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Overcoming the Challenges of API Complexity

Pharmaceutical drug molecules are becoming increasingly complex, posing challenges in formulation development and manufacturing. This is particularly true of small molecule drug APIs and peptides, both of which have a growing tendency towards complexity.

Our approach to these challenges in both cases is to begin with the end objective in mind by applying a variety of capabilities early in the process to support the later stages of drug development. These include:

  • Particle sizing and reduction
  • Process and complex chemistry
  • “Route scouting” to find new synthetic production routs for APIs
  • Reducing complexity
  • Eliminating hazardous or expensive solvents
  • Shortening the production cycle
  • Finding solutions to other technical problems

The importance of this type of process understanding was underscored in an article by Pharma’s Almanac, which argued that it has become central to successful drug synthesis:

“As small molecule APIs become increasingly complex, the development of robust, high-yielding, and cost-effective synthetic routes becomes more challenging. Strategies that emphasize a high level of process understanding facilitate more effective route design and analytical method development.”

In many cases with small molecule drugs, the primary challenge is solubility, which impacts the bioavailability — and thus the efficacy — of the drug. This has been a growing problem for many years as drugs have become increasingly insoluble. Sanjay Konagurthu, senior director of science and innovation, Pharma Services for Thermo Fisher Scientific, summed up the problem in a recent article published by PharmTech:

“Small molecules are still the largest segment of drug development in the industry. Oral and injectables dominate the pharmaceutical pipelines. In terms of oral drug delivery, it is currently estimated that 70–90% of small molecules in the pipelines have solubility and bioavailability challenges. This number has doubled compared to over 10 years ago.”

The article goes on to recommend that outsourcing partners should play a crucial and integral role in formulation strategy. A partner can provide expertise in CMC, technology, and regulatory affairs, or can act as a traditional pharmaceutical R&D department for the sponsor company. In addition, a knowledgeable CMO partner can help bolster product knowledge throughout all phases of a program lifecycle.

As a class, peptides have grown more complex as technologies and methodologies emerge to construct ever-larger chains. Even in their smallest, most simplified forms, peptides have always been a particularly difficult drug class due to challenges with bioavailability.

Despite their many advantages — including lower toxicity, high potency, and high selectivity — they tend to break down quickly, especially in the stomach. This has typically led to them being delivered by injection or infusion, but these alternatives have their own challenges since peptides also degrade rapidly in the bloodstream. The need to use such delivery mechanisms also impedes broader market acceptance.

In the last two decades, however, technology and research have enabled drug manufacturers to realize the full promise of this class by making it possible to synthesize specific peptide chains precisely and cost-effectively. The changes have come about thanks to multiple advances in chemistry, biology, genomics, dosage formulation, combined with rapid shifts in our understanding of human health and exponential improvements in technology (from computational power & informatics to spectrometry, imaging and more).

The result has been a growing use of synthetic peptides in therapeutics, diagnostics, and antibody production. They’re also being used as tools for understanding biological processes.

Confronting API Complexity

Whether due to the solubility challenges mentioned above, the need for increasingly complicated delivery methodologies, the emergence of high-potency compounds or other characteristics of small molecule or large peptide chemistry, pharmaceutical drug discovery and subsequent process development continue to grow in complexity.

 

Neuland has expertise in both solution phase and solid phase synthesis methodologies. We’ve also developed proprietary technology, a preparative HPLC technique which delivers 10 to 20 times better throughput compared to the standard preparative HPLC technique. These capabilities enable Neuland to offer the highest quality peptide products at competitive rates. Contact us for more details.

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