Optimization of Carrier-Based Dry Powder Inhaler Performance: A Review
Abstract
:1. Introduction
2. Formulation Parameters Affecting DPI Performance
2.1. Modification of Carrier Size and Surface Roughness
2.2. Optimization of Carrier and API Morphology
2.3. Addition of Extra Components
- Lactose fines: One of the most important factors controlling the release of drugs from the surface of carrier particles is the adhesive forces among the carrier and drug particles, and one of the ways to control these forces is by adding fine particle size components [49]. It has been observed in multiple studies that adding fines can increase the fine particle fraction [50]. The mechanism of this increase is related to fine lactose particles occupying the high-energy active sites present on the surface of the carrier and leaving the low-energy binding sites for the drug particles, including other mechanisms such as redistribution of the drug and change in dynamics of triboelectric forces [10,51]. The addition of inert fine carriers such as lactose particles is preferred over other fines due to the known safety profile of lactose. It is important to note that these high-energy active sites represent surface disorders resulting from dislocation in a crystal lattice or distortion of the crystal lattice, leading to exposed surface molecular groups and strong interaction with the drug particle. The drug particles have a higher affinity towards these higher-energy sites, leading to stronger interaction between carrier and drug particles. Therefore, it is a common practice to blend lactose fines and carrier particles before adding the drug. If the fines are added below the adhesive saturation limit of the carrier, the fines will preferentially occupy the high-energy active sites [19]. The other proposed mechanism for an increase in fine particle fraction is the formation of fine particle multiplets, which could either help in the dispersion of drug particles and ease of drug release from the surface of these multiplets, or these multiplets could be small enough to reach the deeper parts of the lungs [50]. Another important consideration is the concentration of added fines; it has been shown by previous studies that adding fines in the concentration of 10–15% leads to an increase in fine particle fraction including the concentration of fines already present in the carrier [10]. This increase in FPF was on the order of 60–70%. However, adding fines in very high concentrations often leads to a decrease in FPF, which could be attributed to an increase in the number of bigger-sized fine aggregates [10]. Also, added fines may compromise the flow of the formulation making the powder handling difficult for processes such as blending and encapsulation [52]. The selection of fine concentration varies for different types of carriers due to the variation in surface characteristics of different carriers [10]. The theoretical surface area calculation could provide an initial estimate of the highest fine load. It has been shown in previous studies that the chemical nature of fines plays a less significant role in improving the respirable fraction of the formulation [23]. It is also important to consider the amount of intrinsic fines in the carrier as they also contribute to the improvement in aerosol performance. It was demonstrated by Islam et al. that binary blends of salmeterol xinafoate and various grades of carrier lactose when mixed with increasing concentrations of fine lactose led to an increase in the FPF. However, the increase in FPF was only observed up to 15%, and a further increase in fine concentration did not produce a change in FPF. Additionally, the concentration of fines can also be controlled by removing them externally using methods such as air jet sieving, air washing, or decantation. However, one should also consider the impact of change in surface characteristics imparted by the method of fine removal. For example, air jet sieving and air washing of fines might introduce electrostatic charging, which could lead to a decrease in the formulation aerosol performance [53].
- Force control agents: In addition to adding sugar fines, force control agents (FCAs) are also added, such as leucine, lecithin, and magnesium stearate [11], to improve the aerosol performance of DPIs [54]. Magnesium stearate (MgSt) is one of the most used FCAs and has also been employed in marketed products, such as Novartis’ seebri Breezhaler, Ultibrom Breezhaler, and GSK’s Relvar Ellipta, Anoro Ellipta, and Incruse Ellipta [55]. FCAs are known to improve the aerosol performance of a DPI formulation by occupying high energy active sites on the surface of the carrier particles in a similar fashion to extrinsic fines thus creating a surface smoothening effect leading to ease of drug detachment from the surface of the carrier particle [54,56]. Additionally, the method of blending carriers with FCA impacts the overall aerosol performance. For example, high-shear blending has been shown to produce blends with better aerosol performance [57]. There are multiple mechanisms explaining the increase in aerosol performance using FCAs. One of the mechanisms is related to the ease of removal of drug particles from magnesium stearate carrier particles, which could be attributed to the weaker interaction of the drug with the carrier, as demonstrated by previous studies. This interaction could also be measured by the work of adhesion between the API–carrier and the work of cohesion between API-API particles, as shown in previous studies [58]. It was established that the work of cohesion between SS particles was 407.5 mJ/m2, and the work of adhesion between SS and MgSt was 311.6 mJ/m2. Therefore, it was easier to detach SS from the surface of the carrier [58]. It was also established by Li et al. (2023) that 0.25–0.5% is the optimum concentration using both low- and high-shear blending for optimum aerosol performance. They also established that powder rheology evaluation can also be useful in predicting factors that affect aerosol performance [55]. Additionally, it is also important to consider the concentration of MgSt that is allowed by the FDA in per unit dose is 0.13 mg as per the inactive ingredient database [59,60]. The distribution of FCAs on the surface of carrier particles can be evaluated using multiple methods, such as Atomic Force Microscopy, Raman spectroscopy, or Time-of-flight secondary ion mass spectrometry (ToF-SIMS) and X-ray photoelectron spectroscopy (XPS) [61]. The following Table 1 lists some of the most commonly used DPI excipients, their functionality, and their development stage.
2.4. Optimization of Drug Loading
2.5. Impact of Capsule Type
3. Inhaler Device Consideration
3.1. Flow Through the Inhaler Device and Device Resistance Optimization
3.2. Optimization of Device Design
4. Process Parameters
4.1. Blending
4.2. Milling
4.3. Filling/Encapsulation
5. Impact of Particle Engineering
Particle Size Control Techniques
- Micronization or Milling: As discussed in previous sections of this article, there are multiple techniques for milling APIs, with air jet and ball mill being the most commonly used ones for DPI manufacturing. An air jet mill consists of a cylindrical grinding chamber equipped with tangential nozzles for directing the air. High-velocity gas jets accelerate the particles, leading to collisions between particles, as well as between particles and the chamber walls. Within the mill chamber, particles experience both centrifugal and drag forces. The centrifugal force pushes the particles toward the chamber’s outer edge, while the gas’s radial velocity component creates a drag force that pulls the particles toward the central outlet. Particles exit the chamber when the radial drag force surpasses the centrifugal force. The key parameters to be optimized include the feed rate, feed pressure, and grind pressure [127,128]. The operation of a ball mill involves both crushing and grinding actions, primarily carried out by large and small balls, respectively. Achieving a balanced combination of crushing and grinding requires an appropriate distribution of ball sizes. In many industries, it is standard practice to use a mixture of ball sizes rather than balls of uniform size. This approach ensures efficient grinding of API particles of varying sizes [129]. In one study using salbutamol sulfate, the grind pressure played a crucial role in determining the particle size distribution and ensuring the physical stability of the powder and feed rate had minimal impact on the quality of the powder. A higher feed rate led to a greater concentration of product in the grinding chamber and reduced the distance between particles, resulting in coarser particles. The feed pressure did not significantly affect the particle size [127]. Another study evaluating inhalable microparticles of Amifostine (AMF) using wet ball milling and jet milling demonstrated that microparticles wet-ball-milled with non-polar solvents exhibited higher inhalation efficiency compared with wet-ball-milled with polar solvents. Additionally, wet ball milling outperformed jet milling across all samples. Wet ball milling using a polar solvent led to a decrease in hydrate content and led to a modification of crystallinity and inhalation efficiency. In wet ball milling, the crystal structure is influenced by changes in hydrate content influenced by the solvent polarity. Moreover, the transformation of the unstable form (dehydrated) into a stable form (trihydrate) reduces agglomeration due to the hygroscopic nature of free water, thereby decreasing inhalation efficiency. Hence, non-polar solvent wet ball milling, which better maintains stable crystallinity and high inhalation efficiency, is preferable for producing inhalable particle sizes [130] In another study, the difference between wet and dry ball milling was discussed by employing quartz as the model API. The final powder product size, specifically the median particle size at the grinding limit, was approximately 2 µm under dry conditions and around 0.5–0.6 µm under wet conditions. Thus, the particle size achieved through wet grinding was about one-fourth of that achieved through dry grinding. Also, particle size distribution by ball milling achieved through wet grinding with small balls was narrower. Conversely, the broader particle size distribution was achieved during dry grinding with small balls [131]. However, it is important to take into consideration the influence of ball milling on the crystallinity of the API. In general, ball (wet and dry) milling introduces high mechanical stress, causing surface defects and leading to amorphization. However, milling performed above Tg can induce crystallization due to increased molecular mobility. Therefore, it is important to evaluate different milling techniques in addition to optimizing final particle size and product performance.
- Spray-Drying: Spray-drying has been gaining popularity in DPI manufacturing due to its ability to efficiently create respirable particles. Particles created via spray-drying generally have a spherical shape, with aerodynamic diameter usually between 1 and 5 µm and exhibiting a narrow size distribution. Additionally, it offers the advantage of generating carrier-free DPI formulations [64]. Typically, spray-drying involves multiple critical steps, where first one is the atomization of feed solution into a spray, drying of the atomized droplets at high temperatures, and separation of dried particles from the air followed by collection of these particles [49,132]. Several elements affect the properties and aerodynamic behavior of these powders, such as the design of the nozzle, the viscosity of the solution being fed into the system, and the temperature at the outlet [133]. Additionally, the carrier selection also influences the spray-drying and consequently DPI performance. For example, when azithromycin was evaluated with different carriers (lactose, mannitol, L-leucine, and glycine), the scanning electron microscopy images of powders containing L-leucine exhibited the most uniform distribution. Using lactose as the carrier caused the particles to become wrinkled, while mannitol produced particles that were more spherical and smoother. However, the respirable fractions values were observed in decreasing order of L-leucine > glycine > lactose > mannitol. Mannitol exhibited the lowest in vitro deposition of the drug because it produced the largest particle size with broad PSD. The lower RF of lactose may be attributed to its poor flowability. The highest RF achieved with a formulation containing leucine was attributed to two main factors: good flowability and suitable particle size with a narrow PSD [134]. In another study, the effect of solvent on DPI formulation was investigated, where ethanol was evaluated as the solvent and β-estradiol as the model drug. Raising the ethanol concentration in the solvent before spray-drying reduced the yield of the resulting powder. Conversely, the powder yield improved with increasing concentration of leucine in the formulation [135]. In a different study, jet milling and spray-drying were compared using bosentan hydrate as the drug. The spray-dried particle exhibited a spherical and smooth morphology with an amorphous solid state. This could be due to the rapid evaporation of the solvent during spray drying, which allows insufficient time for crystallization. On the other hand, the jet-milled samples exhibited an irregular shape with a rough texture and a crystalline solid state with relatively high moisture content. The irregular and non-spherical form of jet-milled samples contributed to a smaller aerodynamic diameter, resulting in better aerosol dispersion [136].
- Supercritical Fluid Processing (SCF): Supercritical fluid processing is a sophisticated technique utilized in DPI formulations to achieve precise control over particle size and morphology. It involves the use of supercritical fluids, such as carbon dioxide or ethane, as solvents or antisolvents in particle formation processes [140]. By adjusting pressure and temperature conditions, supercritical fluid processing enables the production of particles with tailored properties, including size, shape, and surface morphology. This technique offers several advantages over conventional methods, including the absence of organic solvents, low processing temperatures, and high product purity. Supercritical fluid processing is particularly suitable for producing nanoparticles and microparticles with narrow particle size distributions (PSD) and uniform properties, making it a promising tool for enhancing the performance of DPI formulations. However, this might not be applicable to all API’s. For example, Richardson et al. (2007) evaluated salbutamol-sulfate-containing drug substances manufactured by supercritical fluid as compared with marketed micronized formulation, and no significant differences were observed in inhalation performance. Moreover, the DPI performance for Salbutamol manufactured using SCF processing led to more inter-batch variability in inhalation performance [141]. Additionally, Rehman et al. (2004) evaluated Terbutaline Sulfate (TBS), and it was observed that SCF led to better aerosol performance, with particle sizes consistently within the respirable range [142].
- Electrohydrodynamic Atomization: Electrohydrodynamic atomization (EHDA) is a technique used in the development of DPI formulations to produce fine and uniform particles through electrostatic forces. EHDA involves the generation of a high-voltage electric field between a liquid formulation and a grounded electrode, inducing the formation of a Taylor cone at the liquid–air interface. As the electric field strength increases, the liquid jet emanating from the Taylor cone undergoes rapid stretching and fragmentation, resulting in the production of fine droplets. These droplets subsequently evaporate to form dry powder particles with controlled size and morphology. The drop size (D) or consequently the particle size is controlled by the liquid flow rate and the fluid properties, such as conductivity, surface tension, and density, and it can be predicted by the following Equation (3):
- where c is a constant, is the density of the liquid, is the permittivity of the free space, is the conductivity of the liquid, is the applied flow rate [143]. Ijsebaert et al. (2001) evaluated EHDA for the development of a DPI for beclomethasone dipropionate at different process conditions. It was observed that higher flow rates resulted in an increase in particle size (1.58 µm at 1 mL/h vs. 4.55 µm at 3 mL/h) [143]. Additionally, no significant variations within particles were observed at similar process conditions. This technique could be employed for heat-sensitive drugs, as it operates at ambient temperatures and does not require the use of organic solvents. It is important to note that this process requires the use of a volatile solvent most commonly ethanol, and therefore, solubility becomes a significant concern and should be evaluated at earlier stages of drug product development.
6. Novel Technologies
- Particle Replication in Non-Wetting Templates (PRINT): PRINT technology represents a cutting-edge approach to improving particle properties by leveraging the principles of soft lithography and allows for precise control over particle size, shape, and surface characteristics. The process involves using perfluoropolyether elastomers as molding templates on a silicone master plate, where preparticle material is filled into molds and pulled out from them using an adhesive [144]. PRINT technology helps in creating micro- to nano-sized particulate matter with desired properties and most importantly with uniform PSD. Additionally, other particle properties such as surface roughness and porosity can also be controlled, leading to improved powder flowability and dispersibility resulting in enhanced DPI performance.
- Thin-Film Freezing (TFF) Technology: The TFF technique stands as a novel advancement in the realm of dry powder inhalation (DPI) formulations. This method involves the fast freezing of a liquid formulation containing the active pharmaceutical ingredient (API) and stabilizer solution within a controlled fluid dynamic system. Upon application, the liquid formulation is quickly spread as a thin film onto a cryogenically frozen surface, inducing the rapid conversion of liquid droplets into solid frozen droplets of 2–3 mm in diameter [145]. The frozen mass is then lyophilized, resulting in dry powder particles with a particle size as small as 200 nm, suitable for inhalation [146]. Moreover, TFF allows the incorporation of higher drug loads into the formulation, which is difficult to achieve by other conventional methods and results in homogenous batches with lower variation in particle properties [147]. TFF technology could be highly beneficial for formulations requiring high drug load, small particle size, and complete amorphization. In a study by Praphawatvet et al. (2022), it was demonstrated that voriconazole particles produced using TFF were low-density and composed of nanoaggregates with improved FPF (73.6 ± 3.2%1) and MMAD (3.03 ± 0.17 μm) [145]. Similarly, other studies also depicted improved inhalation performance using TFF technology [47,148,149]. However, TFF technology requires the preparation of a solution containing API and other excipients in an organic solvent, such as ACN, which could be challenging for some of the manufacturing processes. Additionally, in some cases, due to the amorphous nature of the produced material, it could lead to a decrease in stability by moisture sorption. However, this could be handled by using excipients, such as mannitol or trehalose instead of lactose [150]. The TFF process is required to be optimized for each compound due to changes in solubility in different solvents, which consequently changes the fluid dynamics of the solvent–API system [151].
- Ink JET Printing (IJP): IJP has emerged as a promising technique for the formulation of various types of dosage forms, such as tablets and size-controlled particles [152,153]. IJP becomes really useful in controlling particle morphology in the development of inhalation particles. In this method, liquid formulations containing the API and excipients are deposited dropwise onto suitable substrates using a digital imaging system. By precisely controlling the deposition pattern and composition of the liquid droplets, IJP allows for the creation of particles with defined sizes, shapes, and surface properties. One notable example of the application of IJP in inhalation particle preparation is the development of salbutamol sulfate-loaded alginate aerogel microspheres. Researchers utilized IJP to deposit liquid materials containing salbutamol sulfate onto substrates, resulting in the formation of spherical microspheres with high porosity. These aerogel microspheres exhibited enhanced fine particle fraction (FPF) compared with powders produced using conventional methods, highlighting the effectiveness of IJP in tailoring particle morphology for improved aerosolization efficiency and pulmonary delivery. In conclusion, particle engineering plays a pivotal role in optimizing DPI formulations, ensuring effective drug delivery and therapeutic efficacy. Continued research and innovation in this field are essential for addressing current challenges and advancing the development of next-generation DPIs tailored to meet the evolving needs of patients with respiratory conditions.
Study Reference | Optimization Mechanism | Formulation Components/Product |
---|---|---|
Steckel, et al., 1997 [26] | Modification of carrier lactose size | Spinhaler and Easyhaler |
Kaialy et al., 2014 [36] | Modification of carrier physical properties by spray-drying | Spray-dried mannitol and albuterol sulfate |
Kaialy et al., 2011 [44] | Modification of particle shape | Mannitol and salbutamol sulfate |
Zeng et al., 2000 [45] | Modification of carrier and API shape | Lactose and salbutamol sulfate |
Singh et al., 2015 [54] | Addition of force control agents | Surface-modified lactose (SML) and fluticasone propionate |
Spahn et al., 2022 [63] | Blending equipment | Rifampicin, Magnesium stearate and lactose |
Hertel et al., 2017 [94] | Blending parameters | Inhalac 70, Inhalac 400, and Inhalac 230 |
Steckel et al., 2006 [107] | Milling conditions | Lactose crystals |
Brodka-Pfeiffer et al., 2003 [112] | Ball milling parameters | Salbutamol sulphate |
Sibum et al., 2020 [122] | Filling process optimization using Omnidose | Amikacin formulation |
Stranzinger et al., 2023 [123] | Filling process optimization | Lactohale 300, Lactohale 220 and Inhalac 500 |
Rabban and Seville 2005 [135] | Spray-drying | β-estradiol, Leucine |
Lee et al., 2016 [136] | Spray-drying and jet milling | Bosentan hydrate |
Richardson et al., 2007 [141] | Supercritical Fluid Processing (SCF) | Salbutamol sulfate |
Rehman et al., 2004 [142] | Supercritical Fluid Processing (SCF) | Terbutaline sulfate |
Praphawatvet et al., 2022 [145] | Thin-Film Freezing (TFF) technology | Voriconazole |
Mangal et al., 2019 [109] | Co-jet milling | Ciprofloxacin HCl, magnesium stearate, Leucine |
Ljsebaert et al., 2001 [143] | Electrohydrodynamic Atomization | Beclomethasone dipropionate |
7. Conclusions
Funding
Conflicts of Interest
Abbreviations
∆P | Pressure drop across the inhaler |
%RSD | Relative Standard Deviation |
API | Active Pharmaceutical Ingredient |
BAM | Breath-Actuated Mechanism |
BSA | Bovine Serum Albumin |
CAB | Cohesive Adhesive Balance |
CFD | Computational Fluid Dynamics |
Ds | Surface fractal dimension |
DD | Delivered Dose |
DPI | Dry Powder Inhaler |
ED | Emitted dose |
Edispersion | Energy of Dispersion |
ER | Elongation ratio |
FCA | Force Control Agent |
FPD | Fine Particle Dose |
FPF | Fine Particle Fraction |
GRAS | Generally Recognized as Safe |
HPMC | Hydroxypropyl methylcellulose |
L/min | Liter per minute |
MgSt | Magnesium stearate |
NGI | Next-Generation Impactor |
pMDIs | Pressurized Meter Dose Inhaler |
ToF-SIMS | Time-of-flight secondary ion mass spectrometry |
tdispersion | Time for Dispersion |
Vaf | Volume airflow |
XPS | X-ray photoelectron spectroscopy |
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Excipients | Functionality | Development Stage |
---|---|---|
Lactose Monohydrate [18] | Carrier, enhances flowability and dispersion | Marketed (Pulmicort Flexhaler, Spiriva Handihaler, Advair Diskus) |
Mannitol [18] | Carrier and an alternative to lactose | Marketed (e.g., Exubera) |
Glucose [20,21,23] | Carrier | Marketed (e.g., BronchoDual) |
Trehalose [20,21,23] | Bulking agent for low-dose APIs, Stabilize sensitive drugs (proteins, peptides) | Underdevelopment |
Leucine, Trileucine, Isoleucine [62] | Stabilizer and enhances aerosolization (forms hydrophobic shell during spray drying) | Underdevelopment |
Magnesium Stearate [63] | Carrier coating, reduces cohesive forces | Marketed (e.g., SkyeProtect™) |
Poloxamer [64] | As a surfactant for the formation of light and porous particles | Underdevelopment |
Bile Salts [65] |
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Mehta, T.; Najafian, S.; Patel, K.; Lacombe, J.; Chaudhuri, B. Optimization of Carrier-Based Dry Powder Inhaler Performance: A Review. Pharmaceutics 2025, 17, 96. https://doi.org/10.3390/pharmaceutics17010096
Mehta T, Najafian S, Patel K, Lacombe J, Chaudhuri B. Optimization of Carrier-Based Dry Powder Inhaler Performance: A Review. Pharmaceutics. 2025; 17(1):96. https://doi.org/10.3390/pharmaceutics17010096
Chicago/Turabian StyleMehta, Tanu, Saeed Najafian, Komalkumar Patel, Justin Lacombe, and Bodhisattwa Chaudhuri. 2025. "Optimization of Carrier-Based Dry Powder Inhaler Performance: A Review" Pharmaceutics 17, no. 1: 96. https://doi.org/10.3390/pharmaceutics17010096
APA StyleMehta, T., Najafian, S., Patel, K., Lacombe, J., & Chaudhuri, B. (2025). Optimization of Carrier-Based Dry Powder Inhaler Performance: A Review. Pharmaceutics, 17(1), 96. https://doi.org/10.3390/pharmaceutics17010096