Spray Freeze-drying Technique Research Articles

Combination of α-lactalbumin and gum arabic for microencapsulation of L-menthol: The effects on flavor release during storage and rehydration

L-menthol-containing food products generally show the flavor loss during storage due to their high volatility. The hydrophobicity of L-menthol also causes the inadequate flavor release during rehydration. In this study, the stability of L-menthol was enhanced by microencapsulation and the effect of different powder drying techniques was also investigated. The highest efficiency (76.58–78.66 %) and loading content (18.58–28.35 mg/g) of encapsulations were obtained by using a mass ratio of 2:1(α-LA: GA). Then they were dried by non-thermal spray freeze drying (SFD) technique compared to spray drying (SD) and freeze-drying (FD) process. The SFD particles were shown to be spherical and porous with the highest porosity (86.82 %). α-LA/GA based microparticles with spherical shapes were demonstrated to largely enhance flavor retention during high humidity storage. In addition, the porous structures of SFD powders could cause rapid rehydration in liquid models, and the release behaviors of loaded L-menthol followed the Fickian diffusion. Consequently, the SFD technique shows great potential to produce microparticles by regulating the release behaviors of L-menthol during storage and rehydration.

The Study of Spray-Freeze-Drying Technique for Development of Novel Combination pMDIs, Part II: In Vitro and In Vivo Evaluations

AbstractThe mometasone furoate (MF) and formoterol fumarate dihydrate (FF) inhalable microparticles prepared by different methods, such as micronized active pharmaceutical ingredients (APIs), microparticles of APIs prepared by spray-freeze drying technique (SFD APIs), and phospholipid microparticles of APIs prepared by SFD (SFD Lip-APIs), showed different inhaled drug delivery characteristics. Study on the physicochemical characteristics of those microparticles and the effect of matrix excipients on pharmacokinetic (PK) behaviors of inhalable microparticles is helpful for the development of new methods for inhalable microparticles with excellent performance of inhalation characteristics. In this study, the crystal state of the microparticles was investigated by powder X-ray diffraction and differential scanning calorimetry. The density was investigated by a bulk density method. The suspension and dispersion characteristics were determined by observing its state in hydrofluoroalkane (HFA). Meanwhile, the PK behaviors of SFD Lip-APIs in beagle dogs were also investigated by airway administration to evaluate the effect of phospholipids on drug release. The results indicated that the presence of phospholipids prevents the formation of solid bridges bonding to each other during SFD of pure drug solutions. In comparison to the conventional micronized microparticles, inhalable drug–phospholipid microparticles were easily dispersed and suspended in HFA. The embedded drugs were in a crystal state that endowed a better physical stability, and most interestingly, have similar PK behavior to the control (a mixed solution of MF/FF), suggesting that the phospholipids, as matrix excipients, had no effect on absorption. Given above, our designed SFD phospholipid microparticles may represent an efficient carrier for pulmonary delivery of MF and FF for further clinical treatment.

Ointment containing spray freeze-dried metronidazole effective against rosacea

Rosacea is a chronic, inflammatory skin disease that affects about 10% of the population. Metronidazole-containing ointments are typically recommended for the daily treatment of symptoms. For increasing bioavailability and effectiveness, it is needed to reduce the particle size. Therefore, micronized metronidazole was prepared by spray freeze-drying (SFD) method, then its most important features were examined such as morphology, crystallinity and particle size. The anti-inflammatory effect of the as-prepared agent was tested on a mouse model of rosacea for effectiveness against oedema and redness of the ears, and it was compared to a reference cream.Metronidazole size was reduced successfully by SFD to 2.7 μm from 162.6 μm. The material was non-porous and preserved its crystalline state. The spray freeze-dried metronidazole mixed into ointment was effective against oedema and ear-redness. The ointment reduced oedema in five times lower doses (2 × 0.04 mg metronidazole) and the ear-redness in half dose (2 × 0.2 mg metronidazole) than the cream containing reference metronidazole (2 × 0.2 mg and 2 × 0.4 mg metronidazole, respectively). In conclusion, the SFD technique is an adequate and gentle procedure for reducing the size of metronidazole, which is highly effective in rosacea.

Morphology transformation of thermosensitive metronidazol by spray freeze-drying

Spray freeze-drying (SFD) is an effective method for reducing the size of thermosensitive organic substances that are sparingly soluble in water. Despite the advantages of the method, its use has not yet become widespread. We aimed at studying SFD technique for metronidazole as a heat-sensitive active pharmaceutical ingredient for reducing its particle size and investigated the morphological and physical parameters of the modified drug.The obtained particles were crystalline in all cases and their sizes were two and one order of magnitude smaller using water or dimethyl sulphoxide solutions, respectively, as compared to the initial reference metronidazole. The particle size varied depending on the experimental parameters (atomization pressure, peristaltic pump speed), although, the operating parameters had a smaller effect on the size of the materials than the applied concentration of starting solution, regardless of the solvent. The as-prepared samples had a microcrystalline structure that is retained for a long time.

A comparative study of encapsulation of carotenoid enriched-flaxseed oil and flaxseed oil by spray freeze-drying and spray drying techniques

Encapsulation of carotenoid enriched flaxseed oil was performed by spray freeze-drying by using sixteen different emulsion formulations. Emulsions, which contain various concentrations of carotenoid enriched flaxseed oil (6, 9, 12 and 15% w/w) and ratios of maltodextrin/(pectin+wax) (3:1, 6:1, 9:1 and 12:1 g/g), were encapsulated to determine the emulsion formulation with the highest encapsulation efficiency. The best-chosen emulsion formulation was processed also with spray drying to compare the produced powders in terms of the encapsulation efficiency, moisture content, particle size, flowing and morphological properties. It was found that the spray freeze-drying technique had a lower encapsulation efficiency but better flow properties. The effect of carotenoids was discussed for both encapsulation techniques and oxidative stability of the powders at 45 d of storage. Moreover, the addition of carotenoids resulted in products that were more stable in terms of oxidation.

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

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.

Stability of Instant Coffee Foam by Nanobubbles Using Spray-Freeze Drying Technique

Instant coffee with stable foam is considered to be an important parameter for consumer preference and acceptability. For foam sustenance, nanoscale bubbles are more useful compared with microbubbles, due to their high specific area and high stagnation in the liquid phase (without undesirable liquid drainage). The technique that produces nanobubbles in coffee would concomitantly produce and preserve the coffee foam, the best. Spray-freeze drying (SFD) is known to be more effective for the production of instant coffee, compared with conventional spray drying (SD) and freeze drying (FD) techniques. However, its efficiency in the production of nanobubbles has not been explored. To address the issue, in the present study, SFD has been employed to produce instant coffee, and the findings have been compared with SD and FD. The coffee powder obtained with SFD produced a foam with higher stability that also comprised of nanobubbles, in contrast to SD and FD powders. The FE-SEM analysis of SFD foam showed the presence of nanobubbles in the range of 100–200 nm. When the beverage was prepared, the SFD coffee powder dissolved in water at 90 °C produced an excellent foam. The said foam structure was intact up to 2400 s (40 min), and lost only 89.5 ± 2 mm of foam height, during the experiment. Thus, apart from instant coffee, a stable foam in coffee comprising nanobubbles can also be achieved through the SFD.

The use of spray freeze drying for dissolution and oral bioavailability improvement of Azithromycin

Azithromycin is a poorly water-soluble drug with a low bioavailability. The main purpose of this investigation was to increase the solubility and dissolution of Azithromycin by the preparation of its solid dispersions, using the spray freeze drying (SFD) technique. The physicochemical properties of solid dispersions and interactions between the drug-polymer were evaluated using UV–Vis, FT-IR, DSC and PXRD. The surface morphology of the samples was observed by SEM. In order to carry out an assessment of the drug released, the dissolution test was performed. The in vitro drug released profiles were studied and it was found that the dissolution rate of the solid dispersion SFD sample (SFD-SD) was higher than the intact drug. In addition, the saturation solubility of the SFD-SD was significantly higher than the pure drug. The FT-IR spectra showed there was no chemical incompatibility between the drug and polyvinyl alcohol (PVA). The DSC thermograms revealed no possible physical interaction between the drug and the carrier. The surface morphology of samples showed the amorphous state and the distribution of the drug within the carrier particles. The dissolution of the SFD-SD formulation was increased up to 8.9 times more than pure drug utilizing the SFD technique.

Enhancement of oral bioavailability of vitamin E by spray-freeze drying of whey protein microcapsules

Vitamin E microcapsules were effectively prepared using three different techniques: spray drying, freeze-drying and spray freeze-drying with whey protein isolate as an encapsulating agent. The quality of microcapsules was evaluated by particle size distribution, surface morphology, encapsulation efficiency, moisture content, flow properties (Hausner ratio), dissolution properties and in vivo oral bioavailability. Vitamin E microcapsules prepared by spray drying, freeze-drying and spray freeze-drying techniques showed maximum encapsulation efficiencies of 89.6±2.58, 86.1±1.44, and 89.3±2.56 respectively. Both freeze-dried and spray freeze-dried microcapsules showed excellent dissolution behavior with higher ODmax and dissolution rates (k0) than the spray-dried microcapsules due to the presence of numerous porous internal structures. Oral bioavailability study performed in male Wistar rats showed enhanced values of maximum plasma concentration (Cmax) and area under the curve (AUC) for spray freeze-dried microcapsules. The overall results demonstrate that the spray freeze-drying based microencapsulation technique could be a promising strategy to enhance the oral bioavailability of poorly water-soluble bioactive compounds like vitamin E.

Effect of drying conditions on cellulose nanocrystal (CNC) agglomerate porosity and dispersibility in polymer nanocomposites

The microstructure of CNC particles depends strongly on the drying method employed during manufacturing. The effect of different drying techniques, including spray drying, freeze drying, and spray freeze drying (SFD), on microstructure of cellulose nanocrystal (CNC) particles was studied. Conventional drying methods (i.e. spray and freeze drying) yielded packed and dense agglomerates of CNC. Capillary forces and ice crystal growth play key roles in CNC aggregation during spray and freeze drying, respectively. It was found that, in the absence of these forces, in the SFD technique, the dispersed state of CNC in water could be frozen in. Thus, SFD of CNC suspension resulted in a powder with porous structure. A filament-like agglomerate structure consisting of nanofibers was formed at low CNC concentrations (ca. <2wt.%), while a spherical foam structure was obtained at higher CNC concentrations. Polypropylene (PP) nanocomposites containing spray dried CNC, freeze dried CNC, and spray freeze dried CNC (CNCSFD) were prepared via melt mixing in an internal batch mixer. Optical light and scanning electron microscopy coupled with rheological properties showed better dispersion of CNCSFD agglomerates. Moreover, PP samples containing CNCSFD showed significant increases in mechanical properties.

Inhalable budesonide porous microparticles tailored by spray freeze drying technique

Budesonide is a poorly water soluble corticosteroid used in the treatment of asthma and chronic obstructive pulmonary disease (COPD). The aim of the present study was to develop micronized porous particles containing budesonide in a mannitol-based dry powder formulation using spray freeze drying (SFD) technique. Hydroxy propyl beta cyclodextrine (HPbCD) and/or l-leucine were employed as complementary excipients and their effects on the particle shape and morphology of processed powders were evaluated. As well, the produced particles were characterized in terms of thermal behavior, porosity, dissolution rate and suitability for pulmonary delivery. The results demonstrated that aerosolisation performance of the microparticles containing both l-leucine and HPbCD were considerably improved in comparison to other formulations and the fine particle fraction (FPF) increased substantially. Different ratios of excipients resulted in the formation of particles with different aerodynamic behaviors.

Preparation of redispersible liposomal dry powder using an ultrasonic spray freeze-drying technique for transdermal delivery of human epithelial growth factor.

In this work, an ultrasonic spray freeze-drying (USFD) technique was used to prepare a stable liposomal dry powder for transdermal delivery of recombinant human epithelial growth factor (rhEGF). Morphology, particle size, entrapment efficiency, in vitro release, and skin permeability were systematically compared between rhEGF liposomal dry powder prepared using USFD and that prepared using a conventional lyophilization process. Porous and spherical particles with high specific area were produced under USFD conditions. USFD effectively avoided formation of ice crystals, disruption of the bilayer structure, and drug leakage during the liposome drying process, and maintained the stability of the rhEGF liposomal formulation during storage. The reconstituted rhEGF liposomes prepared from USFD powder did not show significant changes in morphology, particle size, entrapment efficiency, or in vitro release characteristics compared with those of rhEGF liposomes before drying. Moreover, the rhEGF liposomal powder prepared with USFD exhibited excellent enhanced penetration in ex vivo mouse skin compared with that for powder prepared via conventional lyophilization. The results suggest that ultrasonic USFD is a promising technique for the production of stable protein-loaded liposomal dry powder for application to the skin.

Effect of formulation ingredients on the physical characteristics of salmeterol xinafoate microparticles tailored by spray freeze drying

Series of microparticles containing salmeterol xinafoate (SX) as active pharmaceutical ingredient (API) and lactose, mannitol or trehalose as a bulking agents were prepared using spray freeze drying (SFD) technique and the effects of sugar type and presence of hydroxy propyl beta cyclodextrin (HPβCD) on the physical properties of powders were evaluated. Precipitation of salmeterol in the presence of lactose and mannitol resulted in the formation of irregular shapes of microparticles with broad size distributions. However application of trehalose resulted in the formation of porous particles with spherical morphology. Addition of cyclodextrin in the formulations was generally helpful for formation of porous and spherical particles with narrow size distribution with a mean size of 10–30μm. Dissolution of SX from processed particles was substantially higher (∼90% drug release in 30min) than that of unprocessed drug and physical mixture of drug and cyclodextrin (∼22% drug release in 30min). This study showed that, processing of SX by SFD technique could be a constructive approach to the production of various forms of drug and drastic changes in the physical characteristics of microparticles could be achieved by changing the composition of bulking agent and cyclodextrin.

Lipid–polymer composite microspheres for colon-specific drug delivery prepared using an ultrasonic spray freeze-drying technique

Lipid–polymer composite microspheres (LP-MS) for colon-specific drug delivery were prepared using an ultrasonic spray freeze-drying technique. These microspheres, which consist of the pH-sensitive polymer Eudragit S100 and the non-polar lipid Compritol 888 ATO, were characterized by morphological and physicochemical properties. It was found that the LP-MS have a spherical lipid porous matrix with a smooth pH-sensitive polymer film on both internal and external surfaces, and the insoluble drug 10-hydroxycamptothecin was dispersed in an amorphous state in the carrier. Morphological changes of microparticles under different pH conditions were observed by confocal laser scanning microscopy, which showed that the lipid matrix in LP-MS restricted the swelling property of the polymer at pH 6.8. In drug release studies, less than 15% of the drug was released below pH 6.8, whereas more than 30% was released with a sustained-release model at pH 7.4. The LP-MS could provide a promising vehicle for colon drug delivery.

Dissolution Characteristics of Composite Particles Using a Spray Freeze Drying

A spray freeze drying (SFD) method, using a spray nozzle, liquid N(2) and a lyophilizer, was developed to prepare composite particles of a poorly water-soluble drug. The resultant particles were found to have a porous structure. The purpose of the present research was to prepare a sustained release formulation using the SFD technique. Tolbutamide (TBM)and Eudragit S were used as model drugs and pH-dependent carrier, respectively. Eudragit S is a polymer that is soluble at or above pH 7.0. Morphological evaluation of the composite particles revealed that they had a porous structure with a significantly larger specific surface area than bulk TBM. The physicochemical properties of the particles were found to be dependent on the drug to carrier ratio, with the crystallinity of the TBM decreasing as the proportion of Eudragit S increased. Dissolution tests in solutions of pH 1.2 and pH 6.8 showed that the release profiles of TBM from the SFD composite particles were improved compared to bulk TBM, through the use of the pH-dependent carrier. On the other hand, following compression of the composite particles, sustained release was observed in a solution of pH 6.8, whereas almost no dissolution occurred in a solution of pH 1.2.

Comparison of Spray Freeze Drying and the Solvent Evaporation Method for Preparing Solid Dispersions of Baicalein with Pluronic F68 to Improve Dissolution and Oral Bioavailability

The objective of this study was to prepare solid dispersions consisting of baicalein and a carrier with a low glass transition/melting point (Pluronic F68) by spray freeze drying (SFD). We compared these powders to those produced from the conventional solvent evaporation method. In the SFD process, a feeding solution was atomized above the surface of liquid nitrogen following lyophilization, which resulted in instantaneously frozen microparticles. However, solid dispersions prepared by the solvent evaporation method formed a sticky layer on the glass flask with crystalline baicalein separated out from the carrier. The powder samples were characterized by scanning electron microscopy (SEM), powder X-ray diffraction (PXRD), surface area measurement, differential scanning calorimetry, and Fourier transform infrared spectrometry. SEM and PXRD results suggested that the majority of baicalein in the SFD-processed solid dispersion was in the amorphous state, which has a higher specific surface area than pure baicalein. However, the majority of baicalein was recrystallized in the solid dispersion at the same composition prepared by the solvent evaporation method, which showed a similar dissolution rate to the physical mixture. SFD product was physically and chemically stable after being stored at 40 °C with low humidity for 6 months. After enzyme hydrolysis, baicalein in the SFD product displayed a significantly shorter T (max) and higher C (max) than pure baicalein after oral dosing. The relative bioavailability of the SFD product versus pure baicalein determined by comparing the AUC(0-12) was 233%, which demonstrated the significantly improved oral bioavailability of baicalein produced by the SFD technique.

Inhalable nanoparticles, a non-invasive approach to treat lung cancer in a mouse model

Doxorubicin-loaded nanoparticles (NPs) were incorporated into inhalable effervescent and non-effervescent carrier particles using a spray–freeze drying technique. The prepared inhalable powders were tested in a tumor bearing Balb/c mouse model. Control mice were treated with blank inhalable NPs, inhalable lactose powder containing free doxorubicin, and intravenous injections of a suspension of doxorubicin NPs, doxorubicin solution, or saline solution. The survival of treatment groups was plotted with Kaplan–Meier curves. Animals treated with inhalable effervescent nanoparticle powder containing 30 μg doxorubicin showed a highly significant improvement in survival compared to all other treatment groups. Mice in control groups treated with doxorubicin solution or doxorubicin NPs as intravenous injection, died in less than 50 days. Inhalable free doxorubicin showed high cardiac toxicity. Pathological samples showed large tumor masses in the lungs of animals not treated or treated with i.v. injections of doxorubicin NPs or doxorubicin solution. The lungs of animals treated with inhalable effervescent doxorubicin NPs showed fewer and much smaller tumors compared to the control groups, as visualized by MRI imaging which confirmed the observed pathology results. The present study demonstrates that inhalable effervescent doxorubicin NPs are an effective way to treat lung cancer. This non-invasive route of administration might change the way lung cancer is treated in the future.

Fabrication of FOX-7 quasi-three-dimensional grids of one-dimensional nanostructures via a spray freeze-drying technique and size-dependence of thermal properties

1,1-Diamino-2,2-dinitroethylene (C2H4N4O4, FOX-7) quasi-three-dimensional (3D) grids, a promising high-energy-density material with superior sensitivity properties, were synthesized by a spray freeze-drying technique. The FOX-7 3D grids were constructed from one-dimensional nanostructures. The sizes and structures of the FOX-7 3D grids strongly depend on the concentration of the aqueous solution of FOX-7. A possible formation mechanism of this structure was proposed in detail. Thermal analysis reveals that decrease in average particle sizes of FOX-7 grids results in a lower decomposition temperature and a much higher decomposition rate, which is in agreement with those reported about inorganic nanomaterials.

Spray-freeze-drying of whey proteins at sub-atmospheric pressures

Spray-freeze-drying (SFD) involves spraying a solution into a cold medium, and freeze-drying the resultant frozen particles, which can be performed by contacting the particles with a cold, dry gas stream in a fluidized bed, typically at atmospheric pressure. This enables much faster drying rates than are usually possible by conventional freeze-drying, due to the small particle sizes involved. However, the quantities of gas required for atmospheric fluidized bed freeze-drying are prohibitively expensive. This has led to a process modification whereby fluidization is performed at sub-atmospheric pressures, which still allows rapid freeze-drying, but using much less gas. This study demonstrates the fluidized bed SFD technique at sub-atmospheric pressures (0.1 bar) using whey protein isolate solution (20% w/w solids) at gas inlet drying temperatures ranging from −10 °C to −30 °C. The process yields a powder consisting of highly porous particles and shows little loss of solubility for β-lactoglobulin and α-lactalbumin, the principal proteins in the isolate. A wet basis moisture content of 8.1% was achieved after freeze-drying at −10 °C for only 1 h, while at 30 °C a longer drying time (100 min) produced a wetter product (14% w.b.).

Novel Spray Freeze-Drying Technique Using Four-Fluid Nozzle-Development of Organic Solvent System to Expand Its Application to Poorly Water Soluble Drugs

Spray freeze-drying (SFD) technique using four-fluid nozzle (4N), which is a novel particle design technique previously developed by authors, has been further developed to expand its application in pharmaceutical industry. The organic solvent was utilized as a spray solvent to dissolve the poorly soluble drug instead of conventional aqueous solution. Acetonitrile solution of the drug and aqueous solution of the polymeric carrier were separately and simultaneously atomized through 4N, and collided each other at the tip of nozzle edge. The spray mists were immediately frozen in the liquid nitrogen to form a suspension. Then, the iced droplets were freeze-dried to prepare the composite particles of the drug and carrier according to our proprietary method developed before. The resultant composite particles with phenytoin prepared by using acetonitrile (4N-SFD-MeCN system) were deeply characterized compared to those using aqueous solution (4N-SFD-aqua system) from morphological and physicochemical perspectives. The characteristic porous structure was observed in 4N-SFD-MeCN particles as well as 4N-SFD-aqua particles. However, it was found that the size and quantity of pore in 4N-SFD-MeCN particles were smaller than those of 4N-SFD-aqua particles. As a result, the former particles had 2- to 3-times smaller specific surface area than the latter particles independent of the type of carrier loaded. The slight difference of release profiles from the particles prepared between both systems was discussed from the microscopically structural viewpoint. In addition, ciclosporin was applied to organic solvent SFD system because this drug was poorly water soluble and cannot be applied to conventional aqueous SFD system. The release profiles from SFD particles were dramatically improved compared to the bulk material, suggesting that the new SFD technique using organic solvent has potential to develop the novel solubilized formulation for poorly water-soluble active pharmaceutical ingredients (APIs).