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Normalized relative transmission profiles indicate a slower destabilization process as more trileucine is added to the formulation and the suspended particles become more wrinkled.
Source publication
Purpose
The effects of particle size and particle surface roughness on the colloidal stability of pressurized pharmaceutical suspensions were investigated using monodisperse spray-dried particles.
Methods
The colloidal stability of multiple suspensions in the propellant HFA227ea was characterized using a shadowgraphic imaging technique and quantit...
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Effects of surface roughness on the colloidal stability of pressurized pharmaceutical suspensions were isolated and investigated using spray-dried monodisperse particles. Trileucine was used as a shell former to produce particles with different levels of surface roughness. It has been demonstrated that more rugose particles lead to more stable susp...
Citations
... The highly rugose surface structure of the particles is effective in improving the powder dispersibility and has been reported to create potential drug loading sites [38,39]. The engineered porous particles are based on phospholipids and have a sponge-like structure as shown in Fig. 1d. ...
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.
... literature [1][2][3][4]. Applications such as contaminant transport in the subsurface, virus spreading in the air, transport of pharmaceutical suspensions, and polymer transport in porous media are just few examples of the broad application in engineering and applied science [5][6][7][8]. Among the suspended particles applications, the polymer applications are of utmost importance. ...
The study of polymer flooding is of utmost relevance due to the diversity of applications. This paper proposes an innovative mathematical and computational model for polymer flooding that efficiently couples the process in the near-well region and the reservoir. For the mathematical model, in addition to the single-phase flow and transport equations, we postulate closure relationships for the adsorption isotherms, mechanical retention kinetics, and non-Newtonian pseudoplastic behavior. For the computational model, we propose a space-time domain decomposition method based on a predictor-corrector strategy. The resulting system of equations is discretized by the finite element method and linearized by the Newton-Raphson method. Moreover, we apply a consistent flux method to obtain the flow at the boundaries and quantify the injectivity ratio. Then, we validate the accuracy of the proposed method by comparing the discrete solutions with analytical and high-fidelity solutions. We also discuss the loss of injectivity due to the non-Newtonian behavior, mechanical retention, and formation damage at 2D and 3D domains that replicate a five-spot injection pattern. The numerical simulations show that the proposed computational model accurately captures the solutions with low computational costs in several scenarios for polymer injection in porous media.
... The interfacial adsorption of surface-active molecules decreases the surface energy of the dried particles because of the outward orientation of their hydrophobic tails (Jong et al., 2016;Vartiainen et al., 2016). Furthermore, some surface-active shell formers, like trileucine (Carrigy et al., 2019b;Lechuga-Ballesteros et al., 2008;Ordoubadi et al., 2021a), undergo early phase-separation near the droplet surface resulting in highly rugose particles with decreased contact area (Wang H. et al., 2019). Some of the most effective shell formers have two or more of these properties. ...
... This is because a surfaceactive dispersibility enhancer needs to make a saturated monolayer on the surface before the precipitation of other components so that the final dried particle will contain a fully packed hydrophobic shell. This shell can potentially decrease the surface energy of the particles and possibly result in wrinkled surfaces, which would in turn improve aerosol properties (Mangal et al., 2015;Wang H. et al., 2019). It should be noted that besides making the monolayer, the surface-active molecules will eventually either crystallize or phase separate into a glass based on the previous discussions. ...
Spray drying is gaining traction in the pharmaceutical industry as one of the processing methods of choice for the manufacture of solid dosage forms intended for pulmonary, oral, and parenteral delivery. This process is particularly advantageous because of its ability to produce engineered particles with improved efficacy and stability by combining active pharmaceutical ingredients or biologics with appropriate excipients. Moreover, due to its high throughput, continuous operation, and ability to produce thermostable solid powders, spray drying can be a manufacturing method of choice in the production of drugs and other formulations, including vaccines, for global distribution. Formulation design based on a mechanistic understanding of the different phenomena that occur during the spray drying of powders is complicated and can therefore make the use of available particle formation models difficult for the practitioner. This review aims to provide step-by-step guidance accompanied by critical background information for the successful formulation design of spray-dried microparticles. These include discussion of the tools needed to estimate the surface concentration of each solute during droplet drying, their times and modes of solidification, and the amount of glass stabilizers and shell formers required to produce stable and dispersible powders.
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... Furthermore, the dried lipid particles showed a composite structure with high rugosity, which has been demonstrated to be a key feature of highly dispersible particles with good aerosol performance (63,64). A large specific surface area of 18.3 m 2 /g was recorded for these particles. ...
... In comparison, the control batch performed slightly better than batch #4. However, even with the lower particle rugosity for the particles from batch #4, the powder still performed very well, meaning that the rugose particle surface is very effective in improving powder dispersibility (63,69), with the improvement plateauing at higher rugosities. Considering that the total lung dose of commercially available dry powder inhalers typically ranges from 5 to 40% (70)(71)(72), the achieved numbers show substantial improvement and great potential for DPI applications. ...
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.
... 3 In contrast, a positive effect was the reduction of particle-particle interactions due to nano-level roughness. [4][5][6] Furthermore, differences in surface roughness can also affect powder behavior in terms of particle velocity and the diversity of directions as it exits the device and moves within the lungs. 7,8 The dimpled structure and increased roughness of a golf ball allow for a four-times greater travel distance than does a smooth ball because of its reduced drag and lift. ...
Introduction
Dry powder inhalations are an attractive pharmaceutical dosage form. They are environmentally friendly, portable, and physicochemical stable compared to other inhalation forms like pressurized metered-dose inhalers and nebulizers. Sufficient drug deposition of DPIs into the deep lung is required to enhance the therapeutic activity. Nanoscale surface roughness in microparticles could improve aerosolization and aerodynamic performance. This study aimed to prepare microspheres with nanoscale dimples and confirm the effect of roughness on inhalation efficiency.
Methods
The dimpled-surface on microspheres (MSs) was achieved by oil in water (O/W) emulsion-solvent evaporation by controlling the stirring rate. The physicochemical properties of MSs were characterized. Also, in vitro aerodynamic performance of MSs was evaluated by particle image velocimetry and computational fluid dynamics.
Results
The particle image velocimetry results showed that dimpled-surface MSs had better aerosolization, about 20% decreased X-axial velocity, and a variable angle, which could improve the aerodynamic performance. Furthermore, it was confirmed that the dimpled surface of MSs could cause movement away from the bronchial surface, which helps the MSs travel into the deep lung using computational fluid dynamics.
Conclusion
The dimpled-surface MSs showed a higher fine particle fraction value compared to smooth-surface MSs in the Andersen Cascade Impactor, and surface roughness like dimples on microspheres could improve aerosolization and lung deposition.
... The evident roughness of microparticles from Run 5 may explain the FPF that was about 70%. Surface roughness decreases the contact area between adjacent microparticles, thus reducing the inter-particulate cohesive forces [31]. This observation is in agreement with Chew et al. who demonstrated how the increase in surface roughness of spray-dried bovine serum albumin particles can result in enhancement of the aerodynamic performance, in Dense particle Empty shell-particle Droplet P e ≤ 1 P e > 1 Figure 9. Drying of droplets containing particles of low (left) and high (right) Péclet number. ...
... The evident roughness of microparticles from Run 5 may explain the FPF that was about 70%. Surface roughness decreases the contact area between adjacent microparticles, thus reducing the inter-particulate cohesive forces [31]. This observation is in agreement with Chew et al. who demonstrated how the increase in surface roughness of spray-dried bovine serum albumin particles can result in enhancement of the aerodynamic performance, in Dense particle Empty shell-particle Droplet P e ≤ 1 P e > 1 Figure 10. ...
... The evident roughness of microparticles from Run 5 may explain the FPF that was about 70%. Surface roughness decreases the contact area between adjacent microparticles, thus reducing the inter-particulate cohesive forces [31]. This observation is in agreement with Chew et al. who demonstrated how the increase in surface roughness of spray-dried bovine serum albumin particles can result in enhancement of the aerodynamic performance, in terms of fine particle fraction [32]. ...
Inhalation of Calcium Phosphate nanoparticles (CaPs) has recently unmasked the potential of this nanomedicine for a respiratory lung-to-heart drug delivery targeting the myocardial cells. In this work, we investigated the development of a novel highly respirable dry powder embedding crystalline CaPs. Mannitol was selected as water soluble matrix excipient for constructing respirable dry microparticles by spray drying technique. A Quality by Design approach was applied for understanding the effect of the feed composition and spraying feed rate on typical quality attributes of inhalation powders. The in vitro aerodynamic behaviour of powders was evaluated using a medium resistance device. The inner structure and morphology of generated microparticles were also studied. The 1:4 ratio of CaPs/mannitol led to the generation of hollow microparticles, with the best aerodynamic performance. After microparticle dissolution, the released nanoparticles kept their original size.
... To improve the aerosolization characteristics of the powder, a specific class of excipients labeled as shell formers or dispersibility enhancers have been used; these include leucine [7,[9][10][11] and trileucine [12][13][14]. ...
... Trileucine is a tripeptide composed of three leucine residues and is used in the spray drying of pharmaceutical microparticles mostly as a dispersibility enhancer to produce low-density, non-cohesive and rugose particles [13,15,16]. It is a strongly surface-active material, typically does not crystallize during spray drying nor upon storage, and has a low aqueous solubility of about 6.8 mg/mL at neutral pH [12]. ...
... It is a strongly surface-active material, typically does not crystallize during spray drying nor upon storage, and has a low aqueous solubility of about 6.8 mg/mL at neutral pH [12]. These characteristics have been reported to be responsible for considerable increase of surface roughness and efficient dispersibility enhancement of particles containing small quantities of trileucine in the formulation [13,14,17]. Furthermore, the high surface coverage of trileucine in spray-dried particles and its high glass transition temperature of ~104 • C are believed to be responsible for its considerable improvement in the stability of biologics and bacteriophages during production and upon storage [12,17]. ...
The formation of trileucine-containing spray-dried microparticles intended for pulmonary delivery was studied in depth. A single-particle method was employed to study the shell formation characteristics of trileucine in the presence of trehalose as a glass former, and an empirical correlation was proposed to predict the instance of shell formation. A droplet chain instrument was used to produce and collect monodisperse particles to examine morphology and calculate particle density for different levels of trileucine. It was observed that the addition of only 0.5 mg/mL (10% w/w) trileucine to a trehalose system could lower dried particle densities by approximately 1 g/cm3. In addition, a laboratory-scale spray dryer was used to produce batches of trileucine/trehalose powders in the respirable range. Raman spectroscopy demonstrated that both components were completely amorphous. Scanning electron microscopy and time-of-flight secondary ion mass spectrometry were used to study the particle morphologies and surface compositions. For all cases with trileucine, highly rugose particles with trileucine coverages of more than 60% by mass were observed with trileucine feed fractions of as little as 2% w/w. Moreover, it was seen that at lower trileucine content, smaller and larger particles of a polydisperse powder had slightly different surface compositions. The surface activity of trileucine was also modeled via a modified form of the diffusion equation inside an evaporating droplet that took into account initial surface adsorption and eventual surface desorption due to droplet shrinkage. Finally, using the Flory-Huggins theory, it was estimated that at room temperature, liquid-liquid phase separation would start when the trileucine reached an aqueous concentration of about 18 mg/mL. Besides the surface activity of trileucine, this low concentration was assumed to explain the substantial effect of trileucine on the morphology of spray-dried particles due to early phase separation. The methodology proposed in this study can be used in the rational design of trileucine-containing microparticles.
... Many different types of monodisperse droplet generators have been reported (Liu, Chen, and Selomulya 2015), and one type utilizing vibration forces generated by piezoelectric transducers has been commonly used in research studies (Rogers et al. 2012b(Rogers et al. , 2012aFu et al. 2011). A custom-designed vibrating orifice atomizer (Azhdarzadeh et al. 2016) integrated with a custom laboratory spray dryer (Wang, Nobes, and Vehring 2019;Ivey et al. 2018) has been discussed previously in detail. In this system, the pressurized liquid feed formed a liquid jet through an orifice plate installed in the atomizer. ...
... The jet then disintegrated into monodisperse droplets under a specific frequency provided by a function generator. Compared with the monodisperse droplet chain dispenser, the vibrating orifice atomizer operated with a much higher vibration frequency in the 100-200 kHz range (Wang, Nobes, and Vehring 2019). As a result, monodisperse spray drying is able to produce over a thousand times more droplets, and consequently more final product, than the monodisperse droplet chain within the same time. ...
... Each ink-jet device can be placed in an individual nozzle and supplied with liquid feed using individual tubing. However, this design of multiple ink-jet devices is not compatible with the custom spray dryer currently in use in our lab (Wang, Nobes, and Vehring 2019), and the re-design and re-manufacturing of the hardware is very time-consuming. Brenn designed a 62-hole plate to produce 62 liquid jets simultaneously and used laser drilling for manufacturing (Brenn, Durst, and Tropea 1996). ...
The purpose of this study was twofold: to investigate leucine crystallization kinetics in co-solvent spray drying for a deeper understanding of the morphology and formation process of spray-dried crystalline particles, and also to develop multi-orifice plates using gallium focused ion beam milling in order to increase the production rate of monodisperse spray drying. A monodisperse spray drying technique using a vibrating orifice atomizer equipped with a gallium focused ion beam-manufactured dual-orifice plate was used to produce model particles in this study. The dual-orifice plate achieved an average production rate of 23.8 ± 2.0 mg/hr for the model particles, which allowed sufficient production of monodisperse powders for microscopic and spectroscopic analysis as well as fragility testing, within a reasonable spray drying time period. Leucine was dissolved in a water-ethanol co-solvent at ratios of 0.25/0.75 w/w, 0.5/0.5 w/w, and 1/0 w/w, and then spray dried at inlet temperatures of 20, 40, and 80 °C. Crystallinity of the spray-dried particles was confirmed by Raman spectroscopy. Numerical models were used to predict the crystallization and drying kinetics for the different co-solvent ratios and drying temperatures. Increasing the time available for crystallization correlated qualitatively with a larger crystal size. Changes in particle morphology affected the fragility of the particles, as illustrated in electron microscope images. This work highlights the importance of controlling crystal size and particle morphology via solvent environment and drying temperature in the design and manufacture of microparticles for desired powder properties.
Copyright © 2021 American Association for Aerosol Research
... Some particles of a slightly larger size can be observed in the images. These particles were dried from doublets or triplets due to droplet coalescence, which is a known phenomenon reported previously in monodisperse spray drying using a microjet atomizer (Ivey et al., 2018;Wang et al., 2019). The trehalose particles generally had spherical shapes with small dimples on the particle surface, a trait that has also been observed in previous studies Ordoubadi et al., 2019;Wang et al., 2019). ...
... These particles were dried from doublets or triplets due to droplet coalescence, which is a known phenomenon reported previously in monodisperse spray drying using a microjet atomizer (Ivey et al., 2018;Wang et al., 2019). The trehalose particles generally had spherical shapes with small dimples on the particle surface, a trait that has also been observed in previous studies Ordoubadi et al., 2019;Wang et al., 2019). Spray-dried particles of trehalose/trileucine 97/3 and trehalose/pullulan 70/30 had highly corrugated particle surfaces, which are caused by the early formation and subsequent collapse of amorphous trileucine and pullulan shells when they still lack mechanical strength. ...
This study investigates the ability of various shell-forming excipients to preserve the dispersibility of dry powder dosage forms, e.g., nasally administered vaccines, upon exposure to a high-humidity environment. Trehalose combinations using leucine, pullulan, or trileucine were selected as the candidate excipient systems, and the powder dispersibility of these systems was compared with that of pure trehalose particles. Scaled-up monodisperse spray drying was used to produce sufficient quantities of uniform-sized particles for powder dispersibility analysis. Particle size, crystallinity, and morphology of the powders before and after exposure to moisture were characterized by an aerodynamic particle sizer, Raman spectroscopy, and scanning electron microscopy, respectively. Three two-component particle systems composed of trehalose/trileucine (97/3 w/w), trehalose/pullulan (70/30 w/w), and trehalose/leucine (70/30 w/w) were first formulated and their dispersibility, characterized as the emitted dose from dry powder inhalers, was then compared with that of trehalose particles. The formulation containing 30% leucine maintained the highest emitted dose (90.3 ± 10%) at a 60 L/min flow rate after 60 min exposure to 90% RH and 25 °C, showing its superior protection against exposure to humidity compared with the other systems. Further investigations under more challenging conditions at 15 L/min flow rate on the trehalose/leucine system with various compositions (70/30, 80/20, 90/10 w/w) showed that a higher leucine concentration generally provided better protection against moisture and maintained higher powder dispersibility, probably due to higher surface coverage of crystalline leucine and a thicker leucine shell around the particles. The study concludes that leucine may be considered an appropriate shell-forming excipient in the development of dry powder formulations in order to protect the dosage forms against humidity during administration.
... The experimental set-up for monodisperse and polydisperse spray drying has been discussed elsewhere (Ivey et al., 2018b;Wang et al., 2019). The aerodynamic particle size distributions were measured in-line with the spray drying process using a time-of-flight aerodynamic particle sizer (3321, TSI, Shoreview, MN, USA) (Ivey et al., 2018a). ...
We describe a new instrument and method for measuring compressed bulk density of respirable pharmaceutical powders under low compression pressure: the modulated compression tester. The instrument modulates compression and decompression steps, allowing scrutiny of the overall compression response of samples. Compared to established methods for the determination of density and related parameters for pharmaceutical powders, this instrument has the capability of measuring smaller samples. The relative humidity can also be controlled in the instrument (3 % to 95 % RH), allowing assessment of the effect of moisture on compression response. We have used the instrument to determine the compressed bulk density of Trehalose, Leucine, Trileucine, and Mannitol powders of varying crystalline and amorphous compositions and particle size and size distribution, demonstrating that the new modulated compression tester is suitable for low pressure (< 1200 kPa) density measurement of respirable powders (< 10 μm) and expensive active pharmaceutical ingredients available in limited quantities (typical sample mass requirement of < 100 mg). In addition, the modulation feature of the instrument allows the analysis of the transition from plastic to semi-elastic compression response. The outputs and features of this instrument are useful for formulation development, quality control measurements, discerning between different or similar powders due to differences in the compression response, and optimizing powder compression parameters for pharmaceutical applications.
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