PRACTICAL CONSIDERATIONS
DIFFERENCES BETWEEN LABORATORY AND
LARGER SCALE PROCESSES
Petr Beňovský
DIFFERENCES BETWEEN ACADEMIC AND PROCESS
CHEMISTRIES
Academic – Discovers, reveals, disputes, confirms, brings new
knowledge.
Small amount of material.
Process – Selects, optimizes, seeks for efficiency, defines control
points, considers efficiency and environment (also
safety).
Role of chemical engineers.
Relatively large amount of material.
BASIC CONSIDERATIONS
Laboratory (medicinal) chemistry (mg – g) has to be diverse
and flexible; chromatography is very common;
Can be done by a synthetic chemist only;
Process (up-scaled) pathway (kg – 1000 kg) must provide
reliable results, the procedure is expected to be robust,
repeatable, simple, economic, focuses on safety (both
operators and patients); chromatography is to be avoided;
Must be done in mutual cooperation of a synthetic chemist
(thinks in steps) and a chemical engineer (thinks in unit
operations)
BASIC CONSIDERATIONS
What is scale-up?
Transferring a lab-scale chemical process to pilot or commercial
equipment with:
• same yield
• same selectivity
• same quality
Scale-up is NOT a simple linear increase in geometric dimensions
BASIC CONSIDERATIONS
What is scale-up?
MORE
• understanding of critical parameters
• how to control them
• ability to predict performance at any scale
BASIC CONSIDERATIONS
Laird, T. – How to Minimise Scale Up Difficulties
1. Appropriate conditions
2. Correct dosing time
3. Hazards
4. Mass transfer issues
5. Solvent extractions
6. Optimising using statistical methods
Laird, T. Chemical Industry Digest, p. 51, July 2010
BASIC CONSIDERATIONS
The best way to minimize the scaleup
problems is by important data
gathering and detailed process
understanding.
DIMENSIONAL ANALYSIS
Ideally, dimensions in geometry, velocities of the components,
forces on the system, temperatures and concentrations should be
kept constant between different scales
• Surface area per volume ratio (serious consequences for heat
removal and heat input during process scale-up);
• Kinematic similarity – they exists when two systems have the
same shape and the ratios of the velocities between corresponding
places are also equal; Fluid dynamics – the Reynolds number (Re)
– it increases during scale-up at a constant stirrer speed as the
diameter of the stirrer increases;
• Hydrodynamic similarity – they exists when the ratios of forces
between corresponding places are also equal in both systems;
DIMENSIONAL ANALYSIS
• Thermal similarity – temperature differences between
corresponding places in a system have a constant ratio with one
another (temperature profile, heat transfer area);
• Chemical similarity – concentration differences between
corresponding places in two systems have a constant ratio to one
another (ratio between the chemical conversion rate, rate of
molecular diffusion).
DIMENSIONAL ANALYSIS
Reactor Size
[L]
Surface Area
[m2]
Surface Area /
Volume [m2/L]
Factor
Lab Scale
0.5 0.02 0.04 28.6
10 0.20 0.02 14.3
Pilot Plant
Scale
380 2.32 0.0061 4.4
Large
Production
38 000 53.0 0.0014 1
Maintaining geometrical similarities for various scales is not
practical in batch processing as the jacket heat-exchange area
per unit reduces significantly with a scale
DIMENSIONAL ANALYSIS
Reynolds number
- gives a measure of the degree of turbulence or the ratio of inertial
force to viscous force (the higher Reynolds number the higher
turbulence of the system)
Re = ND2 ρ/μ (mostly for homogeneous systems)
Re … Reynolds number
N … rotational speed (revolutions per second)
D … diameter of the stirrer (m)
μ/ρ … kinematic viscosity (m2/s)
LAMINAR VS. TURBULENT FLOW
Laminar flow – is characterized by smooth or regular
paths of fluid particles. The fluid flows in parallel layers with
minimal lateral mixing.
Turbulent flow – is characterized by irregular movement
of particles. Lateral mixing is very high.
MIXING
DIMENSIONAL ANALYSIS
Maintaining total similarity of all possible scale-up parameters on
different scales cannot be established and, in fact, is almost
impossible;
A reliable batch process scale-up cannot be simulated in generally
applicable mathematical models without a clear understanding of all
process and reaction mechanisms;
Regime analysis – significance/trade-off of particular similarities –
can be done in an early stage of process development;
DIMENSIONAL ANALYSIS
Regime analysis can be done in an early stage of the process development:
• If heat effects are relative small, then the thermal similarity will be easily
maintained;
• If reaction rate is slow compared to the mixing time, a turbulent regime is not
that relevant anymore;
• For very rapid reactions any limitation in diffusion might be the ratecontrolling
step and the chemical reaction is a subject to a hydrodynamic
regime and the energy input should get priority;
• if in a heterogeneous reaction the particle size and, therefore, the dissolution
rate is an important process parameter, the chemical regime might dictate a
stirrer rate on large scale where all particles are free from bottom of the
reactor;
DIMENSIONAL ANALYSIS
Stirrer rate and diameter of the stirrer are important parameters to
play with in the early stages of process development and that in any
realistic process scale-up the larger scale-reactor will always
represent higher tip speed and longer circulating and mixing times
than on the smaller scale. For heterogeneous processes this fact
might have serious consequences.
DIMENSIONAL ANALYSIS
Widely used scale-up rule is the equal power per unit of volume criterion and
has given accurate results in many cases. This rule has been concluded to be
the best in almost any scale-up problem.
For non-laminar flow (high Reynolds number), with constant geometry and the
same stirrer type
P/V = P0 x r x N3 x D2 = constant
P0 … power number of the stirrer
r … density
N … stirrer speed
D … diameter of the stirrer
DIMENSIONAL ANALYSIS
Parameter Power P/V Q/V Tip Speed
Reynolds
number
Equal P 1.0 10-3 0.0215 0.215 2.15
Equal P/V 103 1.0 0.215 2.15 21.5
Equal N 105 102 1.0 10 102
Equal Tip
Speed
102 0.1 0.1 1.0 10
Equal
Reynolds
number
0.1 10-4 10-2 0.1 1.0
Table represents effects of various scale-up strategies from 1 L to 1000 L
Q/V … the liquid pumping capacity of the stirrer per volume
BASIC CONSIDERATIONS
Why is scale-up so difficult?
• There are no standard approaches for doing quantitative process scale-up;
• Textbooks on scale-up are limited;
• Scale-up practice largely depends upon individual experience;
• There is a shortage of people with the right experience;
• The success of process scale-up depends to a great extent on the
communication and transfer of information between the chemists and the
chemical engineers;
• There are no systematic ways for a chemical engineer to ask a chemist what
information is required for process scale-up and vice versa;
• Companies and chemical engineering community are not learning from the
success and failures that are occuring on a daily basis throughout the industry;
• There is a gap between how chemical engineers and chemists want the
process to run in the plant and how the operators actually run it, due to lack of
training or involvement.
BASIC CONSIDERATIONS
Process development should be defined as the
process of converting a synthetic route into an
optimum, robust, safe and economic process for
manufacturing the chemical of desired quality at
the desired ultimate scale within a reasonably
desired period of time;
BASIC CONSIDERATIONS
• SAFETY
• TEMPERATURE CONTROL
• TEMPERATURE RANGE
• MOBILE (TRANSFERABLE) STREAMS
• INCREASE EFFECTIVITY (MINIMIZE SOLVENTS, INCREASE CONCENTRATION
WHERE POSSIBLE)
• STABILITY OF COMPONENTS DURING REACTION AND HOLD ONS
• SIMULATE LARGE SCALE CONDITIONS IN LABORATORY (prolonged additions,
heat accumulation, stability of reactants and products, etc.)
• GET INFORMATION ABOUT PROPERTIES (solubilities, pH tolerance, …)
BASIC CONSIDERATIONS
• DETERMINE CONTROL POINTS (in process controls)
• KEEP IT SIMPLE
• ANTICIPATE FATE OF VOLATILE REAGENTS
• DEVELOP EFFICIENT AND STRAIGHTFORWARD WORK UP
PROCEDURE
• CONSIDER INERT ATMOSPHERE TO AVOID THE PRESENCE OF
MOISTURE AND OXYGEN
• ASSUME SCRUBBING FOR ANNOYING OR TOXIC OFF-GASES
• SUGGEST RESISTANT MATERIAL
CHARGING
• Weighing of reagents (differential, reactors mounted on a load
cell);
• Charging of liquids (by weight or by volume) – use the same
approach in the laboratory – density of liquids will change
slightly with temperature;
• Recommended accuracy (tolerance) - volumes + 5%, weights +
2%;
• Different transfer times considering a laboratory scale and the
production (large) scale;
SOLVENT CONSIDERATIONS
Watch out hydrocarbon solvents with even number of carbons (toxicity, electrostatic buildup);
Classification of solvents – ICH Harmonised Guideline Q3C – Impurities: Guideline for
Residual Solvents
Class 1 – solvents to be avoided (known human carcinogens, strongly suspected human
carcinogens, and/or environmental hazards, e.g. carbon tetrachloride (concentration
limit 4 ppm), 1,2-dichloroethane (5 ppm), 1,1,1-trichloroethane (1500 ppm), benzene
(2 ppm))
Class 2 – solvents to be limited (non-genotoxic animal carcinogens, agents of irreversible
toxicity, e.g. acetonitrile (410 ppm), chlorobenzene (360 ppm), chloroform (60 ppm),
N,N-dimethylformamide (880 ppm), hexane (290 ppm), methanol (3000 ppm), Nmethylpyrrolidone
(530 ppm), toluene (890 ppm))
Class 3 – solvents with low toxic potential (permissible daily exposure 50 mg or more per
day, e.g. acetic acid, acetone, ethyl acetate, heptane, 2-propanol, triethylamine)
Solvents for which no adequate toxicological data was found – a manufacturer is asked to
supply justification for residual levels of these solvents (e.g. diisopropyl ether, petroleum ether,
trifluoroacetic acid)
WORK UP
IN PROCESS CONTROLS (IPCs)
Off-line analysis
In-line analysis
On-line analysis
WORK UP
Efficiency – e.g. crystallization directly from the reaction mixture;
– labor cost is very important;
Extractions are generally preferred over filtration to remove impurities;
Column chromatography is rare and very expensive;
WORK UP
• Includes operations after the reaction was declared complete;
• Such operations include quenching the reaction both to remove
impurities and facilitate product isolation and to allow safe
handling of process streams, even after product isolation.
• Quenching reactive species
• pH adjustment
• Filtration
• Precipitation
• Extractions
• Concentration (including azeotropic distillation)
• (Chromatography)
WORK UP
Typical time and money saving technique
TELESCOPING
The reaction proceeds further without full isolation of an
intermediate, with advantage even without any quench;
Pushing a reaction to completion – removal of side products
WORK UP
Gallou, F. et al J. Org. Chem. 70, 6960 (2005)
WORK UP
QUENCHING REACTIONS
Safe decomposition of excessive reagents stops a reaction
WORK UP
QUENCHING REACTIONS
Careful with halogenated solvents (e.g. dichloromethane) in the
presence of azides (diazidomethane !!)
VERY CAREFUL
Recent issue with the formation of nitrosamines (e.g. limit in
Valsartan (320 mg dose) will be 0.03 ppm in 2021
WORK UP
EXTRACTIONS
• Used to separate neutral compounds from water soluble
components;
• Solid Phase Extraction (SPE) – separate compounds of significant
different polarity;
• Solubility or miscibility of organic solvents with water;
• Separation of layers
• pH value adjustment – extra opportunities;
• Ionic strength;
• Solubility at higher temperatures;
WORK UP
EXTRACTIONS
Zegar, S. et al Org. Process Res.
Dev. 11, 747 (2007)
WORK UP
EXTRACTIONS
Convenient Aqueous Solutions for Extractions
Solvent
pH of 0.1 N
solution
Relative Solubility
in Organic
Solvents
Comments
HCl 1.1 High Corrosive, volatile
H2SO4 1.2 Low
AcOH 2.9 High Weak acid
Na2HPO4 8.5 Low
NaHCO3 8.4 Low
NH3 11.1 Moderate Volatile
Na2CO3 11.6 Low
Na3PO4 12.0 Low
WORK UP
FILTRATION
Polish Filtration – an operation to remove trace amounts of insoluble
impurities before other operations – passing a process stream through
in-line filters with different porosity;
Very important for crystallizations, avoiding emulsions;
Ultrafiltration – protein separation through membranes;
WORK UP
PERVAPORATION
Pervaporation through membranes – specific for some solvents – a
processing method for the separation of the mixtures of liquids by
partial vaporization through a nonporous or porous membranes;
Separation of components is based on a difference on a transport rate
of individual components through the membrane;
Pervaporation is effective for solutions containing traces or minor
amounts of the component to be removed;
Hydrophilic membranes for dehydration of alcohols containing small
amount of water, hydrophobic membranes for removal of traces of
organic compounds from aqueous solutions;
WORK UP
PERVAPORATION
Hydrophilic membranes – commercially most successful membranes
are formed from polyvinyl alcohol or polyimides;
Hydrophobic membranes – based on polydimethylsiloxane
PRINCIPAL
The pressure difference on sides of a membrane (usually atmospheric
vs. vacuum), permeate goes through a membrane, retentate does not
go through and thus it is separated.
WORK UP
PERVAPORATION
WORK UP
CHROMATOGRAPHY
Best to avoid, technically difficult and expensive on large-scale, but still used in
special cases (preparative chromatography);
Solid Phase Extraction
Simulated Moving Bed Chromatography
https://www.youtube.com/watch?v=Harx2khTuEc
EFFICIENT PROCESS DEVELOPMENT
• Anticipate and avoid problems
• Do experiments at minimum and maximum ranges to confirm
robustness/sensitivity in cases where a particular parameter is significant
• Identify critical impurities within the whole process and their fate
• Get maximum allowed level of critical impurities
• How to proceed if the specification criteria in IPCs are not met?
• Pay attention to details, observe unusual changes
• Avoid systematic errors
• Take into account future process validation
PROCESS VALIDATION
• The cumulative effort to demonstrate reliable processing and product quality;
• The fruition of the labor of process chemists and engineers, the ultimate tests of how well
one understands the process;
• Before 1970s little attention has been paid to efficient process development;
• 1987 – FDA – Guideline on General Principles of Process Validation (validation is defined as
establishing documented evidence which provides a high degree of assurance that a
specific process will consistently produce a product meeting its predetermined
specifications and quality attributes);
• 2008 – FDA – process validation is the collection and evaluation of data, from the process
design stage throughout production, which establishes scientific evidence that a process
is capable of consistently delivering quality products; the quality is built up into the
product through process understanding and cannot be tested in batches – quality by
design (QbD)
Anderson, N.G. et al Org.Process Res.Dev. 15, 162 (2011)