Even as firms invest in advanced technologies, collaboration throughout the pipeline remains key.

by Raymond E Peck, CEO of VxP Pharma

Every drug dosage form (solid or otherwise) begins with an active pharmaceutical ingredient (API). That API can take a wide range of forms, from pure crystalline and noncrystalline compounds to multicomponent systems of cocrystals, including hydrates, solvates and salts. But these solid-state compounds can form according to a variety of structures. Variations in structure, known as polymorphs, can significantly impact the API’s stability, solubility, and pharmacokinetics.

To add further complexity to these challenges, polymorphs often take shape unpredictably, leading to surprising variations in a drug’s chemical properties. And because it’s next to impossible to know in advance how many polymorphs exist for a given compound, competitors may create and patent newly discovered polymorphs of known APIs, leaving those APIs’ original discoverers with smaller shares of the drug markets they helped create.

In light of all these concerns, it’s no surprise that pharmaceutical developers and contract manufacturing organizations (CMOs) have invested billions in solid-state salt screening technologies like X-ray Powder Diffraction (XPRD). But even as technology continues to advance, major blind spots remain in the solid-state landscape.

A number of advances in salt screening technology have moved the field forward.

A number of advances in salt screening technology have moved the field forward.

A number of advances in salt screening technology have moved the field forward.

The vast majority of APIs exhibit polymorphism. In the field of solid-state drug development, uncertainty is the norm, making well-planned polymorph searches crucial to long-term business success. Although it’s all but impossible that any given search will discover all possible crystalline forms, a thorough salt screening procedure can at least pinpoint many common variations. The more polymorphs a firm can discover, the better engineers can design formulations around these variations (and patent them) before their competitors do.

While XPRD remains the go-to technology for screening polymorphs, a growing number of labs are also investing in tools for infrared, Raman, and nuclear magnetic resonance (NMR) spectroscopies, in order to more quickly and precisely characterize crystal forms. In addition, many labs have acquired equipment for thermogravimetry, thermal scanning calorimetry and hot-stage microscopy, to analyze polymorphs’ structural stability, solvation and desolvation rates, and other mechanical properties.

But even with a full toolkit of advanced salt screening equipment, the combination of limited sample sizes with vast numbers of potential polymorphs continues to present significant challenges. In response, many researchers have turned to new techniques for data gathering and analysis.

Some CMOs are now able to perform polymorph salt screening at scale.

In the world of salt screening, small sample volumes are par for the course. Labs are routinely assigned to conduct 1,000 or more crystallizations using only three to five grams of material. And while advances in XPRD have helped researchers screen and classify crystal forms more rapidly, the sheer number of necessary experiments can still lead to cumbersome screening pipelines.

Pharma companies and CMOs have responded with a variety of interrelated adaptations. Many have automated as much of the screening process as possible, using high-throughput analytics to screen and characterize hundreds of polymorphs. Others, meanwhile, choose to limit their search space by performing more targeted salt screening. Still others have developed proprietary technologies for simulating crystalline forms with the lowest lattice energy and highest bioavailability (and thus the highest market value), and proactively seeking to create those specific polymorphs.

Effective salt screening requires collaboration throughout the pipeline.

Effective salt screening requires collaboration throughout the pipeline.

But even once the ideal crystalline forms have been discovered, the development and production process is only just beginning. To move drugs to market as quickly as possible, developers need the help of collaborators in the CMO space.

Effective salt screening requires collaboration throughout the pipeline.

Once solid-state experts have screened for likely polymorphs, the next step is to scale up the technique, and create a robust production process around that optimized crystalline form. Throughout that pipeline, the solid-state drug will be subjected to environmental stresses, not to mention regulatory challenges and legal issues.

For all these reasons, a growing number of pharma developers now enlist the help of CMOs throughout the development and production stages. In fact, quite a few smaller pharma firms now develop solid-state drugs through active collaboration with CMOs, with the specific intent of leaving production and testing in the contract manufacturer’s hands.

Investment in solid-state salt screening and production continues to climb. While the up-front costs of analysis may run into the millions, the rewards for developers and CMOs alike can be enormous. As collaboration between these partners continues to tighten, the coming years are likely to see further significant steps forward in solid-state manufacturing.

In addition to being a writer and speaker, Raymond E Peck is the Founder and CEO of VxP Pharma Services and VxP Biologics, both based in Indianapolis Indiana.

About the Author:

Ray Peck