Back to News

Why Chemistry Still Matters: The Heart of Successful CRDMO Execution

The development of small molecule drugs relies heavily on chemistry. As these compounds progress from discovery through preclinical studies, clinical trials to commercial manufacturing, chemistry enables the rational design, optimization, and control of every step in the development lifecycle.

Jayadeva Sajankila, Vice President – Operations, Aragen Lifesciences emphasizes about how chemistry plays an role in enabling Contract Research, Development and Manufacturing Organizations (CRDMOs) to transform molecular entities into effective therapeutics.

Despite advances in automation, regulatory sciences, and digital technologies, chemistry remains a core scientific discipline enabling Contract Research, Development and Manufacturing Organizations (CRDMOs) to transform molecular entities into effective therapeutics.” The CRDMOs provide services from route design to final dosage form manufacture, with chemistry expertise informing every decision, from synthetic pathway selection to impurity
clearance.

Reaction Mechanisms and Kinetics: Enabling Predictability and Control

Comprehending reaction mechanisms and kinetics is fundamental to successful API development. A reaction
mechanism details the transformation of reactants into products, allowing chemists to anticipate side reactions, control stereochemistry, and select reagents and catalysts that ensure high product quality and regulatory compliance.

Concepts like transition state theory and intermediate mapping enables chemists to predict how factors
like temperature, solvent polarity, and catalyst structure affect reaction outcomes. In asymmetric hydrogenations, for example, ligand–substrate interaction knowledge ensures high enantiomeric excess, vital in complex API synthesis.

Kinetic studies provide quantitative data on reaction rates and influencing factors. Techniques such as reaction calorimetry and real-time spectroscopy derive rate laws and activation energies, ensuring scalable and reproducible processes.

A noteworthy tool is the Kinetic Isotope Effect (KIE), where specific hydrogen atoms are replaced with
deuterium to reveal the rate-determining steps of a reaction. This has improved Suzuki–Miyaura crosscoupling reactions by optimizing bases and ligands for better selectivity, yield, and efficiency. Advances in palladium-catalyzed coupling and metalla-aromatic reactions underscore the value of mechanistic understanding. Integrated with analytics, these insights ensure scalable processes that meet regulatory standards.

Thermodynamics and Solid-State Chemistry: Controlling Form and Function

Thermodynamics and solid-state chemistry are central to controlling the physicochemical behavior of APIs.
Thermodynamic parameters like Gibbs free energy and entropy guides solubility, crystallization, and
phase stability. Chemists use this to predict polymorph,solvate, and salt behavior, aiding purification and
ensuring stability and bioavailability.

Solid-state chemistry focuses on molecular packing, lattice energy, and intermolecular interactions in
crystalline and amorphous forms. Polymorphism affects dissolution, mechanical properties, and shelf
life. Crystallography and phase behavior are crucial for controlling solid forms. Tools like thermodynamic phase
diagrams and computational models (e.g., COSMO-RS) help in solvent selection and process optimization.

Integrating thermodynamic modeling with solid-state characterization, CRDMOs to develop crystallization
protocols ensuring polymorphic purity, particle size, and morphology—critical for product quality and intellectual
property protection.

Formulation Chemistry: Intermolecular Interactions

Formulation chemistry optimizes the bioavailability and stability of drug products. Intermolecular
interactions—such as hydrogen bonding, π–π stacking, van der Waals forces, dipole–dipole interactions, and
ionic interactions—impact the solubility, stability, bioavailability, and overall performance of drug substances, particularly high-potency APIs (HPAPIs). Understanding these interactions is key to designing formulations that are both effective and manufacturable.

For example, hydrogen bonding affects crystallite size, polymorph stability, and API–excipient compatibility.
π–π stacking and van der Waals interactions control aggregation and stability, while ionic interactions are
key in salt formation and solubility. These forces are crucial in formulation strategies like solid dispersion development, salt screening, and co-crystal engineering

Chemical modifications to APIs, such as altering logP, pKa, or hydrogen-bond profiles, strategically adjust
intermolecular interactions. For instance, Dipyridamole was prodrugged for solubility, and Lopinavir was modified
for better absorption. In developing amorphous solid dispersions, optimizing drug–excipient interactions is
key. A favorable ∆δp (difference in solubility parameters) indicates high miscibility. Techniques like differential
scanning calorimetry (DSC), dynamic vapor sorption (DVS), and X-ray photoelectron spectroscopy provide
insight interaction, guiding formulation.

Co-crystal engineering enhances the solubility and stability of poorly soluble drugs by forming co-crystals
with a co-former through non-covalent interactions. This method allows the API to adopt new crystal lattices without altering its pharmacological activity.

For example, the Theophylline–nicotinamide co-crystal significantly improves Theophylline’s solubility, while the Losartan–saccharin enhances both solubility and bioavailability for antihypertensive treatments.

Scale-Up and Technology Transfer: Chemistry in Action

Scale-up in chemical processes is the transition from lab-scale experiments to full-scale manufacturing,
ensuring that reactions can be efficiently and safely performed on a larger scale while maintaining product
quality and stability. Key chemistry-driven factors include:

• Thermodynamic Optimization: Efficient heat transfer and mixing prevent thermal runaways. Reaction calorimetry, guided by enthalpy data, ensures safe thermal profiles.
• Solvent Selection for Crystallization: Polarity and temperature affect solubility. Van’t Hoff plots help select solvents and optimize crystallization conditions.
• Managing Reaction Kinetics and Intermediates: Reactive intermediates can degrade products.
  Real-time spectroscopy and modelling help manage them effectively.
• pH and Reflux Time Control: pH influences ionization; reflux time affects conversion. Mechanistic insight helps optimize both for purity and yield.
• Continuous Manufacturing: Offers precise control over process variables, improving reproducibility—especially for sensitive or highvolume APIs.
• Critical Process Parameters (CPPs) and Critical Quality Attributes (CQAs): These are important for successful technology transfer requires. Defining and controlling CPPs like temperature, pH, and solvent choice, supported by mechanistic studies and stability testing, ensures regulatory compliance and consistent product quality during commercialization.

Flow Chemistry: Advancing Process Efficiency

Flow chemistry offers precise control of kinetics and thermodynamics in continuous systems, where
reactants move through microreactors or tubular reactors under tightly regulated temperature, pressure,
and residence time. Residence time-the duration reactants spend in the reactor-is a key parameter,
directly impacting reaction rate, conversion, selectivity, and product quality by dictating molecular interactions.

Flow systems finely tune residence time to match kinetics, outperforming traditional batch methods.
For example, in the Simmons-Smith reaction, precise residence time control prevents intermediate decomposition and ensures efficient ring formation. In nitrations, critical for nitroaromatic compounds in antibiotics and cardiovascular drugs, short residence times reduce over-nitration and thermal risks. Optimized residence times in Grignard additions and transitionmetal-catalyzed couplings enhance reactivity and minimize side products, crucial for building complex APIs.

Flow reactors maintain steady-state conditions, stabilizing challenging short-lived intermediates like
carbenes and diazonium salts. Integrated in-line analytical tools (FTIR, UV-Vis, HPLC) enable real-time
monitoring and dynamic adjustment of residence time and stoichiometry, supporting multistep reactions.

For CRDMOs, flow chemistry offers faster process development, improved safety, and scalable, energy efficient production.

Biocatalysis: Enabling Selective and Efficient Chemical Transformations

Biocatalysis uses enzymes as natural catalysts to accelerate reactions under mild, aqueous conditions,
making it highly valuable for CRDMOs. Its high stereoselectivity and substrate specificity are ideal for
enantiomerically pure APIs, ensuring drug efficacy and safety. Enzyme-catalyzed reactions occur at specific
active sites, offering precise control over chemo-, regio-, and stereoselectivity.

Advances in enzyme engineering and immobilization allow tailored properties and expanded reaction scope
via techniques like directed evolution. In continuous flow systems, biocatalysis enhances scalability and
sustainability. For CRDMOs, this enables cost-effective, selective, and eco-friendly manufacturing

Bioconjugation: Bridging Chemistry and Biology

Bioconjugation enables covalent attachment of drugs or probes to biomolecules like proteins or nucleic acids,
foundational for diagnostics, delivery, and imaging.

One of the most impactful applications of bioconjugation is in Antibody-Drug Conjugates (ADCs), targeted
cancer therapies that combine monoclonal antibodies with potent cytotoxins via a chemical linker. This system
relies on precise chemical engineering for effective, safe, and targeted drug delivery.

Linker Chemistry in ADC Design

The linker is critical to ADC performance, affecting pharmacokinetics and drug release. It must be stable
in circulation but cleavable at the target site. Linkers fall into two main categories:

• Cleavable linkers respond to stimuli such as acidic pH, enzymatic cleavage (e.g., cathepsin
  B-sensitive peptides), or reducing conditions (e.g., disulfide bonds).
• Non-cleavable linkers, such as thioethers, rely on the complete antibody degradation to release the drug.

For example, trastuzumab emtansine (T-DM1) uses a non-cleavable thioether linker (SMCC) to attach the
cytotoxic payload DM1, ensuring high plasma stability and controlled release upon internalization.

Advances in Conjugation Chemistry

The chemical method used to attach the drug to the antibody significantly affects ADC homogeneity,
stability, and therapeutic index. Traditional approaches like lysine or cysteine conjugation often result in
heterogeneous drug-to-antibody ratios (DARs). Modern ADCs employ site-specific conjugation techniques
such as:

• Engineered cysteines or unnatural amino acids (e.g., p-acetylphenylalanine) that enable selective
  reactions like click chemistry or oxime ligation.
• Enzyme-mediated strategies, using transglutaminase, sortase A, or glycosyltransferases, allow precise modification at defined peptide or glycan sites, enhancing reproducibility and pharmacological predictability.

Bioorthogonal and Responsive Chemistries

Click reactions—particularly strain-promoted azidealkyne cycloaddition (SPAAC)—offer high selectivity
and are increasingly used to create ADCs that release drugs only after reaching the tumor microenvironment.
These strategies provide spatiotemporal control and reduce systemic toxicity.

Hydrophilicity and Payload Optimization

Many potent cytotoxic drugs are highly hydrophobic, risking aggregation and rapid clearance. Chemical
solutions to this challenge include:

• PEGylated linkers, which enhance solubility, reduce aggregation, and shield labile functional
  groups.
• Hydrophilic-hydrophobic balance tuning within the linker architecture, which improves delivery
  and release kinetics, especially in high-DAR constructs.

Conclusion

Chemistry remains central to drug development and manufacturing. CRDMOs apply chemical expertise—understanding mechanisms, solid-state behaviour, and formulation science—to efficiently scale discoveries into therapies. Advances in flow chemistry, biocatalysis, and conjugation support selective and sustainable manufacturing. Through predictive modelling and process control, chemistry enables high-quality, compliant therapeutics. As technologies evolve, chemistry remains the engine driving innovation and patient impact.