Influence of carrier surface fines on dry powder inhalation formulations

Background: The performance of carrier-based dry powder inhalation formulations strongly depends on particle interactions between the drug and the carrier. Among other factors like particle size and shape, surface properties of the interacting partners play a decisive role. This study aims at investigating the effect of carrier surface characteristics on the in vitro deposition of ordered mixtures containing salbutamol sulfate as a drug and lactose and mannitol as model carrier compounds. Methods: The wet decantation method was used to remove the carrier fines adhered to the carrier surface and to obtain smoother carrier surfaces. In vitro deposition was investigated using the Next Generation Impactor. Results: In comparison to the formulations containing untreated carriers, the removal of carrier fines by wet decantation leads to a reduced in vitro deposition. This is possibly caused by an increase in the surface smoothness and an increase in the number of high energetic spots.     

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.     

Carrier-free combination dry powder inhaler formulation of ethionamide and moxifloxacin for treating drug-resistant tuberculosis

This study aimed to develop a combination dry powder formulation of ethionamide and moxifloxacin HCl as this combination is synergistic against drug-resistant Mycobacterium tuberculosis (Mtb). L-leucine (20% w/w) was added in the formulations to maximize the process yield. Moxifloxacin HCl and/or ethionamide powders with/without L-leucine were produced using a Buchi Mini Spray-dryer. A next generation impactor was used to determine the in vitro aerosolization efficiency. The powders were also characterized for other physicochemical properties and cytotoxicity. All the spray-dried powders were within the aerodynamic size range of <5.0?µm except ethionamide-only powder (6.0?µm). The combination powders with L-leucine aerosolized better (% fine particle fraction (FPF): 61.3 and 61.1 for ethionamide and moxifloxacin, respectively) than ethionamide-only (%FPF: 9.0) and moxifloxacin-only (%FPF: 30.8) powders. The combination powder particles were collapsed with wrinkled surfaces whereas moxifloxacin-only powders were spherical and smooth and ethionamide-only powders were angular-shaped flakes. The combination powders had low water content (<2.0%). All the powders were physically stable at 15% RH and 25?±?2?°C during 1-month storage and tolerated by bronchial epithelial cell-lines up to 100?µg/ml. The improved aerosolization of the combination formulation may be helpful for the effective treatment of drug-resistant tuberculosis. Further studies are required to understand the mechanisms for improved aerosolization and test the synergistic activity of the combination powder.     

Influence of surface interaction between drug and excipient in binary mixture for dry powder inhaler applications

The present study documents the drug-excipient incompatibility in the physical mixtures and its influence on bulk homogeneity and flowability for dry powder inhalers (DPI) applications. Binary mixtures with the model drugs (aceclofenac; salbutamol sulphate) and lactose monohydrate were prepared separately at varied drug loading (1–33 wt.%), and their physicochemical properties were assessed using various characterization techniques. The DSC, P-XRD and FT-IR studies show a significant shift in the signature peak of drug and excipient while ss-NMR, LC-MS show the absence of peaks. In contrast, new peaks are observed in LC-MS and GC studies. The insights are comprehended through a series of XPS studies. The findings indicated the formation of condensed or addition compound. This is attributed to an interaction between polar protic groups (-NH-, -COOH, -OH) and hemiacetal carbon (HO-C-OR) of drug and excipient in the solid-state. It induces crystal strain and alters bulk properties related to mixing (relative standard deviation, %RSD), cohesion and flow function coefficient (FFC). However, surface modification of excipient using MgSt and aerosil R972 (model nano-particle) eliminates such inter-particle interactions, crystal level changes. It improves the bulk properties of binary mixtures pivotal for DPI performance.     

Development of dry powder inhaler formulation loaded with alendronate solid lipid nanoparticles: solid-state characterization and aerosol dispersion performance

Alendronate sodium is a bisphosphonate drug used for the treatment of osteoporosis and acts as a specific inhibitor of osteoclast-mediated bone resorption. Inhalable solid lipid nanoparticles (SLNs) of the alendronate were successfully designed and developed by spray-dried and co-spray dried inhalable mannitol from aqueous solution. Emulsification technique using a simple homogenization method was used for preparation of SLNs. In vitro deposition of the aerosolized drug was studied using a Next Generation Impactor at 60?L/min following the methodology described in the European and United States Pharmacopeias. The Carr’s Index, Hausner ratio and angle of repose were calculated as suitable criteria for estimation of the flow behavior of solids. Scanning electron microscopy showed spherical particle morphology of the respirable particles. The proposed spray-dried nanoparticulate-on-microparticles dry powders displayed good aerosol dispersion performance as dry powder inhalers with high values in emitted dose, fine particle fraction and mass median aerodynamic diameter. These results indicate that this novel inhalable spray-dried nanoparticulate-on-microparticles aerosol platform has great potential in systemic delivery of the drug.     

Influence of surface characteristics of modified glass beads as model carriers in dry powder inhalers (DPIs) on the aerosolization performance

The aim of this work is to investigate the effect of surface characteristics (surface roughness and specific surface area) of surface-modified glass beads as model carriers in dry powder inhalers (DPIs) on the aerosolization, and thus, the in vitro respirable fraction often referred to as fine particle fraction (FPF). By processing glass beads in a ball mill with different grinding materials (quartz and tungsten carbide) and varying grinding time (4?h and 8?h), and by plasma etching for 1?min, glass beads with different shades of surface roughness and increased surface area were prepared. Compared with untreated glass beads, the surface-modified rough glass beads show increased FPFs. The drug detachment from the modified glass beads is also more reproducible than from untreated glass beads indicated by lower standard deviations for the FPFs of the modified glass beads. Moreover, the FPF of the modified glass beads correlates with their surface characteristics. The higher the surface roughness and the higher the specific surface area of the glass beads the higher is the FPF. Thus, surface-modified glass beads make an ideal carrier for tailoring the performance of DPIs in the therapy of asthma and chronically obstructive pulmonary diseases.     

Numerical investigation of powder dispersion mechanisms in Turbuhaler and the contact electrification effect

Powder dispersion in dry powder inhalers (DPI) is affected by factors such as device design and flow rate, but also electrification due to particle–particle/device collisions. This work presented a CFD-DEM study of powder dispersion in Turbuhaler®, aiming to understand the effect of electrostatic charge on the dispersion mechanisms. The device geometry was reconstructed from CT-scan images of commercial Turbuhaler device. Different work functions were applied to the active pharmaceutical ingredient (API) powder and the device wall. Electrostatic charges were accumulated on the API particles due to contact potential difference (CPD) between the particles and the device wall. Results showed that both the chamber and the spiral mouthpiece played an important role in de-agglomeration of powders caused by particle–wall impactions. With increasing flow rates, the performance of the device was improved with higher emitted dose (ED) and fine particle fractions (FPF). The electrostatic charging of the particles was enhanced with higher CPD and higher flow rates, but the electrostatic charging had a minimum effect on powder dispersion and deposition with slight reduction in ED and FPF. In conclusion, the van der Waals force is still the dominant adhesive inter-particle force, and the dispersion efficiency is affected by the flow rate rather than contact electrification of particles. Future work should focus on the effect of highly charged particles emitted from the inhaler on the deposition in the airway.     

Solventless dry powder coating for sustained drug release using mechanochemical treatment based on the tri-component system of acetaminophen,carnauba wax and glidant

Objective: Solventless dry powder coating methods have many advantages compared to solvent-based methods: they are more economical, simpler, safer, more environmentally friendly and easier to scale up. The purpose of this study was to investigate a highly effective dry powder coating method using the mechanofusion system, a mechanochemical treatment equipped with high compressive and shearing force.Materials and methods: Acetaminophen (AAP) and carnauba wax (CW) were selected as core particles of the model drug and coating material, respectively. Mixtures of AAP and CW with and without talc were processed using the mechanofusion system.Results: Sustained AAP release was observed by selecting appropriate processing conditions for the rotation speed and the slit size. The dissolution rate of AAP processed with CW substantially decreased with an increase in talc content up to 40% of the amount of CW loaded. Increasing the coating amount by two-step addition of CW led to more effective coating and extended drug release. Scanning electron micrographs indicated that CW adhered and showed satisfactory coverage of the surface of AAP particles.Conclusion: Effective CW coating onto the AAP surface was successfully achieved by strictly controlling the processing conditions and the composition of core particles, coating material and glidant. Our mechanochemical dry powder coating method using the mechanofusion system is a simple and promising means of solventless pharmaceutical coating.     

The Effect of Relative Humidity on Electrostatic Charge Decay of Drugs and Excipient Used in Dry Powder Inhaler Formulation

Electrostatic forces arising from charge accumulation on drug and excipient powders cause agglomeration and adhesion of particles to solid surfaces and problems during the manufacture and use of many pharmaceutical dosage forms, including dry powder inhalers (DPIs). The ability of materials to dissipate the acquired charge is therefore important and the aim of this work was to investigate the charge decay of salbutamol sulfate, ipratropium bromide monohydrate and α-lactose monohydrate. Differences in tri-phasic charge decay rates of the three materials in the order ipratropium bromide > lactose > salbutamol sulfate were demonstrated after corona charging and all materials showed an increased decay rate as the relative humidity was increased up to 86%. Preformulation knowledge of charge accumulation and decay in such materials will contribute to formulation, manufacture and performance of pharmaceutical dosage forms in general, and in particular DPIs.     

The effect of nano-sized stainless steel powder addition on mechanical and physical properties of micropowder injection molded part

Micropowder injection molding (μPIM) is a new technology that has potential in the mass production of microcomponents. A bulk material of nanoparticles possesses completely different properties from those of large-sized particles. The main objective of this study is to study the effects of nano-sized powder addition on the μPIM process of powder-polymer mixtures for the fabrication of miniature parts. The binder systems consist of polyethylene glycol (PEG), polymethyl methacrylate (PMMA), and stearic acid (SA) with different powder loading blended with powders. The results indicate that increasing the nanopowder content to 30 wt.% increased the powder loading and decreased the injection and sintering temperatures. The sintered parts had densities of 96% of the theoretical value. High physical and mechanical properties of the sintered specimen were achieved with the 30 wt.% nano-sized powder sintered at 1200 °C at a heating rate of 5 °C/min under vacuum atmosphere. A significant reduction of the surface roughness of the sintered parts using the nano–microhybrid powder (S_a = 0.365 μm) was observed compared with the sintered parts with only micropowder (S_a = 1.002 μm). Using nanopowders, the hardness also increased from 182 HV to 221 HV with a linear shrinkage of approximately 9%, which is less than that of the micropowders (18%).     

Screening of sugars and cyclodextrins as carriers in montelukast dry powder inhalers processed by spray freeze drying

The purpose of this study was to develop a site targeting montelukast sodium (MTK) microparticles as a respiratory drug delivery system using the spray freeze drying (SFD) process. A range of sugars and cyclodextrins (CDs) were screened as carrier in order to find compatible excipients for the preparation of dry powder inhalers (DPIs). The physical characteristics of collected powders were studied by scanning electron microscopy (SEM), laser light scattering, differential scanning calorimetry (DSC), and X-ray diffraction (XRD). The aerodynamic behavior of the particles was also assessed using twin stage impinge (TSI). In the presence of simple sugars as carriers, highly porous particles in irregular shapes were produced. The use of CDs resulted in the formation of spherical particles with high porosity. Among all carriers that were used during the preparation of powders, raffinose had the best aerodynamic behavior with a fine particle fraction (FPF) of 60 % in sugar groups, while the lowest FPF was related to trehalose as carrier. Powders containing CDs mostly showed proper aerodynamic behavior, especially in formulations containing alfa-cyclodextrin (A-CD), beta-cyclodextrin (β-CD), and highly branched cyclic dextrin (HBCD). Overall, data indicated that the CDs were excellent excipients for use with MTK for respiratory drug delivery.     

The effect of limestone powder,fly ash and silica fume on the properties of self-compacting repair mortars

Self-compacting repair mortars (SCRM) are preferred for the rehabilitation and repair of reinforced concrete structures especially at narrow mould systems. Self compactability and stability are susceptible to ternary effects of chemical and mineral admixture type and their content. In this study, the effect of limestone powder (LP) on the properties of SCRM has been compared with other mineral additives (silica fume (SF) and fly ash (FA) and their combinations) effects. Fresh properties, flexural and compressive strengths and water absorption properties of mortars were determined. The use of SF in mortars significantly increased the dosage of superplasticiser (SP). At the same constant SP dosage (0·8%) and mineral additives content (30%), LP can better improve the workability than that of control and FA mixtures by 19% and 27%. However, the results of this study suggest that certain FA, SF and LP combinations can improve the workability of SCRMs, more than FA, SF and LP alone. LP can have a positive influence on the mechanical performance at early strength development while SF improved aggregate-matrix bond resulting from the formation of a less porous transition zone in mortar. SF can better reducing effect on total water absorption while FA and LP will not have the same effect, at 28 days.     

The effect of ethanol on the formation and physico-chemical properties of particles generated from budesonide solution-based pressurized metered-dose inhalers

The aerosol performance of budesonide solution-based pressurized metered-dose inhalers (HFA 134a), with various amounts of ethanol (5–30%, w/w) as co-solvents, was evaluated using impaction and laser diffraction techniques. With the increase of ethanol concentration in a formulation, the mass median aerodynamic diameter was increased and the fine particle fraction showed a significant decline. Although data obtained from laser diffraction oversized that of the impaction measurements, good correlations were established between the two sets of data. Particles emitted from all the five formulations in this study were amorphous, with two different types of morphology – the majority had a smooth surface with a solid core and the others were internally porous with coral-like surface morphology. The addition of ethanol in the formulation decreased the percentage of such irregular-shape particles from 52% to 2.5% approximately, when the ethanol concentration was increased from 5% to 30%, respectively. A hypothesis regarding the possible particle formation mechanisms was also established. Due to the difference of droplet composition from the designed formulation during the atomization process, the two types of particle may have gone through distinct drying processes: both droplets will have a very short period of co-evaporation, droplets with less ethanol may be dried during such period; while the droplets containing more ethanol will undergo an extra condensation stage before the final particle formation.     

Investigation of the molecular state of 4-aminosalicylic acid in matrix formulations for dry powder inhalers using solid-state fluorescence spectroscopy of 4-dimethylaminobenzonitrile

Carrier-free method is an alternative approach for dry powder inhaler (DPI) formulations, which overcome poor drug mobility and distribution. Here we investigated the properties of an active pharmaceutical ingredient (API) within composite particles. We used highly-branched cyclic dextrin (HBCD) as the excipient matrix that was prepared using a spray-drying technique. 4-Aminosalicylic acid (4-ASA) and 4-dimethylaminobenzonitrile (DMABN) were selected as a hydrophilic second-line antitubercular agent and a surrogate for 4-ASA as a model compound, respectively. The spray-dried particles (SDPs) containing 4-ASA or DMABN with HBCD had geometric median diameters (D₅₀) of 2.34 ± 0.07 μm and 2.26 ± 0.10 μm, respectively. Further, the in vitro aerodynamic properties were similar for SDPs containing 4-ASA and DMABN with HBCD. To determine the properties of APIs within composite particles, we performed solid-state fluorescence spectroscopy of DMABN. As a candidate excipient, hydroxypropyl methylcellulose (HPMC) was compared to HBCD. We determined the intensity ratio of twisted intramolecular charge transfer (TICT) emission to locally excited emission within the excipient matrix environment. The HBCD matrix environment was better than HPMC to trigger a more robust TICT reaction of DMABN. A potent state-changing interaction of APIs occurred in the HBCD matrix environment versus another excipient environment.     

Improved effect of autoclave processing on size reduction,chemical structure,nutritional, mechanical and in vitro digestibility properties of fish bone powder

Global fisheries production has increased up to 200 MT which resulted in 20 MT of waste. Discards or by-products from aquatic processing have remained a big challenge for waste management and their efficient use for human food. In the present study, we prepared fish bone powder (FBP) from grass carp (Ctenopharyngodon idella) using autoclave processing and compared its characteristics with simple heat treatment as well as with size reduction process. The results showed that autoclave processing with reduced particle size significantly (p < 0.05) increased ζ-potential (15.2 mV) and facilitated size reduction (5.2 µm), while only heat treatment improved the proximate composition. The collagen denaturation was followed using Fourier Transform Infrared Spectroscopy (FTIR) at 1338 cm⁻¹ peak while amide regions, such as amide I (1590–1720 cm⁻¹), amide II (1560 cm⁻¹) and amide III (1237 cm⁻¹), carbonate (870 cm⁻¹) and phosphate (565 and 1030 cm⁻¹) groups were identified in all treatments. The scanning electron microscopy showed the variation in particle size, and porous structure of FBP. Moreover, calcium and protein in vitro digestibility was significantly high in autoclave processing groups. The results of amino acid analysis at intestinal stage of in vitro model digestion depicted that the concentration of essential amino was higher than the cereal proteins. The results propose the feasibility of using autoclave processing as an alternative to the thermal treatment to prepare FBP.     

The effect of an added seed on the phase transformation and the powder properties in the fabrication of Al2O3 powder by the sol-gel process

-Al₂O₃ powder was produced by the sol-gel process. The prepared sol-gels were seeded with 1.5 wt% powder (0.12m). The phase transformation of Boehmite into -Al₂O₃ and also the particle size distribution of the transformed -Al₂O₃ were strongly influenced by seeding and the heating rate during calcination. -Al₂O₃ seed particles have been shown to act as a nuclei for the transition of - to -Al₂O₃ and also to increase the driving force of the phase transformation, which consequently lowers the transformation temperature by about 200 °C. The particles derived from the seeded sol-gels retarded the formation of vermicular microstructures and were finer than those in the unseeded case. The seeding and the control of the heating rate during calcination could inhibit the grain growth due to transformation into -Al₂O₃. Fine particles which are homogeneous and have a high sinterability at lower temperatures could be obtained.     

The effect of composition segregation on the friction and wear properties of ZA48 alloy in dry sliding condition

In this study, the effect of composition segregation on the wear resistance of high aluminum zinc-based alloy is investigated. The test results show that the improving wear resistance is due to a combined action of α and η phase. The rich solid solution of α−Al has higher strength and load bearing capability than of η phase. Under the action of the sliding friction, the hard α phase was protruded from matrix and acted as a loading phase. The η phase helped to act as a type of natural lubricant in sliding wear situations. Meanwhile, the iron transferred from the steel ring to block and forced to the recess continuously, which forms a thin protective film at the contact surface, then the load bearing capability of the test alloy would be improved.     

Artificial neural network analysis of the effect of matrix size and milling time on the properties of flake Al-Cu-Mg alloy particles synthesized by ball milling

In this study, the effect of matrix size and milling time on the particle size, apparent density, and specific surface area of flake Al-Cu-Mg alloy powders was investigated both by experimental and artificial neural networks model. Four different matrix sizes (28, 60, 100, and 160?µm) and five different milling times (0.5, 1, 1.5, 2, and 2.5?h) were used in the fabrication of the flake Al-Cu-Mg alloy powders. A feed forward back propagation artificial neural network (ANN) system was used to predict the properties of flake Al-Cu-Mg alloy powders. For training process, the ANN models of the flake size, apparent density, and specific surface area have the mean square error of 0.66, 0.004, and 0.01%. For testing process, it was obtained that the R² values were 0.9984, 0.9998, and 0.9932 for the flake size, apparent density, and specific surface area, respectively. The degrees of accuracy of the prediction models were 95.145, 99.705, and 94.25% for the flake size, apparent density, and specific surface area, respectively.     

Comparative study on the properties of amorphous carbon layers deposited from 1-hexene and propylene for dry etch hard mask application in semiconductor device manufacturing

Amorphous carbon layers (ACLs) were prepared by plasma enhanced chemical vapor deposition (PECVD) from 1-hexene (C₆H₁₂) and propylene (C₃H₆) as a carbon source at different temperatures for dry etch hard mask of semiconductor devices manufacturing process. The deposition rate of ACL deposited at 550 °C from C₆H₁₂ and C₃H₆ was 5050 Å/min and 6360 Å/min. Although the deposition rate of ACL deposited from C₆H₆ was lower than that from C₃H₆, normalized deposition rate of ACL deposited from C₆H₁₂ was 1.64 times higher than that from C₃H₆. The relative amount of hydrocarbon contents measured by FTIR (Fourier transformation infrared) and TDS (thermal desorption spectroscopy) was decreased with the increase of deposition temperature. Raman results showed that the numbers and size of graphite cluster of ACLs deposited from each source were increased with the increase of deposition temperature. The extinction coefficient of ACL deposited at 550 °C from C₆H₁₂ was 0.51 and that from C₃H₆ was 0.48. The density of ACL deposited at 550 °C from C₆H₁₂ was 1.48 g/cm³ and that from C₃H₆ was 1.45 g/cm³. The dry etching rate of ACL deposited at 550 °C from C₆H₁₂ was 1770 Å/min and that from C₃H₆ was 1840 Å/min. The deposition rate, dry etch rate and the amount of hydrocarbon contents of ACLs deposited from each carbon source were decreased with the increase of deposition temperature but extinction coefficient and density were increased with the increase of deposition temperature. We concluded that the variation behavior of the deposition characteristics and film properties of ACLs from C₆H₁₂ with the increase of deposition temperature was the same as those of ACLs from C₃H₆. The high density and low dry etch rate of ACL from C₆H₁₂ can be explained by less hydrocarbon incorporation during deposition and these properties are more favorable for the dry etch hard mask application in semiconductor device fabrication.     

The effect of laser energy input on the microstructure,physical and mechanical properties of Ti-6Al-4V alloys by selective laser melting

Selective laser melting is an advanced manufacturing process which can control the microstructure evolution and mechanical properties of as-manufactured products via various processing parameters. In this study, the porosity/relative density, surface quality, microstructure and mechanical properties were investigated on the selective laser melted Ti-6Al-4V alloy specimens fabricated with a wide range of laser energy inputs. It was found that the microstructure of selected laser melted Ti-6Al-4V alloys is typical of acicular martensites α′. Quantitative analysis reveals that the relative density, martensitic lath size and microhardness increase with the laser energy input. The surface quality is also substantially affected by the energy input.