Crystalline Mannitol Research Articles

Spray freeze dried cannabidiol with dipalmitoylphosphatidylcholine (DPPC) for inhalation and solubility enhancement

Pulmonary delivery is an efficient route of administration to deliver cannabidiol (CBD) due to the high bioavailability and fast onset of action. The major formulation challenge is the poor aqueous solubility of CBD. This study aimed to produce inhalable CBD powders with enhanced solubility and characterise their solid-state properties. CBD was spray freeze dried with mannitol or trehalose dihydrate with and without dipalmitoylphosphatidylcholine (DPPC). All four powders had acceptable yields at > 70 % with porous and spherical particles. The two crystalline mannitol powders contained less residual solvent than both amorphous trehalose ones. The addition of DPPC did not affect the crystallinity and residual solvent level of the powders. Instead, DPPC made the particles more porous, decreased the particle size from 19-23 µm to 11–13 µm, and increased CBD solubility from 0.36 µg/mL to over 2 µg/mL. The two DPPC powders were dispersed from a low resistance RS01 inhaler, showing acceptable aerosol performance with emitted fractions at 91–93 % and fine particle fractions < 5 µm at 34–43 %. These formulations can be used as a platform to deliver CBD and other cannabinoids by inhalation.

Freeze-dried nanocrystal dispersion of novel deuterated pyrazoloquinolinone ligand (DK-I-56-1): Process parameters and lyoprotectant selection through the stability study

Recently, nanocrystal dispersions have been considered as a promising formulation strategy to improve the bioavailability of the deuterated pyrazoloquinolinone ligand DK-I-56-1 (7‑methoxy-2-(4‑methoxy-d3-phenyl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one). In the current study, the freeze-drying process (formulation and process parameters) was investigated to improve the storage stability of the previously developed formulation. Different combinations of lyoprotectant (sucrose or trehalose) and bulking agent (mannitol) were varied while formulations were freeze-dried under two conditions (primary drying at -10 or -45 °C). The obtained lyophilizates were characterized in terms of particle size, solid state properties and morphology, while the interactions within the samples were analyzed by Fourier transform infrared spectroscopy. In the preliminary study, three formulations were selected based on the high redispersibility index values (around 95%). The temperature of primary drying had no significant effect on particle size, but stability during storage was impaired for samples dried at -10 °C. Samples dried at lower temperature were more homogeneous and remained stable for three months. It was found that the optimal ratio of sucrose or trehalose to mannitol was 3:2 at a total concentration of 10% to achieve the best stability (particle size < 1.0 μm, polydispersity index < 0.250). The amorphous state of lyoprotectants probably provided a high degree of interaction with nanocrystals, while the crystalline mannitol provided an elegant cake structure. Sucrose was superior to trehalose in maintaining particle size during freeze-drying, while trehalose was more effective in keeping particle size within limits during storage. In conclusion, results demonstrated that the appropriate combination of sucrose/trehalose and mannitol together with the appropriate selection of lyophilization process parameters could yield nanocrystals with satisfactory stability.

Evaluating spray gelation and spray freeze drying as the granulation method to prepare oral tablets of amorphous drug nanoplex

Amorphous drug nanoplex represents one of the most promising solubility enhancement strategies of poorly-soluble drugs. Solubility enhancement capability of nanoplex hitherto has been demonstrated for nanoplex suspension and lyophilized/spray-dried nanoplex, but not for its oral tablets. Using ciprofloxacin as the model poorly-soluble drug, we investigated spray gelation (SG) of alginate and spray freeze drying (SFD) with cryoprotective mannitol, as the nanoplex’s granulation methods. Both granules were evaluated in terms of their morphology, physical form, flowability, drug content, preparation yield, dissolution profile, drug solubility enhancement, and storage stability. Subsequently, tablets of the granules were prepared and characterized in terms of their drug content uniformity, weight variation, friability, hardness, dissolution profile, and solubility enhancement. The results showed that nanoplex in SG granules was embedded in dense amorphous alginate matrix, while nanoplex in SFD granules was dispersed in porous crystalline mannitol particles. Despite their distinct morphology, physical form, and dissolution profile, the two granules exhibited similar drug solubility enhancements. Both granules were readily compacted into tablets with minimal changes in their dissolution and solubility enhancement after tableting. The present work demonstrated SG and SFD as viable granulation methods of nanoplex, with SG granules exhibiting superior flowability, stability, but lower yield.

In-situ investigation of solid phase evolution during lyophilization of mannitol-based antibody formulations using an XRPD climate chamber

Crystalline mannitol is commonly used as bulking agent in antibody formulations to provide structure to the lyophilized cake and prevent collapse. Depending on the lyophilization process conditions mannitol can either crystallize as α-, β-, δ-mannitol, mannitol-hemihydrate, or transition to its amorphous state. While crystalline mannitol helps to create a firmer cake structure this is not true for amorphous mannitol. The hemihydrate is also an undesired physical form as it may reduce the drug product stability by releasing bound water molecules into the cake. Our aim was to simulate lyophilization processes in an X-ray powder diffraction (XRPD) climate chamber. In the climate chamber, the process can be carried out fast with low sample quantities to determine optimal process conditions. Insights on the emergence of desired anhydrous mannitol forms helps to adjust the process parameters in larger scale freeze-dryers. In our study we have identified the critical process steps for our formulations and then varied relevant process parameters, which were the annealing temperature, annealing time and temperature ramp rate of the freeze-drying process. Furthermore, the effect of the presence of antibodies on excipient crystallization was investigated by performing the studies on placebo solutions versus two respective antibody formulations. A comparison of the products obtained in a freeze-dryer and the simulated process in the climate chamber showed good accordance demonstrating the method as suitable tool to identify ideal process conditions on a laboratory scale.

Unveiling the importance of process parameters on droplet shrinkage and crystallization behaviors of easily crystalline material during spray drying

This study investigated droplet shrinkage and crystallization behaviors of easily crystalline mannitol model material. Different sized droplets were generated from feeds of different solid contents and dried into uniform microparticles via a microfluidic jet spray dryer. The droplet shrinkage behavior was characterized by comparing the size of dried microparticles and initially atomized droplets. Morphology and polymorphs of the microparticles were analyzed via SEM and XRD. Droplet shrinkage and crystallization behaviors were shown to be closing related to size, morphology, and polymorph of the spray dried microparticles. Droplets with small size or low solid content followed perfect shrinkage behavior, while droplets with larger sizes or higher solid contents demonstrated less shrinkage due to the earlier precipitation of a crust. Dense, partially hollow, or hollow spherical particles with different polymorphs (mixture of α- and β-mannitol or fully β-mannitol) were obtained depending on the process parameters, indicating the occurrence of different crystallization behaviors.

Scaled-Up Production and Tableting of Grindable Electrospun Fibers Containing a Protein-Type Drug.

The aims of this work were to develop a processable, electrospun formulation of a model biopharmaceutical drug, β-galactosidase, and to demonstrate that higher production rates of biopharmaceutical-containing fibers can be achieved by using high-speed electrospinning compared to traditional electrospinning techniques. An aqueous solution of 7.6 w/w% polyvinyl alcohol, 0.6 w/w% polyethylene oxide, 9.9 w/w% mannitol, and 5.4 w/w% β-galactosidase was successfully electrospun with a 30 mL/h feeding rate, which is about 30 times higher than the feeding rate usually attained with single-needle electrospinning. According to X-ray diffraction measurements, polyvinyl alcohol, polyethylene oxide, and β-galactosidase were in an amorphous state in the fibers, whereas mannitol was crystalline (δ-polymorph). The presence of crystalline mannitol and the low water content enabled appropriate grinding of the fibrous sample without secondary drying. The ground powder was mixed with excipients commonly used during the preparation of pharmaceutical tablets and was successfully compressed into tablets. β-galactosidase remained stable during each of the processing steps (electrospinning, grinding, and tableting) and after one year of storage at room temperature in the tablets. The obtained results demonstrate that high-speed electrospinning is a viable alternative to traditional biopharmaceutical drying methods, especially for heat sensitive molecules, and tablet formulation is achievable from the electrospun material prepared this way.

Enhanced Aerosolization of High Potency Nanoaggregates of Voriconazole by Dry Powder Inhalation.

Invasive pulmonary aspergillosis is a deadly fungal infection with a high mortality rate, particularly in patients having undergone transplant surgery. Voriconazole, a triazole antifungal pharmaceutical product, is considered as a first-line therapy for invasive pulmonary aspergillosis, and exhibits efficacy even for patients who have failed other antifungal drug therapies. The objective of this study is to develop high potency nanoaggregates of crystalline voriconazole composition for dry powder inhalation using the particle engineering process, thin film freezing. In this study, mannitol at low concentrations acted as a surface texture-modifying agent, and we evaluated the physicochemical and aerodynamic properties of the voriconazole formulations containing different amounts of mannitol. In vitro aerosol performance data demonstrated that powder formulations consisting of 90 to 97% (w/w) voriconazole were the optimum for inhalation with a fine particle fraction (% of delivered dose) as high as 73.6 ± 3.2% and mass median aerodynamic diameter of 3.03 ± 0.17 μm when delivered by a commercially available device. The thin film freezing process enabled phase-separated submicron crystalline mannitol to be oriented such as to modify the surface texture of the crystalline voriconazole nanoaggregates, thus enhancing their aerosolization. Addition of as low as 3% (w/w) mannitol significantly increased the fine particle fraction (% of metered dose) of voriconazole nanoaggregates when compared to compositions without mannitol (40.8% vs 24.6%, respectively). The aerosol performance of the voriconazole nanoaggregates with 5% (w/w) mannitol was maintained for 13 months at 25 °C/60% RH. Therefore, voriconazole nanoaggregates having low amounts of surface texture-modifying mannitol made by thin film freezing are a feasible local treatment option for invasive pulmonary aspergillosis with high aerosolization efficiency and drug loading for dry powder inhalation.

Mechanisms by which crystalline mannitol improves the reconstitution time of high concentration lyophilized protein formulations

Lyophilized high concentration protein formulations often have long and variable reconstitution times. The aim is to understand the role of crystalline mannitol in lowering the reconstitution time of these formulations. Novel methods were developed for quantifying the effect of crystalline mannitol on cake attributes influencing reconstitution, specifically, cake wettability, liquid penetration into the cake and cake disintegration. Amorphous and partially crystalline cakes were obtained by varying the freeze-drying conditions, particularly, the freezing rate (slow vs. fast), annealing (annealed vs. unannealed), and primary drying (aggressive vs. conservative). Mannitol crystallinity was quantified using X-ray powder diffractometry. Phase separation of crystalline mannitol from the amorphous, protein rich matrix improved wettability of the cake solids and promoted penetration of the reconstitution fluid into the cake interior. The partially crystalline cakes offered less resistance to crushing in the dry state than the amorphous cakes. Crystalline mannitol provided “weak points” in the freeze-dried cakes, potentially enabling easier cake disintegration upon addition of the reconstitution fluid. There was no evident correlation between the degree of crystallinity and reconstitution time. While crystalline mannitol generally decreased reconstitution time by favorably affecting the cake attributes influencing reconstitution, it did not always reduce reconstitution time.

Characterization of mannitol granules and powder: A comparative study using two flowability testers

In the manufacture of tablets, especially in direct tableting processes, the flowability of excipient powders and formulated powders is one of the most important characteristics. In the past two decades, orally disintegrating tablets (ODTs) have been prepared as popular solid dosage forms for elderly patients. Many types of mannitol granules have been developed and marketed as new pharmaceutical excipients for ODTs, owing to the solubility and palatability of mannitol. Characterizing the flow behaviors of these mannitol granules is essential to their use.The flowability of mannitol excipients was the focus of the present study. A fine crystalline mannitol powder, eight commercial types of mannitol granules and four types of mannitol mixture granules were evaluated. Two flowability testers were used for comparing and analyzing the samples’ flowabilities. A variety of methodologies were used: an assessment using Carr’s index, a shear test and a dynamic flow test. Mannitol powder showed the lowest Carr’s index, meaning the lowest flowability. Spherical mannitol granules showed the lowest angle of internal friction in the shear test and extremely low basic flow energy in the dynamic flow test. Larger granules showed relatively high values for Carr’s index, but also a relatively high total flow energy.

Deformation behavior of crystallized mannitol during compression using a rotary tablet press simulator

Mannitol is commonly used as a pharmaceutical excipient for tablets; the most widely used oral dosage form for drug delivery. For tableting, mannitol is provided in two different forms: native crystals and textured particles. In order to optimize its formulation, a good understanding of the mechanical behavior mechanism of mannitol is necessary. Thus, the aim of this study is to evaluate the deformation mechanism of native mannitol crystals presenting different particle sizes. Pharmaco-technical and compression studies were performed using mannitol with different mean diameters (160 µm, 50 µm and 25 µm). Lactose (monohydrate) and microcrystalline cellulose were used as brittle and plastic reference materials, respectively. Tableting tests and mathematical models, HECKEL and WALKER, were used to study the deformation mechanism of mannitol (β). Mean Yield Pressure (Py) and WALKER coefficient (W) values showed that the studied crystalline mannitol presents a deformation mechanism close to brittle material. A particle-size analyzer was used at different pulverization pressures to show the high sensibility of the mannitol particles to fragmentation when exposed to high pressures, especially for particles presenting 160 µm size. Scanning Electron Microscopy (SEM) was used to show the fragmentation after high-pressure measurements.

Twin-screw granulation: Understanding the mechanical properties from powder to tablets

Granulation is a technique commonly used before tabletting because it solves powder handling problems and ensures uniform filling of the compression dies. However, granulation can have an adverse impact on powder transformation into a tablet; i.e. tabletability.The aim of this work is to examine the effect of continuous wet granulation using twin-screw granulator (TSG) on the tabletability of the granulated materials. Also, the study investigates the mechanisms that dictate the change in tabletability after wet granulation using TSG.Granules and tablet properties were characterised using a range of mechanical and X-ray analysis techniques. It was found that wet granulation using TSG has an impact on the tabletability of the granulated pharmaceutical excipients. The presented work suggests that there is a correlation between the yield pressure, plastic and elastic work of the primary powder and the percentage of change in tabletability after granulation. The study found that plastically deformable materials like microcrystalline cellulose (MCC) experience a significant reduction of tabletability (up to 67%) when granulated compared with the direct compression of its powder. On the other hand, brittle materials like crystalline mannitol C160 or calcium phosphate dibasic anhydrous maintain their tabletability after twin-screw granulation.The presented results show that the granule size of microcrystalline cellulose and mannitol 100 SD does not affect tabletability for the range studied. However increasing the strength of granules was found to cause reduction of the tabletability. On the other hand, the granule size of mannitol C160 and calcium phosphate dibasic anhydrous did affect its tabletability.

Mechanism of echogenicity of echogenic liposomes

Liposomes prepared by a freeze-drying technique in the presence of mannitol have proved to be echogenic. However, the mechanism of echogenicity is not well understood. Here, we attempt to explain it. It was observed that only freeze-dried mannitol (without lipids) generates a strong scattered response because it generates bubble upon dissolution in water. The bubble generation was confirmed optically under an optical microscope. During the dissolution of the crystalline mannitol, the concentration of mannitol becomes locally very high. As the solute (mannitol) concentration increases, the saturated dissolved gas concentration decreases. Therefore, the dissolved gas in the solution near the dissolving crystal is in a supersaturated state. Upon sufficient supersaturation, bubble nucleation takes place. We found that freeze-dried crystalline excipients such as mannitol facilitate bubble nucleation compared to freeze-dried glassy excipient such as trehalose because of differences in surface morphology.

Inhalable siRNA-loaded nano-embedded microparticles engineered using microfluidics and spray drying

Medicines based on small interfering RNA (siRNA) are promising for the treatment of a number of lung diseases. However, efficient delivery systems and design of stable dosage forms are required for inhalation therapy, as well as cost-effective methods for manufacturing of the final product. In this study, a 3D-printed micromixer was used for preparation of siRNA-dendrimer nanocomplexes, which were subsequently processed into microparticle-based dry powders for inhalation using spray drying. By applying the disposable micromixer, nanocomplexes were prepared of an average hydrodynamic diameter comparable to that of nanocomplexes prepared by manual mixing, but with narrower size distribution and low batch-to-batch variation. The nanocomplexes were processed into nanoembedded microparticles using different saccharide excipients. Data showed that siRNA integrity and bioactivity are retained after processing, and nanocomplexes could be reconstituted from the dry powders. The amorphous saccharide excipients trehalose and inulin provided better stabilization than crystalline mannitol, and they enabled full reconstitution of the nanocomplexes. In particular, a binary mixture of trehalose and inulin showed optimal stabilization, and enhanced cellular uptake and gene silencing efficiency. This study demonstrates that inexpensive and scalable micromixers can be used to optimize the production of siRNA-dendrimer nanocomplexes, and they can be applied in combination with spray drying for the engineering of dry powder formulations suitable for delivery of siRNA to the therapeutic target site.

Role of mannitol on the echogenicity of echogenic liposomes (ELIPs)

Although echogenic liposomes (ELIP), specially prepared lipid-bilayer coated vesicles, have proved quite effective as scatterers, the exact mechanism of their echogenicity is not well understood. However, freeze-drying in presence of mannitol has proved to be a critical component of the elaborate preparation protocol of these ELIPs. Here, we investigate the role played by mannitol in ensuring echogenicity. We investigated mannitol along with other similar sugars, such as sucrose, trehalose, and xylitol. Mannitol when freeze-dried assumes a crystalline state, while other sugars adopt glassy states. Aqueous solutions of each sugar were prepared and freeze-dried. The freeze-dried samples were re-dissolved in water and the scattered response from the solution was measured. While the solution of mannitol was found echogenic, indicating production of bubbles, others were not. If the sample was freeze-thawed before dissolution, it was not echogenic. The crystalline state of the excipient, mannitol, was necessary for echogenicity. Furthermore, other excipients such as glycine and meso-erythritol, which attain crystalline state upon freeze-drying, also were found to give rise to echogenicity in solution. The production of bubbles by crystalline mannitol upon dissolution indicates a possible mechanism of echogenicity of ELIPs.

The Development of Self-nanoemulsifying Liquisolid Tablets to Improve the Dissolution of Simvastatin.

The aim of this work was to develop self-nanoemulsifying liquisolid tablets (SNELT) to enhance the dissolution profile of poorly water-soluble simvastatin. SNELT present a unique technique of incorporating self-nanoemulsifying drug delivery systems (SNEDDS) into tablets. Optimized SNEDDS containing different oils, Cremophor® RH 40 (surfactant) and Transcutol® HP (co-surfactant), at different ratios, were used as liquid vehicles and loaded on carrier material, microcrystalline cellulose (MCC), and coating material, Cab-o-sil® H-5 (nanosize colloidal silicon dioxide) powders at different loading factors (L f ) and fixed excipient ratio (R = 20). The effect of using different carrier materials, granulated mannitol, crystalline mannitol, and maltodextrin with MCC at different ratios, and different coating materials, Aeroperl® 300 (granulated silicon dioxide) at different excipient ratios (R), was also emphasized. Liquisolid powders with acceptable flowability, compressibility, and tablet weight were compressed into tablets. Results revealed that powders with L f = 0.2 possessed the most preferable properties to be tableted. SNELT with MCC and Cab-o-sil® H-5 were able to generate nanoemulsions and to enhance the cumulative percent of drug dissolved at 60min significantly to reach up to 90%. Furthermore, using carrier material (granulated mannitol/MCC at ratio 3:1) enabled SNELT to disperse into nanoemulsion (Z-average = 25.7nm) and improved the dissolution profile significantly to reach 99% at 60min. Cab-o-sil® H-5 proved to be a better coating material compared to Aeroperl® 300. In conclusion, developed SNELT were promising in enhancing in vitro dissolution of simvastatin and excipients highly affect SNELT's performance.

In-situ crystallization of particles in a counter-current spray dryer

This paper evaluated the potential of counter current spray drying to produce engineered crystalline particles in-situ. One main feature of the counter current spray dryer is in inducing droplet drying history with a progressively increasing drying rate; in contrast to a co-current spray dryer in which the particle is immediately confronted with high driving force of evaporation. In addition, counter current dryer provides higher residence time for particles within the drying chamber. This work explored the manipulation of these unique features of counter current spray drying to control the crystallinity of the particles formed. Sucrose, lactose and mannitol were spray dried as model materials exhibit contrasting crystallization. Counter current spray drying was suitable in producing well defined crystalline lactose particles mainly due to the higher residence time. The produced lactose particles were composed of agglomeration of fine thin lactose crystals. Surprisingly, the counter current spray drying with relatively lower initial evaporation rate resulted in amorphous mannitol particles. Fully crystalline mannitol was produced when the feed spray temperature was elevated leading to rapid supersaturation. This may be an important strategy to control the crystallinity of mannitol particles particularly for pharmaceutical application. Similar feed pre-heating strategy in conjunction with counter current spray drying was used for sucrose drying. Crystalline sucrose was achieved with relatively lower drying temperature. This will be a valuable strategy for producing free flowing sucrose particles specifically for the food industry.

Effects of cooling rate in microscale and pilot scale freeze-drying – Variations in excipient polymorphs and protein secondary structure

Microscale freeze-drying makes rapid process cycles possible for early-stage formulation development. To investigate the effects of equipment scale and cooling rate on the solid state properties and the protein’s secondary structure of a sample, three binary formulations of catalase were prepared and freeze-dried with sucrose, mannitol, or (2-hydroxypropyl)-β-cyclodextrin (HP-β-CD). The protein's secondary structure was assessed using attenuated total reflection Fourier transform infrared spectroscopy (FTIR-ATR). The solid state properties were assessed using differential scanning calorimetry (DSC) and X-ray diffraction (XRD). The results were interpreted with respect to the biological activity of catalase after its reconstitution. According to the results of both the protein secondary structure and the reconstituted biological activity, scale-up could be achieved with the sucrose-catalase formulation when it was prepared at a high cooling rate and with the mannitol-catalase formulation when prepared at a low cooling rate. However, differences in the polymorph composition of crystalline mannitol were noted. No cooling rate influence was found with the HP-β-CD formulation. The results clearly indicate that the effects of the cooling rate should be closely examined during microscale formulation development and scale-up of the freeze-drying process.

A Holistic Multi Evidence Approach to Study the Fragmentation Behaviour of Crystalline Mannitol.

Mannitol is an essential excipient employed in orally disintegrating tablets due to its high palatability. However its fundamental disadvantage is its fragmentation during direct compression, producing mechanically weak tablets. The primary aim of this study was to assess the fracture behaviour of crystalline mannitol in relation to the energy input during direct compression, utilising ball milling as the method of energy input, whilst assessing tablet characteristics of post-milled powders. Results indicated that crystalline mannitol fractured at the hydrophilic (011) plane, as observed through SEM, alongside a reduction in dispersive surface energy. Disintegration times of post-milled tablets were reduced due to the exposure of the hydrophilic plane, whilst more robust tablets were produced. This was shown through higher tablet hardness and increased plastic deformation profiles of the post-milled powders, as observed with a lower yield pressure through an out-of-die Heckel analysis. Evaluation of crystal state using x-ray diffraction/differential scanning calorimetry showed that mannitol predominantly retained the β-polymorph; however x-ray diffraction provided a novel method to calculate energy input into the powders during ball milling. It can be concluded that particle size reduction is a pragmatic strategy to overcome the current limitation of mannitol fragmentation and provide improvements in tablet properties.

Production and Characterization of Rapidly Dissolving Cryopellets

The procedure described in this study provides a platform technology for rapidly dissolving, single-dosed cryopellets. The different steps during cryopellet production were investigated, covering droplet generation, droplet freezing in liquid nitrogen (LN₂) as well as cryopellet properties. With the setup developed, uniform droplets between 4 and 14 μL were produced. The freezing behavior was similar to approaches reported in the literature. A weight loss reported for droplets frozen in LN₂ could not be confirmed. Mechanical stability as observed with texture analysis as well as dissolution time increased with increasing solid content. All cryopellets immediately disintegrated when in contact with the dissolution medium. The dissolution times of amorphous sucrose and trehalose-based cryopellets at different solid content levels were comparable. Crystalline mannitol cryopellets showed in general a higher dissolution time. The formation of δ-mannitol potentially makes the cryopellets suitable as an intermediate product for tableting.

Multi-breath dry powder inhaler for delivery of cohesive powders in the treatment of bronchiectasis

A series of co-engineered macrolide–mannitol particles were successfully prepared using azithromycin (AZ) as a model drug. The formulation was designed to target local inflammation and bacterial colonization, via the macrolide component, while the mannitol acted as mucolytic and taste-masking agent. The engineered particles were evaluated in terms of their physico-chemical properties and aerosol performance when delivered via a novel high-payload dry powder Orbital™ inhaler device that operates via multiple inhalation manoeuvres. All formulations prepared were of suitable size for inhalation drug delivery and contained a mixture of amorphous AZ with crystalline mannitol. A co-spray dried formulation containing 200 mg of 50:50 w/w AZ: mannitol had 57.6% ± 7.6% delivery efficiency with a fine particle fraction (≤6.8 µm) of the emitted aerosol cloud being 80.4% ± 1.1%, with minimal throat deposition (5.3 ± 0.9%). Subsequently, it can be concluded that the use of this device in combination with the co-engineered macrolide–mannitol therapy may provide a means of treating bronchiectasis.