Spray drying allows to convert a liquid into powder form by drying with a hot air. Thermally-sensitive materials from foods and pharmaceutical industries are the main application as they may require extremely consistent, fine particle size.



This application note is based on content from Pohlen et al. [1]. Simvastatin (CAS number 79902-63-9) is a cholesterol-lowering agent with a low bioavailability of 5% [2,3]. This API is formulated as a lipid based drug delivery system for oral uptake. Two technologies, which are spray drying and fluidized bed layering technologies were compared with respect to the process and product characteristics of otherwise similar Simvastatin loaded dry emulsion systems. Investigated parameters are the process yield, encapsulation efficiency, relative product stability, particle morphology, drug content, and the relative increase in bioavailability.

Enhancing bioavailability

Some of the recently discovered new chemical entities (NCE) show a low solubility and high permeability (BCS class II), or even low permeability in the case of very high lipophilicity (BCS class IV).

Material Company
Simvastatin Krka, SI

Magnesium stearate,

Tween® 20

Merck, D
Pharmacoat 603 ShinEtsu, JAP
Miglyol® 812 Sasol, D
Pearlitol SD 200 Roquette, F
CELLETS® 200 HARKE Pharma, D
Avicel® PH 101,

Lactose mesh 200

Lek, d.d., SI

Table 1: Used Material and origin.

This means a major challenge for formulation development in terms of assuring drug bioavailability [4,5]. A strategy for increasing the solubility are lipid based drug delivery systems (LBDDS). As main advantage, they are likely to solubilize the API and make it available for the absorption into the bloodstream [6]. Additionally, converting the liquid or semi-solid LBDDS into solid dosage forms eliminates undesired characteristics such as a lack of chemical stability and product portability, susceptibility for drug recrystallization and costly manufacturing [7]. Furthermore, solid dosage form solutions allow benefits, such as easy powder processing, flow and compression behavior, controlled drug release, improved patient safety. Among others, dry emulsions are a type of solidified LBDDS and allow carrying and releasing the encapsulated lipophilic API. In the following, some solidification process technologies are introduced. The required parameter for Wurster fluidized bed and spray drying are displayed in Table 2 and Table 3, respectively.

Opposite to the spray drying process, the fluidized bed process employs CELLETS® 200 as starter beads for layering. Several formulations are composed by Pohlen et al., the materials are listed in Table 1.

Parameter Value
Setup Glatt Fluidized bed Dryer Model GPCG-1 (Glatt, D)

Schlick nozzle

0.8 mm
cap opening diameter 2.50 mm
Inlet airflow rate 130 m3/h
Inlet air temperature 47 °C to 56 °C
outlet air / product temperature 34 °C
spraying rate 5 g/min to 9 g/min
atomizing air pressure 2 bar
Gap to Wurster insert bottom edge 17.5 mm
Drying time 180 s @ 42 °C
Starter pellets 200 g


1000 g

Table 2: Parameters and values for Fluidized bed layering.

Parameter Value
Setup Mini Spray Dryer B-290 (Büchi, CH)


1.4 mm
cap opening diameter 2.20 mm
Inlet airflow rate 28 m3/h
Inlet air temperature 145°C to 175 °C
outlet air / product temperature 75 °C to 80 °C
spraying rate 6 g/min
Drying time 180 s @ 80 °C
Starter pellets 200 g


1000 g

Table 3: Parameters and values for spray drying.

Process yield

Spray drying results on average in lower process yield than the fluidized bed results. The process yield for spray drying experiments is in average value of 71.5 %, and of 83.3 % for fluidized bed layering experiments. It is assumed, that in spray drying process adhesion of the smallest particles to the cyclone walls or outtake through the air stream occur.

Drug content

An averaged API content at 9.34 mg/g in fluidized bed experiments, and at 22.2 mg/g for spray dried dry emulsions is reached. Although spray drying offers a much higher drug content and more flexible formulations, the content variation between replicates is increased. The use a swirl air generator in the fluidized bed equipment increases process stability and allows an even larger amount of oil to be incorporated. It is possible increase the maximum amount of API to 22 mg/g onto the starter pellets. Anyhow, the fluidized bed technology suffers from sticky effects of oil phases which is not a big deal in spray drying processes.

Encapsulation efficiency

A low encapsulation efficiency shall be avoided as it causes drug losses during processing and increased production costs. The encapsulation efficiency in fluidized bed experiments is at 80.0 %, compared to spray drying experiments being at 68.4 %. A main issue of the spray drying technology might be higher process temperature leading to a higher risk of API degradation. Spray drying also suffers from a larger surface-to-volume area which might induce an increased risk of oxidation during the drying process.

Morphology and particle size

The main advantage of fluidized bed technology is the use of starter pellets, which are perfectly spherical starter beads. Following, API coating results in highly spherical coated particles with a high level of monodispersity and an average particle size around 336 µm (D50 value). Not mentionable, that spray drying technology results in smaller average particle sizes at 56 µm (D50 value), but the morphology shows a coarse, rough and undefined surface. In turn, dry emulsion layered pellets have better flow properties [8].

Redispersibility and oil droplet size

All re-dispersed oil droplets have a size of a few micrometers between less than 1 µm and less than 7 µm. Fluidized bed layering technology generally leads to larger droplets. Considering also the probable bimodal nature of the droplet size distribution, fluidized bed layering provides a narrower size distribution and thus better results. In turn, the fluidized bed technology might provide slightly better bioavailability.

Product stability

Stability is measured by means of the one-month relative drug content stability. The particles produced in the fluidized bed technology show a better one-month relative drug content stability than particles produced by spray drying. This might be caused by the higher monodispersity, larger particles and smoother surfaces. All properties minimize the risk of API gradation, treatment failure, or toxicity.


Both technologies show a superior dissolution behavior compared to the dissolution of pure crystalline API (less than 3 %) or a generic API tablet (less than 10 %). It has to be stated, that both technologies allow dissolution rates of more than 80 % within the first 30 minutes, wherein the Spray drying products show a slightly better and faster dissolution rate.


Bioavailability of formulations from fluidized bed layered dry emulsion pellets provide the highest increase in relative bioavailability within the examined formulations, confirming that fluidized bed technology is superior to spray drying technology for potent or low dose APIs.


Fluidized bed layering and spray drying technology have been selected for analyzing the properties of dry emulsions. Simvastatin was selected as API, encapsulated in the dry emulsion.

Fluidized bed layering technology uses starter cores, such as CELLETS® as a dry emulsion carrier system, while spray drying does not.

The main advantage of the fluidized bed technology is the higher process yield, the better encapsulation efficiency and redispersibility, the defined morphology of the product causing better process handling and product stability.

Spray drying technology allows a higher drug content with better chances of formulation variation, and an even faster and more complete dissolution (Figure 1).

Advantages of technological methods compared to a pure API usage.

Figure 1: Advantages of technological methods compared to a pure API usage.


[1] M. Pohlen, J. Aguiar Zdovc, J. Trontelj, J. Mravljak, M. G. Matjaž, I. Grabnar, T. Snoj and R. Dreu, Eur J Pharm Biopharm (2021), S0939-6411(21)00353-2, doi:10.1016/j.ejpb.2021.12.004

[2] S. Geboers, J. Stappaerts, J. Tack, P. Annaert and P. Augustijns, Int. J. Pharm. 510 (2016) 296-303, doi:10.1016/j.ijpharm.2016.06.048

[3] T. Taupitz, J.B. Dressman and S. Klein, Eur J Pharm Biopharm. 84 (2013) 208-218, doi:10.1016/j.ejpb.2012.11.027.

[4] T. Das, C.H. Mehta and U.Y. Nayak, Drug Discov. Today 25(7) (2020) 1206-1212,  doi:10.1016/j.drudis.2020.04.016

[5] G.L. Amidon, H. Lennernäs, V.P. Shah and J.R. Crison, Pharm. Res. 12 (1995) 413-420,  doi:10.1023/a:1016212804288.

[6] H. Mu, R. Holm and A. Müllertz, Int. J. Pharm. 453 (2013) 215-224, doi:10.1016/j.ijpharm.2013.03.054.

[7] P. Joyce, T.J. Dening, T.R. Meola, H.B. Schultz, R. Holm, N. Thomas and C.A. Prestidge, Adv. Drug Deliv. (2018), doi:10.1016/j.addr.2018.11.006.

[8] X. Fu, D. Huck, L. Makein, B. Armstrong, U. Willen and T. Freeman, Particuology. 10 (2012) 203-208, doi:10.1016/j.partic.2011.11.003

Fig. 3: Dissolution as a function of time. Black: ASD layered pellets (FB). Red: ASD pellets from direct pelletization (SB). Blue: physical mixture.


Amorphous solid dispersions layered pellets solve a problem of poorly water soluble drugs. Speaking about oral drug formulations, drug carrier solutions based on starter cores are suitable for several drug classes and open new opportunities for modified drug release profiles. Layering and coating techniques, such as Wurster fluid bed process at different batch sizes, are well established.

However, an increasing number of poorly water soluble drugs challenges modern formulations. A novel approach improving the solubility of those drugs is to formulate them as amorphous solid dispersions (ASD) with a suitable polymer candidate [1]. In this study, Nifedipine was used as a model drug. Nifedipine manages angina, high blood pressure, Raynaud’s phenomenon, and premature labor [2].

Formulation & techniques

ASD formulations can be performed by hot-melt extrusion or spray drying technique. Both techniques have disadvantages such that hot-melt extrusion cannot be employed for temperature-sensitive drugs [3], and spray drying needs a further compaction step not to result in fine powder with poor flowability, broad particle size distribution and high sensitivity to electrostatic charge. Therefore, a further compaction step is required to obtain a freely flowable product [4].

In this context, two techniques for the preparation of ASDs are compared: A 6”-Wurster fluid bed with Type-C bottom plate (Glatt, Germany) and spouted bed (ProCell5™ with Zig-Zag-sifter, Glatt, Germany) are used.

A: GF3™ (fluidized bed); B: ProCell5™ (spouted bed)

Fig. 1: A: 6”-Wurster fluid bed; B: ProCell5™ spouted bed.

The formulation contains the drug and a stabilizing co-polymer (Kollidon®, KVA64, BASF, Germany). Nifedipine and Kollidon are mixed resulting in a drug load of 40 % (w/w) and dissolved in Acetone (30 % w/w solid content).

Parameter FB SB
Spray rate [g/min] 20 20-35
Product temp. [°C] 50-60 50-60
Process gas temp. [°C] 65 80
Process air flow [m³/h] 180-200 65-120
Spraying nozzle diameter [mm] 1.2 1.2
Spraying pressure [bar] 2.0 0.5

Table 1: Manufacturing parameters for fluid bed (FB) and spouted bed (SB).

In the fluid bed process, microcrystalline pellets (Cellets® 500, IPC Dresden, Germany) were layered with the spraying solution such that a drug load of 21.8 % (w/w) is reached. In the spouted bed process, fine powder is generated by spray drying, further agglomeration and layering. An overview on the process parameters is given in Table 1.

Dissolution Tests

Dissolution tests were conducted in a PBS buffer at pH 6.8 and 37 °C (± 0.5 °C). A physical mixture of Nifedipine and KVA64 (40 % w/w drug load) is used as reference.


In the following, results from both experiments, which are amorphous solid dispersions layered pellets (fluid bed) and ASD pellets from direct pelletization (spouted bed) are compared.

Flowability and particle size

ASD layered pellets show a better sphericity, higher level of monodispersity and better flowability properties than the ASD pellets from direct pelletization (Figure 2). Nonetheless, it has to be pointed out that both techniques result in a high particle quality for capsule filling. Analysis data is shown in Table 2.

Parameter FB SB
10 [µm] 824 ± 23 559 ± 28
D50 [µm] 943 ± 13 732 ± 50
D90 [µm] 1091 ± 11 1374 ± 410
Bulk density [g/L] 427 280
Flowability [s/100g] 12.1 16.2

Table 2: Analysis of ASD layered pellets (FB) and ASD pellets from direct compaction (SB).

SEM images of processed pellets. A: ASD layered pellets based on Cellets® (FB)

Fig. 2a: SEM images of processed pellets. A: ASD layered pellets based on Cellets® (FB)

SEM images of processed pellets. B: ASD pellets from direct palletization (SB)

Fig. 2b: SEM images of processed pellets. B: ASD pellets from direct pelletization (SB)

Dissolution profiles

Independent from the processing technique, pellets achieved an approximately factor 2 higher end concentration than the physical mixture. Pellets obtained from the fluid bed process showed a clear supersaturation phase after 1 hour and a generally higher dissolution rate than pellets obtained from the spouted bed process. Contrarily, the dissolution rate of the latter pellets approaches the supersaturation phase more continuously after 3 hours.

Fig. 3: Dissolution as a function of time. Black: ASD layered pellets (FB). Red: ASD pellets from direct pelletization (SB). Blue: physical mixture.

Fig. 3: Dissolution as a function of time. Black: ASD layered pellets (FB). Red: ASD pellets from direct pelletization (SB). Blue: physical mixture.


Both techniques, fluid bed and spouted bed as well, can be employed for manufacturing amorphous solid dispersions with good flow properties and dissolution profiles. Both techniques can be scaled up to pilot and production scale for batch or continuous manufacture of freely flowable ASDs. Cellets® serve stable and reliable cores for this venture.


We gratefully acknowledge Dr. Annette Grave and Dr. Norbert Pöllinger (Glatt Pharmaceutical Services, Germany), and Prof. Karl G. Wagner and Marius Neuwirth (University Bonn, Germany).


[1] T. Vasconcelos, B. Sarmento, and P. Costa, Drug Discovery Today, 12(23): 1068-1075 (2007)

[2] “Nifedipine”. The American Society of Health-System Pharmacists. Retrieved: Sept 17, 2019.

[3] J. Breitenbach, European Journal of Pharmaceutics and Biopharmaceutics, (54)2: 107-117 (2002)

[4] I. Weuts et al., Journal of Pharmaceutical Sciences, (100)1: 260-274 (2011)