Investigation of Drug-Excipient Compatibility Studies Using Validated RP-HPLC Method for Azelnidipine and Telmisartan Tablets

Aims: The Drug-Excipient compatibility testing was conducted at an early product development stage to determined that Excipients were compatible with drugs used in formulation and to distinguish as many degradation products as possible using validated gradient RP-HPLC method. Study Design: Drug-Excipient Compatibility study was conducted in glass vials at different stability conditions namely, at 30 0 C + 2 0 C/75% + 5% RH, 40 0 C + 2 0 C/ 75% + 5% RH for 04 weeks and another set of closed vials were stored in stability chamber at temperature 60C + 2C for 02 weeks. Methodology: Samples were analyzed by validated RP-HPLC method using Inertsil C-18 Column 150 × 4.6 mm ×5 μm, column oven temperature 40°C, flow rate 1.5 mL/min, Injection volume 10 μL with run time 12.0 minutes at 254 nm using Acetonitrile and buffer as mobile phase in gradient mode. Results: The developed method meets all system suitability parameters and found specific to determine the drug in the presence of Excipient as no interference was observed at the Retention time (Rt) of analyte. Conclusion: There was no physical and chemical incompatibility observed with Drug-Excipient and did not observe significant increase in the related substances. Original Research Article Kumar et al.; JPRI, 33(41B): 233-242, 2021; Article no.JPRI.73027 234

0 C + 2 0 C/75% + 5% RH, 40 0 C + 2 0 C/ 75% + 5% RH for 04 weeks and another set of closed vials were stored in stability chamber at temperature 60 0 C + 2 0 C for 02 weeks. Methodology: Samples were analyzed by validated RP-HPLC method using Inertsil C-18 Column 150 × 4.6 mm ×5 µm, column oven temperature 40°C, flow rate 1.5 mL/min, Injection volume 10 µL with run time 12.0 minutes at 254 nm using Acetonitrile and buffer as mobile phase in gradient mode. Results: The developed method meets all system suitability parameters and found specific to determine the drug in the presence of Excipient as no interference was observed at the Retention time (Rt) of analyte. Conclusion: There was no physical and chemical incompatibility observed with Drug-Excipient and did not observe significant increase in the related substances.

INTRODUCTION
Drug-Excipient compatibility method was developed by which possible stability problems occurs due to interaction of drug substances with excipients in finished formulation can be forecast [1]. Drug-excipient compatibility study is an essential in the preformulation phase of the progress of all dosage forms.
[2] The probable physical and chemical interactions of drugs and excipients can change the physical, chemical, therapeutic property and constancy of the dosage form. Drug-excipient compatibility study provides the details of drug degradation, mechanism of drug-excipient interaction like physical, chemical and biopharmaceutical. [3] Various thermal and non-thermal method of analysis, are used to detect incompatibility between drug and excipient. [4] When the nature of interaction is determined further steps can be taken to improve the stability of drug and its dosage form. From these studies, we can conclude that consequential use of thermal and non-thermal method provides data for drug-excipient interaction which help in assortment of excipient for the improvement of stable dosage form. In addition to examine the interactions between the API and the excipients, the effect of factors such as humidity and temperature is explored in these studies. Such factors are known to speed up the degree of drugexcipient interactions by changing the physicochemical properties or rate of degradation of the drugs and excipients. [5][6] During these studies bulk drug and excipients comes into contact with each other as physical admixtures in a fixed ratio, or as a preliminary dosage form; subject to several stress conditions. The physico-chemical and performance attributes of the bulk drug and excipients are then estimated using one or more analytical techniques [7][8][9][10][11].

Chromatographic conditions and instrument
HPLC instrument (Agilent make, model-LC-1210 with empower software) equipped with Photodiode-Array Detection (PDA) detector was used with Inertsil C-18 column 150×4.6 mm, 5 µm particle size at temperature 40°C.The flow rate of mobile phase was at 1.5 mL/min in gradient mode, λ max 254 nm, injection volume 10 µL and run time of analytical method was 12 mins.

Preparation of Buffer solution
Accurately weighed and transferred the 4.0 gm of Ammonium dihydrogen orthophosphate in to 2000 mL of HPLC grade water, mixed well and sonicated till dissolved. Adjusted the pH of buffer to 3.0 ± 0.05 with dilute Ortho-phosphoric acid and filtered through 0.45 pm PVDF membrane filter and degassed.

Preparation of Diluent/ Blank solution
The buffer and Acetonitrile (25:75 % v/v) was mixed and sonicated, and same used as blank solution.

Preparation of stock and standard solutions
The

Storage and Analysis of samples
Prepare Drug: Excipient compatibility samples and charging for stability at different stability conditions 30 0 C + 2 0 C/ 75% + 5% RH, 40 0 C + 2 0 C/ 75% + 5% RH for 04 weeks and 60 ± 2°C for 02 weeks and then analyzed for physical (appearance, color etc.) and chemical stability. Accurate amount of drug and excipient were mixed and placed in glass vials. Each vial was labeled with the amount of drug and excipient. The total weight of drug excipient blend in a vial was usually kept at about 2 gm & 3 gm (Drug: Excipient in 1:1 ratio & 1:1:1 ratio.) The above samples of Drug-Excipient mixtures were analyzed at the end of above mentioned time interval by using validated RP-HPLC method.

System Suitability
System suitability parameters were performed by injecting blank in single and six replicate injections of standard solution ( Fig. 1, 2). The % RSD for area and Rt of Azelnidipine and Telmisartan peak obtained from six replicate standard injections should be not more than (NMT) 2.0, Tailing Factor NMT 2.0, Theoretical Plates NLT 2000 and Resolution factor not less than (NLT) 2.0., obtained results were presented in Table 2.

Specificity
Specificity of the developed method was measured to analyze response in presence of any interfering factors (like excipients, related substances etc.).
There was no any interference from blank, placebo and excipients at the retention time of Azelnidipine and Telmisartan peak. Retention time of main peak from sample preparation should be similar to that of standard preparation

Analysis of Drug-Excipient Samples
Drug-Excipient mixtures were analyzed by using validated RP-HPLC method ( Fig. 3-8). After performing System Suitability and Specificity, samples were analyzed with freshly prepared standard solution.    Azelnidipine  Azelnidipine  Azelnidipine  Azelnidipine The % difference in peak area counts was NMT 5%. Hence samples were found stable during Drug-Excipient studies at above mentioned conditions
The binary mixtures which were tested at stability condition, did not changes any physical or chemical parameters. The colour, texture of the test samples remained same in, side by side comparison with samples stored under ambient conditions. The analytical data of mixtures in the ratio of 2 gm (Drug: Excipient in 1:1 ratio) & 3 gm (Drug: Drug: Excipient in 1:1:1 ratio) did not show significant increase in the related substance from initial. Hence it is concluded that, all the excipients selected were compatible with the drug substance.

DISCLAIMER
The products used for this research are commonly and predominantly use products in our area of research and country. There is absolutely no conflict of interest between the authors and producers of the products because we do not intend to use these products as an avenue for any litigation but for the advancement of knowledge. Also, the research was not funded by the producing company rather it was funded by personal efforts of the authors.

CONSENT
It is not applicable.

ETHICAL APPROVAL
It is not applicable.