Articles
James Netterwald, PhD, MT(ASCP)
Senior Editor
Finding every polymorph for a drug candidate is key, as a drug’s success or failure depends on which structural variant is used.
A solid drug's effectiveness is inextricably related to its bioavailability, which is, in turn, dependent upon the drug's solubility in human body fluids. One of the peculiar
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characteristics of solid drugs is that they are polymorphic, meaning they can morph into different crystalline forms when precipitated from solutions of different solvents. "My understanding is that at least two-thirds of pharmaceutical molecules show polymorphic behavior," says Sohrab Rohani, PhD, professor of chemical and biochemical engineering at the University of Western Ontario in Canada.
Although some polymorph forms may still be soluble in body fluids, the more thermodynamically stable a crystal is, the less soluble it will be. The reason for this is that "each polymorph has a different potential energy level," says Hui-Yin Harry Li, PhD, president of Wilmington Pharma-Tech, Newark, Del. "It is like a waterfall, where the solution has the highest energy, and is therefore at the top, and the most stable crystalline form has the lowest energy level, so it is at the bottom."
Discovering this polymorphic behavior is crucial, as the case of Norvir (ritonavir) demonstrates. The drug, a protease inhibitor from Abbott Laboratories, Abbott Park, Ill., had to be pulled from the market in 1998 and reformulated after the emergence of a polymorph cut the drug's bioavailability by half (See "The Lessons of Norvir"). While researchers have come a long way, polymorph screening is still not completely predictable, so scientists are continuing to develop new tools and methods for screening. There are also US Food and Drug Administration (FDA) requirements on purity that must be adhered to and potential issues related to the patentability of new polymorphs.
After a clinical drug candidate is identified, it is necessary to do polymorph screening to find the most stable crystalline form or polymorph that is water-soluble. "I think that for brand pharmaceuticals, it is extremely important at the beginning to look at different polymorphs of a particular compound in order to address future possible complications," Rohani says. It is important to identify the right polymorphs before scaling up manufacturing of the drug for phase I clinical trials because this ensures that the same material will be produced continuously throughout the life of the drug.
In addition, "the reason you do polymorph testing is that the polymorphic form of the material can have an effect on the safety and efficacy of the drug during clinical trials," says Patrick Stahly, PhD, chief operating officer for SSCI Inc., West Lafayette, Ind., a company which performs contracted polymorph screening for many pharmaceutical companies. Stahly says roughly 90% of the materials screened at SSCI have multiple solid forms. But because these solid forms differ dramatically from one another both in their shape and in their physical properties, he has found that only 50% of them are true polymorphs. This means they are solid forms that have the same empirical formula and chemical composition, but different crystalline arrangements.
The polymorph screening process itself is an in vitro test, where the material is crystallized by many different methods. Once the crystals have been created and sorted, the most important physical property for each crystal, water solubility, is determined. "For compounds that have high water solubility, usually the difference in solubility of polymorphic forms is not an issue; they will both be very water soluble," says Stahly. The most thermodynamically stable polymorphs are selected because they have no thermodynamic drive to convert into another form while being manufactured and tested.
Purity
The FDA requires that the polymorph chosen by a manufacturer for further development have a certain level of purity. Solvents used to crystallize the polymorph must be
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chosen from a list of solvents recommended by the International Conference for Harmonization. The guidelines recommend class II and class III solvents, but not class I solvents, which include benzene and dioxane. "If you use [class I solvents], you need to prove that you don't have any of them remaining in your drug product," says Li.
"Molecular impurities that are somewhat close in nature to the drug molecule can actually attach to the drug at different phases of crystallization, preventing the growth of that particular phase and leading to the development of different polymorphs," says Rohani. Any impurity can either inhibit or induce the crystallization process, and impurities, therefore, have a significant impact on polymorph screening.
Furthermore, before a drug can be used in a phase I clinical trial, it must be at least 98% pure, with no single impurity greater than 0.5%, and all impurities greater than 0.1% need to be identified. "This is common practice for pharmaceutical chemists," says Li. "When we have a compound at 98 to 99%, we say it is pure enough."
FDA regs, other legalities
For a pharmaceutical company, bringing a drug to market is a lengthy and costly process, and every step is tightly regulated by the FDA. In 1998, after the Norvir case and
| The Lessons of Norvir Norvir (ritonavir) from Abbott Laboratories, Abbott Park, Ill., is a protease inhibitor for the treatment of HIV/AIDS. The history of the drug is a good illustration of the effect of polymorphism, says Patrick Stahly, PhD, chief operating officer for SSCI Inc., West Lafayette, Ind., a company that performs contracted polymorph screening. Like all drugs, the effectiveness of Norvir, which was approved in 1996, depended on its bioavailability in the bloodstream of the patient. "Ritonavir is not bioavailable in the solid form, so it has to be given as a solution; its final formulation consists of a solution-filled gel cap," says Stahly. The drug was on the market for 18 months when, during manufacturing, the gel caps failed their dissolution test. When the company's chemical engineers looked inside the gel caps, they found a new crystalline form. The new polymorph had about half the bioavailability of the original drug on the market. Attempts to remove this new form failed, and ultimately Abbott had to take Norvir off the market to reformulate it. During the reformulation period, they found that the drug is relatively unstable thermally, and they empirically determined that it needed to be kept at a low temperature while the gel caps were being manufactured. "Later, the manufacturer found that one of the degradation products of ritonavir actually seeds the formation of the new polymorph. . . . This was something that was basically unpredictable," says Stahly. |
other problems related to polymorphism, the FDA issued guidelines that caused drug companies to pay more attention to polymorph screening. "Now, of course, when you submit an IND [Investigational New Drug application] and an NDA [New Drug Application] for new drug compounds, it is required by the FDA to submit polymorph information," says Li.
Another issue is that each new polymorph is potentially patentable. So if one pharmaceutical company produces a polymorph of a drug already being produced and marketed by another company, the new drug can be patented despite its similarity to the preexisting agent. Some of these cases have led to lawsuits between big pharma and its relatively smaller competitors, further highlighting the need for a drug manufacturer to identify all possible polymorphs of their products. "If big pharma spends $100 million just to identify a compound, it would be silly for the company not to identify the more stable crystalline form to prevent another company from patenting it," says Li.
Polymorph screening is required early in this development process. If a compound fails polymorph screening at this point, the scientists must go back to the beginning, hunting for a new compound from scratch. "Some of the newer technologies actually can allow you to do a bit of that screening in late discovery, that is, to help you select among a set of potential clinical candidates," says Stahly. "These technologies will allow one to determine if there will be development problems or not from a physical point of view . . . so that can help in selecting the appropriate candidate."
Currently, polymorph screening is an empirical process involving a survey of analytical techniques that yields a two-dimensional picture of a polymorphic crystal. Although most researchers using these methods acquire some information about the solid state, they cannot predict the crystal structure just yet.
According to Stahly, the main limitation of current polymorph screening is this lack of predictability. No matter how many samples one generates for a compound or how thorough a screen is, there is no way to say with confidence that all of the polymorphs have been found. "But there are a number of people who are working very hard to predict structure," says Stahly. "As the screening technology advances, we can look at what we have found and locate what we have predicted, and say we feel confident that we have found everything."
The Future
One of the people hard at work developing new methods for detecting different polymorphs early in the drug discovery process is Adam Matzger, PhD. "The thing that we have developed is called polymer-induced heteronucleation," says Matzger, an associate professor of chemistry and macromolecular science at the University of Michigan, Ann Arbor. This new method uses polymers that are floating in solution or at the bottom of the solution. The polymer acts as a site for the molecules to dock and ultimately turn into a crystal. "Because the polymer surfaces have chemical differences, this can lead to differences in the polymorph that is formed."
According to Matzger, the problem is that methods traditionally used to find polymorphs involve changing either the temperature or the solvent, which change the shape of the crystal. He adds that with the polymer method the solvent and temperature are held constant but the polymer is changed. The shape of the crystal becomes a reliable way to identify whether or not a new polymorph has been produced during a screen. If he finds that the two different polymorphs have indistinguishable shapes, Matzger performs a second screen using Raman spectroscopy and a final screen using X-ray diffraction.
"There just has not been much new out there," Matzger says. "If you look in the literature, you'll find people putting new methods forward and proposing different ways, but they did not find any new polymorphs. And it is hard to validate one of these new methods without finding new forms."
This article was published in Drug Discovery & Development magazine: Vol. 9, No. 9, September, 2007, pp. 22-26.
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