Search Results (47)

Chronic lung infection is the main predictor of morbidity and mortality in cystic fibrosis (CF), and current pharmacological alternatives are ineffective against Pseudomonas aeruginosa infections. We developed ciprofloxacin (CIP) for inhalation, aiming at improving its solubility through the formation of an amorphous solid dispersion (ASD) using gelatin (GA). CIP and GA were dissolved in varying ratios and then spray-dried, obtaining CIP-GA microspheres in a single step. The dissolution rate, size distribution, morphology, and aerodynamic properties of CIP-GA microspheres were studied, as well as their antimicrobial activity on P. aeruginosa biofilms. Microspheres formulated with a higher GA ratio increased the dissolution of CIP ten-fold at 6 h compared to gelatin-free CIP. Formulations with 75% GA or more could form ASDs and improve CIP’s dissolution rate. CIP-GA microspheres outperformed CIP in eradicating P. aeruginosa biofilm at 24 h. The spray-drying process produced CIP-GA microspheres with good aerodynamic properties, as indicated by a fine particle fraction (FPF) of 67%, a D₅₀ of 3.52 μm, and encapsulation efficiencies above 70%. Overall, this study demonstrates the potential of gelatin to enhance the solubility of poorly soluble drugs by forming ASDs. As an FDA-approved excipient for lung delivery, these findings are valuable for particle engineering and facilitating the rapid translation of technologies to the market. Full article

Objectives: Micelles, liposomes, and solid lipid nanoparticles (SLNs) are promising drug delivery vehicles; however, poor aqueous stability requires post-processing drying methods for maintaining long-term stability. The objective of this study was to compare the potential of lipid-based micelles, liposomes, and SLNs for producing stable re-dispersible spray-dried powders with trehalose or a combination of trehalose and L-leucine. This study provides novel insights into the implementation of spray drying as a technique to enhance long-term stability for these lipid-based nanocarriers. Methods: Aqueous dispersions of LDV-targeted micelles, liposomes, and SLNs loaded with paclitaxel (PTX) were converted into re-dispersible powders using spray drying. The physicochemical properties of the nanocarriers were determined via scanning electron microscopy (SEM), Karl Fischer titration, differential scanning calorimetry (DSC), and dynamic light scattering (DLS). Short-term stability of all nanocarrier formulations was compared by measuring particle size, polydispersity index (PDI), and paclitaxel retention over 7 days at room temperature and at 4 °C. Results: Paclitaxel-loaded micelles, liposomes, and SLN formulations were successfully converted into well-dispersed spray-dried powders with acceptable yields (71.5 to 83.5%), low moisture content (<2%), and high transition temperatures (95.1 to 100.8 °C). SEM images revealed differences in morphology, where nanocarriers spray-dried with trehalose or a combination of trehalose and L-leucine produced smooth or corrugated particle surfaces, respectively. Reconstituted spray-dried nanocarriers maintained their nanosize and paclitaxel content over 7 days at 4 °C. Conclusions: The results of this study demonstrate the potential for the development of spray-dried lipid-based nanocarriers for long-term stability. Full article

Poor water solubility of drugs is a limiting factor for their bioavailability and pharmacological activity. Many approaches are known to improve drug solubility, and among them, the physical method, solid dispersions (SDs), is applied. SDs are physical mixtures of a drug and a carrier, sometimes with the addition of a surfactant, which can be obtained by milling, cryomilling, spray-drying, or lyophilization processes. In this study, solid dispersions with etodolac (ETD-SDs) were prepared by the milling method using different carriers, such as hypromellose, polyvinylpyrrolidone, copovidone, urea, and mannitol. Solubility studies, dissolution tests, morphological assessment, thermal analysis, and FTIR imaging were applied to evaluate the SD properties. It was shown that the ball-milling process can be applied to obtain SDs with ETD. All designed ETD-SDs were characterized by higher water solubility and a faster dissolution rate compared to unprocessed ETD. SDs with amorphous carriers (HPMC, PVP, and PVP/VA) provided greater ETD solubility than dispersions with crystalline features (urea and mannitol). FTIR spectra confirmed the compatibility of ETD with tested carriers. Full article

PROTACs, proteolysis targeting chimeras, are bifunctional molecules inducing protein degradation through a unique proximity-based mode of action. While offering several advantages unachievable by classical drugs, PROTACs have unfavorable physicochemical properties that pose challenges in application and formulation. In this study, we show the solubility enhancement of two PROTACs, ARV-110 and SelDeg51, using Poly(vinyl alcohol). Hereby, we apply a three-fluid nozzle spray drying set-up to generate an amorphous solid dispersion with a 30% w/w drug loading with the respective PROTACs and the hydrophilic polymer. Dissolution enhancement was achieved and demonstrated for t = 0 and t = 4 weeks at 5 °C using a phosphate buffer with a pH of 6.8. A pH shift study on ARV-110-PVA is shown, covering transfer from simulated gastric fluid (SGF) at pH 2.0 to fasted-state simulated intestinal fluid (FaSSIF) at pH 6.5. Additionally, activity studies and binding assays of the pure SelDeg51 versus the spray-dried SelDeg51-PVA indicate no difference between both samples. Our results show how modern enabling formulation technologies can partially alleviate challenging physicochemical properties, such as the poor solubility of increasingly large ‘small’ molecules. Full article

Designing spray-dried particles for inhalation aims at specific physicochemical properties including a respirable aerodynamic diameter and adequate powder dispersibility. Leucine, an amphiphilic amino acid, has been shown to aid in optimizing bulk powder properties. Mannitol, a model crystalline active and common bulking agent, was co-sprayed with leucine at several excipient ratios, ethanol/water ratios, and spray dryer outlet temperatures in order to experimentally probe the underlying particle formation mechanisms in this binary crystalline system. During the droplet drying of two crystallizing components, the material that nucleates first will preferentially enrich the surface. It is desired to have a completely crystalline leucine shell to improve powder properties, however, mannitol competes with leucine for the surface depending on excipient concentration and manufacturing parameters. The resulting particles were studied initially and at a two-month timepoint via solid state characterization, visual analysis, and particle size analysis in order to detect changes in bulk powder properties. It was determined that, similar to systems where only leucine can crystallize, initial leucine saturation in the formulation dictates powder characteristics. Full article

Electrostatic precipitators (ESP) are especially known for the efficient separation of micron and submicron particles from aerosols. Wet electrostatic precipitators are particularly suitable for highly resistive materials. Using these, particles can be directly transferred into a liquid for further processing or safer handling, which is advantageous for either hazardous or valuable materials. In this work, a wet ESP, which enables the separation of highly resistive particles into a heated liquid, was designed and investigated. To do this, spray-dried drug particles were embedded in a molten sugar alcohol to enhance the drug dissolution rate. After cooling, the solidified product showed advantageous properties such as a high drug dissolution rate and easy handling for further processing. For the design of the wet ESP, different discharge electrode configurations were tested. A wall film served as the collection electrode, which was generated by a specially designed distributer die. A laminar flow regime was achieved with a homogeneous film serving as the collection electrode, which is particularly important for a high separation efficiency. A prototype was designed and constructed in this respect. The particle separation into hot liquids or onto hot surfaces is challenging due to thermal effects in ESPs. The influence of thermophoresis and drag force on the particle transport was investigated, and optimum operation parameters were found for the present ESP. A broad field of applications can be covered with the presented device, where particles are embedded in even hot liquids to form liquid suspensions or, as it is presented here, solid dispersions. The dissolution of the drug-containing solid dispersion was studied in vitro. A remarkably faster drug dissolution was observed from the solid dispersion, as compared to a powder mixture of the drug and xylitol. Full article

This study aimed to prepare glycyrrhizin–apigenin spray-dried solid dispersions and develop PVA filament-based 3D printlets to enhance the dissolution and therapeutic effects of apigenin (APN); three formulations (APN1–APN3) were proportioned from 1:1 to 1:3. A physicochemical analysis was conducted, which revealed process yields of 80.5–91% and APN content within 98.0–102.0%. FTIR spectroscopy confirmed the structural preservation of APN, while Powder-XRD analysis and Differential Scanning Calorimetry indicated its transformation from a crystalline to an amorphous form. APN2 exhibited improved flow properties, a lower Angle of Repose, and Carr’s Index, enhancing compressibility, with the Hausner Ratio confirming favorable flow properties for pharmaceutical applications. In vitro dissolution studies demonstrated superior performance with APN2, releasing up to 94.65% of the drug and revealing controlled release mechanisms with a lower mean dissolution time of 71.80 min and a higher dissolution efficiency of 19.2% compared to the marketed APN formulation. This signified enhanced dissolution and improved therapeutic onset. APN2 exhibited enhanced antioxidant activity; superior cytotoxicity against colon cancer cells (HCT-116), with a lower IC50 than APN pure; and increased antimicrobial activity. A stability study confirmed the consistency of APN2 after 90 days, as per ICH, with an f2 value of 70.59 for both test and reference formulations, ensuring reliable pharmaceutical development. This research underscores the potential of glycyrrhizin–apigenin solid dispersions for pharmaceutical and therapeutic applications, particularly highlighting the superior physicochemical properties, dissolution behavior, biological activities, and stability of APN2, while the development of a 3D printlet shell offers promise for enhanced drug delivery and therapeutic outcomes in colon cancer treatment, displaying advanced formulation and processing techniques. Full article

Amorphous solid dispersions (ASDs) enable formulations to improve the solubility of poorly soluble active pharmaceutical ingredients (APIs). The amorphous state is reached through the disruption of the crystalline lattice of an API resulting in an increased apparent solubility with faster disintegration. Nevertheless, this form is characterized by a high-energy state which is prone to re-crystallization. To ensure a stable ASD, excipients, e.g., polymers that form a matrix in which an API is dispersed, are used. The applicable polymer range is usually linked to their solubility in the respective solvent, therefore limiting the use of hydrophilic polymers. In this work, we show the applicability of the hydrophilic polymer, polyvinyl alcohol (PVA), in spray-dried solid dispersions. Using a three-fluid nozzle approach, this polymer can be used to generate ASDs with a targeted dissolution profile that is characterized by a prominent spring and desired parachute effect showing both supersaturation and crystallization inhibition. For this purpose, the polymer was tested in formulations containing the weakly basic drug, ketoconazole, and the acidic drug, indomethacin, both classified as Biopharmaceutics Classification System (BSC) class II drugs, as well as the weakly basic drug ritonavir classified as BCS IV. Furthermore, ritonavir was used to show the enhanced drug-loading capacity of PVA derived from the advantageous viscosity profile that makes the polymer an interesting candidate for spray drying applications. Full article

In this study, we addressed various challenges associated with the consumption of functional lipids from the Ericerus pela (Chavannes), including unfavorable taste, insolubility in water, difficulty in oral intake, low bioavailability, and low psychological acceptance. Our study focused on the microencapsulation of policosanol, the key active component of insect wax, which is a mixture of functional lipids secreted by the Ericerus pela (Chavannes). We developed two innovative policosanol products, microcapsules, and effervescent tablets, and optimized their preparation conditions. We successfully prepared microcapsules containing insect wax–derived policosanol using the spray-drying method. We achieved 92.09% microencapsulation efficiency and 61.67% powder yield under the following conditions: maltodextrin, starch sodium octenyl succinate, and (2-hydroxy)propyl-β-cyclodextrin (HPβCD) at a ratio of 1:1:1, core-to-wall materials at a ratio of 1:10, 15% solid content, spray dryer feed temperature at 60 °C, inlet air temperature at 140 °C, and hot-air flow rate at 0.5 m³/min. The microcapsules exhibited a regular spherical shape with a minimal water content (1.82%) and rapid dispersion in water (within 143.5 s). These microcapsules released policosanol rapidly in simulated stomach fluid. Moreover, effervescent tablets were prepared using the policosanol-containing microcapsules. The tablets showed low friability (0.32%), quick disintegration in water (within 99.5 s), and high bubble volume. The microcapsules and effervescent tablets developed in this study presented effective solutions to the insolubility of policosanol in water. These products were portable and offered customizable tastes to address the psychological discomfort related to insect-based foods, thus providing a novel strategy for the consumption and secondary processing of insect lipids. Full article

We prepared hybrid nanocrystal–amorphous solid dispersions (HyNASDs) to examine their supersaturation capability in the release of a poorly soluble drug, itraconazole (ITZ), a slow crystallizer during dissolution. The HyNASD formulations included a polymer (HPC: hydroxypropyl cellulose, Sol: Soluplus, or VA64: Kollidon-VA64) and a surfactant (SDS: sodium dodecyl sulfate). Additionally, the dissolution performance of the HyNASDs and ASDs was compared. To this end, wet-milled aqueous nanosuspensions containing a 1:5 ITZ:polymer mass ratio with/without SDS as well as solutions of the same ratio without SDS in dichloromethane were spray-dried. XRPD–DSC confirmed that ASDs were formed upon spray drying the solution-based feeds, whereas HyNASDs (~5–30% amorphous) were formed with the nanosuspension-based feeds. SDS aided to stabilize the ITZ nanosuspensions and increase the amorphous content in the spray-dried powders. During dissolution, up to 850% and 790% relative supersaturation values were attained by HyNASDs with and without SDS, respectively. Due to the stronger molecular interaction between ITZ–Sol than ITZ–HPC/VA64 and micellar solubilization by Sol, Sol-based HyNASDs outperformed HPC/VA64-based HyNASDs. While the ASD formulations generated greater supersaturation values (≤1670%) than HyNASDs (≤790%), this extent of supersaturation from a largely nanocrystalline formulation (HyNASD) has not been achieved before. Overall, HyNASDs could boost drug release from nanoparticle-based formulations and may render them competitive to ASDs. Full article

Particulate amorphous solid dispersions (ASDs) have been recognised for their potential to enhance the performance of various solid dose forms, especially oral bioavailability and macromolecule stability. However, the inherent nature of spray-dried ASDs leads to their surface cohesion/adhesion, including hygroscopicity, which hinders their bulk flow and affects their utility and viability in terms of powder production, processing, and function. This study explores the effectiveness of L-leucine (L-leu) coprocessing in modifying the particle surface of ASD-forming materials. Various contrasting prototype coprocessed ASD excipients from both the food and pharmaceutical industries were examined for their effective coformulation with L-leu. The model/prototype materials included maltodextrin, polyvinylpyrrolidone (PVP K10 and K90), trehalose, gum arabic, and hydroxypropyl methylcellulose (HPMC E5LV and K100M). The spray-drying conditions were set such that the particle size difference was minimised, so that it did not play a substantial role in influencing powder cohesion. Scanning electron microscopy was used to evaluate the morphology of each formulation. A combination of previously reported morphological progression typical of L-leu surface modification and previously unreported physical characteristics was observed. The bulk characteristics of these powders were assessed using a powder rheometer to evaluate their flowability under confined and unconfined stresses, flow rate sensitivities, and compactability. The data showed a general improvement in maltodextrin, PVP K10, trehalose and gum arabic flowability measures as L-leu concentrations increased. In contrast, PVP K90 and HPMC formulations experienced unique challenges that provided insight into the mechanistic behaviour of L-leu. Therefore, this study recommends further investigations into the interplay between L-leu and the physico-chemical properties of coformulated excipients in future amorphous powder design. This also revealed the need to enhance bulk characterisation tools to unpack the multifactorial impact of L-leu surface modification. Full article

Bulk nanobubbles (BNBs) have widespread applications in various fields of science due to numerous peculiar characteristics. Despite significant applications, only limited investigations are available on the application of BNBs in food processing. In the present study, a continuous acoustic cavitation technique was used to generate bulk nanobubbles (BNBs). The aim of this study was to evaluate the influence of BNB incorporation on the processability and spray drying of milk protein concentrate (MPC) dispersions. MPC powders were reconstituted to the desired total solids and incorporated with BNBs using acoustic cavitation as per the experimental design. The control MPC (C-MPC) and BNB-incorporated MPC (BNB-MPC) dispersions were analyzed for rheological, functional, and microstructural properties. The viscosity significantly decreased (p < 0.05) at all the amplitudes studied. The microscopic observations of BNB-MPC dispersions showed less aggregated microstructures and greater structural differences compared with C-MPC dispersions, therefore lowering the viscosity. The viscosity of BNB incorporated (90% amplitude) MPC dispersions at 19% total solids at a shear rate of 100 s⁻¹ significantly decreased to 15.43 mPa·s (C-MPC: 201 mPa·s), a net decrease in viscosity by ~90% with the BNB treatment. The control and BNB incorporated MPC dispersions were spray-dried, and the resultant powders were characterized in terms of powder microstructure and rehydration characteristics. Focused beam reflectance measurement of the BNB-MPC powders indicated higher counts of fine particles (<10 μm) during dissolution, signifying that BNB-MPC powders exhibited better rehydration properties than the C-MPC powders. The enhanced powder rehydration with the BNB incorporation was attributed to the powder microstructure. Overall, reducing the viscosity of feed by BNB incorporation can enhance the performance of the evaporator. This study, therefore, recommends the possibility of using BNB treatment for more efficient drying while improving the functional properties of the resultant MPC powders. Full article

Spray-dried amorphous solid dispersions of new chemical entities and pH-dependent soluble polymer hydroxypropyl methylcellulose acetate succinate (HPMC-AS) were found to form solid agglomerates in the gastrointestinal tract of rodents after oral administration. These agglomerates, referring to descriptions of intra-gastrointestinal aggregated oral dosage forms termed pharmacobezoars, represent a potential risk for animal welfare. Previously, we introduced an in vitro model to assess the agglomeration potential of amorphous solid dispersions from suspensions and how it can be reduced. In this work, we investigated if the in vitro effective approach of viscosity enhancement of the vehicle used to prepare suspensions of amorphous solid dispersions could reduce the pharmacobezoar formation potential following repeated daily oral dosing to rats as well. The dose level of 2400 mg/kg/day used in the main study was determined in a dose finding study carried out in advance. In the dose finding study, MRI investigations were carried out at short time intervals to gain insights into the process of pharmacobezoar formation. Whereas MRI investigations underlined the importance of the forestomach for the formation of pharmacobezoars, viscosity enhancement of the vehicle reduced the incidence of pharmacobezoars, delayed the onset of pharmacobezoar formation and reduced the overall mass of pharmacobezoars found at necropsy. Full article

Spray drying is one of the most frequently used solvent-based processes for manufacturing amorphous solid dispersions (ASDs). However, the resulting fine powders usually require further downstream processing when intended for solid oral dosage forms. In this study, we compare properties and performance of spray-dried ASDs with ASDs coated onto neutral starter pellets in mini-scale. We successfully prepared binary ASDs with a drug load of 20% Ketoconazole (KCZ) or Loratadine (LRD) as weakly basic model drugs and hydroxypropyl-methyl-cellulose acetate succinate or methacrylic acid ethacrylate copolymer as pH-dependent soluble polymers. All KCZ/ and LRD/polymer mixtures formed single-phased ASDs, as indicated by differential scanning calorimetry, X-ray powder diffraction and infrared spectroscopy. All ASDs showed physical stability for 6 months at 25 °C/65% rH and 40 °C/0% rH. Normalized to their initial surface area available to the dissolution medium, all ASDs showed a linear relationship of surface area and solubility enhancement, both in terms of supersaturation of solubility and initial dissolution rate, regardless of the manufacturing process. With similar performance and stability, processing of ASD pellets showed the advantages of a superior yield (>98%), ready to use for subsequent processing into multiple unit pellet systems. Therefore, ASD-layered pellets are an attractive alternative in ASD-formulation, especially in early formulation development at limited availability of drug substance. Full article

The impact of residual drug crystals that are formed during the production and storage of amorphous solid dispersions (ASDs) has been studied using micron-sized seed crystals in solvent-shift (desupersaturation) and dissolution tests. This study examines the impacts of the seed size loading on the solution-mediated precipitation from griseofulvin ASDs. Nanoparticle crystals (nanoseeds) were used as a more realistic surrogate for residual crystals compared with conventional micron-sized seeds. ASDs of griseofulvin with Soluplus (Sol), Kollidon VA64 (VA64), and hydroxypropyl methyl cellulose (HPMC) were prepared by spray-drying. Nanoseeds produced by wet media milling were used in the dissolution and desupersaturation experiments. DLS, SEM, XRPD, and DSC were used for characterization. The results from the solvent-shift tests suggest that the drug nanoseeds led to a faster and higher extent of desupersaturation than the as-received micron-sized crystals and that the higher seed loading facilitated desupersaturation. Sol was the only effective nucleation inhibitor; the overall precipitation inhibition capability was ranked: Sol > HPMC > VA64. In the dissolution tests, only the Sol-based ASDs generated significant supersaturation, which decreased upon an increase in the nanoseed loading. This study has demonstrated the importance of using drug nanocrystals in lieu of conventional coarse crystals in desupersaturation and dissolution tests in ASD development. Full article