On the Feasibility of Rugose Lipid Microparticles in Pressurized Metered Dose Inhalers with Established and New Propellants.

Pressurized metered dose inhalers (pMDIs) require optimized formulations to provide stable, consistent lung delivery. This study investigates the feasibility of novel rugose lipid particles (RLPs) as potential drug carriers in pMDI formulations. The physical stability of RLPs was assessed in three different propellants: the established HFA-134a and HFA-227ea and the new low global-warming-potential (GWP) propellant HFO-1234ze. A feedstock containing DSPC and calcium chloride was prepared without pore forming agent to spray dry two RLP batches at inlet temperatures of 55 °C (RLP55) and 75 °C (RLP75). RLPs performance in pMDI formulations was compared to two reference samples that exhibit significantly different performance when suspended in propellants: well-established engineered porous particles and particles containing 80% trehalose and 20% leucine (80T20L). An accelerated stability study at 40 °C and relative humidity of 7% ± 5% was conducted over 3 months. At different time points, a shadowgraphic imaging technique was used to evaluate the colloidal stability of particles in pMDIs. Field emission electron microscopy with energy dispersive X-ray spectroscopy was used to evaluate the morphology and elemental composition of particles extracted from the pMDIs. After 2 weeks, all 80T20L formulations rapidly aggregated upon agitation and exhibited significantly inferior colloidal stability compared to the other samples. In comparison, both the RLP55 and RLP75 formulations, regardless of the propellant used, retained their rugose structure and demonstrated excellent suspension stability comparable with the engineered porous particles. The studied RLPs demonstrate great potential for use in pMDI formulations with HFA propellants and the next-generation low-GWP propellant HFO-1234ze.

Particle Engineering via Supramolecular Assembly of Macroscopic Hydrophobic Building Blocks.

Tailoring the hydrophobicity of supramolecular assembly building blocks enables the fabrication of well-defined functional materials. However, the selection of building blocks used in the assembly of metal-phenolic networks (MPNs), an emerging supramolecular assembly platform for particle engineering, has been essentially limited to hydrophilic molecules. Herein, we synthesized and applied biscatechol-functionalized hydrophobic polymers (poly(methyl acrylate) (PMA) and poly(butyl acrylate) (PBA)) as building blocks to engineer MPN particle systems (particles and capsules). Our method allowed control over the shell thickness (e.g., between 10 and 21 nm), stiffness (e.g., from 10 to 126 mN m-1 ), and permeability (e.g., 28-72 % capsules were permeable to 500 kDa fluorescein isothiocyanate-dextran) of the MPN capsules by selection of the hydrophobic polymer building blocks (PMA or PBA) and by controlling the polymer concentration in the MPN assembly solution (0.25-2.0 mM) without additional/engineered assembly processes. Molecular dynamics simulations provided insights into the structural states of the hydrophobic building blocks during assembly and mechanism of film formation. Furthermore, the hydrophobic MPNs facilitated the preparation of fluorescent-labeled and bioactive capsules through postfunctionalization and also particle-cell association engineering by controlling the hydrophobicity of the building blocks. Engineering MPN particle systems via building block hydrophobicity is expected to expand their use.

Spray Freeze Drying of Biologics: A Review and Applications for Inhalation Delivery.

Biopharmaceuticals have established an indisputable presence in the pharmaceutical pipeline, enabling highly specific new therapies. However, manufacturing, isolating, and delivering these highly complex molecules to patients present multiple challenges, including the short shelf-life of biologically derived products. Administration of biopharmaceuticals through inhalation has been gaining attention as an alternative to overcome the burdens associated with intravenous administration. Although most of the inhaled biopharmaceuticals in clinical trials are being administered through nebulization, dry powder inhalers (DPIs) are considered a viable alternative to liquid solutions due to enhanced stability. While freeze drying (FD) and spray drying (SD) are currently seen as the most viable solutions for drying biopharmaceuticals, spray freeze drying (SFD) has recently started gaining attention as an alternative to these technologies as it enables unique powder properties which favor this family of drug products. The present review focus on the application of SFD to produce dry powders of biopharmaceuticals, with special focus on inhalation delivery. Thus, it provides an overview of the critical quality attributes (CQAs) of these dry powders. Then, a detailed explanation of the SFD fundamental principles as well as the different existing variants is presented, together with a discussion regarding the opportunities and challenges of SFD as an enabling technology for inhalation-based biopharmaceuticals. Finally, a review of the main formulation strategies and their impact on the stability and performance of inhalable biopharmaceuticals produced via SDF is performed. Overall, this review presents a comprehensive assessment of the current and future applications of SFD in biopharmaceuticals for inhalation delivery.

Development of a Workflow to Engineer Tailored Microparticles Via Inkjet Printing.

PURPOSE: New drug development and delivery approaches result in an ever-increasing demand for tailored microparticles with defined sizes and structures. Inkjet printing technologies could be promising new processes to engineer particles with defined characteristics, as they are created to precisely deliver liquid droplets with high uniformity. METHODS: D-mannitol was used as a model compound alone or co-processed with the pore former agent ammonium bicarbonate, and the polymer polyethylene glycol 200. Firstly, a drop shape analyzer was used to characterize and understand ink/substrate interactions, evaporation, and solidification kinetics. Consequently, the process was transferred to a laboratory-scale inkjet printer and the resulting particles collected, characterized and compared to others obtained via an industrial standard technique. RESULTS: The droplet shape analysis allowed to understand how 3D structures are formed and helped define the formulation and process parameters for inkjet printing. By adjusting the drop number and process waveform, spherical particles with a mean size of approximately 100 µm were obtained. The addition of pore former and polymer allowed to tailor the crystallization kinetics, resulting in particles with a different surface (i.e., spike-like surface) and bulk (e.g. porous and non-porous) structure. CONCLUSION: The workflow described enabled the production of 3D structures via inkjet printing, demonstrating that this technique can be a promising approach to engineer microparticles.

Near Elimination of In Vitro Predicted Extrathoracic Aerosol Deposition in Children Using a Spray-Dried Antibiotic Formulation and Pediatric Air-Jet DPI.

PURPOSE: This study evaluated the in vitro aerosol performance of a dry powder antibiotic product that combined a highly dispersible tobramycin powder with a previously optimized pediatric air-jet dry powder inhaler (DPI) across a subject age range of 2-10 years. METHODS: An excipient enhanced growth (EEG) formulation of the antibiotic tobramycin (Tobi) was prepared using a small particle spray drying technique that included mannitol as the hygroscopic excipient and trileucine as the dispersion enhancer. The Tobi-EEG formulation was aerosolized using a positive-pressure pediatric air-jet DPI that included a 3D rod array. Realistic in vitro experiments were conducted in representative airway models consistent with children in the age ranges of 2-3, 5-6 and 9-10 years using oral or nose-to-lung administration, non-humidified or humidified airway conditions, and constant or age-specific air volumes. RESULTS: Across all conditions tested, mouth-throat depositional loss was < 1% and nose-throat depositional loss was < 3% of loaded dose. Lung delivery efficiency was in the range of 77.3-85.1% of loaded dose with minor variations based on subject age (~ 8% absolute difference), oral or nasal administration (< 2%), and delivered air volume (< 2%). Humidified airway conditions had an insignificant impact on extrathoracic depositional loss and significantly increased aerosol size at the exit of a representative lung chamber. CONCLUSIONS: In conclusion, the inhaled antibiotic product nearly eliminated extrathoracic depositional loss, demonstrated high efficiency nose-to-lung antibiotic aerosol delivery in pediatric airway models for the first time, and provided ~ 80% lung delivery efficiency with little variability across subject age and administered air volume.

Inhalable Nanoparticle-based Dry Powder Formulations for Respiratory Diseases: Challenges and Strategies for Translational Research.

The emergence of novel respiratory infections (e.g., COVID-19) and expeditious development of nanoparticle-based COVID-19 vaccines have recently reignited considerable interest in designing inhalable nanoparticle-based drug delivery systems as next-generation respiratory therapeutics. Among various available devices in aerosol delivery, dry powder inhalers (DPIs) are preferable for delivery of nanoparticles due to their simplicity of use, high portability, and superior long-term stability. Despite research efforts devoted to developing inhaled nanoparticle-based DPI formulations, no such formulations have been approved to date, implying a research gap between bench and bedside. This review aims to address this gap by highlighting important yet often overlooked issues during pre-clinical development. We start with an overview and update on formulation and particle engineering strategies for fabricating inhalable nanoparticle-based dry powder formulations. An important but neglected aspect in in vitro characterization methodologies for linking the powder performance with their bio-fate is then discussed. Finally, the major challenges and strategies in their clinical translation are highlighted. We anticipate that focused research onto the existing knowledge gaps presented in this review would accelerate clinical applications of inhalable nanoparticle-based dry powders from a far-fetched fantasy to a reality.

Microfluidic Particle Engineering of Hydrophobic Drug with Eudragit E100─Bridging the Amorphous and Crystalline Gap.

Co-processing active pharmaceutical ingredients (APIs) with excipients is a promising particle engineering technique to improve the API physical properties, which can lead to more robust downstream drug product manufacturing and improved drug product attributes. Excipients provide control over critical API attributes like particle size and solid-state outcomes. Eudragit E100 is a widely used polymeric excipient to modulate drug release. Being cationic, it is primarily employed as a precipitation inhibitor to stabilize amorphous solid dispersions. In this work, we demonstrate how co-processing of E100 with naproxen (NPX) (a model hydrophobic API) into monodisperse emulsions via droplet microfluidics followed by solidification via solvent evaporation allows the facile fabrication of compact, monodisperse, and spherical particles with an expanded range of solid-state outcomes spanning from amorphous to crystalline forms. Low E100 concentrations (≤26% w/w) yield crystalline microparticles with a stable NPX polymorph distributed uniformly across the matrix at a high drug loading (∼89% w/w). Structurally, E100 incorporation reduces the size of primary particles comprising the co-processed microparticles in comparison to neat API microparticles made using the same technique and the as-received API powder. This reduction in primary particle size translates into an increased internal porosity of the co-processed microparticles, with specific surface area and pore volume ∼9 times higher than the neat API microparticles. These E100-enabled structural modifications result in faster drug release in acidic media compared to neat API microparticles. Additionally, E100-NPX microparticles have a significantly improved flowability compared to neat API microparticles and as-received API powder. Overall, this study demonstrates a facile microfluidics-based co-processing method that broadly expands the range of solid-state outcomes obtainable with E100 as an excipient, with multiscale control over the key attributes and performance of hydrophobic API-laden microparticles.

Towards a better understanding of the role of stabilizers in QESD crystallizations.

Quasi-emulsion solvent-diffusion crystallization (QESD) is a type of spherical crystallization which can be used as a particle design method to improve the flowability and micromeritic properties of drugs or excipients. Spherical particles are generated by dispersing a solvent phase in an antisolvent so that a transient emulsion is formed. Within the droplets the material can crystallize and agglomerate into spherical, hollow particles. Surfactants, such as surface-active polymers like hypromellose, are often required to stabilize the quasi-emulsion. To gain further understanding for the role of the stabilizer, a new screening-method was developed which compared different surface active polymers in solution at similar dynamic viscosities rather than at a set concentration. The dynamic viscosities of a low-viscosity grade hypromellose solution used in the previous publications describing the QESD crystallization of metformin hydrochloride by the authors was used as a target value. QESD crystallizations of metformin hydrochloride (MF) and celecoxib showed that the type of stabilizer and whether it is dissolved in the solvent or antisolvent has an effect on the agglomerates. For MF, the type of hypromellose used can have a significant influence on the properties of the agglomerates. More polymers could be used to stabilize the transient emulsion of celecoxib than previously found in literature. Furthermore, QESD crystallizations seem to be more robust when the stabilizer is dissolved in the antisolvent, however this can lead to a reduced drug load of the agglomerates.

Improving the Manufacturability of Cohesive and Poorly Compactable API for Direct Compression of Mini-tablets at High Drug Loading via Particle Engineering.

PURPOSE: To utilize a particle engineering strategy to improve the manufacturability of a cohesive and poorly compactable API at high drug loading for direct compression of mini-tablets. METHODS: A high-shear mixer was used for wet milling during the API manufacturing process to obtain target particle size distributions. The targeted particles were characterized and formulated into blends by mixing with excipients. The formulated blends were compressed directly into mini-tablets using a compaction simulator. The tablet hardness, weight variation, and friability of the mini-tablets were characterized and compared with mini-tablets prepared with hammer milled APIs. RESULTS: Compared to the hammer milled APIs, the wet milled APIs, had smoother surface, narrower particle size distributions and demonstrated a better flow properties. Moreover, the mini-tablets produced with the wet milled APIs exhibited better weight uniformity, robust tablet mechanical strength and ultimately better friability. In addition, unlike the hammer milled process, the wet milling process is controllable and easy to scale up. CONCLUSIONS: This study successfully implemented API particle engineering through a high shear wet milling process to produce particles suitable for robust drug product manufacturing.

Spray Dried Rugose Lipid Particle Platform for Respiratory Drug Delivery.

PURPOSE: To develop a new lipid-based particle formulation platform for respiratory drug delivery applications. To find processing conditions for high surface rugosity and manufacturability. To assess the applicability of the new formulation method to different lipids. METHODS: A new spray drying method with a simplified aqueous suspension feedstock preparation process was developed for the manufacture of rugose lipid particles of 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC). A study covering a wide range of feedstock temperatures and outlet temperatures was conducted to optimize the processing conditions. Aerosol performance was characterized in vitro and in silico to assess the feasibility of their use in respiratory drug delivery applications. The applicability of the new spray drying method to longer-chain phospholipids with adjusted spray drying temperatures was also evaluated. RESULTS: Highly rugose DSPC lipid particles were produced via spray drying with good manufacturability. A feedstock temperature close to, and an outlet temperature lower than, the main phase transition were identified as critical in producing particles with highly rugose surface features. High emitted dose and total lung dose showed promising aerosol performance of the produced particles for use as a drug loading platform for respiratory drug delivery. Two types of longer-chain lipid particles with higher main phase transition temperatures, 1,2-diarachidoyl-sn-glycero-3-phosphocholine (DAPC) and 1,2-dibehenoyl-sn-glycero-3-phosphocholine (22:0 PC), yielded similar rugose morphologies when spray dried at correspondingly higher processing temperatures. CONCLUSIONS: Rugose lipid particles produced via spray drying from an aqueous suspension feedstock are promising as a formulation platform for respiratory drug delivery applications. The new technique can potentially produce rugose particles using various other lipids.

Advancements in Particle Engineering for Inhalation Delivery of Small Molecules and Biotherapeutics.

Dry powder inhalation formulations have become increasingly popular for local and systemic delivery of small molecules and biotherapeutics. Powder formulations provide distinct advantages over liquid formulations such as elimination of cold chain due to room temperature stability, improved portability, and the potential for increasing patient adherence. To become a viable product, it is essential to develop formulations that are stable (physically, chemically and/or biologically) and inhalable over the shelf-life. Physical particulate properties such as particle size, morphology and density, as well as chemical properties can significantly impact aerosol performance of the powder. This review will cover these critical attributes that can be engineered to enhance the dispersibility of inhalation powder formulations. Challenges in particle engineering for biotherapeutics will be assessed, followed by formulation strategies for overcoming the hurdles. Finally, the review will discuss recent examples of successful dry powder biotherapeutic formulations for inhalation delivery that have been clinically assessed.

Multicomponent Droplet Drying Modeling Based on Conservation and Population Balance Equations.

The aim of this work is to present a modeling tool to describe drying kinetics and delineate evolving physical and chemical behavior of multicomponent droplets during drying. Conservation equations coupled with population balance equations (PBE) are used to achieve this goal. Modeling results are gauged with single salt-water droplet drying from literature and show congruent trends. This model is then extended to a more complex system: various droplet sizes containing methanol (solvent), Felodipine (active ingredient), and PVP (polyvinylpyrrolidone as excipient). The FIB-SEM (Focused-Ion Beam Scanning Electron Microscopy) imaging results from spray-dried particles produced with similar formulation and processing conditions are consistent with phase behavior predicted by the model. The results show competing impacts of transport phenomena on the intermittent shell formation process and final particle structure and chemical heterogeneity. Solute diffusion, solvent efflux, and intra-drop flow impact the model system. It is found that shell formation follows a fluctuating profile where the initial precipitation of the dissolved species on the droplet surface is dampened, and nucleated particles become dispersed periodically until the shell becomes strong enough to withstand internal circulations. These internal effects are dependent on droplet size and are pronounced for larger droplets. That is, the particle phase behavior and physical nature are functions of the atomized droplet size. Stemming understating from this study would inform an optimized unit, operating in target design space. This would provide better product quality control and minimize discrepancies observed in process development during the early phase vs. commercial scale.

Computational Fluid Dynamics (CFD) Guided Spray Drying Recommendations for Improved Aerosol Performance of a Small-Particle Antibiotic Formulation.

PURPOSE: The objective of this study was to implement computational fluid dynamics (CFD) simulations and aerosol characterization experiments to determine best-case spray drying conditions of a tobramycin excipient enhanced growth (Tobi-EEG) formulation for use in a pediatric air-jet dry powder inhaler (DPI). METHODS: An iterative approach was implemented in which sets of spray drying conditions were explored using CFD simulations followed by lead candidate selection, powder production and in vitro aerosol testing. CFD simulations of a small-particle spray dryer were performed to capture droplet drying parameters and surface-averaged temperature and relative humidity (RH) conditions in the powder collection region. In vitro aerosol testing was performed for the selected powders using the pediatric air-jet DPI, cascade impaction, and aerosol transport through a pediatric mouth-throat (MT) model to a tracheal filter. RESULTS: Based on comparisons of CFD simulations and in vitro powder performance, recommended drying conditions for small-particle powders with electrostatic collection include: (i) reducing the CFD-predicted drying parameters of κavg and κmax to values below 3 µm2/ms and 114 µm2/ms, respectively; (ii) maintaining the Collector Surface RH within an elevated range, which for the Tobi-EEG formulation with l-leucine was 20-30 %RH; and (iii) ensuring that particles reaching the collector were fully dried, based on a mass fraction of solute CFD parameter. CONCLUSIONS: Based on the newly recommended spray dryer conditions for small particle aerosols, delivery performance of the lead Tobi-EEG formulation was improved resulting in >60% of the DPI loaded dose passing through the pediatric MT model.

Control of Drug-Excipient Particle Attributes with Droplet Microfluidic-based Extractive Solidification Enables Improved Powder Rheology.

PURPOSE: Industrial implementation of continuous oral solid dosage form manufacturing has been impeded by the poor powder flow properties of many active pharmaceutical ingredients (APIs). Microfluidic droplet-based particle synthesis is an emerging particle engineering technique that enables the production of neat or composite microparticles with precise control over key attributes that affect powder flowability, such as particle size distribution, particle morphology, composition, and the API's polymorphic form. However, the powder properties of these microparticles have not been well-studied due to the limited mass throughputs of available platforms. In this work, we produce spherical API and API-composite microparticles at high mass throughputs, enabling characterization and comparison of the bulk powder flow properties of these materials and greater understanding of how particle-scale attributes correlate with powder rheology. METHODS: A multi-channel emulsification device and an extractive droplet-based method are harnessed to synthesize spherical API and API-excipient particles of artemether. As-received API and API crystallized in the absence of droplet confinement are used as control cases. Particle attributes are characterized for each material and correlated with a comprehensive series of powder rheology tests. RESULTS: The droplet-based processed artemether particles are observed to be more flowable, less cohesive, and less compressible than conventionally synthesized artemether powder. Co-processing the API with polycaprolactone to produce composite microparticles reduces the friction of the powder on stainless steel, a common equipment material. CONCLUSIONS: Droplet-based extractive solidification is an attractive particle engineering technique for improving powder processing and may aid in the implementation of continuous solid dosage form manufacturing.

Spray freeze-drying for inhalation application: process and formulation variables.

High porous particles with specific aerodynamic properties were processed by the spray freeze-drying (SFD) method. Comprehensive knowledge about all aspects of the SFD method is required for particle engineering of various pharmaceutical products with good flow properties. In this review, different types of the SFD method, the most frequently employed excipients, properties of particles prepared by this method, and most recent approaches concerning SFD are summarized. Generally, this technique can prepare spherical-shaped particles with a highly porous interior structure, responsible for the very low density of powders. Increasing the solubility of spray freeze-dried formulations achieves the desired efficacy. Also, due to the high efficiency of SFD, by determining the different features of this method and optimizing the process by model-based studies, desirable results for various inhaled products can be achieved and significant progress can be made in the field of pulmonary drug delivery.

Combatting intracellular pathogens using bacteriophage delivery.

Intracellular pathogens reside in specialised compartments within the host cells restricting the access of antibiotics. Insufficient intracellular delivery of antibiotics along with several other resistance mechanisms weaken the efficacy of current therapies. An alternative to antibiotic therapy could be bacteriophage (phage) therapy. Although phage therapy has been in practice for a century against various bacterial infections, the efficacy of phages against intracellular bacteria is still being explored. In this review, we will discuss the advancement and challenges in phage therapy, particularly against intracellular bacterial pathogens. Finally, we will highlight the uptake mechanisms and approaches to overcome the challenges to phage therapy against intracellular bacteria.

Manufacturing Stable Bacteriophage Powders by Including Buffer System in Formulations and Using Thin Film Freeze-drying Technology.

PURPOSE: Bacteriophage (phage) therapy has re-gained attention lately given the ever-increasing prevalence of multi-drug resistance 'super-bugs'. To develop therapeutic phage into clinically usable drug products, the strategy of solidifying phage formulations has been implemented to diversify the dosage forms and to overcome the storage condition limitations for liquid phage formulations. METHOD: In our work, we hypothesize and tested that an advanced technology, thin film freeze-drying (TFFD), can be used to produce phage containing dry powders without significantly losing phage viability. Here we selected T7 phage as our model phage in a preliminary screening study. RESULTS: We found that a binary excipient matrix of sucrose and leucine at ratios of 90:10 or 75:25 by weight, protected phage from the stresses encountered during the TFFD process. In addition, we confirmed that incorporating a buffer system in the formulation significantly improved the survival of phage during the initial freezing step and subsequent sublimation step in the solidifying processes. The titer loss of phage in SM buffer (Tris/NaCl/MgSO4) containing formulation was as low as 0.19 log plaque forming units, which indicated that phage function was well preserved after the TFFD process. The presence of buffers markedly reduced the geometric particle sizes as determined by a dry dispersion method using laser diffraction, which indicated that the TFFD phage powder formulations were easily sheared into smaller powder aggregates, an ideal property for facilitating a variety of topical drug delivery routes including pulmonary delivery through dry powder inhalers, nebulization after reconstitution, and intranasal or wound therapy, etc. CONCLUSION: From these findings, we show that introducing buffer system can stabilize phage during dehydration processes, and TFFD, as a novel particle engineering method, can successfully produce phage containing powders that possess the desired properties for bioactivity and potentially for inhalation therapy.

Spray-Congealing and Wet-Sieving as Alternative Processes for Engineering of Inhalation Carrier Particles: Comparison of Surface Properties, Blending and In Vitro Performance.

PURPOSE: Traditionally, α-lactose monohydrate is the carrier of choice in dry powder inhaler (DPI) formulations. Nonetheless, other sugars, such as D-mannitol, have emerged as potential alternatives. Herein, we explored different particle engineering processes to produce D-mannitol carriers for inhaled delivery. METHODS: Wet-sieving and spray-congealing were employed as innovative techniques to evaluate the impact of engineering on the particle properties of D-mannitol. To that end, the resulting powders were characterized concerning their solid-state, micromeritics and flowability. Afterwards, the engineered carrier particles were blended with inhalable size beclomethasone dipropionate to form low dose (1 wt%) DPI formulations. The in vitro aerosolization performance was evaluated using the NEXThaler®, a reservoir multi-dose device. RESULTS: Wet-sieving generated D-mannitol particles with a narrow particle size distribution and spray-congealing free-flowing spherical particles. The more uniform pumice particles with deep voids and clefts of wet-sieved D-mannitol (Pearl300_WS) were beneficial to drug aerosolization, only when used in combination with a ternary agent (10 wt% of 'Preblend'). When compared to the starting material, the spray-congealed D-mannitol has shown to be promising in terms of the relative increase of the fine particle fraction of the drug (around 100%), when used without the addition of ternary agents. CONCLUSIONS: The wet-sieving process and the related aerosolization performance are strongly dependent on the topography and structure of the starting material. Spray-congealing, has shown to be a potential process for generating smooth spherical particles of D-mannitol that enhance the in vitro aerosolization performance in binary blends of the carrier with a low drug dose.

A Novel Computational Approach Coupled with Machine Learning to Predict the Extent of Agglomeration in Particulate Processes.

Solid particle agglomeration is a prevalent phenomenon in various processes across the chemical, food, and pharmaceutical industries. In pharmaceutical manufacturing, agglomeration is both desired in unit operations like wet granulation and undesired in unit operations such as agitated filter drying of highly potent active pharmaceutical ingredients (API). Agglomeration needs to be controlled for optimal physical properties of the API powder. Even after decades of work in the field, there is still very limited understanding of how to quantify, predict, and control the extent of agglomeration, owing to the complex interaction between the solvent and the solid particles and stochasticity imparted by mixing. Furthermore, a large size of industrial scale particulate process systems makes it computationally intractable. To overcome these challenges, we present a novel theory and computational methodology to predict the agglomeration extent by coupling the experimental measurements of agglomeration risk zone or "sticky zone" with discrete element method. The proposed model shows good agreement with experiments. Further, a machine learning model was built to predict agglomeration extent as a function of input variables, such as material properties and processing conditions, in order to build a digital twin of the unit operation. While the focus of the present study is the agglomeration of particles during industrial drying processes, the proposed methodology can be readily applied to numerous other particulate processes where agglomeration is either desired or undesired.

Spray-Dried Inhalable Powder Formulations of Therapeutic Proteins and Peptides.

Respiratory diseases are among the leading causes of morbidity and mortality worldwide. Innovations in biochemical engineering and understanding of the pathophysiology of respiratory diseases resulted in the development of many therapeutic proteins and peptide drugs with high specificity and potency. Currently, protein and peptide drugs are mostly administered by injections due to their large molecular size, poor oral absorption, and labile physicochemical properties. However, parenteral administration has several limitations such as frequent dosing due to the short half-life of protein and peptide in blood, pain on administration, sterility requirement, and poor patient compliance. Among various noninvasive routes of administrations, the pulmonary route has received a great deal of attention and is a better alternative to deliver protein and peptide drugs for treating respiratory diseases and systemic diseases. Among the various aerosol dosage forms, dry powder inhaler (DPI) systems appear to be promising for inhalation delivery of proteins and peptides due to their improved stability in solid state. This review focuses on the development of DPI formulations of protein and peptide drugs using advanced spray drying. An overview of the challenges in maintaining protein stability during the drying process and stabilizing excipients used in spray drying of proteins and peptide drugs is discussed. Finally, a summary of spray-dried DPI formulations of protein and peptide drugs, their characterization, various DPI devices used to deliver protein and peptide drugs, and current clinical status are discussed.