Citric Acid: A Multifunctional Pharmaceutical Excipient: Pharmaceutics

pharmaceutics
Review
Citric Acid: A Multifunctional Pharmaceutical Excipient
Maria Lambros 1, *, Thac (Henry) Tran 1 , Qinqin Fei 1 and Mike Nicolaou 2
1 Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences,

309 E Second Street, Pomona, CA 91766, USA; thac.tran@westernu.edu (T.T.); qfei@westernu.edu (Q.F.)
2 Doric Pharma LLC, 5270 California Ave, Suite 300, Irvine, CA 92617, USA; mnicolaou@doricpharma.com
* Correspondence: mlambros@westernu.edu
Abstract: Citric acid, a tricarboxylic acid, has found wide application in the chemical and phar-
maceutical 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: citric acid; excipient; formulation; citrates; lyophilization; co-crystals; co-amorphous;

proteolytic inhibitor; effervescence; taste masking
Citation: Lambros, M.; Tran, T.; Fei,

Q.; Nicolaou, M. Citric Acid: A 1. Introduction
Multifunctional Pharmaceutical The global production of citric acid in 2020 reached 2.39 million tons, and by 2026, citric
Excipient. Pharmaceutics 2022, 14, 972. acid production is projected to increase to 2.91 million tons [1]. The pharmaceutical industry
https://doi.org/10.3390/ utilizes 12% of the global production, whereas 70% is utilized by the food industry [2].
pharmaceutics14050972 Citric acid has many applications, including in flavoring, buffering, and as a chelating agent
Academic Editors: Lidia Tajber, in the food and beverage industry. Many drinks and sweets have an appealing tart taste
Janina Lulek, Adam Voelkel and owing to citric acid. It is also used as a pH regulator [3]. Its effervescence in the presence
Marcin Skotnicki of carbonates make it useful as tablet disintegrant, in instant drinks, and in personal care
products, such as bath tablets [4,5]. Citric acid monohydrate is the usual form of citric
Received: 11 February 2022
acid sold on the commercial market. It is produced via crystallization from cold, saturated
Accepted: 23 April 2022
solutions through slow evaporation. Citric acid anhydrous is produced from hot, saturated
Published: 30 April 2022
solutions of citric acid [6].
Publisher’s Note: MDPI stays neutral Citric acid is a weak tricarboxylic acid found in citrus fruits like lemons, which contain
with regard to jurisdictional claims in 7–9% citric acid according to their dry weight. The three carboxylate groups of citric acid
published maps and institutional affil- monohydrate have different pKa values, namely 3.15, 4.78, and 6.40 [7]. Until 1919, lemons
iations. were the main source of citric acid (Figure 1). Afterwards, the fungus Aspergillus niger was
used for the production of citric acid at commercial scale [8]. Since then, other Aspergillus
species such as A. flavus, A. awamori, A. nidulans, and A. wentii have been used to produce
citric acid in the presence of sugars; however, A. niger remains the main source of citric acid
Copyright: © 2022 by the authors.
production. Yeasts can also be used to produce citric acid from carbohydrates and n-alkanes.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
Yeasts used for such a purpose include the genera Candida, Saccharomyces, Zygosaccharomyces,
distributed under the terms and
Kloeckera, Torulopsis, Debaryomyces, Pichia, Torula, Yarrowia, and Hansenula [8–10].
conditions of the Creative Commons The tribasic salt of citric acid, trisodium citrate, is commercially available in both anhy-
Attribution (CC BY) license (https:// drous and dihydrate forms. The anhydrous form dissolves faster than its dihydrate form.
creativecommons.org/licenses/by/ Furthermore, the anhydrous form of trisodium citrate is porous and has good flowability,
4.0/). even in the presence of moisture, due to its ability to take up water or other fluids. It is
Pharmaceutics 2022, 14, 972. https://doi.org/10.3390/pharmaceutics14050972 https://www.mdpi.com/journal/pharmaceutics

Pharmaceutics 2022, 14, 972 2 of 18
maceutics 2022, 14, x FOR PEER REVIEW

also used as a carrier for liquids while retaining its flowability and compressibility [11].
Detailed analyses of the structural, spectral, and thermal properties of anhydrous citric
acid have been reported [12].
Figure 1. Chemical structure and molecular formula of citric acid.
The tribasic salt of citric acid, trisodium citrate, is commercially available in bo

hydrous and dihydrate forms. The anhydrous form dissolves faster than its dihy
form. Furthermore, the anhydrous form of trisodium citrate is porous and has good
ability, even in the presence of moisture, due to its ability to take up water or other f
It is also used as a carrier for liquids while retaining its flowability and compress
[11]. Detailed analyses of the structural, spectral, and thermal properties of anhy
citric acid have been reported [12].
Figure Chemical
Citric1. Acid
2.Figure and structure and molecular
Physiological formula of citric acid.
1. Chemical structureConsiderations
and molecular formula of citric acid.
2.1. CitricAcid
2. Citric Acidand
Transporters
Physiological Considerations
2.1. Citric Acid Transporters
Citric
The acid, along with
tribasic salt its
ofmetabolic
citric intermediates
acid, trisodium of the Krebs cycle
citrate, (citric acid
Citric acid, along with its metabolic intermediates of the Krebs cycle (citricis commercia
acid cycle)
such as citrates,succinates,
succinates, and alpha-ketoglutarate, is transported by certain memb
hydrous and
such as citrates,
the
dihydrate forms. The
and alpha-ketoglutarate, anhydrous
is transported form
by certain dissolves
members of f
thesolute
solute carrier family
carrier family 13 (SLC13)
13 (SLC13) transporters,
transporters, namely, namely,
SLC13A2 or SLC13A2 or Na+/dicarbo
Na+ /dicarboxylate
form. Furthermore,
cotransporter
cotransporter 1,1,NaDC1;
NaDC1; the anhydrous
SLC13A3
SLC13A3 or Naor formcotransporter
+ /dicarboxylate of trisodium
Na+/dicarboxylate cotransportercitrate
3, NaDC3; is por
3, NaDC3
and
+
ability,
SLC13A5, even
SLC13A5, Na+/citrate
Na in the
/citrate presence
cotransporter, NaCT,
cotransporter, of moisture,
(Figure
NaCT, due
2) [13–16].
(Figure to its
2) Citrates
[13–16]. are ability to metabo
metabolized
Citrates are take u
mainly in the liver [17].
It is also used as a carrier for liquids while retaining its flowabi
[11]. Detailed analyses of the structural, spectral, and thermal p
citric acid have been reported [12].
2. Citric Acid and Physiological Considerations

2.1. Citric Acid Transporters
Citric acid, along with its metabolic intermediates of the Kreb
such as citrates, succinates, and alpha-ketoglutarate, is transporte
the solute carrier family 13 (SLC13) transporters, namely, SLC13A
cotransporter 1, NaDC1; SLC13A3 or Na+/dicarboxylate cotran
SLC13A5, Na+/citrate cotransporter, NaCT, (Figure 2) [13–16]. C
Figure 2. The different citrate transporters and their locations in the body.
Figure 2. The different citrate transporters and their locations in the body.
SLC13A2 is expressed in epithelial tissues with high metabolic needs, such as those
SLC13A2
in kidneys and is expressed
small intestine.inItepithelial tissues with
takes up protonated high
citrates metabolic
in the needs,2−such as
form of citrates
inand succinates
kidneys and into theintestine.
small cell and plays an important
It takes role in the
up protonated transport
citrates of citrates
in the form of in citrates
urine [15,18]. The citrates in urine bind calcium, forming soluble complexes and reducing
succinates into the cell and plays an important role in the transport of citrates in
Ca2+ supersaturation of urine; therefore, the presence of citrates in the urine prevents the
[15,18].
formation ofcitrates
The in urine
kidney stones bind calcium,
by forming complexesforming soluble
with Ca2+ ions and complexes and reducin
inhibiting crystal
supersaturation of urine;[13].
formation and aggregation therefore, the presence of citrates in the urine prevents th
mation of kidney stones by forming complexes with Ca2+ ions and inhibiting cryst
mation and aggregation [13].
The SLC13A3 transporter cotransports Na+ and dicarboxylate or tricarboxylat
in a pH-dependent manner. The tricarboxylate transport activity of SLC13A3 is op
The SLC13A3 transporter cotransports Na+ and dicarboxylate or tricarboxylate ions

in a pH-dependent manner. The tricarboxylate transport activity of SLC13A3 is optimal
at pH 5.5–6.5 [19]. This transporter is found in the kidneys, specifically on the basolateral
membranes of the renal proximal tubules as well as in other tissues such as brain, pancreas,
liver, and eye [18].
The SLC13A5 or sodium-coupled citrate transporter (NaCT) is selective for tricar-
boxylate citrate at pH 7.4. It is located in the liver and brain. It is a regulator of metabolic
function, energy production, glycolysis, and lipid synthesis [20]. Mutations in the SLC13A5
transporter affect citrate binding and transport and cause epileptic encephalopathy with
seizures [21]. Increased expression of the SLC13A5 gene is linked to type 2 diabetes, glu-
coneogenesis, and non-alcoholic fatty liver disease. SLC13A5 is the mammalian homolog
of the Indy (I am not dead yet) gene, which is highly expressed in the liver. Reduced ex-
pression of the Indy gene in lower organisms is associated with longevity [22]. The deletion
of SLC13A5 in mice mimics caloric restriction, without reducing the intake of calories and
protects mice from hepatic fat accumulation and aging-induced obesity [23].
2.2. Citrates and Tight Junctions/Absorption

Citrates chelate calcium resulting in disruption of tight junction integrity. Indeed,
calcium chelation is an effective way to loosen up tight junctions and increase paracellular
absorption [24]. This was shown in a previous study using ruthenium red, an electron-
dense compound that does not permeate cells and is used as a marker of tight junction
integrity. The transcellular electrical resistance of the duodenum and jejunum was reduced
in the presence of sodium citrate. Goblet cells, which have tight junctions, were surrounded
by abundant ruthenium red deposition in the presence of citrates [25]. Calcium from
milk mixed with fruit juice containing citrates was shown to have higher uptake and
transport through Caco 2 cells compared to calcium from baby formula, which lacks
citrate [26]. Furthermore, citric acid enhances the calcium availability as is shown by
an in vitro simulated gastrointestinal digestion method [27]. In the presence of citric
acid, the intestinal pH is reduced, while the absorption of calcitonin is increased [28].
Because citrates increase GI absorption through their interference with tight junctions,
they may also increase the absorption of other ions, such as lead and aluminum. Citrate-
enhanced GI absorption of lead and aluminum has been shown in numerous studies [29,30].
Dietary citric acid from lemon juice, when consumed together with Al(OH)3 , increases
the absorption of aluminum, as shown by high amounts of Al3+ in the bones or blood
or by aluminum excretion in urine. This may result in acute aluminum toxicity, which is
especially undesirable in the case of patients who suffer from chronic kidney dysfunction.
Extensive aluminum deposition in bones has been found in patients who receive citrate in
combination with Al(OH)3 [30,31].
The ability of citric acid to remove inorganic matter via complexation makes its use
popular in dentistry. Solutions containing 5–50% citric acid are used to irrigate the root
canal and to remove inorganic components of the root dentine surface of the canal wall
and increase its permeability in order for the filling materials to adapt to the root canal and
increase the bond strength of resin endodontic sealers to root dentine [32–34].
2.3. Proteolytic Inhibitor

The absorption of protein drugs is hindered not only by absorption barriers such as
the intestinal wall but also by the action of proteolytic enzymes that degrade proteins and
reduce their concentration, thereby reducing absorption. Reducing the activity of these
proteolytic enzymes (chymotrypsin, trypsin) enhances the absorption of protein drugs; this
can be achieved by reducing the pH in the local microenvironment of the enzyme or by
reducing the concentration of calcium ions [35].
Citric acid is used in oral protein and peptide formulations as it inhibits proteolysis.
For example, the enteric-coated tablet TBRIA™, which contains citric acid, is an oral
formulation of salmon calcitonin used in the treatment of postmenopausal osteoporosis.
Pharmaceutics 2022, 14, x FOR PEER REVIEW 4 of 19
pharmaceutical ingredients (APIs) are released along with the citric acid. The presence of
citric acid keeps the pH low enough to inhibit the activity of proteolytic enzymes so that
After the degradation of the enteric coating in the duodenum, the protein or peptide active
they cannot degrade the protein or peptide APIs, facilitating better absorption[24,36,37],.
pharmaceutical ingredients (APIs) are released along with the citric acid. The presence of
Citric acid has also been used to avoid the proteolysis of salmon calcitonin in a mini-
citric acid keeps the pH low enough to inhibit the activity of proteolytic enzymes so that
sphere emulsion-based
they cannot formulation
degrade the protein [38]. APIs, facilitating better absorption [24,36,37].
or peptide
CitricCitrates
acid hasmay impair
also been usedtheto activity
avoid theof proteolytic
proteolysis enzymes
of salmon via calcium
calcitonin chelation. Both
in a mini-sphere
citrates and EDTA
emulsion-based chelate [38].
formulation Ca2+ and reduce the activity of chymotrypsin. The proteolysis
Citrates
of insulin, may impair
which is mainlythe due
activity of proteolytic enzymes
to chymotrypsin, via calcium
is significantly chelation.
reduced Both
in the presence
citrates
of andatEDTA
citrates pH >chelate Ca2+ and
7, as calcium reduce thewith
complexes activity of chymotrypsin.
citrates The proteolysis
in this pH range resulting in the
of insulin, of
reduction which is mainly due
chymotrypsin to chymotrypsin,
activity. While citricis significantly
acid acts asreduced
a calciumin the
ionpresence
chelator at pH
of citrates at pH > 7, as calcium complexes with citrates in this pH range resulting in the
> 7, at pH 3–4 range, citric acid exerts inhibitory action against proteolytic enzymes acting
reduction of chymotrypsin activity. While citric acid acts as a calcium ion chelator at pH > 7,
as an acidifier [37]. Figure 3 shows the calculated concentration of different forms of citric
at pH 3–4 range, citric acid exerts inhibitory action against proteolytic enzymes acting as
acid such as[37].
an acidifier H2Cit -, HCit2−, and Cit3−, and the chelation activity at various pH levels [37].
Figure 3 shows the calculated concentration of different forms of citric
Citrate
acid such as H2 Cit , HCit2−for
chelating −activity , anddivalent cations
Cit3− , and is maintained
the chelation activity ateven after
various pHinteraction
levels [37]. of cit-
rates with chitosan chains; chitosan citrate at pH 6.5 enhances the penetration
Citrate chelating activity for divalent cations is maintained even after interaction of citrates of peptidic
drugs and shows
with chitosan chains;strong inhibition
chitosan citrate at of
pHzinc dependent
6.5 enhances peptidasesofsuch
the penetration as carboxypepti-
peptidic drugs
and shows strong inhibition of
dase A and leucine aminopeptidase [39].zinc dependent peptidases such as carboxypeptidase A and
leucine aminopeptidase [39].
Figure 3. Percent fractions of various citric acid (CA) species and their chelation activity calculated at
Figure 3. Percent fractions of various citric acid (CA) species and their chelation activity calculated
different pH values. The chelation activity (boldly dashed line) is at its maximum above pH 7, when
at different pH values. The chelation activity (boldly dashed line) is at its maximum above pH 7,
the Cit 3− concentration is also at its highest. Reprinted with permission from Ref. [37] Copyright
when the Cit 3- concentration is also at its highest. Reprinted with permission from Ref. [37] Copy-
2014, Elsevier.
right 2014, Elsevier.
2.4. Bone and Citrates
2.4. Bone andisCitrates
Citrate an important part of bone structure. Eighty percent of the body’s total
citrate content
Citrate is found
is an in thepart
important bones. It is strongly
of bone structure.bound to the
Eighty surfaces
percent of of
thethe apatitetotal cit-
body’s
nanocrystals
rate content isand stabilizes
found in thethem
bones.[40]. Citrates
It is stronglyalsobound
play antoimportant roleof
the surfaces in the
newapatite
bone nano-
regeneration. It has been shown that citrate is secreted by osteoblasts and
crystals and stabilizes them [40]. Citrates also play an important role in new bone regen- is incorporated
into bone during bone formation [41,42]. Citrates regulate apatite nanocrystal growth,
eration. It has been shown that citrate is secreted by osteoblasts and is incorporated into
affecting bone strength, stability, and fracture resistance [43], via incorporation between
bone during bone formation [41,42]. Citrates regulate apatite nanocrystal growth, affect-
mineral platelets forming citrate bridges between the platelets [44]. Citric acid used in
ing bone strength,
superficial stability,
demineralization of and
toothfracture resistance
root surfaces enhances [43],
the via incorporation
proliferation between min-
and spreading
eral platelets forming citrate bridges between
of osteoblasts and the regeneration of cementum [45,46]. the platelets [44]. Citric acid used in super-
ficial Citric
demineralization
acid has been usedof tooth root surfaces
in biomimetic enhances
materials the proliferation
as a scaffold and spreading
for osteogeneration via of
deposition ofand
osteoblasts hydroxyapatite [47]. The
the regeneration of presence
cementum of citrate,
[45,46]. either in the cell culture media or
in theCitric
polymeraciditself,
hassupports
been used osteoblast proliferation
in biomimetic and differentiation,
materials as a scaffold andforenhances the
osteogeneration
deposition of apatite, thereby enhancing the strength of the material [42,48].
via deposition of hydroxyapatite [47]. The presence of citrate, either in the cell culture Crosslinked,
media or in the polymer itself, supports osteoblast proliferation and differentiation, and
enhances the deposition of apatite, thereby enhancing the strength of the material [42,48].
Crosslinked, urethane-doped octanediol citrate polymers show enhanced hydroxyapatite
urethane-doped octanediol citrate polymers show enhanced hydroxyapatite binding, while

citric acid supplementation promotes osteoblast culture [49]. Citric acid-based hydroxy-
apatite materials form strong biomimetic and biocompatible composite scaffolds that have
been produced employing click chemistry and can be used as osteogenic implants to repair
orthopedic defects [50].
3. Citric Acid in Formulations

3.1. Citric Acid in Taste-Masking and Effervescence
The effectiveness of a therapeutic treatment depends on patient compliance. Taste
acceptance by the patient enhances compliance. This is especially important with orally
disintegrating tablets (ODTs), as the drug is released in the mouth [51]. Such ODTs are used
to improve the oral delivery of therapeutics in children, in elderly patients with dysphagia,
and in patients with epileptic seizures [52,53]. Several of these drugs have an unpleasant
or bitter taste, making patient compliance difficult, and taste-masking is important in
such cases.
Citric acid is used to mask the bitter taste of drugs and improve their palatability. In
fact, the presence of citric acid is positively correlated with acidity, sour taste, citrus aroma
and flavor, and is negatively correlated with bitterness [54]. For example, epinephrine has
a bitter taste, and while the addition of two artificial sweeteners, aspartame and potassium
acesulfame, can reduce the bitterness to an acceptable level, bitterness was only reduced
to an undetectable level following the addition of citric acid into these formulations [55].
Similarly, the addition of citric acid along with sweeteners reduced the bitter taste of
olopatadine, mirtazapine, and diclofenac [55–58]. Additionally, concentration of 1% citric
acid was used to mask the bitterness of famotidine in microspheres incorporated into orally
disintegrating tablets [59].
Effervescent formulations that contain citric acid and sodium bicarbonate can achieve
a pleasant mouthfeel sensation on the tongue and in the mouth [60]. It has been shown
that the unpleasant taste of functionalized calcium carbonate and calcium phosphate was
masked in effervescent formulations containing citric acid [60]. Additionally, citric acid
can be used to stimulate salivary glands and is considered as one of the most effective
stimulants to induce high salivary flow [61,62]. The ability of citric acid to mask taste has
been evaluated using human volunteers and e-tongues [63].
Effervescence is commonly used in orally administered pharmaceutical formulations.
The term “effervesce” refers to the release of gas when an acid and base interact with water.
Usually, the acid is citric acid, and the base is sodium bicarbonate or sodium carbonate [64].
While several other acids can be used in place of citric acid, such as malic, fumaric, tartaric,
and adipic acids, citric acid is most widely used in effervescence formulations because it
imparts a pleasant citrus-type flavor and acts as a flavor enhancer [65]. Effervescent tablets
or powders in the presence of water or another liquid, such as saliva, release gas as carbon
dioxide (CO2 ) and can be used to produce carbonated liquid drinks.
Since effervescence can quickly disperse active compounds and allows rapid dissolu-
tion, it is used in the administration of pharmaceuticals, particularly in patients who face
difficulty in swallowing a tablet or capsule [66]. Another advantage of effervescence is
that it also allows quick dispersion of the active compounds in the oral cavity as well as
absorption through oral mucosal and, in this way, the first-pass effect can be avoided, lead-
ing to increased bioavailability of the drug and faster activity onset [5,67]. Effervescence
may increase buccal absorption since the citric acid in the formulation sequesters calcium
ions (Ca2+ ), making the tight junctions more permeable, thereby promoting paracellular
transport [35].
An effervescent mixture may contain citric acid and sodium bicarbonate, or carbonate.
The molar ratio of citric acid to bicarbonates is 1:3 as is shown below (1). When carbonates
are used instead of bicarbonates, the molar ratio of citric acid to carbonates can be 2:3 (2).
Effervescence has been used to enhance the solubility of poorly soluble drugs such as ator-
vastatin, cefuroxime, ketoconazole, metronidazole [68], buspirone [69], fentanyl citrate [70],
and bismuth subcitrate [71].
2 in H O
CitrH3 + 3NaHCO3 −−−−→ Na3 Citr + 3CO2 ↑ +3H2 O (1)
Citric Acid Sodium Bicarbonate Trisodium Citrate Carbon Dioxide Water
2 in H O
2CitrH3 + 3Na2 CO3 −−−−→ 2Na3 Citr + 3CO2 ↑ +3H2 O (2)
Citric Acid Sodium Carbonate Trisodium Citrate Carbon Dioxide Water
The effervescence reaction of citric acid with bicarbonates, which releases CO2 , is
also used to develop tablets that float in the stomach. The CO2 gas produced during the
effervescent reaction is trapped within the gel polymers of the tablet, initiating buoyancy.
The buoyant tablets float in the gastric juice of the stomach for a longer time compared
to regular tablets, releasing the drug to be absorbed by the stomach over longer periods,
thus increasing its bioavailability [72]. This technology is used for drugs that are unstable
or not soluble at intestinal pH [73], and has been expanded for used in extended-release
floating granules [74]. Effervescent, gastro-retentive floating tablets of verapamil [75],
calcium disodium edentate [76], ciprofloxacin [77], dipyridamole [73], lisinopril [78], and
venlafaxine [79] are examples of this technology.
3.2. Citric Acid in the Lyophilization Process

Citric acid is a common excipient in lyophilized formulations [80]. Lyophilization
or freeze-drying is an important process of pharmaceutical significance and is used in
the preservation of labile pharmaceuticals. Lyophilization involves removal of frozen
water from a formulation via sublimation to produce a powder that can be reconstituted
before use. The lyophilized products are amorphous, solid-state, glassy materials that are
considered to be supercooled liquids. Important parameters in the lyophilization process
include buffering, for pH control, and the glass transition temperature, Tg. Components
of the buffer during the freeze-drying process may crystallize and affect the pH of the
solution. When buffer components of the solution crystallize at subzero temperatures,
phase separations, solid phases, and liquid phases are created within the solution, which
have different pH values depending on the freezing rate and components [81]. Phase
separation during the lyophilization process must be avoided as it may lead to pH changes
and degradation of the formulation components.
Citrate buffers are used extensively in lyophilized products because they usually
do not crystallize during the process and remain amorphous, with minimal pH changes,
unlike sodium phosphate buffers, which are known to crystallize during lyophilization [82].
Mannitol is an important lyoprotectant for peptides and proteins and should remain
amorphous and not crystallize during lyophilization [83,84]. The presence of 1% or 5% of
sodium citrate in mannitol solutions has been shown to inhibit mannitol crystallization
during lyophilization [85]. The crystallization process is also pH dependent. Citric acid
solutions are crystallized at pH 4 and not at pH 5 or 6 [86]. It has been also reported that
1 M citric solutions exhibit long-lived, large-scale inhomogeneities, i.e., supramolecular
structures [87].
During lyophilization, sucrose in the presence of citric or other acids inverts (converted
into fructose and glucose), even at low temperatures and with very low amounts of water
(less than 0.1%); for this reason, care must be exercised. The inversion of sugar must be
avoided as the products from sugar inversion may react with other components of the
formulation and cause decomposition. Although sucrose inversion depends on the pH
of the solution, it may also happen after lyophilization. This is due to citric acid, even in
the solid state, retaining its degree of ionization and possibly causing sucrose protonation,
which in turn results in sucrose inversion [88].
The glass transition temperature, Tg, of anhydrous citric acid is 11 ◦ C, whereas the
Tg of citric acid monohydrate (that is, in the presence of an equimolar amount of water or
8.6% water content) is −25 ◦ C. The glass transition temperature of the maximally freeze-
concentrated solution, Tg0 , of citric acid is −53 ◦ C [80,89]. The low Tg and Tg0 of hydrated
citric acid explains the difficulty in keeping pure citric acid from crystallizing when in
amorphous state [80]. Citric acid shows significant changes in its viscosity in the vicinity of
the Tg, with non-Arrhenius behavior over a broad range of temperatures, as is observed
with other small molecules [89].
Using a system of trehalose–citrate and sulfonephthalein with a pH indicator as
a probe, it has been shown that at a certain pH, the protonation of sulfonephthalein
was higher in the lyophilized state compared to its protonation in solution before the
lyophilization [90].
3.3. Citric Acid in Polymers

The three carboxylic groups and one hydroxyl group of citric acid allow it to react and
crosslink with other biocompatible multifunctional materials such as glycerol, cellulose,
and sebacic acid via condensation reactions, forming crosslinked ester copolymers capable
of drug delivery. The advantages of condensation reaction include that it is considered
“green”, is catalyst-free, and enables ester bond formation.
Reacting citric acid with glycerol under a range of temperatures (90–150 ◦ C) results
in the formation of biodegradable ester copolymers. Incorporating the antibiotic gen-
tamycin into this polymer resulted in effective bacterial killing [91]. The kinetics of citric
acid and glycerol polycondensation at three different temperatures was recently stud-
ied [92]. The generation of citric acid–glycerol copolymers in the presence of benzene and
p-toluenesulfonic acid (PTSA) has also been reported [93]; however, this type of synthesis
raises concerns regarding biocompatibility because both benzene and PTSA are known
carcinogens [91]. Biocompatible poly(diol citrate) elastomers were formed by reacting
citric acid with different type of diols. The mechanical properties, such as the stiffness and
degradation characteristics, can be controlled through the choice of the diol used and the
crosslinking density [94]. The polyfunctionality of citric acid, its low cost, and its ability to
react in polycondensation reactions with other nontoxic materials without requiring cata-
lysts make it an important component used for the formation of biomaterials in regenerative
engineering. An insightful review of design considerations and uses of citric-acid-based
polymeric biomaterials in regenerative engineering has been published [49].
Hydrogels consisting of crosslinked polymers derived from citric acid, polyethylene
glycol 200, and maleic acid can be used for drug delivery purposes [95]. Owning to its
multifunctionality, citric acid can form dendrimers with polyethylene glycol that can trap
small drug molecules such as mefenamic acid, diclofenac, and naproxen. The trapped small
molecules are released in a controlled manner for up to seven hours [96,97].
Crosslinking of citric acid with cyclodextrins (CDs) produces polymers that can en-
hance the solubility of poorly soluble drugs compared to cyclodextrin monomers [98].
Cyclodextrins are water-soluble cyclic polysaccharides. They have a cone shape, and the
external surface of the cone is hydrophilic, while the internal surface, which is the cavity
of the cone, is hydrophobic. Lipophilic drugs partition into the cyclodextrin cavity. The
formation of drug–cyclodextrin complexes enhances the solubility and bioavailability of
drugs that are difficult to solubilize. The three main types of cyclodextrins (CDs), namely
alpha-CDs, beta-CDs, and gamma-CDs, have different cavity sizes, with gamma-CDs
having the largest cavity and broadest solubility. Citric acid is used as a crosslinking
agent to graft beta-cyclodextrins to hydroxypropylmethylcellulose (HPMC) hydrogel films
for ketoconazole delivery (Figure 4) [99]. The citric acid–cyclodextrin polymers formed
through a polycondensation reaction between cyclodextrin and citric acid are non-toxic
and environmentally safe. Citric acid–CD polymers enhance the solubility of drugs, such
as albendazole [100], ciprofloxacin [101], ethoxzolamide [102], doxorubicin [103], bupiva-
caine, risperidone, paliperidone, and promethazine [104]. Citric acid has been used to
develop coatings for biodegradable cardiovascular stents. Specifically, the biodegradable
alloy of Mg-Zn-Y-Nd was coated with successive layers of polydopamine, citric acid, and
Arg-Gly-Asp (RGD) peptide. The surface that was created is hemocompatible and allows
Pharmaceutics 2022, 14, x FOR PEER REVIEW 8 of 19
coatings for biodegradable cardiovascular stents. Specifically, the biodegradable alloy of

Mg-Zn-Y-Nd was coated with successive layers of polydopamine, citric acid, and Arg-
Gly-Asp (RGD) peptide. The surface that was created is hemocompatible and allows for
endothelization, while inhibiting smooth muscle cell adhesion and proliferation, overall
for endothelization, while inhibiting smooth muscle cell adhesion and proliferation, overall
improving
improving the thebiocompatibility
biocompatibility of the
of the Mg Mg
alloyalloy stents
stents [105,106].
[105,106]. Extensive
Extensive reviewsreviews
of the of the
role of citric acid as a crosslinker can be found in references [107,108].
role of citric acid as a crosslinker can be found in references [107,108].
Figure 4. Citric
Figure 4. Citricacid,
acid,with
withitsits 3 carboxyl
3 carboxyl groups
groups and and one hydroxyl
one hydroxyl group,group, canasserve
can serve as a crosslinker
a crosslinker
between polymer molecules and as a linker to link cyclodextrins and a polymer, such
between polymer molecules and as a linker to link cyclodextrins and a polymer, such as HPMC. as HPMC.
Reprinted withpermission
Reprinted with permission from
from Ref.Ref.
[99].[99]. Copyright
Copyright 2016 2016 Elsevier.
Elsevier.
3.4. Co-Amorphous Drugs and Co-Crystals

3.4. Co-Amorphous Drugs and Co-Crystals
3.4.1. Co-Amorphous Drugs
3.4.1.When
Co-Amorphous Drugs
comparing the solubility and dissolution rate of the crystalline versus amor-
phousWhen
form of comparing the solubility
a drug, the amorphous formand dissolution
is more soluble andrate ofhave
will the acrystalline versus amor-
faster dissolution
rate. The amorphous form, however, may not be thermodynamically stable
phous form of a drug, the amorphous form is more soluble and will have a faster dissolu- and will revert,
in time,
tion rate.toThe
the amorphous
crystalline form.
form,Tohowever,
overcomemay this not
instability, initial efforts are focused
be thermodynamically stable and will
revert, in time, to the crystalline form. To overcome this instability, initial barrier,
on mixing the drug substance with a polymer, whereby polymer chains act as a efforts are fo-
separating the drug molecules from each other. Additionally, intermolecular interactions
cused on mixing the drug substance with a polymer, whereby polymer chains act as a
between the polymer and the drug contribute to providing a stable amorphous solid disper-
barrier,
sion (ASD)separating thedisadvantages
mixture. The drug molecules from
of these eachareother.
ASDs Additionally,
that: (a) the polymersintermolecular
represent a in-
teractions between the polymer and the drug contribute to providing
high percentage of the drug–polymer mixture, requiring a larger tablet (or more tablets) to a stable amorphous
solid
deliverdispersion
the required (ASD) mixture.
drug dose, The in
resulting disadvantages of these
dosage form burden ASDs
[109]; arehydroscopic
(b) the that: (a) the poly-
mers represent
tendencies of thea polymer
high percentage
may result of inthemoisture
drug–polymer
absorption,mixture,
a lower requiring a larger tablet
glass transition
temperature, Tg, and increased molecular motility, resulting in phase separation
(or more tablets) to deliver the required drug dose, resulting in dosage form burden [109]; between
the the
(b) polymer and the drug
hydroscopic and eventual
tendencies of there-crystallization
polymer may result of the in
drug [109,110].
moisture absorption, a lower
An alternative solution to avoid the drawbacks of polymer–drug
glass transition temperature, Tg, and increased molecular motility, resulting ASDs is to use co-
in phase sep-
amorphous formulations (Figure 5A). These are combinations of low molecular weight
aration between the polymer and the drug and eventual re-crystallization of the drug
compounds, such as a low MW drug with another drug or with a low MW excipient. For
[109,110].
compounds, such as a low MW drug with another drug or with a low MW excipient. F
the drug–excipient category, the excipient, i.e., the co-former, is a low molecular weig
substance such as an amino acid or carboxylic acid (e.g., citric acid). The co-amorpho
formulations between a drug and citric acid can achieve higher drug solubility and dis
lution rates compared to the drug alone in its crystalline form [111]. Citric acid, havi
hydrogen bonding ability due to the three carboxylic groups and one hydroxyl group a
a lowthemolecular weight,
drug–excipient is useful
category, as a co-former
the excipient, to formisco-amorphous
i.e., the co-former, a low molecular structures
weight [11
The co-amorphous
substance such assystem
an amino ofacid
ketoconazole–citric acidcitric
or carboxylic acid (e.g., showedacid).exceptional stability due
The co-amorphous
its decreased molecular mobility and the presence of structural factors (thedisso-
formulations between a drug and citric acid can achieve higher drug solubility and three carb
lution rates compared to the drug alone in its crystalline form [111]. Citric acid, having
ylic groups and one hydroxyl group, which provide opportunities for hydrogen bon
hydrogen bonding ability due to the three carboxylic groups and one hydroxyl group and
between
a lowketoconazole
molecular weight,andiscitric
usefulacid) [113]. Co-amorphous
as a co-former formulations
to form co-amorphous of[112].
structures acyclovir a
citricThe
acid formulated in a PEG ointment resulted in enhanced acyclovir
co-amorphous system of ketoconazole–citric acid showed exceptional stability due to penetration co
pareditsto
decreased molecular
crystalline mobility
acyclovir and the presence
[114,115]. Mixtures of structural factors (theand
of paracetamol threecitric
carboxylic
acid at a 50
groups and one hydroxyl group, which provide opportunities for hydrogen bonds between
ratio formed an amorphous blend, having strong hydrogen bond interactions betwe
ketoconazole and citric acid) [113]. Co-amorphous formulations of acyclovir and citric acid
paracetamol
formulatedand citricointment
in a PEG acid that were
resulted stable under
in enhanced drypenetration
acyclovir conditions for attoleast
compared crys- 27 wee
[116].talline acyclovir [114,115]. Mixtures of paracetamol and citric acid at a 50:50 ratio formed
an amorphous blend, having strong hydrogen bond interactions between paracetamol and
citric acid that were stable under dry conditions for at least 27 weeks [116].
(A) (B)
Figure 5. A5.schematic
Figure ofofco-amorphous
A schematic (A)
co-amorphous (A) and
and co-crystals
co-crystals (B). (B).
A loratadine–citric acid co-amorphous system prepared using the solvent evaporation

A loratadine–citric acid co-amorphous system prepared using the solvent evapo
technique had enhanced physical stability [117]. Citric acid and sulfathiazole co-milled
tion together
technique hada co-amorphous
formed enhanced physicalpreparation stability [117].upCitric
that was stable acidat and
to 28 days RH 10%sulfathiazole
[118].
milled together formed a co-amorphous preparation that was stable
At higher RH, the co-amorphous sulfathiazole crystallized to different polymorphs. up to 28 days at R
Ad-
10% ditionally,
[118]. At separation
higher RH, thecitric
of the co-amorphous sulfathiazoleindomethacin–citric
acid from the co-amorphous crystallized to different
acid po
preparations containing more the 30% citric acid was observed [119].
morphs. Additionally, separation of the citric acid from the co-amorphous indomethac Sometimes, in order
to enhance stability, instead of using citric acid alone as a co-former, citric acid can be
citricused
acidaspreparations containing more the 30% citric acid was observed [119]. Som
a part of the co-former as was the case for citric acid–L-arginine, which was used
times,asin order to enhance
a co-former stability,[120].
for carbamazepine instead ofacid
Citric using
cancitric acid
interact withalone
basicasdrugs
a co-former,
and cit
acid can
formbe used asbonds
hydrogen a part of thetoco-former
leading as was the
drug amorphization andcase for citric
increased acid–L-arginine,
solubility [121]. The wh
solubility of difficult to solubilize basic drugs such as haloperidol and
was used as a co-former for carbamazepine [120]. Citric acid can interact with basic dru itraconazole was
increased when these drugs interacted with citric acid and formed stable amorphous solid
and form hydrogen bonds leading to drug amorphization and increased solubility [12
dispersions [122,123].
The solubility of difficult to solubilize basic drugs such as haloperidol and itraconaz
was increased when these drugs interacted with citric acid and formed stable amorpho
3.4.2. Co-Crystals
solid dispersions [122,123].
The co-formers that form co-amorphous structures, under certain preparation, time, rel-
ative humidity (RH), and temperature conditions, can also form co-crystals. In co-crystals,
the co-formers can interact stoichiometrically and form a 3D ordered structure that leads to
3.4.2. Co-Crystals
a crystal lattice (Figure 5B). Co-crystals can be formed by any pair of electron donors and
The co-formers
acceptors, whereas that formsalts
crystalline co-amorphous structures,
of weak acids or under
bases require certain
proton transferpreparation,
between tim
the components [124]. Co-crystals represent a homogeneous phase of one type
relative humidity (RH), and temperature conditions, can also form co-crystals. In co-cr of a crystal
lattice and are not mixtures of two different phases of pure crystalline components [125].
tals, the co-formers can interact stoichiometrically and form a 3D ordered structure t
leads to a crystal lattice (Figure 5B). Co-crystals can be formed by any pair of electr
donors and acceptors, whereas crystalline salts of weak acids or bases require proton
transfer between the components [124]. Co-crystals represent a homogeneous phase of
one type of a crystal lattice and are not mixtures of two different phases of pure crystalline
components [125]. An important distinction between co-crystals and solvates is that co-
crystals are made of an API and a co-former, which in their pure state are solid under
ambient conditions, whereas solvates contain a solvent or water as a guest molecule [126–
128]. Co-crystals areAnof interestdistinction
important in the pharmaceutical
between co-crystalsindustry because
and solvates an API
is that in co-crys-
co-crystals are made
tal form has a better dissolution rate than in its pure crystal form or other
of an API and a co-former, which in their pure state are solid under ambient forms, such as
conditions,
salts, hydrates, or whereas
polymorphs solvates[129,130].
contain a solvent or water as a guest molecule [126–128]. Co-crystals are
of interest in the pharmaceutical
When citric acid interacts with APIs to form industry because ancitric
co-crystals, API inacid
co-crystal
is theform has a better
co-former
dissolution rate than in its pure crystal form or other forms, such as salts, hydrates, or
that combines with the API through hydrogen bonds, π-stacking, and van der Waals
polymorphs [129,130].
forces to form these co-crystals
When citric[126,131]. Physical
acid interacts mixtures
with APIs to formof theophylline
co-crystals, and iscitric
citric acid acid
the co-former
at 1:1 stochiometric ratio
that whenwith
combines stored at 55
the API °C and
through 75% RH
hydrogen forπ-stacking,
bonds, 24 h are andtransformed
van der Waals intoforces
co-crystals [125,132]. Grinding theophylline and citric◦ acid together for 60 min or using at
to form these co-crystals [126,131]. Physical mixtures of theophylline and citric acid
1:1 stochiometric ratio when stored at 55 C and 75% RH for 24 h are transformed into
slow solvent evaporation can also be used to form co-crystals [133]. Acoustic resonant
co-crystals [125,132]. Grinding theophylline and citric acid together for 60 min or using
granulation is a new slowefficient technique that
solvent evaporation resulted
can also be usedintocomplete theophylline–citric
form co-crystals [133]. Acoustic acidresonant
co-crystal formation (Figure is6),a new
granulation as well as simultaneous
efficient granule
technique that resulted formation,
in complete whereas high-
theophylline–citric acid co-
shear wet granulationcrystalresulted
formation in(Figure
a low 6), as well as simultaneous
co-crystal yield [134].granule formation,
Mixtures of whereas
paracetamolhigh-shear
wet granulation resulted in a low co-crystal yield [134]. Mixtures
and citric acid, through slow solvent evaporation, formed co-crystals at a 2:1 paracetamol- of paracetamol and citric
acid, through slow solvent evaporation, formed co-crystals at a 2:1 paracetamol-to-citric
to-citric acid stochiometric molar ratio [131].
acid stochiometric molar ratio [131].
Figure 6. Theophylline (A) and citric acid (B) through resonant acoustic wet granulation form a
Figure 6. Theophylline (A) and
co-crystal (C). citric acidwith
Reprinted (B)permission
through resonant acoustic
for Ref. [134]. wet2021
Copyright granulation
MDPI. This form a co-
image is licensed
crystal (C). Reprinted with permission
under CC BY 4.0. for Ref. [134]. J. Pharm. Sci. 2010.
As discussed above, theophylline, and other xanthines such as caffeine can form
As discussed above, theophylline, and other xanthines such as caffeine can form co-
co-crystals with citric acid and the presence of water assists in this formation. Table 1
crystals with citriclists
aciddifferentthe
and presence
API–citric of water assists
acid co-crystals, in this formation.
their stochiometric Table
ratio, methods 1 lists
of preparation
different API–citricandacid co-crystals,
techniques their
used for stochiometric
their ratio, acid
study. Caffeine–citric methods of preparation
co-crystals and
at a 1:1 stoichiometric
techniques used for their
ratio canstudy. Caffeine–citric
be formed acid co-crystals
using liquid (water)-assisted at a 1:1
grinding stoichiometric
[135,136]. ratioacid
Caffeine–citric
co-crystals show two polymorphs [137]. Cafcit ® caffeine citrate, a marketed product
can be formed using liquid (water)-assisted grinding [135,136]. Caffeine–citric acid co-
for infantile apnea, is formulated using caffeine–citric acid co-crystals [138]. Anhydrous
crystals show twotheophylline–citric
polymorphs [137]. Cafcit® caffeine citrate, a marketed product for in-
acid co-crystals are prepared in ethanol, while theophylline–citric acid
fantile apnea, is formulated using(1:1:1),
co-crystal hydrates caffeine–citric acid co-crystals
which are prepared [138].three
in water, contain Anhydrous theo- in
types of molecules
phylline–citric acidtheco-crystals are theophylline,
crystal, namely prepared incitricethanol, while
acid, and theophylline–citric
water. Since citric acid as aacid co- is
co-former
water-soluble
crystal hydrates (1:1:1), whichandaretakes up moisture,
prepared its co-crystals
in water, containarethree
pronetypes
to conversion. Theophylline–
of molecules in
citric acid co-crystal hydrates can convert to and from anhydrous theophylline–citric
the crystal, namely theophylline, citric acid, and water. Since citric acid as a co-former is
acid co-crystal, depending on the relative humidity or excipients that affect the water
water-soluble andactivity
takes [139].
up moisture, its co-crystals are prone to conversion. Theophyl-
line–citric acid co-crystal hydrates can convert to and from anhydrous theophylline–citric
acid co-crystal, depending on the relative humidity or excipients that affect the water ac-
tivity [139].
Table 1. Co-crystals of different APIs and citric acid, their stochiometric ratio, and methods of
preparation and study.
Co-Crystal Stochiometric Ratio Methods of Preparation Techniques Used to Study References

X-ray, FTIR, DSC, Dynamic
Berberine Chloride–Citric
1:1 Grinding Water Vapor Sorption [140]
Acid
(DVS) HPLC, Dissolution
X-ray, FTIR, DSC, TGA,
Dapagliflozin–Citric Acid 1:1 Evaporation 1 HNMR, HPLC, [141]
SEM, DVS, dissolution
X-ray, DSC, TGA, DVS,
Nefiracetam–Citric Acid 2:1 Slow Evaporation [142]
HPLC UV
X-ray, DSC, TGA, Raman,
IR, NMR
Liquid-Assisted Grinding Elemental Analysis
Nitrofurantoin–Citric Acid 1:1 [143,144]
Slow Evaporation DSC, reflectance FTIR,
Polarized Light
Microscopy
Dry Grinding
Piracetam–Citric Acid Not Reported X-ray, DSC, FT-Raman [145]
Liquid-Assisted Grinding
Praziquantel–Citric Acid 1:1 Liquid-Assisted Grinding DSC, X-ray, IR [146]
Slow Evaporation
DSCFTIR, , Stability
Theophylline–Citric Acid 1:1 Dry Grinding [132,133]
Studies
Liquid-Assisted Grinding
X-ray, DSC, Raman
Paracetamol–Citric Acid 2:1 Slow Evaporation [131]
Spectroscopy
Caffeine–Citric Acid 1:1 Liquid-Assisted Grinding X-ray, DSC, FTIR [136,147]
Ternary Phase Diagrams,
Solubility, DITA
Agomelatine–Citric Acid 1:1 Cooling Crystallization [148,149]
(Discontinuous Isoperibolic
Thermal Analysis)
Creatine–Citric Acid 1:1 Co-milling in Humid Air X-Ray, TGA, DSC, NMR [150]
3.5. Citric Acid in Formulations, Injection Pain and Other Issues

Citric acid has wide use in formulations, including in parenteral administration dosage
forms, such as intramuscular or subcutaneous injections. Injections that contain an acid are
painful [151,152]. There are several papers in the literature that attribute injection pain to
the presence of citric acid or a citric or citrate buffer. Comparing the injection pain caused
by different buffers, the formulation with a citrate buffer caused more pain [153]. For
example, adalimumab (Humira® ), which is administered through subcutaneous injection
for the treatment of rheumatoid arthritis, ulcerative colitis, and Crohn’s disease, also comes
in a citrate-free version [151,154].
Citric acid activates the acid-sensing ion channel 1 (ASIC1), while neutral citrate does
not. The latter chelates calcium ions that act as inhibitors to the ASIC1 [151]. Citric acid
also acts on TDAG8 coupled with TRPV1 to induce itching-like behavior in mice [152].
In general, protons are the major culprits involved in injection pain. Injection pain is
unpleasant and may contribute to patient non-compliance, leading patients to skip doses
or stop therapy altogether, with detrimental effects on their therapeutic outcomes. To
avoid injection pain, clinicians add a small amount of bicarbonate into the injection just
before administration. Also, eliminating citrates from the formulation may avoid injec-
tion pain. However, since citric acid chelates extracellular Ca2+ that normally inhibits
ASIC1, adding inhibitors of ASIC1 or adding supplemental Ca2+ may also help in avoiding
injection pain, without the need to eliminate citrates from the formulation [151]. Better
understanding the mechanism of pain caused by citric acid will have important positive
therapeutic implications.
Humidity plays an important role in formulation. Crystalline solids at certain relative
humidity (RH) turn to solution or deliquesce [155,156]. When RH rises and falls it will
cause deliquescence and efflorescence (crystallization), respectively, leading to instabilities.
Anhydrous crystalline citric acid at 25 ◦ C and 75% RH turns from solid to solution, deliques-
cence, whereas citric acid monohydrate is more resistant to humidity and it deliquesces at a
higher RH, 78%, at the same temperature [155]. Blends of citric acid with deliquescent solid
components result in a lower deliquescent point than deliquescent points of the individual
components. For example, the deliquescent points of sucrose and citric acid are 85% and
75% RH, respectively at 25 ◦ C [157], whereas, at the same temperature blends of sucrose
and citric acid, have a lower deliquescent point, 64% RH. This may result in chemical (i.e.,
sucrose inversion) and physical (i.e., caking) instabilities [158].
In the case of co-crystals, when the relative humidity is high enough, 98% RH at RT,
citric acid, a highly soluble co-former, predisposes the co-crystal to convert between anhy-
drous and hydrated forms, to deliquesce, or to dissociate, in which case the individual com-
ponents form hydrates [124]. This was the case with theophylline–citric acid where the an-
hydrous co-crystal was converted to hydrate, as well as with caffeine–citric acid co-crystals
where the co-crystal deliquesced and formed a caffeine hydrate, at 98% RH [124,135,139].
Furthermore, impurities at trace level or other excipients such as fructose and xylitol in this
type of co-crystal decrease the deliquescent point and affect its stability [139,159].
4. Conclusions
Citric acid is an important excipient in many types of pharmaceutical formulations. Its
three carboxylic groups and one hydroxyl group provide the functionality and versatility
required for its many applications. In this review, we have discussed the fundamental
strategies that take advantage of its functionality and have summarized its uses in pharma-
ceutical formulations. The presence of citric acid in formulations solves many problems
but also causes some challenges. Understanding the physicochemical interactions of citric
acid with the active pharmaceutical ingredients and other excipients in formulations will
promote rational formulation design and effective therapeutics.
Author Contributions: Writing—original draft preparation, M.L.; writing—review, T.T., Q.F. and M.N.;
editing, M.L. and T.T. All authors have read and agreed to the published version of the manuscript.
Funding: This work was funded by NIH/NCI grant (R41CA247009) to M.L.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: 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.
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Citric Acid: A Multifunctional Pharmaceutical Excipient: Pharmaceutics

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Citric Acid: A Multifunctional Pharmaceutical Excipient: Pharmaceutics

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pharmaceutics

1 Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences,

Keywords: citric acid; excipient; formulation; citrates; lyophilization; co-crystals; co-amorphous;

Citation: Lambros, M.; Tran, T.; Fei,

Pharmaceutics 2022, 14, 972. https://doi.org/10.3390/pharmaceutics14050972 https://www.mdpi.com/journal/pharmaceutics

maceutics 2022, 14, x FOR PEER REVIEW

The tribasic salt of citric acid, trisodium citrate, is commercially available in bo

2. Citric Acid and Physiological Considerations

The SLC13A3 transporter cotransports Na+ and dicarboxylate or tricarboxylate ions

2.2. Citrates and Tight Junctions/Absorption

2.3. Proteolytic Inhibitor

Pharmaceutics 2022, 14, 972 4 of 18

urethane-doped octanediol citrate polymers show enhanced hydroxyapatite binding, while

3. Citric Acid in Formulations

3.2. Citric Acid in the Lyophilization Process

3.3. Citric Acid in Polymers

coatings for biodegradable cardiovascular stents. Specifically, the biodegradable alloy of

3.4. Co-Amorphous Drugs and Co-Crystals

A loratadine–citric acid co-amorphous system prepared using the solvent evaporation

Co-Crystal Stochiometric Ratio Methods of Preparation Techniques Used to Study References

3.5. Citric Acid in Formulations, Injection Pain and Other Issues

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