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Review
. 2021 Mar 15;13(3):389.
doi: 10.3390/pharmaceutics13030389.

Co-Amorphous Drug Formulations in Numbers: Recent Advances in Co-Amorphous Drug Formulations with Focus on Co-Formability, Molar Ratio, Preparation Methods, Physical Stability, In Vitro and In Vivo Performance, and New Formulation Strategies

Jingwen Liu  1 , Holger Grohganz  1 , Korbinian Löbmann  1 , Thomas Rades  1 , Nele-Johanna Hempel  1
Affiliations
Review

Co-Amorphous Drug Formulations in Numbers: Recent Advances in Co-Amorphous Drug Formulations with Focus on Co-Formability, Molar Ratio, Preparation Methods, Physical Stability, In Vitro and In Vivo Performance, and New Formulation Strategies

Jingwen Liu et al. Pharmaceutics. .

Abstract

Co-amorphous drug delivery systems (CAMS) are characterized by the combination of two or more (initially crystalline) low molecular weight components that form a homogeneous single-phase amorphous system. Over the past decades, CAMS have been widely investigated as a promising approach to address the challenge of low water solubility of many active pharmaceutical ingredients. Most of the studies on CAMS were performed on a case-by-case basis, and only a few systematic studies are available. A quantitative analysis of the literature on CAMS under certain aspects highlights not only which aspects have been of great interest, but also which future developments are necessary to expand this research field. This review provides a comprehensive updated overview on the current published work on CAMS using a quantitative approach, focusing on three critical quality attributes of CAMS, i.e., co-formability, physical stability, and dissolution performance. Specifically, co-formability, molar ratio of drug and co-former, preparation methods, physical stability, and in vitro and in vivo performance were covered. For each aspect, a quantitative assessment on the current status was performed, allowing both recent advances and remaining research gaps to be identified. Furthermore, novel research aspects such as the design of ternary CAMS are discussed.

Keywords: co-amorphous; co-formability; in vivo studies; molar ratio optimization; physical stability; poorly water soluble drugs; solid dispersion.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The three critical quality attributes (CQA) of co-amorphous drug delivery systems (CAMS): (1). co-formability, (2). physical stability, and (3). dissolution performance. The blue bricks represent a drug molecule and the green, red, and yellow bricks indicate co-formers. The yellow circles indicate e.g., silica gel.
Figure 2
Figure 2
Column diagram showing the number of studies by year from 1989 to the year 2020.
Figure 3
Figure 3
Percentage of the different classes of co-amorphous drug delivery systems (CAMS) reported in the literatures.
Figure 4
Figure 4
(a) Percentage of how often a specific drug has been reported in different studies (1, 2, 3, 4, 5, or >5 times), (b) Percentage of how often one of the top five used drugs was reported in studies compared to other drugs.
Figure 5
Figure 5
Percentage of stated rationales for co-former selection in the investigated CAMS.
Figure 6
Figure 6
Percentage of studies using certain molar ratios, various molar ratios, and molar ratio optimization in the reported CAMS.
Figure 7
Figure 7
Percentage of the different preparation methods used to obtain CAMS in the reviewed studies, (a) Using the thermodynamic or kinetic pathway or other preparation methods, (b) Using different preparation methods of the thermodynamic pathways, and (c) Using different preparation methods of the kinetic pathways.
Figure 8
Figure 8
(a) Percentage of studies including physical stability tests or not and under which humidity conditions, (b) percentage of studies that included physical stability tests with respect to the storage temperature, and (c) percentage of studies that included physical stability tests with respect to the length of the storage period.
Figure 9
Figure 9
Percentage of studies with and without in vitro dissolution/solubility tests and with in vitro dissolution and in vivo tests.
Figure 10
Figure 10
Percentage of binary CAMS and ternary CAMS in the reviewed literature.
See this image and copyright information in PMC

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