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. 2020 Dec 10;5(50):32466-32480.
doi: 10.1021/acsomega.0c04588. eCollection 2020 Dec 22.

Lyophilized Amorphous Dispersion of Telmisartan in a Combined Carrier-Alkalizer System: Formulation Development and In Vivo Study

Khater A S Al-Japairai  1   2 , Hala M Alkhalidi  3 , Syed Mahmood  1 , Samah H Almurisi  2 , Abd Almonem Doolaanea  2 , Taha A Al-Sindi  4 , Bappaditya Chatterjee  2   5
Affiliations

Lyophilized Amorphous Dispersion of Telmisartan in a Combined Carrier-Alkalizer System: Formulation Development and In Vivo Study

Khater A S Al-Japairai et al. ACS Omega. .

Abstract

Telmisartan suffers from low oral bioavailability due to its poor water solubility. The research work presents a formulation of solid dispersed (SD) telmisartan formulation as a ternary mixture of a drug, a polymeric carrier (poly(vinylpyrrolidone) (PVP) K30), and an alkalizer (Na2CO3). The preparation method, which was lyophilization of an aqueous solution containing the ingredients, was free from any organic solvent. The developed SD formulations resulted in a significant improvement in in vitro dissolution (>90% drug dissolution in 15 min) compared to pure telmisartan. Solid-state characterization by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and X-ray diffraction (XRD) studies indicated the conversion of crystalline telmisartan into an amorphous form. Fourier transform infrared (FTIR) spectroscopy revealed the drug-polymer interaction that was responsible for reducing the chances of recrystallization. A short-term stability study showed that selected SD formulations were stable in terms of in vitro dissolution and retained their amorphous structure in ambient and accelerated conditions over 2 months. Selected formulations (drug/PVP K30/Na2CO3 as 1:1:2 or 1:2:2 weight ratio) resulted in >2.48 times relative oral bioavailability compared to marketed formulations. It was considered that the incorporation of an alkalizer and a hydrophilic polymer, and amorphization of telmisartan by lyophilization, could enhance in vitro dissolution and improve oral bioavailability.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Miscibility of telmisartan with PVP K30 (polymer) at varying concentrations; polymer conc w/w: concentration of PVP K30 in water.
Figure 2
Figure 2
In vitro dissolution profile of telmisartan solid dispersion with the alkalizer (F1, F2) and without the alkalizer (F12, F13). The value within parentheses against each formulation represents the composition by weight ration of telmisartan/PVP K30/Na2CO3. Each time point is representative of mean data ± SD (n = 3).
Figure 3
Figure 3
In vitro dissolution profile of all SDtelmi formulations, marketed formulation (marketed TEL), pure telmisartan (pure TEL), physical mixture (PM F1 and PM F2). The value within parentheses against each formulation represents the composition by weight ratio of telmisartan/PVP K30/Na2CO3. Each time point is representative of mean data ± SD (n = 3).
Figure 4
Figure 4
In vitro dissolution profile of all solid dispersed telmisartan coded as (A) F1, F2, F3, F6, F9; (B) F4, F7, F10; and (C) F5, F8, F11. The value within parentheses against each formulation represents the composition by weight ration of telmisartan/PVP K30/Na2CO3. Each time point is representative of mean data ± SD (n = 3).
Figure 5
Figure 5
FTIR spectra of (A) pure telmisartan, PVP K30, Na2CO3, and individual binary mixture of telmisartan with PVP K30 and Na2CO3 and (B) pure telmisartan and solid dispersion formulations of telmisartan (F1, F2, and F3). The value within parentheses against each formulation represents the composition by weight ration of telmisartan/PVP K30/Na2CO3. The encircled zone of spectra indicated the characteristic telmisartan peak at 1694.11 cm–1.
Figure 6
Figure 6
SEM micrographs of pure telmisartan, PMtelmi (physical mixture 1:1:1 weight ratio of telmisartan, Na2CO3, and PVP K30), and solid dispersion formulations (F1, F2, F3). The value within parentheses against each formulation represents the composition by weight ratio of telmisartan/PVP K30/Na2CO3.
Figure 7
Figure 7
DSC thermograms of pure telmisartan, PVP K30, ternary physical mixture of telmisartan/PVP K30/Na2CO3 (PM), and solid dispersion of telmisartan (F1, F2, F3).
Figure 8
Figure 8
Powder X-ray diffractograms of (A) telmisartan, (B) PVP K30, (C) Na2CO3, (D) ternary physical mixture of equal weight ratio of telmisartan/PVP K30/Na2CO3, and (E–G) solid dispersion formulations of telmisartan (F1, F2, and F3).
Figure 9
Figure 9
In vitro dissolution study of THE short-term stability sample for solid dispersionS of telmisartan (F1, F2, and F3) in ambient and accelerated conditions. Each time point is representative of mean data ± SD (n = 3).
Figure 10
Figure 10
Powder X-ray diffractograms of the stability study sample of three solid dispersions of telmisartan (F1, F2, and F3) at 2 months time point kept under accelerated conditions. The value within parentheses against each formulation represents the composition by weight ratio of telmisartan/PVP K30/Na2CO3.
Figure 11
Figure 11
Plasma concentration vs time profile for raw telmisartan (raw TEL), marketed formulation (marketed TEL), and solid dispersion of telmisartan (F1, F2). Each data is represented as mean data ± SD (n = 3). The value within parentheses against each formulation represents the composition by weight ratio of telmisartan/PVP K30/Na2CO3. The sample was collected at 12 h after 8 h. However, no telmisartan was detected at 12 h.
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