"Making drugs is neither easy nor cheap – but catalysts, flow chemistry and a knowledge of intermolecular interactions can help."
Active pharmaceutical ingredients (APIs) are inherently complex, and synthesis can require multiple, diverse reaction steps. Strict regulation surrounds API development, such as restricting levels of impurities - making product isolation and purification high priorities. This leads to lengthy or multi-step manufacturing processes and loss of efficiency. In practice, the process of streamlining drug development is challenging. But processes can be accelerated by applying technological innovation from early concept to optimising formulation.
Advanced catalytic activity
The first task in any drug development process is the API synthesis. APIs are complex structures, typically containing multiple chiral centres, and synthesis requires many precise stereoselective reactions. The tasks of finding the shortest, most efficient reaction pathway requires chemical innovation and creativity. And this is where our strength in catalysis plays an important role.
Many pharmaceutical compounds contain chiral centres. Cipralex (left) is an antidepressant and Levofloxacin (right) is an antibiotic defined by the WHO as an essential medicine.
In chemistry, many different reactions can lead to the same structure. This presents various opportunities to implement catalysis into any API development process. Specific catalysts are stereoselective and are often able to react at selected reaction sites, reducing the prospect of unwanted side reactions. Careful catalyst choice could reduce multiple reaction steps to a single, stereoselective step, avoiding the need for separation. We use modelling and knowledge of reaction mechanisms to determine the right reactions for the most effective production of the API.
Experimental catalysis screening can be used to optimise the production process, commonly involving specific catalyst kits. By choosing the right process, involving the most up-to-date, innovative chemistry to synthese the right molecule, unnecessary delays can be prevented.
Combining technologies with collaborations
It can be challenging to scale up processes that work on a laboratory scale but these can be overcome through collaborations and the sharing of scientific expertise. We work closely with our customers to make sure the reaction process and catalysts are right for them.
For example, continuous flow reactions can improve API manufacture. One recent process development we worked on through a collaborative development agreement with Snapdragon Chemistry Inc involved the integration of continuous reaction pathways into API synthesis.
Continuous reaction processes work by applying a constant flow of raw reagents while simultaneously removing products. The advantage of these methodologies is, little production downtime and shortening the API production process. In fact, it is possible that a month-long batch process could be shortened to just a single day using continuous manufacture technology and continually removing the API product reduces the opportunities for unwanted side-reactions to occur, whilst continuous product purification and isolation can also be integrated, further accelerating the synthetic process.
Selecting the appropriate solid form
Following API synthesis, the next task is addressing how the drug is administered. Molecules can have different solid forms, a term that incorporates a molecule’s potential crystalline and amorphous structures. Most drugs are crystalline, and combinations of the API with various guests – such as solvent or other salt crystals - can exist in multiple orientations.
Even aspirin comes in a range of polymorphs, which must be controlled for the final tablet.
We have expertise in developing optimal polymorphs, salt forms, crystal morphology and controlled particles through our knowhow in solid form sciences. We offer one of the broadest and most reliable services to ensure effective identification, development and manufacture of your drug candidates and commercial products.
Understanding the molecular solid form enables physiochemical properties such as solubility, stability and bioavailability to be investigated. Due to the wide variety of possible formulation combinations, the appropriate form will depend on the method of drug administration. Properties of oral formulations will need to be fundamentally different to an intravenous formulation.
API’s solid form can be manipulated to fine-tune the desired physiochemical properties. To achieve this, two properties of the API are commonly changed in the development process: co-crystallisation and selecting an appropriate salt form. However, solid form manipulation must be performed on a case-by-case basis. What works for one oral formulation is not always guaranteed to work for other formulations.
Developing a different co-crystal of the API will alter the solid form due to the involvement of different intermolecular interactions. Co-crystal screening is needed owing to the inherent unpredictability entailed by different combinations of co-crystals.
Most drugs available on the market exist as salts which necessitate synthesis with an appropriate counter-ion. Changing this counter-ion allows for the optimisation of the physiochemical properties needed for the specific formulation. We can screen various counter-ions can optimise this process.
Different solid forms must be frequently characterised throughout the development process to determine whether the formulation conforms to the desired physical or chemical properties. Characterisation methods typically employed include: x-ray powder diffraction, which identifies the crystalline form of the drug; infra-red, nuclear magnetic resonance and Raman spectroscopic techniques, which are used to measure intermolecular interactions; and finally, other methods can measure properties including melting points, phase transformations and solubility.
Looking to the future
Reducing the number of synthetic stages, rapidly identifying the relevant physical forms of the product and making it stable in a bioavailable, formulated form all help to accelerate the time to develop and deliver the drug to the patient. It is fundamental to ensure product quality is held to the highest standard and is focused on delivering effective, timely patient care.