Imputities Evaluation of Pharmaceuticals Satinder Ahuja

Imputities Evaluation of Pharmaceuticals

The subject of impurities evaluation of pharmaceutical compounds has been insufficiently addressed in the scientific literature up to this time. Reasons for this shortcoming are many and varied. As a matter of fact, because of the apparent negativity attached to the word, there is no clear definition for impurity in the pharmaceutical world. Terms such as by-products, transformation products, degradation products, interaction products, and related products are frequently used. The impurities related to residual solvents used in the preparation of pharmaceutical compounds or marketed drug products are frequently referred to as organic volatile impurities (OVI). And the impurities relating to the inert ingredients ( excipients) used in pharmaceutical formulations or pharmaceutical adjuvants used in the preparation of the marketed drug products are rarely mentioned. 

It is necessary to incorporate stringent tests to control the impurities arising from different sources that are variously de­scribed, as explained above. This fact is also evident from the re­quirements of the Federal Food, Drug, and Cosmetic Act and from a large number of pharmacopeias that provide tests for the control of specific impurities. A new drug development process should include an armamentarium of physicochemical tests to fully define  the purity of a pharmaceutical compound prior to performance of extensive pharmacologic and toxicologic studies. This is essential to assure that the observed pharmacologic or toxicologic effects are truly due to the compound of interest and not due to impurities. Furthermore, it is important to ensure that the product formulated for marketing does not generate any impurities during its shelf life that could cause deleterious effects. 

This book discusses various sources of impurities, methods utilized to isolate and characterize them (including those methods that do not require pre-separation, such as GC/MS and HPLC/MS), analytical methods used for evaluation and control, and applica­tions to various classes of drug products (marketed products as well as those under development). Chiral impurities are also discussed from the standpoint of their origin, analytical meth­odology, and regulatory perspective for controlling them. 

The book is intended to be a valuable resource for a large number of analysts and administrative personnel involved in assuring the quality of pharmaceutical products. It may be of in­terest to the academic world as a textbook that aligns teaching with industrial needs. Regulatory authorities are likely to find this book useful, since it attempts to provide state-of-the-art information on the field. 

I would like to thank the forerunners in this field for their many contributions. And I thank my wife for her patience during the time this book was being written and published. 

There is no precise definition for "impurity," because of the apparent negativity attached to this word in the pharmaceutical sciences (1). Webster's dictionary defines impurity as something that is impure or makes something else impure. A better definition of an impure substance may be as follows: a substance of interest mixed or impregnated with an extraneous or usually inferior substance. Personally, I like a simple definition for an impurity, that is, any material that affects the purity of the material of interest, viz., active ingredient or drug substance. The impurities are not necessarily always inferior. From the standpoint of its usage, the drug substance is compromised in terms of purity even if it contains another material with superior pharmacological or toxicological properties. At first pass this may not be readily clear; however, on further thought it would become apparent that if we are to ensure that an accurate amount of the drug substance is being administered to the patient, then we must assess its purity independently from the extraneous materials. Therefore any ex­traneous material present in the drug substance has to be considered an impurity even if it is totally inert or has superior pharmacological properties. 

A number of terms have been commonly used to describe an impurity or impurities: 

Intermediate Penultimate intermediate By-products Transformation products Interaction product Related products Degradation products 

Some of these terms denote potential sources of impurities; 

e.g., intermediaries; others tend to de-emphasize the negativity,

e.g., related products. Let's review them individually:

Intermediates: The compounds produced during synthesis of the desired material are called intermediates, especially if they have been isolated and characterized. The most important criterion is characterization, i.e., they cannot be just potential reaction products theorized to occur (see By-products below). The theorized com­pounds are best designated as potential intermediates. 

Penultimate Intermediate: As the name suggests, this is the last compound in the synthesis chain prior to the production of the final desired compound. Sometimes confusion arises when the desired material is a salt of a free base or acid. In the opinion of this author, it is inappropriate to label the free acid or base as the penultimate intermediate if the drug substance is a salt. 

By-products: The unplanned compounds produced in the reaction are generally called by-products. It may or may not be possible to theorize all of them. Hence, they present a thorny problem to the analytical chemist. 

Transformation Products: This is a relatively nondescript term which relates to theorized and non-theorized products that may be 

produced in the reaction. Transformation products are very similar to by-products, except the term tends to connote that more is known about the reaction products. 

Interaction Products: This term is slightly more comprehensive and more difficult to evaluate than the two described above, i.e., by-products and transformation products, in that it considers interactions that could occur between various involved chemicals-­intentionally or unintentionally. 

Related Products: As mentioned, the term related products tends to suggest that the impurity is similar to the drug substance and thus tends to play down the negativity frequently attached to the term impurity. These products can have similar chemical structure and potentially similar biological activity; however, as we shall discuss later, this by itself does not provide any guarantee to that effect. 

Degradation Products: The compounds produced due to decomposition of the material of interest or active ingredient are often referred to as degradation products. We also need to concern ourselves with the products produced from degradation of other compounds that may be present as impurities in the drug substance.


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