Preparation Of Polymeric Albumin Nanoparticles by A One-Step Spray Drying Process

The field of pharmaceutical formulation has evolved tremendously over time. Initially, pharmaceutical formulation was largely based on individualized compounding, in which pharmacists combined, mixed, or modified ingredients to prepare medicines for individual patients. With industrialization, however, the focus shifted from patient-specific preparation to the large-scale production of standardized dosage forms, including tablets, capsules, liquids, injections, and other pharmaceutical products. As the field advanced, scientists recognized that simply incorporating the correct drug dose into a dosage form did not necessarily ensure the desired therapeutic effect. Drug performance could be limited if the active pharmaceutical ingredient failed to disintegrate, dissolve, permeate biological membranes, or become adequately absorbed. This realization established the importance of preformulation studies and the evaluation of properties such as aqueous solubility, dissolution rate, particle size, crystal form and polymorphism, salt form, pKa, lipophilicity, stability, hygroscopicity, and membrane permeability [1, 2].

Formulation science subsequently progressed from simply delivering a drug dose to controlling the rate, duration, and site of drug release. Higuchi established the theoretical foundations of diffusion-controlled drug release from ointments and solid matrices [3]. Later, Langer and Folkman demonstrated the sustained release of biologically active proteins and other macromolecules from polymeric systems over extended periods [4]. These developments contributed to the emergence of technologies such as matrix tablets, reservoir systems, enteric and other functional coatings, osmotic-release tablets, biodegradable microspheres, drug-eluting implants, and long-acting injectable formulations [5-8]. This period fundamentally changed the role of pharmaceutical formulation. Formulation was no longer viewed merely as the process of manufacturing a tablet or capsule; instead, it became a means of engineering a drug product to control its release profile, maintain therapeutic concentrations, reduce dosing frequency, improve patient adherence, and enhance overall treatment performance.

Today, formulation science has entered an era of increasingly complex therapeutic modalities, including biologics, proteins, peptides, and nucleic acid-based medicines. Although significant progress has been made in delivering these molecules, researchers continue to explore more stable, efficient, targeted, and patient-friendly delivery strategies. At the same time, modern pharmaceutical development increasingly follows Quality by Design principles, with a strong emphasis on understanding how drug-substance properties, excipient characteristics, process parameters, and manufacturing operations influence the quality, safety, and performance of the final drug product [9]. Alongside advances in formulation science, numerous manufacturing technologies have been developed and refined to enable the reproducible production of increasingly complex pharmaceutical dosage forms. Modern formulation and manufacturing approaches include spray drying, hot-melt extrusion, lyophilization, nanoparticle and lipid nanoparticle preparation, microfluidic and controlled-mixing processes, long-acting injectable systems, implantable delivery systems, inhalable powders, microneedle-based systems, and three-dimensional printing. These technologies have supported the development of advanced dosage forms such as amorphous solid dispersions, nanoparticles, liposomes, microspheres, long-acting injectables, inhalable formulations, and delivery systems for biologics and nucleic acids [10-14]. Consequently, manufacturers no longer select a process based solely on its ability to produce a dry, stable, or easily handled product. Instead, formulation processes are increasingly selected and optimized to control critical product characteristics, including particle size, morphology, porosity, crystallinity, drug distribution, release behavior, stability, bioavailability, and biological performance [15]. While some of these technologies were developed specifically for pharmaceutical applications, others originated in different industries and were subsequently adapted to address pharmaceutical challenges [16]. Spray drying is a prominent example of such a technology. Initially used in the food, dairy, and chemical industries for drying and powder production, spray drying was later adopted by the pharmaceutical industry because it can rapidly convert liquid feedstocks into dry powders through a single, scalable, and potentially continuous process [9, 17, 18]. The evolution of spray drying closely reflects the broader transformation of pharmaceutical formulation. What began primarily as a method for solvent removal and powder production has developed into a versatile particle-engineering and formulation platform [15]. Today, spray drying is used not only to produce stable powders but also to improve drug solubility, dissolution, bioavailability, stability, delivery, and therapeutic performance [10, 19]. This progression has established spray drying as an important technology in developing modern pharmaceutical products.

The evolution of spray drying from a conventional drying method to an advanced pharmaceutical formulation platform can be traced back to the early process patented by Samuel Percy in 1872. Percy described a method in which a liquid was dispersed into fine droplets and exposed to heated air to remove moisture and produce a dried material. Although the original purpose of the process was primarily solvent removal and powder production, its fundamental principles remain central to modern spray drying [9]. The spray-drying process can generally be divided into five major stages: (1) preparation of the liquid feed, (2) atomization of the feed into fine droplets containing dissolved or suspended components, (3) drying of the droplets through contact with a heated drying gas, (4) separation and transport of the dried particles to the collection unit, and (5) recovery of the final powder. Feed preparation typically begins by dissolving or dispersing the drug and selected excipients in an appropriate liquid medium, most commonly water. Depending on the formulation, the feed may be prepared as a solution, suspension, emulsion, or another suitable dispersion. Feed uniformity is essential because variations in concentration or dispersion stability can affect atomization, drying behavior, drug distribution, and the properties of the final particles. Accordingly, appropriate mixing, stirring, homogenization, or other dispersion techniques may be used to obtain a uniform and stable feed [20]. For conventional small-molecule formulations, the drug and excipients are often sufficiently robust to tolerate standard mixing conditions. Greater care is required when preparing feeds containing biologics such as proteins, peptides, vaccines, or nucleic acids. These molecules may be sensitive to shear stress, interfacial exposure, temperature, pH changes, and prolonged processing [21]. Consequently, mixing conditions may need to be carefully controlled or customized to minimize aggregation, denaturation, or loss of biological activity [22, 23]. Solvent selection is also a critical consideration during feed preparation. Organic solvents may be used when the drug or excipients have limited aqueous solubility, and their greater volatility may permit rapid solvent removal under comparatively mild drying conditions. However, organic solvents introduce additional concerns related to toxicity, flammability, residual-solvent limits, process safety, and compatibility with sensitive biological molecules [24-26]. They may also destabilize proteins by disrupting their native structure or altering intermolecular interactions. For these reasons, water is generally preferred for biologic-containing spray-drying feeds whenever adequate solubility, stability, and processability can be achieved [27]. Feedstock preparation is a critical step in spray drying because liquid-feed properties strongly influence both process performance and final-product characteristics. Parameters such as viscosity affect feed pumpability and atomization, while concentration, density, surface tension, and solvent boiling point can significantly alter droplet formation and drying behavior [15]. For example, more concentrated feeds generally produce larger particles because each droplet contains more dissolved or suspended solids. In contrast, feeds with lower surface tension tend to atomize more readily and may generate smaller droplets and, consequently, smaller particles [28-30].

Just as feedstock properties are critical determinants of the desired product quality, spray-drying process parameters also play an equally important role in governing the characteristics of the final product. Key process variables include inlet temperature, outlet temperature, feed rate, atomizer type, atomization frequency or pressure, drying gas flow rate, and pump speed. These parameters influence droplet formation, drying kinetics, particle size, morphology, residual moisture content, and overall process yield. Consequently, developing a spray-drying method for a specific formulation generally requires systematic optimization of both formulation and processing conditions [31-33]. Each process parameter can affect product quality through a different mechanism. For example, inlet temperature is a critical determinant of drying rate and particle formation. Excessively high inlet temperatures may promote rapid solvent evaporation, resulting in altered or undesirable particle morphology and, for thermally sensitive materials, potential degradation. Conversely, an inlet temperature that is too low may result in insufficient drying, leading to particles with elevated residual moisture, increased stickiness, poor powder recovery, or incomplete formation of the desired solid product [34-36]. Therefore, careful selection and fine-tuning of spray-drying parameters are essential to achieve reproducible particle characteristics and the intended critical quality attributes of the formulation. Although relatively high inlet temperatures are commonly used during spray drying, the droplets do not immediately reach the temperature of the incoming drying gas. During the initial constant-rate drying stage, solvent evaporation continuously removes heat from the droplet surface. As long as the surface remains saturated with moisture, the droplet temperature generally remains close to the wet-bulb temperature of the drying conditions [18]. Once most of the surface moisture has evaporated and particle formation progresses, the drying rate decreases, and the particle temperature may begin to rise toward the outlet-gas temperature. This evaporative-cooling effect is one of the reasons spray-drying can be suitable for certain heat-sensitive pharmaceutical materials [16, 18, 37].

Atomizer type and atomization conditions are important process variables in spray drying because they directly influence droplet formation and, consequently, the size and characteristics of the resulting particles. Pressure, two-fluid, rotary, and vibrating-mesh atomizers generate droplets through different mechanisms and are therefore suited to different feed properties and target particle sizes. In general, smaller droplets tend to produce smaller dried particles, whereas larger droplets result in larger particles. Two-fluid nozzles are often preferred for more viscous feeds or when smaller particles are desired, while pressure nozzles are commonly used at larger production scales. In vibrating-mesh nano spray dryers, droplet size is influenced by the mesh aperture, atomization frequency, and feed properties such as viscosity and surface tension. Thus, careful selection and optimization of the atomization system are critical for controlling particle size distribution and achieving the desired product characteristics [17, 38, 39].

After drying, the particles are separated from the drying gas and descend into a collection chamber, where the final powder is recovered and stored under appropriate conditions. The efficiency of this separation and collection step can also affect product yield, particularly when very small or low-density particles are produced [40]. In addition to feed properties, operating parameters such as inlet temperature, feed rate, drying-gas flow, atomizer type, and atomization frequency or pressure play an important role in determining final product quality. The interactions among these variables influence particle size, morphology, porosity, residual moisture, yield, and product stability. Therefore, although spray drying may appear relatively straightforward, achieving the desired product quality requires careful optimization and fine-tuning of both formulation and process parameters.

The ability to control particle characteristics through the combined optimization of formulation composition and spray-drying conditions also creates an opportunity to extend the application of spray drying beyond conventional powder production toward the development of solid carrier systems. In particular, direct preparation of nanosized carriers by spray drying is of interest because it could combine the advantages of nanoscale drug delivery with the physical stability and handling benefits of a dry formulation. Albumin is particularly attractive for this purpose because of its biocompatibility, biodegradability, and established ability to associate with a wide range of therapeutic molecules [41-43]. However, preparing solid albumin-based nanoparticles by spray drying remains relatively underexplored, and achieving nanometer-sized particles requires careful consideration of both protein matrix properties and processing conditions.

Accordingly, this work investigated whether a chemically crosslinked bovine serum albumin (BSA) matrix could be directly spray-dried to produce solid particles within the nanometer size range. The study examined how BSA concentration, excipient composition, and spray-drying conditions affected formulation processability and particle formation. The effects of Tween and arginine concentrations were investigated as formulation variables, while the crosslinking behavior of BSA with glutaraldehyde was evaluated to determine an appropriate matrix preparation time before spray drying. Feed viscosity was also examined in relation to sprayability, recognizing that acceptable bulk viscosity alone may not necessarily ensure successful atomization, particularly for protein-rich formulations.

The broader rationale for developing this system is to establish a BSA-based formulation and spray-drying framework that could serve as a platform technology for drug delivery. Rather than developing a carrier around a single therapeutic molecule, establishing a reproducible solid albumin nanoparticle system first may allow the carrier matrix and manufacturing approach to be adapted later to incorporate different therapeutic agents. The resulting particles were therefore characterized for particle size and size distribution, surface charge, morphology, and swelling behavior to evaluate the fundamental physicochemical characteristics of the developed carrier system.

MATERIALS AND METHODS

Materials

Bovine serum albumin (BSA) powder (Fraction V, nuclease- and protease-free) was purchased from VWR International. Glutaraldehyde solution (Grade I, 25% in water), 2,4-Dinitrophenylhydrazine (DNPH, reagent grade), and Arginine hydrochloride (reagent grade) were purchased from Sigma-Aldrich (St. Louis, MO, USA). HPLC-grade acetonitrile and polysorbate 80 NF (Tween 80) were purchased from Professional Compounding Centers of America (PCCA, Houston, TX, USA).

Equipment

Spray-dried particles were prepared using a Büchi Nano Spray Dryer B-90 HP (BÜCHI Labortechnik AG, Flawil, Switzerland). Particle size, size distribution, and zeta potential measurements were performed using a Brookhaven dynamic light scattering (DLS) particle size and zeta potential analyzer (Brookhaven Instruments Corporation, Holtsville, NY, USA). Scanning electron microscopy (SEM) was performed at the University of Massachusetts Boston using a ZEISS Sigma 500 scanning electron microscope (Carl Zeiss Microscopy GmbH, Jena, Germany). Viscosity measurements were performed using a portable microVISC™ viscometer (RheoSense, Inc., San Ramon, CA, USA). High-performance liquid chromatography (HPLC) analysis was performed using an Agilent 1260 Infinity II HPLC system (Agilent Technologies, Santa Clara, CA, USA) to evaluate the crosslinking behavior of the BSA matrix. Syringe disk filters with a pore size of 0.45 µm were obtained from Sigma-Aldrich (St. Louis, MO, USA). Differential scanning calorimetry (DSC) was performed using a Discovery DSC 25 differential scanning calorimeter with Tzero™ pans and lids (TA Instruments, New Castle, DE, USA).

Preparation of BSA Crosslinked Matrix

Bovine serum albumin (BSA) was dissolved in ultrapure water under gentle magnetic stirring. A low stirring speed was maintained to minimize foaming and air incorporation. A typical batch volume of 50 mL was prepared, with BSA concentrations ranging from 0.5% to 5.0% w/v. Two independent batches were prepared at each concentration (Table 1). After complete dissolution, glutaraldehyde was added as the crosslinking agent to achieve final concentrations of 0.5% and 1.0% v/v. Formulations with BSA concentrations above 2% w/v were prepared primarily for preliminary viscosity and sprayability assessments. Based on these evaluations, 2% w/v crosslinked BSA was selected as the highest concentration used for subsequent particle preparation. Tween and arginine were incorporated into selected crosslinked BSA formulations to investigate their effects on particle size. These excipients were evaluated individually and in combination and were added after completion of the crosslinking reaction, immediately before spray drying.

 

 

Figure 1 HPLC Chromatographs of 2,4-DNPH (retention time of ~2.8 min) and 2,4-DNPH derivatized glutaraldehyde (retention time of ~7.1 min).

 

 

Figure 2 Residual glutaraldehyde concentration during BSA crosslinking, demonstrating a plateau after 12 hours. The embedded table shows the exact concentration at each time point.

 

 

Figure 3 Zeta potential and particle size of spray-dried BSA (0.5% w/v) cross-linked with GA (0.5% v/v). A) Zeta Potential (-30 mV) and B) Particle size (793 nm), n = 3.

 

 

Figure 3 DSC thermograms of non-crosslinked BSA and BSA matrices crosslinked with 0.5% w/v glutaraldehyde, demonstrating a shift in the thermal transition following chemical crosslinking (Blue: BSA, Green: crosslinked BSA, 1%w/v and Red: crosslinked BSA, 5%w/v)

 

 

Figure 4 SEM of the spray-dried BSA nanoparticles exhibits a smooth surface and spherical morphology.

 

 

Figure 5. Particle size of different cross-linked BSA nanoparticle suspensions over 6 hours. Data presented as mean ± SD (n = 3). No change in particle size demonstrates suspension stability and retention of mean particle size.

Previous studies have reported that BSA nanoparticles dispersed in an aqueous medium can maintain their colloidal stability for up to two months when stored at 4 °C, with no significant changes in particle diameter or size distribution [61]. Evaluating particle stability and swelling behavior in an aqueous environment is particularly important because drug release from polymeric matrices can be governed by the relative progression of diffusion, swelling, and matrix erosion fronts.

CONCLUSIONS

The present study demonstrates the feasibility of developing solid albumin-based nanoparticles using spray drying and highlights the importance of considering both formulation composition and process conditions during method development. In addition to establishing conditions suitable for producing nanosized BSA particles, the study identified several practical challenges associated with spray drying crosslinked protein matrices. In particular, the results showed that viscosity alone could not predict sprayability, as higher BSA concentrations caused substantial nebulizer clogging even when viscosities remained within the instrument's recommended operating range. This finding emphasizes the need to consider protein concentration, matrix characteristics, atomization behavior, and other feed properties collectively when developing spray-drying processes for protein-based systems.

Formulation variables also played an important role in controlling particle characteristics. The incorporation of Tween 80 and arginine hydrochloride reduced particle size under selected conditions, demonstrating that excipient selection can be used alongside process optimization to influence particle formation. Similarly, the choice of nebulizer and atomization frequency substantially affected the resulting particles. Transitioning from the medium to the small nebulizer and increasing the atomization frequency favored the generation of smaller particles, further demonstrating the importance of appropriately selecting and optimizing spray-drying parameters to achieve the desired product characteristics. More broadly, this work supports the use of spray drying as a versatile manufacturing approach for producing solid nanoscale carrier systems. Compared with multistep processes that may require particle formation followed by a separate drying operation, spray drying can convert a liquid feed directly into a dry particulate product in a single process. Its scalability, relatively short processing time, and ability to control particle characteristics by manipulating formulation and operating variables make it particularly attractive for pharmaceutical applications. The use of albumin further strengthens this approach because of its biodegradability, biocompatibility, and established suitability as a drug-carrier material. Although the direct preparation of spray-dried albumin nanoparticles remains comparatively underexplored, this study's findings provide a foundation for further development of such systems. The combination of spray drying with an albumin-based matrix may therefore represent a useful platform for incorporating therapeutic agents, including molecules that may benefit from rapid drying and conversion into a solid-state carrier system. In addition, the functional groups present on albumin provide opportunities for subsequent surface modification and attachment of targeting ligands, potentially enabling the development of more selective drug-delivery systems.Overall, this study establishes a practical framework for producing and optimizing spray-dried albumin nanoparticles and demonstrates that successful nanoscale particle formation depends on the combined influence of matrix composition, excipient selection, and spray-drying parameters. Further studies incorporating therapeutic agents, evaluating drug-loading and release behavior, and investigating biological performance will be important to determine the broader applicability of this platform for pharmaceutical drug delivery.

DECLARATION OF COMPETING INTEREST

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

ACKNOWLEDGEMENTS

Financial support for this project was provided by the School of Pharmacy at the Massachusetts College of Pharmacy and Health Sciences as well as Massachusetts Life Sciences Center-Capital Grants.

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