Comparative Solid-State Stability of Perindopril Active Substance vs. Pharmaceutical Formulation

Abstract

This paper presents the results obtained after studying the thermal stability and decomposition kinetics of perindopril erbumine as a pure active pharmaceutical ingredient as well as a solid pharmaceutical formulation containing the same active pharmaceutical ingredient (API). Since no data were found in the literature regarding the spectroscopic description, thermal behavior, or decomposition kinetics of perindopril, our goal was the evaluation of the compatibility of this antihypertensive agent with the excipients in the tablet under ambient conditions and to study the effect of thermal treatment on the stability of perindopril erbumine. ATR-FTIR (Attenuated Total Reflectance Fourier Transform Infrared) spectroscopy, thermal analysis (thermogravimetric mass curve (TG-thermogravimetry), derivative thermogravimetric mass curve (DTG), and heat flow (HF)) and model-free kinetics were chosen as investigational tools. Since thermal behavior is a simplistic approach in evaluating the thermal stability of pharmaceuticals, in-depth kinetic studies were carried out by classical kinetic methods (Kissinger and ASTM E698) and later with the isoconversional methods of Friedman, Kissinger-Akahira-Sunose and Flynn-Wall-Ozawa. It was shown that the main thermal degradation step of perindopril erbumine is characterized by activation energy between 59 and 69 kJ/mol (depending on the method used), while for the tablet, the values were around 170 kJ/mol. The used excipients (anhydrous colloidal silica, microcrystalline cellulose, lactose, and magnesium stearate) should be used in newly-developed generic solid pharmaceutical formulations, since they contribute to an increased thermal stability of perindopril erbumine.

Keywords: ASTM E698; comparative stability; decomposition; isoconversional kinetic study; perindopril erbumine; perindopril tert-butylamine; pharmaceutical formulation; thermal stability.

Figure 1

Structural formula of PER (perindopril erbumine dihydrate). The dotted line between the carboxylate moiety and the charged amine suggest the H-bonding interaction in the formation of the binary adduct.

Figure 2

ATR-FTIR spectra recorded on spectra range 4000–650 cm⁻¹ in solid state for: (a) perindopril tert-butylamine as the pure active pharmaceutical ingredient (PER_as); (b) PER_as kept for 24 h in isothermal conditions at 90 °C and (c) a commonly-used generic tablet containing the same active pharmaceutical ingredient (API) as PER_as (PER_pf). The spectral range 2400–2000 cm⁻¹ was suppressed due to the presence of ATR background bands.

Figure 3

Simultaneously-determined TG (thermogravimetric mass curve), DTG (derivative thermogravimetric mass curve), and normalized HF (heat flow) curves in oxidative air atmosphere at β = 5 °C·min⁻¹ for: (a) PER_as in the temperature range of 40–400 °C and (b) PER_pf in the temperature range of 40–500 °C.

Figure 4

Kissinger kinetic method linear plottings for PER_as (a) and PER_pf (b).

Figure 5

ASTM E698 kinetic method linear plottings for PER_as (a) and PER_pf (b). The different colored dots represent the DTG_peaks at different heating rates.

Figure 6

The progress of reaction vs. temperature for PER_as (a) and PER_pf (b).

Figure 7

Linear plotting of Friedman method at selected heating rates for PER_as (a) and PER_pf (b).

Figure 8

Linear plotting of Flynn-Wall-Ozawa method at selected heating rates for PER_as (a) and PER_pf (b). The different colored dots represent the DTG_peaks at different heating rates.

Figure 9

Linear plotting of Kissinger-Akahira-Sunose method at selected heating rates for PER_as (a) and PER_pf (b).