Small molecule synthesis occurs on three scales:

1) Small-scale synthesis to support pre-clinical research (1 mg to ~20 g)
2) Process-development synthesis to support safety and clinical trials (~20 g to ~100 kg), and
3) Large-scale drug manufacturing (brand-name and generic) processes to support sale of an approved medicine (>100 kg)

Small-Scale Synthesis
In pre-clinical research, teams of chemists synthesize compounds using bench-top techniques. Molecular modeling, which helps chemists visualize the shape of molecules and how they may bind to protein targets, may be employed in the design of targeted groups of compounds. Targeted groups of compounds are often synthesized in batches of 20-50 using rapid-parallel synthesis. Synthesis and in vitro testing, followed by modeling and/or information from X-ray analysis of active compounds, is used iteratively to result in optimized compounds.

Combinatorial synthesis is a process by which one type of chemical reagent is combined with other chemical reagents in a matrix to produce many different products all at once (usually on milligram scale). Compounds can be produced singly or in mixtures. Combinatorial synthesis may use solid-state or solution-state chemistry to provide libraries where new and unexpected scaffolds are sought.

At the basic research stage, synthetic routes are often designed to allow access to the largest number of analogs. After a compound has been selected for development, its synthetic route is used to produce the small process batches required for pre-clinical in vivo safety studies.

Process-Development Synthesis
To support clinical trials, process chemists develop an optimized, efficient synthetic route that allows the consistent, reproducible manufacture of high-purity material on multi-kilogram scales. Such syntheses often take place in pilot plants and are executed under strict regulatory (Good Manufacturing Practice [GMP]) guidelines.⁸⁴

The active pharmaceutical ingredients (API) produced by pilot plant preparation is made into pills, capsules or other formulations. Other formulations may include nasal sprays, dermal patches, sub-cutaneous injections, slow-release capsules, and sublingual wafers. The drug materials are combined with excipients (non-drug materials) that maximize stability, and ensure reproducible solubility, distribution, and exposure in vivo.

In 2015, the first formulation of a pill produced by commercial scale 3-D printing was approved by the Unites States Food and Drug Administration (FDA). The 3-D printed pill is porous and disintegrates rapidly when swallowed with water – helpful for patients who have trouble swallowing pills.⁸⁵

Brand-Name and Generic Drug Manufacturing
In the last decade, large pharmaceutical firms have increasingly downsized or eliminated in-house manufacturing capacity, outsourcing this function to contract research organizations (CRO).^86,87 Small biotech firms have also begun to forge these types of partnerships.⁸⁸

Many CROs focus on new advances in process chemistry.⁸⁹  Some new small molecule drug candidates have complex structures and may require longer synthetic routes and efficient chiral separations. Expertise in bio-catalysts helps manufacturers produce pure intermediates on a large scale.⁹⁰ Combinatorial chemistry techniques can be very helpful in the screening of bio-catalysts^91,92 and metal catalysts⁹³, allowing the rapid identification of the optimal reagent.

Recently, chemistry CROs have begun to adopt advances in chemistry and engineering to gain efficiencies.  For example, preparation of product through continuous reaction can offer advantages such as reduced waste, improved purity, and allow for rapid change in scale and transfer of technical methods.^94,95  Chemical syntheses lack efficiency in that they may require many steps before the penultimate intermediates can be combined into the final product.  Greater convergence in synthetic schemes is desirable, and could be enabled by advances in synthetic chemistry.⁹⁶  Chemical engineers and process chemists work together to bring data and statistical analysis tools like Process Design and Modeling to the management of small molecule manufacturing to optimize efficiency.^97,98

In the United States, oversight of the manufacture and sale of a brand-name drug is limited to a single company for the duration of patent protection, although the API or intermediates leading to the product may come from several out-sourced companies.⁹⁹ Maintaining a high-quality API is critical for patent protection and is a concern of FDA.¹⁰⁰ After patent protection has expired, companies that make generic drug can produce and sell the drug, and often do so at discounted prices. Generic drug companies can offer discounts because they have not had to fund the original discovery and clinical development of the drug. Generic drug companies are required by FDA to demonstrate bioequivalence of the small molecule API to the brand-name version, but are not required to replicate the safety and efficacy studies required for initial FDA approval.¹⁰¹