Preformulation – Solid State Chemistry

Even as the sector moves forward in terms of innovation, many ongoing hurdles remain.

by Susan Thompson, Technical Director of VxP Pharma

An ideal physical structure exists for every active pharmaceutical ingredient (API). Many solid-state molecules can form according to a wide variety of crystalline structures, exhibiting a diverse range of physical shapes and lattice energies. The more stable, soluble and bioavailable a given structure is, the more successful the resulting drug is likely to be.

The variability of crystalline structures (polymorphs) can also lead to significant intellectual property pitfalls. If a company patents one form of a solid-state molecule, but their competitor discovers another form with the same (or better) properties, the original developer may have no legal recourse against that competitor.

What’s more, each new polymorph of a solid-state molecule requires specialized screening for pharmacokinetics and toxicology. Tiny variations in crystalline structure can lead to unforeseen hurdles at any stage of the development and production process, creating a clear need for precise prediction of their behavior in formulations, within a wide range of environmental conditions.

These challenges have created a rapidly growing market for contract manufacturing organizations (CMOs) and contract development and manufacturing organizations (CDMOs) specializing in solid-state formulation and preformulation chemistry. But even as screening techniques continue to advance, companies in this sector still face many of the same risks around the patentability and production of the solid-state compounds they develop.

Here are four trends that currently define the solid-state pharmaceutical landscape, along with the most significant recent developments in each of them.

Complexities continue to present challenges around the patentability of polymorphs.

Complexities continue to present challenges around the patentability of polymorphs.

Complexities continue to present challenges around the patentability of polymorphs.

Polymorphism is the ability of a molecule to take on a variety of different crystal structures as it forms. Different polymorphic structures can significant impact the taste and color of a drug; not to mention its bioavailability, solubility and other pharmaceutical properties. The challenge of simulating all the possible alternative polymorphs of a given molecule has proven a major one for chemists since the late 1990s. In many ways, it remains the greatest challenge in solid-state pharmaceutical chemistry to this day.

A related set of difficulties lies in the fact that the number of effective polymorphs of a given molecule can be notoriously difficult to predict. In the past, pharmaceutical development companies have patented just one or two known polymorphs of their drugs, only to be surprised by competitors who’ve discovered equally effective polymorphs not covered under the original patent.

These variations may sometimes even offer pharmaceutical or regulatory advantages over previously discovered forms. In a 2007 paper in the journal Molecular Pharmaceutics, Andrew Trask provided an overview of what he described as “cocrystals.” The paper defines a cocrystal as “a distinct solid-state material with, in general, a unique and unpredictable structure and physical property profile.” In other words, a “crystalline molecular complex” could comprise a wide range of related hydrates and solvents.

According to Trask, the patentability of a given cocrystal depends on the three factors of novelty, utility and nonobviousness. As far as utility, the precedent has already been set by salts, of which more than 24,000 are patented in the US alone. Since cocrystals are formed in the same ways as other salts, it seems entirely feasible that tens of thousands of polymorphs, based on known crystalline structures, still remain to be patented.

The patentable therapeutic utility of a given cocrystal, meanwhile, is typically a function of the utility of its parent API. In some cases, the cocrystal may even provide greater utility than its parent, in the form of more ideal solubility, stability or bioavailability. Properties like compressability, flowability and hygroscopicity can also vary according to crystalline structure, often in unexpected ways. All these factors make many cocrystals nonobvious from the perspective of patentability.

In light of all these considerations, Trask’s paper makes a strong argument for the commercial advantages to be gained by actively detecting and screening new polymorphs of existing structures. Even if the parent API is already patented and well-known, researchers can often obtain new commercialized drug forms simply by performing solid-form screening, patenting useful polymorphs, and proceeding with development and manufacturing from there.

These facts already represent the business realities of the solid-state pharmaceutical sector. As might be expected in such a competitive landscape, CMOs have poured millions of dollars into new facilities and equipment for the express purposes of screening, detecting and improving upon polymorphs of existing APIs.

Effective toolkits are highly crucial for polymorph detection and screening.

Effective toolkits are highly crucial for polymorph detection and screening.

Effective toolkits are highly crucial for polymorph detection and screening.

Due to this interwoven web of engineering and legal challenges, many pharmaceutical companies and CMOs have invested heavily in technologies for predicting, detecting and screening polymorphs of the drugs they make.

One of the most popular analytical methods is X-ray powder diffraction (XRPD). A typical XRPD study involves immersing a compound in a variety of solvents (usually around eight, but sometimes as many as 50), while subjecting the compound to an array of crystallization techniques, with the goal of creating single crystals. Although this approach used to be fairly inefficient, new research has narrowed the range of necessary solvents down to about 20, while slurring components in multiple solvents in order to obtain quicker results.

In addition to XRPD, researchers frequently use a range of other techniques to discover relationships between different crystalline forms, analyze individual forms’ behavior under stress conditions, and select forms that are most suitable for ongoing development and manufacturing. For example, many labs use techniques like thermogravimetry, thermal scanning calorimetry and hot-stage microscopy to pinpoint polymorphs’ solvation and desolvation rates, melting points, water uptake, physical stability, and form changes upon drying.

Another popular complementary technique is gravimetric vapor sorption, which measures water sorption and desorption. This technique is useful for informing environmental handling guidelines that can help prevent the formation of hydrates, or dehydration upon exposure to lower-than-expected humidity. Many researchers also use a battery of additional techniques, such as infrared, Raman, and nuclear magnetic resonance (NMR) spectroscopies, to detect differences between crystalline forms that XRPD may have missed.

All these analytical techniques have well-established histories. But as the market for solid-state pharmaceutical chemistry continues to grow, an increasing number of academics and corporate-sponsored researchers have been adding new approaches to the polymorph analysis toolkit.

Some CMOs have developed proprietary techniques for structural simulation and prediction.

Solid-state pharmaceuticals require highly specialized manufacturing processes. Flow characteristics can vary widely from one batch to the next; and learning to design and optimize manufacturing pipelines around these random variations can be a lifetime’s work. Thus, a growing number of academic institutions (beginning with the Solid State Pharmaceuticals Cluster (SSPC), launched in Limerick, Ireland in 2008) now provide PhD-level training in the creation of pharmaceutical solids.

One area of particular focus in academia has been polymorph prediction: the study of predicting the wide variety of structures into which a given molecule can crystallize. PhD chemists trained in polymorphic prediction can help create clearer guides for experimental screening, analyze and confirm experimental results, and improve understanding and handling of various component crystals, such as cocrystals, hydrates and solvates.

For example, chemists can also search through a wide range of crystal structures, evaluating their free energies as a function of temperature and pressure; this arriving at optimal crystal structures with ideal global minimum energies. Chemists accomplish this by generating millions of triad crystal structures, then ranking them according to their lattice energy. In simple terms, they simulate molecules with a simplified structure of balls and springs (representing atoms and bonds) that bend according to specific rules, along with a forcefield that describes the balls’ and springs’ behavior under the processes of stretching, bending and rotation.

Until fairly recently, these forcefields were fairly generic from one molecular simulation to the next. But in 2007, a group of researchers used advanced quantum-mechanical calculations to develop individualized forcefields for each specific molecule to be analyzed. With they used these new-and-improved forcefields to analyze the structures of crystals, they consistently arrived at much more accurate results about the lattice energy of those molecules’ most stable forms. These new forcefield models went into commercial use in 2009, and have remained in use ever since.

Then, in 2010, another group of researchers succeeded in developing a novel type of production screen for analyzing physical stresses on solid-state chemicals. In particular, this new screen examines the influences of factors like temperature and humidity on APIs, excipients, and formulations containing both. The screen can provide accurate results on molecules of any size; a critical asset in the area of solid-state chemistry, where larger molecules often lead to complex mechanical stresses.

In one promising initial study of this production screen, the researchers analyzed the popular hair-loss drug finasteride. They were able to characterize a set of solvated APIs for the drug, and pinpoint the solid-state behavior (including solubility and recrystallization properties) of three finasteride solvates. In fact, they discovered that the “new” finasteride forms were actually isostructural members of an already well-known family of finasteride solvates; and that these additional forms could be created through established finasteride manufacturing processes.

While much of this solid-state research originally began in academia, its later phases are typically corporate-sponsored and proprietary. If the sector ever reaches a point of maturity at which fundamental methods like these can be shared more widely, a new burst of innovating manufacturing and screening techniques will be sure to follow. However, in the meantime, manufacturers themselves have proven to be significant drivers of advancement.

Increasing involvement of solid-state CMOs throughout the pipeline

Until the arrival of these advanced simulation techniques, new polymorphic structures could only be discovered by actually creating them in a lab environment. In fact, for many pharmaceutical development firms, this is still often the case. Even when researchers are able to discover new polymorphs through simulation, the processes of detecting, screening and reliably engineering these crystals at scale remain major challenges throughout the solid-state sector.

With those challenges in mind, a growing number of pharma firms are turning to CMOs to characterize, screen, select and develop their solid-state compounds. The number of CMOs and CDMOs who specialize in solid-state manufacturing has risen sharply over the past ten years. In fact, a rising number of CMOs are devoting significant percentages of their facilities and equipment exclusively to this area of drug production.

This one-small niche now represents a multi-million-dollar industry, in which CMOs compete not only in terms of cost-effective screening and manufacturing, but also in the active improvement of solid-state compounds. Many CMOs now work on an ongoing basis to improve the stability, solubility and bioavailability of polymorphs, cocrystals, salts and amorphous materials, with an eye toward boosting the effectiveness and marketability of APIs.

The ways in which CMO invests in solid-state capabilities vary widely; but over the past seven years, several overarching themes have emerged. Many CMOs have installed spectroscopic equipment, along with powder and X-ray diffraction (XRD) tools, with the express goal of developing solid-state formulations and preformulations. Quite a few have also invested in logistical reorganization and staff training, to create specialized pipelines for polymorph identification, formulation analysis, crystallinity determination, and salt screen and selection. A growing number have also implemented developed proprietary transmission systems, which enable them to perform high-throughput screening of polymorphs.

In short, polymorph screening is becoming less and less the domain of the pharma development firm, and increasingly the specialty of the CMOs on which those firms rely. As in so many other areas of pharmaceutical contract manufacturing (most notably the manufacturing of solid oral dosage forms and high-potency compounds), an increasing number of high solid-state CMOs aim to provide specialized end-to-end solutions for their clients, providing teams of trained experts dedicated to moving a product from concept to market under a single roof.

From the perspectives of polymorph prediction, detection, patentability and manufacturing, an integrated pipeline of well-trained experts is essential. Such expertise not only helps pharma companies stay ahead of competitors in terms of innovation, but also protects existing solid-state assets from threats. In the long term, however, the market is likely to be moved forward not so much by siloed, proprietary screening techniques, as by increased collaboration between development firms, CMOs, and CDMOs throughout the production process.

In addition to being an author and speaker, Susan Thompson serves as the Technical Director of Indianapolis based VxP Pharma.


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