The drying of the spray continues until the desired moisture content in the dried particles is achieved, and the product is recovered from the air. It is a unique drying process since it involves both particle formation and drying. Process parameters such as inlet and outlet temperature of the drying medium and the atomisation pressure influence the physico-chemical properties of the produced powders. The characteristics of the spray dried powder can be controlled, and the powder properties can be maintained constant throughout the continuous operation. With the different designs of spray dryers available, it is possible to select a dryer layout to produce either fine or coarse particle powders, agglomerates or granulates [1].

Fig. 1. Schematic overview of a spray dryer (www.niro.com)

The manner is which the spray contacts the drying air is an important factor in spray dryer design, as this had great bearing on dried product properties by influencing droplet behaviour during spray drying [1]. The different spray drying systems are open cycle, closed cycle and semi-closed cycle (Fig. 2). Open cycle systems are applied to spray dry aqueous feeds. The majority of the industrial spray dryers handle aqueous feeds and use this system. Air for drying is drawn from atmosphere and the exhaust drying air is discharged to atmosphere [2]. Before discharge the exhaust air is cleaned using combinations of cyclones, bag filters, electrostatic precipitators and scrubbers. Direct and indirect heating are applicable. Closed cycle spray dryers are used to handle flammable solvents, highly toxic products and oxygen sensitive products to avoid atmospheric pollution and/or to establish complete recovery of the evaporated solvent. The closed cycle system is based upon recycling and reusing the gaseous drying medium, which usually is an inert gas such as nitrogen. Drying chambers are incorporated with a cyclone/bag filter, solvent vapour condenser, exhaust drying medium particulate cleaning in wet scrubbers and indirect drying medium heating [2]. Semi-closed cycle systems are classified into either the partial recycle mode (recycling of up to 60% of the exhaust air as inlet air to the dryer, for effective heat utilization) or the self-inertising mode.

Fig. 2. Schematic outline of spray drying systems: open cycle (A), closed cycle (B) and semi-closed cycle (C) (www.niroinc.com)

Spray drying consists of 4 process stages. In the first stage the liquid feed is atomised into a spray of droplets. The atomisation stage must create a spray that when in contact with the drying medium creates optimal conditions for evaporation leading to a dry wall operation and discharging a dried product of the required properties from the drying chamber and associated dry particulate collectors [1]. The are 3 basic designs of atomisers, defined by the source of energy utilised in the droplet formation process: centrifugal energy in rotating wheel or disc atomisers, kinetic energy in pneumatic nozzle atomisers and pressure energy in pressure nozzle atomisers. Atomisers are selected according the droplet sizes to be produced in order to meet the powder specifications (Table 1) [2].

Table 1 – Median droplet size of different atomisation devices [2]

Atomisation device	Median Droplet Size (µm)
Rotary atomiser (wheel)	10 – 200
Pneumatic nozzle (two/three-fluid)	5 – 100
Pressure nozzle	30 – 350

Rotary atomisers (Fig. 3C) consist of a rotating wheel or disc. The liquid feed is introduced centrally. Rotary atomizers are reliable, easy to operate and can handle fluctuating feed rates. Further advantages include their ability to handle high feed rates and abrasive feeds [1].

Fig. 3. Schematic outline of atomisation devices: two-fluid nozzle (A), pressure nozzle (B) and rotary atomiser (C) (www.niro.com)

Pneumatic nozzle atomisation (Fig. 3A) uses compressed air to creating high frictional forces over liquid surfaces causing liquid disintegration into spray droplets, while pressure nozzle atomisation (Fig. 3B) applies liquid feed under pressure. The feed is forced to rotate within the nozzle, resulting in cone-shaped spray patterns emerging from the nozzle orifice. Sprays from pressure nozzles are generally less homogeneous and coarser than sprays from wheels [1].

Fig. 4. Schematic outline of spray-air contact modes: co-current (A), counter-current (B) and mixed flow (C) chamber (www.buchi.com)

The second stage involves the spray-air contact, mixing and droplet/particle flow. In a co-current flow (Fig. 4A), the feed is atomised and sprayed through the drying chamber in the same direction as the flow of the heated drying medium. The droplets come into contact with the heated drying medium resulting in an optimal solvent evaporation for spray drying of heat-sensitive materials such as enzymes, peptides and proteins. In a counter-current flow design (Fig. 4B), the atomised feed and heated drying medium move in the opposite direction through the drying chamber. A counter-current flow design combines a heat treatment and also a particle agglomeration effect, resulting in increased powder flowability and median particle size for non-heat-sensitive products [1]. Spray dryer designs that combine co-current and counter-current flow modes are classified as mixed flow spray dryers (Fig. 4C). The typical fountain-type system yields coarse free-flowing spray dried powders that can be produced in drying chambers of relatively small dimensions, but the powders are subjected to higher particle temperature because partially dried particles enter the hottest region of the drying chamber near the drying medium dispense The third stage combines drying and particle formation. Evaporation of the solvent takes place immediately after contact between spray droplets and the drying air. Diffusion of solvent from within the droplet maintains saturated surface conditions, resulting in a constant drying rate. When the solvent content becomes too low to maintain a saturated surface, a dry layer starts to form at the droplet surface. The atomisation of a concentrated feed suspension decreases the drying load since less water in a droplet needs to be evaporated. In addition, it is easier to achieve moisture removal from suspension-type droplets than solution-type droplets especially when the latter involves diffusion-limited film-forming characteristics at the surface [1].

Finally, particle separation from the drying air and dried product discharge takes place in the drying chamber and associated particle collection systems (cyclone, filter bag, scrubber).

APPLICATIONS IN PHARMACEUTICAL TECHNOLOGY AND DRUG DELIVERY

Directly compressible powder

Excipient and co processed excipient production

Spray drying can be used to modify the size distribution, crystal habit, crystallinity content, polymorphism and moisture content if particles resulting in improved compactability.

Spray dried lactose is by far the most commonly encountered spray dried pharmaceutical excipient and is produced by spray drying a slurry containing lactose crystals. The spray dried product contains a mixture of crystals of α-lactose monohydrate and spherical agglomerates of small crystals held together by amorphous lactose [3]. Spray dried lactose was found to have significantly improved compaction properties compared to its crystalline forms. De Boer et al. [4] stated that amorphous lactose consolidated rather by plastic deformation than by particle fragmentation.

However, as specific material properties are required to allow direct compression, materials have been coprocessed via spray drying to obtain compounds having superior properties (flowability, hygroscopicity and compactability) for direct compression compared to the individual excipients or their physical mixtures [5]. During co processing no chemical changes occur and all the reflected changes show up in the physical properties of the particles [3]. Several co-spray dried excipients for direct compression are commercially available: Starlac^® (a-lactose monohydrate and maize starch), Cellactose^® (a-lactose monohydrate and powdered cellulose), Microcelac^® (a-lactose monohydrate and microcrystalline cellulose), Prosolv^® (microcrystalline cellulose and silicon dioxide) and F-Melt^® (mannitol, xylitol, inorganic excipient and disintegrating agent, developed for fast dissolving dosage forms) [6].

Cellactose^®, a coprocessed spray dried filler/binder for direct compression and composed of 25% w/w powdered cellulose and 75% w/w a-lactose monohydrate, had a higher tablet tensile strength compared to physical powder mixtures containing 25% w/w Elcema P-100 and 75% w/w lactose for direct compression (Tablettose^®) [7].

Gohel and Jogani [5] developed a multifunctional coprocessed directly compressible excipient containing lactose, polyvinylpyrrolidone and croscarmellose sodium. This product had a better flowability, compactability and tablet disintegration than a-lactose monohydrate. Hauschild and Picker [8] evaluated a coprocessed compound based on a-lactose monohydrate and maize starch for tablet formulation. Compared to its physical mixture the coprocessed material had a better flowability, a higher tablet crushing force and a faster tablet disintegration. Heckel analysis showed that the spray dried mixture deformed plastically with limited elasticity, whereas the physical mixture exhibited a predominantly elastic behaviour. Microcelac^® 100, a coprocessed spray dried filler/binder for direct compression and composed of 25% w/w microcrystalline cellulose and 75% w/w a-lactose monohydrate, showed superior flow and binding properties compared to physical mixtures of microcrystalline cellulose with different lactoses grades e.g. a-lactose monohydrate (lactose 100M), anhydric f3-lactose (Pharmatose^® DCL21) and spray dried lactose (Pharmatose^® DCL11)[9].

Improved drug compressibility

Acetazolamide, an inhibitor of carbonic anhydrase, is a poorly compressible drug and usually produced through a wet granulation process. It is soluble in boiling water and in an alkaline solution. Di Martino et al. [10] compared the compressibility of acetazolamide crystals obtained by three different crystallisation processes. Firstly acetazolamide crystals were dissolved in a diluted ammonia solution and recrystallized by neutralisation with a hydrochloridric solution. Crystals of polymorphic form II were obtained. Secondly acetazolamide crystals were dissolved in boiling demineralised water and afterwards cooled down slowly to room temperature. Only crystals of polymorphic form I were detected. Finally an ammonia solution of acetazolamide was spray dried and by this method a mixture of polymorphic form I and II was obtained. The spray dried crystals were characterised by an excellent compressibility and the absence of capping tendency while the pure polymorphic forms I and II could not be compressed into tablets [10].

Encapsulation

A microcapsule can be either an individually coated solid particle or liquid droplet, or a matrix containing many small, fine core particles. Matrix microcapsules containing drug substance and a biodegradable polymer are usually prepared by spray drying in order to obtain controlled drug release formulations [11].

Palmieri et al. [12] coprocessed ketoprofen and common pH dependent polymers (Eudragit^® S and L, cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), hydroxypropylmethylcellulose phthalate (HPMCP)) via spray drying in order to prepare ketoprofen gastro-resistant microspheres. Acrylic polymers (Eudragit^® S and L) showed a compactability comparable with ketoprofen/Avicel^® PH 101 mixtures in contrast with the poor compactability of binary spray dried microspheres containing CAP, CAT and HPMCP. Gastro-resistance was obtained for all microspheres, although changes in drug release at low pH values were observed. Drug release was lower for microspheres containing acrylic polymers in comparison with the enteric cellulose derivates.

Binary microspheres (drug/polymer ratio: 1/2, 1/1, 2/1, 3/1, 4/1, 6/1, 9/1, 19/1) containing acetaminophen and a polymer (Eudragit^® RS and RL, ethylcellulose) were manufactured via co-spray drying to prepare controlled-release solid dosage forms [13]. The compaction properties gradually improved when decreasing the acetaminophen concentration, independent of the type of polymer present in the microspheres. Although the dissolution behaviour of the microspheres was similar to that of the pure drug, tablets containing drug substance and polymer (Eudragit^® RS and RL, ethylcellulose) showed controlled drug release. Eudragit^® RL was less effective in slowing down the acetaminophen release because of its permeable and swellable properties.

Burke et al. [14] compared spray drying and spray-freeze drying to encapsulate darbepoetin alfa in poly (lactide-co-glycolide). In vitro and in vivo drug release was evaluated for all microsphere formulations. Formulations prepared via spray drying and spray-freeze drying showed similar in vitro drug release, while in vivo studies detected darbepoetin alfa in serum during 4 weeks.

Feed solutions of ketoprofen/polymer (cellulose acetate butyrate (CAB), hydroxypropylmethylcellulose phthalate (HPMCP)) mixtures in different weight ratios were spray dried in order to study the in vitro release behaviour [15]. The microparticles were formulated in hard gelatine capsule shells or compacted into tablets with the addition of maltose or hydroxypropylmethylcellulose (HPMC). All microsphere-filled capsules resulted in a rapid drug release although the microparticles with the highest concentration of CAB had the lowest release rate. In addition, tablets containing HPMC showed an initial quick release of ketoprofen during the first hour followed by a prolonged release.

Increased bioavailability

Spray drying can be used to enhance the solubility and dissolution rate of poorly soluble drugs. This usually occurs via the formation of pharmaceutical complexes or via the development of solid dispersions [11].

Complex formation

Cyclodextrins can be used to increase the solubility and bioavailability of poorly water soluble drug substances. Physical mixtures (1/1) containing carbamazepine and βcyclodextrin were compared with identical solid complexes prepared via spray drying and freeze drying. These binary mixtures were blended with hydroxypropylmethylcellulose prior to compression [16]. Evaluation was based on solubility studies and in vitro release profiles. The water solubility of carbamazepine increased with increasing β-cyclodextrin content. A stronger interaction between drug substance and β-cyclodextrin was obtained in the solid complexes rather than in a simple physical mixture. In addition, binary complexes prepared via spray drying and freeze drying showed faster drug release in comparison with the physical mixtures because of an improvement in drug solubility.

Suihko et al. [17] studied the physico-chemical properties of physical mixtures, and spray
dried and freeze dried solid complexes of tolbutamide and hydroxypropyl-β-cyclodextrin.Pure hydroxypropyl-β-cyclodextrin and its tolbutamide complex were amorphous, whereas spray dried and freeze dried tolbutamide were polymorphic forms I and II, respectively.

Formation of solid dispersions

Valdecoxib is a selective cyclooxygenase-2 inhibitor, administered orally as an analgesic and anti-inflammatory drug. It is relatively insoluble in water. Ambike et al. [18] developed solid dispersions of valdecoxib and a hydrophilic polymer by co-spray drying. The selected hydrophilic carriers were polyvinylpyrrolidone K30 (PVP) and hydroxypropylcellulose (HPC). The saturation solubility, dissolution rate and stability of the spray dried drug, the solid dispersions and their corresponding physical mixtures were compared with the pure drug substance. All spray dried samples as well as the physical mixtures suggested increased saturation solubility and dissolution rate immediately after processing. Additionally DSC and XRPD experiments of the spray dried valdecoxib and the solid dispersions showed the generation of an amorphous form of the drug. During stability testing, the saturation solubility and dissolution rate of the solid dispersions decreased gradually over a testing period of three months. Drug crystallinity was discovered after 1 month and 15 days for respectively the drug/PVP and drug/HPC solid dispersion. The pure spray dried valdecoxib was characterized by a drastical drop in saturation solubility within 15 days.

Takeuchi et al. [19] obtained solid dispersions of indomethacin with non-porous (Aerosil^® 200) and porous silica (Sylysia^® 350) by spray drying an ethanol solution of indomethacin and suspended silica particles. The solid dispersions were compared with pure spray dried indomethacin concerning dissolution rate and stability. The crystallinity of spray dried indomethacin was lower, probably because of the rapid drying rate from the ethanol solution. Spray drying an ethanol solution of indomethacin in combination with silica obtained the drug in an amorphous state irrespective of the type of silica formulated. Additionally the dissolution properties of indomethacin were improved with both types of silica. Both solid dispersions and the pure spray dried indomethacin were stored for 2 months at 40°C and 75% RH. The solid dispersions with silica did not crystallise, whereas the pure spray dried form did.

Curcumin, a naturally occurring highly lipophilic molecule, has a very low aqueous solubility. Paradkar et al. [20] used spray drying to produce solid dispersions of curcumin in different ratios with polyvinylpyrrolidone (PVP). They compared the solid dispersions with their corresponding physical mixtures. Dissolution properties of the spray dried powders improved due to the formation of an amorphous drug. Physical mixtures of curcumin and PVP showed negligible release even after 90 min, while the spray dried particles were characterised by a complete release within 30 min.

Palmieri et al. [21] carried out in vivo and in vitro studies with solid dispersions of lonidamine in polyethylene glycol 4000 (PEG) and polyvinylpyrrolidone K29/32 (PVP) for several drug/polymer ratios ranging from 1/9 to 9/1. They evaluated the dissolution rate and water solubility improvement of the drug/PEG and drug/PVP solid dispersions and compared their results with the corresponding physical mixtures. The water solubility of lonidamine was increased by the solid dispersion formation, the highest increase in solubility corresponded to the highest polymer content. During in vivo testing, they recorded an increase in bioavailability after administration of lonidamine solid dispersions in PEG and PVP.

Dry powder aerosols & heat sensitive materials

Spray drying is an excellent method for the production of dry powder formulations since particle size distribution and residual moisture content of the spray dried powders can be easily controlled by the process conditions. In addition, the processing of heat sensitive materials is feasible because the cooling effect caused by the solvent evaporation. Hence, the actual temperature of the dried product is far below the outlet temperature of the drying air. Bosquillon et al. [22] developed an aerosol formulation for the systemic delivery of human growth hormone in rats. Spray drying a mixture of human growth hormone, lactose and dipalmitoylphosphatidylcholine yielded dry powders for pulmonary administration. Dry powder inhalation resulted in high absorption of human growth hormone, the absolute bioavailability reached 23% and the bioavailability relative to a subcutaneous injection was 56%. In contrast intratracheal instillation of a human growth hormone solution had a threefold lower systemic absorption.

Coprocessing via spray drying of bovine serum albumin (BSA) and maltodextrin (ratio: 1/1) was applied to produce dry powder aerosols for inhalation of proteins after blending with αlactose monohydrate, modified lactoses (containing between 2.5 and 10% w/w fine particle lactose) or micronised polyethylene glycol 6000 [23].

Adler and Lee [24] investigated process stability, storage stability and surface activity of lactate dehydrogenase in co-spray dried powders. Trehalose was used as stabilising carrier.

At higher inlet drying air temperature, the resulting lower residual moisture content of the spray dried powder provided excellent storage properties, although more protein inactivation occurred. The addition of stabilising carriers (e.g. carbohydrates, amino acids) reduced the protein inactivation during spray drying. In addition, Coppi et al. [25] developed an oral formulation for lactate dehydrogenase using alginate microparticles were as a carrier to protect lactate dehydrogenase against inactivation in the gastro-intestinal tract and to improve enzyme absorption. In addition, stabilising agents (carboxymethylcellulose sodium, polyacrylic acid sodium, lactose) were added to overcome the enzymatic activity loss during spray drying.

Broadhead et al. [26] evaluated the spray drying of β-galactosidase and the influence of process and formulations parameters. Process yield was maximised at high outlet drying air temperature, although a strong decrease in enzymatic activity was measured. In addition, different stabilisers (mannitol, sucrose, arginine hydrochloride, trehalose) were tested to improve enzymatic activity, identified trehalose as the most suitable.

Sucrose was selected as suitable stabilising agent during spray drying of oxyhemoglobin and trypsinogen [27, 28]. In the absence of sucrose spray drying of oxyhemoglobin approximately 50% methemoglobin was formed, which is not suitable to transport oxygen. However, the addition of sucrose (0.25 M) as a protective agent to the feed reduced the methemoglobin production to 4%.

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28. S.T. Tzannis, S.J. Prestrelski, Activity-stability considerations of trypsinogen during spray drying: effects of sucrose, J. Pharm. Sci. 88 (3) (1999) 351–359.

Received on 05.02.2012

Modified on 18.03.2012

Accepted on 06.04.2012

Research Journal of Pharmaceutical Dosage Forms and Technology. 4(2): March-April 2012, 74-79