Many teams rely on trial and error, but strategic partnerships can significantly streamline toxicology testing.
by Susan Thompson, Technical Director at VxP Pharma
A number of interrelated factors can have an impact on the delivery of a solid-state drug. Differing crystal forms (polymorphs) of the same drug can also exhibit widely differing solubility and dissolution rates. Varying properties like these can significantly impact the pharmacokinetics and pharmacodynamics of an active pharmaceutical ingredient (API).
Even so, many labs continue to pursue formulation development with a trial-and-error process, resulting in wasted time and resources. In order to reduce variability in the testing and production processes, researchers need to adopt robust simulation and screening practices. The more quickly they can understand the system, the more cost-effectively they can bring the drug to market.
Forced degradation studies speed up the API’s breakdown in various ways.
Solid state pharmaceutical chemicals can break down due along a wide range of different kinetic pathways. In order to determine a drug candidate’s stability, extremes of temperature, chemical aggregation, mechanical force, chemical damage, and other stressors must be applied according to known and suspected degradation pathways. The API’s reactions to each stressor must be carefully recorded and analyzed at each step of the process.
Various types of forced degradation studies should be performed throughout the development process. The drug product should be tested at high- and low-dose concentrations, as well as in any configurations unique to a specific product. Each sample should be subjected to stress from high temperatures, kinetic force, and any other likely pathways of degradation; but care must be taken not to exceed the intensity of realistic potential stressors.
Throughout each stress trial, the solid state chemical should be analyzed for all likely responses to each stressor; for example, breakdown of molecular bonds, loss of chemical groups, physical weakening, changes in appearance, or any other functional or structural alterations. Some of these results may be immediately obvious, while others may only become apparent through analytical methods such as electrophoresis or chromatography.
Photolytic stability studies evaluate the API’s reactions to light and air.
Photodegradation typically results from exposure to air and sunlight, and takes the forms of hydrolysis and oxidation reactions. Unlike degradation due to kinetic factors or temperature extremes, photodegradation can occur even in ordinary storage conditions, if a pharmaceutical’s packaging material fails to provide adequate protection from sunlight. Thus, before a drug candidate is prepared for shipping, its photolytic stability must be assessed.
To initiate a photochemical reaction, the solid state chemical is bombarded with photons, whose energy is absorbed by the API’s molecules. This absorbed energy rapidly pushes the configuration of that molecular structure into an excited state, which may or may not be kinetically stable, depending on a range of chemical and environmental factors. If the molecular structure is unable to maintain its stability, it may decompose into high-energy fragments, which react with other molecular fragments as they dissipate into the surrounding environment as pollutants.
Once a chemical’s level of photolytic sensitivity has been determined, the API can be protected by introducing certain additives into the formulation, by adding packaging that filters out light at certain wavelengths, and/or by attaching warning labels that alert handlers to transport and store the drug in locations free from damaging light sources.
Oxidative stability studies examine the API’s resistance to oxidation reactions.
In an oxidation reaction, electrons are transferred between molecules, resulting in a gain of oxygen relative to other atoms. This reaction, causes the breakdown of many types of organic and inorganic molecules. The exact rate at which it occurs in a given solid-state chemical depends on many factors, including temperature and pH, as well as presence of water, certain acids, and other catalysts.
Despite the fact that oxidation poses a hazard to many drug products, its precise chemical pathways have been studied relatively little in comparison with other threats such as photodegradation. To some degree, however, this lack of research on oxidation is justified, because oxidative degradation can be mitigated simply by keeping the drug out of direct sunlight, and by adding antioxidants to the drug formulation.
In addition to evaluations on kinetic and temperature-related degradation, and photolytic and oxidative stability, some solid state pharmaceuticals may also require studies of special conditions that may lead to degradation, such as hydrolysis and other chemical reactions. These conditions can be as unique as the pharmaceutical products to which they apply, and thus must be selected and studied on an individual basis. A CMO with experience in stability studies will tailor these recommendations around the conditions of a given product and facility, in order to ensure minimal loss throughout the manufacturing phase.
Informed toxicology analysis depends on many interrelated factors.
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.
Polymorph detection and screening require both expertise and effective toolkits.
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.
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.
CMOs are increasingly contributing their expertise throughout the solid-state 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.
Since crystalline size, form, surface area and other properties can all impact the behavior of an API, a growing number of research teams are partnering with formulation experts and material scientists before animal testing even begins. These experts can often provide more accurate estimates of an API’s bioavailability and toxicology, helping drug researchers pinpoint and reduce variability much earlier in the testing phase.
These early screenings test not only for varying polymorphs, but also for thermodynamic form relationships, cocrystals, and possible improvements in formulation composition. The more of these “moving parts” can be locked down before further testing begins, the more cost-effectively solid-state drugs can be characterized and moved into the clinical trial phase.
In fact, rigorous testing early in the development pipeline can help increase the value of the drug, by reducing risk, shortening the regulatory pathway, and highlighting new opportunities for patents and improvements. Due diligence can have significant positive impact throughout the entire design cycle, and long after.
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In addition to being an author and speaker, Susan Thompson serves as the Technical Director of Indianapolis based VxP Pharma. |
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