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Review
. 2022 Apr 30;14(5):972.
doi: 10.3390/pharmaceutics14050972.

Citric Acid: A Multifunctional Pharmaceutical Excipient

Maria Lambros  1 , Thac Henry Tran  1 , Qinqin Fei  1 , Mike Nicolaou  2
Affiliations
Review

Citric Acid: A Multifunctional Pharmaceutical Excipient

Maria Lambros et al. Pharmaceutics. .

Abstract

Citric acid, a tricarboxylic acid, has found wide application in the chemical and pharmaceutical industry due to its biocompatibility, versatility, and green, environmentally friendly chemistry. This review emphasizes the pharmaceutical uses of citric acid as a strategic ingredient in drug formulation while focusing on the impact of its physicochemical properties. The functionality of citric acid is due to its three carboxylic groups and one hydroxyl group. These allow it to be used in many ways, including its ability to be used as a crosslinker to form biodegradable polymers and as a co-former in co-amorphous and co-crystal applications. This paper also analyzes the effect of citric acid in physiological processes and how this effect can be used to enhance the attributes of pharmaceutical preparations, as well as providing a critical discussion on the issues that may arise out of the presence of citric acid in formulations.

Keywords: citrates; citric acid; co-amorphous; co-crystals; effervescence; excipient; formulation; lyophilization; proteolytic inhibitor; taste masking.

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Conflict of interest statement

The company had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.

Figures

Figure 1
Figure 1
Chemical structure and molecular formula of citric acid.
Figure 2
Figure 2
The different citrate transporters and their locations in the body.
Figure 3
Figure 3
Percent fractions of various citric acid (CA) species and their chelation activity calculated at different pH values. The chelation activity (boldly dashed line) is at its maximum above pH 7, when the Cit 3− concentration is also at its highest. Reprinted with permission from Ref. [37] Copyright 2014, Elsevier.
Figure 4
Figure 4
Citric acid, with its 3 carboxyl groups and one hydroxyl group, can serve as a crosslinker between polymer molecules and as a linker to link cyclodextrins and a polymer, such as HPMC. Reprinted with permission from Ref. [99]. Copyright 2016 Elsevier.
Figure 5
Figure 5
A schematic of co-amorphous (A) and co-crystals (B).
Figure 6
Figure 6
Theophylline (A) and citric acid (B) through resonant acoustic wet granulation form a co-crystal (C). Reprinted with permission for Ref. [134]. Copyright 2021 MDPI. This image is licensed under CC BY 4.0.
See this image and copyright information in PMC

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