Impact of spray drying nozzle and chamber design onpowders properties

Goncalo Diogo Russo Poeiras

Thesis to obtain the Master of Science Degree in

Chemical Engineering

SupervisorsProfessor Doctor Maria Dina Ramos Afonso

Doctor Joao Pedro dos Santos Vicente

Examination CommitteeChairperson: Professor Doctor Francisco Manuel da Silva Lemos

Supervisor: Doctor Joao Pedro dos Santos VicenteMembers of the Committee: Professor Doctor Sebastiao Manuel Tavares da Silva Alves

October 2018

Acknowledgments

I would like to thank my parents for their friendship, encouragement and caring over all these years,

for always being there for me and without whom this project would not have been possible.

I would also like to acknowledge my thesis supervisors Prof. Dina Afonso and Dr. Joao Vicente for

their insight, support and sharing of knowledge that have contributed to this thesis success. I would like

to thank Tiago Porfırio as well for his willingness to help me and always answer my questions.

Thank you to all my friends that helped me grow as a person and were always there for me during

the good and bad moments in my life.

Last but not least, a word of gratitude to Catarina Lopes for all her love, patience and endless support

throughout the last few years.

To each and every one of you – Thank you.

Abstract

When developing spray drying processes, scaling up from lab to pilot or manufacturing scale can

significantly impact the product critical quality attributes such as the particle size distribution, morphol-

ogy, level of residual solvents, density and flowability. These factors may strongly influence downstream

processing and the properties of the final dosage forms.

In this work, the influence of the nozzle type was studied and it was concluded that the powders

produced by the nozzles 2 and 3 presented higher bulk densities, more shriveled particles and higher

particle sizes due to the production of larger droplets and with lower distribution spans. The residual

acetone content of the powders were practically identical in all nozzles. Powders produced by the

nozzles 2 and 3 presented poor behavior in forced flow conditions, and good behavior in unconfined

environments, when compared to the powders produced by the nozzle 1.

Furthermore, the influence of spray drying chamber design and gas distribution was also studied. It

was concluded that, in this case study, the chamber design did not affect the critical quality attributes of

the powders. Regarding the distinct gas distributors, it was concluded that the distributor A produced a

powder with a lower content of acetone, meaning higher drying rates than distributors B and C.

Keywords

Spray drying; Flowability; Atomization; Chamber dimensions; Gas distribution

iii

Resumo

Ao desenvolver processos de secagem por atomizacao, a passagem da escala laboratorial para a

escala piloto ou industrial pode afetar significativamente os atributos crıticos de qualidade do produto,

como por exemplo, a distribuicao do tamanho de partıculas, morfologia, teor de solventes residuais,

densidade e fluidez. Estes fatores podem influenciar o processamento a jusante e as propriedades dos

produtos finais.

Neste trabalho, estudou-se a influencia do tipo de atomizador concluindo-se que os pos produzi-

dos pelos atomizadores 2 e 3 apresentaram densidades mais elevadas, mais partıculas enrugadas e

tamanhos de partıcula maiores devido a producao de gotıculas maiores e com menores intervalos de

distribuicao de tamanhos. O teor residual de acetona nos pos foi praticamente identico em todos os

atomizadores. Os pos produzidos pelos atomizadores 2 e 3 apresentaram comportamentos piores em

condicoes de fluxo forcado e bom comportamento em ambientes nao confinados, quando comparados

aos pos produzidos pelo atomizador 1.

Alem disso, a influencia do desenho da camara de secagem e da distribuicao de gas tambem foi es-

tudada. Concluiu-se que, neste estudo de caso, o desenho da camara nao afetou os atributos crıticos de

qualidade dos pos. Relativamente aos diferentes distribuidores de gas, concluiu-se que o distribuidor A

produziu pos com menor teor de acetona, indicando maiores taxas de secagem do que os distribuidores

B e C.

Palavras Chave

Secagem por atomizacao; Atomizacao; Dimensoes da camara; Distribuicao de gas

v

Contents

1 Introduction 1

1.1 Summary and Motivations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

1.2 Thesis Outline and Objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

2 Literature Review 5

2.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

2.2 Spray drying . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

2.2.1 Atomization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

2.2.2 Gas-droplets contact . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

2.2.3 Droplets’ drying . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

2.2.4 Dried product separation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

2.3 Thermodynamics of spray drying . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

2.3.1 Mass and heat balances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

2.4 Scale-up challenges . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

2.4.1 Atomization set-up . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

2.4.2 Chamber dimensions and gas distribution . . . . . . . . . . . . . . . . . . . . . . . 16

2.5 Downstream . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

2.5.1 Powder flowability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

3 Materials and Methods 21

3.1 Materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

3.2 Design of Experiments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

3.3 Analytical Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

3.3.1 Density measurements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

3.3.2 Laser diffraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

3.3.3 Gas chromatography (GC) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

3.3.4 Scanning electron microscopy (SEM) . . . . . . . . . . . . . . . . . . . . . . . . . 26

3.3.5 Stability and Variable Flow Rate (SVFR) program in FT4 Powder Rheometer . . . 26

vii

4 Results and Discussion 29

4.1 Effect of the feed flow rate on the powders properties . . . . . . . . . . . . . . . . . . . . . 31

4.2 Comparison between the properties of the powders produced by the nozzles 1, 2 and 3 . 32

4.2.1 Bulk density . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32

4.2.2 Morphology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32

4.2.3 Particle size distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

4.2.4 Residual solvent content . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35

4.2.5 Flowability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36

4.3 Comparison between the properties of the powders produced in spray drying units with

distinct designs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43

4.3.1 Bulk density . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43

4.3.2 Morphology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43

4.3.3 Particle size distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43

4.3.4 Residual solvent content . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45

4.3.5 Flowability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45

4.4 Comparison between the powders produced with various gas distributors. . . . . . . . . . 47

5 Conclusions and Future Work 49

viii

List of Figures

2.1 Typical spray drying system. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

2.2 Liquid-gas flow modes in spray drying chambers. Adapted from K. Masters [1]. . . . . . . 12

2.3 Droplet temperature and solvent content profile during the drying process. . . . . . . . . . 13

2.4 Agitated vacuum dryer - Ekato VPT (Ekato System GmbH, Schopfheim, Germany) [2] . . 18

2.5 Rotary drum dryer - Pfaundler CDB (Pfaundler Inc., Rochester, NY) [3] . . . . . . . . . . . 18

2.6 Non-cohesive powder (left-hand side) and cohesive powder (right-hand side). . . . . . . . 20

2.7 Cohesive powders may form a stable rathole in funnel flow. . . . . . . . . . . . . . . . . . 20

3.1 Design of experiments for the nozzle 1 (left) and nozzles 2 and 3 (right) in the spray dryer

X. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

3.2 Additional design of experiments to assess the influence of the feed flow rate. . . . . . . . 24

3.3 Design of experiments for the spray dryer Y. . . . . . . . . . . . . . . . . . . . . . . . . . . 24

3.4 Structure of the default stability and variable flow rate method sequence. C: conditioning

cycle, T: test cycle, Split: vessel splitting to provide an accurate volume of powder [4]. . . 26

3.5 Measurement of flow energy using the FT4 Powder Rheometer. . . . . . . . . . . . . . . . 27

4.1 SEM images of spray dried powders from tests 10 (left), 6 (middle) and 11 (right). All

images have the same scale. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

4.2 Comparison between bulk densities of powders produced by nozzles 1, 2 and 3. . . . . . 32

4.3 SEM images of powders produced by the highest droplet size nozzle 1 test (left), nozzle 3

(middle) and nozzle 2 (right) at the outlet temperature of 60oC. All images have the same

scale. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

4.4 Comparison between the particle sizes of the powders produced by the nozzles 1, 2 and 3. 33

4.5 Temperature effect on the particle size of the spray dried powders using the nozzle 1. . . 34

4.6 Particle size distributions of the spray dried powders with the nozzle 2 at 40oC (top), 50oC

(middle) and 60oC (bottom) outlet temperatures. . . . . . . . . . . . . . . . . . . . . . . . 35

ix

4.7 Comparison between the acetone content of the spray dried powders produced by the

nozzles 1, 2 and 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36

4.8 Comparison between the BFE of the spray dried powders produced by the nozzles 1 and 3. 37

4.9 Comparison between the SE of the spray dried powders produced by the nozzles 1 and 3. 38

4.10 Comparison between the SI of the spray dried powders produced by the nozzles 1 and 3. 40

4.11 Comparison between the FRI of the spray dried powders produced by the nozzles 1 and 3. 41

4.12 Comparison between the Hausner ratio of the spray dried powders produced by the noz-

zles 1 and 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42

4.13 Comparison between the bulk densities of the powders produced in the dryer units X and Y. 43

4.14 SEM images of the powders produced with identical droplet sizes in the spray dryer X

(first row) and in the spray dryer Y (second row) at the outlet temperature of 40oC (left),

50oC (middle) and 60oC (right). All images have the same scale. . . . . . . . . . . . . . . 44

4.15 Comparison between the particle sizes of the powders produced in the spray dryers X

and Y. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44

4.16 Comparison between the residual acetone content of powders produced in each dryer unit. 45

4.17 Flowability parameters of the spray dried powders produced in the dryer units X and Y. . . 46

x

List of Tables

2.1 Influence of the main parameters on the spray drying process performance [5]. . . . . . . 9

2.2 Comparison between the various atomizers’ features [1]. . . . . . . . . . . . . . . . . . . . 11

3.1 Flowability scale [6]. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

4.1 Spray drying process parameters and properties of the powders from the tests 10, 6 and

11, in the dryer X with the nozzle 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

4.2 Average particle size distribution span of the spray dried powders produced by each nozzle. 34

4.3 Spray drying process parameters and data of the experimental tests with distinct gas

distributors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47

xi

xii

Nomenclature

Cfeed Solids concentration in the feed solution, %

Fatom Atomization gas flow rate, kg/h

Fdrying Drying gas flow rate, kg/h

Ffeed Feed flow rate, kg/h

RSin Relative saturation of inlet gas, %

RSout Relative saturation of outlet gas, %

Tcond Condenser temperature, oC

Tin Inlet gas temperature, oC

Tout Outlet gas temperature, oC

API Active pharmaceutical ingredient

ASD Amorphous solid dispersion

BFE Basic flowability energy, mJ

FRI Flow rate index

GC Gas chromatography

HEPA High efficiency particulate arrestance

SDD Spray dried dispersion

SE Specific energy, mJ/g

SEM Scanning electron microscopy

SI Stability index

SVFR Stability and variable flow rate

xiii

xiv

1Introduction

Contents

1.1 Summary and Motivations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

1.2 Thesis Outline and Objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

1

2

1.1 Summary and Motivations

Spray drying is a method for producing a dry powder from a liquid feed, and one of the advantages

of this technology is the ability to control the particles size, density and surface area. This particle engi-

neering depends on several factors including the type of atomizer, dimensions of the drying chambers,

flow rates and temperatures of the liquid and gas streams. The spray drying technology has several

applications in the pharmaceutical field, namely in the production of inhalation drugs, amorphous solid

dispersions or modified release composite particles.

During the development of new drugs, the production of different amounts of a material is often

mandatory in order to meet the requirements of the clinical program. For example, the material amounts

can vary from hundreds of grams in the initial stages to tons in the commercial phases. As a result,

one of the problems inherent to successive scale-up is the need to keep product properties unchanged

throughout the program [7].

Whenever a shift from lab to production scale is made the configuration and dimensions of the spray

drying equipment should be adjusted. Such adjustments involve but are not limited to a) change in

feeding system; b) atomization device type, location and conditions; c) drying gas distributor system;

d) chamber dimensions; e) exhaust gas duct and; f) shift from open loop to closed loop mode. These

modifications may vary the droplet spray formation, droplet size distributions and their trajectories, evap-

oration rate, drying time, solvent mass in the drying air and the wall deposition profiles. Consequently,

critical quality attributes such as particle size, bulk density and residual solvent content are affected [8,9].

Therefore, further research still needs to be done in this field to increase enlightenment and predictability

throughout scale-up activities.

1.2 Thesis Outline and Objectives

Therefore, this thesis will consist in assessing the influence of the distinct types of atomization de-

vices, equipment design and drying gas dispersing systems in the properties of the materials produced,

especially regarding the particles size, bulk density, residual solvent content, morphology and flowability.

This dissertation can be divided into four main parts. Chapter 2 presents the state of the art where the

spray drying technology is reviewed and the most relevant scale-up challenges are discussed. Chap-

ter 3 briefly describes the experimental procedures used in the production of the powders, the main

equipments used and the analytical tests performed. The fourth chapter includes the results obtained

and respective discussion. The final chapter of this thesis comprises the conclusions of this study and

suggests future work.

3

4

2Literature Review

Contents

2.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

2.2 Spray drying . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

2.3 Thermodynamics of spray drying . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

2.4 Scale-up challenges . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

2.5 Downstream . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

5

6

2.1 Introduction

Spray drying is a unit operation capable of transforming solutions or suspensions into a dried partic-

ulate form by spraying the feed into a gaseous drying medium.

It is reported that about 40% of new active pharmaceutical ingredients (APIs) in development exhibit

low aqueous solubility and poor dissolution limiting oral bioavailability [10, 11]. Amorphous solid dis-

persions (ASDs), which are molecular dispersions of drug, polymer(s), and/or other excipient(s), offer

many advantages for the delivery of APIs with low aqueous solubility since they combine the benefits

of increased solubility and stability of amorphous forms of the drug. Overall, the ASDs promote faster

dissolution and higher dissolved drug concentrations [9]. In the pharmaceutical field, spray drying is a

widely used unit operation to prepare ASDs, due to its ability to control the size, density and surface

area of the particles. [12–14].

The first patent concerning this technology was registered in 1872 [15], but the spray dryers by that

time were primitive devices. There were problems with the process efficiency, continuous process perfor-

mance, and process safety, jeopardizing its successful utilization. Since then, the spray drying method

underwent a tremendous evolution which, coupled with improved understanding of fluid dynamics, en-

abled its use in milk powder production. This was its first industrial application, but the real progress

in spray drying technology was driven by World War II, during which the need for transporting large

amounts of food led to a search for new methods to reduce food’s weight and volume, as well as better

conservation techniques [16]. During the post-war period the application of the spray drying method was

also directed toward several industrial fields, ranging from food and dairy, pharmaceutical, cosmetics,

ceramics, paints, textile, plastics, paper, fertilizers and detergents [1,14].

7

2.2 Spray drying

The spray drying process, shown in figure 2.1, comprises three major phases.

First of all, a spray solution - which consists of API and polymer dissolved in a common solvent - is

delivered to an atomizer inside a spray-drying chamber. Organic solvents are typically used to produce

spray dried dispersions because the API tends to be poorly water-soluble, and nitrogen drying gas is

employed to provide an inert processing atmosphere.

Next, by applying a force, atomization transforms the liquid stream into fine droplets, which interact

with a drying gas at higher temperature. During this drying phase, the solvent contained within the

dispersion droplets is vaporized, leading to the formation of solid product particles.

Finally, the dried particles are separated from the drying medium by an appropriate device, typically

a cyclone separator and/or a filter bag.

Most laboratory-scale spray dryers operate in a open-loop mode where the drying gas flows through

the chamber only once before it is vented to the appropriate waste stream. Many large pilot-scale and

production-scale spray dryers operate in closed-loop where the solvent rich drying gas flows through a

condenser, is reheated, and inserted back into the drying chamber.

Upon the process completion, the particles are often post-dried in a secondary drying step to reduce

the solvent content down to acceptable limits [8,12,14,16].

Figure 2.1: Typical spray drying system.

As depicted in figure 2.1, the spray drying process is characterized by a wide range of process

8

parameters. The quality requirements of the final product can be fulfilled by manipulating several pro-

cess parameters. These include drying temperatures, inlet (Tin) and outlet (Tout), drying gas flow rate

(Fdrying), liquid feed flow rate (Ffeed), atomization energy, pressure (Pfeed) for pressure nozzles and

atomization gas flow rate (Fatom) for two-fluid nozzles and condenser temperature (Tcond). Moreover,

other relevant formulation parameters comprise feed composition (API/carrier/solvent), solids concen-

tration (Cfeed), solvent type, viscosity and surface tension. The influence of the main parameters on the

process performance and product characteristics are displayed in table 2.1.

Table 2.1: Influence of the main parameters on the spray drying process performance [5].

Parameter RemarksInlet drying gas temperature(Tin)

Increases outlet temperature (Tout). Consequently reduces the relative saturation (RSout) of the drying gas.Increases drying rate, yield and less sticky product.

Drying gas flow rate(Fdrying)

Increases Tout and reduces RSout.May decrease particle size.

Feed flow rate(Ffeed)

Decreases Tout.Increases RSout

Condenser temperature(Tcond)

Lower Tcond promotes solvent removal from the drying gas, decreasing RSout and boosting product dryness.

Atomization energy(Fatom, Pfeed)

Decreases droplet and particle sizes. Pfeed is dependent of Ffeed in pressure nozzles.

Solids concentration(Cfeed)

Less liquid to vaporize causes increase in Tout.Due to more solids in the droplet, particle size may increase.Increases throughput.

Viscosity andsurface tension

Both result in larger droplets and consequently larger particles.

9

2.2.1 Atomization

The formation of a spray (atomization) is a key characteristic of spray drying. The selection and

operation of the atomizer is extremely important in achieving economic production of top-quality dry

particulate products. The atomization can be performed using two-fluid, ultrasonic, rotary, or pressure

nozzles, which differ on the type of energy involved.

Rotary atomizers

In rotary atomizers, the liquid is fed into the center of the rotating wheel or disk and flows towards

the edge. The centrifugal force results in the liquid stream breaking down into small droplets, and the

formation of a wide spray pattern. Material adhesion to the drying chamber walls can be a limiting factor

whenever handling expensive drugs. Nevertheless, rotary atomizers offer the most effective means of

atomization used in spray drying technology [16].

Pressure nozzles

Pressure nozzles generate fine droplets by pressurizing a liquid feed by a pump and forcing the liquid

feed through the nozzle orifice. The angle at which the atomization occurs varies from device to device,

usually in the range of 40–160o [16], allowing the use of narrow chambers. This type of nozzles are

not suitable for the drying of high viscosity feeds. Besides, a major drawback is the difficulty to vary the

droplet size at constant feed flow rate, since the operating pressure - which is inversely proportional to

the droplet size - depends on it. In order to vary the droplet size at constant feed flow rate it is necessary

to vary the nozzle dimensions and/or design. Pressure nozzles are more suitable for the production of

medium to large particles and produce powders with a narrower particle size distribution than the other

atomizers [16].

Two-fluid nozzles

The operation principle of two-fluid nozzles is based on the creation of strong frictional forces over

liquid surfaces, by operating at high atomizing gas velocities, to come into contact with the feed, causing

liquid disintegration into spray droplets. The droplets size depends on the ratio of the gas stream, usually

nitrogen, to the liquid stream, allowing the droplet size control at constant feed flow rate. Also, these

nozzles have the advantage of handling highly viscous feeds that cannot be atomized conveniently by

other techniques and the ability to produce small particle sizes.

The liquid may come into contact with the atomizing gas inside the nozzle head (internal mixing) or

when the liquid exits the orifice (external mixture). The internal mixing nozzle tends to use less atomiz-

ing gas than the external mixing atomizer and it is more suitable for higher viscosity feeds. In spite of

10

requiring more atomizing gas, the external mixing nozzles may be preferred if the liquid to be atomized

contains solids, in order to prevent clogging [1].

Ultrasonic nozzles

In ultrasonic nozzles the liquid feed flows into the vicinity of a sonic generator, which breaks the liquid

into droplets. They are known to produce very homogeneous fine sprays with very narrow droplet size

distributions [17]. However, these nozzles are not generally applied in industrial spray dryers due to

capacity restrictions.

Atomizer selection

The atomizer is selected mainly based upon the feed nature, the drying chamber design, the desired

dried product throughput and its properties. Features of the various atomizer types are listed in table

2.2.

Table 2.2: Comparison between the various atomizers’ features [1].

Feature Rotary atomizer Pressure nozzle Two-fluid nozzle Ultrasonic nozzle

Droplet size adjustment Easy (by rotationspeed)

Hard (by pressure)/ impossible at con-stant feed flow rate

Easy (by gas-liquidratio)

Easy (by frequency)

Optimal range of droplet sizes µm 20-200 30-400 5-75 10-100 µm

Droplet size distribution Narrow Narrow Wide Very narrow

Suitability for low/high feed flowrates

Yes/Yes Possible/Yes Yes/Yes but expen-sive (high amount ofcompressed gas)

Yes/No

Suitability in handling highly viscousfeeds/suspensions

Yes No Yes Problematic

Wide spray pattern - tendency toform wall deposits

Yes No No No

Tendency to block/choke No Possible No No

In the pharmaceutical industry, the most common atomizers are the pressure nozzle and the two-fluid

nozzle due to their reduced tendency to form wall deposits (when compared to rotary atomizers) and

their ability to produce most droplet sizes at desired production rates. Pressure nozzles are preferred

in applications requiring higher particle sizes or narrower size distributions. Exceptions include feeds

with very high viscosities or large suspended particles, which may block and/or corrode the pressure

nozzles. When targeting smaller particles, the two-fluid nozzles are the preferred choice due to their

ability to handle and control particle sizes in the fine range [1,8,14,16].

11

2.2.2 Gas-droplets contact

Immediately after the atomization, the feed droplets are mixed with the drying gas, usually nitrogen

(ideally, the gas is also HEPA filtered). This contact can occur in several ways: co-current, counter-

current and mixed flow mode.

In co-current flow mode, the contact between the liquid spray and the drying gas is in the same di-

rection. Drying gas inlet and atomizer are positioned at the top of the drying chamber. This configuration

leads to contact between the feed and the highest temperature drying gas, since the latter has not yet

exchanged its heat with the surroundings, thus the dried product is heated the least. This arrangement

is widely used in the pharmaceutical industry due to the handling of heat sensitive products [1,16].

Alternatively, counter-current drying procedures can be employed, i.e., the drying gas flows in oppo-

site direction to the liquid spray. This flow mode offers great heat transfer efficiency, but it subjects the

dried particles to the highest temperature.

There are also dryer designs that combine both flow modes designated by mixed flow dryers. All

these flow modes are sketched in figure 2.2.

Figure 2.2: Liquid-gas flow modes in spray drying chambers. Adapted from K. Masters [1].

The drying chamber dimensions may vary from a diameter to length ratio of 5:1 (or even higher) in

the case of pressure nozzles or two-fluid nozzles and 2:1 in the case of rotary atomizers [16]. Large

droplets are very difficult to dry since they bear enough momentum to escape the gas whirl and are

directed towards the chamber walls leading to deposits. Hence, taking into account the drying chamber

dimensions is important for spray drying process optimization.

12

2.2.3 Droplets’ drying

As a droplet is exposed to the drying gas, it undergoes three stages, illustrated in figure 2.3. Initially,

the droplets are subjected to rapid heating without evaporation. Then, at stage 1, the solvent evaporates

at constant temperature (wet bulb temperature, Twb), which results in decreasing the droplet size. After-

wards, in stage 2, the drying rate begins to decrease due to the formation of a solid phase at the droplet

surface. Any heat transfer to the droplet at this stage increases the particle temperature. At stage 3,

the solvent content reaches equilibrium, thus it will remain unchanged while the product is exposed to

constant temperature and relative saturation conditions.

Figure 2.3: Droplet temperature and solvent content profile during the drying process.

The droplet evaporation rate may determine the final morphology and density for many formulations.

In the case of cold/slow drying, the droplet temperature is below the solvent boiling point when the

droplet skin forms, causing the particle to shrivel. This results in denser particles since there is enough

time for the solute to migrate to the droplets’ center and come in close proximity. In the case of hot/fast

drying, the droplet temperature is near or above the solvent boiling point when droplet skin forms. This

causes the vapor pressure in the particle to keep it “inflated” when it dries, producing particles of lower

density. Depending on the permeability of the skin and within the particle, porous or hollow particles are

obtained [8,12].

13

2.2.4 Dried product separation

After the drying process, the dried particles are separated from the drying gas by appropriate devices,

usually cyclones and/or bag filters. The cyclone is very efficient in separating dispersed particles from

the continuous gas phase due to the creation of a centrifugal force by the rapid rotation of the gas. The

particles are directed toward the device walls and settle down due to gravitational forces. In bag filters,

the gas flows through a fabric which retains the solid particles. Bag filters are more efficient (95-98% for

cyclones and 98-99.9% for bag filters [1]) and have the advantage of separating smaller particles than

the cyclones. On the other hand, cyclones may operate continuously and can handle most products and

higher gas temperatures than bag filters.

Finally, as the product is separated from the drying gas, it has to be handled according to whether the

powder is packed directly or requires additional treatment. In continuous spray drying processes, distinct

kinds of devices may be used to transport the product to suitable containers or to further processing.

When working in a batch system, the product is frequently discharged into a sealed container.

Thereafter, secondary drying is commonly carried out to remove residual solvents and moisture that

remained within the particle interstice of the spray dried dispersion (SDD).

2.3 Thermodynamics of spray drying

The interplay between the spray dryer configuration, process and formulation variables can overly

complicate the process design. To understand the contribution of the process and formulation parame-

ters on ASDs, it is essential to envisage the thermodynamics underlying spray drying and the mecha-

nisms of particles formation.

2.3.1 Mass and heat balances

All the key thermodynamic spray drying process parameters and outlet conditions that affect product

attributes can be related through fundamental mass and energy balances using the spray dryer chamber

as a control volume.

Thus, for a steady state operation with no deposit build-up [1,12]:

Mass balance

Ffeed(1− Cfeed) + FdryingRSin = Ffeed Cfeed Crsolv + FdryingRSout (2.1)

where Ffeed is the solution feed flow rate, Cfeed is the solids concentration in the feed solution, Fdrying

is the drying gas flow rate, RSin and RSout are the inlet and outlet relative saturations and Crsolv is the

14

residual solvent content in the dried product.

The outlet relative saturation, RSout, is given by Eq. 2.2 [1,12].

RSout =y Pt

Pv(Tout)(2.2)

y =Ffeed(1− Cfeed)/MWsolvent

Ffeed(1− Cfeed)/MWsolvent + Fdrying/MWgas(2.3)

where y is the solvent mole fraction in the gas mixture, Pt is the total pressure in the spray dryer cham-

ber, Pv(Tout) is the equilibrium vapor pressure of the spray solvent evaluated at the temperature Tout,

MWsolvent and MWgas are the molecular weights for the respective species.

Heat balance

To simplify the heat balance some assumptions were made: 1) the solids and the relative saturation

at the inlet were neglected when determining the feed streams enthalpies; 2) the enthalpy variation of

the feed solution is given by the enthalpy variation of the solvents. Enthalpies of mixture and dissolution

were neglected; 3) the mean heat capacity was estimated by averaging the specific heat capacities over

the temperature range of interest [1,12].

FdryingCpgas(Tin − Tout) = Ffeed(1− Cfeed)[∆Hvap + Cpsolv(Tout − Tfeed)] +QL (2.4)

QL = UA(Tout − Troom) (2.5)

where Cpgas and Cpsolv refer to the mean specific heat capacities of the drying gas and the solvent,

respectively, Tin, Tout, Tfeed and Troom are the inlet, outlet, feed and room temperatures, ∆Hvap is the

solvent enthalpy of vaporization, QL is the heat loss to the ambient surroundings, U is the overall heat

transfer coefficient and A is the spray dryer walls surface area.

Using the mass and heat balances calculations, it was possible to determine the inlet conditions

required to achieve the desired output parameters, such as Tout and RSout, or vice-versa.

15

2.4 Scale-up challenges

Developing a robust lab-scale method is a prerequisite for any scale-up [18]. This stage is very useful

as a guideline for modeling of thermodynamics, atomization and drying kinetics. However, the spray dry-

ing process design space might need verification, optimization and validation at various scales because

some inherent characteristics of both equipments may differ, such as the atomization device type, loca-

tion and conditions; design and positioning of the gas dispersing system; and chamber dimensions [8].

These adjustments can change droplet size distribution, velocity and density in the spray plume, spray

length, angle and type (i.e., hollow or full cone), gas-droplet contact, as well as particle trajectories, res-

idence time and accumulation profile [19]. All these features can significantly impact the product critical

quality attributes such as the particle size distribution, morphology, level of residual solvents, density

and flowability. These factors may strongly influence downstream processing and the properties of the

capsule or tablet, e.g., hardness, friability, disintegration time, dissolution rate [5]. A careless scale-up

strategy may lead to considerable losses of expensive materials and ultimately jeopardize the timelines

of a clinical program [7].

2.4.1 Atomization set-up

Atomization set-up is a fundamental parameter in spray drying set-up since it has direct influence on

the particle size of the product obtained.

When scaling up, characteristics inherent to each set-up can impact the product critical quality at-

tributes. These characteristics include droplet size, droplet size distribution, velocity, density in the

spray plume and spray angle. Ultrasonic nozzles produce droplets with lower size distribution spans

when compared with two-fluid (i.e., >2 span) and pressure nozzles (i.e., 1.5-2 span) [17]. According to

Poozesh et al. [20], the distribution span may dramatically influence the final particle attributes, namely

the homogeneity, yield, bulk powder moisture content, etc. The absence of such pressures and gas

streams in the atomization by ultrasonic energy results in the development of a droplet fog wherein the

average velocity of the individual droplets is very low compared to those produced by other atomizing

techniques, i.e. over 100-fold lower [21,22].

2.4.2 Chamber dimensions and gas distribution

The spray drying chamber dimensions and gas distribution are relevant variables since they affect

the gas flow aerodynamics and consequently drying kinetics and droplet residence times. A chamber

with a bigger volume potentially leads to a longer residence time, thus a lower moisture content [23].

However, this may also lead to higher extent of thermal degradation [24]. It is also important to remark

that heat loss from the dryer walls and accumulation profiles vary between scales [1].

16

Assuming plug flow inside the spray dryer, the gas mean residence time can be estimated by di-

viding the spray dryer volume by the gas volume flow rate. Using this approach and by experimentally

determining particles mean residence time, Schmitz-Schug et al. [24] found out that the particle mean

residence time was longer than the gas mean residence time. This can be explained by the presence of

recirculation zones and powder backflow inside the drying chamber as well as by temporary particle de-

position on the dryer walls. The calculated mean residence time of air was 1.1 s for the laboratory-scale

spray dryer and 12 s for the pilot-scale dryer. Conversely, the particle mean residence times were 24.8

s for the laboratory-scale dryer and 90.2 s for the pilot-scale spray dryer, respectively.

Experiments of Thybo et al. [25] showed that scaling-up based on matching atomizer droplet size

distributions was not successful for the applied formulations, as the criterion did not account for the

differences in droplet temperature and residence time histories between the spray dryers.

17

2.5 Downstream

After the spray drying process, the product collected will most likely be subjected to a secondary

drying step and then formulated into tablets or capsules, which are the most popular final dosage forms.

Typically, 2-10% of solvent remains in the SDD particles that are collected from the cyclone [17]. A

secondary drying process is necessary to remove this residual solvent in order to meet final residual

solvent specification [26, 27] and to help maintain the physical and chemical stability of the SDD. Com-

mon unit operations used in the secondary drying include tray dryers (vacuum or convection), agitated

vacuum dryers such as the Ekato VPT (Fig. 2.4), and biconical rotary drum dryers such as the Pfaundler

CDB (Fig. 2.5). Other pharmaceutical unit operations that involve heat and mass transfer for the solvent

removal may also be used.

Figure 2.4: Agitated vacuum dryer - Ekato VPT (Ekato System GmbH, Schopfheim, Germany) [2]

Figure 2.5: Rotary drum dryer - Pfaundler CDB (Pfaundler Inc., Rochester, NY) [3]

18

Tablets and capsules are the most advantageous final dosage forms to deliver drugs orally to pa-

tients. However SDDs are not ideal for conversion into tablets or capsules and require downstream

processing. For large-scale manufacturing, powder flowability is a relevant attribute regardless of the

intended final dosage form. Spray dried powders generally have a relatively small particle size and low

bulk density resulting in poor flowability. A precompaction step can be employed for low bulk density

solid dispersions to improve their flowability [28]. Furthermore, dry granulation and wet granulation are

viable strategies to improve solid dispersion handling [8].

2.5.1 Powder flowability

Downstream processing of spray dried dispersions involve several powder handling steps, compris-

ing stirring, blending, transfer, storage, compaction and feeding to a press or a dosator. For example, in

pharmaceutical tableting, the tablet properties such as weight uniformity, density, mechanical strength

and disintegration rate are directly affected by the amount of powder inserted into the die before com-

paction [29]. Poor flowability can lead to higher production costs due to unexpected interventions, low

yield and unplanned process redesign [30–33]. As a consequence, the characterization of powders flow

properties is often required for reliable design and consistent processes operation.

Powders behaviors depend on the processes they are subjected to. For example, a less cohesive

powder will separate into individual particles and flow freely when unconfined, e.g., in a rotary drum

dryer or at the outlet of a hopper or bin, during discharge. Such powders tend to perform well in a

tablet press, flowing freely into the die and forming a strong tablet; compressive forces are transmitted

effectively through the powder plug [34]. However, the powder under forced convection will perform

poorly since high pressures are required to push even a small amount of product. On the other hand,

more cohesive powders flow quite poorly in an unconfined environment, as they may break into lumps

formed of agglomerated powder held together by cohesive forces. Flow additives may be useful to

achieve acceptable flowability for many processing steps [35, 36]. Under forced convection, a more

cohesive powder may flow well, as the entrained air can act as a lubricant [34], e.g., in tablet presses

with force feed mechanism (paddle wheels) or in an agitated dryer.

To predict a powder behavior in any of these processes a variety of methods for characterizing pow-

der flow has been developed. Commonly reported methods in the pharmaceutical industry, according to

the European Pharmacopoeia [37], are the angle of repose, compressibility index or Hausner ratio, flow

rate through an orifice and shear cell.

Individually, the test methods do not represent all the conditions that powders undergo in their manu-

facture and application. Therefore, several characterization methods are required to ensure a complete

understanding of a given powder behavior in distinct unit operations of an industrial process.

The Freeman Technology 4 (FT4) powder rheometer might be an advantageous tool because it is

19

Figure 2.6: Non-cohesive powder (left-hand side) and cohesive powder (right-hand side).

Figure 2.7: Cohesive powders may form a stable rathole in funnel flow.

designed to characterize powders under various conditions resembling large-scale production environ-

ments [38]. Besides, the powder rheometer performs rheology, permeability, compressibility and shear

tests. Dumarey et al. [39] showed that the measurements provided by the FT4 powder rheometer are

relevant to understand the effect of the raw material attributes on a roll compaction process and thus

the final tablet quality. Still, there is an increased interest in establishing comparisons between powder

rheology methods [40–43].

20

3Materials and Methods

Contents

3.1 Materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

3.2 Design of Experiments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

3.3 Analytical Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

21

22

3.1 Materials

Drug A and deionized water were supplied from Hovione FarmaCiencia SA (Loures, Portugal). Hy-

droxypropyl methylcellulose acetate succinate (HPMCAS-HG) and acetone were obtained from ShinEtsu

Pharma & Food Materials Distribution GmbH (Wiesbaden, Germany) and Drogas Vigo, S.A. (Porrino,

Spain), respectively.

3.2 Design of Experiments

Drug A and HPMCAS-HG (30:70) were dissolved in a solvent system composed by 97% acetone

and 3% water, totalizing a solids concentration of 10%. The solution was dried in spray dryer X and in

spray dryer Y.

In the spray dryer X, the aspirator rate was set to 100% and the inert loop was enabled in conjunction

with a condenser at 0oC. The solid particles were collected by a high efficiency cyclone. This dryer was

equipped with either nozzle 1, 2 or 3. The following design of experiments (Fig. 3.1) was conceived to

study the influence of the nozzles on the powders properties.

Figure 3.1: Design of experiments for the nozzle 1 (left) and nozzles 2 and 3 (right) in the spray dryer X.

The feed flow rate was set to 1.8 kg/h for all experiments. As the nozzle 2 could not properly atomize

the solution at this throughput, the latter was reduced to 0.9 kg/h for the experiments done with this

nozzle. To assess the influence of the lower feed flow rates on the powders properties, two additional

points of feed flow rate were added to the design of experiments of the nozzle 1 at constant outlet

temperature of 50oC and constant ratio of atomizing gas to feed flow rates (Fig. 3.2).

In the spray dryer Y the aspirator rate was set to 100% with a condenser at 0oC. This dryer was

equipped with nozzle 1 at 1.8 kg/h feed flow rate and the solid particles were collected by a low efficiency

23

Figure 3.2: Additional design of experiments to assess the influence of the feed flow rate.

cyclone. The following design of experiments (Fig. 3.3) was conceived to study the influence of the

chamber design and three distinct gas distributors on the powders properties.

Figure 3.3: Design of experiments for the spray dryer Y.

24

3.3 Analytical Methods

3.3.1 Density measurements

A 10 mL tarred graduated cylinder was used to determine the bulk and tapped densities of the spray

dried powders. The bulk volume used for the calculation of the bulk density was directly read from the

cylinder. Triplicates were made, and the mean value was taken to define the bulk density.

The tapped density was obtained by mechanically tapping a graduated measuring cylinder containing

the powder sample. The final tapped volume was read after 500 taps.

Recently, the Hausner ratio has become a simple, fast, and popular method for predicting powder

flow characteristics and it was calculated as follows:

Hausner ratio =ρtappedρbulk

(3.1)

The generally accepted flowability scale is listed in Table 3.1.

Table 3.1: Flowability scale [6].

Hausner ratio Flow character1.00-1.11 Excellent1.12-1.18 Good1.19-1.25 Fair1.26-1.34 Passable1.35-1.45 Poor1.46-1.59 Very poor> 1.60 Very, very poor

3.3.2 Laser diffraction

Spray dried powders were analyzed using the Helos laser diffraction instrument in combination with

the Rodos dry dispersing unit (both Sympatec GmbH, Clausthal, Germany). Smaller particles produced

by the nozzle 1 were analyzed using a R4 lens having a focal length of 200 mm, while larger particles

produced by the nozzles 2 and 3 were analyzed through a R5 lens with a focal length of 500 mm. A

pressure of 5 bar was used to disperse the particles with a feeding rate of 18 mm/s.

3.3.3 Gas chromatography (GC)

SDD samples (100 mg) were analyzed by gas chromatography, using the HP 6890 Series gas chro-

matograph equipped with Flame Ionization Detection and an Agilent G1888 Headspace Auto Sampler.

The Agilent J&W DB-624 capillary column (60 m length × 0.32 mm internal diameter, and 1.8 µm film

thickness) was used for the quantification of residual solvents. Analysis were performed using an oven

25

programming at an initial temperature of 32C for 5 min followed by a ramp rate of 0.5C/min until 37C,

then 8C/min ramp rate until 85C, followed by 30C/min ramp rate until a temperature of 220C with a

hold time of 2 min and the total run time was 27.50 min. The injector temperature was set at 225C with

a split ratio of 2:1. The detector temperature was maintained at 270C. Nitrogen was used as carrier

gas with a flow rate of 30 mL/min. The injection volume of the samples was 1 mL.

3.3.4 Scanning electron microscopy (SEM)

The morphology of the spray dried particles was investigated by SEM (Phenom Pro Desktop SEM,

Phenom-World B.V., Eindhoven, The Netherlands) operating at 10 kV. The samples were mounted on

stubs using double sided conductive carbon tabs.

3.3.5 Stability and Variable Flow Rate (SVFR) program in FT4 Powder Rheome-

ter

The samples were analyzed using a standard method provided by the FT4 Powder Rheometer (Free-

man Technology Ltd., Tewkesbury, UK). The default SVFR method comprises a stability method contain-

ing seven test cycles and a variable flow rate method containing four test cycles (Fig. 3.4). The SVFR

method was applied to measure the flow characteristics of the spray dried powders using a 25 mm x 25

mL vessel and a 23.5 mm blade. Duplicates were made for each SDD.

Figure 3.4: Structure of the default stability and variable flow rate method sequence. C: conditioning cycle, T: testcycle, Split: vessel splitting to provide an accurate volume of powder [4].

In the sequence upper line, the powder bed is conditioned followed by a splitting procedure to remove

excess powder. The middle line illustrates the stability method consisting of seven pairs of conditioning

and test cycles. The blade tip speed is 100 mm/s during the tests in the middle line. The sequence

26

lower line illustrates the structure of the variable flow rate method and the numbers in the brackets are

the blade tip speed during each test cycle. During the blade movement in the test cycles, the total

energy required to move the powder downwards and upwards is measured (Fig. 3.5). Prior to all tests,

a conditioning cycle is performed to improve the powder bed uniformity. This conditioning step consists

of the blade moving downward through the powder after which the blade moves upward. As such, the

powder is intended to be sliced and lifted and thereby prepared for the next measurement [44].

Figure 3.5: Measurement of flow energy using the FT4 Powder Rheometer.

The following equations define the output parameters from the SVFR method.

Basic flowability energy,BFE(mJ) = Energy Test 7 (3.2)

Specific energy, SE(mJ/g) =Up Energy Test 6+Up Energy Test 7

2

SplitMass(3.3)

Stability index, SI =Energy Test 7

Energy Test 1(3.4)

Flow rate index, FRI =Energy Test 11

Energy Test 8(3.5)

27

28

4Results and Discussion

Contents

4.1 Effect of the feed flow rate on the powders properties . . . . . . . . . . . . . . . . . . 31

4.2 Comparison between the properties of the powders produced by the nozzles 1, 2

and 3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32

4.3 Comparison between the properties of the powders produced in spray drying units

with distinct designs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43

4.4 Comparison between the powders produced with various gas distributors. . . . . . 47

29

30

4.1 Effect of the feed flow rate on the powders properties

The spray dried powders obtained from the tests 10, 6 and 11 were analyzed and the results were

displayed in Table 4.1.

Table 4.1: Spray drying process parameters and properties of the powders from the tests 10, 6 and 11, in the dryerX with the nozzle 1.

Test 10 6 11

Parameters

Ffeed (kg/h) 1.6 1.8 2.0Tin (oC) 116 122 128Tout (oC) 50 50 50Fatom/Ffeed 1.97 1.97 1.97

Results

Bulk density (g/mL) 0.203 0.198 0.207Particle size, Dv50 (µm) 11.16 8.24 11.8Particle size distribution span 2.6 3.3 2.6Acetone content (ppm) 36619 38808 40547BFE (mJ) 20.70 22.38 18.88SE (mJ/g) 6.09 6.39 5.82SI 1.11 1.27 1.16FRI 3.16 3.22 3.11Hausner ratio 1.49 1.53 1.48

The rise of the feed flow rate caused an increase in the acetone content in the gaseous stream

(whose flow rate remained constant), which in turn led to an increase in the acetone content in the spray

dried powders [10,14]. No explanation was found for the smaller particle size and higher distribution span

of test 6, which in turn caused an increase in all flowability parameters, indicating a worse rheological

behavior. According to Fitzpatrick et al. [45], the reduction of the particle size often tends to decrease the

flowability of a given granular material due to the increased surface area per mass unit. The remaining

properties were similar in the three tests, including the particles morphology (Fig. 4.1).

Figure 4.1: SEM images of spray dried powders from tests 10 (left), 6 (middle) and 11 (right). All images have thesame scale.

31

4.2 Comparison between the properties of the powders produced

by the nozzles 1, 2 and 3

4.2.1 Bulk density

The bulk density data of the spray dried powders produced by the nozzles 1, 2 and 3 were plotted

against the outlet relative saturation, RSout (Eq. 2.2), in Fig. 4.2.

Figure 4.2: Comparison between bulk densities of powders produced by nozzles 1, 2 and 3.

There was a difference of the bulk densities of the powders produced by the nozzle 1 and those by

nozzles 2 and 3. The higher density powders produced by the nozzles 2 and 3 can be due to the higher

droplet sizes and lower droplet velocities when compared with the droplets produced by the nozzle 1.

These factors led the droplet to have a higher drying time which allowed the solute to migrate into the

droplet’s center, and when dried, formed an higher density particle.

4.2.2 Morphology

The slower drying of the droplets produced by the nozzles 2 and 3 was also confirmed by the SEM

images of the powders produced by the three nozzles at an outlet temperature of 60oC (Fig. 4.3).

Since the three powders were produced at an outlet temperature of 60oC, which is near the boiling

point of the solvent system used, there is a higher probability of the particles being inflated due to the

rising vapor pressure inside them. The higher percentage of shriveled, high density particles in the

32

Figure 4.3: SEM images of powders produced by the highest droplet size nozzle 1 test (left), nozzle 3 (middle) andnozzle 2 (right) at the outlet temperature of 60oC. All images have the same scale.

samples produced by nozzles 2 and 3, confirmed the slower drying of the droplets produced by these

atomizers.

4.2.3 Particle size distribution

The sizes of the droplets produced by the nozzles 1, 2 and 3 were estimated with a tool developed

by Hovione.

The droplets generated by nozzles 2 and 3 were larger than those produced by the nozzle 1, further

developing larger-sized particles, as can be observed in Fig. 4.4. The particle size was represented by

the Dv50 value which is the median of the powder particle size distribution.

Figure 4.4: Comparison between the particle sizes of the powders produced by the nozzles 1, 2 and 3.

33

The temperature also affected the SDDs particle size. Close to the solvent boiling point, the temper-

ature caused a ballooning effect in the particles [5] as presented in Fig. 4.5.

Figure 4.5: Temperature effect on the particle size of the spray dried powders using the nozzle 1.

The size distribution spans of the powders produced by the nozzles 1, 2 and 3 were listed in Table

4.2.

Table 4.2: Average particle size distribution span of the spray dried powders produced by each nozzle.

Atomizer Particle size distribution span (µm)Nozzle 1 2.8±0.2Nozzle 2 2.0±0.2Nozzle 3 1.5±0.1

The size distribution span of the particles produced by the nozzle 2 were higher than those produced

by the nozzle 3 due to the bimodal distributions obtained (Fig. 4.6), indicating two distinct populations.

This fact could have been caused by an improper atomization and/or poor spray formation during the

spray drying runs.

It is clear from the distributions in Fig 4.6 that the higher the temperature, the higher the distribution

density of the larger particles population. Meaning that at 60oC a higher amount of larger particles were

dried compared to the runs at 50oC and 40oC. Given the large droplet sizes, at the lower temperatures

of 40oC and 50oC, most likely they had not enough energy to dry before hitting the walls. Besides,

the yields for the spray drying runs at 40oC, 50oC and 60oC were 19%, 22% and 27%, reinforcing this

conclusion.

34

Figure 4.6: Particle size distributions of the spray dried powders with the nozzle 2 at 40oC (top), 50oC (middle) and60oC (bottom) outlet temperatures.

4.2.4 Residual solvent content

In Chapter 4.1, it was concluded that the feed flow rate affected the acetone content in the SDDs,

therefore caution is needed while comparing the experimental results plotted in Fig. 4.7.

Overall, the results were very close together. However, as the gas chromatography analysis were

performed on only one sample per powder, the results variability is unknown. Nonetheless, the acetone

content of the powders produced by the nozzle 2 tend to be somewhat lower, due to the lower feed flow

rate aforementioned in Chapter 4.1.

35

Figure 4.7: Comparison between the acetone content of the spray dried powders produced by the nozzles 1, 2 and3.

4.2.5 Flowability

The flowability of the spray dried powders produced was characterized by the FT4 Powder Rheome-

ter Stability and Variable Flow Rate program and by the Hausner ratio. To carry out the SVFR program

a large sample per test was required, thus it was not affordable to analyze all SDDs.

Basic Flowability Energy, BFE

BFE represents the energy required to displace a powder sample during downwards testing. This

measurement simulates a high stress environment since the powder is pushed against the vessel bot-

tom. Thus, a lower BFE means a more easily displaceable powder.

By observing the experimental data of the powders produced by the nozzles 1 and 3 in Fig. 4.8 it can

be concluded that the BFE is lower when the density is lower, the particle size is higher and the residual

solvent content is lower.

Comparing the results of both nozzles, the BFE of the SDD produced by the nozzle 3 was signifi-

cantly higher, mainly due to its higher density, i.e., a higher energy is required to displace the sample.

The particle size and acetone content did not correlate with the nozzle 3 results but, according to the

correlations with the nozzle 1 results, a powder with a larger particle size and a lower residual solvent

content is less cohesive, hence more easily displaceable.

36

Figure 4.8: Comparison between the BFE of the spray dried powders produced by the nozzles 1 and 3.

37

Specific Energy, SE

SE represents the energy required to displace a powder sample in an upwards movement. Thus, a

lower SE means a more easily displaceable powder in low stress environments.

By observing Fig. 4.9, similar conclusions are drawn as for the previous BFE data (Fig. 4.8).

Figure 4.9: Comparison between the SE of the spray dried powders produced by the nozzles 1 and 3.

The powders produced by the nozzle 1 showed lower SE values, meaning that they are more easily

displaced in low stress environments when compared with the powder produced by the nozzle 3.

38

Stability Index, SI

The stability index measures the flow energy variation during repeated testing. If SI is nearly unitary,

the powder is stable throughout the tests since the energy required to displace it is nearly constant.

Whether the SI is higher than 1, the powder requires more energy to be displaced along the tests,

meaning that it may have suffered de-aeration, agglomeration, segregation, moisture uptake and/or

electrostatic charging. If the SI is lower than 1, the probable causes are friction, de-agglomeration,

additive over blending and/or vessel and blade coating by additive [4].

It was impossible to draw sound conclusions from the data plotted in Fig 4.10, except that the spray

dried powders showed SI higher than 1. As they were cohesive powders, they might have been de-

aerated, agglomerated and/or caked.

Flow Rate Index, FRI

The flow rate index measures the flow energy variation when the blade tip speed is reduced. Usually,

cohesive powders are more sensitive to flow rate variations than non-cohesive or granular materials,

mainly due to the high air content in the cohesive materials. This air acts as a lubricant, reducing

interparticle contact and allowing the material to be more compressible - all of which reduce the energy

required to promote flow. At low flow rates more air is excluded as the material becomes, at least locally,

more highly consolidated by the blade. This consolidated zone extends much further ahead of the blade

when the latter moves slowly, thus the total energy consumed is correspondingly higher [4].

The experimental results obtained are depicted in Fig. 4.11 and it can be concluded that the sensitiv-

ity to the flow rate decreases when the bulk density and the particle size were higher, i.e., less cohesive

powders.

The SDD produced by the nozzle 3 presented a much lower FRI meaning that it was less cohesive

than the powders produced by the nozzle 1.

39

Figure 4.10: Comparison between the SI of the spray dried powders produced by the nozzles 1 and 3.

40

Figure 4.11: Comparison between the FRI of the spray dried powders produced by the nozzles 1 and 3.

Hausner ratio

The Hausner ratio measures the ability of the powder particles to rearrange and it is an indicator of the

compressibility. It also measures the powders cohesiveness since generally, the structure of a cohesive

powder collapses significantly on tapping whilst a free flowing material has low tendency for further

consolidation. Therefore, a drop in Hausner Ratio indicates a decrease in the powder cohesiveness.

Given the results displayed in Fig. 4.12, similar correlations and conclusions are drawn as for the

previous FRI data (Fig. 4.11).

The powders produced by nozzles 2 and 3 are less cohesive than the powders produced by the noz-

41

zle 1. The former presented lower Hausner ratios, due to their higher bulk densities and particles sizes.

According to the conventionally accepted flowability scale, given in Table 3.1, the powders produced by

nozzles 2 and 3 exhibited fair to poor flow behavior, whereas those produced by the nozzle 1 presented

a flow character that ranked from poor to very, very poor.

Figure 4.12: Comparison between the Hausner ratio of the spray dried powders produced by the nozzles 1 and 3.

42

4.3 Comparison between the properties of the powders produced

in spray drying units with distinct designs

4.3.1 Bulk density

The bulk density results of the spray dried powders produced in spray dryers and Y are displayed in

Fig. 4.13.

Figure 4.13: Comparison between the bulk densities of the powders produced in the dryer units X and Y.

The results obtained revealed that the bulk density of the powders produced in distinct units operating

under identical conditions are quite similar.

4.3.2 Morphology

The SEM images of the spray dried powders in both units at various temperatures are displayed in

Fig 4.14. It can be concluded that the powders had similar particle morphologies, regardless of the unit

in which they were produced.

4.3.3 Particle size distribution

Similar conclusions to the ones reported in the Sections 4.3.1 and 4.3.2 can be drawn by observing

the results displayed in Fig. 4.15.

As expected, the particle size distribution depended mainly on the atomization parameters, which

were identical in both units.

43

Figure 4.14: SEM images of the powders produced with identical droplet sizes in the spray dryer X (first row) and inthe spray dryer Y (second row) at the outlet temperature of 40oC (left), 50oC (middle) and 60oC (right).All images have the same scale.

Figure 4.15: Comparison between the particle sizes of the powders produced in the spray dryers X and Y.

44

4.3.4 Residual solvent content

The experimental data of the acetone content of the spray dried powders produced in both units are

displayed in Fig. 4.16.

Figure 4.16: Comparison between the residual acetone content of powders produced in each dryer unit.

The powders dried at high evaporation rates, i.e., low relative saturations, revealed lower acetone

content, as expected. In fact, as the evaporation rate was similar in both units, the acetone content

should also be similar. The results obtained portrayed this reasoning in Fig. 4.16.

4.3.5 Flowability

Flowability results from the combination of a material’s physical properties that influence material

flow, such as, bulk density, particle size and morphology, and moisture content. Since all of these

properties were similar in the spray dried powders produced in the spray dryers X and Y, it was expected

that the flow behavior would also be similar, which turned out to be correct as plotted in Fig. 4.17.

45

Figure 4.17: Flowability parameters of the spray dried powders produced in the dryer units X and Y.

46

4.4 Comparison between the powders produced with various gas

distributors.

SDDs were produced in the spray dryer Y with the nozzle 1 and three distinct gas distributors under

similar operating conditions, regarding the outlet temperature, feed flow rate and atomization gas flow

rate. Table 4.3 compares the results obtained for these experiments.

Table 4.3: Spray drying process parameters and data of the experimental tests with distinct gas distributors.

Distributor A B C

Process parameters

Ffeed (kg/h) 1.8 1.8 1.8Tin (oC) 90 97 93Tout (oC) 40 40 40Fatom/Ffeed 1.56 1.56 1.56

Powder properties

Bulk density (g/mL) 0.219 0.208 0.211Particle size, Dv50 (µm) 9.06 9.24 9.23Span 2.4 2.6 2.6Acetone content (ppm) 48055 49088 51211BFE (mJ) 21.33 21.04 22.09SE (mJ/g) 6.27 5.33 6.12SI 1.40 1.19 1.17FRI 3.08 3.04 3.06Hausner ratio 1.47 1.45 1.50

Distributor A presented lower heat losses because it needed a lower inlet temperature of 90oC (com-

pared to 97oC and 93oC of distributors B and C, respectively) to achieve a similar outlet temperature of

40oC.

All spray powders had similar bulk densities. However, those produced by the distributor A had lower

particle sizes and distribution spans, which was unexpected and no reason has been found so far.

As for the acetone content, the powder produced with the distributor A had lower acetone content

followed by B, and C with the highest value. These results prove that the distributor A provided the

highest drying rates when compared to B and C, leading to the lowest residual solvent content.

The flow parameters of the SDDs were relatively similar, thus the differences in the rheological be-

havior of the powders were not relevant.

47

48

5Conclusions and Future Work

Contents

5.1 Conclusions and Future Work . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51

49

50

5.1 Conclusions and Future Work

When developing spray drying processes, lab-scale testing is an essential step towards its success-

fulness. Many challenges, which are not fully understood, arise while scaling up to pilot or industrial

scale [25]. Thus, the main goal of this thesis was to assess the influence of scale up on powders’ critical

quality properties.

For the current spray drying process, it was concluded that i) bulk density, particle morphology and

residual solvent content could be controlled by manipulation of the outlet drying temperature/relative

saturation and ii) particle size depended mainly on the droplet size and outlet drying temperature/relative

saturation.

Regarding flowability, there was no single parameter describing this bulk powder property, that de-

pended on the operating conditions to which the powder is exposed. However, the FT4 Powder Rheome-

ter stability and variable flow rate test, though requiring a large sample, provided useful results to de-

scribe the powders flow behavior under various conditions. For example, the Basic Flowability Energy

(BFE) and the Specific Energy (SE) are good indicators of the powder behavior under forced flow con-

ditions such as in tablet presses with forced feed mechanism or in an agitated dryer. On the other hand,

the Flow Rate Index (FRI) and the Hausner ratio, which represent the powders cohesiveness, are good

indicators of the powders behavior in unconfined environments, such as in a rotary drum dryer or at the

outlet of a hopper or bin.

When moving from a process with a nozzle 1 to a process with a nozzle 2 or 3, and vice versa,

the powder properties may change. In the case study of this thesis, the powders produced by the

nozzles 2 and 3 presented higher bulk densities, more shriveled particles and higher particle sizes due

to the production of larger droplets with lower distribution spans. The acetone content of the powders

did not vary with the nozzle type. The variation in the bulk density, particle size and distribution span

affected their flowability. The powders produced by the nozzles 2 and 3 presented higher BFE and SE

values, corresponding to a poor behavior in forced flow conditions, and lower FRI and Hausner ratios,

representing a good behavior in unconfined environments, when compared to the powders produced by

the nozzle 1.

Moreover, it was concluded that the lab-scale process development may be performed either in the

spray dryer X or the spray dryer Y, as the unit design did not affect the critical quality attributes of the

powders, in this case study.

As for the various gas distributors of the spray dryer Y, it was concluded that the distributor A pro-

duced a powder with a lower content of acetone, indicating higher drying rates than the distributors B

and C.

The current study can be significantly improved and extended by producing powders with other noz-

zle types. Although tough to implement on a laboratory scale due to difficulties in atomizing viscous

51

solutions at low flow rates, their viscosities can be reduced by performing the study at lower solids con-

centrations. It would also be interesting to study the influence on powders properties of simultaneously

increasing scale and changing the atomizing device.

The study of the flowability behavior of spray dried powders can also be improved by implementing

many other methods including angle of repose, flow rate through an orifice and FT4 Powder Rheometer

shear cell testing, for example.

It would also be crucial to study the influence of spray dried powders properties on the drying effi-

ciency of secondary drying applications, such as in an agitated dryer or in a rotary drum dryer, and even

on the final dosage properties and its processing, i.e., tablet presses and/or capsule filling.

52

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