Evaluating Impurities in Drugs (Part I of III) - Pharmaceutical Technology

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Evaluating Impurities in Drugs (Part I of III)
In Part I of a three-part article, the authors discuss what constitutes an impurity and the potential sources of impurities in APIs and finished drug products.


Pharmaceutical Technology
Volume 36, Issue 2, pp. 46-51

Transformation products

Transformation products deal with theorized and nontheorized products produced in a reaction. They can be synthetic derivatives of byproducts and are closely related to byproducts.


Figure 6: Chloro impurity-formation scheme of salmeterol. HPLC is high-performance liquid chromatography. MDC is methylenedichloride; AlCl3 is aluminum chloride.
A reaction where transformation products occur is the formation of chloro acetyl derivative of salicylaldehyde during the acylation reaction of salicylaldehyde with bromo acetyl bromide using methylenedichloride (MDC) and aluminum chloride (AlCl3). Mechanistically, the formation of chloroacetyl derivative using bromoacetyl bromide could not be expected, but hypothetically, it could occur as a transformation reaction due to halogen exchange. During Friedel–Craft acylation with Lewis acid AlCl3 in methylene dichloride, the Lewis acid forms an ionized complex [Cl–AlCl2–Br]–, which eventually undergoes halogen exchange with the bromo acylium ion to yield the chloro acetyl derivative. Formation of this impurity in reaction is as high as 7–20%, which is an uncontrolled impurity in the manufacturing process. Nevertheless, this impurity would not affect the purity of the final drug substance because the reaction of the transformed impurity with 2 (see Figure 6, Part I) forms the desired product, salmeterol. The presence of the chloro impurity also has been confirmed by experiment (see Figure 6, Part II).

Interaction products

The term interaction product deals with the interaction of two or more intermediates/compounds with various chemicals, intentionally or unintentionally. An interaction product is slightly more comprehensive than byproducts and transformation products. Two types of interaction products that are commonly encountered are drug substance–excipient interactions and drug substance–container/closure interactions.

Related products

The term related products means that the impurity has similar structure as that of the drug substance and may exhibit similar biological activity. This structural similarity by itself, however, does not provide any guarantee of similar activity. An example of a related product is 8-fluoro olanzapine.

Degradation products

Impurities formed by decomposition or degradation of the end product during manufacturing of the bulk drug are called degradation products. The term also includes degradation products resulting from storage, formulation, or aging. Parts II and III of this article will discuss the types and sources of the degradation products in further detail.

Tautomer impurities

Tautomers are readily interconvertible constitutional isomers that coexist in equilibrium. For APIs or drug molecules that exhibit tautomerism, there has been a confusion in identifying the two tautomeric forms. If one tautomer is thermodynamically stable and is the major form, the other tautomer should be considered as an impurity or simply termed as a tautomer of the API or drug molecule. To the best of the authors' knowledge, there has been no literature relating to the isolation, synthesis, or characterization of a tautomeric impurity(-ies) from the final API.

Linezolid is an treatment for nosocomial infections involving gram-positive bacteria. Oxazolidinones possess a unique mechanism of bacterial protein synthesis inhibition (38–39). Linezolid has an N-acetyl group (–NH–CO–CH3) due to that lactam–lactim tautomerism, which may occur during the synthesis but also may be stable. An effective analytical method needs to be developed to identify both tautomers.

A key starting raw material of pemetrexed disodium 2,4-diamino-6-hydroxy-pyrimidine shows the keto-enol form occurring in different ratios and which will be converted to the final drug using a known synthesis (see Figure 3).

Tautomers vary in their kinetic and thermodynamic stability, thereby making it difficult to determine whether they could be separated, isolated, or analyzed. Keeping this in mind, the use of the term impurity for tautomers in a final API/drug moiety presumably will be an important discussion in near future.

Conclusion

Part I of article highlights the origination and classification of impurities and provides a perspective on impurities in drug substances and drug products. The impurity profile of a drug substance is on increasing importance for ensuring the quality of drug products. Whatever the class of impurity, its identification and adequate control is a tremendous challenge for process-development chemists. Because no two drugs are alike, neither are two development pathways. Each drug candidate poses a different challenge in terms of impurities, and establishing efficient ways for the isolation and control of impurities is a key task in process development.

Part II of this article, to be published in the March 2012 issue of Pharmaceutical Technology, will discuss chiral and polymorphic impurities. Part III, to be published in the April 2012 issue of Pharmaceutical Technology, will discuss genotoxic and stability impurities.

Kashyap R. Wadekar, PhD,* is a research scientist (II), Mitali Bhalme, PhD, is an associate research scientist, S. Srinivasa Rao is a research associate, K. Vigneshwar Reddy is a research associate, L. Sampath Kumar is a research chemist, and E. Balasubrahmanyam is a research chemist, all with Neuland Laboratories, 204 Meridian Plaza, 6-3-854/1, Ameerpet, Hyderabad, India, tel. 91 40 30211600,

*To whom all correspondence should be addressed.

Submitted: Sept. 19, 2011; Accepted Nov. 28, 2011.


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