Flow synthesis

This is the heart of the process, where the main reaction takes place. Feedstocks are fed at a constant rate into a narrow channel, and the chemical transformation proceeds continuously as they flow. The reaction is completed in the flow, not in a vessel.

The key is the narrowness of the channel. The narrower it is, the more instantly heat and mixing are transferred, so even exothermic or fast reactions can be controlled without temperature swings or side reactions.

To increase output, you run longer rather than build a bigger vessel. That is why conditions optimized in the lab can be carried straight over to large-scale production, which is the greatest practical advantage on the shop floor.

Feedstocks are pumped at a constant rate and react continuously in a narrow channel. The narrower the channel, the more efficiently heat and mixing are transferred, so temperature swings are kept down even for exothermic or fast reactions. Scale is gained not by building a bigger vessel as in batch but by running longer, so conditions optimized in the lab transfer readily to large-scale production.

Alternatives in practice

• Coil/tube-type flow reaction (R&D to kilo lab) · Vapourtec R-Series (R2 + R4, PFA/SS coil reactors) / Uniqsis FlowSyn (glass chip + coil) — Suited to small-scale, high-variety screening. Channel volume is variable, so residence time can be set flexibly
• CSTR cascade / continuous oscillatory baffled reactor (COBR) · AM Technology Coflore ACR (agitated cell reactor) / NiTech DN15 continuous oscillatory baffled reactor (COBR) — Strong with solid slurries, long residence times and slow reactions. An alternative for systems where plate-type reactors clog
• Batch reaction (conventional method, control) · Mettler Toledo OptiMax 1001 / EasyMax 102 synthesis workstation — For comparison controls and initial condition screening. Used to check exotherm and scale constraints

A step that puts hazardous reactions with explosive or toxic reagents, such as hydrogenation and oxidation, into flow. Charging everything at once in batch lets hazardous material accumulate, and flow avoids that.

At the moment of reaction, the amount of hazardous material in the system is very small. The risk in case of an incident is therefore small, and aggressive conditions such as high temperature and pressure can be approached safely.

The catalyst is fixed in a packed bed (trickle bed). The readily ignitable palladium catalyst does not have to be handled directly, and catalyst filtration after the reaction is also unnecessary, which is where it pays off in practice.

Reactions that use hydrogen gas or toxic or explosive reagents build up a dangerous quantity when charged all at once in batch. In flow, the amount of hazardous material in the system at any moment of reaction is very small, so you can safely push to high temperature and pressure. If the catalyst is fixed in a packed bed, you avoid handling the readily ignitable palladium catalyst, and no filtration step is needed.

Alternatives in practice

• Continuous photoredox / photohalogenation · Corning Advanced-Flow G1 Photo Reactor / Vapourtec UV-150 photochemical reactor (E-Series) — For transformations that are difficult thermally, such as radical generation and photoredox. No gas is needed, which reduces hazard
• Gas-liquid segmented (Taylor) flow oxidation / carbonylation · Vapourtec gas supply module (gas/liquid reactor) + mass flow controller (Bronkhorst EL-FLOW Select) — Gaseous reagents such as O2, CO and ethylene react efficiently in slug flow with a large specific surface area
• Membrane (tube-in-tube) gas-liquid contacting reaction · Teflon AF-2400 tube-in-tube reactor (Uniqsis Gas Addition module, etc.) — Gas is dissolved in a controlled amount through the membrane. Supplies H2/CO2/O2 uniformly without headspace

A monitoring step in which a window is placed in the piping to look at the contents while they flow. Infrared (FTIR) or Raman measures the composition, and how far the reaction has progressed is followed in real time.

The weakness of flow is that it is hard to draw out a sample midway and check it. So the disappearance of the feedstock and the growth of the product are watched continuously, and flow rate or temperature is corrected the moment they drift.

Quality is assured while the product is being made, rather than noticed after a defect has been produced. This is the idea behind PAT (process analytical technology), and it is central to quality assurance in continuous manufacturing.

In flow it is hard to draw out the contents and check them, so a window is placed in the piping and the composition is observed by infrared or Raman while the stream flows. The disappearance of the feedstock and the growth of the product can be followed in real time, so flow rate or temperature can be corrected the moment they drift. This is the core of the PAT approach, which assures quality while the product is being made rather than noticing after a defective product has been made.

Alternatives in practice

• In-line/on-line UV-Vis spectroscopy · Avantes AvaSpec-ULS2048CL-EVO spectrometer + flow-through cell / Ocean Insight Flame-S + fiber-optic probe — Fast and low-cost for systems with a chromophore. Continuous trend of concentration and conversion
• On-line HPLC/UHPLC with automated sampling · Agilent 1260 Infinity II Online LC System (with Online Sample Manager) — Quantitation of complex reactions that need separation. Related substances can also be tracked, but time resolution is low
• Benchtop NMR on-line monitoring · Magritek Spinsolve (60/80 MHz, flow cell / PTFE tubing reaction monitoring kit) / Bruker Fourier 80 — Structure-selective and quantitative. Directly tracks functional group conversion. Not suited to paramagnetic or low-concentration samples

An evaluation step that checks how uniformly molecules flow inside the reactor. A tracer such as a dye is injected, and the spread in the time until it appears at the outlet is measured.

Ideally all molecules stay in the reactor for the same length of time. In practice some exit quickly and others lag, and this spread is the residence time distribution (RTD).

When the spread is large, the extent of reaction is not uniform and impurities increase. It is unglamorous but effective basic data that underpins scale-up design and reactor evaluation.

This checks how uniformly material flows through a flow reactor. Ideally every molecule stays in the reactor for the same length of time, but in practice some molecules exit quickly and others lag. When this spread (the residence time distribution) is large, the extent of reaction is not uniform and impurities increase. It is basic data that underpins scale-up and process design.

Alternatives in practice

• CFD prediction of mixing and RTD · Ansys Fluent / Siemens Simcenter STAR-CCM+ (CFD software) — Channel design and dead-volume assessment before measurement. Complementary to experimental tracers
• Mixing time assessment by the Villermaux–Dushman method · Iodide-iodate competitive reaction system + UV-Vis (I3⁻ detected at 353 nm, using the Avantes/Ocean Insight spectrometers above) — Quantifies micromixing performance. Assesses molecular-diffusion-level mixing that RTD hardly captures

A step in which a "stop solution" is merged at the reactor outlet to deactivate the remaining reagents. In continuous flow, over-reaction and decomposition proceed during residence unless the reaction is stopped promptly.

Acid, base, water or the like is fed in metered amounts, fixing the conversion (how far the reaction is allowed to go) on the spot. Think of it as cutting the reaction off exactly where intended.

At the same time the pH is adjusted to create a phase suited to the next liquid-liquid extraction. In-line treatment that stops and neutralizes while monitoring the pH is the key to a smooth downstream step.

In continuous flow, if the reaction is not stopped promptly at the reactor outlet, over-reaction and decomposition proceed during residence. The standard step is to merge a quench solution (acid, base, water, etc.) in-line, fix the conversion, and then create the pH and phase suited to the downstream liquid-liquid extraction.

Alternatives in practice

• Quench and workup in a CSTR · AM Technology Coflore ACR / stirred tank (Mettler Toledo OptiMax 1001) — For highly exothermic quenches and for neutralizations accompanied by solid precipitation. Residence time is easy to secure
• Automatic acid/base dosing and merging by in-line pH feedback control · Hamilton Polilyte Plus pH electrode + Coriolis pump linked to a PID controller (Bronkhorst CORI-FILL dosing) — Automatically tracks the target pH. Holds the neutralization point constant even in streams with varying composition

A step that washes the post-reaction mixture with water, removes impurities and leftover reagents, and separates the organic and aqueous phases. The aim is to take out cleanly only the organic phase that contains the product.

In batch, you wait for the two phases to separate in a separatory funnel, but in flow you cannot wait. A membrane is therefore used that passes only the organic phase and repels the aqueous phase.

Because the phases are separated instantly in the flowing stream, even mixtures that emulsify and are hard to separate can be processed continuously without stopping. It is an unglamorous linchpin that supports the entrance to continuous purification.

After the reaction, impurities and leftover reagents are removed by washing with water. In batch, you wait for the two phases to separate in a separatory funnel, but in flow you cannot wait. A membrane is therefore used that passes only the organic phase and repels the aqueous phase, separating the phases instantly in the flowing stream. Even mixtures that emulsify and are hard to separate can be processed continuously without stopping.

Alternatives in practice

• Continuous countercurrent multistage extraction · Karr reciprocating-plate extraction column (Koch Modular) / Rousselet Robatel BXP series centrifugal extractors — For systems with low partition coefficients that need many stages. High throughput but large equipment
• Gravity-settling continuous decanter · Continuous liquid-liquid settler/decanter (CINC V02 centrifugal separator) — Suited to systems with a large density difference and high flow rates. Avoids the risk of membrane clogging
• In-line acid/base scavenger / solid-phase extraction · SiliCycle SiliaBond Propylsulfonic Acid / SiliaBond Carbonate packed cartridges — Captures trace basic/acidic impurities. An alternative for emulsified systems where liquid-liquid separation is difficult

A step that removes metal catalysts such as palladium left over from cross-coupling or hydrogenation within the flow. The product stream is passed through a fixed bed packed with a scavenger.

Residual metal would exceed the API (drug substance) elemental impurity limits (ICH Q3D), so it is always removed. Even trace amounts are toxic and cannot be overlooked.

A cartridge packed with silica that grabs metals with thiol groups and the like is inserted in series in the piping, and a single pass brings the level down to within the specification. This is a labor saving unique to continuous purification.

In metal-catalyzed reactions such as cross-coupling and hydrogenation, residual metal exceeds the API elemental impurity limits (ICH Q3D), so the standard is to pass the product stream through a fixed bed of metal scavenger for continuous removal. In flow, packed cartridges are inserted in series and processed in a single pass.

Alternatives in practice

• Metal capture on a fixed bed of fibrous scavenger · Johnson Matthey Smopex-234 (thiol fiber) / Smopex-111 fixed bed — High flow rate and low pressure drop, suited to large-volume processing. The fibrous form has short diffusion paths and fast capture
• Polystyrene-based thiourea / triamine resin cartridges · Biotage MP-TMT (trimercaptotriazine resin) / PhosphonicS Si-Thiol series resins — An alternative for strongly acidic / HF-based systems where silica is unsuitable. Watch for resin swelling

A step that exchanges the solvent used for the reaction for one suited to the next crystallization and adjusts the concentration. In the original solvent, crystals form with difficulty and do not take the intended crystal form.

The solvent is exchanged using equipment that forms a thin film and evaporates quickly, or continuous distillation, while keeping the heating time short. The point is not to heat for long.

Because it is done in a short time, decomposition is limited even for heat-labile compounds. It sets up, continuously within the flow, the solvent stage on which the success of crystallization depends.

The solvent is exchanged for one suited to the next crystallization, and the concentration is adjusted. In the solvent used for the reaction, crystals may not form readily or may not take the desired crystal form. In flow, the solvent is exchanged with equipment that forms a thin film and evaporates quickly, or with continuous distillation, keeping the heating time short. This limits decomposition of heat-labile compounds.

Alternatives in practice

• Solvent exchange by continuous membrane (organophilic nanofiltration) · Evonik PuraMem / DuraMem series OSN membrane modules — Solvent exchange of heat-labile compounds at low temperature. No evaporation energy is needed, but it depends on the solvent resistance of the membrane
• Falling-film / short-path distillation · Buss-SMS-Canzler falling-film evaporator / UIC KDL short-path distillation unit — For concentrating high-boiling or thermally unstable products. Short residence time keeps the heat load down

A step that takes the dissolved API out as crystals; it is the most important step in determining purity and physical properties. How well it goes here largely decides later dissolution and stability.

Crystal form (polymorph) and size determine dissolution, stability and ease of tableting. So the aim is not simply to solidify the API but to build the intended crystals.

MSMPR is a method in which vessels are connected in series and temperature and residence time are kept constant. Its strength is that uniform particles are produced every time and batch-to-batch variation can be reduced.

This is the most important step, determining purity and physical properties, in which the dissolved API is taken out as crystals. The crystal form (polymorph) and size govern dissolution, stability and ease of tableting. In continuous crystallization, vessels are connected in series or the solution is flowed through narrow tubes, keeping temperature and residence time constant and producing uniform particles every time. Batch-to-batch variation is reduced.

Alternatives in practice

• Plug-flow continuous crystallization (PFC) · NiTech DN15/DN6 continuous oscillatory baffled crystallizer (COBC) — Narrow RTD gives a uniform crystal size distribution. Excellent reproducibility of particle size on scale-up
• Batch cooling / antisolvent crystallization (control) · Mettler Toledo OptiMax 1001 + EasySampling, ParticleTrack E25 (FBRM) — For initial exploration of polymorph and particle size, and as a control. Used to establish conditions before moving to continuous
• Ultrasound-assisted continuous crystallization (sonocrystallization) · Hielscher UIP1000hdT ultrasonic processor + flow cell — Promotes primary nucleation to obtain fine, uniform crystals. Effective for eliminating seeding and suppressing agglomeration

A solid-liquid separation step that removes the mother liquor from the crystal slurry, washes out the remaining impurities, and dries off the solvent left in the crystals. It finishes the crystals into a "usable solid."

A large amount of residual solvent causes problems for safety and stability. That is why three stages are needed: filtration to remove the liquid, washing to flush out mother-liquor impurities, and drying to drive off the solvent.

In continuous mode, rotary filters or carousel-type units that perform filtration, washing and drying in a single machine are used to take out the crystals within the flow without interruption.

The liquid is removed from the crystal slurry, impurities left in the mother liquor are washed out, and the solvent remaining in the crystals is dried off. A large amount of residual solvent causes problems for safety and stability. In continuous mode, rotary filters or carousels that perform filtration, washing and drying in a single unit are used to take out the crystals continuously within the flow.

Alternatives in practice

• Solid-liquid separation by continuous centrifugation · Rousselet Robatel continuous peeler centrifuge / Ferrum continuous decanter centrifuge — For deliquoring highly wet cakes and fine-particle slurries. Avoids filter media clogging and gives high throughput
• Continuous drying (fluidized bed / conductive) · Glatt GPCG fluidized bed dryer (continuous mode) / Buss-SMS-Canzler contact thin-film dryer — A stand-alone drying step after filtration. Conductive drying allows lower temperature and shorter time for heat-labile crystals

An identification step that confirms at the molecular level that the substance obtained really is the target API. Mistaking a different compound or an isomer would be fatal, so it is done rigorously.

Nuclear magnetic resonance (NMR) reads the arrangement of hydrogens and carbons and supports the molecular skeleton. It is the work of checking that the molecule has been assembled according to the blueprint.

High-resolution mass spectrometry then pins down the molecular weight as well. By establishing the structure from both skeleton and mass, no doubt is left about its validity.

This confirms at the molecular level that the substance obtained really is the target API. Mistaking a different compound or an isomer would be fatal. Nuclear magnetic resonance (NMR) reads the arrangement of hydrogens and carbons and supports the molecular skeleton. Together with mass spectrometry, the molecular weight is also confirmed and the structure is established.

Alternatives in practice

• Single-crystal X-ray structure analysis (determination of absolute configuration) · Rigaku XtaLAB Synergy / Bruker D8 VENTURE (PHOTON III detector, Cu/Mo sources) — Determines configuration and crystal structure unambiguously. Requires a good-quality single crystal
• Functional group confirmation and identification by FTIR/Raman · Thermo Nicolet iS50 FTIR (ATR) / Bruker MultiRAM Raman — Functional group identification and comparison with the reference standard. Rapid, as a complement to NMR/MS
• Optical rotation / specific rotation measurement · Anton Paar MCP 5300 / Rudolph Autopol VI polarimeter — Simple confirmation of identity and purity of optically active compounds. A qualitative indicator of chirality

A step that measures how much of the target API the product contains (content) and how much impurity such as by-products it contains (related substances).

Content bears directly on efficacy and impurities on safety. Covering both in a single test determines whether the product conforms to the specification.

The basic approach is to separate the components one by one by reversed-phase HPLC and measure the amounts by UV detection. It confirms that no impurity exceeds the specification and supports the release decision.

This measures how much of the target API the product contains (content) and how much impurity such as by-products it contains (related substances). Content bears directly on efficacy and impurities on safety. The basic approach is to separate the components by reversed-phase HPLC and measure the amounts by UV detection, confirming that no impurity exceeds the specification.

Alternatives in practice

• Identification and quantitation of trace impurities by LC-MS/MS · Sciex Triple Quad 7500 / Agilent 6470 LC-TQ / Waters Xevo TQ-XS — Structural assignment and high-sensitivity quantitation of trace related substances not adequately separated by UV
• Charged aerosol detection (CAD) / ELSD · Thermo Vanquish Charged Aerosol Detector / Agilent 1290 Infinity II ELSD — General-purpose quantitation of compounds without chromophores, counterions and excipients
• Optical purity by chiral HPLC/SFC · Waters ACQUITY UPC2 (SFC) + Daicel CHIRALPAK IG/IC columns — Confirmation of enantiomeric excess (linked to step 12). For optical isomers that cannot be separated by reversed phase

A step indispensable for chiral drug substances. It controls how little of the unwanted side is mixed in among molecules (enantiomers) that are mirror images of each other, like a right hand and a left hand.

Enantiomers can have completely opposite efficacy or safety, so ICH Q6A and the FDA chiral policy require that a purity specification be set.

Both enantiomers are separated and quantitated by HPLC with a polysaccharide-based chiral column, and the ee (enantiomeric excess) is kept within the specification in release testing. It is the guardian of optical purity.

For chiral drug substances, ICH Q6A and the FDA chiral policy require that a specification for enantiomeric purity be set and controlled. The standard step is to separate and quantitate the unwanted enantiomer by chiral-column HPLC and confirm the ee (enantiomeric excess) in release testing.

Alternatives in practice

• Chiral SFC (supercritical fluid chromatography) · Waters ACQUITY UPC2 / Agilent 1260 Infinity II SFC + Daicel CHIRALPAK IG-3/IC-3 — CO2-based, fast, high resolution and low solvent use. Easy to extend to preparative scale
• Separation and quantitation of volatile enantiomers by chiral GC · Agilent 8890 GC + Agilent CP-Chirasil-Dex CB (cyclodextrin) column — For enantiomers that are volatile or can be derivatized. Effective for small molecules that are difficult to separate by HPLC

A step that controls impurities that can damage genes and may cause cancer even in very small amounts down to extremely low levels.

Since the NDMA contamination problem with the antihypertensive valsartan, nitrosamines in particular have come under strict scrutiny. Caution is required in flow synthesis that uses hazardous reagents.

Mutagenic impurities formed as by-products are reliably detected by high-sensitivity mass spectrometry at the ppb (parts per billion) level. What counts is the sensitivity to catch amounts too small to see.

Impurities that can damage genes and may cause cancer even in very small amounts are controlled down to extremely low levels. Since the NDMA contamination problem with valsartan, nitrosamines in particular have come under strict scrutiny. Flow synthesis often involves reactions that use hazardous reagents, so mutagenic impurities formed as by-products are reliably detected by ppb-level high-sensitivity mass spectrometry.

Alternatives in practice

• Volatile mutagens (alkyl halides, etc.) by headspace GC-MS · Agilent 8890 GC + 7697A headspace sampler + 5977B MSD — High-sensitivity screening of volatile alkylating agents. Avoids matrix interference
• Screening by high-resolution MS (Orbitrap) · Thermo Orbitrap Exploris 240 (full-scan high resolution) — Comprehensive search for unknown mutagens and estimation of molecular formula. Target-independent detection
• Mutagenicity prediction by (in silico) structure-activity relationship · Lhasa Derek Nexus / Instem Leadscope (ICH M7 (Q)SAR) — Prioritization and classification before measurement. For narrowing down the impurities to be tested

A step that measures the amount of organic solvent left in the crystals and confirms that it is within a safe range. Some solvents are toxic or carcinogenic and cannot be overlooked.

Upper limits are set by class in ICH Q3C and elsewhere, and it must be shown that they are not exceeded. It also serves as a check on whether drying was sufficient.

Headspace GC, which heats the solid and takes in the components that vaporize, separates and quantitates the volatile solvents in one run. It also supports the adequacy of the drying step.

This measures the amount of organic solvent left in the crystals and confirms that it is within a safe range. Some solvents are toxic or carcinogenic, and upper limits are set by class. Headspace GC, which heats the solid and takes in the components that vaporize, separates and quantitates the volatile solvents in one run. It also supports the adequacy of the drying step.

Alternatives in practice

• Identification confirmation by headspace GC-MS · Agilent 8890 GC + 7697A HS + 5977B MSD / Shimadzu HS-20 + GCMS-QP2020 NX — Identification of unknown peaks and co-eluting solvents. Verifies misassignments by FID
• Direct-injection GC (nonvolatile / high-boiling solvents) · Agilent 8890 GC (split/splitless injection) + FID — Quantitation of high-boiling solvents that partition poorly into the headspace (DMSO, NMP, etc.)
• Residual solvent screening by 1H-NMR · Bruker AVANCE NEO 400 MHz / Magritek Spinsolve 80 — Simple, with little sample preparation. Semi-quantitates multiple solvents at once. Inferior to GC-HS in the trace range

A step that confirms which crystal form (polymorph) the API is in. Even for the same molecule, a different arrangement of the crystal changes its properties as if it were a different substance.

A different arrangement changes solubility and stability, affecting efficacy and shelf life. That is why checking that the intended form has been produced is indispensable.

X-ray powder diffraction returns a "fingerprint" pattern unique to each crystal. It can tell at a glance whether the intended polymorph has been produced and whether another form is mixed in.

This confirms which crystal form (polymorph) the API is in. Even for the same molecule, a different arrangement of the crystal changes solubility and stability, which affects efficacy and shelf life. X-ray powder diffraction gives a fingerprint-like pattern of the crystal and determines whether the intended polymorph has been produced and whether another form is mixed in.

Alternatives in practice

• Differential scanning calorimetry (DSC) / thermogravimetric analysis (TGA) · TA Instruments Discovery DSC 2500 / TGA 5500, Mettler Toledo DSC 3+ — Thermal behavior of melting point, polymorphic transition and desolvation. Used together with XRPD to distinguish hydrates/solvates
• Dynamic vapor sorption (DVS) · Surface Measurement Systems DVS Intrinsic / TA Instruments Q5000 SA — Evaluation of hygroscopicity, hydrate formation and deliquescence. Humidity-dependent stability of polymorphs
• Solid form confirmation by Raman / solid-state NMR (ssNMR) · Bruker MultiRAM Raman / Bruker AVANCE NEO 400 ssNMR (CP/MAS) — Evaluation of the local environment of the crystal structure and amorphous content. Complements the XRPD amorphous halo

A step that measures the spread in size and the shape of the crystal particles. How fine the particles are affects both drug performance and ease of manufacture.

Particle size governs solubility (absorption) and also determines how easily the material flows and mixes in later formulation steps. Particles that are too small or too large are both hard to handle.

Laser diffraction measures the size distribution of the particles in one run and confirms that crystallization reproduces the intended particle size. It is an indicator that supports the stability of continuous crystallization.

This measures the spread in size and the shape of the crystal particles. Particle size governs solubility (absorption) and how easily the material flows and mixes in the later formulation steps. Laser diffraction measures the size distribution of the particles in one run and confirms that crystallization reproduces the intended particle size. It is an important indicator that supports the stability of continuous crystallization.

Alternatives in practice

• Particle size and shape by image analysis (dynamic/static) · Malvern Panalytical Morphologi 4 / Sympatec QICPIC (dynamic image analysis) — Also provides individual particle shape and aspect ratio. Strong for distinguishing needles and agglomerates
• In-line FBRM (chord length distribution) · Mettler Toledo ParticleTrack G400 (FBRM) — Real-time in-process monitoring. Tracks the trend of particle size change during crystallization
• Sieving (coarse particles) · Retsch AS 200 vibratory sieve shaker + test sieves (JIS/ASTM standard sieves) — Simple particle size check for coarse particles and agglomerates. Low cost but not applicable to fines

A step that measures whether metal catalysts such as the palladium used in the reaction, or heavy metals that dissolved out of the equipment, remain in the product. They are toxic even in trace amounts and are therefore controlled.

It is especially important in flow synthesis, which makes heavy use of metal catalysts. It shows that the product is within the specification, against ICH Q3D, which sets upper limits for elemental impurities.

The sample is dissolved in acid and atomized in a plasma, and ICP-MS (mass spectrometry) quantitates each element in one run with high sensitivity. It is also the final confirmation of the effect of scavenger removal.

This measures whether metal catalysts such as the palladium used in the reaction, or heavy metals derived from the equipment, remain in the product. They are toxic even in trace amounts, and upper limits are set. It is especially important because flow synthesis makes heavy use of metal catalysts. The sample is dissolved in acid and atomized in a plasma, and mass spectrometry quantitates each element in one run with high sensitivity.

Alternatives in practice

• Elemental analysis by ICP-OES (optical emission spectrometry) · Agilent 5800/5900 ICP-OES / PerkinElmer Avio 560 — For relatively high-concentration elements and high-matrix samples. More robust and less prone to interference than ICP-MS
• Atomic absorption spectrometry (AAS) · Agilent 240/280 FS AA / PerkinElmer PinAAcle 900 (flame / graphite furnace) — Targeted quantitation of a single element or specific metal (residual catalyst Pd, etc.). Low cost
• On-line/in-line control of residual catalyst + scavenging verification · Confirmation by step 6 SiliCycle SiliaMetS scavenger + outlet ICP-MS (Agilent 7900) — Assures metal removal performance within the process. Preventive control that lowers the burden on final ICP-MS

A step that measures how much water the product contains. Water affects stability, the judgment of whether the material is a hydrate, and the basis of the content calculation, so it is pinned down accurately.

The Karl Fischer method uses a reagent that reacts only with water and quantitates water selectively and with high sensitivity. Its strength is that it can single out and measure only the water.

From this result it is confirmed whether the drying step was sufficient and whether the product is within the specification. It is one of the checks that close out the quality of the final solid.

This measures how much water the product contains. Water affects stability, the judgment of whether the material is a hydrate, and the content calculation. The Karl Fischer method uses a reagent that reacts only with water and quantitates water selectively and with high sensitivity. It supports that the drying step was sufficient and that the result is within the specification.

Alternatives in practice

• Loss on drying (LOD) · Mettler Toledo HE73/HC103 halogen moisture analyzer / constant-temperature dryer + analytical balance (Mettler Toledo XPR) — Simple evaluation of total volatiles. Does not distinguish water from other volatiles but is routine in GMP
• Thermogravimetric evaluation of water and volatiles by TGA · TA Instruments Discovery TGA 5500 / Mettler Toledo TGA/DSC 3+ — Distinguishes hydrate water / adsorbed water / solvent from the dehydration temperature range. Used with XRPD/DSC to determine the form