Development and validation of novel analytical methods for the quantitative

determination of active ingredients, impurities and degradation products of

By

Tarekegn Tadesse Unade (B.pharm, MSC)

A research concept note prepared for the requirements of partial fulfillment

January, 2019

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 1. Introduction

1.1. Background

Infectious disease is one of the major causes of morbidly and mortality globally, particularly in
developing nations. Drug resistance is a significant bottleneck in combating these diseases and
regarded as a big homework for scientists for the development of newer agents. Starting from the
era of sulfonamides Pharmaceutical researchers has been working to develop efficacious and safe
products to combat these aliments for centuries. Modern pharmaceutical companies have faced
repeated crises when new forms of antibiotic resistance emerged in previously susceptible
pathogens. In each of these crises, the industry has rallied to bring forward new therapeutic
approaches.

Pharmaceutical research in the last few decades has resulted in the launch of numerous anti-
infective drugs. The advanced and extremely potent drugs have found their applicability in
treating various types of ailments. Because these drug substances are highly potent, a few of the
impurities associated with these are also found to be very toxic. If these impurities are passed on
to the drug substance or drug product can lead to serious toxicological consequences. More
importantly, a number of such agents were approved to be marketed globally but their efficacy
until the end of their shelf life and the safety of the marketed products was not addressed well. In
line with this, no appropriate analytical method has been developed to evaluate safety and
efficacy of some of these recently marketed anti-infective.

Safety and efficacy of pharmaceuticals are two basic problems with importance in drug therapy.
Instability of pharmaceuticals can cause a change in physical, chemical, pharmacological, and
toxicological properties of the active pharmaceutical ingredients (API), thereby affecting its
safety and efficacy. Hence, the pharmacists should take cognizance of various factors such as
drug stability, possible degradation products, mechanisms and routes of degradation, and
potential inter- actions with excipients utilized in the formulation to ensure the delivery of their
therapeutic values to patients.

But to assess the safety and efficacy of pharmaceutical products development and validation of
appropriate analytical methodology is mandatory. These developed analytical methodologies
need to be fast, accurate precise and sensitive etc according to the international guidelines. So the
purpose of this project is to develop novel stability indicating analytical methods for the
determination of most recently developed anti-infective pharmaceutical preparations. The type
method to be developed could be novel HPLC and other available instrumental methods

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 1.2. Overview of analytical method development and validation

Drug analysis reveals the identification characterization & determination of the drugs in mixtures
like dosage forms & biological fluids. During manufacturing process and drug development the
main purpose of analytical methods is to provide information about potency (which can be
directly related to the requirement of a known dose), impurity (related to safety profile of the
drug), bioavailability (includes key drug characteristics such as crystal form, drug uniformity and
drug release ), stability ( which indicates the degradation products ), and effect of manufacturing
parameters to ensure that the production of drug products is consistent.

Analytical methods development and validation play important roles in the discovery,
development, and manufacture of pharmaceuticals. The official test methods for newly
developed pharmaceuticals requires developing methods to be used by quality control
laboratories to ensure the identity, purity, potency, and performance of drug products.

When there are no authoritative methods are available, new methods are being developed for
analysis of novel products. Method development can take a number of forms. At one extreme, it
may involve adapting an existing method, making changes so that it is suitable for a new
application. It requires a lot of effort, and there is a degree of doubt initially to whether the
method will be successful. It involves working on various ideas simultaneously and then finally
picking one of those

Method validation is the process of proving that a particular developed analytical method is
acceptable for its intended use. Validation is an important requirement in the practice of an
analytical process. Method validation can be interpreted as the process of defining an analytical
requirement, and confirming that the method under consideration has performance capabilities
consistent with that the application requires. The most commonly validated analytical methods in
drug analysis include: Identification tests, Potency assays, quantitative tests for impurities, limit
test for the control of impurities and Specific tests.Developed analytical method is validated for
the following parameters: accuracy, precision,

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1.3 Significance of the study

Development and validation of analytical methods for the determination of these newly
developed anti-infective pharmaceutical preparations is mandatory. These methods are needed
for assurance of quality, safety and efficacy of pharmaceuticals. The need for these advanced
methods is not only because of the safety but also because of the increasingly vigilant and
stringent regulatory requirements. In general, development of analytical methods is important
due to:- development of new drugs , continuous improvements in manufacturing processes for
existing drugs and , revision of threshold limits for individual and total impurities of drugs by
regulatory authorities.

2. Objectives
General objective

• To develop and validate novel analytical methods for newly developed anti-infective
drugs

Specific objectives

• To develop and validate analytical methods for the identification test of newly developed
anti-infective drugs
• To develop and validate stability indicating analytical method for the determination of
newly developed anti-infective drugs
• To develop and validate methods for the detection and determination of likely impurities
in the newly developed anti-infective drugs
3. Methods
Recently marketed anti-infective pharmaceutical products for which no stability indicating
analytical methods have ever been developed will be selected and appropriate method for their
determination will be developed. The developed method will be validated for the common
parameters like accuracy, precision, linearity, and limit of detection, limit of quantification,
robustness and others. Furthermore, applicability studies for the available dosage forms will be
performed as the standard protocols.

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References

Bush K.(2014).why it is important to continuous discovery of antibacterial drugs. ASM News,

Kumar A et al (2012). Method development and validation: Skills and tricks. Chromatography
research international . doi:10.1155/2012/713273.
Ravisnaker P. and Navya N.(2015). A review on step-by-step analytical method validation .IOSR
journal of pharmacy 5:07-19.

Srinivas M. (2013). Quantitative determination of active pharmaceutical ingredients, related

WHO (2005).globalization and infectious diseases, Geneva Switzerland