Screening and detecting polymorphism when developing and manufacturing active pharmaceutical ingredients (APIs) is an ongoing
challenge for pharmaceutical manufacturers. Polymorphism is the ability of a compound to exist in more than one crystalline structure. Different solid forms can possess different
properties, including solubility, which can in turn affect the bioavailability of the drug.
Polymorph screening and detection
"The investigation of polymorphic forms of a drug substance is valuable to the pharmaceutical industry, as the differences
in the physical properties of different solid forms can be problematic in the later stages of development and formulation,"
says Chris Frampton, chief scientific officer at SAFC-Pharmorphix (Cambridge, UK). "Different solid forms can show differences in properties such as aqueous thermodynamic solubility, melting
point and hygroscopicity, which in turn can affect bioavailability, processability, and stability, respectively."
One of the more well-chronicled examples of polymorphism occurred in ritonavir, the API in "Norvir," a protease inhibitor
developed by A bbott Laboratories (Abbott Park, IL). The drug was approved in 1996, and in mid-1998, Abbott encountered manufacturing difficulties with the
capsule formulation, according to the company's 1998 annual report. Ritonavir exhibited conformational polymorphism of two
unique crystal lattices that had significantly different solubility properties (1). The formation of the polymorph caused
Abbott to pull the drug from the market and reformulate.
A recent analysis by SSCI, the solid-state chemistry business of Aptuit (Greenwich, CT), showed that of 245 compounds it has screened, 89% had multiple solid forms (see Figure 1). Approximately
50% of the compounds showed polymorphism, 37% were hydrates, and 31 were solvates, outlines Stephen Byrn, head of the scientific
advisory board of Aptuit and head of the Department of Industrial and Physical Pharmacy at Purdue University.
Other research conducted by Professor Ulrich Griesser at the University of Innsbruck shows a lower incidence of multiple solid
forms in organic molecules: polymorphism (36%), hydrates (28%), and solvates (10%) (2).
"The difference in prevalence of 51% versus 36% probably reflects the fact that many organic chemists do not search for polymorphs
when preparing new compounds," explains Byrn. "In contrast, compounds submitted to SSCI/Aptuit are drug candidates. Another
factor that may explain the differences in prevalence of polymorphs is the fact that SSCI/Aptuit would tend to get problem
compounds, including materials that have a large numbers of polymorphs."
Challenges in polymorph screening
A review of several APIs and new chemical entities (NCEs) shows not only the prevalence of other solid forms but also the
challenges in detecting these forms.
The polymorphism of acetaminophen shows the challenges in screening for polymorphs (see Figure 2).
"The crystal structures for two known crystal forms of acetaminophen (monoclinic and orthorhombic) have been published," explains
Frampton (3, 4). "The monoclinic form is the thermodynamically stable crystal form at room temperature with respect to the
orthorhombic form. Evidence for a third, metastable, form has been published (5, 6). To date, however, it has not been possible
to isolate any crystalline material to enable a full crystal structure or physicochemical property determination."