In the early 1990’s SSCI, Inc. began working with Parke-Davis Warner-Lambert by providing X-ray diffraction measurements on samples manufactured at its Holland, Michigan manufacturing facility. One of the compounds under investigation was atorvastatin calcium.
Atorvastatin had been synthesized by Bruce Roth at Warner-Lambert and patented in 1987 (US Patent 4,681,893). It was under development as a potent inhibitor of cholesterol biosynthesis. It was generally known that atorvastatin was a potential treatment for familial hypercholesterolemia. Atorvastatin calcium was the fourth “statin” under development, and it was expected to have rather low sales.
Atorvastatin calcium was being scaled up to the 50 kg scale in late 1993. The goal was to develop a process that was amenable to large-scale production and produce product in a form that could be easily filtered and dried. In addition, developing a stable solid form of atorvastatin calcium was desired. However, the Roth synthesis and all other manufacturing processes for atorvastatin calcium produced the amorphous form. This amorphous form was unstable and had to be protected from heat, oxygen, and moisture. Then in the late 90’s, atorvastatin crystallized; four crystalline forms, I, II, III, and IV, were isolated in this first crystallization study. Forms I, II, and IV were discovered at the Holland, Michigan facility, and Form III was discovered at SSCI in Indiana. Patents pertaining to the forms were filed in 1999 (US 5,969,156) and 2000 (US 6,121,461). Form I was of particular interest and its X-ray diffraction pattern and SSNMR were provided in US Patent 5,969,156. The crystalline forms were much more stable than the amorphous form. Thus, the first round of crystal studies produced four new forms. US Patent 5,969,156 also described how to prepare crystals of the calcium salt from the sodium salt by a salt exchange and also described the preparation of Form I by slurry methods. The broadest claim of this patent claimed crystalline atorvastatin with three X-ray lines, meaning that atorvastatin, as it was known at that time, could be characterized as Form I instead of Forms II, III, and IV by these three lines. Other claims of this patent described the other forms in terms of SSNMR lines.
Later, in 2003, another patent on atorvastatin calcium crystal forms discovered at SSCI appeared (US 6,605,729) which described Forms V through XIX of atorvastatin calcium. This patent represents the discovery of 15 more forms of atorvastatin calcium and utilized X-ray diffraction, SSNMR, and Raman spectroscopy for characterization. This patent states that the precise conditions required to produce these new forms must be determined empirically and provided a few methods found to be suitable in practice. Thus, this second round of crystallization studies produced 15 additional forms.
Then in 2011, a third patent authored by both Pfizer scientists and SSCI scientists appeared, describing 11 additional forms of atorvastatin calcium. This patent, US 8,026,376, was filed in 2005. This patent describes the forms using X-ray diffraction, small angle X-ray diffraction, SSNMR, and F-19 SSNMR. Thus, this third round of crystallization studies produced 11 additional forms.
A review of SciFinder, using the search terms atorvastatin AND polymorph AND X-ray shows 36 references. Many of these are from the 2004 to 2011 timeframe and may describe additional crystal forms.
In summary, atorvastatin calcium represents perhaps the compound with the greatest number of claimed polymorphs. As with the ROY and Ritonavir examples, late-appearing polymorphs of important materials that are extensively studied may be the rule and not the exception; these three compounds appear to verify McCrone’s statement that the number of polymorphs that exist for a given form depends upon the time and money spent to discover those forms.
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