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Formulation and optimization of sildenafil citrate-loaded PLGA large porous microparticles using spray freeze-drying technique: A factorial design and in-vivo pharmacokinetic study

Hend Shahin, Bhavani Prasad Vinjamuri, Azza A.Mahmoud, Suzan M.Mansour, Mahavir Bhupal Chougule, Lipika Chablani

Abstract

The oral administration of sildenafil citrate (SC) for the treatment of pulmonary arterial hypertension is associated with several drawbacks. The study aimed to design and formulate SC-loaded inhalable poly (lactic-co-glycolic acid) [PLGA] large porous microparticles (LPMs) for pulmonary delivery. A factorial design was used to study the effect of the composition of LPMs on physicochemical properties. The study also evaluated the effect of glucose and L-leucine concentration on the formulation. The developed LPMs demonstrated an acceptable yield% (≤48%), large geometric particle size (>5µm) with a spherical and porous surface, and sustained drug release (up to 48 h). Increasing the concentration of poly(ethyleneimine) from 0.5% to 1% in SC-loaded LPMs led to an increase in entrapment efficiency from ~3.02% to ~94.48%. The optimum LPMs showed adequate aerodynamic properties with a 97.68 ± 1.07% recovery, 25.33 ± 3.32% fine particle fraction, and low cytotoxicity. Intratracheal administration of LPMs demonstrated significantly higher lung deposition, systemic bioavailability, and longer retention time (p < 0.05) compared to orally administered Viagra® tablets. The study concluded that SC-loaded LPMs could provide better therapeutic efficacy, reduced dosing frequency, and enhanced patient compliance.

Keywords

Sildenafil citrate, Large porous microparticles, Spray-freeze drying, Pulmonary arterial hypertension, Pulmonary drug delivery, Inhalable dry powder, Design of experiment

The application of freeze-drying as a production method of drug nanocrystals and solid dispersions – A review

Emilia Jakubowska, Janina Lulek

Abstract

This work reviews the examples of the application of lyophilization and its cryogenic modifications as the production method of solid dispersions and drug nanocrystals, two formulation approaches aimed at increasing the solubility, dissolution rate and oral bioavailability of poorly water soluble drugs. A brief recapitulation of freeze-drying basics is presented and the review is organized according to application and product type, with the consideration of different cryogenic techniques, e.g. spray freezing into liquid, as well as the combinations of lyophilization with other nanonization methods in pharmaceutical technology. The review focuses on freeze-drying as a particle engineering tool for the size reduction and surface area enhancement in the generation of nanosized drug particles, both as simple nanocrystals and as their dispersions within water soluble micro- or nanoparticulate matrices, instead of the use of lyophilization as a mere drying or solidification method. Therefore, attention is given to the relationships between formulation and process parameters (e.g. freezing rate), and the properties of the obtained material: particle size, porosity, surface area, morphology, polymorphism and dissolution behavior.

Keywords

Lyophilization, Freeze-drying, Nanocrystals, Solid dispersions, Nanonization

Influence of three types of freezing methods on physicochemical properties and digestibility of starch in frozen unfermented dough

Yong Yang, Shuaishuai Zheng, Zhen Li, Zhili Pan, Zhongmin Huang, Jianzhong Zhao, Zhilu Ai

Abstract

Three types of freezing methods, namely, spiral tunnel freezing method (SF), cryogenic refrigerator freezing method (RF) and liquid nitrogen spray freezing method (LF), were applied to frozen unfermented dough. The particle size distribution and SEM results showed freezing methods reduced the average particle size of starch granules and destroyed the surface microstructure, especially RF, and the damaged starch content and swelling power of starch after treatment increased. Gelatinization and pasting properties of starches changed to varying degrees, indicating freezing methods caused the internal rearrangement of starch molecules. This view could also be inferred from X-ray diffraction (XRD) and Fourier Transform infrared spectroscopy (FT-IR) data. The relative crystallinity (35.51%–38.56%) and the R_1047/1022 (0.562–0.590) were increased, compared with the control (32.44%, 0.559, respectively). Meanwhile, freezing treatment improved the digestibility of starch by promoting the combination of enzymes and starch, especially RF. Larger ice crystals formed by RF with slower freezing rate produced larger damage to starch structure, more likely to promote the binding with enzymes. LF with faster freezing rate had less effect on the starch composition than RF and SF with slower freezing rate. The data obtained clarified the influence of freezing methods on the structure and properties of starch in a yeast-free dough system, and enriched the knowledge regarding the effect of freezing technology on food components.

Keywords

Freezing methods, Frozen unfermented dough, Starch digestibility, Ordered structure, Relative crystallinity

Effect of Ca2+ and Mg2+ ions on the sintering and spectroscopic properties of cr‐doped yttrium aluminum garnet ceramics

Przemysław Gołębiewski, Helena Węglarz, Magdalena Nakielska, Anna Wajler

Abstract

In this work, we investigated the effects of Ca2+ and Mg2+ ions and annealing temperature on the spectroscopic parameters of chromium‐doped yttrium aluminum garnet ceramics (Cr:YAG). Samples were obtained with either a separate or a simultaneous addition of calcium and magnesium oxides. To achieve this, aqueous suspensions were prepared using Y2O3, Al2O3, Cr2O3, MgO, and CaO high‐purity powders as raw materials. The obtained suspensions were freeze‐granulated, pressed into pellets, debinded, and subjected to reactive sintering in vacuum at 1715°C for 6 h. Each material was annealed in air with temperatures between 1300 and 1700°C. Samples were also compared to Cr:YAG ceramics with the addition of silica as a sintering aid. All the materials obtained were then exposed to 445 nm excitation, and emission spectra in the visible and infrared wavelengths were recorded. The results showed that the emission spectra of Cr:YAG ceramics varied according to the annealing conditions: as‐sintered samples exhibited strong emissions of around 680 nm and, after air annealing, of around 1400 nm. This phenomenon is attributed to the Cr3+→Cr4+ transition. Samples doped solely with MgO exhibited the highest emission intensity in the infrared region. Thus, Mg2+ ions provided the best conversion efficiency of chromium ions.

Keywords

Cr:YAG, Q‐switching, transparent ceramics, yttrium aluminum garnet

Formulation and evaluation of inhalable microparticles of Rizatriptan Benzoate processed by spray freeze-drying

Mahsa Keyhan shokouh, Homa Faghihi, Majid Darabi, Maryam Mirmoeini, Alireza Vatanara

Abstract

The aim of the current study was to prepare and evaluate inhalable microparticles of Rizatriptan benzoate in order to further benefit from its pulmonary delivery, the expected enhanced bioavailability and accelerated onset of action. The spray freeze drying (SFD) technique was used to produce microparticles consisting of a fixed amount of a sugar which was either mannitol or trehalose and an amino acid component including leucine, phenylalanine or serine. The powders were then characterized for particle size distribution, morphology, thermal properties and in vitro aerosolization performance. It was demonstrated that various formulations of inhalable Rizatriptan could be efficiently aerosolized and offered acceptable fine particle fraction (FPF) ranging up to 61.1%. In particular, a spray-freeze-dried powder composed of trehalose and phenylalanine showed the most superior inhalation performance (FPF = 61.1%), indicating better dispersion properties of those spherical porous microparticles with less adhesion and agglomeration. These results successfully demonstrated that Rizatriptan could be engineered into respirable microparticles to be proposed as a promising delivery system for fast and effective control of migraine attacks.

Keywords

Rizatriptan benzoate. Spray freeze drying, Inhalation, Carbohydrates, Amino acids

Engendering Unprecedented Activation of Oxygen Evolution via Rational Pinning of Ni Oxidation State in Prototypical Perovskite: Close Juxtaposition of Synthetic Approach and Theoretical Conception

Rebecca Pittkowski, Spyridon Divanis, Mariana Klementová, Roman Nebel, Shahin Nikman, Harry Hoster, Sanjeev Mukerjee, Jan Rossmeisl, Petr Krtil

Abstract

Rational optimization of the OER activity of catalysts based on LaNiO3 oxide is achieved by maximizing the presence of trivalent Ni in the surface structure. DFT investigations of the LaNiO3 catalyst and surface structures related to it predict an improvement in the OER activity for these materials to levels comparable with the top of the OER volcano if the La content is minimized while the oxidation state of Ni is maintained. These theoretically predicted structures of high intrinsic OER activity can be prepared by a templated spray-freeze freeze-drying synthesis followed by a simple postsynthesis exfoliation-like treatment in acidic media. These nanocrystalline LaNiO3-related materials confirm the theoretical predictions, showing a dramatic improvement in OER activity. The exfoliated surfaces remain stable in OER catalysis, as shown by an in-operando ICP-OES study. The unprecedented OER activation of the synthesized LaNiO3-based materials is related to a close juxtaposition of the theoretical conception of ideal structural motifs and the ability to engender such motifs using a unique synthetic procedure, both principally related to stabilization and pinning of the Ni oxidation state within the local coordination environment of the perovskite structure.

Keywords

electrocatalysis, oxygen evolution, rational catalyst design, DFT

Particle Size Reduction Techniques of Pharmaceutical Compounds for the Enhancement of Their Dissolution Rate and Bioavailability

Rahul Kumar, Amit K. Thakur, Pranava Chaudhari, Nilanjana Banerjee

Abstract

In pharmaceutical research and development, various new chemical entities (NCE) are found to be poorly water-soluble. Therefore, solubility enhancement, a key factor for higher bioavailability, is a major challenge in pharmaceutical industries. Particle size reduction is one such method that increases the surface area of the pharmaceutical compounds and subsequently leads to a higher dissolution rate and bioavailability. Conventional processes such as milling, high-pressure homogenization, and spray drying are well established and widely used for particle size reduction. However, a few disadvantages such as a broader particle size distribution (PSD) and thermal and chemical degradation of the product are major concerns for the product quality. Non-conventional processes such as liquid anti-solvent crystallization, supercritical anti-solvent process, rapid expansion of supercritical solutions, particles from gas saturated solutions, and pulsed laser ablation are emerging as potential alternatives to overcome the disadvantages of conventional processes. This review critically summarizes the milling, spray drying, high-pressure homogenization, liquid anti-solvent crystallization, spray freeze-drying, supercritical carbon dioxide (SCCO2)–based micronization processes, pulsed laser ablation and combinative techniques. The success of these processes in enhancing the dissolution rate and bioavailability of many active pharmaceutical ingredients (APIs) has been critically examined. The advantages and limitations of these processes are also discussed. Finally, opportunities for future research are also proposed.

Keywords

Anti-solvent, Milling, Particle size reduction, Powder, Spray drying, Supercritical carbon dioxide

Effects of drying method and excipient on the structure and physical stability of protein solids: Freeze drying vs. spray freeze drying

Tarun Tejasvi Mutukuri, Nathan E. Wilson, Lynne S. Taylor, Elizabeth M. Topp, Qi Tony Zhou

Abstract

This study aims to determine the impacts of drying method and excipient on changes in protein structure and physical stability of model protein solids. Protein solids containing one of two model proteins (lysozyme or myoglobin) were produced with or without excipients (sucrose or mannitol) using freeze drying or spray freeze drying (SFD). The protein powders were then characterized using solid-state Fourier transform infrared spectroscopy (ssFTIR), differential scanning calorimetry (DSC), circular dichroism spectrometry (CD), size exclusion chromatography (SEC), BET surface area measurements and solid-state hydrogen deuterium exchange with mass spectrometry (ssHDX-MS). ssFTIR and CD could identify little to no difference in structure of the proteins in the formulation. ssHDX-MS was able to identify the population heterogeneity, which was undetectable by conventional characterization techniques of ssFTIR and CD. ssHDX-MS metrics such as Dmax and peak area showed a good correlation with the protein physical instability (loss of the monomeric peak area by size exclusion chromatography) in 90-day stability studies conducted at 40 °C for lysozyme. Higher specific surface area was associated with greater loss in monomer content for myoglobin-mannitol formulations as compared to myoglobin-only formulations. Spray freeze drying seems a viable manufacturing technique for protein solids with appropriate optimization of formulations. The differences observed within the formulations and between the processes using ssHDX-MS, BET surface area measurements and SEC in this study provide an insight into the influence of drying methods and excipients on protein physical stability.

Keywords

Freeze drying, Spray freeze drying, Protein structure, Biopharmaceutical processing, Solid formulation, Solid-state hydrogen/deuterium exchange with mass spectrometric analysis (ssHDX-MS)

A Kinetic Model for Spray-Freezing of Pharmaceuticals

Abstract

Spray freeze-drying (SFD), which includes spray-freezing into droplets and dynamic vacuum drying, presents a promising alternative approach to manufacture dried pharmaceuticals more efficiently than conventional vial freeze-drying. Without reliable predictive models for the SFD conditions of interest, any respective process development still relies on empirical approaches. In this work, we propose an improved modeling framework to describe the fast freezing (<1 s) that sub-millimeter droplets undergo in the present SFD process. The modeled freezing rate accounts for both the kinetics of ice growth and droplet heat transfer mechanisms. Computational fluid dynamics (CFD) simulations and experiments on bulk spray-freezing are combined to refine and validate the proposed reduced-order model. While this study is limited to water-sucrose solutions, the present modeling approach can be extended to other pharmaceutical excipients. For the cooling rates of interest, model results indicate that droplets with initial sucrose concentration higher than 20% w/w will transit to a glassy state before completion of crystallization and, consequently, devitrification is expected during post spray-freezing manipulation of the bulk material. In practice, such compact model does not only allow quantification of process parameters that cannot be measured in real time but also enable the choice of optimal spraying conditions for production of free-flowing, high-quality frozen droplets that meet the target product profile.

Keywords

Crystallization, Freeze-drying, In silico modeling, Lyophilization, Mechanistic modeling, Microsphere(s), Powder technology(s), Spray freeze-drying, Sucrose