Reduction of maillard browning in spray dried low-lactose milk powders due to protein polysaccharide interactions.

Lactose hydrolysed concentrated milk was prepared using ß-galactosidase enzyme (4.76U/mL) with a reaction period of 12 h at 4 °C. Addition of polysaccharides (5 % maltodextrin/ß-cyclodextrin) to concentrated milk either before or after lactose hydrolysis did not result in significant differences (p > 0.05) in degree of hydrolysis (% DH) of lactose and residual lactose content (%). Three different inlet temperatures (165 °C, 175 °C and 185 °C) were used for the preparation of powders which were later characterised based on physico-chemical and maillard browning characteristics. Moisture content, solubility and available lysine content of the powders decreased significantly, whereas, browning parameters i.e., browning index, 5-hydroxymethylfurfural, furosine content increased significantly (p < 0.05) with an increase in inlet air temperature. The powder was finally prepared with 5 % polysaccharide and an inlet air temperature of 185 °C which reduced maillard browning. Protein-polysaccharide interactions were identified using Fourier Transform infrared spectroscopy, fluorescence spectroscopy and determination of free amino groups in the powder samples. Maltodextrin and ß-cyclodextrin containing powder samples exhibited lower free amino groups and higher degree of graft value as compared to control sample which indicated protein-polysaccharide interactions. Results obtained from Fourier Transform infrared spectroscopy also confirmed strong protein-polysaccharide interactions, moreover a significant decrease in fluorescence intensity was also observed in the powder samples. These interactions between the proteins and polysaccharides reduced the maillard browning in powders.

Selection of lubricant type and concentration for orodispersible tablets.

Lubricants are essential for most tablet formulations as they assist powder flow, prevent adhesion to tableting tools and facilitate tablet ejection. Magnesium stearate (MgSt) is an effective lubricant but may compromise tablet strength and disintegratability. In the design of orodispersible tablets, tablet strength and disintegratability are critical attributes of the dosage form. Hence, this study aimed to conduct an in-depth comparative study of MgSt with alternative lubricants, namely sodium lauryl sulphate (SLS), stearic acid (SA) and hydrogenated castor oil (HCO), for their effects on the tableting process as well as tablet properties. Powder blends were prepared with lactose, sodium starch glycolate or crospovidone as the disintegrant, and a lubricant at different concentrations. Angle of repose was determined for the mixtures. Comparative evaluation was carried out based on the ejection force, tensile strength, liquid penetration and disintegratability of the tablets produced. As the lubricant concentration increased, powder flow and tablet ejection improved. The lubrication efficiency generally decreased as follows: MgSt > HCO > SA > SLS. Despite its superior lubrication efficacy, MgSt is the only lubricant of four evaluated that reduced tablet tensile strength. Tablet disintegration time was strongly determined by tensile strength and liquid penetration, which were in turn affected by the lubricant type and concentration. All the above factors should be taken into consideration when deciding the type and concentration of lubricant for an orodispersible tablet formulation.

Nanoscale colocalized thermal and chemical mapping of pharmaceutical powder aerosols.

Inhalation of pharmaceutical aerosol formulations is widely used to treat respiratory diseases. Spatially resolved thermal characterization offers promise for better understanding drug release rates from particles; however, this has been an analytical challenge due to the small particle size (from a few micrometers down to nanometers) and the complex composition of the formulations. Here, we employ nano-thermal analysis (nanoTA) to probe the nanothermal domain of a pharmaceutical aerosol formulation containing a mixture of fluticasone propionate (FP), salmeterol xinafoate (SX), and excipient lactose, which is widely used to treat asthma and chronic obstructive pulmonary disease (COPD). Furthermore, atomic force microscopy-infrared spectroscopy (AFM-IR) and AFM force measurements are performed to provide nanochemical and nanomechanical information to complement the nanothermal data. The colocalized thermal and chemical mapping clearly reveals the surface heterogeneity of the drugs in the aerosol particles and demonstrates the contribution of the surface chemical composition to the variation in the thermal properties of the particles. We present a powerful analytical approach for in-depth characterization of thermal/chemical/morphological properties of dry powder inhaler particles at micro- and nanometer scales. This approach can be used to facilitate the comparison between generics and reference inhalation products and further the development of high-performance pharmaceutical formulations.

A catalytic membrane approach as a way to obtain sweet and unsweet lactose-free milk.

The growing need in the current market for innovative solutions to obtain lactose-free (L-F) milk is caused by the annual increase in the prevalence of lactose intolerance inside as well as the newborn, children, and adults. Various configurations of enzymes can yield two distinct L-F products: sweet (ß-galactosidase) and unsweet (ß-galactosidase and glucose oxidase) L-F milk. In addition, the reduction of sweetness through glucose decomposition should be performed in a one-pot mode with catalase to eliminate product inhibition caused by H2O2. Both L-F products enjoy popularity among a rapidly expanding group of consumers. Although enzyme immobilization techniques are well known in industrial processes, new carriers and economic strategies are still being searched. Polymeric carriers, due to the variety of functional groups and non-toxicity, are attractive propositions for individual and co-immobilization of food enzymes. In the presented work, two strategies (with free and immobilized enzymes; ß-galactosidase NOLA, glucose oxidase from Aspergillus niger, and catalase from Serratia sp.) for obtaining sweet and unsweet L-F milk under low-temperature conditions were proposed. For free enzymes, achieving the critical assumption, lactose hydrolysis and glucose decomposition occurred after 1 and 4.3 h, respectively. The tested catalytic membranes were created on regenerated cellulose and polyamide. In both cases, the time required for lactose and glucose bioconversion was extended compared to free enzymes. However, these preparations could be reused for up to five (ß-galactosidase) and ten cycles (glucose oxidase with catalase).

"A lactose-modified chitosan accelerates chondrogenic differentiation in mesenchymal stem cells spheroids".

Spheroids derived from human mesenchymal stem cells (hMSCs) are of limited use for cartilage regeneration, as the viability of the cells progressively decreases during the period required for chondrogenic differentiation (21 days). In this work, spheroids based on hMSCs and a lactose-modified chitosan (CTL) were formed by seeding cells onto an air-dried coating of CTL. The polymer coating can inhibit cell adhesion and it is simultaneously incorporated into spheroid structure. CTL-spheroids were characterized from a morphological and biological perspective, and their properties were compared with those of spheroids obtained by seeding the cells onto a non-adherent surface (agar gel). Compared to the latter, smaller and more viable spheroids form in the presence of CTL as early as 4 days of culture. At this time point, analysis of stem cells differentiation in spheroids showed a remarkable increase in collagen type-2 (COL2A1) gene expression (~700-fold compared to day 0), whereas only a 2-fold increase was observed in the control spheroids at day 21. These results were confirmed by histological and transmission electron microscopy (TEM) analyses, which showed that in CTL-spheroids an early deposition of collagen with a banding structure already occurred at day 7. Overall, these results support the use of CTL-spheroids as a novel system for cartilage regeneration, characterized by increased cell viability and differentiation capacity within a short time-frame. This will pave the way for approaches aimed at increasing the success rate of procedures and reducing the time required for tissue regeneration.

Effect of drug load on the aerosolisation propensity of binary adhesive mixtures for inhalation.

The aim of this study was to investigate how the propensity for aerosolisation in binary adhesive mixtures was affected by the drug load, and to determine whether these findings could be linked to different blend states. Binary blends of two different lactose carriers, each with varying size and morphology, were prepared together with budesonide. In vitro aerosolisation studies were conducted at four different pressure drops, ranging from 0.5 to 4 kPa, utilising a Next Generation Impactor. Several dispersion parameters were derived from the relationship between the quantity of dispersed API and the pressure drop. The evolution of the parameters with drug load was complex, especially at low drug loads. While similar responses were observed for both carriers, the range of drug load that could be used varied significantly. The choice of carrier not only influenced the capacity for drug loading but also affected the spatial distribution of the API within the mixture, which, in turn, affected its aerosolisation propensity. Thus, the drug dispersion process could be linked to different configurations of the lactose carrier and budesonide in the blends, i.e. blend states. In conclusion, the study suggests that the concept of blend states can provide an explanation for the complex dispersion process observed in adhesive blends.

The effect of unloading and ejection conditions on the properties of pharmaceutical tablets.

This study investigates decompression and ejection conditions on tablet characteristics by comparing compact densities and tensile strengths made using regular rigid dies and custom-built die systems that enable triaxial decompression. Die-wall pressure evolution during decompression and ejection stresses did not meaningfully impact the density and tensile strength of the materials tested: microcrystalline cellulose, crystalline lactose monohydrate, and mannitol. Furthermore, the apparent differences in tensile strength between rectangular cuboids and cylindrical compacts are unrelated to decompression and ejection conditions, but rather a consequence of their shapes and of the test configurations. This suggests that elastic and plastic deformations that may occur during decompression and ejection are not significantly influenced by die-wall pressure evolution. We thus conclude that while triaxial decompression and constraint-free ejection may allow the production of defect-free compacts for materials that otherwise are defect prone using a rigid die, they seem to pose no benefits when the materials already produce defect-free compacts using a rigid die.

Tableting behavior of freeze and spray-dried excipients in pharmaceutical formulations.

Most of biopharmaceuticals, in their liquid form, are prone to instabilities during storage. In order to improve their stability, lyophilization is the most commonly used drying technique in the pharmaceutical industry. In addition, certain applications of biopharmaceutical products can be considered by oral administration and tablets are the most frequent solid pharmaceutical dosage form used for oral route. Thus, the tableting properties of freeze-dried products used as cryo and lyoprotectant could be a key element for future pharmaceutical developments and applications. In this study, we investigated the properties that might play a particular role in the specific compaction behavior of freeze-dried excipients. The tableting properties of freeze-dried trehalose, lactose and mannitol were investigated and compared to other forms of these excipients (spray-dried, commercial crystalline and commercial crystalline milled powders). The obtained results showed a specific behavior in terms of compressibility, tabletability and brittleness for the amorphous powders obtained after freeze-drying. The comparison with the other powders showed that this specific tableting behavior is linked to both the specific texture and the physical state (amorphization) of these freeze-dried powders.

Critical attributes of fine excipient materials in carrier-based dry powder inhalation formulations: The particle shape and surface properties.

The potential of fine excipient materials to improve the aerodynamic performance of carrier-based dry powder inhalation (DPI) formulations is well acknowledged but not fully elucidated. To improve the understanding of this potential, we studied two fine excipient materials: micronized lactose particles and silica microspheres. Inhalation formulations, each composed of a coarse lactose carrier, one of the two fine excipient materials (0.0-15.0 % w/w), and a spray-dried drug (fluticasone propionate) material (1.5 % w/w) were prepared. The physical structure, the flow behavior, the aerosolization behavior, and the aerodynamic performance of the formulations were studied. The two fine excipient materials similarly occupied carrier surface macropores. However, only the micronized lactose particles formed agglomerates and appeared to increase the tensile strength of the formulations. At 2.5 % w/w, the two fine excipient materials similarly improved drug dispersibility, whereas at higher concentrations, the micronized lactose material was more beneficial than the silica microspheres. The findings suggest that fine excipient materials improve drug dispersibility from carrier-based DPI formulations at low concentrations by filling carrier surface macropores and at high concentrations by forming agglomerates and/or enforcing fluidization. The study emphasizes critical attributes of fine excipient materials in carrier-based DPI formulations.

The impact of diluents on the compaction, dissolution, and physical stability of amorphous solid dispersion tablets.

Amorphous solid dispersion (ASD) is an effective approach for enhancing the solubility, dissolution, and bioavailability of poorly water-soluble drugs. However, these metastable forms can transform into more thermodynamically stable but less soluble crystalline forms. Despite this challenge, research on processing ASDs into solid dosage forms, such as tablets, is lacking. This work aims to fill this gap by investigating the impact of common diluents on the tableting behavior, dissolution, and physical stability of ASDs composed of itraconazole and hypromellose acetate succinate. Four widely used diluents found in commercially available ASD tablets were selected for the study: microcrystalline cellulose (MCC), anhydrous lactose, starch, and mannitol. The performance of ASD tablets varied significantly depending on the diluent used. Tablets prepared with MCC exhibited higher mechanical strength than those formulated using other diluents. ASD tablets containing mannitol and lactose revealed a faster release rate than those composed of MCC or starch. Notably, the study highlighted that the physical stability of ASDs within a tablet is not solely dependent on the amount of sorbed water; crystalline diluents like lactose and mannitol were found to facilitate ASD recrystallization within a tablet. In summary, the study underscores the importance of excipient selection, considering factors such as mechanical strength, dissolution rate, and physical stability of ASD tablets. These findings offer valuable insights into the selection of excipients for downstream ASD tablet development, leading to improved manufacturability, physical stability, and the overall quality of ASD drug products.

Gram-scale chemical synthesis of galactosyllactoses and their impact on infant gut microbiota in vitro.

Galactooligosaccharides (GOS) are widely used as a supplement in infant nutrition to mimic the beneficial effects found in prebiotic human milk oligosaccharides (HMOs). However, the complexity of the GOS mixture makes it challenging to ascertain which of the GOS components contribute most to their health benefits. Galactosyllactoses (GLs) are lactose-based trisaccharides containing a ß-galactopyranosyl residue at the 3'-position (3'galactosyllactose, 3'-GL), 4'-position (4'-galactosyllactose, 4'-GL), or the 6'-position (6'-galactosyllactose, 6'-GL). These GLs are of particular interest as they are present in both GOS mixtures and human milk at early stages of lactation. However, research on the potential health benefits of these individual GLs has been limited. Gram quantities are needed to assess their health benefits but these GLs are not readily available at this scale. In this study, we report the gram-scale chemical synthesis of 3'-GL, 4'-GL, and 6'-GL. All three galactosyllactoses were obtained on a gram scale in good purity from cheap and commercially available lactose. Furthermore, in vitro incubation of GLs with infant faecal microbiota demonstrates that the GLs were able to increase the abundance of Bifidobacterium and stimulate short chain fatty acid production.

Crystal size, a key character of lactose crystallization affecting microstructure, surface chemistry and reconstitution of milk powder.

Lactose crystallization during storage deteriorates reconstitution performance of milk powders, but the relationship between lactose crystallization and reconstitution is inexplicit. The objective of this study is to characterize crystalline lactose in the context of formulation and elucidate the complex relationship between lactose crystallization and powder functionality. Lactose in Skim Milk Powder (SMP), Whole Milk Powder (WMP) and Fat-Filled Milk Powder (FFMP) stored under 23 %, 53 % and 75 % Relative Humidity (RH) at 25  â„ƒ for four months was compared. Lactose, surface chemistry and microstructure of FFMP stored at 25 â„ƒ and 40 â„ƒ at 23 % to 75 % RH for four months were also analyzed and interpreted. At the same RH, FFMP crystallized in the same pattern as WMP. At 53 % RH, FFMP and WMP differentiated from SMP in terms of lactose morphology as well as the ratio between anhydrous α-lactose and anhydrous ß-lactose. Lactose remained amorphous at 23 % RH, crystallized predominantly to α/ß-lactose (1:4) at 40 to 58 % RH and to α-lactose monohydrate at 75 % RH. The crystallinity index was similar for all powders containing crystalline lactose. The estimated crystallite size increased from approx. 0.1 to 20 µm with increasing RH and temperature. When amorphous lactose crystallized into crystals below approx. 0.1 µm at 25 °C and 43 % RH, the microstructure and surface lipid were comparable to that of the reference powder. This powder reconstituted into a stable suspension system comparable to that of reference (well performing) powders. These results demonstrate that crystallite size is the key property linking lactose crystallization and reconstitution. Our finding thus indicates limiting crystallite size is important for maintaining desired product quality.

Reproducibility of inverse gas chromatography under infinite dilution: Results and interpretations of an interlaboratory study.

Over the last years, inverse gas chromatography (IGC) proved to be a versatile and sensitive analytical technique for physicochemical properties. However, the comparability of results obtained by different users and devices remains a topic for debate. This is the first time, an interlaboratory study using different types of IGC instruments is reported. Eight organizations with different IGC devices defined a common lab measurement protocol to analyse two standard materials, silica and lactose. All data was collected in a standard result form and has been treated identically with the objective to identify experimentally observed differences and not potentially different data treatments. The calculated values of the dispersive surface energy vary quite significantly (silica: 22 mJ/m2 - 34 mJ/m2, lactose 37 mJ/m2 - 51 mJ/m2) and so do the ISP values and retention volumes for both materials. This points towards significant and seemingly undiscovered differences in the operation of the instruments and the obtained underlying primary data, even under the premise of standard conditions. Variations are independent of the instrument type and uncertainties in flow rates or the injected quantities of probe molecules may be potential factors for the differences. This interlaboratory study demonstrates that the IGC is a very sensitive analytical tool, which detects minor changes, but it also shows that for a proper comparison, the measurement conditions have to be checked with great care. A publicly available standard protocol and material, for which this study can be seen as a starting point, is still needed to judge on the measurements and the resulting parameters more objectively.

Selective anomer crystallization from aqueous solution: Monitoring lactose recovery under mutarotation limitation via attenuated total reflection Fourier-transform spectroscopy and theoretical rate analysis.

Lactose is typically produced via cooling crystallization either from whey or whey permeate (edible grade) or from aqueous solution (pharmaceutical grade). While in solution, lactose is present in 2 anomeric forms, α- and ß-lactose. During cooling crystallization under standard process conditions, only α-lactose crystallizes, depleting the solution of α-anomer. In practice, mutarotation kinetics are often assumed to be much faster than crystallization. However, some literature reports limitation of crystallization by mutarotation. In the present research, we investigate the influence of operating conditions on mutarotation in lactose crystallization and explore the existence of an operation regimen where mutarotation can be disregarded in the crystallization process. Therefore, we study crystallization from aqueous lactose solutions by inline monitoring of concentrations of α- and ß-lactose via attenuated total reflection Fourier-transform spectroscopy. By implementing a linear cooling profile of 9 K/h to a minimum temperature of 10°C, we measured a remarkable increase in ß/α ratio, reaching a maximum of 2.19. This ratio exceeds the equilibrium level by 36%. However, when the same cooling profile was applied to a minimum temperature of 25°C, the deviation was significantly lower, with a maximum ß/α ratio of 1.72, representing only an 8% deviation from equilibrium. We also performed a theoretical assessment of the influence of process parameters on crystallization kinetics. We conclude that mutarotation needs to be taken into consideration for efficient crystallization control if the crystal surface area and supersaturation are sufficiently high.

Lactose hydrolysis in packed-and fluidized-bed reactors using a recombinant ß-galactosidase immobilized on magnetic core-shell capsules.

The objective of this study was to develop a bioprocess for lactose hydrolysis in diverse dairy matrices, specifically skim milk and cheese whey, utilizing column reactors employing a core-shell enzymatic system featuring ß-galactosidase fused to a Cellulose Binding Domain (CBD) tag (ß-galactosidase-CBD). The effectiveness of reactor configurations, including ball columns and toothed columns operating in packed and fluidized-bed modes, was evaluated for catalyzing lactose hydrolysis in both skim milk and cheese whey. In a closed system, these reactors achieved lactose hydrolysis rates of approximately 50% within 5 h under all evaluated conditions. Considering the scale of the bioprocess, the developed enzymatic system was capable of continuously hydrolyzing 9.6 L of skim milk while maintaining relative hydrolysis levels of approximately 50%. The biocatalyst, created by immobilizing ß-galactosidase-CBD on magnetic core-shell capsules, exhibited exceptional operational stability, and the proposed bioprocess employing these column reactors showcases the potential for scalability.

Investigations on Compaction Behavior of Kollidon®SR-Based Multi-component Directly Compressed Tablets for Preparation of Controlled Release Diclofenac Sodium.

The physics of tablets mixtures has gained much attention lately. The purpose of this work is to evaluate the compaction properties of Kollidon® SR (KSR) in the presence of different excipients such as Microcrystalline cellulose (MCC), Monohydrous lactose (MH Lactose), Poly (vinyl acetate) (PVA100), and a water-soluble drug Diclofenac sodium (DNa) to prepare once daily formulation. Tablets were prepared using direct compression and were compressed into flat-faced tablets using hydraulic press at various pressures. The combination of MCC and KSR in the tablets showed reduced porosity, and almost constant low Py values as KSR levels increased; also, KSR-DNa tablets had higher percentage porosity and crushing strength values than KSR-MH Lactose tablets. The crushing strengths of KSR-MCC tablets were larger than those of KSR-DNa tablets. Ternary mixture tablets comprised of KSR-MCC-DNa showed decreased porosities and low Py values as the percentage of KSR increased especially at high compression pressures but had higher crushing strengths compared to KSR-DNa or MCC-DNa binary tablets. KSR-MH Lactose-DNa ternary tablets experienced lower porosities and crushing strengths compared to KSR-MCC-DNa tablets. Quaternary tablets of KSR-PVA100-MCC-DNa showed lower porosity and Py values than quaternary tablets obtained using similar proportion of MH Lactose instead of MCC. In conclusion, optimum quaternary tablets were obtained with optimum crushing strengths, relatively low Py, and moderate percentage porosities among all prepared quaternary tablets. The drug release of the optimum quaternary tablets demonstrated similar in vitro release profile compared to that of the marketed product with a mechanism of release that follows Korsmeyer-Peppas model.

Impact of high shear blending on distribution of magnesium stearate on lactose for dry powder inhaled formulations.

The use of magnesium stearate along with lactose in Dry Powder Inhaler (DPI) formulations is increasing. The impact of different conditions of high shear blending on the distribution of magnesium stearate on lactose particles was investigated in this study. The formulated blends were manufactured using high shear blending of pre-blended coarse and fine lactose particles with 1.0% (w/w) magnesium stearate under different blending conditions, specifically blending speed and time. The effects of blending conditions on the distribution of magnesium stearate on lactose particles were clearly identifiable by characterizing the formulated blends by means of rheological evaluations, scanning electron microscopy, and chemical surface analysis using time-of-flight secondary ion mass spectrometry (ToF-SIMS). Rheological properties were significantly affected in blends with magnesium stearate compared to blends without magnesium stearate. Blending speed exhibited a strong influence on the distribution of magnesium stearate on lactose surface, while blending time had relatively minor effect.

Influence of Pasteurization on Maillard Reaction in Lactose-Free Milk.

In order to improve the safety and quality of lactose-free milk (LFM) Maillard reaction products (MRPs), this study used raw cow's milk as raw material and lactase hydrolysis to prepare LFM, which was heat-treated using pasteurization and then placed in storage temperatures of 4 °C, 25 °C and 37 °C to investigate the changes in the Maillard reaction (MR). The results of the orthogonal test showed that the optimal conditions for the hydrolysis of LFM are as follows: the hydrolysis temperature was 38 °C, the addition of lactase was 0.03%, and the hydrolysis time was 2.5 h. Under these conditions, the lactose hydrolysis rate reached 97.08%, and the lactose residue was only 0.15 g/100 g as determined by high-performance liquid chromatography (HPLC), complying with the standard of LFM in GB 28050-2011. The contents of furoamic acid and 5-hydroxymethylfurfural were determined by high-performance liquid chromatography, the color difference was determined by CR-400 color difference meter, and the internal fluorescence spectrum was determined by F-320 fluorescence spectrophotometer. The test results showed that the variation range of furosine in lactose-free milk after pasteurization was 44.56~136.45 mg/100g protein, the range of 5-hydroxymethylfurfural (HMF) was 12.51~16.83 mg/kg, the color difference ranges from 88.11 to 102.53 in L*, from -0.83 to -0.10 in a*, and from 1.88 to 5.47 in b*. The furosine content of LFM during storage at 4, 25, and 37 °C ranged from 44.56 to 167.85, 44.56 to 287.13, and 44.56 to 283.72 mg/100 g protein, respectively. The average daily increase in protein content was 1.18-3.93, 6.46-18.73, and 15.7-37.66 mg/100 g, respectively. The variation range of HMF was 12.51~17.61, 12.51~23.38, and 12.51~21.1 mg/kg, and the average daily increase content was 0.03~0.07, 0.47~0.68, and 0.51~0.97 mg/kg, respectively. During storage at 4 °C, the color difference of LFM ranged from 86.82 to 103.82, a* ranged from -1.17 to -0.04, and b* ranged from 1.47 to 5.70. At 25 °C, color difference L* ranges from 72.09 to 102.35, a* ranges from -1.60 to -0.03, b* ranges from 1.27 to 6.13, and at 37 °C, color difference L* ranges from 58.84 to 102.35, a* ranges from -2.65 to 1.66, and b* ranges from 0.54 to 5.99. The maximum fluorescence intensity (FI) of LFM varies from 131.13 to 173.97, 59.46 to 173.97, and 29.83 to 173.97 at 4, 25, and 37 °C. In order to reduce the effect of the Maillard reaction on LFM, it is recommended to pasteurize it at 70 °C-15 s and drink it as soon as possible during the shelf life within 4 °C.

Microstructural insight into inhalation powder blends through correlative multi-scale X-ray computed tomography.

Dry powder inhalers (DPI) are important for topical drug delivery to the lungs, but characterising the pre-aerosolised powder microstructure is a key initial step in understanding the post-aerosolised blend performance. In this work, we characterise the pre-aerosolised 3D microstructure of an inhalation blend using correlative multi-scale X-ray Computed Tomography (XCT), identifying lactose and drug-rich phases at multiple length scales on the same sample. The drug-rich phase distribution across the sample is shown to be homogeneous on a bulk scale but heterogeneous on a particulate scale, with individual clusters containing different amounts of drug-rich phase, and different parts of a carrier particle coated with different amounts of drug-rich phase. Simple scalings of the drug-rich phase thickness with carrier particle size are used to derive the drug-proportion to carrier particle size relationship. This work opens new doors to micro-structural assessment of inhalation powders that could be invaluable for bioequivalence assessment of dry powder inhalers.

Conversion of liquid chitosan-based nanoemulsions into inhalable solid microparticles: Process challenges with polysaccharide.

Solid particles ≤5 µm are essential to allow lower lung deposition and macrophage phagocytosis of anti-tubercular drugs. Decorating liquid nanoemulsion of anti-tubercular drug with macrophage-specific chitosan and chitosan-folate conjugate and spray drying the nanoemulsion with lactose produced oversized solid particles due to polysaccharide binding effects. This study designed solid nanoemulsion using lactose as the primary solid carrier and explored additives and spray-drying variables to reduce the binding and particle growth effects of chitosan. Deposition of magnesium stearate on lactose negated chitosan-inducible excessive lactose-liquid nanoemulsion binding and solid particle growth. Moderating the adhesion of chitosan-decorated liquid nanoemulsion onto lactose produced smooth-surface solid microparticles (size: 5.45 ± 0.26 µm; roughness: ∼80 nm) with heterogeneous size (span: 1.87 ± 1.21) through plasticization of constituent materials of nanoemulsion and lactose involving OH/N-H, C-H, CONH and/or COO moieties. Smaller solid particles could attach onto the larger particles with minimal steric hindrance by smooth surfaces. Together with round solid particulate structures (circularity: 0.919 ± 0.002), good pulmonary inhalation beneficial for treatment of pulmonary tuberculosis as well as other diseases is conferred.