Advancing technologies are helping developers discover polymorphs more rapidly than ever. But production and legal issues can pose significant challenges.
An active pharmaceutical ingredient (API) can take many forms. This is particularly true of solid-state compounds, whose salts can form according to an unpredictable range of structures. These crystalline structural variations, known as polymorphs, may occasionally have little or no impact on the API’s chemical properties; but in the vast majority of cases, polymorphic crystal formations alter to the stability, solubility, and other physical properties of the API.
These alterations to the API’s crystals can cause unexpected effects throughout the manufacturing pipeline, resulting in ineffective formulations. But if polymorphs can be detected early in the drug development process, and sorted from one another via automated screening, the drug’s developers may be able to patent the additional polymorphs, thus gaining valuable intellectual property, while simultaneously cornering the market on competitors who might attempt to patent those same crystalline variations as their own.
Given the far-reaching impact of polymorphs on a drug’s properties (not to mention the competitive landscape surrounding that drug) most manufacturers of solid-state pharmaceuticals now partner with contract manufacturing organizations (CMOs) who specialize in polymorph screening. Armed with techniques like X-ray Powder Diffraction (XPRD) and nuclear magnetic resonance (NMR) spectroscopy, these expert CMOs are able to rapidly detect polymorphs, separate them from other crystals, and analyze their chemical properties.
The following analysis covers several of the most significant recent developments in polymorph screening, along with their implications for solid-state pharmaceutical developers.
Several key technologies have increased the speed and accuracy of polymorph screening.
In any crystalline formation process, a few polymorphs will predominate, while other variations will be less common, and some may appear so rarely that they’re never detected at all. However, every solid state drug manufacturer has a vested interest in discovering as many polymorphs as practically feasible, for the sake of more precise manufacturing, expanded research potential, and tighter control over intellectual property.
While it may not be possible to discover every polymorph within a limited time window, advancing technologies have significantly increased the speed at which batches of crystals can be screened. Once a new polymorph had been detected, the screening equipment can be programmed to proactively watch for it, even as teams of engineers work to analyze its structure, desolvation rate, and other physical and chemical attributes.
XPRD has been the primary polymorph screening technique for decades, and it remains an essential tool for labs around the world. In more recent years, leading-edge CMOs have complemented their XPRD screening with infrared and nuclear magnetic resonance (NMR) spectroscopies, which sometimes detect polymorphs that X-rays miss. Some labs may further supplement these scanning technologies with specialized thermogravimetry analysis, thermal scanning calorimetry, and hot-stage microscopy, which can detect polymorphs based on minuscule structural differences.
The inherent limitation of all these techniques has always been the capacity of human investigators to manually analyze batches of crystals. But over the past few years, some forward-looking labs have finally broken this longstanding barrier, by developing new computerized screening systems that far exceed the speed of human experts. These new systems that represent today’s most exciting frontier in polymorph screening.
New computerized techniques enable rapid polymorph screening on a large scale.
Even with an array of complementary screening technologies, human engineers still need computerized assistance to screen samples of crystals at the speed demanded by today’s drug development pipelines. Labs often receive only three to five grams of base material, from which they’re expected to produce 1,000 or more crystallizations. In each of those crystallizations, engineers are expected to detect as many polymorphs as possible; often on a timeline of a few days or weeks.
This kind of processing capacity lies outside the range of even the most talented experts; so it’s no surprise that the most cutting-edge labs have automated as much of the process as possible, intervening manually only when necessary. Today’s automated screening systems are faster, more efficient, and more accurate than ever before. These high-throughput systems use analytical algorithms to characterize hundreds of polymorphs every day, and even to focus their searches on specific polymorph profiles.
A few labs have developed even more advanced analysis techniques. Some, for example, use computerized simulations to predict polymorphs with high bioavailability and low lattice energy, then assign their high-throughput analytics systems to screen for polymorphs matching those target profiles. This precise focus enables labs to minimize time and resources invested in screening less-valuable polymorphs, while maximizing the number of marketable polymorphs they discover.
Through a combination of varied screening techniques, high-speed automated screening, and targeted polymorph profiling, today’s leading-edge labs are discovering more useful polymorphs every week. Even so, not all pharma developers are taking advantage of these abilities. Developers who continue to rely on XPRD, and to screen crystalline batches manually, are now falling behind their more forward-looking competitors.
Partnership with knowledgeable CMOs is crucial for polymorph screening success.
The discovery of a potentially marketable polymorph is only the first step in commercial success. Once that discovery has been made, the developer then needs to develop a formulation around the polymorph, produce and test a pilot batch of the formulation, perform in vitro and in vivo toxicology screenings, complete clinical trials, and (if all goes well) expand the solid-state manufacturing process to a commercial scale, and obtain regulatory approval for the drug.
A failure at any one of those stages can set the project back by weeks or even months. However, by partnering with an experienced CMO, discoverers of a valuable polymorphs can successfully navigate the challenges of patenting, testing, validating and gaining regulatory approval for their drugs. The earlier in the development process such a partnership is formed, the more efficiently the drug can succeed in clinical trials and advance to commercial production.
Furthermore, partnership with a knowledgeable CMO can help prevent polymorph-related intellectual property issues from turning into costly lawsuits and legal entanglements. An expert partner can determine whether the polymorph is patentable as a distinct discovery (it often is) and complete the patent paperwork before the drug even enters production; giving the manufacturer a distinct advantage over would-be competitors in the solid-state space.
As polymorph screening technology advances, the gap between forward-looking developers and outdated traditionalists continues to widen. It’s no longer the largest or longest-lived pharma organizations who corner the solid-state market; it’s those most ready to adapt to new trends, adopt new technologies, and discover and patent valuable polymorphs before their competitors do.