Advances in coamorphous drug delivery systems

Abstract

In recent years, the coamorphous drug delivery system has been established as a promising formulation approach for delivering poorly water-soluble drugs. The coamorphous solid is a single-phase system containing an active pharmaceutical ingredient (API) and other low molecular weight molecules that might be pharmacologically relevant APIs or excipients. These formulations exhibit considerable advantages over neat crystalline or amorphous material, including improved physical stability, dissolution profiles, and potentially enhanced therapeutic efficacy. This review provides a comprehensive overview of coamorphous drug delivery systems from the perspectives of preparation, physicochemical characteristics, physical stability, in vitro and in vivo performance. Furthermore, the challenges and strategies in developing robust coamorphous drug products of high quality and performance are briefly discussed.

Keywords: API, active pharmaceutical ingredient;; AUC, area under plasma concentrations-time curve; BCS, bio-pharmaceutics classification systems; Bioavailability; Characterization; Cmax, maximum plasma concentration; Coamorphous; Css, plasma concentration at steady state; DSC, differential scanning calorimetry; DVS, dynamic vapor sorption; Dc, relative degree of crystallization; Dissolution; FT-IR, fourier transform infrared spectroscopy; HME, hot melt extrusion; HPLC, high performance liquid chromatography; IDR, intrinsic dissolution rate; LFRS, low-frequency Raman spectroscopy; LLPS, liquid—liquid phase separation; MTDSC, modulated temperature differential scanning calorimetry; NMR, nuclear magnetic resonance; P-gp, P-glycoprotein; PXRD, powder X-ray diffraction; Physical stability; Preparation; RH, relative humidity; SEM, scanning electron microscope; TGA, thermogravimetric analysis; Tg, glass transition temperature; Tmax, time of maximum plasma concentration; UV, ultraviolet spectroscopy.

Graphical abstract

Figure 1

Classification of amorphous mixtures based on the co-formers.

Figure 2

Evolution of the glass transition temperature (T_g) of indomethacin (Ind)-tryptophan (Trp) and furosemide (Fur)-tryptophan (Trp) ball milled for 3, 5, 7, 10, 15, 30, 45, 60, and 90 min, respectively. (Adapted from the Ref. with the permission. Copyright © 2015 American Chemical Society).

Figure 3

(a)−(c) The representative X-ray diffraction patterns for pure ezetimib (EZB), ezetimib 10:1 indapamide (IDP), and ezetimib 1:1 indapamide measured after specified time period. (d) The relative degree of crystallization D_c of amorphous EZB, EZB 10:1 IDP, and EZB 1:1 IDP as a function of storage time at T=297 K and RH = 25%. (Adapted from the Ref. with the permission. Copyright © 2015 American Chemical Society).

Figure 4

IR spectra of amorphous ketoconazole (KTZ), coamorphous ketoconazole (KTZ)−oxalic acid (OXA) and amorphous oxalic acid (OXA). (Adapted from the Ref. with the permission. Copyright © 2018 American Chemical Society).

Figure 5

Temperature dependence of α-relaxation times of (a) amorphous ketoconazole (KTZ), (b) coamorphous KTZ-oxalic acid(OXA), (c) KTZ-succinic acid (SUC), (d) KTZ-citric acid (CIT), and (e) KTZ-tartaric acid (TAR). (Adapted from the Ref. with the permission. Copyright © 2018 American Chemical Society).

Figure 6

Enthalpy relaxation profiles of amorphous tranilast (TRL) and diphenhydramine hydrochloride (DPH), and coamorphous TRL-DPH (1:1) at T_g−20 °C. (Adapted from the Ref. with the permission. Copyright 2017 © Elsevier)

Figure 7

Phase separation for the terfenadine-acetylsalicylic acid coamorphous mixture detected by Fourier transform infrared imaging after 11 days of storage. The upper image illustrates the intensity of the characteristic peak of terfenadine while the lower illustrates the intensity of the characteristic peak of acetylsalicylic acid. The middle image represents the IR images of terfenadine (blue line) and acetylsalicylic acid (red line), the black arrow indicate the characteristic peaks for individual components. (Adapted from the Ref. with the permission. Copyright © 2014 American Chemical Society).

Figure 8

Intrinsic dissolution rate of the coamorphous naproxen (NAP)-indomethacin (IND) binary mixture demonstrates a synchronized drug release. (Adapted from the Ref. with the permission. Copyright © 2011 American Chemical Society).

Figure 9

Mean plasma concentration of hydrochlorothiazide (HCT) vs. time profile of pure crystalline HCT, pure amorphous HCT, coamorphous of HCT and respective physical mixtures. (Adapted from the Ref. with the permission. Copyright 2017 © Elsevier)

Figure 10

Fishbone diagram of coamorphous formulation development.