Pharmaceutical Particle Engineering via Nano Spray Drying-Process Parameters and Application Examples on the Laboratory-Scale

Spray drying plays a crucial role in the processing of pharmaceutical products such as pills, capsules, and tablets as it is used to convert drug-containing liquids into dried powdered forms. Nano spray drying is in particular used to improve drug formulation by encapsulating active ingredients in polymeric wall materials for protection and delivering the drugs to the right place and time in the body. The nano spray dryer developed in the recent years extends the spectrum of produced powder particles to the submicronand nanoscale with very narrow size distributions and sample quantities in the milligram scale at high product yields. This enables the economical use of expensive active pharmaceutical ingredients and pure drugs. The present paper explains the concept of nano spray drying in the laboratory-scale and discusses the influence of the main process parameters on the final powder properties like particle size, morphology, encapsulation efficiency, and drug loading. Application results of nano spray drying for the formulation and encapsulation of different drugs are reviewed.

Typically, the drug is dissolved in a polymeric carrier solution and atomized into hot gas to evaporate the solvent, resulting in particles containing the drug dispersed in an amorphous polymer matrix [9].Polymers such as hydroxypropyl methylcellulose or its acetate succinate have become the first choice for the preparation of stable solid dispersions as they are resistant to water absorption [3].A few spraydried pharmaceutical products are on the market for inhalation therapies.In 2013, the US Food and Drug Administration approved Novartis TOBI® Podhaler™ with 28 mg Tobramycin inhalation powder per capsule for the treatment of cystic fibrosis patients with Pseudomonas aeruginosa bacteria in the lungs.The Tobramycin inhalation powder is manufactured using PulmoSphere™ technology, an emulsion-based spray drying process that produces spherical hollow-porous particles (Figure 1).
The dried particles have a geometric mean diameter of about 1 to 2.7 μm and a mean mass diameter of < 4 μm, which is ideal for delivering the drug to the lower respiratory [5,6].Spray dried powder consists of 28 mg Tobramycin active ingredient with distearoylphosphatidylcholine calcium chloride and sulfuric acid for pH adjustment.The drug is packaged in a hypromellose capsule containing 28 mg of active ingredient each.The capsules are stored individually

Introduction
Spray drying is a simple, fast, continuous, and scalable drying technology that is well established in the pharmaceutical industry for excipient production, microencapsulation, or granulation [1].Many pharmaceutical products such as pills, capsules, and tablets are processed in dried powdered form.Progress was made in introducing spray-drying technology to the pharma-in aluminum blister packs of four to protect them from moisture in the environment.Pharmaxis commercialized spray dried inhalable mannitol (sugar alcohol) powders Aridol/Osmohale TM and Bronchitol TM in 2011 and 2012 for diagnosis of asthma by detecting active airway inflammation through measuring bronchial hyperresponsiveness [7].Mannitol is crystalline after spray drying and physically stable due to its low glass transition temperature.It rehydrates the airway/lung surface and promotes a productive cough.Bronchitol dry powder helps to increase mucus clearance and improves the lung function and the quality of life of people living with cystic fibrosis.
Already in 2006, Exubera® (Pfizer/Nektar Therapeutics) became the first inhaled human insulin approved for use in type 1 or type 2 diabetes [8].Exubera powder was prepared by spray drying 60% recombinant human insulin mixed with glycine, mannitol, and sodium citrate as stabilizers.The spray dried powders exhibited good flowability, low moisture content, and good storage stability at room temperature.The aerosolized insulin had a mass median aerodynamic diameter of approximately 3 μm.The spray-dried insulin powder was packaged in blisters containing 1 mg or 3 mg of insulin.Despite the promise of a new delivery system, Exubera was not profitable in the insulin market and the product was withdrawn in 2007 because of low sales.New strategies for the administration of inhaled insulin are being further investigated.
In May 2015, the FDA approved Raplixa, the first sterile, spray dried fibrin seal powder used to control adult bleeding during surgery [8].The powder is applied to the sampling site directly from the vial or by using a low-pressure spray device.The fibrin sealant then dissolves in the blood and begins to clot the blood.Raplixa comprises spray-dried thrombin and spraydried fibrinogen, which are aseptically mixed and filled into a single vial.Each gram of Raplixa contains 79 mg fibrinogen and 726 IU thrombin.This eliminates the need to combine fibrinogen and thrombin before use  and the product can be stored at room temperature.Commercial supplies of Raplixa sealing powder are produced at the sterile production facilities of Nova Laboratories by aseptic spray drying.
From a technological point of view spray drying offers flexibility in particle formulation.By tuning the spray drying parameters, it is possible to manipulate the particle properties, e.g.particle size, shape, morphology, surface roughness, or surface composition.
In the course of the rapid progress of nanoencapsulation techniques, nano spray drying technology has also developed, in particular at Buchi Labortechnik AG (Switzerland), with the development of the Nano Spray Dryer B-90 [10][11][12][13][14].The laboratory-scale nano spray dryer enables the formulation of drugs with solid colloidal particles in the submicron range.Detailed information on the formation of nanocapsules by the nano spray drying technology can be found in several review studies [10][11][12][13][14][15][16][17][18][19][20][21][22][23][24], in particular in a recently published book chapter and review paper by Arpagaus et al. [17,19].The term nanoparticle in the pharmaceutical industry is typically defined as solid colloidal particles with sizes below 1 µm [10,14,23,25,26].Nano spray drying enables the encapsulation of active ingredients in polymeric wall materials providing enhanced environmental protection (e.g. against oxidation, light, and temperature), stability, handling, storage, and controlled drug release properties.The nanonization and structural change improves the particle solubility and redispersibility of the final drug product in aqueous solutions.
This study explains the concept of nano spray drying, the influence of the main process parameters on the powder properties (e.g.particle size, morphology, encapsulation efficiency, drug loading), and discusses different pharmaceutical applications realized in the laboratory-scale.

Process Parameters of a Nano Spray Dryer
Figure 2 shows a schematic representation and the functional principle of a nano spray dryer.The adjustable process parameters (e.g.drying gas flow rate, inlet temperature, and spray rate) and formulation variables (e.g.feed composition, solid concentration) are colored in black.The resulting parameters like the drying gas outlet temperature, the droplet and dried particle size, the product yield, and others are marked in grey.Overall, nano spray drying offers flexibility for formulation and a whole range of process parameters influence the final spray dried particle properties.
The droplet generation is based on vibrating mesh technology, which has been adapted from nebulizers used in aerosol drug delivery (Figure 3).A piezoelectric actuator vibrates a small replaceable spray cap at ultrasonic frequency.The cap comprises a thin perforated metal mesh containing a series of tiny laser drilled holes.Figure 3 illustrates a typical hole in the mesh.The piezoelectric vibration leads to a fast upward and downward movement of the spray mesh, thus ejecting millions of precisely sized droplets through the holes into the drying chamber.The droplet size depends on the mesh size and the physicochemical properties of the fluid, such as viscosity and surface tension.Spray meshes are available with 4.0, 5.5, and 7.0 µm hole diameters [19].With a 4.0 µm spray mesh approximately 3 to 8 µm water droplets are produced [12,19,27].
The co-current drying gas flow is heated up to the set inlet temperature and directs the particles to the electrostatic particle collector.The dried particles are electrostatically charged and captured at high efficiency [14,20].The flow of the drying gas is laminar, which makes the system suitable for gentle drying heatsensitive products with a low risk of degradation or loss of activity.The drying gas exits the spray dryer in a purified form and the outlet temperature is measured.
The electrostatic particle collector can capture submicron particles (< 1 μm) at a separation efficiency greater than 99% for small solid batches of 30 to 500 mg [10,12,14,15] (Figure 4).The electrostatic precipitator can even collect thin-walled particles without breaking [29,30].The particles are gently removed from the internal surface of the collecting electrode cylinder by utilizing the particle scraper and particle collecting paper that are included in the delivery of the laboratory instrument.Uniquely high yields of 76 to 96% are obtained, thus enabling the economical use of expensive pharmaceutical ingredients and pure drugs.
During spray drying, the cooling effect of the evaporating solvent keeps the droplet temperature low, so that heat sensitive products like proteins, peptides, hormones, or amino acids can be stabilized  in nanopowder forms at optimized product yields and dried with negligible degradation.
Table 2 gives an overview of the main process parameters and their influence on the output parameters (i.e.outlet temperature, droplet size, feed rate) and the final product properties (i.e.particle size, moisture content, yield, stability).The thickness of each arrow illustrates the strength of the related influence.
The key parameters controlling the final particle size are the spray mesh size and the solid concentration.The submicron size is typically reached when a 4.0 µm spray mesh and diluted solutions of 0.1 to 1% (w/v) are used.
Several authors investigated the investigated the relationship between spray mesh aperture size and particle size of drugs.The spray mesh size determines directly the size of the droplets and consequently the dried solid particles.As examples, Figure 5 and Figure 6 shows some SEM images of the model protein bovine serum albumin and the asthma drug fluorometholone obtained with a 4.0, 5.5, and 7.0 μm spray mesh respectively.The average particle size decreased with decreasing mesh aperture size producing smaller droplet, for the fluorometholone particles 620 ± 268, 795 ± 285, and 856 ± 344 nm for mesh aperture sizes of 4.0, 5.5, and 7.0 µm, respectively.The bovine serum Table 2: Influence of the main process parameters in nano spray drying (/ strong, / weak increasing/decreasing influence, -minimal or no influence) (adapted from [19]).Particles of approximately 0.7, 1.7, and 2.6 μm mean size were achieved at 1% (w/v) solid concentration (pictures from [14] with permission from Elsevier).For example, acetone-water mixtures dissolve steroidal dexamethasone well, and the low viscosity of the acetone allows higher flow rates through the vibrating spray mesh, which shortens the processing time [48].

Process parameter
Compared to water, organic solvents generate slightly smaller droplets due to their lower surface tension, viscosity, and density [54].In addition, organic solvents enable lower drying temperatures because of the lower boiling points.Dichloromethane (40 °C) or acetone (56 °C) lead to fast drying and prevent particles from sticking to the walls or agglomerating.The evaporation temperature is lower than the melting temperature or the glass transition temperature of certain polymers (Table 3).
The selection of a suitable matrix excipient is essential for the encapsulation of drugs by nano spray drying to achieve the desired decomposition of the particles and the drug release in the lungs.
• Mannitol, chitosan, leucine, lactose, and trehalose are widely used due to their high aqueous solubility and low toxicity.
• The hygroscopic excipient mannitol is especially advantageous for the treatment of bacterial infections in cystic fibrosis [70,71].
The validity of these results is supported by various reports [14,17,19,31].It should be noted here that at an ultrasonic vibration frequency of 100 kHz and assuming 100 active holes per spray mesh, a fine mist of around 10 million droplets per second is produced.Table 3 presents the particle sizes that have been realized by nano spray drying for various pharmaceutical applications.The key parameters controlling the final particle size are the spray mesh size [14,31,32] and the solid concentration [10][11][12]14,27].Smaller droplets are favored by a higher viscosity, a lower surface tension, and a smaller spray mesh [14,15,[33][34][35].The region of submicron particle size is typically reached when using a 4.0 µm spray mesh and diluted solutions of 0.1 to 1% (w/v).Further reduction of particle size is possible by further dilution, as demonstrated in several studies [10,14,31,33,[36][37][38][39].
Depending on the application, an optimized set of process parameters can be found, e.g. by design of experiment studies, as shown by several authors [10,15,16,19].The selection of the organic solvent is based on the drug solubility and the encapsulating wall materials, as well as on the required drying temperatures.For aqueous applications, the outlet temperatures range between 28 and 59 °C [20].The optimal drying temperatures of for example poly(lacticco-glycolic acid) (PLGA) dissolved in dichloromethane lies in a range of 29 to 32 °C [16].
The selection of the organic solvent is based on the solubility of the drug and the encapsulating wall materials (e.g.excipients).The mixing ratio is adjusted to allow the complete dissolution of the compounds [61].balance the surface-to-viscous forces inside of the drying droplet and enable the formation of a smooth spherical surface.Composite particles prepared from suspensions and nano spray drying provide a high specific surface area.Most nano spray dried drugs tend to be amorphous due to the too short drying time to form crystalline structures.To prevent recrystallization, the dried powders are stored under dry and controlled conditions.Of primary interest for pharmaceuticals are the effects on the particle size, morphology, yield, productivity, encapsulation efficiency, drug loading, drug release profile, and stability.Table 5 summarizes some representative literature data on encapsulation efficiency and drug exposure.Particles with an encapsulation efficiency of over 95% and an adjustable drug load were produced.Further information on yield and optimized process parameters of nano spray drying are given.
Table 4 summarizes typical process parameters of various wall materials (excipients) used as dispersants, binders and stabilizers in the nano spray drying of pharmaceuticals at laboratory-scale.
The morphology of particles prepared by nano spray drying depends on the drying conditions and the feed properties.Dense, hollow, porous, composites, and encapsulated structures (i.e.single-core, multicore, irregular, or multi-walled) with spherical, wrinkled, shriveled, or even doughnut-like shapes can be obtained [19].Figure 7 illustrates some examples of nano spray dried particles including salbutamol, albuterol in mannitol, cyclosporine in PLGA, trehalose, β-galactosidase in trehalose, and bovine serum albumin.
The nano spray drying process is gentle and contributes to maintaining the stability and activity of heat-sensitive materials, such as peptides, proteins, hormones and amino acids.This has been confirmed for example by nano spray drying bacitracin (polypeptide antibiotic) [82] or insulin-like growth factor I (anabolic peptide) encapsulated in trehalose, silk fibroin and polysorbate [86] (see Table 4).
To sum up, Table 6 lists typical experimental process parameters for nano spray drying that can be used as first guess values for applying identical or similar substances.The main organic solvents used to dissolve poorly water-soluble drugs are ethanol, acetone, and DCM.With highly diluted solutions containing 0.1 to 1% (w/v) solids concentrations, finest solid particles down to 100 nm can be obtained by nano spray drying.
Pure drug particles in the nanosize dimensions and the amorphous state offer higher absorption rates and bioavailability and encourage future developments in this research area.Nanocapsules, with their reduced size and large specific surface area, provide pronounced improvement in controlled drug release and bioavailability.This enables the generation of target drug delivery systems.Under optimized conditions, uniquely high product yields of about 76 to 96% can be achieved to process small sample amounts of substances in the range of 10 mg to 2.5 g.
The number of applications reviewed in this study underlines the versatility of the nano spray drying technology to develop nanomedicines.As illustrated in Figure 4 the drug-loaded nano spray dried powders are administered through various ways, such as: • pulmonary (e.g.optimized respirable particles of 1 to 5 µm size), • oral (e.g.poorly water-soluble drugs like diuretic furosemide [10], pain reducing nimesulide [100], blood vessels dilating nicergoline [67], fever reducing indomethacin [99], anti-inflammatory dexamethasone [46], or steroidal hormone mecigestone [109]), • intravenous (e.g.simvastatin in PLGA as cancer chemotherapeutics, antipsychotic clozapine and risperidone in PLGA, or small interfering RNAs loaded  monoclonal antibodies, recombinant proteins, or siRNA-based therapeutics.Moreover, nano spray drying enables the encapsulation of drugs in polymers with high efficiency of over 95% and adjustable drug loading.

Conclusions
Nano spray drying has been successfully applied for a wide range of pharmaceutical applications on a laboratory-scale, such as increasing the bioavailability of poorly soluble drugs by nanoisation and structural modification, as well as the encapsulation of nanoparticles, nanoemulsions and nanosuspensions in biocompatible polymeric wall materials for sustained drug release.Encapsulation efficiencies of over 95% are achieved by adjustable drug loadings.Smallest sample amounts ranging from 10 mg to 2.5 g with uniquely high yields of over 95% can be processed, which enables the economical use of valuable active pharmaceutical ingredients.
Compared to conventional spray drying processes, nano spray drying relies on vibrating mesh technology to produce an ultrafine spray.A highly efficient electrostatic powder collector to extend the size spectrum of separable particles to the nanoscale.
The most important adjustable process parameters are the drying gas temperature, the drying gas flow rate, the spray mesh size, the solvent type, the solids concentration in the feed, and the selection of the corresponding excipients, stabilizers and surfactants.Depending on the application, an optimized set of parameters can be found.Submicron spray dried particles can be formed down to a size of only 100 nm with diluted solutions of 0.1 to 1% (w/v) solids concentration.Different particle morphologies can be created, including dense, hollow and porous particles with spherical, wrinkled, or donut shapes.
The drying process is gentle and contributes to maintaining the stability and activity of heat-sensitive materials, such as peptides, proteins, hormones and amino acids.The prepared drug loaded particles are administered in various ways, including pulmonary, oral, intravenous, topically, ophthalmic, intraperitoneal, intravesical, or even cerebral, which underlines the versatility of the nano spray drying technology.
With the introduction of the Nano Spray Dryer B-90 from Büchi Laboretechnik AG (Switzerland) in 2009, the nano spray drying of protein nanotherapeutics became reality on a laboratory-scale [14].It is expected that the increased customer demand for the laboratory product, combined with promising new applications, will promote and stimulate the development of more industry-relevant models [13].In order to further explore the potential of nano spray drying, future research should focus on further commercialization of this technology on a pilot and industrial scale.The demand for larger quantities of powder and for the scale-up of nano spray drying technology is increasing.To achieve this, however, equipment designed for a larger scale is required.
A possible scale-up solution for droplet formation and throughput increase are several vibrating mesh atomizers in parallel arrangement (e.g.like ultrasonic humidifiers) or a larger nozzle unit.Industrial-scale electrostatic particle collectors with mechanical rapping devices can be installed for the collection of nanoparticles with an automatic cleaning system to continuously remove the separated particles from the collecting.
The main application trends in nano spray drying are seen in the areas of pulmonary drug delivery, nanotherapeutics, the encapsulation of nanoemulsions with poorly water-soluble active ingredients and the formulation of nanocrystals for a higher bioavailability.

Figure 3 :
Figure 3: Vibrating mesh technology to produce an ultrafine spray in a nano spray dryer (adapted from [19]).

Figure 4 :
Figure 4: Principle of an electrostatic powder collector implemented in the nano spray dryer to extend the size spectrum of separable particles to the nanoscale (adapted from [19]).

Table 6 :
Typical first-guess experimental process parameters for nano spray drying of pharmaceuticals.

Table 3 :
Influence of spray mesh size on final nano spray dried particle size in nm (n.a.= data not available).

Table 4 :
Different wall materials applied for encapsulation of pharmaceuticals by nano spray drying (n.a.= not available).

Table 5 :
Published studies on nano spray dried drug delivery applications structured by administration routes (Drug loading (%) = Amount of drug in particles/Total mass of particles, Encapsulation efficiency (%) = Amount of drug in particles/Initial drug amount, n.a.= not available).