Continuous Crystallization: Equipment and Operation

Liu, Yiqing C.; Nagy, Zoltan K.

doi:10.1007/978-3-030-41524-2_5

Yiqing C. Liu⁵ &
Zoltan K. Nagy^5,6

Part of the book series: AAPS Advances in the Pharmaceutical Sciences Series ((AAPS,volume 42))

2022 Accesses
4 Citations

Abstract

Crystallization is an economical separation and purification unit operation commonly used in the pharmaceutical industry as the last drug substance manufacturing step to obtain crystalline form active pharmaceutical ingredient (API). The quality attributes of crystallization products such as purity, crystal size, crystal shape, and polymorphic form heavily influence downstream processes and may even affect the final product performance. Crystallization is one of last missing links in end-to-end continuous pharmaceutical manufacturing development because of its complex two-phase and stochastic nature. Recent advances and remaining challenges in the development of laboratorial- and industrial-scale continuous crystallization equipment, techniques, and control strategies are discussed in this chapter accompanied by a brief overview of crystallization theories as well as process analytical technology (PAT) applications in crystallization processes. The integration of continuous crystallization is also discussed in this chapter.

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Abbreviations

AFC:: Antifouling control
API:: Active pharmaceutical ingredient
ATR-FTIR:: Attenuated total reflection-Fourier transform infrared
ATR-NIR:: Attenuated total reflection-near-infrared
ATR-UV/Vis:: Attenuated total reflection-ultraviolet/visible
CFC:: Continuous filtration carousel
CFD:: Computational fluid dynamics
CIP:: Cleaning in place
COBC:: Continuous oscillatory baffled crystallizer, also known as OFBC
CSD:: Crystal size distribution
DBC:: Dynamic baffle crystallizer, also known as OBR
FBRM:: Focused beam reflectance measurement
GC:: Gas chromatography
HPLC:: High-performance liquid chromatography
MOM:: Method of moment
MS:: Mass spectrometry
MSMPR:: Mixed-suspension-mixed-product removal
MSZW:: Metastable zone width
NMR:: Nuclear magnetic resonance
OABA:: Ortho-aminobenzoic acid
OBC:: Oscillatory baffled crystallizer
OBR:: Oscillatory baffle reactor, also known as DBC
OFBC:: Oscillatory flow baffled crystallizer, also known as COBC
PAT:: Process analytical technology
PBM:: Population balance model
PFC:: Plug flow crystallizer
PSD:: Particle size distribution
PVM:: Particle vision measurement
RTD:: Residence time distribution
SASR:: Solvent-to-antisolvent ratio
SEM:: Scanning electron microscopy
STC:: Stirred tank crystallizer
UPLC:: Ultra-performance liquid chromatography
XRD:: X-ray diffraction
A :: [m²] Heat transfer area
B :: [#·s⁻¹·m⁻³] Secondary nucleation rate
b :: - Secondary nucleation order
C :: [kg/m³] olution concentration
C _in :: [kg/m³] Inlet solution concentration
C _p :: [J·K⁻¹·kg⁻¹] Specific heat
D :: [m] Reactor diameter
d _c :: [m] Crystal size
∆C :: [kg/m³] Absolute supersaturation
∆H _c :: [J/kg] Heat of crystallization
D _im :: [m] Impeller diameter
D _p :: [m] Mass mean size of particles in suspension
d _s :: [m] Seed size
E _b :: [J/mol] Secondary nucleation temperature dependence
E _g :: [J/mol] Crystal growth temperature dependence
f :: [#/m⁴] Population distribution of particles
f _in :: [#/m⁴] Population distribution of particles at the inlet
G :: [m/s] Growth rate
g :: - Crystal growth order
g _c :: [m/s²] Gravitational acceleration constant
h :: [W·K⁻¹·m⁻²] Heat transfer coefficient
J :: [#·s⁻¹·m⁻³] Primary nucleation rate
k _b :: Empirical Secondary nucleation kinetic constant
k _g :: Empirical Crystal growth kinetic constant
k _j :: Empirical Primary nucleation kinetic constant
k _v :: - Shape factor
L :: [m] Crystal characteristic length
L ₀ :: [m] Nuclei size
M :: [kg/m³] Solid (magma) density
m :: Empirical Secondary nucleation solid concentration dependence
m _c :: [kg] Crystal mass
m _s :: [kg] Seed mass
N _js :: [rad/s] Minimum rotational speed required for suspension
Q _agg :: [#·s⁻¹·m⁻⁴] Agglomeration mechanism
Q _break :: [#·s⁻¹·m⁻⁴] Breakage mechanism
Q· _i :: [m³/s] Volumetric flow rate out of the ith MSMPR
Q· _in :: [m³/s] Inlet volumetric flow rate
Q _nuc :: [#·s⁻¹·m⁻⁴] Nucleation mechanism
Q· _out :: [m³/s] Outlet volumetric flow rate
R :: [J·mol⁻¹·K⁻¹] Gas constant
Re_o:: - Oscillatory Reynolds number
S :: - Supersaturation ratio
s :: - Relative supersaturation
St:: - Strouhal number
T :: [K] Temperature
t :: [s] Time
Tw:: [K] Heat transfer wall temperature
V :: [m³] Slurry volume
X :: - Weight percentage of solid to liquid content
x _o :: [m] Oscillation amplitude
z :: [m] Length along a PFR
Z _c :: Empirical Zwietering constant
δ :: [m⁻¹] Dirac delta function at L₀
μ :: [Pa·s] Viscosity
μj :: - jth moment of population distribution
ν :: [m²/s] Kinematic viscosity
ρ _c :: [kg/m³] Crystal density
ρ _sol :: [kg/m³] Solution density
ω :: [Hz] Oscillation frequency

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Yiqing C. Liu & Zoltan K. Nagy
Department of Chemical Engineering, Loughborough University, Loughborough, UK
Zoltan K. Nagy

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Zoltan K Nagy
Faculty of Pharmacy, Cairo University, Cairo, Egypt
Arwa El Hagrasy
Department of Chemical and Biochemical Engineering, The University of Sheffield, Sheffield, UK
Jim Litster

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Liu, Y.C., Nagy, Z.K. (2020). Continuous Crystallization: Equipment and Operation. In: Nagy, Z., El Hagrasy, A., Litster, J. (eds) Continuous Pharmaceutical Processing. AAPS Advances in the Pharmaceutical Sciences Series, vol 42. Springer, Cham. https://doi.org/10.1007/978-3-030-41524-2_5

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