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

Latest Issue
PharmTech

Latest Issue
PharmTech Europe

Evaluating Impurities in Drugs (Part II of III)
In Part II of a three-part article, the authors examine impurities from chiral molecules, polymorphic contaminants, and genotoxic impurities.


Pharmaceutical Technology
Volume 36, Issue 3, pp. 58-72

Polymorphic impurities

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).


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.
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.


ADVERTISEMENT

blog comments powered by Disqus
LCGC E-mail Newsletters

Subscribe: Click to learn more about the newsletter
| Weekly
| Monthly
|Monthly
| Weekly

Survey
Which of the following business challenge poses the greatest threat to your company?
Building a sustainable pipeline of products
Attracting a skilled workforce
Obtaining/maintaining adequate financing
Regulatory compliance
Building a sustainable pipeline of products
30%
Attracting a skilled workforce
27%
Obtaining/maintaining adequate financing
14%
Regulatory compliance
30%
View Results
Eric Langer Outsourcing Outlook Eric LangerBiopharma Outsourcing Activities Update
Cynthia Challener, PhD Ingredients Insider Cynthia Challener, PhDAppropriate Process Design Critical for Commercial Manufacture of Highly Potent APIs
Jill Wechsler Regulatory Watch Jill Wechsler FDA and Manufacturers Seek a More Secure Drug Supply Chain
Sean Milmo European Regulatory WatcchSean MilmoQuality by Design?Bridging the Gap between Concept and Implementation
Medicare Payment Data Raises Questions About Drug Costs
FDA Wants You!
A New Strategy to Tackle Antibiotic Resistance
Drug-Diagnostic Development Stymied by Payer Concerns
Obama Administration Halts Attack on Medicare Drug Plans
Source: Pharmaceutical Technology,
Click here