Scott V. Jermain

Capsule-based dry powder inhalers (cDPIs) are widely utilized in the delivery of pharmaceutical powders to the lungs. In these systems, the fundamental nature of the interactions between the drug/formulation powder, the capsules, the inhaler device, and the patient must be fully elucidated in order to develop robust manufacturing procedures and provide reproducible lung deposition of the drug payload. Though many commercially available DPIs utilize a capsule-based dose metering system, an in-depth analysis of the critical factors associated with the use of the capsule component has not yet been performed. This review is intended to provide information on critical factors to be considered for the application of a quality by design (QbD) approach for cDPI development. The quality target product profile (QTPP) defines the critical quality attributes (CQAs) which need to be understood to define the critical material attributes (CMA) and critical process parameters (CPP) for cDPI development as well as manufacturing and control.

The aim of this study was to evaluate the benefits of a ternary amorphous solid dispersion (ASD) that was designed as an immediate-release tablet with a high drug load (e.g., 40% w/w) to produce heightened maintenance of drug supersaturation during dissolution testing, which will be henceforth referred to as the “maintenance ability”. Ternary ASD granules were produced by hot melt extrusion (HME) and were comprised of itraconazole (ITZ) 50%, hypromellose (HPMC) 20%, and mesoporous silica (XDP) 30%, where amorphous ITZ incorporated into HPMC was efficiently absorbed in XDP pores. The ternary ASD granules containing a high-viscosity HPMC (AF4M) produced a significantly heightened maintenance ability of drug supersaturation in neutral pH dissolution media in which crystalline ITZ solubility is below 1 μg/mL. The final tablet formulation contained 80% w/w of the ASD granules (40% w/w ITZ), had an acceptable size, and exhibited both sufficient tablet hardness and disintegration. The dissolution behavior of the ternary ASD tablet exhibited a supersaturation maintenance ability similar to that of the ASD granules. Under neutral conditions, the ternary ASD tablet showed immediate and higher ITZ release compared with the binary ASD tablets, and this phenomenon could be explained by the difference in ITZ/AF4M particle size in the tablet. In high-resolution scanning electron microscopy (SEM), it was observed that ITZ and AF4M in the ternary formulation could easily form nano-sized particles (<1 μm) during the absorption process into/onto XDP pores prepared by HME, which contributed to the immediate ITZ release from the ternary ASD tablet under neutral pH conditions. Therefore, the ternary ASD containing high-viscosity HPMC and mesoporous silica prepared by HME made it possible to design a high ASD content, small-size tablet with an ideal dissolution profile in biorelevant media, and we expect that this technology can be applied for continuous HME ASD manufacturing.

Oral delivery of poorly water-soluble, weakly basic drugs may be problematic based on the drugs’ intrinsic properties. Many drugs in this subset have overcome barriers to delivery following successful formulation as amorphous solid dispersions (ASDs). To process drugs as ASDs, multiple commercially relevant technologies have been developed and become well understood. However, ASD-producing technologies like spray drying and KinetiSol produce ASDs with vastly differing particle characteristics. Ultimately, the objective of this study was to assess whether processing an ASD of identical composition utilizing two different ASD-producing technologies (KinetiSol and spray drying) may impact the oral bioavailability of a weakly basic drug. For this study, we selected a weakly basic drug (Boehringer Ingelheim research compound 639667, BI 667) and processed it with an anionic polymer (hypromellose acetate succinate MMP grade (HPMCAS-MMP)) to evaluate whether the processing technology could modulate drug release in acidic and neutral media. Multiple characterization techniques (specific surface area (SSA), particle size distribution (PSD), scanning electron microscopy (SEM)) were utilized to evaluate the surface characteristics and differences in particles produced by KinetiSol and spray drying. Molecular interactions and drug–polymer miscibility of the processed particles were assessed using Fourier transform infrared spectroscopy and solid-state nuclear magnetic resonance, respectively. In vitro nonsink, pH-shift dissolution in biorelevant media and dissolution/permeation studies were conducted to better understand the release of BI 667 based on processing technology and particle size distribution. Finally, an in vivo male Beagle dog study was conducted to assess the impact of processing technology on oral bioavailability. In this study, we demonstrate that particles produced by KinetiSol have enhanced oral bioavailability compared with spray-dried particles when delivering a weakly basic drug processed with an anionic polymer. The findings of this study demonstrate that by utilizing KinetiSol, drug release may be controlled such that supersaturation in acidic media is inhibited and supersaturation of the drug is designed to occur in neutral media, ultimately enhancing oral bioavailability.

KinetiSol^® is a high-shear, fusion-based technology capable of producing stable amorphous solid dispersions (ASDs) without the assistance of solvent. KinetiSol^® has proven successful with multiple challenging BCS class II and IV drugs, where drug properties like thermal instability or lack of appreciable solubility in volatile solvents make hot melt extrusion or spray drying unfeasible. However, there is a necessity to characterize the ASDs like those made by the KinetiSol^® process, in order to better understand whether KinetiSol^® is capable of homogeneously dispersing drug throughout a carrier in a short (®-processed samples. Powder blend homogeneity and content uniformity were evaluated, and all samples demonstrated a meloxicam concentration % relative standard deviation of ≤2.0%. SEM/EDS was utilized to map elemental distribution of the processed samples, which confirmed KinetiSol^®-processed materials were homogeneous at a 25 µm² area. Utilizing Raman spectroscopy, we were able to verify the amorphous content of the processed samples. Finally, we utilized ssNMR ¹H spin-lattice relaxation measurement to evaluate the molecular miscibility of meloxicam with the polymer at 1% w/w drug load, for the first time, and determined the processed sample was highly miscible at ∼200 nm scale. In conclusion, we determined the KinetiSol^® process is capable of producing ASDs that are homogeneously and molecularly well-dispersed drug-in-polymer at drug concentrations as low as 1% w/w.