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The efficiency and breadth of HTE make the technique more effective than standard approaches during discovery and early development. In some cases, traditional chemistry can be iterative. The results from one experiment inform the design of the next until the optimal reaction conditions are found. This approach slows the drug development process.
HTE enables teams to survey a much larger amount of design space in a shorter period of time. Companies can use HTE to find potential hits and start optimizing the reaction conditions in a second, more-focused screen in less time when compared to iterative methodologies.
Performing experiments at very small scales allows researchers to generate a larger data set from limited amounts of starting materials. For example, a chemist with just 48mg of starting material can execute 24 distinct experiments on a microwell plate at a 2mg scale, which maximizes the use of available material while, at the same time, reducing reagent and catalyst requirements.
Running tens of small-scale experiments in parallel yields rich datasets that facilitates informed decision making about the next steps for further optimization. By maximizing the early understanding of reactions, this technique overcomes the limitations scientists face in discovery and early development by providing a fundamental understanding of critical reaction parameters before moving to larger scales.
The plates, pipettes, spatulas, and other hardware needed to perform HTE are widely available. However, the knowledge and analytical methods that are critical to the effective design, execution, and analysis of HTE experiments are less so.
Subject matter expertise is critically needed to design and optimize synthetic protocols using HTE and to ensure the data generated can be used to inform next steps. Also, after completing a panel of experiments, investigators need robust analytical methods to efficiently generate vast amounts of reliable data, which can drive the crafting of a strategic plan.
Piramal Pharma Solutions has proven its mastery of HTE across multiple projects. Next, we look at three examples of how Piramal used the technique to overcome some of the challenges its customers have faced during discovery and early development.
A customer that was struggling to efficiently produce an API enlisted Piramal to develop a drug substance process within two months. The Piramal team zeroed in on a transformation that was generating a regioisomeric impurity at 25% during a key step. To improve the drug substance purity and yield, the group needed to quickly develop conditions to reduce the formation of the impurity.
Piramal used a 100-experiment plate to quickly assess many solvents and bases. In this example, the experiments proceeded overnight, and the scientist arrived the next morning to completed reactions that were ready for analysis.
These experiments produced some products with regioisomeric impurity levels of 1% or less. Piramal then advanced the most promising reactions into a second HTE to further refine critical parameters, optimize the conversion, and both understand and control impurity generation. The two-stage HTE process
was executed over a two-week period from inception to completion, compared to potentially up to three months if traditional methods were employed. This allowed Piramal to adhere to the client's tight deadline for producing the API.
On another project, Piramal used HTE to identify an optimized synthetic protocol for a C-N coupling reaction. First, the team screened a variety of ligands, which produced two hits. Piramal then included the two ligands in another HTE that evaluated different copper sources where a reaction with an initial yield of 20% was increased to 62%.
Using HTE, Piramal quickly found the most promising conditions for the C-N coupling reaction. The fast turnaround enabled the team to move forward with replicating the reaction on a larger scale and confirm the reproducibility of the process.
Piramal faced two challenges when approaching a C-C coupling procedure. First, the reaction was not previously reported in the literature. Second, only a small quantity of starting material was available. These challenges required Piramal's researchers to maximize the data and insights generated from every milligram of available material.
The team was able to run 24 experiments at 2mg scale and found reaction conditions that yielded the product in an acceptable yield and purity. Through the HTE, Piramal discovered a procedure, with a 40% yield, that could be further optimized and developed. The success of the project showed the power of a well-designed and executed experimental protocol to uncover promising reaction conditions using minimal material quantities.
The case studies described above validate the power of HTE for accelerating R&D, optimizing processes, conserving materials, and streamlining resources. HTE's strengths make the approach a perfect fit for discovery and early development. To efficiently lay the foundation for success at later stages of development, companies are performing HTE to quickly identify and optimize reactions using limited amounts of starting materials. Piramal has a track record of using its subject matter expertise and rapid, reliable analytical method development capabilities to design, perform, and analyze HTE reaction sequences, which positions client projects for success. Companies that partner with Piramal can secure a source of process data to inform their R&D decisions and accelerate the progress of life-changing therapies to the patients who need them.
For more information contact:
Narendra Ambhaikar, Ph.D.
Head - API R&D
narendra.ambhaikar@piramal.com
John Riley, Ph.D.
Director, North America API Technical Support
Advancing Organic Chemistry Using High-Through-put Experimentation
Flow chemistry as a tool for high throughput exper-imentation
Piramal Pharma Solutions (PPS) is a Contract Development and Manufacturing Organization (CDMO) offering end-to-end development and manufacturing solutions across the drug life cycle. We serve our customers through a globally integrated network of facilities in North America, Europe, and Asia. This enables us to offer a comprehensive range of services including drug discovery solutions, process and pharmaceutical development services, clinical trial supplies, commercial supply of APIs, and finished dosage forms. We also offer specialized services such as the development and manufacture of highly potent APIs, antibody-drug conjugations, sterile fill/finish, peptide products and services, and potent solid oral drug products. PPS also offers development and manufacturing services for biologics including vaccines and gene therapies, made possible through Piramal Pharma Limited's associate company, Yapan Bio Private Limited.
