CHAPTER 3CHAPTER 3CHAPTER 3CHAPTER 3

Rationale for Selection of

Drugs and Objective of Study

Section Title Page No.

3.1 Rationale for selection of drugs 62

3.2 Objectives of study 64

3.4 References 65

Rationale for Selection of Drugs and Objectives of Study

62

3.1 Rationale for selection of drugs

Development of fixed dose combination is always a challenging task. Chemical

incompatibility is an important factor influencing drug stability. ASP and ATR fixed dose

combination was approved by CDSCO in India on 18th Jan 2008. The chemical structure

reveals that ASP is an ester moiety, and very susceptible to hydrolysis under different

hydrolytic conditions. Decomposition of ASP into salicylic acid is well-known. On the other

hand, ATR is an organic acid with a pKa of 4.46 and it is an acid-labile moiety which gets

converted into lactone under acidic conditions. (Vora and Kadav 2821-37)

So far, no reports are available regarding the comprehensive study on degradation behavior of

ATR and ASP in the presence of each other. From the reported data of the degradation profile

of individual drugs, it was thought to evaluate the chemical stability of ASP and ATR in

combination. By considering challenge of development of FDCs it was endeavored to study

degradation behavior of ASP and ATR in combination. Main rationale behind selecting this

combination was to study the possible chemical incompatibility between ASP and ATR due to

their structure in addition to monitor the degradation behavior of both drugs using simple RP-

HPLC method.

TAP was approved as a drug by USFDA in June 2008 and it was approved for marketing in

India by CDSCO in April 2011. Up till now it is not official in any pharmacopoeia. From

literature search it was revealed that few analytical methods are available for estimation of

TAP from bulk or formulations as summarized in literature review. Recently two research

papers were published as stability indicating assay (SIAM) of TAP using liquid

chromatographic technique.

Kathirvel et.al. has also reported method for impurity profiling of TAP. But no significant

forced degradation was reported in any condition. (Kathirvel, Satyanarayana and Devalarao 1-

8)

Marathe et.al has also not reported any degradation of TAP under stress conditions. Though

TAP has tertiary nitrogen in its structure, there are chances of formation of n-oxide

degradation product under oxidative stress conditions. But, both the reported work has not

shown any discussion based on structure of drug. Thus it was thought to study degradation

behavior TAP of at length using modern analytical tools like LC-MS/MS. (Marathe et al. 34-

41)

Chapter 3

63

FBX got approval as a drug by USFDA in February 2009 and it was approved for marketing

in India by CDSCO in November 2009.Very limited reports are available for estimation of

FBX from bulk, formulation as discussed in literature review.

Sahu et al published one stability indicating UPLC method for FBX recently in 2012 and

reported degradation of FBX in alkaline conditions. (Sahu, Shaharyar and Siddiqui 1-7)

Another author Mukthinuthalapati et al has also reported SAIM for FBX using LC-PDA

method. They reported that FBX is stable under all stress conditions without showing any

degradation. Apart from that, oxidative stress degradation chromatogram, shows one

additional peak which is not in accordance with manuscript of paper. As there is a conflict in

reported data of two methods of FBX it was a thought to study degradation behavior of FBX

at length up to characterization of degradation product if achieved any. (Mukthinuthalapati et

al. 1–8)

Structure of FBX has carboxylic functional group and nitrile functional group which are prone

to degradation in stress conditions. Based on this hypothesis, FBX was selected as moiety to

study further for degradation profile.

As per stability guidelines of WHO by conducting forced degradation studies and

subsequently providing complete information via scientific publications, will avoid the

repetitive studies for generic manufacturers of same drugs. (WHO2009)

Rationale for Selection of Drugs and Objectives of Study

64

3.2 Objectives of study

To monitor the quality of drugs, sensitive analytical methods are necessary which can

selectively quantify drug as well as its impurities or degradation products if present. Thus it

will ensure quality of drug substance or drug product throughout its shelf life. Hence by

considering importance of stress studies, present work was initiated with following main

objectives.

� Development and validation of stability indicating assay method for ASP and ATR alone

as well as in combination.

� To study the degradation behavior of ASP and ATR in different combination ratios.

� To study the degradation behavior of ASP and ATR in marketed fixed dose combination.

� Development and validation of stability indicating assay method for TAP.

� Characterization of major degradation products of TAP using LC-MS/MS studies.

� Postulate the degradation pathway and plausible mechanism for formation of degradation

products of TAP.

� Development and validation of stability indicating assay method for FBX.

� To study degradation behavior of FBX in marketed dosage form.

� Characterization of major degradation products of FBX using LC-MS/MS studies.

� Postulate the degradation pathway and plausible mechanism for formation of degradation

products of FBX.

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65

3.3 References

Kathirvel, Singaram, Suggala Venkata Satyanarayana, and Garikapati Devalarao.

"Application of a Validated Stability-Indicating Lc Method for the Simultaneous Estimation

of Tapentadol and Its Process-Related Impurities in Bulk and Its Dosage Form." Journal of

Chemistry (2013): 1-8.

Marathe, Gajanan M, et al. "Stability Indicating Rp-Hplc Method for the Determination of

Tapentadol in Bulk and in Pharmaceutical Dosage Form." International Journal of ChemTech

Research 5.1 (2013): 34-41.

Mukthinuthalapati, Mathrusri Annapurna, et al. "Development and Validation of a Stability-

Indicating Rp-Hplc Method for the Determination of Febuxostat (a Xanthine Oxidase

Inhibitor)." Journal of Chromatographic Science (2012): 1–8.

Sahu, Kapendra, Mohammad Shaharyar, and Anees A Siddiqui. "Establishment of Inherent

Stability of Febuxostat and Development of a Validated Stability-Indicating Method by Uplc

According to Ich Requirement." Medicinal Chemistry Research (2012): 1-7.

Vora, DN, and AA Kadav. "Validated Ultra Hplc Method for the Simultaneous Determination

of Atorvastatin, Aspirin, and Their Degradation Products in Capsules." Journal of Liquid

Chromatography & Related Technologies® 31.18 (2008): 2821-37.

WHO2009. "Stability Testing of Active Pharmaceutical Ingredients and Finished

Pharmaceutical Products." 2009. Vol. 953 of WHO Technical Report Series.