A Review on Development of Stability Indicating Analytical Methods for drugs in Bulk and Pharmaceutical Dosage Form

 

Rahul D. Khaire*, P. Y. Pawar

Padmashree Dr. Vithalrao Vikhe Patil Foundation’s College of Pharmacy, Vadgaon Gupta Road Vilad Ghat, MIDC, Ahmednagar, Maharashtra 414111.

 

ABSTRACT:

High performance liquid chromatography (HPLC) is an important analytical tool in analyzing drug stability. HPLC methods should be able to separate, detect, and quantify the various drug-related degradants. Forced degradation studies (chemical and physical stress testing) of new chemical entities and drug products are essential to help develop and demonstrate the specificity of such stability-indicating methods. In addition to demonstrating specificity, forced degradation studies can be used to determine the degradation pathways and degradation products of the APIs that could form during storage, and facilitate formulation development, manufacturing, and packaging. ICH guidelines demonstrate certain degradation conditions like light, oxidation, dry heat, acidic, basic, hydrolysis etc. ICH Q1A, QIB and Q2B exemplify the forced degradation studies. This review overviews the approaches and trends that are used in forced degradation studies.

 

 

 

INTRODUCTION:

Forced degradation is a technique where different stress conditions are applied over drug substances and which in turn different degradation products are produced.¹ These studies are also called as stress testing or stress degradation studies. These methods are mainly used for the determination of stability of molecule under accelerated conditions.² It is known that regulatory documentation process, selection of proper storage and package conditions, and selection of formulation are dependent on the stability of molecules.³ In forced degradation process, general conditions such as light, heat, humidity, and oxidation are accelerated

 
individually or in combination with automated stress to accelerate the degradation of the molecule by physical or chemical means.^4,5 As per the International Committee for Harmonization (ICH) guidelines, the stability of the molecule, different degradative pathways, and validation of the developed stability procedures are studied using forced decomposition studies. The details of drug molecules that undergoes degradation and the different products that are formed with respect to time changes under the impact of different environmental parameters and understanding of stability data are well explained using the Food and Drug Administration (FDA) and ICH guidelines.^6,7 Degradation studies are important to determine the degradation routes and stability of pharmaceuticals under various stress conditions. Characterization of the degradants produced is usually carried out according to ICH guidelines. Different analytical equipment are employed to determine the stability studies. For instance, high-performance liquid chromatography-ultraviolet (HPLC-UV) and HPLC-photodiode array detector (PDA) are two common equipment to study the stability indicating method (SIM) development and validation purpose, while LC coupled to mass spectrometry (LC-MS) has become the authentic technique for characterization of degradant products (DP). LC-MS has gained enormous importance due to its high DP sensitivity and selectivity and in addition also provides a detailed structural information about the different DP.⁸

 

Need for forced degradation of drugs:

Studies on forced degradation of drug molecules are very important in the following aspects.^1-3

1.    To develop methods to determine stability.

2.    To determine the degradation pathways.

3.    For determination of intrinsic stability of drug in dosage forms.

4.    To study the chemical properties of molecules.

5.    For production of stable formulations.

6.    To determine the structure of decomposition products.

 

ICH Guidelines:

The ICH guidelines which discuss about forced degradation studies are ICH Q1A, ICH Q1B – photostability testing of new drug substances and drug product

ICH Q2B – Validation of analytical procedures: Methodology.

ICH Q3A impurities in new drug substances

ICH Q3B impurities in new products

 

Table 1: Frequently used conditions for forced degradation studies

 

Selection of Degradation Conditions^{1-3,5,8,10,12-17}:

Stability of drugs can be determined using normal conditions such as high temperature and pH. Later, the drug molecules were subjected to additional stress to study the stability. To study the degradation, the solution containing the drug sample was refluxed for a definite time. During this time, if any degradation products were observed, the process would be stopped; further isolation, identification, and characterization of the observed degradation products will be carried out.

 

Factors Affecting Degradation:

Following are the different factor which causes degradation of drug substances. They are:

·      Moisture

·      Excipients

·      Temperature

·      pH

·      Oxygen

·      Light

 

Characterization of Degradants:

Detection of impurities can be done by thin layer chromatography (TLC), electrophoresis, colorimetric, and gel filtration techniques, while separation and isolation of degradants in pure form can be done using reversed-phase HPLC, TLC, gas chromatography, and supercritical fluid chromatography. Notably, the determination of degradants pathways is carried out using LC-MS/MS technique. The degradative pathways can be determined on the basis of fragmentation patterns that are observed. The characterization of degradants produced was determined using advanced analytical techniques such as LC-MS, LC-NMR, and LC-MS/MS methods.

 

CONCLUSION:

Forced degradation studies are the prominent way to develop degradation pathways and to identify the degradation products of the active ingredients, further it facilitates the elucidation of degradants structure. Forced degradation studies also facilitate the chemical and physical stability analysis of drug substances and drug products. This assists to develop formulation manufacturing conditions, storage conditions and determine the expiry date of a drug formulation.

 

REFERENCES:

1.     Jain, D.; Basniwal, P. K. Forced Degradation and Impurity Profiling : Recent Trends in Analytical Perspectives. J. Pharm. Biomed. Anal. 2013, 86, 11– 35, DOI: 10.1016/j.jpba.2013.07.013

2.     ozet, E.; Lebrun, P.; Debrus, B.; Boulanger, B.; Hubert, P. Design Spaces for Analytical Methods. Trends Anal. Chem. 2013, 42, 157– 167, DOI: 10.1016/j.trac.2012.09.007

3.     ICH. Final Concept Paper ICH Q14: Analytical Procedure Development and Revision of Q2(R1) Analytical Validation; ICH, 2018.

4.      International conference on harmonization of technical requirements for registration of pharmaceuticals for human use. ICH Harmonised Tripartite Guideline, Validation of Analytical Procedures: Text and Methodology Q2(R1); ICH, 2005.

5.     Faizan Dosani, Nawaz Hakam, Aman Vyawahare, Swanand Patharkar, Kalpak Gajbhiye. Development and Validation of Stability Indicating Method of UV-Spectrophotometry for the Estimation of Flavoxate in Bulk and Tablet Dosage form. Asian Journal of Pharmaceutical Analysis. 2022; 12(1):6-2. doi: 10.52711/2231-5675.2022.00002.

6.     Manda Pravalika, Jorige Archana. A New Validated Spectroscopic Method for the estimation of Sodium Benzoate in Soft drinks. Asian Journal of Pharmaceutical Analysis. 2022; 12(1):13-6. doi: 10.52711/2231-5675.2022.00003

7.     Vinod Ahirrao, Rajiv Jadhav, Kiran More, Rahul Kale, Vipul Rane, Jaydeo Kilbile, Mohammad Rafeeq, Ravindra Yeole. An Accurate and Precise Analytical Method for Estimation of Active Sulfur Trioxide and Sulfuric acid in Triethylamine Sulfur Trioxide Complex. Asian J. Pharm. Ana. 2022; 12(1):17-2. doi: 10.52711/2231-5675.2022.00004.

8.     Jyoti Sonawane, Sonali Rathod, Sonali Suryawanshi, Durgesh Kale, Chaudhari Amit. Development and Validation of RP-HPLC Method for Estimation of Lacosamide in Bulk and Its Pharmaceutical Formulation. Asian Journal of Pharmaceutical Analysis. 2022; 12(1):23-8. doi: 10.52711/2231-5675.2022.00005.

9.     D. D. Masne, R. D. Chakole, M. S. Charde. QbD Approached in Method Development, Validation and Degradation Profiling of Aripiprazole a Antidepressent Agent. Asian Journal of Pharmaceutical Analysis. 2022; 12(1):29-4. doi: 10.52711/2231-5675.2022.00006.

10.   A. Suneetha, B. Chandra Sekhar, K. Sudheer Babu. DOE Assisted RP-HPLC Method Development and Validation for Estimation of L-Cysteine and Cystine with Dansyl Chloride derivatization in Presence of Amino Acid Mixture. Asian Journal of Pharmaceutical Analysis. 2022; 12(1):35-2. doi: 10.52711/2231-5675.2022.00007.

11.   Ceema Mathew, Sunayana Varma. Green Analytical Methods based on Chemometrics and UV spectroscopy for the simultaneous estimation of Empagliflozin and Linagliptin. Asian Journal of Pharmaceutical Analysis. 2022; 12(1):43-8. doi: 10.52711/2231-5675.2022.0000.

12.   Hamid Khan. Analytical Method Development in Pharmaceutical Research: Steps involved in HPLC Method Development. Asian J. Pharm. Res. 2017; 7(3): 203-207.

13.   Anand Gupta, Vaishali Jadhav, Ashish Jain. Analytical Method Development and Validation of Ticagrelor from Bulk and Formulation. Asian J. Pharm. Res. 2019; 9(3):141-146.

14.   Sonali Mahaparale, Diksha Banju. Recent Analytical Methods of Anti-Helmintic Agents. Asian J. Pharm. Res. 2019; 9(3):209-218.

 

 

 

Received on 11.05.2022       Modified on 14.07.2022

Accepted on 03.09.2022   ©Asian Pharma Press All Right Reserved

Asian J. Pharm. Ana. 2022; 12(4):261-263.