Polymorphism, the ability of a compound to exist in more than one crystalline form, affects the physical, chemical, and biological
properties of a compound in question (37). These properties may influence several issues in pharmaceutical systems, such as
processing characteristics, drug stability, and bioavailability. Demonstrating an understanding of the polymorphs in a given
drug is an area of regulatory scrutiny in new drug applications (38).
The International Conference on Harmonization's Q6A guideline, Specification: Test Procedure and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances, outlines when and how polymorphic forms should be monitored and controlled (39). For stability concerns, the most stable
form is normally used in the formulation. The metastable polymorphic form, however, may be inadvertently generated due to
temperature, mechanical treatment, and moisture during processing or storage of the drug product (40).
Contamination of polymorphic impurities can adversely influence the stability and performance of the final drug product. Moreover,
FDA requires development of validated methods for analysis of the proportion of crystalline forms throughout the drug's retest
period and shelf life (41).
For example, olanzapine crystallizes in more than 25 crystalline forms, of which Form II has been designated the most stable
form and is used in the dosage form (42, 43). Olanzapine discolors in the presence of air (44). Polymorphic Forms I and II
show very minor differences in their diffractograms. Evaluating olanzapine Form I for the presence of Form II, therefore,
becomes very important.
Salmeterol xinafoate is known to exist in two crystalline polymorphic forms, with Form I being stable and Form II being the
metastable polymorph under ambient conditions (45). These polymorphs have been characterized using differential scanning calorimetry,
X-ray powder diffractometry, thermogravimetric analysis, and inverse gas chromatography (46). Commercial salmeterol xinafoate
is a micronized form with the same crystal structure as that of Form I. The commercial drug, however, can contain traces of
the Form II polymorph that is formed during the micronization process.
Exceptional case impurities
When a new process is developed, such as to overcome patent issues, it generally begins with new key starting materials, intermediates,
reagents, or solvents that may react differently to give byproducts or process impurities. For example, in the synthesis of
linezolid and pemetrexed disodium, several process impurities can be formed due to different process approaches.
Pharmaceutical companies can develop new processes based on raw materials, solvents, reagents, process conditions (i.e., temperature),
and new polymorphs. Using new materials or processes, they may encounter several impurities that may not have been not present
in the basic or initial synthesis of an API. After publication of monographs in the United States Pharmacopeia, European Pharmacopoeia, British Pharmacopoeia, Indian Pharmacopoeia, and Japanese Pharmacopoeia, they may not have a control of those impurities that are formed due to different process approaches. After publication of
the monograph, companies have to change the analytical method or control these impurities as nonpharmacopeial impurities,
including genotoxic impurities, with separate analytical methods, such as high-performance liquid chromatography (HPLC) or
gas chromatography (GC).
For example, during the synthesis of linezolid, impurities based on a bis-linezolid compound and a bis-benzyl impurity
are formed due to the non-infringed patent process (47–49). Some published patents have different potential process impurities,
which cannot be separated in a single HPLC method, and which result from synthetic routes different from the synthetic route
in the basic patent (47–55).
Pemetrexed disodium heptahydrate, the API in Eli Lilly's Alimta, is a multitargeted antifolate used to treat mesothelioma
and a second-line treatment for non-small-cell lung cancer. Alimta also is under investigation for multiple other cancers
(56). Each non-infringed process patent has different potential impurities (see Figure 1, Process Impurities 1, 2, 3, and
4) (57–60). It may not be possible to analyze these impurities in a single HPLC method.
Figure 1: Reaction scheme for different process approaches for pemetrexed sodium impurities, respectively labeled as 1, 2,
3, and 4 (Refs. 57–60). Ph. Eur. is European Pharmacopoeia.