SubscribeSolvias launches its first full-scale HTS Screening Service for asymmetric homogeneous hydrogenation.
Abstract
The fully automated system utilizes standard 96-well plates combined with analysis by Supercritical Fluid Chromatography (SFC), HPLC, and GC. This new system guarantees rapid screening of ligands, metals, additives and reaction conditions in up to 200 experiments per day.
The instrument is designed to handle all industrially relevant conditions including pressures up to 100 bar (1400 psi). The fully integrated solution was designed in conjunction with Symyx Technologies, Inc., and has been specially adapted for Solvias Homo-geneous Catalysis Services. Our customers will benefit from:
- Rapid identification of the optimum catalyst system resulting from the screening of approx. 700 chiral ligands representing the current state of the art for chemocatalysis including Solvias proprietary ligands (over 60 %) as well as patent-free and other proprietary ligands (40 %).
- High degree of confidence that all important leads have been found.
- Results can be obtained using less starting material. Due to the low reaction volumes used by the system, extended screenings for process optimization can now be performed using very small amounts of starting material (as little as 3 g) and can typically be completed in 5-8 working days.
- Identification of novel reactions. For targets that are known to be extremely difficult to convert or have never previously been selectively hydrogenated, HTS allows to broadly screen previously untried reactions to find useful conditions.
- Fast tuning of ligand structure. Due to themodularity of Solvias chiral ligands, rapid ligand tuning from screening hits is assured.
The Solvias HTS Screening Service is not limited to catalytic hydrogenation. The instrument will also perform CX-coupling reactions. In addition, it is designed to handle carbon monoxide. This capability will allow Solvias to expand its services to include HTS screening for carbonylation and hydroformylation reactions as well as CX-coupling chemistry. Solvias projects to add these screening services by Q4, 2006.
Solvias High Throughput Catalysis Screening Platform by Symyx
Screening Modules: Designed to Meet Your Needs!
The screening modules listed below are now available for custom screening. These modules are flexibly designed to accommodate the needs of our customers and are based on more than 20 years of experience successfully implementing asymmetric homogeneous hydrogenation processes from laboratory to production scale.
96-well plate pressure reactor
Two general screening situations exist:
1) Customer target with known precedence for successful asymmetric hydrogenation (either at Solvias or in the literature) for a similar prochiral substructure (includes similar substitution patterns, functional groups, etc.).
Experimental design primarily based upon previous experience with related substrates. Multi-plate screening modules typically are run in an iterative fashion to ensure that findings from earlier screening plate(s) will be incorporated in the next plate(s). Several screening packages are available (Table 1).
The following Solvias' Screening Modules are available:
"Initial" Screening Module
Entry level screening. Determination if target can be successfully hydrogenated by applying a predefined set of conditions (all relevant metals, key ligand chelation types, focused set of reaction conditions). The results are predictive in nature. Due to the limited number of experiments employed, the catalyst system identified for the investigated target typically will require further optimization in a later module.
"Standard" Screening Module
Two iterative screening plates are run, resulting in leads that are readily amenable to small-scale production. Limited additional development effort is required. Typically, this level of screening is utilized for substrates where a reasonable level of precedence exists, either at Solvias or in the literature.
"Extended" Screening Module
Substrates are screened using 4-5 iterative plates, thus refining leads to the point where the catalyst system(s) identified are suitable for use in larger-scale production processes. Typically, sterics and electronics for a given ligand system, as well as key additives, solvent choices, and important reaction conditions have been pre-examined with HTS. Leads from the Extended Screening Module are suitable candidates for the catalysis process development program (see below).
"Comprehensive" Screening Module
Full HTS-based optimization of important leads identified during the initial 2-4 plates. Maximum level of confidence that ideal catalyst and corresponding reaction system (additives, pressure, temperature, solvent, etc.) have been found and optimized for desired transformation.
Systems identified during the Comprehensive Screening Module are ideal candidates for further catalytic process development (optimisation, fine tuning, quality risk and risk analysis) directly in larger, non-HTS equipment.
Solvias' extensive ligand library
| Module | |||||
|---|---|---|---|---|---|
| Initial | Standard | Extended | Comprehensive | Options | |
| Time | 1 week | 1 week | 2-3 weeks | 3-5 weeks | |
 | |||||
| Substrate Quantity | 2.5-4 g | 3-6 g | 6-9 g | 8-15 g | |
| Activities Prior to Screening | Transfer of analytical method(s), adaption to HTS Scouting exp. (activity, conversion) | Transfer of analytical method(s), adaption to HTS Scouting exp. (activity, conversion) | Transfer of analytical method(s), adaption to HTS Scouting exp. (activity, conversion) | Transfer of analytical method(s), adaption to HTS Scouting exp. (activity, conversion) | ● Development of analytical method(s) ● Synthesis of starting material ● Purification of starting material ● Synthesis of reference products (i. e. racemate) |
Primary Screening 96 experiments (1 plate) | Inital screening (max. 4 MP/16 KL) 1 validation exp. (ca. 0.2 g scale in 50 ml LAK) | Initial screening (max. 4 MP/16 KL) | Initial screening (max. 4 MP/16 KL) | Initial screening (max. 4 MP/16 KL) | ● Additional validation exp. on 1-5 g scale ● Manufacturing of 5-100 g of product using optimum catalyst system |
| Secondary Screening 192 experiments (2 plates) | Iterative screening Validation exp. (0.5 g scale) in 50 ml LAK | Iterative screening (1-6 MP/KL, HPL and LPL; 1-3 solvents/additives) | Iterative screening (1-6 MP/KL, HPL and LPL; 1-3 solvents/additives) | ● Intellectual property support for patenting ● Quality-risk analysis ● Extended optimization with DoE of selected catalyst system, non-HTS ● Additional validation exp. on 1-5 g scale | |
| Ligand and Catalyst Optimisation 288-384 experiments (3-4 plates) | Extended screening 2nd and 3rd iterative screening ● Optimisation of ligand structure (KL, HPL, LPL) ● Variation/ optimisation of additives and solvents ● Variation of p and T, ton (s/c) ● Validation exp. (0.5 g scale) | Extended screening 2nd and 3rd iterative screening ● Optimisation of ligand structure (KL, HPL, LPL) ● Variation/ optimisation of additives and solvents ● Variation of p and T, ton (s/c) | ● Catalysis process development program for resulting leads ● Additional validation exp. on 1-5 g scale ● Metal removal support | ||
| HTS-based Catalysis Process Optimisation 480 experiments (>5 plates) | Additional screening. ● Extensive screening for poorly precedented targets ● Systematic study of impact of selected parameters ● Extended parameter optimisation on mol scale ● Validation exp. (0.5 g scale) | ● Catalysis process development program for resulting leads ● Additional validation exp. on 1-5 g scale ● Metal removal support | |||
| Deliverables by Solvias | Experimental assessment of chemical feasibility: Identification of preliminary leads Recommendations for further system tuning | Reliable assessment of achieving customer specifications: Identification of promising leads Recommendations for next stage development and scale-up | ● Extensive assessment of all relevant catalysts ● Identification of best lead ● Ranking of catalyst / ligand systems based on customer requirements ● Realistic forecast of process development effort required ● Determination of economic benefit for selected catalyst system(s) | ● Full exploration of experimental data ● Identification of best lead ● Ranking of catalyst / ligand systems based on customer requirements ● Realistic forecast of process development effort required ● Determination of economic benefit for selected catalyst system(s) | |
Explanations
KL (Key Ligands) Solvias, third party owned and patent free ligands (2006: approx. 55 ligands), often selected ligands, privileged systems with broad scope
HPL (High Priority Ligands) Solvias, third party owned and patent free ligands (2006: approx. 200 ligands), frequently selected ligands
LPL (Low Priority Ligands) Solvias, third party owned and patent free ligands (2006: approx. 400 ligands), rarely chosen ligands, new ligands, systems with narrow scope
MP Metal precursor (Ru, Ir, Rh, (Pd, Pt) based)
LAK Laboratory autoclave (non-HTS)
Ligand Library > 700 chiral ligands, 65 % Solvias owned, 25 % third party ligands, 10 % patent free ligands
Client Provided Materials Ideally: High purity substrate with low halogen content (i. e. Cl- ions); solubility data of starting material in various solvents; analytical method(s) for conversion and selectivity; reference samples to spike analytics; toxicity data for starting material and product, if available.
2) Customer target without known precedence for successful asymmetric hydrogenation.
Preliminary screening using a wide variety of catalyst systems to broadly examine the experimental space followed by 1-2 iterative screening plate(s) to further investigate potential leads. The experimental design is "random" in nature to ensure the maximum likelihood of identifying an acceptable solution (see Table 2).
"Investigative" Screening Module: A series of 5-7 plates are run incorporating a "random" experimental design to fully explore the experimental space. This is followed by 1-2 iterative plates where the resulting leads are further optimized.
If preferred, a more custom designed, iterative mode is also offered for these challenging tar-gets, starting with an Initial Screening Module. Upon approval by the client, more plates can be added to further explore the experimental space in a more stepwise manner.
In cases where the analytical method (typically chiral HPLC) or analytical standards cannot be provided by the client, Solvias can develop or prepare them prior to screening. Substrate purity is often key to achieving a favorable result. Solvias can also perform any necessary substrate purification prior to screening (i.e. scavenger treatment, charcoal treatment, crystallization, precipitation, and column chromatography on gram to kilogram scale).
| Module | No. of Experiments | Time | Scope of Work | Substrate | Required Deliverables |
|---|---|---|---|---|---|
| "Investigative" Screening Module | 672-960 experiments (7-10 plates) | 3-5 weeks | ● Full exploration of experimental space ● All metals, ligand classes, solvents, additives and conditions (p,T) are screened; maximum diversity screen ● Large degree of "random" - screening followed by 1-2 plates of iterativescreening of new leads | 8-15 g depending on m. w. | ● Broadest experimental assessment of chemical feasibility including description of best results obtained ● Identification, verification and initial optimisation of identified leads ● Information on scope of any novel transformations ● Recommendations for further system tuning |
Integration of HTS into Solvias Catalysis Process Development Strategy
In the last 2 years, catalytic asymmetric hydrogenation has become accepted as a reliable and scalable synthesis tool in the chemical industry. It is an acknowledged statement that enantiopure molecules can be efficiently produced by this technology. Thanks to this growing acceptance of asymmetric hydrogenation in early stage development of pharmaceutical intermediates and products, companies both large and small are investigating the use of homogeneous catalysis1 and have significantly expanded the number of targets to be evaluated.
The increased demand for screening services combined with the rapid expansion of Solvias' ligand portfolio resulted in the decision to invest in a true HTS system. High through-put screening is essential to provide faster, more comprehensive answers for Solvias' customers while consuming less starting material during the screen since substrate availability is a key constraint in early stage drug development. Also, novel prochiral targets that lack any experimental precedence for successful asymmetric hydrogenation can be investigated efficiently using HTS.
The integration of true HTS into Solvias' Catalysis Services significantly expands the developmental capability and capacity of the catalysis team and its infrastructure as the need for rapid catalysis development, optimization, scale-up and material production has dramatically grown. Early stage targets are typically on very tight developmental timelines and the ability of Solvias to respond to our customers quickly and cost-effectively is key to the success of our catalysis services program.
What additional services can Solvias pro-vide following a successful Catalysis HTS Screening?
After the screening program has been completed the following services are available for fast optimization of reaction conditions and subsequent quality/risk assessment.
Optimisation: The optimization of reaction conditions is typically carried out using semi-automated parallel autoclaves (up to 24 reactions) with 8 ml reaction volume. These can be performed under high pressure using a variety of conditions (> 100 bar).
Super Critical Fluid Chromatography, the solution for debottlenecking the analytical throughput
Fine Tuning, Quality Risk and Risk Analysis
Twenty-four 50 ml reactors permit very accurate fine tuning (reaction kinetics) using only 1 mmol of substrate per reaction. These can be performed under high pressure using a variety of conditions (> 100 bar, various alloys). DSC and pressure RC-1 are available to carry out the risk analysis. Specifications for starting materials, catalyst, solvents additives and gases are defined.
- Scale-up and Proof of Concept: A large selection of autoclaves (sizes, alloys, stirrer type, etc.) are available ranging from 100 ml to 50 l. Sequential scale up of the catalysis process permits accurate projection of performance and yields during production.
These experiments will also provide the customer with significant amounts of material for use in their development program (multi-kg quantities). Solvias' scale-up investigations are specifically designed, executed and fully documented to ensure smooth and trouble-free technology transfer to the targeted production facilities. Full consideration is given to the customer's available equipment and expertise. - Kilo-scale Production: High-pressure reactors with volumes of 8 l, 16 l and 50 l are available for the timely production of multi-kg quantities.
Conclusions
High throughput screening technology (HTS) is essential to fully exploit the power of asymmetric homogeneous catalysis in the production of enantiopure products. HTS also gives the highest possible assurance that potential catalyst hits are not missed. In early stage drug development, the time and material savings are critical advantages over conventional screening techniques.
The addition of HTS will allow Solvias to realize the full potential of its catalysis development program. Solvias has designed different levels of HTS-based catalysis screening to efficiently identify catalyst hits for a given target, including the evaluation of atypical hydrogenation substrates.
Once the initial screen has been completed, leads can be further optimized to identify preferred reaction conditions, followed by scale-up to verify the performance of the process prior to technology transfer. Multi-kilogram quantities of product can be efficiently produced at Solvias to support early stage drug development requirements. Solvias has many years of scale-up and manufacturing experience (> 40 pilot scale processes developed, > 20 production scale processes introduced) and works closely with customers and their CMOs to adapt the process for large scale manufacturing.
Reference
1 Marc Thommen, "Homogeneous asymmetric hydrogenation: Mature and fit for early stage drug development",Spec. Chem. Magazine 2005, May Issue.