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. 2024 Nov 21;16(12):1488.
doi: 10.3390/pharmaceutics16121488.

Co-Amorphization, Dissolution, and Stability of Quench-Cooled Drug-Drug Coamorphous Supersaturating Delivery Systems with RT-Unstable Amorphous Components

Yan-Fei Zhang  1 , Qian Yao  2 , Xiao-Ying Lin  1 , Ying-Hui Ma  1 , Hui-Feng Zhang  1 , Huan Yu  1 , Shang-Qiang Mu  3 , Chuang Zhang  1 , Hao Geng  1 , Cheng-Yi Hao  1 , Li-Li Zuo  1 , Di Wu  1 , Yue Li  2 , Li-Li Jin  2 , Nian-Qiu Shi  1   2
Affiliations

Co-Amorphization, Dissolution, and Stability of Quench-Cooled Drug-Drug Coamorphous Supersaturating Delivery Systems with RT-Unstable Amorphous Components

Yan-Fei Zhang et al. Pharmaceutics. .

Abstract

Background: Supersaturating drug delivery systems (SDDSs) have gained significant attention as a promising strategy to enhance the solubility and bioabsorption of Biopharmaceutics Classification System (BCS) II drugs. To overcome challenges associated with polymer-based amorphous SDDS (aSDDS), coamorphous (CAM) systems have emerged as a viable alternative. Among them, "drug-drug" CAM (ddCAM) systems show considerable potential for combination drug therapy. However, many drugs in their pure amorphous forms are unstable at room temperature (RT), complicating their formation and long-term stability profiles. Consequently, limited knowledge exists regarding the behavior of ddCAMs containing RT-unstable components formed via quench cooling. Methods: In this study, we used naproxen (NAP), a RT-unstable amorphous drug, in combination with felodipine (FEL) or nitrendipine (NTP), two RT-stable amorphous drugs, to create "FEL-NAP" and "NTP-NAP" ddCAM pairs via quench cooling. Our work used a series of methods to perform a detailed analysis on the co-amorphization, dissolution, solubility, and stability profiles of ddCAMs containing RT-unstable drugs, contributing to advancements in co-amorphization techniques for generating SDDS. Results: This study revealed that the co-amorphization and stability profiles of ddCAMs containing RT-unstable components produced via a quench-cooling method were closely related to drug-drug pairing types and ratios. Both quench-cooling and incorporation into coamorphous systems improved the dissolution, solubility, and physical stability of individual APIs. Conclusions: Our findings provide deeper insight into the co-amorphization, dissolution, and stability characteristics of specific drug-drug coamorphous systems FEL-NAP and NTP-NAP, offering valuable guidance for developing new ddCAM coamorphous formulations containing some RT-unstable drugs.

Keywords: coamorphization and stability; combination therapy; quench cooling; supersaturating drug delivery systems (SDDS); “drug–drug” coamorphous system (ddCAM).

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Chemical structures of (A) felodipine (FEL); (B) naproxen (NAP); (C) nitrendipine (NTP).
Figure 2
Figure 2
HPLC chromatogram results for crystalline FEL (A), FEL-related samples of FEL-NAP (1:1) (B), crystalline NAP (C), NAP-related samples of FEL-NAP (1:1) (D), NAP-related samples of NTP-NAP (1:1) (E), crystalline NTP (F), and NTP-related samples of NTP-NAP (1:1) (G).
Figure 3
Figure 3
(A) PXRD results for crystalline FEL, crystalline NAP, FEL-NAPPM (1:1), amorphous FEL, FEL-NAP (1:1), FEL-NAP (1:2), and FEL-NAP (2:1); (B) PXRD results for crystalline NTP, crystalline NAP, NTP-NAPPM (1:1), amorphous NTP, NTP-NAP (1:1), NTP-NAP (1:2), and NTP-NAP (2:1).
Figure 4
Figure 4
SEM images of (A) crystalline FEL; (B) crystalline NTP; (C) crystalline NAP; (D) FEL-NAPPM (1:1) (FEL: white arrow and NAP: red arrow); (E) FEL-NAP (1:1); (F) the physical mixture NTP-NAPPM (1:1) (NTP: green arrow and NAP: red arrow); (G) NTP-NAP (2:1).
Figure 4
Figure 4
SEM images of (A) crystalline FEL; (B) crystalline NTP; (C) crystalline NAP; (D) FEL-NAPPM (1:1) (FEL: white arrow and NAP: red arrow); (E) FEL-NAP (1:1); (F) the physical mixture NTP-NAPPM (1:1) (NTP: green arrow and NAP: red arrow); (G) NTP-NAP (2:1).
Figure 5
Figure 5
(A) DSC thermograms of all samples, including crystalline FEL, crystalline NAP, FEL-NAPPM (1:1), amorphous FEL, FEL-NAP (1:1), FEL-NAP (1:2), and FEL-NAP (2:1); (B) DSC thermograms of all samples including crystalline NTP, crystalline NAP, NTP-NAPPM (1:1), amorphous NTP, NTP-NAP (1:1), NTP-NAP (1:2), and NTP-NAP (2:1).
Figure 6
Figure 6
(A) FT-IR spectra of crystalline FEL, crystalline NAP, FEL-NAPPM (1:1), FEL-NAP (1:1), FEL-NAP (1:2), and FEL-NAP (2:1); (B) FT-IR spectra of crystalline NTP, crystalline NAP, NTP-NAPPM (1:1), NTP-NAP (1:1), NTP-NAP (1:2), and NTP-NAP (2:1); (C,D) Spatial structures (black balls represent carbon atoms, grey balls represent hydrogen atoms, red balls represent oxygen atoms, blue balls represent nitrogen atoms, and green balls represent chlorine atoms) of FEL-NAP (C) and NTP-NAP (D).
Figure 7
Figure 7
(A) Dissolution profiles of FEL-related samples containing equivalent amounts of FEL (50 mg), including FEL-NAP (1:1, 1:2, and 2:1), amorphous FEL, FEL-NAPPM (1:1), and crystalline FEL, in 900 mL of 0.1 M hydrochloric acid (37 °C). (B) Dissolution profiles of NAP-related samples containing equivalent amounts of NAP (50 mg), including FEL-NAP (1:1, 1:2, and 2:1), FEL-NAPPM (1:1), and crystalline NAP, in 900 mL of 0.25% SDS solution (pH = 7.2, 37 °C). (C) Dissolution profiles of NTP-related samples containing equivalent amounts of NTP (50 mg), including NTP-NAP (1:1, 1:2, and 2:1), amorphous NTP, NTP-NAPPM (1:1), and crystalline NTP, in 900 mL of 0.1 M hydrochloric acid solution (37 °C). (D) Dissolution profiles of NAP-related samples containing equivalent amounts of NAP (50 mg), including NTP-NAP (1:1, 1:2, and 2:1), NTP-NAPPM (1:1), and crystalline NAP, in 900 mL of 0.25% SDS solution (pH = 7.2, 37 °C). Error bars represent the standard deviation, n = 3.
Figure 8
Figure 8
(A,B) Solubility of FEL-related samples including FEL-NAP (1:1, 1:2, and 2:1), amorphous FEL, FEL-NAPPM (1:1), and crystalline FEL in 900 mL H2O at 37 °C for 24 h (A) and 48 h (B). (C,D) Solubility of NAP-related samples including FEL-NAP (1:1, 1:2, and 2:1), FEL-NAPPM (1:1), and crystalline NAP in 900 mL H2O at 37 °C for 24 h (C) and 48 h (D). Error bars represent the standard deviation, n = 3; * p < 0.05, ** p < 0.01, *** p < 0.001.
Figure 9
Figure 9
(A,B): Solubility of NTP-related samples including NTP-NAP (1:1, 1:2, and 2:1), amorphous NTP, NTP-NAPPM (1:1), and crystalline NTP in 900 mL H2O at 37 °C for 24 h (A) and 48 h (B). (C,D) Solubility of NAP-related samples including NTP-NAP (1:1, 1:2, and 2:1), NTP-NAPPM (1:1), and crystalline NAP in 900 mL H2O at 37 °C for 24 h (C) and 48 h (D). Error bars represent the standard deviation, n = 3; n.s. (No significance), * p < 0.05, ** p < 0.01, *** p < 0.001.
Figure 10
Figure 10
PXRD results for (A) amorphous FEL (0 month), (A1) amorphous FEL (1 month), (B) FEL-NAP (1:1) (0 month), (B1) FEL-NAP (1:1) (1 month), (C) FEL-NAP (1:2) (0 month), (C1) FEL-NAP (1:2) (1 month), (D) FEL-NAP (2:1) (0 month), (D1) FEL-NAP (2:1) (1 month), (E) amorphous NTP (0 month), (E1) amorphous NTP (1 month), (F) NTP-NAP (2:1) (0 month), and (F1) NTP-NAP (2:1) (1 month).
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