A simple technique to produce spray-dried porous particles for inhalatory administration was developed. The particles were produced using water as solvent, Sodium Cromoglycate as model drug and ...ammonium bicarbonate as pore forming agent. A central composite design was employed to study the influence of the: pore-forming agent concentration (in the drug aqueous solution fed to the spray dryer) and air inlet temperature on: process yield and powder properties. The powder particle size distribution, moisture content, densities and estimated aerodynamic diameters were studied. Also, particles morphology, hygroscopicity, surface area, in vitro aerosolization properties, dissolution rate and stability were evaluated for some selected samples. In addition, a novel friability test was proposed for mechanical resistance evaluation of the porous materials.
A pore forming agent concentration of 1.25% (w/w) and an air inlet temperature of 170 °C were the optimal process parameters to produce porous particles suitable for inhalatory administration. The process yield was high and it was demonstrated that the particles were free of ammonium bicarbonate. The porous powder, obtained by a simple and scalable technique, exhibited low tap density, good stability even at long storage periods (12 months), appropriate mechanical resistance, high initial dissolution rate and excellent aerosolization performance.
Large porous inhalatory spray-dried particles obtained without using organic solvents and employing ammonium bicarbonate as pore forming agent. Display omitted
•Development of spray-dried inhalable porous particle without using organic solvents.•Cromoglycate porous particles with adequate in vitro aerosolization properties.•Appropriate long term stability of porous Cromoglycate inhalable particles.•Stable porous Cromoglycate inhalable particles even under mechanical stress.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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•A mathematical model for inhalable powder production in a spray dryer is developed.•Particle size and aerodynamic diameter are well predicted being very sensitive to droplet ...size.•Particle density values are predicted with errors smaller than 6.4%.•The highest error in the product temperature prediction is 12%.•Predictions of particle density could be improved by including intra-particle phenomena.
Spray drying is widely applied in many industries, such as the pharmaceutical, food, detergents, polymers, to convert liquids in solid particles. However, it still requires continuous innovation in order to provide more sophisticated particles, which are difficult to design by using only empirical approaches. In this context, a steady-state mathematical model for a co-current spray dryer is developed to give a more phenomenological insight in the production of inhalable particles. The model includes mass, energy and momentum balances for both particulate and gaseous phases. Particularly, and as a model inhalable compound, ciprofloxacin hydrochloride (CIP) aqueous solutions are studied. Several experimental data, obtained in a Mini-Spray Dryer B-290, BÜCHI, were available. In addition, droplet size measurements were carried out by using laser diffraction. The effect of the binary nozzle operating conditions on the mean droplet size was analyzed and a correlation to predict the mean Sauter diameter was established. The experimental data are used to fit and validate the proposed model. The validated model is used to perform parametric studies in order to evaluate the effect of the main process variables on the final product properties (e.g., particle size and density, powder moisture content) and to track key powder attributes for pulmonary administration.
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GEOZS, IJS, IMTLJ, IZUM, KILJ, KISLJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
The binomial coefficient of two words u and v is the number of times v occurs as a subsequence of u. Based on this classical notion, we introduce the m-binomial equivalence of two words refining the ...abelian equivalence. Two words x and y are m-binomially equivalent, if, for all words v of length at most m, the binomial coefficients of x and v and respectively, y and v are equal. The m-binomial complexity of an infinite word x maps an integer n to the number of m-binomial equivalence classes of factors of length n occurring in x. We study the first properties of m-binomial equivalence. We compute the m-binomial complexity of two classes of words: Sturmian words and (pure) morphic words that are fixed points of Parikh-constant morphisms like the Thue–Morse word, i.e., images by the morphism of all the letters have the same Parikh vector. We prove that the frequency of each symbol of an infinite recurrent word with bounded 2-binomial complexity is rational.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Pressurized metered dose inhalers (pMDIs) are devices widely used for drug delivery in the respiratory tract. In this work, a mathematical model to predict the complete particle size distribution ...(PSD) of the aerosol generated by a pMDI is developed. The model combines the equations developed by Clark in 1999 that describe the flow within the inhaler, the Linear Instability Sheet Atomization (LISA) model and a method based on the Maximum Entropy Principle (MEP). Mathematically it is found that the PSD can be represented by a lognormal function with geometric standard deviation equal to 1.56. The model does not contain fitting parameters and is validated with experimental information for a formulation containing salbutamol and HFA-134a as drug and propellant, respectively. Simulations are performed to explore how the propellants HFA-134a and HFA-227ea affect the PSD of the aerosol generated by the inhaler.
Comparison of the predicted and experimental PSDs. Display omitted
•A model to predict the particle size distribution generated by a pMDI is developed.•The PSD is well described by a lognormal function with a geometric standard constant.•The model allows to analyze how the formulation properties impact the aerosol size.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Mucous plugs in the respiratory system of cystic fibrosis patients are often infected, typically by Pseudomonas aeruginosa. Nebulized levofloxacin is effective against P. aeruginosa, but the ...administration and cleaning process is time-consuming. To address this limitation, dry powder inhalers are a potential alternative if a high required dose could be loaded. The objective of this study was to develop and characterize an excipient-free levofloxacin powder produced by a solvent-free spray drying method. The obtained particles were small, rounded and crystalline. Under pharmacopoeial impactor conditions, high emitted, fine particle and respirable fractions were achieved, even with high drug loadings. Variations in the impactor pump's air flowrate did not significantly affect the aerodynamic performance. After 12 months' storage critical attributes remained largely unchanged. The developed system allows for the same dose delivery as the marketed product for nebulization using only four capsules, highlighting its potential in cystic fibrosis treatments.
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•Excipient-free levofloxacin microparticles were developed by spray drying.•Levofloxacin microparticles displayed favorable aerodynamic parameters.•Mass median aerodynamic diameters kept low at different impactor conditions studied.•Variations in air flowrate did not significantly influence respirable fraction.•Particles' critical quality attributes were well-preserved after 12 months' storage.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Near-infrared spectroscopy (NIRS) is nowadays an established analytical technique in the pharmaceutical industry. The aim of this review is to present the progress of NIRS in providing useful ...information for pharmaceutical particle technology. NIR methods are now developed to characterize a wide variety of materials (active pharmaceutical ingredients, excipients, co-processed powders, and physical mixtures) and pharmaceutical dosage forms (conventional, modified drug release technologies, and phytomedicines). This review also provides a number of spectra to illustrate the fundamental understanding of NIRS which has been gained. The sampling that must occur prior to the acquisition of near-infrared spectra is also discussed, as well as developments in monitoring mixing, tableting, and coating. This review will be valuable for product formulation and process engineering specialists.
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IJS, IZUM, KILJ, NUK, PILJ, SAZU, UL, UM, UPUK
The use of valved holding chambers (VHCs) is recommended when pressurized metered dose inhalers (pMDI) are prescribed. These medical devices decrease actuation-inhalation coordination difficulties, ...improve drug delivery and reduce oropharyngeal deposition. In this work, an in vitro and in silico analysis of two commercial VHCs is performed. Both devices are antistatic and are similar in length, volume, shape, but have different valve design (valve seat and flaps). Experimental results, using a Next Generation Impactor, showed that the VHCs differ in their performance, so they are not interchangeable. However, when flaps are not present in commercial VHCs and its 3D prototypes (designed with the same body volume and wall material), the differences in emitted fraction are not significant. In addition, studies performed with computational fluid dynamics showed that the highest particle deposition occurs by impact on the valve. Thus, while multiple factors of VHCs influence the delivered dose, in this work it has been shown that the main one to be considered is the valve design.
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•An in vitro and in silico analysis of two commercial VHCs is performed.•VHCs are not interchangeable when used with valve flaps.•The differences in emitted fraction are not significant when the flaps are removed.•CFD studies show that the highest particle deposition occurs by impact on the valve.•It has been shown that the main factor to be considered is the valve design.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The testing of pharmaceutical aerosols includes measuring the aerodynamic particle size distribution, which is usually performed on cascade impactors. In the next generation impactor (NGI), the ...aerosol dose is introduced through an induction port (IP), being separated into different aerodynamic diameter ranges by seven stages and a micro‐orifice collector. The IP plays an important role in estimating the oropharyngeal deposition fraction. While the IP retains mainly large particles, it also tends to retain particles in the respirable range. In this work, the deposition of particles in the IP of an NGI is studied, both experimentally and through computational fluid dynamic (CFD) simulations. Experimental tests are conducted both with the pressurized metered‐dose inhaler (pMDI) alone and in conjunction with a cylindrical valved holding chamber (VHC). For each case, the total mass deposition that occurs in the VHC, IP, and NGI stages is measured, as well as the mass median aerodynamic diameter of the aerosol leaving the IP. The CFD simulations show minimal variations in results regardless of the injection method due to the relatively low velocity and spray angle of the pMDI‐generated aerosol. If the flap‐valve is removed from the VHC, significant particle deposition occurs upstream or within the valve region, with downstream air recirculation contributing to small particle deposition. Based on the CFD results, a correlation is proposed to accurately predict the particle escape fraction of the IP and VHC, which allows estimation of the tannin distribution of particles collected in the NGI stages, especially those corresponding to the range of respirable particles.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
HLA-G is considered to be an immune checkpoint molecule, a function that is closely linked to the structure and dynamics of the different HLA-G isoforms. Unfortunately, little is known about the ...structure and dynamics of these isoforms. For instance, there are only seven crystal structures of HLA-G molecules, being all related to a single isoform, and in some cases lacking important residues associated to the interaction with leukocyte receptors. In addition, they lack information on the dynamics of both membrane-bound HLA-G forms, and soluble forms. We took advantage of
strategies to disclose the dynamic behavior of selected HLA-G forms, including the membrane-bound HLA-G1 molecule, soluble HLA-G1 dimer, and HLA-G5 isoform. Both the membrane-bound HLA-G1 molecule and the soluble HLA-G1 dimer were quite stable. Residues involved in the interaction with ILT2 and ILT4 receptors (α3 domain) were very close to the lipid bilayer in the complete HLA-G1 molecule, which might limit accessibility. On the other hand, these residues can be completely exposed in the soluble HLA-G1 dimer, due to the free rotation of the disulfide bridge (Cys42/Cys42). In fact, we speculate that this free rotation of each protomer (i.e., the chains composing the dimer) could enable alternative binding modes for ILT2/ILT4 receptors, which in turn could be associated with greater affinity of the soluble HLA-G1 dimer. Structural analysis of the HLA-G5 isoform demonstrated higher stability for the complex containing the peptide and coupled β2-microglobulin, while structures lacking such domains were significantly unstable. This study reports for the first time structural conformations for the HLA-G5 isoform and the dynamic behavior of HLA-G1 molecules under simulated biological conditions. All modeled structures were made available through GitHub (https://github.com/KavrakiLab/), enabling their use as templates for modeling other alleles and isoforms, as well as for other computational analyses to investigate key molecular interactions.
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