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Spray drying is a way to generate protein solids (powders), which is also true for lyophilization. Sugars are used to protect proteins from conformational changes and chemical degradations arising from drying processes and storage conditions such as the humidity. The influence of trehalose and humidity on the conformation and hydration of spray-dried recombinant human granolucyte colony stimulating factor (rhG-CSF) and recombinant consensus interferon-alpha (rConIFN) was investigated using Fourier transform IR spectroscopy. The spectral analysis of spray-dried powders in the amide I region demonstrated that trehalose stabilized the alpha-helical conformation of both rhG-CSF and rConIFN proteins. Exposure of the pure protein powders to 33% relative humidity (RH) resulted in the formation of beta sheets and loss of turns but no change in alpha-helical structure. Trehalose reduced the magnitude of the changes in beta sheets and turns. Exposure of the pure protein powders to 75% RH resulted in the loss of alpha-helical conformation with a corresponding increase in beta structures (beta sheets and turns). Trehalose did not protect proteins from the loss of alpha-helical structures, but it reduced the formation of antiparallel beta sheets. Hydrogen-deuterium exchange (H-D exchange) was used to further characterize these hydration-induced conformational changes. At 33% RH the percent exchange of the protein decreased with increasing trehalose content, indicating a greater protection of the protein from H-D exchange by a higher concentration of trehalose. Such protection correlates with decreased conformational changes of the protein by trehalose at this humidity. At 75% RH the degree of H-D exchange of the protein was insensitive to the powder composition in all powders. Surprisingly, the H-D exchange of trehalose was low at about 20-25%, which was nearly independent of the protein/trehalose ratio and humidity, indicating that the exchangeable protons on trehalose molecules are highly protected in protein-containing powders. The observed protein hydration is related to the effect of trehalose on the conformational changes of the protein under humidity.
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The thermoresistance of a cold-adapted subtilisin dried by spray-drying was studied. Proteolytic activity of this enzyme was measured before and after spray-drying. Without chemical additives, spray-drying yields ranged from 2-13%. The use of arabic gum and lactose in the composition of the enzyme solutions allowed the strengthening of the enzyme structures and increased water mobility in the product. Increase of water mobility led to a shorter residence time of the product in the spray-drier and a net yield increase was obtained (yield higher than 50%). The effect of two selective mutations on the thermoresistance to spray-drying of the cold-adapted subtilisin was also investigated. Mutation T85D (introduction of an additional link with an ion Ca2+ necessary for enzyme activity, by substitution of Asp for Thr 85) had no effect on the thermoresistance of the subtilisin to spray-drying. Mutation H121W (introduction of an additional aromatic link by substitution of Trp for His 121) reduced the drying yield from 66% (not modified subtilisin) to 52%. This higher thermosensitivity could be explained by an increase of the hygroscopic character of the modified subtilisin (mutation H121W).
Nanoparticles suspensions very often present a physicochemical instability during their storage. In order to overcome this lack of stability and facilitate the handling of these colloidal systems, the water elimination from the aqueous dispersions to obtain a dry solid form appears as the most promising strategy. The present paper reports the use of the spray-drying technique for the nanocapsules (NC) suspensions conversion into redispersible dried solid particles in presence of different water-soluble excipients as drying auxiliaries. Following the combination of additives solutions with NC suspension, the final dispersion homogeneity was favoured, avoiding phase separations. According to the size measurement after a simple atomisation experiment, the NC, which have a thin and fragile shell structure can withstand the shear forces developed for the feed disintegration in droplets. During drying, certain additives molecules are able to act as NC protectors. The physicochemical characterization of the spray-dried powders included an investigation of their properties, such as residual moisture content, particulate density, morphology and redispersion in water. Using a NC concentration of 1% (w/v), the best result was obtained with the preparation containing 10% (w/v) of lactose which led to more desirable powder morphology and favouring NC suspension reconstitution with only approximately 2% of the size distribution in the micrometer range. The spray-drying technique is an attractive method to improve the NC conservation and facilitate future handling.
A spray-drying method was applied to the recrystallization of phenylbutazone, and the resulting samples were examined by X-ray powder diffractometry, differential thermal analysis, IR spectrophotometry, scanning electron microscopy, and hot-stage photomicroscopy. Three different crystalline forms (delta, beta, and epsilon) could be prepared from methylene chloride solution by varying the drying temperature of sprayed droplets from 120 degrees C to 30 degrees C. Form epsilon, the fifth polymorph of phenylbutazone, was confirmed as a novel crystalline form which could not be prepared by recrystallization techniques. In this spray-drying system the composition of spray-dried samples was shown to be a function of the drying temperature. While the stable form delta was obtained at higher drying temperatures, form epsilon was obtained only under conditions affording a slower evaporation rate of the solvent. The dissolution properties of the pure modifications prepared by recrystallization techniques and the spray-dried samples were evaluated in simulated intestinal fluid. Form epsilon showed excellent in vitro availability and much higher solubility than any other of the forms.
The purpose of this research was to evaluate the influence of dry granulation parameters on granule and tablet properties of spray-dried extract (SDE) from Maytenus ilicifolia, which is widely used in Brazil in the treatment of gastric disorders. The compressional behavior of the SDE and granules of the SDE was characterized by Heckel plots. The tablet properties of powders, granules, and formulations containing a high extract dose were compared. The SDE was blended with 2% magnesium stearate and 1% colloidal silicon dioxide and compacted to produce granules after slugging or roll compaction. The influences of the granulation process and the roll compaction force on the technological properties of the granules were studied. The flowability and density of spray-dried particles were improved after granulation. Tablets produced by direct compression of granules showed lower crushing strength than the ones obtained from nongranulated material. The compressional analysis by Heckel plots revealed that the SDE undergoes plastic deformation with a very low tendency to rearrangement at an early stage of compression. On the other hand, the granules showed an intensive rearrangement as a consequence of fragmentation and rebounding. However, when the compaction pressure was increased, the granules showed plastic deformation. The mean yield pressure values showed that both granulation techniques and the roll compaction force were able to reduce the material's ability to undergo plastic deformation. Finally, the tablet containing a high dose of granules showed a close dependence between crushing strength and the densification degree of the granules (ie, roll compaction force).
An aqueous spray-drying process was used to coat theophylline particles with a cellulose polymer, sodium carboxymethylcellulose (NaCMC) or hydroxypropylmethylcellulose (HPMC). Effect of a plasticizer, citric acid, was studied. Strength of cast films have a direct relationship to the dissolution T50% values of the respective spray-dried products. With varying plasticizer concentrations, changes in interaction between plasticizer and polymer, and in size of crystallized drug crystals, were observed with HPMC films. The plasticizer content also affected the films of NaCMC by bringing about a change in the form and arrangement of the drug. X-ray diffraction analyses of the different spray-dried products revealed a possibility of the predominance of different crystal forms. Spherical spray-dried microcapsules of NaCMC were formed with a 20-30% w/w plasticizer content. With HPMC, as plasticizer concentration was increased there was a corresponding increase in mean size of the spray-dried products. In terms of drug release and formation of spherical particles, a plasticizer concentration of 30% w/w was found to be suitable for both HPMC and NaCMC.
Spray-drying represents a viable alternative to freeze-drying for preparing dry powder dispersions for delivering macromolecules to the lung. The dispersibility of spray-dried powders is limited however, and needs to be enhanced to improve lung deposition and subsequent biological activity. In this study, we investigate the utility of leucine as a dry powder dispersibility enhancer when added prior to spray-drying a model non-viral gene therapy formulation (lipid:polycation:pDNA, LPD). Freeze-dried lactose-LPD, spray-dried lactose-LPD and spray-dried leucine-lactose-LPD powders were prepared. Scanning electron microscopy showed that leucine increased the surface roughness of spray-dried lactose particles. Particle size analysis revealed that leucine-containing spray-dried powders were unimodally dispersed with a mean particle diameter of 3.12 microm. Both gel electrophoresis and in vitro cell (A549) transfection showed that leucine may compromise the integrity and biological functionality of the gene therapy vector. The deposition of the leucine containing powder was however significantly enhanced as evidenced by an increase in gene expression mediated by dry powder collected at lower stages of a multistage liquid impinger (MSLI). Further studies are required to determine the potential of leucine as a ubiquitous dispersibility enhancer for a variety of pulmonary formulations.
The physicochemical and aerodynamic properties of spray dried powders of the drug/drug mixture salbutamol sulphate/ipratropium bromide were investigated. The in vitro deposition properties of spray dried salbutamol sulphate and the spray dried drug/excipient mixtures salbutamol sulphate/lactose and salbutamol sulphate/PEG were also determined. Spray drying ipratropium bromide monohydrate resulted in a crystalline material from both aqueous and ethanolic solution. The product spray dried from aqueous solution consisted mainly of ipratropium bromide anhydrous. There was evidence of the presence of another polymorphic form of ipratropium bromide. When spray dried from ethanolic solution the physicochemical characterisation suggested the presence of an ipratropium bromide solvate with some anhydrous ipratropium bromide. Co-spray drying salbutamol sulphate with ipratropium bromide resulted in amorphous composites, regardless of solvent used. Particles were spherical and of a size suitable for inhalation. Twin impinger studies showed an increase in the fine particle fraction (FPF) of spray dried salbutamol sulphate compared to micronised salbutamol sulphate. Co-spray dried salbutamol sulphate:ipratropium bromide 10:1 and 5:1 systems also showed an increase in FPF compared to micronised salbutamol sulphate. Most co-spray dried salbutamol sulphate/excipient systems investigated demonstrated FPFs greater than that of micronised drug alone. The exceptions to this were systems containing PEG 4000 20% or PEG 20,000 40% both of which had FPFs not significantly different from micronised salbutamol sulphate. These two systems were crystalline unlike most of the other spray dried composites examined which were amorphous in nature.
Cromolyn sodium (CS) was spray dried under constant operation conditions from different water to ethanol feed ratios (50:50-0:100). The spray dried CS samples were characterized for their physicochemical properties including crystallinity, particle size distribution, morphology, density, and water/ethanol content. To determine quantitatively the crystallinity of the powders, an X-ray diffraction (XRD) method was developed using samples with different crystallinity prepared by physical mixing of 100% amorphous and 100% crystalline CS materials. The aerodynamic behavior of the CS samples was determined using an Andersen Cascade Impactor (ACI) with a Spinhaler at an air flow of 60 L/min. Binary mixtures of each spray dried CS powder and Pharmatose 325, a commercial alpha-lactose monohydrate available for DPI formulations, were prepared and in vitro aerosol deposition of the drug from the mixtures was analyzed using ACI to evaluate the effect of carrier on deposition profiles of the spray dried samples. CS spray dried from absolute ethanol exhibited XRD pattern characteristic for crystalline materials and different from patterns of the other samples. The crystallinity of spray dried CS obtained in the presence of water varied from 0% to 28.37%, depending on the ratio of water to ethanol in the feed suspensions. All samples presented different particle size, water/ethanol content, and bulk density values. CS particles spray dried from absolute ethanol presented uniform elongated shape whereas the other samples consisted mainly of particles with irregular shape. Overall, fine particle fraction increased significantly (p < 0.01) with decreasing d50% and water and ethanol content of spray dried CS samples. Significant difference (p < 0.01) in deposition profiles of the drug were observed between corresponding carrier free and carrier blended formulations. The difference in deposition profiles of CS aerosolized from various spray dried samples were described according to the particle size, shape, and water/ethanol contents of the powders. The results of this study indicate that enhanced aerosol performance of CS can be obtained by spray drying of the drug from suspensions containing > or = 87.5% v/v ethanol.
Five experiments were conducted to determine the effects of different wheat gluten (WG) sources (Source 1 = enzymatically hydrolyzed, Source 2 = nonmodified ring-dried, Source 3 = spray-dried, and Source 4 = flash-dried) on growth performance of nursery pigs compared with soybean meal (SBM), spray-dried animal plasma (SDAP), or other specialty protein sources. In Exp. 1, pigs (n = 220, initially 6.1 +/- 2.5 kg) were fed a control diet containing (as-fed basis) 6% SDAP or WG Source 1 or 2. The WG and l-lysine*HCl replaced 50 or 100% of the SDAP. From d 0 to 21, increasing WG (either source) decreased ADG and ADFI (linear, P < 0.01), but improved (linear, P < 0.02) G:F. In Exp. 2, pigs (n = 252, initially 6.2 +/- 3.0 kg) were fed a negative control diet containing no SDAP or WG, diets containing (as-fed basis) 9% WG Source 1 or 5% SDAP, or combinations of WG and SDAP where WG and l-lysine*HCl replaced 25, 50, or 75% of SDAP. From d 0 to 14, pigs fed increasing WG had decreased ADG (linear, P < 0.05). In Exp. 3, pigs (n = 240, initially 7.0 +/- 2.5 kg) were fed a negative control diet, a diet containing (as-fed basis) either 3, 6, 9, or 12% WG Source 3, or a positive control diet containing 5% SDAP. The diets containing 9% WG and 5% SDAP had the same amount of SBM. From d 0 to 7, pigs fed 5% SDAP had greater (P < 0.04) ADG than pigs fed the diet containing 9% WG. From d 0 to 14, increasing WG had no effect on ADG, ADFI, or G:F. In Exp. 4, pigs (n = 200, initially 6.0 +/- 2.4 kg) were fed a negative control diet, the control diet with (as-fed basis) 4.5 or 9.0% WG Source 1, or the control diet with 2.5 or 5.0% SDAP. Diets containing WG and SDAP had similar SBM levels. From d 0 to 7 and 0 to 14, increasing SDAP tended to improve (linear, P < 0.06) ADG, but increasing WG had no effect. In Exp. 5, 170 barrows and gilts (initially 7.5 +/- 2.8 kg) were used to determine the effects of WG Source 1 and 4 compared with select Menhaden fish meal or spray-dried blood cells and a negative control diet (SBM) on the growth performance of nursery pigs from d 5 to 26 postweaning (d 0 to 21 of experiment). No differences were found in ADG or G:F, but pigs fed the diet containing (as-fed basis) 2.5% spray-dried blood cells had greater ADFI than pigs fed the negative control from d 0 to 21. Wheat gluten source had no effect on ADG, ADFI, or G:F. The results of these studies suggest that increasing WG in diets fed immediately after weaning did not improve growth performance relative to SBM or SDAP.
A novel spray-drying technique consisting of feeding a fluid through an ultrasonic atomiser, drying the spray under reduced pressure and collecting the particles in a liquid bath was evaluated. Drying by mild vacuum instead of hot air, as employed in conventional spray-drying, and simple particle recovery render this method suitable for aseptic microsphere preparation. As a model system, the protein bovine serum albumin (BSA) was encapsulated in poly(lactic-co-glycolic acid) microspheres. Particle yields of above 80% exceeded largely values found for conventional laboratory-scale spray-drying equipment. BSA encapsulation efficiency mostly ranged in the region of 60%, with losses probably occurring through partitioning into the aqueous collection bath. Mean particle sizes ranged from 13 to 24 microm, depending on the polymer type and solvent; particle size distributions were excellently reproducible. The microspheres were found to be very porous and exhibited a pronounced 24-h burst release of above 50% of total dose, probably promoted by the porosity. However, when more concentrated polymer solutions (8% instead of 5% (w/w)) were employed, burst release reduced to an average of 16%.
Inhalation of spray-dried particles is a promising delivery route for proteins as an alternative to injection. Changes in the protein structure and aggregation have to be avoided. The effect of mannitol, a stabilizing agent typically used in both liquid and lyophilized protein formulations, on an antibody (IgG1) in a spray-dried powder was studied using different biophysical and chromatographic techniques. At first, different solutions composed of antibody (IgG1) and mannitol at a ratio between 20/80 and 100/0 IgG1/mannitol (100 mg/ml total solid) were investigated for their stability. Protein solutions containing the IgG1 showed mannitol-dependent aggregation. High amounts of mannitol (50-80%) exerted a destabilizing effect on the antibody and the aggregate 9 level increased to 2.6-4.2%. In contrast, solutions with only 20-40% mannitol showed the same amount of aggregates as the pure antibody solution. The antibody mannitol solutions were investigated by circular dichroism (CD) and Fourier transform infrared spectroscopy (FTIR) to evaluate whether changes in the protein secondary structure can be correlated with aggregation. Considering the sensitivity of the used methods and data evaluation, FTIR spectra did not reveal structural changes in the IgG1/mannitol solutions compared to the pure antibody, despite varying aggregate levels. Thermal stress was reflected in perturbations of the secondary structure, but mannitol-dependent aggregation could not be correlated to detectable alterations in the FTIR spectra. Analyzing the CD spectra revealed no distinctive change in the shape of the CD curve, indicating that the protein secondary structure is mainly retained. This is in agreement with the infrared data. Subsequently, the IgG1/mannitol solutions were spray-dried at Tin/Tout of 90/50 degrees C. Using ATR-FTIR for the investigation of the protein amide I band in the spray-dried powder revealed changes in the sub-components of the amide I band. This indicates that the peptide groups (CO and NH) of the protein are found in a different environment in the solid state, compared to the liquid protein formulation. After redissolution of the powders, the native structure of the pure antibody solution was found identical to the protein secondary structure before spray-drying, indicating that the protein secondary structure is not strongly altered in the dry state, and not affected by the spray-drying process. Thus, from the presented study it can be concluded that the formation of antibody aggregates in mannitol formulations cannot be correlated with significant perturbations of the protein secondary structure elements.
As far as we know, spray drying has previously not been applied to oxyhemoglobin, undoubtedly because of the sensitivity of oxyhemoglobin to temperature and oxidation. Our experience with freeze drying encouraged us to perform spray-drying trials in order to compare the results of the two methods, in the absence and the presence of protective compounds. Spray drying of hemoglobin without a protective compound led, as in freeze drying, to formation of a percentage of methemoglobin (50%) that makes it unsuitable for transporting oxygen. In the presence of 0.25 M sucrose (optimum) and at 80-100 degrees C, the functional properties of the hemoglobin were well preserved (methemoglobin approximately 4%), and the residual humidity was limited to approximately 3%. Structural investigation by optical circular dichroism confirmed the results obtained by freeze drying: in the presence of an effective protector, the spectra were similar to those of control hemoglobin and the immediate environment of the heme did not undergo any major change. Electron spin resonance absorption bands in all samples were similar for each value of the spectral decomposition factor, g. This suggests that the structure of the heme is not altered by desiccation and that the protector does not penetrate into the heme pocket since it would have disturbed the symmetry of the crystalline field. Fundamentally, these results are equivalent or similar to those observed with freeze drying; since spray drying is a different process of dehydration, the results indicate a lack of specificity in the phenomena of oxidation or of protection affecting hemoglobin.
An emulsification-spray drying technique is used to prepare poly(D,L-lactic acid) (PDLLA) microparticles loaded with a water soluble, non-steroidal anti-inflammatory drug (NSAID), sodium naproxen (NaNPX). The method involves the preparation of a w/o emulsion in which the water soluble drug is dissolved in the aqueous dispersed phase, while the polymer is dissolved in the organic continuous phase. As a comparison, microparticles were prepared by spraying a suspension of the drug into an organic solution of the polymer. The spray-dried particles were characterized using SEM, DSC, XRD and in vitro release tests. The spray-dried product was then compressed (direct compression) to obtain controlled release matrix tablets. All microparticles release NaNPX within 30 min. The matrix tablets release the drug in 8-10 h; the matrix tablets characterized by the presence of surfactant (due to the emulsion used to obtain the microparticles) have the highest release rate.
Achyrocline satureioides spray-dried extracts, prepared with colloidal silicon dioxide, microcrystalline cellulose + colloidal silicon dioxide (1:1), and beta-cyclodextrin + colloidal silicon dioxide (1:1), were incorporated in a glyceryl monostearate base. The influence of the spray-drying adjuvants on the formulations' physical characteristics, such as spreading properties, oil indexes, viscosities, and the pH determination, were evaluated. The results indicated that the adjuvants influenced the ointments' physical parameters at different levels, although all of them maintained their plastic flow and presented antithixotropic behavior. The presence of colloidal silicon dioxide alone, in the dried extract, imparted the lowest oil index value and an intermediary spreading area to the ointment. The colloidal silicon dioxide content reduction and the substitution of part of it by beta-cyclodextrin or microcrystalline cellulose enhanced the ointments' oil index values, while the best spreading area was reached by the ointment prepared with the spray-dried extract containing colloidal silicon dioxide and microcrystalline cellulose.
The potential of spray-drying technique for the encapsulation in poly(lactide-co-glycolide) (PLGA) microspheres of bovine insulin, a poorly stable peptide, has been investigated. Insulin-loaded microspheres were prepared by spray-drying different feeding liquids containing insulin and PLGA, that is a S/O dispersion, a W/O emulsion or an acetic acid solution. In the case of the emulsion, insulin was also co-encapsulated with either non-ionic surfactants such as polysorbate 20 and poloxamer 188, or complexing agents such as HPbetaCD. In the microspheres prepared from the acetic acid solution of insulin and PLGA, HPbetaCD was tested. Microspheres containing surfactants were aggregated, whereas good quality particles displaying a mean diameter in the range 12.1-27.9 microm were produced in the other cases. Insulin was efficiently loaded inside microspheres except for S/O formulation (only 22% of total insulin content was entrapped). The impact of the microencapsulation process on insulin chemical and conformational stability was assessed by HPLC, circular dichroism and turbidimetry studies. Under the adopted manufacture conditions, insulin was encapsulated in the native state and its chemical and conformational stability was preserved along the fabrication process. The formulations containing only insulin displayed low burst effects (6-11%), whereas the addition of surfactants resulted in much higher burst effects (49-54%) and faster release rate. The co-encapsulation of HPbetaCD slowed down the overall release rate and, in the case of microspheres prepared from the emulsion, allowed a constant insulin release up to 45 days. The study of insulin stability along the release phase showed that insulin was released in the intact form and un-released insulin was stable inside all the microsphere formulations. We conclude that insulin can be effectively encapsulated in PLGA microspheres by the spray-drying technique. Additives with complexing properties such as HPbetaCD have demonstrated a potential in optimizing the release rate of insulin when used in microspheres prepared from W/O emulsions.