometer) and as such, the 10% loading samples may have too low a celecoxib content to be accurately detected.

For this reason, DSC was employed to further determine the nature of the coated API nanoparticles, and the obtained data can be seen in figure 3, for MCC, raw celecoxib (form III) and the 10% and 20% loading samples. The melting endotherm for celecoxib is evident and matches closely with the reported melting point of 161 °C [9]. Samples obtained form 10 % and 20 % loading also display a similar melting endotherm, while displaying no obvious exothermic crystallization event, indicating that the produced samples contain crystalline celecoxib representing the form III polymorph. It should also be noted that these melting peaks are shifted to a slightly lower temperature than that of raw celecoxib. This may be attributed to their smaller size and therefore more rapid melting.

Conclusion

The continuous multi-nozzle spray coating process is a novel single step technology which showed to be successful in the production and isolation of nanoparticles of celecoxib, through the simultaneous precipitation and coating of the API i.e. celecoxib) particles on to micron-sized excipient particles (i.e. MCC). Process yields have been achieved in excess of 60 %, with celecoxib particle sizes ranging from 382 to 426 nm.

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