International Journal of Pharmaceutics 623 (2022) 121924

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International Journal of Pharmaceutics

journal homepage: www.elsevier.com/locate/ijpharm

Cocrystals of tuberculosis antibiotics: Challenges and missed opportunities

Ala’ Salem a, *, Esam Khanfar b, Sándor Nagy a, Aleksandar Széchenyi a, c
a
Institute of Pharmaceutical Technology and Biopharmacy, Faculty of Pharmacy, University of Pécs, Pécs, Hungary
b
Department of Immunology and Biotechnology, Medical School, University of Pécs, Pécs, Hungary
c
Department of Chemistry, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia

A R T I C L E I N F O A B S T R A C T

Keywords: Cocrystals have been extensively used to improve the physicochemical properties and bioavailability of active
Cocrystal pharmaceutical ingredients. Cocrystals of anti-tuberculosis medications are among those commonly reported.
Anti-tuberculosis This review provides a summary of the tuberculosis antibiotic cocrystals reported in the literature, providing the
Drug-drug cocrystal
main results on current tuberculosis medications utilized in cocrystals. Moreover, anti-tuberculosis cocrystals
Solubility
Multidrug-resistant
limitations and advantages are described, including evidence for enhanced solubility, stability and effect. Op­
portunities to enhance anti-tuberculosis medications and fixed dose combinations using cocrystals are given.
Several cocrystal pairs are suggested to enhance the effectiveness of anti-tuberculosis drugs.

1. Introduction
Pharmaceutical cocrystals are multicomponent solids made up of an
active pharmaceutical ingredient (API) and a non-covalently bonded
coformer in the same crystal lattice (Kumar and Nanda, 2021). They
have been used to enhance various aspects of APIs, including the
dissolution (Cao et al., 2018) chemical stability (Gao et al., 2012), and
antibacterial activity (Abidi et al., 2018). For diseases treated by mul­
tiple drugs, combinational therapy can improve the therapeutic effect
and patient compliance, and reduced prescriptions number and costs of
administration. Therefore, drug-drug cocrystals, where the coformer is
also an API, present an opportunity for enhancing the dissolution
(Bordignon et al., 2017; Žegarac et al., 2014), chemical stability (Drozd
et al., 2017), hygroscopicity (Nechipadappu et al., 2017), and in vitro
activity (Serrano et al., 2018) of drug combinations compared to the
original APIs. Drug-drug cocrystals can offer a convenient approach for
diseases treated by a combination of APIs (Bordignon et al., 2017;
Cvetkovski, 2016), such as tuberculosis (Lawn and Zumla, 2011). Thus,
multicomponent cocrystals could aid, at a supramolecular level, in the
combination of drugs (Thipparaboina et al., 2017). Drug-drug cocrystals
present an opportunity to enhance API properties for combined medi­
cations, reducing pill burden and minimize patient errors (Bordignon
et al., 2017). For combination purposes, APIs of the drug-drug cocrystals
are selected on the basis of therapy and crystal engineering supramo­
lecular synthon investigations become secondary (Bordignon et al.,
2017). These cocrystals are even more challenging to rationally design
(Thipparaboina et al., 2017) and only few drug-drug cocrystals are
commercially available despite the vast research on cocrystals (Shaikh
et al., 2018).
Tuberculosis is an infectious disease usually caused by Mycobacte­
rium tuberculosis (Farmer, 2018). It is a major cause of mortality infec­
tion (Bobak et al., 2019; [16]). Globally, tuberculosis was estimated to
infect 10 million, causing 1.41 million deaths in 2019 (WHO, 2020). The
treatment of tuberculosis necessitates the use of multiple medications
for long periods of time. Where the standard regimen consisted of
isoniazid, rifampicin, pyrazinamide and ethambutol dihydrochloride
(EDH) for two months followed by isoniazid and rifampicin for four
additional months (Lawn and Zumla, 2011). However, treatment
regimen choice should be informed by drug susceptibility testing
(Chiang and Lin, 2020). Unfortunately, control of multidrug-resistant
(MDR) tuberculosis is failing (WHO, 1996; granich, 2018; ahmad
et al., 2018), while treatment has advanced very little (Farmer, 2018).
A fixed dose combination (FDC) containing the four anti-tuberculosis
drugs is available for patients convenience. Nonetheless, FDCs have
many stability and quality issues, posing disadvantages to their use. As
pyrazinamide and EDH catalyse the reaction between isoniazid and
rifampicin, causing the degradation of isoniazid to isonicotinyl hydra­
zone. This metabolite can bind to rifampicin forming an insoluble
complex, leading to variable rifampicin bioavailability. Furthermore,
FDCs have physical stability concerns due to the hygroscopic nature of
EDH (Singh et al., 2001; Bhutani et al., 2005). The mechanism of the
reaction between rifampicin and isoniazid as well as the catalytic roles

* Corresponding author at: Institute of Pharmaceutical Technology and Biopharmacy, University of Pécs, 2 Rokus u, Pécs H-7624, Hungary.
E-mail address: ala.salem@aok.pte.hu (A. Salem).

https://doi.org/10.1016/j.ijpharm.2022.121924
Received 11 April 2022; Received in revised form 26 May 2022; Accepted 13 June 2022
Available online 20 June 2022
0378-5173/© 2022 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-
nc-nd/4.0/).
A. Salem et al. International Journal of Pharmaceutics 623 (2022) 121924

Fig. 1. Structure of the first-line anti-tuberculosis drugs. Structures adapted from PubChem.

Fig. 2. Structure of the second-line anti-tuberculosis drugs. Structures adapted from PubChem; Ciprofloxacin structure is used to represent fluoroquinolones.

greatly enhance anti-tuberculosis drugs. In this review we summarize

Table 1
anti-tuberculosis cocrystals reported in the literature, serving as a
Composition of common anti-tuberculosis FDCs.
starting point for future research, and also to identify areas need further
FDC Isoniazid Pyrazinamide EDH Rifampicin investigations with possible opportunities in utilizing cocrystals in the
Rifamate®/IsonaRif® 150 mg – – 300 mg management of tuberculosis.
Rifater® 50 mg 300 mg – 120 mg The components of a cocrystal interact with each other in a defined
75 mg 400 mg - 150 mg
stoichiometric ratio by intermolecular interactions (Li and Matzger,
Combunex® 300 mg – 800 –
mg 2016). However, the components of a FDC are not in stoichiometric
Voractiv®/Myrin-P 75 mg 400 mg 275 150 mg ratio, but rather designed according to the therapeutic dosage (Chellini
Forte®/Rimstar 4- mg et al., 2017). The dose of first-line anti-tuberculosis drugs in common
FDC®/AKuriT-4® FDCs is shown in Table 1. The utilization of cocrystals in FDC to enhance
Adapted from (Blomberg and Fourie, 2003; Organization, 2000; the stability, dissolution or therapeutic efficacy can only be achieved
Antituberculosis). after microbiological, pharmacokinetic and dynamic studies. The
amount of each API should be calculated in accordance with the amount
of EDH and pyrazinamide were reported by Bhutani et al. (Bhutani et al., in the cocrystal pair. FDC containing cocrystals can be designed to
2005). These technological and biopharmaceutical difficulties point to include native APIs as well as cocrystals. In such cases, the influence of
the need for development of alternative formulations (Meirelles et al., cocrystals on the stability and dissolution might be dampened. However,
2019). if the FDC is designed to incorporate the full dose of a target API in
Patients who do not respond to multiple first-line tuberculosis cocrystal form, then the physicochemical benefits brought by cocrys­
medications (Fig. 1) have to use second-line tuberculosis drugs (Fig. 2). tallization are optimized.
These include aminoglycosides, polypeptides, fluoroquinolones, cyclo­
serine, and 4-aminosalicylic acid (4-ASA) (Seddon et al., 2012). Many of 2. First line anti-tuberculosis medications
these antibiotics have been developed decades ago and suffered from
toxic side-effects, administration difficulty and poor activity against 2.1. Isoniazid
Mycobacterium tuberculosis (Farmer, 2018). It is recommended to
manage MDR-tuberculosis with at least four effective antibiotics for 18 Isoniazid, called isonicotinic acid hydrazide, is among the most
to 24 months (Lawn and Zumla, 2011; Adam et al., 2017). Meanwhile, active compounds used in treatment and prophylactic prevention of
trials are set to find shorter and less debilitating regimens (Ahmad et al., tuberculosis infections. In fact, strains resistant to isoniazid and rifam­
2018; H. The Lancet Global, 2018). picin are considered MDR. Isoniazid contains a pyridine nucleus and is a
Cocrystals of anti-tuberculosis drugs have been vastly reported. In structural analog of nicotinic acid, pyridoxine and nicotinamide-adenine
fact, drug-drug cocrystals using anti-tuberculosis APIs are the second dinucleotide (Unissa et al., 2016; Geib et al., 2007). Despite the simple
most reported after nonsteroidal anti-inflammatory drugs (NSAIDs) and chemical structure of this pro-drug, its mechanism of action is complex
before diuretics (Wang et al., 2021). Cocrystals have the potential to (Unissa et al., 2016). Isoniazid acts through the interference of lipid and

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A. Salem et al. International Journal of Pharmaceutics 623 (2022) 121924

Table 2
Cocrystals of isoniazid and their reported advantages.
Co-former Molar ratio Preparation method Observations CCDC No. Ref.

2,3-dihydroxybenzoic acid 1:1 Slow SE at room temp. in 2:1 ethanol: Structure 1005088 (Mashhadi et al., 2014)
acetonitrile
2,4- 1:1 LAG with methanol Structure 1993883 (Mashhadi et al., 2020)
dihydroxycinnamic acid
2,4-dihydroxybenzoic acid 1:1 Slow SE at room temp. using methanol Structure 746450 (Lemmerer et al., 2010)
2-chloro-4-nitro benzoic acid 1:1 Slow SE at room temp. in 6:5 ethanol: Structure 847206 (Lemmerer, 2012)
acetonitrile
2-hydroxycinnamic acid 1:1 Slow SE in methanol Structure 1993881 (Mashhadi et al., 2020)
2-methylresorcinol 1:1 CC hydrate LAG with dichloromethane Structure 1989809 (González-González
et al., 2020)
3- 1:1 Slow SE in methanol Structure 1993886 (Mashhadi et al., 2020)
hydroxycinnamic acid
3,4-dihydroxycinnamic acid 1:1 LAG with methanol Structure 1993885 (Mashhadi et al., 2020)
3,5-dihydroxybenzoic acid 1:1 Slow SE at room temp. in 2:1 ethanol: Structure 1005089 (Mashhadi et al., 2014)
acetonitrile
3-hydroxybenzoic acid 1:1 Slow SE at room temp. in 2:1 ethanol: Structure 1005090 (Mashhadi et al., 2014)
acetonitrile
3-hydroxybenzoic acid- 2- 1:1 CC hydrate Slow SE at room temp. using 2-butanone Structure 746451 (Lemmerer et al., 2010)
butanone
3-hydroxybenzoic acid- 1:1 CC hydrate Slow SE at room temp. using acetone Structure 746452 (Lemmerer et al., 2010)
acetone
4-aminosalicylic acid 1:1 NG; LAG; SE using methanol Enhanced solubility and aqueous 800230– (Drozd et al., 2017;
stability 800239 Grobelny et al., 2011;
800270 Surendran, 2013)
4-hydroxybenzoic acid 1:1; 2 forms Slow SE at room temp. Structure; 746449 (Aitipamula et al.,
CC hydrate 2 forms hydrate CC prepared by Slow SE at hydrates had lower solubility and 935248 2013; Lemmerer, 2012)
room temp. using acetonitrile dissolution rate 935247
4-hydroxycinnamic acid 1:1 Slow SE in methanol Structure 1993884 (Mashhadi et al., 2020)
Adipic acid 2:1 Slow SE at room temp. using methanol Structure 746447 (Lemmerer et al., 2010)
Benzoic acid 1:1 Slow SE in ethanol/acetonitrile (2:1 Solubility of cocrystals tend to (Sarcevica et al., 2013;
mixture); ball milling increase with increasing solubility of Sarceviča et al., 2015)
carboxylic acid
Caffeic acid 1:1; 3 forms LAG with acetonitrile, further grinding Enhanced stability 1018396 (Swapna et al., 2014;
gave form II. Form III obtained by xylene/ 1018397 Rosa et al., 2019)
methanol slow SE at room temp.
Catechol 1:1 LAG with dichloromethane Structure 1989810 (González-González
et al., 2020)
Cinnamic acid 2:1; 2 forms Slow SE in ethanol/acetonitrile (2:1 Solubility of cocrystals tend to 1993882 (Sarcevica et al., 2013;
mixture) or LAG increase with increasing solubility of Mashhadi et al., 2020)
carboxylic acid; structure
Ferulic acid 1:1; 2 forms LAG in acetonitrile, further grinding Enhanced stability 1018398 (Swapna et al., 2014)
resulted in form 2. or by heating form I to
130 ◦ C for 30 min
Fumaric acid 2 forms Slow SE at room temp. using methanol Lower solubility and dissolution rate 935250 (Aitipamula et al.,
935249 2013)
Fumaric acid-pyrazinamide Drug-bridge- SE Enhanced formulation and in vitro/ 1569268 (Liu et al., 2018)
drug ternary vivo synergistic effects
CC
Gallic acid 1:1 Slow SE in at room temp. 2:1 ethanol: Structure 1005087 (Mashhadi et al., 2014)
acetonitrile
Gentisic acid 1:1 Slow SE in methanol Antioxidant, possible enhancement 1980680 (Mashhadi et al., 2021)
of stability for FDC
Glutaric acid 1:1 Slow SE at room temp. using methanol Structure 746446 (Lemmerer et al., 2010)
Glycolic acid 1:1 CC; CC salt LAG Structure 2041155 (Álvarez-Vidaurre et al.,
2041154 2021)
Malonic acid 2:1 Slow SE at room temp. using methanol Structure 746444 (Lemmerer et al., 2010)
Mandelic Acid 1:1 LAG Structure 2041156 (Álvarez-Vidaurre et al.,
2021)
Nicotinamide- Fumaric acid Ternary CC Slow SE at room temp. using methanol Lower solubility and dissolution rate 935251 (Aitipamula et al.,
2013)
Nicotinamide-Succinic acid Ternary CC Slow SE at room temp. using methanol Similar solubility 935252 (Aitipamula et al.,
2013)
Oleanolic acid 1:1 SE, LAG and NG Possible hepatoprotective effect (Fadipe et al., 2017)
Orcinol 1:1 LAG with dichloromethane Structure 1989808 (González-González
et al., 2020)
p-aminobenzoic acid 1:2; form I at SE in 2:1 ethanol: acetonitrile Structure 1554641 (Diniz et al., 2018)
25 ◦ C & II at 1554639
− 5◦ C
p-cyanobenzoic acid 1:1 SE in 2:1 ethanol: acetonitrile Structure 1554637 (Diniz et al., 2018)
Phloroglucinol CC LAG Structure 1989811 (González-González
et al., 2020)
Pimelic acid 1:1 Slow SE at room temp. using methanol Structure 746448 (Lemmerer et al., 2010)
p-nitrobenzoic acid 1:1 SE in ethanol Structure 1554640 (Diniz et al., 2018)
1:1 CC hydrate 1016095 (Mashhadi et al., 2016)
(continued on next page)

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A. Salem et al. International Journal of Pharmaceutics 623 (2022) 121924

Table 2 (continued )
Co-former Molar ratio Preparation method Observations CCDC No. Ref.

Protocatechuic acid (3,4- Slow SE at room temp. in methanol and Lower solubility compared to
dihydroxybenzoic acid) water (1:1) isoniazid; higher stability than
isoniazid; structure
Pyrogallol 1:1 LAG with dichloromethane Structure 1989812 (González-González
et al., 2020)
Quercetin 1:1 Anti-solvent using 2-propanol/n-hexane; Slower drug release; (Yadav et al., 2019; Liu
LAG followed by slow SE hepatoprotective effect; et al., 2020)
enhanced bioavailability of quercetin
Resorcinol 1:1 LAG using acetonitrile Enhanced stability 1018399 (Swapna et al., 2014)
Resveratrol 1:1 Reaction crystallization using methanol Lower solubility; local effect to the 1854680 (Rosa et al., 2019)
skin, cocrystal reduced the amount of
permeated drug
Sebacic acid 2:1 Slow SE in ethanol/acetonitrile (2:1 Solubility of cocrystals tend to (Sarcevica et al., 2013)
mixture) increase with increasing solubility of
carboxylic acid; structure
Suberic acid 2 forms Slow SE in ethanol/acetonitrile (2:1 Solubility of cocrystals tend to (Sarcevica et al., 2013)
mixture); and acetonitrile/ methyl tert- increase with increasing solubility of
butyl ether 1:1 mixture with seed addition carboxylic acid; structure
Succinic acid 2:1 Slow SE at room temp. using different Structure 746445 (Lemmerer et al., 2010;
solvents Lemmerer, 2012)
Syringic acid 1:1 Anti-solvent using 2-propanol/n-hexane Slower drug release; 1865066 (Yadav et al., 2019)
hepatoprotective effect
Vanillic acid 1:1; 2 forms LAG using acetonitrile, further grinding Enhanced stability 1018400 (Swapna et al., 2014;
resulted in form II 1018401 Battini et al., 2018)

CC: cocrystal; CCDC: Cambridge Crystallographic Data Centre; SE: solvent evaporation; LAG: liquid assisted grinding; NG: neat grinding.

nucleic acid biosynthesis in active tubercle bacilli (Papich and Papich,
2016), which is required to build bacterial cell wall (Moradi et al.,
2021).
Isoniazid belongs to the biopharmaceutics classification system class
I or III drugs, therefore, it has not been related to solubility issues.
Furthermore, isoniazid is stable at ambient and accelerated stability
conditions for long periods. However, it has stability issues in anti-
tuberculosis FDC. Solutions to enhance its stability in FDCs have been
fully explored. Therefore, minimizing or preventing isoniazid pharma­
ceutical issues are highly in demand (Diniz et al., 2018).
Controlled release isoniazid tablets were reported using hydrophilic
polymers. However, humidity was among the main factors affecting the
stability of the controlled release formulations (Hiremath and Saha,
2008). To target the site of infection, isoniazid has been formulated as a
dry-powder inhalation. However, even at high excipient concentration,
isoniazid was not adequately protected from moisture. Therefore,
improving the physical stability of isoniazid is necessary to formulate an
effective inhalable form of isoniazid (Sibum et al., 2020). Cocrystals can
enhance the stability of APIs and aid in the development of carrier-free
dry powder inhalable formulations (Wong et al., 2022).
Enhancing the stability of isoniazid may enhance the stability of anti-
tuberculosis FDCs. Cocrystals of isoniazid with caffeic acid, ferulic acid,
resorcinol, and vanillic acid (Swapna et al., 2014) were reported to have
enhanced stability. Similarly, stability advantages brought by cocrys­
tallization include the case of isoniazid cocrystal hydrate with the
antioxidant and anti-bacterial, protocatechuic acid (Mashhadi et al.,
2016). The stability of classic FDC of tuberculosis antibiotics has been
enhanced by cocrystals. Utilizing isoniazid-caffeine/vanillic acid coc­
rystals were reported to have greater stability compared to the classical
drug combination (Battini et al., 2018). Moreover, cocrystal of isoniazid
with gentisic acid may have enhanced stability in FDC, as the hydrazide
functional group in isoniazid which is responsible for rifampicin
degradation, is masked by a hydrogen bond. Furthermore the antioxi­
dant properties of gentisic acid may make this cocrystal useful in
replacing pure isoniazid to formulate more stable FDCs (Mashhadi et al.,
2021). Cocrystal of 4-ASA with isonicotinamide have been shown to
have improved not only stability but also solubility (Drozd et al., 2017).
Moreover, cocrystal of isoniazid with 4-ASA were also reported to be
more stable thermally (Diniz et al., 2018). The temperature-dependent
proton mobility in the isoniazid-4-ASA cocrystal molecular complex
was reported by Grobelny et al. (Grobelny et al., 2011).
Although isoniazid does not suffer from poor water solubility (Diniz
et al., 2018), enhancing the solubility of an API is crucial for bioavail­
ability enhancement (Brouwers et al., 2009). Cocrystals of isoniazid
resulting in enhanced solubility include those of isoniazid with 4-ASA,
which were reported to have higher solubility than 4-ASA in different
pH ranges and also improved aqueous stability (Drozd et al., 2017).
However, the dissolution of isoniazid-4-ASA cocrystal was not compared
to that of pure isoniazid. The solubility of isoniazid cocrystals with
carboxylic acid co-formers was reported to increase with the increasing
solubility of the acid in deionized water (malonic > glutaric > succinic
> pimelic > adipic > suberic > benzoic > sebacic > cinnamic) (Sar­
cevica et al., 2013). Moreover, isoniazid was found to form two poly­
morphic hydrates and cocrystal with 4-hydroxybenzoic acid. The latter
had a higher solubility than the hydrates, they however had lower
dissolution than isoniazid. Cocrystal of isoniazid with fumaric acid were
of lower intrinsic dissolution rate. Ternary cocrystal with nicotinamide-
succinic acid were of similar intrinsic dissolution rate. Nevertheless,
ternary cocrystal with nicotinamide-fumaric acid were able to reach a
higher dissolution but only after 90 min in phosphate buffer (Aitipamula
et al., 2013). The drug-bridge-drug ternary cocrystal of isoniazid with
pyrazinamide using fumaric acid present an interesting example of
isoniazid cocrystals. This intriguing combination was reported to have
enhanced pharmaceutical formulation and a synergistic effect against
tuberculosis (Liu et al., 2018).
Isoniazid cocrystals with many co-formers resulted in advantages
which may rationalize their use. These advantages include a hep­
atoprotective effect for isoniazid cocrystals with syringic acid and
quercetin. These hepatoprotective cocrystals can be useful in the man­
agement of tuberculosis, as idiosyncratic hepatotoxicity is among the
most reported side effects of anti-tuberculosis medications (Yadav et al.,
2019). Conversely, the lower solubility of isoniazid-resveratrol cocrystal
was utilized for topical treatment of cutaneous tuberculosis, as this
cocrystal resulted in 86% reduction in drug permeation (Rosa et al.,
2019). A summary of the isoniazid cocrystals reported in the literature is
shown in Table 2. A mini-review of isoniazid and pyrazinamide coc­
rystals has been recently published by Batisai (Batisai, 2020).
Isoniazid is generally well tolerated (Berg et al., 2004). However, it
commonly causes various gastrointestinal side effects, including nausea,
vomiting, epigastric distress and pancreatitis. Other side effects include,
unsteadiness or clumsiness, tingling, numbness, burning or pain in
hands and feet, dark urine, loss of appetite, weakness or unusual

4
A. Salem et al.
Table 3
Cocrystals of pyrazinamide and their reported advantages.
Co-former
1,4-
dibromotetrafluorobenzene
1,4-diiodotetrafluorobenzene
1-hydroxy-2-naphthoic acid
2,4-dihydroxybenzoic acid
2,5-dihydroxybenzoic acid
2,5-thiophenedicarboxylic
acid
2,6-dichlorobenzoic acid
2,6-dihydroxybenzoic acid
2–chloro-4-nitrophenol
3,4-dihydroxybenzoic acid
3,5-dihydroxybenzoic acid
3-Hydroxybenzoic Acid
4-aminosalicylic acid
4-hydroxybenzoic acid
4-hydroxymandelic acid
5-hydroxyisophthalic acid
(hispta)
Adipic acid
Caffeic acid
Carbamazepine
Citric acid
Diflunisal
Ethenzamide
Ferulic acid
Gallic acid
Glutaric acid
Hydrochlorothiazide
Indole-2-carboxylic acid
Malonic acid
m-aminobenzoic acid
m-hydroxybenzoic acid
o-aminobenzoic acid
(anthranilic acid)
o-hydroxybenzoic acid
(salicylic acid)
o–hydroxy-cinnamic acid
Oxalic acid
p-aminobenzoic acid
p-aminosalicylic acid
p-counmaric acid
p-hydroxybenzoic acid
International Journal of Pharmaceutics 623 (2022) 121924
Molar Preparation method Observations CCDC No. Ref.
ratio
2:1 Ball milling using acetonitrile Structure 1550375 (Choquesillo-Lazarte et al.,
2017)
2:1 Ball milling using acetonitrile Structure 1550374 (Choquesillo-Lazarte et al.,
2017)
CC Slow SE using methanol Structure 864873 (Adalder et al., 2012)
1:1 SE in 1:1 chloroform: methanol Lower solubility; computational structure 1504475 (Sarmah et al., 2017; Al-
analysis Otaibi et al., 2020)
1:1 LAG, SE, melt and slurry Polymorph study and structure 240490 (Abourahma et al., 2011;
McMahon Jennifer et al.,
2005)
1:1 LAG and slow SE using Structure 2026372 (Yang et al., 2022)
methanol
1:1 LAG and slow SE using Structure 2026371 (Yang et al., 2022)
methanol
1:1 LAG using acetonitrile; SE from Lower solubility; computational structure 1504478 (Sarmah et al., 2017; Al-
1:1 toluene: methanol analysis Otaibi et al., 2020;
Rajbongshi et al., 2018)
1:1 LAG and slow SE using Structure 2026376 (Yang et al., 2022)
methanol
1:1 Slow SE using methanol Structure 942698 (Lou et al., 2015)
1:1 SE using acetonitrile Enhanced solubility; computational structure 1504476 (Sarmah et al., 2017; Al-
analysis Otaibi et al., 2020)
1:1 NG at room temp.; Slow SE at Structure (Wang et al., 2019)
room temp. in methanol
1:1; 1:2; LAG using different solvents Enhanced solubility; structure 800271 (Drozd et al., 2017;
CC hydrate Grobelny et al., 2011;
Zhang et al., 2021)
1:1 LAG using acetonitrile Structure 1844155 (Rajbongshi et al., 2018)
CC hydrate LAG and slow SE using Structure 2026375 (Yang et al., 2022)
methanol
1:1 LAG and slow SE using Structure 2069727 (Yang et al., 2022)
methanol
4:1 Reaction crystallization using Structure, lower solubility 1005601 (Wang et al., 2015)
ethyl acetate (methanol or
tetrahydrofuran)
LAG using acetonitrile Structure (Rajbongshi et al., 2018)
Eutectic NG Enhanced carbamazepine dissolution (Sathisaran and Dalvi,
2019)
1:1 Structure, enhanced solubility 1005604 (Wang et al., 2015)
1:1 NG at 80 ◦ C; ball milling with Computational studies (Wu et al., 2020; Évora
ethanol at room temp.; room et al., 2011)
temp. annealing
Eutectic LAG using acetonitrile Evaluation of cocrystal and eutectic formation (Rajbongshi et al., n/a)
1:1 LAG using acetonitrile Possible inhibitory activity against mycobacterium 1504479 (Sarmah et al., 2017;
tuberculosis type II and can be developed as a Rajbongshi et al., 2018; Al-
new anti-tuberculosis drug; structure; lower Otaibi et al., 2019)
solubility
CC Slow SE using methanol Structure 864872 (Adalder et al., 2012)
2:1; 1:1 NG and LAG using ethanol; Enhanced solubility 917631 (Luo and Sun, 2013;
slow SE Ngilirabanga et al., 2020)
CC Reaction crystallization from Computational investigations; structure 989055 (Sheena Mary et al., 2021;
ethyl Wang et al., 2014)
acetate
CC Slow SE using methanol Structure 864874 (Adalder et al., 2012)
1:1 Slow SE Enhanced solubility 917629 (Luo and Sun, 2013)
CC Melt Polymorph study and structure (Abourahma et al., 2011)
1:1 LAG and melt; Slow SE using Polymorph study and structure 919366 (Abourahma et al., 2011;
methanol Lou et al., 2015)
CC LAG, melt, SE and slurry in Polymorph study and structure (Abourahma et al., 2011)
acetonitrile
CC LAG in tetrahydrofuran or Polymorph study and structure (Abourahma et al., 2011)
isopropanol and melt
1:1 LAG and slow SE using Structure 2026374 (Yang et al., 2022)
methanol
1:1 NG and LAG using oxalic acid Structure, computational studies 1486471 (Kulla et al., 2016)
dihydrate
1:1 Different methods Polymorph study and structure 1432365 (Abourahma et al., 2011;
1432366 Thorat et al., 2015)
CC hydrate LAG in water only, SE and Polymorph study and structure (Abourahma et al., 2011)
slurry in water only
LAG using acetonitrile Structure (Rajbongshi et al., 2018)
1:1 Polymorph study and structure 919367
(continued on next page)
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A. Salem et al.
Table 3 (continued )
Co-former Molar Preparation method
ratio
LAG, SE, melt and slurry in
acetonitrile or acetone, Slow SE
using methanol
p–hydroxy-cinnamic acid 1:1 LAG and slow SE using
methanol
p-nitrobenzamide LAG, SE and melt
p-toluenesulfonic acid
Sebacic acid 2:1
Sinapic acid 1:1 LAG with acetonitrile
Succinic acid 2:1 Slow SE
Syringic acid LAG with acetonitrile
Theophylline 2 forms SE, LAG
Trans-aconitic acid 1:1
Vanillic acid CC Slow SE using methanol
CC: cocrystal; CCDC: Cambridge Crystallographic Data Centre; SE: solvent evaporation; LAG: liquid assisted grinding; NG: neat grinding.
tiredness and yellow skin or eyes. Blurry or vision loss, seizures, joint
pain, mood or other mental changes like depression are among the rare
side effects of isoniazid (Moradi et al., 2021; Berg et al., 2004).
Isoniazid possesses functional groups capable of forming hydrogen
bonds (González-González et al., 2020) and it has the potential to be a
supramolecular reagent. However, isoniazid has found very limited use
in cocrystals (Lemmerer et al., 2010). Cocrystals of isoniazid therefore
may offer many opportunities to enhance its properties, such as stability
(Mashhadi et al., 2016; Battini et al., 2018) and solubility (Drozd et al.,
2017; Sarcevica et al., 2013), reduce isoniazid associated hepatotoxicity
(Yadav et al., 2019) and also aid in the management of tuberculosis via
synergistic effect (Liu et al., 2018). Pyridoxine is the antidote and used
in the treatment of isoniazid-induced seizures together with benzodi­
azepines (Geib et al., 2007). The use of pyridoxine and benzodiazepines
as co-formers might prove to be more beneficial. On the other hand,
rifampicin interacts with isoniazid leading to potential isoniazid hepa­
totoxicity (Self et al., 1999). As these APIs are used in combination to
treat tuberculosis, cocrystals of isoniazid or rifampicin can be utilized to
enhance the stability and reduce this undesired interaction. Possible
synergistic effects resulting from drug-drug cocrystals of anti-
tuberculosis drugs should be investigated.
2.2. Pyrazinamide
Pyrazinamide, a cornerstone anti-tuberculosis drug, drastically
shortens the therapy duration from nine to six months (Lamont and
Baughn, 2019). Pyrazinamide has a distinctive mode of action, it in­
terferes with adenosine triphosphate production. Moreover, pyr­
azinamide synergistically affects the pharmacokinetic properties of
bedaquiline and nitroimidazole, new anti-tuberculosis drugs. Nonethe­
less, over half MDR-tuberculosis cases were found to be also pyr­
azinamide resistant. Globally, pyrazinamide resistant tuberculosis
burden annually is estimated to be 1.4 million new cases (Whitfield
et al., 2015).
Pyrazinamide is a class II drug in the biopharmaceutics classification
system. Furthermore, the rate-limiting step for its absorption is its
dissolution. The low aqueous solubility and bioavailability of pyr­
azinamide have hindered its efficient use. Due to the important role of
pyrazinamide in the management of tuberculosis, finding ways to
enhance its solubility is crucial. Different formulation strategies
including particle size reduction, cyclodextrin complexation, amor­
phous solid dispersions, lipid-based formulations and cocrystals have
been proposed to solve this problem (Zhang et al., 2017). An inhalable
pyrazinamide formulation prepared by spray-drying was stabilized by
hyaluronic acid and dipalmitoylphosphatidylcholine (Pham et al.,
2013). Furthermore, polymeric nanoparticle based formulation of pyr­
azinamide has been reported to have a sustained release profile and
significant uptake by macrophages. However, the stability of this
International Journal of Pharmaceutics 623 (2022) 121924
Observations CCDC No. Ref.
(Abourahma et al., 2011;
Lou et al., 2015)
Structure 2026373 (Yang et al., 2022)
Polymorph study and structure (Abourahma et al., 2011)
Computational studies (Al-Otaibi et al., 2019)
Structure, lower solubility 1005602 (Wang et al., 2015)
Structure 1844154 (Rajbongshi et al., 2018)
Enhanced solubility 917630 (Luo and Sun, 2013)
Structure (Rajbongshi et al., 2018)
Structure (Eddleston et al., 2016)
Structure, enhanced solubility 1005603 (Wang et al., 2015)
Structure 864871 (Adalder et al., 2012)
formulation was not assessed beyond the period of three months (Varma
et al., 2015).
Cocrystals of pyrazinamide with 3,5-dihydroxybenzoic acid was also
reported to have enhanced solubility (Sarmah et al., 2017). Cocrystals of
pyrazinamide with glutaric acid, malonic acid, and succinic acid have
been reported to enhance the solubility of pyrazinamide (Luo and Sun,
2013). Pyrazinamide cocrystals with trans-aconitic acid and citric acid
were found to have intrinsic dissolution rates superior to pure pyr­
azinamide (Wang et al., 2015). Moreover, pyrazinamide cocrystals with
3,5-dihydroxybenzoic acid, 2,6-dihydroxybenzoic acid, 2,4-dihydroxy­
benzoic acid and ferulic acid had equilibrium solubilities following the
coformers solubility (Sarmah et al., 2017). Pyrazinamide-4-ASA coc­
rystal had higher dissolution compared to 4-ASA (Drozd et al., 2017)
and is particularly interesting for the management of tuberculosis, as
both APIs are used in the treatment of tuberculosis (Seddon et al., 2012).
Furthermore, cocrystals of pyrazinamide with 2,4-dihydroxy benzoic
acid, 2,6-dihydroxybenzoic acid and 3,5-dihydroxybenzoic acid have
been suggested as new anti-tuberculosis formulations. As molecular
docking examination of these cocrystals exhibited inhibitory activity
against mycobacterium tuberculosis (Al-Otaibi et al., 2020).
The activity of pyrazinamide against mycobacterium tuberculosis may
be significantly enhanced by cinnamic aldehyde, as it has been reported
that pyrazinamide acts synergistically with cinnamic aldehyde in mouse
models (Wan et al., 2022). Therefore, cocrystal of pyrazinamide with
cinnamic aldehyde might be beneficial in the battle against tuberculosis.
Diflunisal, an NSAID, has low solubility and high permeability. Cocrystal
of pyrazinamide with diflunisal may reduce pyrazinamide adverse ef­
fects while improving diflunisal solubility (Wu et al., 2020). Other re­
ported cocrystals of pyrazinamide are shown in Table 3. Eutectics were
also reported for pyrazinamide with benzoic acid, cinnamic acid, sali­
cylic acid, nicotinic acid, isonicotinic acid and saccharin (Rajbongshi
et al., 2018).
Unusual homosynthon was observed in pyrazinamide cocrystal with
monocarboxylic acids equipped with additional hydrogen bonding sites,
like vanillic acid; gallic acid; 1-hydroxy-2-naphthoic acid and indole-2-
carboxylic acid. This homosynthon occurrence is rather unusual as
heterosynthon is more energetically favourable, in the case of cocrystals
(Adalder et al., 2012). In fact, pyrazinamide is able to act as a ligand in
many complexes and has strong hydrogen bonding properties. Pyr­
azinamide has multiple hydrogen-bonding sites, such as a nitrogen
containing electron-rich aromatic heterocycle and a primary amide
group. Pyrazinamide has been described as a good nominee for
embodiment into cocrystals and formulates stable and diverse multi-
dimensional motifs with hydrogen bonding (Zhang et al., 2017; Yang
et al., 2022). Further research is needed to fully utilize the potential of
this API in anti-tuberculosis cocrystals. Pyrazinamide cocrystals with
bedaquiline or nitroimidazole might exploit their synergistic effect
(Whitfield et al., 2015) and further enhance the properties of these APIs.
6
A. Salem et al.
Other anti-tuberculosis drugs might also produce synergistic cocrystals
with pyrazinamide, which can also be utilized to combat MDR-
tuberculosis or enhance drug tolerability.
2.3. Ethambutol dihydrochloride
Ethambutol is among the first line anti-tuberculosis agents (Larsen
et al., 2017). Ethambutol has not been found to be polymorphic in itself
to date. However, the dihydrochloride salt which ethambutol is
formulated into is tetramorphic (Cherukuvada and Nangia, 2013).
Ethambutol dihydrochloride (EDH) is a chiral drug, where the S,S
enantiomer is active, while R,R is inactive (Cherukuvada and Nangia,
2013), and the R,S- diastereomers is 16 times less effective against
Mycobacterium tuberculosis. This structural and stereoisomeric selectivity
is believed to be due to specific enzyme-receptor fit (Rubin-Preminger
et al., 2004). The S,S enantiomer has four known polymorphs (Rubin-
Preminger et al., 2004). This synthetic aminoalcohol is an effective oral
bacteriostatic agent (Rao et al., 2016) and acts by inhibiting cell-wall
biosynthesis (Ethambutol, 2008).
Ethambutol has been formulated into dry powder inhalation by solid
lipid nanoparticles. The formulation was found to be stable for four
weeks at 4 ◦ C (Nemati et al., 2019). Furthermore, a liposomal formu­
lation of ethambutol was reported to have a prolonged drug release.
Nonetheless, the liposomal formulation was found to be stable at 5 ◦ C for
over four months and over one month at ambient conditions (Wiens
et al., 2004). However, the need for cold chain and short stability make
it harder to distribute these formulations to places in need (N.I.o. Health,
Temperature-stable experimental tuberculosis vaccine enters clinical
testing, in, 2019). Therefore, there is a need to enhance the stability of
ethambutol.
A FDC of the four anti-tuberculosis APIs offers a convenient pill for
patients (Ethambutol, 2008). However, the degradation of isoniazid by
rifampicin is catalysed by EDH. The hygroscopic property of EDH is
believed to play a role in the instability of the FDC (Diniz et al., 2017).
Therefore, the use of water-resistant film coating polymers can enhance
the stability of anti-tuberculosis FDC (Bhutani et al., 2004). An attempt
has been made to minimize the interaction of APIs in the fixed-dose
combination by salt formulations of ethambutol. Lower EDH hygro­
scopicity was obtained by preparing EDH oxalate salts (Diniz et al.,
2017). However, ethambutol salts with several protic acids were found
to be hygroscopic. Suggesting that the exploration of other solid forms
like cocrystals, is very important in drug formulation (Cherukuvada and
Nangia, 2013). Cocrystals can be utilized to lower the hygroscopicity of
EDH. Therefore, resulting in more stable fixed-dose anti-tuberculosis
drug formulation.
Another issue of EDH is that it causes dose-dependent ocular neu­
ropathy (Ando et al., 2021). EDH cocrystals present an opportunity to
reduce this side effect while maintaining EDH efficacy. Hepatotoxicity is
another side effect of EDH administration (Ethambutol, 2008). Cocrys­
tallization of EDH with a hepatoprotective co-former might result in a
reduced toxicity. Particularly because pyrazinamide can also cause
hepatotoxicity (Yadav et al., 2019), and these APIs are commonly used
in combination (Lawn and Zumla, 2011). Furthermore, the absorption of
EDH may be inhibited by concomitant antacid administration. As a 20%
serum dose reduction was observed in patients taking antacids with
EDH. On the other hand, rifampicin decreases the EDH renal excretion
(Ethambutol, 2008). Therefore, EDH cocrystal with rifampicin may
prolong EDH activity and result in a synergistic effect. EDH can syner­
gistically increase the effectiveness of antibacterial APIs, like arabino­
galactan, mycolic acids and spermidine by biosynthetic inhibition
specifically altering cell wall of the Mycobacterial cell wall (Rubin-Pre­
minger et al., 2004). Cocrystals of these combinations or other anti-
tuberculosis agents might have a significant effect on the management
of tuberculosis. Surprisingly, to the best of our knowledge, no papers on
EDH cocrystals were published.
7
International Journal of Pharmaceutics 623 (2022) 121924
2.4. Rifampicin
Rifampicin (rifampicin) or rifapentine, the semisynthetic derivative
of rifamycin (Hussain et al., 2021), is among the mainstay anti-
tuberculosis treatment due to its unique activity against non-
replicating bacteria and its ability to penetrate lesions (Onorato et al.,
2021; Grosset and Leventis, 1983). Moreover, rifampicin is an effective
anti-tuberculosis drug against persistent bacteria. Tuberculosis relapse
rate is reduced by the addition of rifampicin to the regimen. Further­
more, the administration of rifampicin and pyrazinamide reduces the
treatment duration (Grosset and Leventis, 1983; Mitchison, 2000).
Rifampicin is a crystalline drug with limited aqueous solubility. Oral
administration of rifampicin is associated with poor oral absorption and
limited drug permeation across the bacterial cell wall. Low solubility of
rifampicin requires a high oral dose administration. Several approaches
have been employed to increase the bioavailability of rifampicin,
including micelles, liposomes, solid lipid and polymeric nanoparticles,
nanoemulsions as well as implants (Hussain et al., 2021).
Solid lipid nanoparticles were utilized to enhance the bioavailability
of rifampicin. However, the stability of this formulation was only tested
in refrigerated conditions (Singh et al., 2015), making its distribution
difficult (N.I.o. Health, 2019). A cyclodextrin complex of rifampicin has
been formulated in an aim to target the site of infection by nebulization
(Tewes et al., 2008). Furthermore, nano-particle formulation was re­
ported for pulmonary delivery of rifampicin (Sung et al., 2009). Simi­
larly, rifampicin loaded microspheres were formulated for a sustained
delivery to the lungs (Doan et al., 2011). However, long term stability
studies of these formulations were not carried out. A widespread dis­
tribution of rifampicin formulations with inferior bioavailability in
South Africa has been reported (McIlleron et al., 2002). Therefore, there
is a need for formulation to enhance the bioavailability and stability of
rifampicin.
Rifampicin is well tolerated by patients. However, rifampicin may
cause hepatic and immunological toxicities, especially at higher doses,
causing orange discoloration of body fluids (Grosset and Leventis, 1983;
Mitchison, 2000). Furthermore, as mentioned earlier, rifampicin in­
teracts with isoniazid to form isonicotinyl hydrazone in the classical
anti-tuberculosis fixed dose combination (Swapna et al., 2018). Coc­
rystallization may help mitigate these side effects and drug interactions
and result in a more tolerated and stable fixed dose combination.
Rifampicin has been reported to have multiple polymorphic, hydrate
and solvate forms, which is possible due to the various possibilities for
hydrogen bonding, ionization and conformational states, allowing the
complex structure to have different crystal packing (Panchagnula et al.,
2006). However, to the best of our knowledge, no papers on rifampicin
cocrystals were published in the literature.
2.5. Streptomycin
Streptomycin was the first aminoglycoside antibiotic to be identified.
It is a protein synthesis inhibitor, belonging to the same class as kana­
mycin and amikacin. The use of streptomycin carries the risk of neuro­
toxicity and ototoxicity (Streptomycin, 2008). However, it is valuable in
the treatment of tuberculosis, particularly in managing MDR-
tuberculosis (Shrestha et al., 2020). This first line anti-tuberculosis
drug is indicated for patients with hepatitis induced by other hepato­
toxic oral anti-tuberculosis agents, like isoniazid, pyrazinamide and
rifampicin. In such cases, a non-hepatotoxic regimen consisting of
streptomycin, EDH and a fluoroquinolone is recommended. Moreover,
in tuberculous meningitis, streptomycin is suggested instead of EDH
(Kumar et al., 2014).
The marketed sulfate salt of streptomycin has compromised oral
bioavailability, and is therefore administered parenterally (Kumar et al.,
2014). However, due to the intramuscular route of administration, it is
met by low patient compliance. Alternatively, pulmonary delivery by
deep powder inhalation (Shiehzadeh et al., 2019), solid lipid
A. Salem et al. International Journal of Pharmaceutics 623 (2022) 121924

Table 4
Cocrystals of 4-aminosalicylic acid and their reported advantages.
Co-former Molar ratio Preparation method Observations CCDC No. Ref.

Caffeine 1:1 SE using methanol and ethanol; LAG Enhanced solubility; structure 1495674 1561332 (Drozd et al., 2017; Andre et al., 2017)
using water, ethanol, or acetone
Carbamazepine 1:1; 1:2:1 LAG, SE and slurry using acetonitrile, 3-4x enhanced solubility and in 1544195–1544197 (Drozd et al., 2017)
hydrate; 1:2:1 acetone, ethanol, methanol, vitro and in vivo activities
methanol tetrahydrofuran & ethyl acetate including antioxidant,
solvate antihaemolytic and anti-
inflammatory
Cytosine LAG using water Structure 914457 (Cherukuvada et al., 2013)
Isonicotinamide 2:1 SE using water Enhanced solubility 1495675 (Drozd et al., 2017)
Itraconazole 1:1 LAG; SE Enhanced solubility of (Vasilev et al., 2021)
itraconazole
Nicotinamide 1:1; CC hydrate SE using acetone ; Enhanced solubility; structure 914459 (Drozd et al., 2017; Cherukuvada et al.,
LAG using water 2013; Sarcevica et al., 2013)
Sulfamethazine 1:1; 2 forms Spray drying; SE using ethanol and Enhanced solubility 1287542 (Serrano et al., 2018; Grossjohann
acetone; LAG et al., 2015; Salem et al., 2021; Walsh
et al., 2018; Salem et al., 2021; Avdeef,
Excipients used: 4-aminosalicylic 2018; Caira, 1992; Serrano et al.,
acid with inulin, microcrystalline 2016)
cellulose, mannitol, chitosan,
dextran, glycine, polyvinyl alcohol
Theophylline 1:1; 1:2 SE using ethanol and chloroform; 1:2 had enhanced solubility; 1:1 1495676 1049826 (Drozd et al., 2017; Fernandes et al.,
LAG had lower solubility 2015)

CC: cocrystal; CCDC: Cambridge Crystallographic Data Centre; SE: solvent evaporation; LAG: liquid assisted grinding; NG: neat grinding.

nanoparticles intranasal (Kumar et al., 2014) and oral (Singh et al.,
2021) formulations are being researched. To the best of our knowledge,
no cocrystals of streptomycin were reported in the literature. However,
the use of streptomycin cocrystals can be designed to enhance its oral
solubility and hence enhance patient satisfaction.
3. Second line anti-tuberculosis medications
3.1. 4-Aminosalicylic acid
There has been renewed interest in the use of para-aminosalicylic
acid (4-ASA) in tuberculosis treatment, due to lack of resistance.
Therefore, this bacteriostatic second-line anti-tuberculosis drug is useful
in the treatment of MDR-tuberculosis (Para-aminosalicylic, 2008; Don­
ald and Diacon, 2015). 4-ASA is classified on the boundary between
classes II and IV according to the biopharmaceutical classification sys­
tem, having low solubility and about eighty percent permeability.
Furthermore, 4-ASA is unstable, as in acid medium it irreversibly un­
dergoes decarboxylation, forming m-aminophenol which is associated
with a color change from colorless to dark-brown. Additionally, 4-ASA
degrades when heated. As m-aminophenol is a toxic compound, it is
crucial to stabilize 4-ASA from decarboxylation. Cocrystallization has
been reported to result in stabilization of 4-ASA from decarboxylation
(Drozd et al., 2017).
The combination of 4-ASA and sulfamethazine in cocrystal form was
proposed to exploit an anti-tuberculosis synergistic effect (Grossjohann
et al., 2015). This cocrystal pair was found to have three polymorphic
forms (Grossjohann et al., 2015; Salem et al., 2021). Nano-sized coc­
rystal of polymorph II were found to have higher dissolution of sulfa­
methazine than non-micronized cocrystal (Salem et al., 2019). The
different habits of polymorph II were reported to have different disso­
lution profiles (Serrano et al., 2016). Moreover, spray dried 4-ASA-sulfa­
methazine cocrystal with excipients had improved tableting
characteristics (Walsh et al., 2018). On the other hand, enhanced solu­
bility was reported for cocrystals of 4-ASA with caffeine (Drozd et al.,
2017; Andre et al., 2017), carbamazepine (Drozd et al., 2017), iso­
nicotinamide (Drozd et al., 2017), nicotinamide (Drozd et al., 2017;
Cherukuvada et al., 2013; Sarcevica et al., 2013) and one form of
theophylline (Drozd et al., 2017; Fernandes et al., 2015). Similarly, 4-
ASA-itraconazol cocrystal resulted in an enhanced solubility of itraco­
nazole (Vasilev et al., 2021). Furthermore, 4-ASA cocrystals with
carbamazepine were reported to have enhanced antioxidant, anti­
haemolytic and anti-inflammatory activities (Drozd et al., 2017). 4-ASA
cocrystals found in the literature and their reported improvements are
shown in Table 4.
While the exact mechanism of action of 4-ASA is not fully understood
(Zheng et al., 2013), it is particularly useful as it may slow the devel­
opment of resistance to isoniazid and streptomycin. A slow-release
granule formulation of 4-ASA may enhance the compliance due to the
gastrointestinal side effects. 4-ASA is recommended to be taken with
acidic drinks as the toxic metabolite it produces is inactive under acidic
conditions (Para-aminosalicylic, 2008; Donald and Diacon, 2015).
Hence, cocrystallizing 4-ASA with acids, isoniazid or streptomycin is
interesting to explore. Moreover, 4-ASA is contraindicated in patients
suffering from renal diseases due to accumulation of toxic metabolites.
4-ASA also interferes with thyroid metabolism and vitamin B12 uptake,
warranting thyroid or vitamin supplements (Para-aminosalicylic, 2008).
Therefore, 4-ASA cocrystal with cobalamin (vitamin B12) may have
clinical usefulness. Cocrystals may aid this agent to be more effective in
the management of tuberculosis.
3.2. Fluoroquinolones
Fluoroquinolones are used in the treatment of MDR-tuberculosis and
may also play a key role in preventing drug-resistant tuberculosis (Thee
et al., 2015). They act by binding type II and IV bacterial topoisomerase
enzymes and DNA gyrase (Jia and Zhao, 2021). Commonly used fluo­
roquinolones in the co-treatment of MDR-tuberculosis include cipro­
floxacin, ofloxacin, sparfloxacin, lomefloxacin, levofloxacin,
gatifloxacin and moxifloxacin. The choice of fluoroquinolone is based on
both in vitro activity and long-term tolerance (Lowther and Bryskier,
2002; Pranger et al., 2011; Ginsburg et al., 2003). Moreover, novel
fluoroquinolones such as garenoxacin, clinafloxacin, lomefloxacin,
sparfloxacin, sitafloxacin, trovafloxacin, grepafloxacin, gemifloxacin
and DC-159a may be of great use in the management of MDR-
tuberculosis and to combat the emerging resistance to fluo­
roquinolones (Pranger et al., 2011).
Synergistic pharmaceutical cocrystals of ciprofloxacin and nor­
floxacin with small molecules were reported to possess unique physical
and biological properties, including higher solubility, and dissolution
rates, stability under accelerated conditions and synergistic effect
against S. aureus and E. coli among others (Anil Kumar Kruthiventi et al.,

8
A. Salem et al. International Journal of Pharmaceutics 623 (2022) 121924

Table 5
Cocrystals of different fluoroquinolones and their reported advantages.
API Co-former Molar Preparation method Observations CCDC Ref.
ratio No.

Ciprofloxacin 2-thiobarbituric-barbituric CC salt Precipitation using water, barbituric Structure 1544127 (Golovnev et al.,
acid-H2O acid and sodium hydroxide 2018)
4-hydroxybenzoic acid 1:1 CC salt Solution-mediated phase Lower solubility 890402 (Martínez-Alejo
transformation, LAG, SE, & reaction et al., 2014)
crystallization using methanol
Citric acid CC NG using methanol and slow SE using (Anil Kumar
acetonitrile Kruthiventi et al.,
2009)
Eugenol CC NG using methanol and slow SE using Enhanced solubility and (Anil Kumar
acetonitrile antimicrobial activity Kruthiventi et al.,
2009)
Ferulic acid CC NG using methanol and slow SE using Enhanced solubility and (Anil Kumar
acetonitrile antimicrobial activity Kruthiventi et al.,
2009)
Hippuric acid CC LAG Structure (Cherukuvada
et al., 2013)
Isoferulic acid CC NG using methanol and slow SE using Enhanced solubility and (Anil Kumar
acetonitrile antimicrobial activity Kruthiventi et al.,
2009)
Isonicotinic acids 1:1 NG and LAG using ethanol Enhanced aqueous solubility (de Almeida et al.,
2019)
Nicotinic acid 1:1 NG and LAG using ethanol Enhanced aqueous solubility (de Almeida et al.,
2019)
Norfloxacin- H2O 1:1 CC Co-precipitation from vapour diffusion Structure 887955 (Pinto Vitorino
hydrate using acetic acid into an aqueous et al., 2013)
alkaline solution
p-aminobenzoic acid 1:1 LAG using ethanol Characterization and thermal study (de Almeida et al.,
2020)
Picolinic acid 1:1 NG and LAG using ethanol Enhanced solubility (Torquetti et al.,
2021)
Pyrazinoic acid 1:1 NG and LAG using ethanol Characterization and thermal study (de Almeida et al.,
2020)
Resorcinol 1:1 Slurry using toluene Cocrystals and ciprofloxacin (Ràfols et al.,
dissolve slower as pH increases 2018)
(from 2.0 to 7.4)
Tartaric acid CC NG using methanol and slow SE using Structure (Anil Kumar
acetonitrile Kruthiventi et al.,
2009)
Lomefloxacin Barbituric acid- isophthalic- 1:1:1 CC Slurry using methanol Enhanced solubility and 1025159 (Zhang et al.,
CH3OH-H2O salt bioavailability 2015)
Barbituric acid-H2O 1:1:1 CC Slurry using methanol Enhanced solubility and 1025158 (Zhang et al.,
salt bioavailability 2015)
Isophthalic acid-H2O 1:1:1 CC Slurry using methanol Enhanced solubility and 1025157 (Zhang et al.,
salt bioavailability 2015)
Levofloxacin Metacetamol 1:1 NG and heating approach Reduced hygroscopicity and (Shinozaki et al.,
enhanced photostability of 2019)
levofloxacin
Saccharin sodium 2:1 Enhanced dissolution (Bandari et al.,
2017)
Stearic acid 1:1 Fast SE using ethanol at 40 C ◦
Enhanced dissolution and bitter (Bandari et al.,
taste masking 2017)
Moxifloxacin 4-hydroxybenzoic acid 1:1 Solution-mediated phase Enhanced solubility 890402 (Martínez-Alejo
transformation, LAG, SE, & reaction et al., 2014)
crystallization using methanol
Trans-cinnamic acid 1:1 Slow SE using dichloromethane at 4 ◦ C Lower moxifloxacin solubility and (Eedara et al.,
for 72 h dissolution rate, therefore, prolong 2019)
the residence time in the lungs
Norfloxacin Adipic acid CC NG using methanol and slow SE using (Anil Kumar
acetonitrile Kruthiventi et al.,
2009)
Biotin CC NG using methanol and slow SE using (Anil Kumar
acetonitrile Kruthiventi et al.,
2009)
Caffeine CC NG using methanol and slow SE using (Anil Kumar
acetonitrile Kruthiventi et al.,
2009)
Catechin hydrate CC NG using methanol and slow SE using (Anil Kumar
acetonitrile Kruthiventi et al.,
2009)
Citric acid CC NG using methanol and slow SE using Enhanced solubility (Anil Kumar
acetonitrile Kruthiventi et al.,
2009)
Curcumin CC
(continued on next page)

9
A. Salem et al. International Journal of Pharmaceutics 623 (2022) 121924

Table 5 (continued )
API Co-former Molar Preparation method Observations CCDC Ref.
ratio No.

NG using methanol and slow SE using (Anil Kumar

acetonitrile Kruthiventi et al.,
2009)
Eugenol CC NG using methanol and slow SE using Enhanced solubility and (Anil Kumar
acetonitrile antimicrobial activity Kruthiventi et al.,
2009)
Ferulic acid CC NG using methanol and slow SE using Enhanced solubility and (Anil Kumar
acetonitrile antimicrobial activity Kruthiventi et al.,
2009)
Geraniol CC NG using methanol and slow SE using (Anil Kumar
acetonitrile Kruthiventi et al.,
2009)
Glutamic acid CC NG using methanol and slow SE using (Anil Kumar
acetonitrile Kruthiventi et al.,
2009)
Glutamine CC NG using methanol and slow SE using (Anil Kumar
acetonitrile Kruthiventi et al.,
2009)
Glycine CC NG using methanol and slow SE using (Anil Kumar
acetonitrile Kruthiventi et al.,
2009)
Isoferulic acid CC NG using methanol and slow SE using Enhanced solubility and (Anil Kumar
acetonitrile antimicrobial activity Kruthiventi et al.,
2009)
Isonicotinamide CC Slow SE at room temp. using chloroform Enhanced aqueous solubility; 617105 (Basavoju et al.,
hydrate structure 2006)
Nicotinic acid CC NG using methanol and slow SE using (Anil Kumar
acetonitrile Kruthiventi et al.,
2009)
Phenyl alanine CC NG using methanol and slow SE using (Anil Kumar
acetonitrile Kruthiventi et al.,
2009)
Piperonol CC NG using methanol and slow SE using (Anil Kumar
acetonitrile Kruthiventi et al.,
2009)
Quercetin dihydrate CC NG using methanol and slow SE using Lower solubility (Anil Kumar
acetonitrile Kruthiventi et al.,
2009)
Resveratrol CC NG using methanol and slow SE using (Anil Kumar
acetonitrile Kruthiventi et al.,
2009)
Riboflavin 1:1 LAG Lower thermal stability of (Ferreira et al.,
riboflavin; structure 2019)
Rosmarinic acid CC NG using methanol and slow SE using (Anil Kumar
acetonitrile Kruthiventi et al.,
2009)
Saccharinate–saccharin 1:1:2 CC Serendipitously obtained by slow SE Structure 658047 (Velaga et al.,
dihydrate hydrate using water and couldn’t be obtained 2008)
again. Only salt was successfully
replicated
Vanillin CC Slow SE using acetonitrile and NG (Anil Kumar
Kruthiventi et al.,
2009)
Ofloxacin D- and L-tartaric acid 1:1 Cocrystallization in aqueous media; Separation of chiral R- and S- (He et al., 2018; He
using different solvents enantiomer et al., 2019)
Diphenic acid CC salt LAG using methanol Enhanced aqueous solubility and 1984435 (Suresh et al.,
intrinsic dissolution; structure 2020)
Oxalic acid 1:2 NG Structure (Limwikrant et al.,
complex 2009)
Sparfloxacin 4-hydroxy methylbenzoate 1:1 LAG using water Enhanced solubility and good 1498304 (Gunnam et al.,
stability; structure 2016)
Ethylbenzoate 1:1; 1:1:3 LAG using water Enhanced solubility and good 1498303 (Gunnam et al.,
hydrate stability; structure 2016)
Isopropyl benzoate 1:1 LAG using water Enhanced solubility and good 1498302 (Gunnam et al.,
stability; structure 2016)
Propyl benzoate 1:1; 1:1:3 LAG using water Enhanced solubility and good 1498301 (Gunnam et al.,
hydrate stability; structure 2016)

CC: cocrystal; CCDC: Cambridge Crystallographic Data Centre; SE: solvent evaporation; LAG: liquid assisted grinding; NG: neat grinding.

2009). Furthermore, the bactericidal activity of ofloxacin with macro­
phages is enhanced when ofloxacin is combined with pyrazinamide
(Sbarbaro et al., 1996). The combination of fluoroquinolones with first-
line anti-tuberculosis drugs has been found to have enhanced effect
(Tomioka et al., 2002). Therefore, cocrystals of fluoroquinolones with
first-line anti-tuberculosis drugs may have real clinical significance.
Cocrystals of different fluoroquinolones found in the literature are
shown in Table 5. Conversely, some fluoroquinolones including trova­
floxacin and gatifloxacin were removed from clinical practice due to
serious side effects (Jia and Zhao, 2021). However, cocrystals seem to be

10
A. Salem et al. International Journal of Pharmaceutics 623 (2022) 121924

Table 6
Cocrystals of ethionamide and their reported advantages.
Co-former Molar Preparation method Observations CCDC No. Ref.
ratio

Adipic acid 1:0.5 LAG using ethanol Enhanced dissolution; structure 1439820 (Mannava et al., 2016)
Baicalein 1:1 LAG using ethyl acetate and Enhanced dissolution of baicalein; reduced 2068929 (Wang et al., 2021)
ethanol; slow SE hepatotoxic effect
Fumaric 1:1 Slow SE using methanol; LAG using Enhanced in vitro bioavailability; enhanced 1439821 (Bordignon et al., 2020; Mannava
acid ethanol dissolution; structure et al., 2016)
Glutaric 1:1 SE using ethanol Enhanced in vitro bioavailability; structure 2019884 (Bordignon et al., 2020; Mannava
acid et al., 2016)
Maleic acid CC; salt NG; slow SE using acetone; ethanol Enhanced in vitro bioavailability; structure 1017367 (Bordignon et al., 2020; de Melo
1017368 et al., 2016)
Malonic Salt Slurry using ethyl acetate; LAG Enhanced in vitro bioavailability; structure 2019883 (Bordignon et al., 2020)
acid using ethanol
Oxalic acid Salt LAG using acetonitrile; slow SE Enhanced dissolution; structure 1439822 (Mannava et al., 2016; de Melo
using ethanol 1407624 et al., 2016)
Saccharin Salt Slow SE using ethanol Structure 1408286 (de Melo et al., 2016)
Salicylic CC; salt LAG, SE, slurry using methanol Enhanced dissolution; selective synthesis of cc and 1958233 (Bernasconi et al., 2020)
acid salt; structure 1936640
Sebacic 1:0.5 LAG using ethanol Enhanced dissolution; structure (Mannava et al., 2016)
acid
Suberic acid 1:0.5 LAG using ethanol Enhanced dissolution; structure 1439823 (Mannava et al., 2016)
Tartaric 1:1 Slow SE using methanol Kryptoracemic cocrystal; enhanced in vitro 2019885 (Bordignon et al., 2020)
acid CC salt bioavailability; structure

CC: cocrystal; CCDC: Cambridge Crystallographic Data Centre; SE: solvent evaporation; LAG: liquid assisted grinding; NG: neat grinding.

underutilized in enhancing the properties of this group of antibiotics.
Cocrystallization of these agents might offer an opportunity to return
these agents to use and enhance the effectiveness of fluoroquinolones
against tuberculosis.
3.3. Ethionamide
Ethionamide and its propyl-analogue prothionamide are thioamides
bactericidal pro-drugs used in the treatment of MDR-tuberculosis.
Ethionamide inhibits mycolic acid synthesis, sharing the same target
as isoniazid (Wang et al., 2021; Ethionamide, 2008; Thee et al., 2016).
Ethionamide may increase the level of other anti-tuberculosis drugs like
isoniazid and cycloserine, potentiating their effect (Ethionamide, 2008).
However, due to hepatotoxicity, it is a second line agent. Hepatotoxicity
of ethionamide is considered to be caused by formation of reactive
oxygen species. Nutraceutical cocrystals can provide a novel method to
reduce drug toxicity. Such as the case of ethionamide cocrystal with the
plant antioxidant baicalein, which reduced the ethionamide associated
hepatotoxicity and resulted in an enhanced dissolution of baicalein
(Wang et al., 2021).
Ethionamide cocrystal with maleic acid were reported to have over
seven times dissolution enhancement compared to ethionamide. Ethi­
onamide salt cocrystal with tartaric acid, a rare kryptoracemic cocrystal,
also had enhanced in vitro bioavailability (Bordignon et al., 2020).
Similarly, ethionamide cocrystals with fumaric acid, and glutaric acid
were reported to have enhanced in vitro bioavailability (Wang et al.,
2021). Furthermore, ethionamide cocrystals with adipic acid, sebacic
acid, suberic acid (Mannava et al., 2016) and salicylic acid (Bernasconi
et al., 2020) were reported to have enhanced dissolution. Published
cocrystals of ethionamide are shown in Table 6. Other cocrystals of

Table 7
Cocrystals of linezolid and their reported advantages.
Co-former Molar Preparation method Observations CCDC Ref.
ratio No.

1,5-naphthalenedisulphonic
acid
2,3-dihydroxybenzoic acid
2,4-dihydroxybenzoic acid
2,5-dihydroxybenzoic acid
3,5-dihydroxybenzoic acid
Benzoic acid
Gallic acid
p-amino benzoic acid
p-hydroxybenzoic acid
Protocatechuic acid
Salicylic acid
γ-resorcylic acid
CC NG; LAG; anti-solvent Testing virtual cocrystal screening methods – (Devarakonda et al., 2009)
CC LAG using water, methanol or Testing virtual cocrystal screening methods – (Khalaji et al., 2021)
toluene
CC LAG using water, methanol or Testing virtual cocrystal screening methods – (Khalaji et al., 2021)
toluene
CC LAG using water, methanol or Testing virtual cocrystal screening methods – (Khalaji et al., 2021)
toluene
CC LAG using water, methanol or Testing virtual cocrystal screening methods – (Khalaji et al., 2021)
toluene
1:1 LAG using methanol or water or Enhanced aqueous solubility, structure; testing 1993998 (Devarakonda et al., 2009;
toluene; NG; anti-solvent virtual cocrystal screening methods Khalaji et al., 2020, 2021)
CC LAG using methanol or water or Modified thermal properties; structure; testing 1993999 (Khalaji et al., 2020; Khalaji
hydrate toluene virtual cocrystal screening methods et al., 2021)
CC LAG using water, methanol, or Testing virtual cocrystal screening methods – (Khalaji et al., 2021)
toluene
CC LAG using methanol or water or Modified thermal properties; structure; testing 1997194 (Devarakonda et al., 2009;
hydrate toluene; NG; anti-solvent virtual cocrystal screening methods Khalaji et al., 2020, 2021)
CC LAG using methanol or water or Enhanced solubility; modified thermal properties; 1994000 (Khalaji et al., 2020; Khalaji
hydrate toluene structure; testing virtual cocrystal screening et al., 2021)
methods
CC NG; LAG; anti-solvent Testing virtual cocrystal screening methods – (Devarakonda et al., 2009)
1:1 LAG using methanol or water or Modified thermal properties; structure; testing 1994001 (Khalaji et al., 2020; Khalaji
toluene virtual cocrystal screening methods et al., 2021)

CC: cocrystal; CCDC: Cambridge Crystallographic Data Centre; SE: solvent evaporation; LAG: liquid assisted grinding; NG: neat grinding.

11
A. Salem et al.
ethionamide can offer an opportunity to enhance the efficacy of this
anti-tuberculosis agent or reduce its associated toxicities. Particularly,
cocrystals of ethionamide with isoniazid among other anti-tuberculosis
agents or antioxidants should be explored.
3.4. Linezolid
Linezolid is the first antibiotic in the new class of oxazolidinone. It
inhibits the synthesis of proteins via a unique mechanism (Linezolid,
2008). Linezolid substantially improves the treatment outcomes of
MDR-tuberculosis (Lee et al., 2019). However, linezolid is not well
tolerated due to peripheral neuropathy, myelosuppression and optic
neuropathy (Olayanju et al., 2019). Cocrystal of linezolid with proto­
catechuic acid had enhanced solubility (Khalaji et al., 2020; Khalaji
et al., 2021). Furthermore, linezolid cocrystal hydrates with gallic acid
and p-hydroxybenzoic acid had modifies thermal properties (Khalaji
et al., 2020). Moreover, linezolid-benzoic acid cocrystal had enhanced
aqueous solubility (Khalaji et al., 2020; Khalaji et al., 2021). Published
cocrystals of linezolid are shown in Table 7. Linezolid is usually used
with bedaquiline in the treatment of extensive drug-resistant tubercu­
losis (Olayanju et al., 2019). Cocrystal of bedaquiline with N-acetyl-
cysteine had higher solubility. Moreover, they are of particular interest
in the management of tuberculosis because both APIs are anti-
tuberculosis and N-acetyl-cysteine has hepatoprotective properties
(Kolhe, 2019). Likewise, cocrystal of linezolid with N-acetyl-cysteine
present an opportunity to gain the same benefits. Cocrystals of linezolid
present an opportunity for tuberculosis management. Linezolid cocrys­
tals with bedaquiline or other anti-tuberculosis are particularly inter­
esting to explore.
3.5. Cycloserine
Cycloserine is an oral second-line anti-tuberculosis bacteriostatic
drug. This broad spectrum antibiotic is used for MDR-tuberculosis as it
does not share cross resistance with other anti-tuberculosis agents (Saraf
et al., 2015). Cycloserine has been shown to be more effective than other
anti-tuberculosis agents, including ethionamide and kanamycin (Court
et al., 2021). However, its dose-related adverse effects including mania
and psychosis limit its use (Saraf et al., 2015). The structural analogue of
cycloserine, terizidone, also shares the same neuropsychiatric toxicity
(Court et al., 2021). However, no cocrystals of cycloserine or terizidone,
to the best of our knowledge, were reported in the literature.
Cocrystals of other anti-tuberculosis drugs such as cycloserine,
kanamycin, viomycin, pretomanid, capreomycin or amikacin, were not
reported in the literature, to the best of our knowledge. Cocrystals have
the potential to enhance the properties of these antibiotics and aid in the
battle against tuberculosis and MDR-tuberculosis. It is apparent that
anti-tuberculosis cocrystals are still underutilized, as many anti-
tuberculosis agents including EDH, rifampicin and streptomycin, had
no or limited cocrystals reported in the literature. Further research ef­
forts should be directed towards finding clinically useful cocrystals with
enhanced properties. Moreover, the combination of cocrystals with
nanotechnology, novel drug delivery systems or inhalable formulations
may offer much needed advantage in tuberculosis treatment.
4. Conclusions
Cocrystals have the ability to enhance technological properties of
APIs. The desired characteristics of cocrystals can be designed via co-
former selection. In this review, the enhanced properties of the first
and second-line anti-tuberculosis drug cocrystals is summarized. Among
the most reported improvement brought about by cocrystals of anti-
tuberculosis drugs were solubility and stability. Moreover, cocrystals
of anti-tuberculosis drugs were also reported to have reduced toxicity
and even synergistic anti-tuberculosis effect. Nevertheless, cocrystals of
anti-tuberculosis drugs have still to reach their full potential. A more
12
International Journal of Pharmaceutics 623 (2022) 121924
focused approach on enhanced properties and microbiological effect of
anti-tuberculosis cocrystals is needed to produce cocrystals to battle
tuberculosis. Suggestions of potentially advantageous pairs and oppor­
tunities to enhance anti-tuberculosis drugs by cocrystal formation were
also presented in this review.
CRediT authorship contribution statement
Ala’ Salem: Conceptualization, Data curation, Writing – original
draft, Investigation. Esam Khanfar: Visualization, Writing – review &
editing. Sándor Nagy: Data curation. Aleksandar Széchenyi: Super­
vision, Writing – review & editing.
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
Acknowledgments
The authors appreciate the support of the academic and technical
staff at the Institute of Pharmaceutical Technology and Biopharmacy in
the University of Pécs.
Funding
This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.
References
Abidi, S.S.A., Azim, Y., Khan, S.N., Khan, A.U., 2018. Sulfaguanidine cocrystals:
Synthesis, structural characterization and their antibacterial and hemolytic analysis.
J. Pharm. Biomed. Anal. 149, 351–357.
Abourahma, H., Cocuzza, D.S., Melendez, J., Urban, J.M., 2011. Pyrazinamide cocrystals
and the search for polymorphs. CrystEngComm 13, 6442–6450.
Adalder, T.K., Sankolli, R., Dastidar, P., 2012. Homo- or Heterosynthon? A
Crystallographic Study on a Series of New Cocrystals Derived from
Pyrazinecarboxamide and Various Carboxylic Acids Equipped with Additional
Hydrogen Bonding Sites. Cryst. Growth Des. 12, 2533–2542.
Adam, M.A.M., Ali, H.M.H., Khalil, E.A.G., 2017. Initial second-line drug resistance of
Mycobacterium tuberculosis isolates from Sudanese retreatment-patients. J. Clin.
Tuberculosis Other Mycobacterial Dis. 9, 21–23.
Ahmad, N., Ahuja, S.D., Akkerman, O.W., Alffenaar, J.-W.-C., Anderson, L.F.,
Baghaei, P., Bang, D., Barry, P.M., Bastos, M.L., Behera, D., Benedetti, A., Bisson, G.
P., Boeree, M.J., Bonnet, M., Brode, S.K., Brust, J.C.M., Cai, Y., Caumes, E.,
Cegielski, J.P., Centis, R., Chan, P.-C., Chan, E.D., Chang, K.-C., Charles, M.,
Cirule, A., Dalcolmo, M.P., D’Ambrosio, L., de Vries, G., Dheda, K., Esmail, A.,
Flood, J., Fox, G.J., Fréchet-Jachym, M., Fregona, G., Gayoso, R., Gegia, M., Gler, M.
T., Gu, S., Guglielmetti, L., Holtz, T.H., Hughes, J., Isaakidis, P., Jarlsberg, L.,
Kempker, R.R., Keshavjee, S., Khan, F.A., Kipiani, M., Koenig, S.P., Koh, W.-J.,
Kritski, A., Kuksa, L., Kvasnovsky, C.L., Kwak, N., Lan, Z., Lange, C., Laniado-
Laborín, R., Lee, M., Leimane, V., Leung, C.-C., Leung, E.-C.-C., Li, P.Z.,
Lowenthal, P., Maciel, E.L., Marks, S.M., Mase, S., Mbuagbaw, L., Migliori, G.B.,
Milanov, V., Miller, A.C., Mitnick, C.D., Modongo, C., Mohr, E., Monedero, I.,
Nahid, P., Ndjeka, N., O’Donnell, M.R., Padayatchi, N., Palmero, D., Pape, J.W.,
Podewils, L.J., Reynolds, I., Riekstina, V., Robert, J., Rodriguez, M., Seaworth, B.,
Seung, K.J., Schnippel, K., Shim, T.S., Singla, R., Smith, S.E., Sotgiu, G.,
Sukhbaatar, G., Tabarsi, P., Tiberi, S., Trajman, A., Trieu, L., Udwadia, Z.F., van der
Werf, T.S., Veziris, N., Viiklepp, P., Vilbrun, S.C., Walsh, K., Westenhouse, J.,
Yew, W.-W., Yim, J.-J., Zetola, N.M., Zignol, M., Menzies, D., 2018. Treatment
correlates of successful outcomes in pulmonary multidrug-resistant tuberculosis: an
individual patient data meta-analysis. The Lancet 392, 821–834.
Aitipamula, S., Wong, A.B.H., Chow, P.S., Tan, R.B.H., 2013. Novel solid forms of the
anti-tuberculosis drug, Isoniazid: ternary and polymorphic cocrystals.
CrystEngComm 15, 5877–5887.
Al-Otaibi, J.S., Sheena Mary, Y., Shyma Mary, Y., Panicker, C.Y., Thomas, R., 2019.
Cocrystals of pyrazinamide with p-toluenesulfonic and ferulic acids: DFT
investigations and molecular docking studies. J. Mol. Struct. 1175, 916–926.
Al-Otaibi, J.S., Mary, Y.S., Armaković, S., Thomas, R., 2020. Hybrid and bioactive
cocrystals of pyrazinamide with hydroxybenzoic acids: Detailed study of structure,
spectroscopic characteristics, other potential applications and noncovalent
interactions using SAPT. J. Mol. Struct. 1202, 127316.
A. Salem et al.
Álvarez-Vidaurre, R., Castiñeiras, A., Frontera, A., García-Santos, I., Gil, D.M., González-
Pérez, J.M., Niclós-Gutiérrez, J., Torres-Iglesias, R., 2021. Weak interactions in
cocrystals of isoniazid with glycolic and mandelic acids. Crystals 11, 328.
Ando, T., Kage, H., Matsumoto, Y., Zokumasu, K., Nagase, T., 2021. Lower dose of
ethambutol may reduce ocular toxicity without radiological deterioration for
Mycobacterium avium complex pulmonary disease. Respiratory Investigation 59,
777–782.
Andre, V., Shemchuk, O., Grepioni, F., Braga, D., Duarte, M.T., 2017. Expanding the Pool
of Multicomponent Crystal Forms of the Antibiotic 4-Aminosalicylic Acid: The
Influence of Crystallization Conditions. Cryst. Growth Des. 17, 6417–6425.
Anil Kumar Kruthiventi, S.R., Rajesh GoudIqbal Javed, Ashwini Nangia, Jaggavarapu
Satyanarayana Reddy. 2009. Synergistic pharmaceutical cocrystals, in.
Antituberculosis combinations from Drugs.com, in.
Avdeef, A., 2018. Cocrystal Solubility Product Prediction Using an in combo Model and
Simulations to Improve Design of Experiments. Pharm. Res. 35, 40.
Bandari, S., Dronam, V.R., Eedara, B.B., 2017. Development and preliminary
characterization of levofloxacin pharmaceutical cocrystals for dissolution rate
enhancement. J. Pharm. Investigat. 47, 583–591.
Basavoju, S., Boström, D., Velaga, S.P., 2006. Pharmaceutical cocrystal and salts of
norfloxacin. Cryst. Growth Des. 6, 2699–2708.
Batisai, E., 2020. Multicomponent crystals of anti-tuberculosis drugs: a mini-review. RSC
Adv. 10, 37134–37141.
Battini, S., Mannava, M.K.C., Nangia, A., 2018. Improved Stability of Tuberculosis Drug
Fixed-Dose Combination Using Isoniazid-Caffeic Acid and Vanillic Acid Cocrystal.
J. Pharm. Sci. 107, 1667–1679.
Berg, J., Blumberg, E.J., Sipan, C.L., Friedman, L.S., Kelley, N.J., Vera, A.Y.,
Hofstetter, C.R., Hovell, M.F., 2004. Somatic complaints and isoniazid (INH) side
effects in Latino adolescents with latent tuberculosis infection (LTBI). Patient Educ.
Couns. 52, 31–39.
Bernasconi, D., Bordignon, S., Rossi, F., Priola, E., Nervi, C., Gobetto, R., Voinovich, D.,
Hasa, D., Duong, N.T., Nishiyama, Y., Chierotti, M.R., 2020. Selective synthesis of a
salt and a cocrystal of the ethionamide-salicylic acid system. Cryst. Growth Des. 20,
906–915.
Bhutani, H., Mariappan, T.T., Singh, S., 2004. An Explanation for the Physical Instability
of a Marketed Fixed Dose Combination (FDC) Formulation Containing Isoniazid and
Ethambutol and Proposed Solutions. Drug Dev. Ind. Pharm. 30, 667–672.
Bhutani, H., Singh, S., Jindal, K.C., Chakraborti, A.K., 2005. Mechanistic explanation to
the catalysis by pyrazinamide and ethambutol of reaction between rifampicin and
isoniazid in anti-TB FDCs. J. Pharm. Biomed. Anal. 39, 892–899.
Blomberg, B., Fourie, B., 2003. Fixed-Dose Combination Drugs for Tuberculosis. Drugs
63, 535–553.
Bobak, C.A., Titus, A.J., Hill, J.E., 2019. Comparison of common machine learning
models for classification of tuberculosis using transcriptional biomarkers from
integrated datasets. Appl. Soft Comput. 74, 264–273.
Bordignon, S., Vioglio, P.C., Priola, E., Voinovich, D., Gobetto, R., Nishiyama, Y.,
Chierotti, M.R., 2017. Engineering codrug solid forms: mechanochemical synthesis
of an indomethacin-caffeine system. Cryst. Growth Des. 17, 5744–5752.
Bordignon, S., Cerreia Vioglio, P., Amadio, E., Rossi, F., Priola, E., Voinovich, D.,
Gobetto, R., Chierotti, M.R., 2020. Molecular crystal forms of antitubercular
ethionamide with dicarboxylic acids: solid-state properties and a combined
structural and spectroscopic study. Pharmaceutics 12, 818.
Brouwers, J., Brewster, M.E., Augustijns, P., 2009. Supersaturating Drug Delivery
Systems: The Answer to Solubility-Limited Oral Bioavailability? J. Pharm. Sci. 98,
2549–2572.
Caira, M.R., 1992. Molecular complexes of sulfonamides. 2.1:1 complexes between drug
molecules: sulfadimidine-acetylsalicylic acid and sulfadimidine-4-aminosalicylic
acid. J. Crystallogr. Spectrosc. Res. 22, 193–200.
Cao, F., Amidon, G.L., Rodríguez-Hornedo, N., Amidon, G.E., 2018. Mechanistic basis of
cocrystal dissolution advantage. J. Pharm. Sci. 107, 380–389.
Chellini, P.R., Mendes, T.O., Franco, P.H.C., Porto, B.L.S., Tippavajhala, V.K., César, I.C.,
Oliveira, M.A.L., Pianetti, G.A., 2017. Simultaneous determination of rifampicin,
isoniazid, pyrazinamide and ethambutol in 4-FDC tablet by Raman spectroscopy
associated to chemometric approach. Vib. Spectrosc. 90, 14–20.
Cherukuvada, S., Nangia, A., 2013. Salts and Ionic Liquid of The Antituberculosis Drug S,
S-Ethambutol. Cryst. Growth Des. 13, 1752–1760.
Cherukuvada, S., Bolla, G., Sikligar, K., Nangia, A., 2013. 4-Aminosalicylic Acid Adducts.
Cryst. Growth Des. 13, 1551–1557.
Chiang, C.-Y., Lin, C.-J., 2020. Principles of chemotherapy for tuberculosis in national
tuberculosis programmes of low- and middle-income countries. Ind. J. Tuberculosis
67, S16–S22.
Choquesillo-Lazarte, D., Nemec, V., Cinčić, D., 2017. Halogen bonded cocrystals of active
pharmaceutical ingredients: pyrazinamide, lidocaine and pentoxifylline in
combination with haloperfluorinated compounds. CrystEngComm 19, 5293–5299.
Court, R., Centner, C.M., Chirehwa, M., Wiesner, L., Denti, P., de Vries, N., Harding, J.,
Gumbo, T., Maartens, G., McIlleron, H., 2021. Neuropsychiatric toxicity and
cycloserine concentrations during treatment for multidrug-resistant tuberculosis. Int.
J. Infect. Dis. 105, 688–694.
Cvetkovski, A.A.A., 2016. Bistra The role of cocrystallization screening for the
assessment of structure-activity relationship in drug development. Macedonian
Pharm. Bull. 345–346.
de Almeida, A.C., Torquetti, C., Ferreira, P.O., Fernandes, R.P., dos Santos, E.C.,
Kogawa, A.C., Caires, F.J., 2019. Cocrystals of ciprofloxacin with nicotinic and
isonicotinic acids: mechanochemical synthesis, characterization, thermal and
solubility study. Thermochim Acta 178346.
de Almeida, A.C., Ferreira, P.O., Torquetti, C., Ekawa, B., Carvalho, A.C.S., dos Santos, E.
C., Caires, F.J., 2020. Mechanochemical synthesis, characterization and thermal
13
International Journal of Pharmaceutics 623 (2022) 121924
study of new cocrystals of ciprofloxacin with pyrazinoic acid and p-aminobenzoic
acid. J. Therm. Anal. Calorim. 140, 2293–2303.
de Melo, C.C., da Silva, C.C.P., Pereira, C.C.S.S., Rosa, P.C.P., Ellena, J., 2016.
Mechanochemistry applied to reformulation and scale-up production of
Ethionamide: Salt selection and solubility enhancement. Eur. J. Pharm. Sci. 81,
149–156.
Devarakonda, S.N., Thaimattam, R., Muppidi, V.K., Kanniah, S.L., Duggirala, N.K., 2009.
Linezolid co-crystals. W.I.P. Organization.
Diniz, L.F., Carvalho, P.S., de Melo, C.C., Ellena, J., 2017. Reducing the Hygroscopicity of
the Anti-Tuberculosis Drug (S, S)-Ethambutol Using Multicomponent Crystal Forms.
Cryst. Growth Des. 17, 2622–2630.
Diniz, L.F., Souza, M.S., Carvalho, P.S., da Silva, C.C.P., D’Vries, R.F., Ellena, J., 2018.
Novel Isoniazid cocrystals with aromatic carboxylic acids: Crystal engineering,
spectroscopy and thermochemical investigations. J. Mol. Struct. 1153, 58–68.
Diniz, L.F., Souza, M.S., Carvalho, P.S., Correa, C.C., Ellena, J., 2018. Modulating the
water solubility and thermal stability of the anti-tuberculosis drug Isoniazid via
multicomponent crystal formation. J. Mol. Struct. 1171, 223–232.
Doan, T.V.P., Couet, W., Olivier, J.C., 2011. Formulation and in vitro characterization of
inhalable rifampicin-loaded PLGA microspheres for sustained lung delivery. Int. J.
Pharm. 414, 112–117.
Donald, P.R., Diacon, A.H., 2015. Para-aminosalicylic acid: the return of an old friend.
Lancet. Infect. Dis 15, 1091–1099.
Drozd, K.V., Manin, A.N., Churakov, A.V., Perlovich, G.L., 2017. Drug-drug cocrystals of
antituberculous 4-aminosalicylic acid: Screening, crystal structures, thermochemical
and solubility studies. Eur. J. Pharm. Sci. 99, 228–239.
Drozd, K.V., Manin, A.N., Churakov, A.V., Perlovich, G.L., 2017. Novel drug–drug
cocrystals of carbamazepine with para-aminosalicylic acid: screening, crystal
structures and comparative study of carbamazepine cocrystal formation
thermodynamics. CrystEngComm 19, 4273–4286.
Eddleston, M.D., Arhangelskis, M., Fábián, L., Tizzard, G.J., Coles, S.J., Jones, W., 2016.
Investigation of an amide-pseudo amide hydrogen bonding motif within a series of
theophylline: amide cocrystals. Cryst. Growth Des. 16, 51–58.
Eedara, B.B., Tucker, I.G., Zujovic, Z.D., Rades, T., Price, J.R., Das, S.C., 2019. Crystalline
adduct of moxifloxacin with trans-cinnamic acid to reduce the aqueous solubility
and dissolution rate for improved residence time in the lungs. Eur. J. Pharm. Sci.
136, 104961.
Ethambutol, Tuberculosis, 88 (2008) 102-105.
Ethionamide. 2008. Tuberculosis, 88, 106-108.
Évora, A.O., Castro, R.A., Maria, T.M., Rosado, M.T., Ramos Silva, M., Matos Beja, A.,
Canotilho, J., Eusébio, M.E., 2011. Pyrazinamide-Diflunisal: A New Dual-Drug Co-
Crystal. Crystal Growth Design 11, 4780–4788.
Fadipe, V.O., Haruna, M.S., Opoku, A.R., 2017. Isoniazid-oleanolic acid: A new dual drug
co-crystal. 17th International Conference and Exhibition on Nanomedicine and
Nanotechnology in Healthcare, Melbourne, Australia.
Farmer, P.E., 2018. Better and safer treatment for multidrug-resistant tuberculosis. The
Lancet 392, 798–800.
Fernandes, J.A., Sardo, M., Mafra, L., Choquesillo-Lazarte, D., Masciocchi, N., 2015. X-
ray and NMR Crystallography Studies of Novel Theophylline Cocrystals Prepared by
Liquid Assisted Grinding. Cryst. Growth Des. 15, 3674–3683.
Ferreira, L.T., Alarcon, R.T., Perpétuo, G.L., Bannach, G., 2019. Investigation and
characterization by TG/DTG–DTA and DSC of the fusion of Riboflavin, and its
interaction with the antibiotic norfloxacin in the screening of cocrystal. J. Therm.
Anal. Calorim. 136, 581–588.
Gao, Y., Gao, J., Liu, Z., Kan, H., Zu, H., Sun, W., Zhang, J., Qian, S., 2012. Coformer
selection based on degradation pathway of drugs: A case study of adefovir
dipivoxil–saccharin and adefovir dipivoxil–nicotinamide cocrystals. Int. J. Pharm.
438, 327–335.
Geib, A.-J., Shannon, M.W., 2007. Chapter 55 - Isoniazid. In: Shannon, M.W., Borron, S.
W., Burns, M.J. (Eds.), Haddad and Winchester’s Clinical Management of Poisoning
and Drug Overdose (Fourth Edition). W.B. Saunders, Philadelphia, pp. 919–925.
Ginsburg, A.S., Grosset, J.H., Bishai, W.R., 2003. Fluoroquinolones, tuberculosis, and
resistance. Lancet. Infect. Dis 3, 432–442.
Golovnev, N.N., Molokeev, M.S., Lesnikov, M.K., Atuchin, V.V., 2018. Two salts and the
salt cocrystal of ciprofloxacin with thiobarbituric and barbituric acids: The structure
and properties. J. Phys. Org. Chem. 31, e3773.
González-González, J.S., Martínez-Santiago, A.M.M., Martínez-Martínez, F.J., Emparán-
Legaspi, M.J., Pineda-Contreras, A., Flores-Alamo, M., García-Ortega, H., 2020.
Cocrystals of Isoniazid with Polyphenols: Mechanochemical Synthesis and Molecular
Structure. Crystals 10, 569.
Granich, R., 2018. Is the global tuberculosis control strategy too big to fail? The Lancet.
Grobelny, P., Mukherjee, A., Desiraju, G.R., 2011. Drug-drug co-crystals: Temperature-
dependent proton mobility in the molecular complex of isoniazid with 4-aminosa­
licylic acid. CrystEngComm 13, 4358–4364.
Grosset, J., Leventis, S., 1983. Adverse effects of rifampin. Rev. Infect. Dis. 5 (Suppl 3),
S440–450.
Grossjohann, C., Serrano, D.R., Paluch, K.J., O’Connell, P., Vella-Zarb, L., Manesiotis, P.,
McCabe, T., Tajber, L., Corrigan, O.I., Healy, A.M., 2015. Polymorphism in
Sulfadimidine/4-Aminosalicylic Acid Cocrystals: Solid-State Characterization and
Physicochemical Properties. J. Pharm. Sci. 104, 1385–1398.
Gunnam, A., Suresh, K., Ganduri, R., Nangia, A., 2016. Crystal engineering of a
zwitterionic drug to neutral cocrystals: a general solution for floxacins. Chem.
Commun. 52, 12610–12613.
H. The Lancet Global, A new era for tuberculosis?, The Lancet Global Health, 6 (2018)
e1045.
A. Salem et al.
He, L., Liang, Z., Yu, G., Li, X., Chen, X., Zhou, Z., Ren, Z., 2018. Green and Efficient
Resolution of Racemic Ofloxacin Using Tartaric Acid Derivatives via Forming
Cocrystal in Aqueous Solution. Cryst. Growth Des. 18, 5008–5020.
He, L., Chen, X., Li, X., Zhou, Z., Ren, Z., 2019. Chiral co-selector induced chirality
switching in the enantioseparation of ofloxacin by forming a co-crystal. New J.
Chem. 43, 15048–15051.
Hiremath, P.S., Saha, R.N., 2008. Controlled Release Hydrophilic Matrix Tablet
Formulations of Isoniazid: Design and In Vitro Studies. AAPS PharmSciTech 9,
1171–1178.
Hussain, A., Altamimi, M.A., Alshehri, S., Imam, S.S., 2021. Assessment of solubility and
Hansen solubility parameters of rifampicin in various permeation enhancers:
Experimental and computational approach. J. Mol. Liq. 328, 115432.
Jia, Y., Zhao, L., 2021. The antibacterial activity of fluoroquinolone derivatives: An
update (2018–2021). Eur. J. Med. Chem. 224, 113741.
Khalaji, M., Wróblewska, A., Wielgus, E., Bujacz, G.D., Dudek, M.K., Potrzebowski, M.J.,
2020. Structural variety of heterosynthons in linezolid cocrystals with modified
thermal properties. Acta Crystallographica Section B 76, 892–912.
Khalaji, M., Potrzebowski, M.J., Dudek, M.K., 2021. Virtual Cocrystal Screening Methods
as Tools to Understand the Formation of Pharmaceutical Cocrystals—A Case Study of
Linezolid, a Wide-Range Antibacterial Drug. Cryst. Growth Des. 21, 2301–2314.
U.D. KOLHE. 2019. Development and evaluation of bedaquiline cocrystal. In:
Pharmaceutics, National Institute of Pharmaceutical Education and Research.
Kulla, H., Greiser, S., Benemann, S., Rademann, K., Emmerling, F., 2016. In situ
investigation of a self-accelerated cocrystal formation by grinding pyrazinamide
with oxalic acid. Molecules 21, 917.
Kumar, M., Kakkar, V., Mishra, A.K., Chuttani, K., Kaur, I.P., 2014. Intranasal delivery of
streptomycin sulfate (STRS) loaded solid lipid nanoparticles to brain and blood. Int.
J. Pharm. 461, 223–233.
Kumar, A., Nanda, A., 2021. In-silico methods of cocrystal screening: a review on tools
for rational design of pharmaceutical cocrystals. J. Drug Delivery Sci. Technol. 63,
102527.
Lamont, E.A., Baughn, A.D., 2019. Impact of the host environment on the antitubercular
action of pyrazinamide. EBioMedicine 49, 374–380.
Larsen, E.M., Stephens, D.C., Clarke, N.H., Johnson, R.J., 2017. Ester-prodrugs of
ethambutol control its antibacterial activity and provide rapid screening for
mycobacterial hydrolase activity. Bioorg. Med. Chem. Lett. 27, 4544–4547.
Lawn, S.D., Zumla, A.I., 2011. Tuberculosis. The Lancet 378, 57–72.
Lee, J.-K., Lee, J.Y., Kim, D.K., Yoon, H.I., Jeong, I., Heo, E.Y., Park, Y.S., Jo, Y.S., Lee, J.
H., Park, S.S., Park, J.S., Kim, J., Lee, S.-M., Joh, J.-S., Lee, C.-H., Lee, J., Choi, S.M.,
Park, J.-H., Lee, S.H., Cho, Y.-J., Lee, Y.J., Kim, S.J., Kwak, N., Hwang, Y.R., Kim, H.,
Ki, J., Lim, J.N., Choi, H.S., Lee, M., Song, T., Kim, H.S., Han, J., Ahn, H., Hahn, S.,
Yim, J.-J., 2019. Substitution of ethambutol with linezolid during the intensive
phase of treatment of pulmonary tuberculosis: a prospective, multicentre,
randomised, open-label, phase 2 trial. Lancet. Infect. Dis 19, 46–55.
Lemmerer, A., 2012. Covalent assistance to supramolecular synthesis: modifying the
drug functionality of the antituberculosis API isoniazid in situ during co-
crystallization with GRAS and API compounds. CrystEngComm 14, 2465–2478.
Lemmerer, A., Bernstein, J., Kahlenberg, V., 2010. One-pot covalent and supramolecular
synthesis of pharmaceutical co-crystals using the API isoniazid: a potential
supramolecular reagent. CrystEngComm 12, 2856–2864.
Li, Z., Matzger, A.J., 2016. Influence of Coformer Stoichiometric Ratio on
Pharmaceutical Cocrystal Dissolution: Three Cocrystals of Carbamazepine/4-
Aminobenzoic Acid. Mol. Pharm. 13, 990–995.
Limwikrant, W., Higashi, K., Yamamoto, K., Moribe, K., 2009. Characterization of
ofloxacin–oxalic acid complex by PXRD, NMR, and THz spectroscopy. Int. J. Pharm.
382, 50–55.
Linezolid, 2008. Tuberculosis 88, 122–125.
Liu, F., Song, Y., Liu, Y.-N., Li, Y.-T., Wu, Z.-Y., Yan, C.-W., 2018. Drug-Bridge-Drug
Ternary Cocrystallization Strategy for Antituberculosis Drugs Combination. Cryst.
Growth Des. 18, 1283–1286.
Liu, F., Wang, L.-Y., Yu, M.-C., Li, Y.-T., Wu, Z.-Y., Yan, C.-W., 2020. A new cocrystal of
isoniazid-quercetin with hepatoprotective effect: The design, structure, and in vitro/
in vivo performance evaluation. Eur. J. Pharm. Sci. 144, 105216.
Lou, M., Mao, S.-H., Luo, Y.-H., Zhao, P., Sun, B.-W., 2015. Synthesis, co-crystal structure
and characterization of pyrazinamide with m-hydroxybenzoic acid, p-
hydroxybenzoic acid and 3,4-dihydroxy benzolic acid. Res. Chem. Intermed. 41,
2939–2951.
Lowther, J., Bryskier, A., 2002. Fluoroquinolones and tuberculosis. Expert Opin. Invest.
Drugs 11, 233–258.
Luo, Y.-H., Sun, B.-W., 2013. Pharmaceutical Co-Crystals of Pyrazinecarboxamide (PZA)
with Various Carboxylic Acids: Crystallography, Hirshfeld Surfaces, and Dissolution
Study. Cryst. Growth Des. 13, 2098–2106.
Mannava, M.K.C., Suresh, K., Nangia, A., 2016. Enhanced bioavailability in the oxalate
salt of the anti-tuberculosis drug ethionamide. Cryst. Growth Des. 16, 1591–1598.
Martínez-Alejo, J.M., Domínguez-Chávez, J.G., Rivera-Islas, J., Herrera-Ruiz, D.,
Höpfl, H., Morales-Rojas, H., Senosiain, J.P., 2014. A Twist in Cocrystals of Salts:
Changes in Packing and Chloride Coordination Lead to Opposite Trends in the
Biopharmaceutical Performance of Fluoroquinolone Hydrochloride Cocrystals.
Cryst. Growth Des. 14, 3078–3095.
Mashhadi, S.M.A., Yunus, U., Bhatti, M.H., Tahir, M.N., 2014. Isoniazid cocrystals with
anti-oxidant hydroxy benzoic acids. J. Mol. Struct. 1076, 446–452.
Mashhadi, S.M.A., Yunus, U., Bhatti, M.H., Ahmed, I., Tahir, M.N., 2016. Synthesis,
characterization, solubility and stability studies of hydrate cocrystal of
antitubercular Isoniazid with antioxidant and anti-bacterial Protocatechuic acid.
J. Mol. Struct. 1117, 17–21.
14
International Journal of Pharmaceutics 623 (2022) 121924
Mashhadi, S.M.A., Yufit, D., Liu, H., Hodgkinson, P., Yunus, U., 2020. Synthesis and
structural characterization of cocrystals of isoniazid and cinnamic acid derivatives.
J. Mol. Struct. 1219, 128621.
Mashhadi, S.M.A., Batsanov, A.S., Sajjad, S.A., Nazir, Y., Bhatti, M.H., Yunus, U., 2021.
Isoniazid-Gentisic acid cocrystallization: Solubility, Stability, Dissolution rate,
Antioxidant and Flowability Properties Studies. J. Mol. Struct. 1226, 129388.
McIlleron, H., Wash, P., Burger, A., Folb, P., Smith, P., 2002. Widespread distribution of
a single drug rifampicin formulation of inferior bioavailability in South Africa. Int. J.
Tuberc. Lung Dis. 6, 356–361.
McMahon Jennifer, A., Bis Joanna, A., Vishweshwar, P., Shattock Tanise, R., McLaughlin
Olga, L., J., 2005. Zaworotko Michael, Crystal engineering of the composition of
pharmaceutical phases. 3. Primary amide supramolecular heterosynthons and their
role in the design of pharmaceutical co-crystals, in. Zeitschrift für Kristallographie -
Crystalline Materials 340.
Meirelles, L., Carazo, E., Borrego-Sánchez, A., Barbosa, R., Moura, T., Aguzzi, C., Sainz-
Diaz, C.I., Viseras, C., Raffin, F., 2019. Design and characterization of a
tuberculostatic hybrid based on interaction of ethambutol with a raw palygorskite.
Appl. Clay Sci. 181, 105213.
Mitchison, D.A., 2000. Role of individual drugs in the chemotherapy of tuberculosis. Int.
J. Tubercul. Lung Dis. : Off. J. Int. Union Against Tubercul. Lung Dis. 4, 796–806.
Moradi, S., Ahmadi, P., Karami, C., Farhadian, N., Balaei, F., Ansari, M., Shahlaei, M.,
2021. Evaluation of the effects of isoniazid and rifampin on the structure and activity
of pepsin enzyme by multi spectroscopy and molecular modeling methods.
Spectrochim. Acta Part A Mol. Biomol. Spectrosc. 253, 119523.
N.I.o. Health. 2019. Temperature-stable experimental tuberculosis vaccine enters clinical
testing, in.
Nechipadappu, S.K., Tekuri, V., Trivedi, D.R., 2017. Pharmaceutical co-crystal of
flufenamic acid: synthesis and characterization of two novel drug-drug co-crystal.
J. Pharm. Sci. 106, 1384–1390.
Nemati, E., Mokhtarzadeh, A., Panahi-Azar, V., Mohammadi, A., Hamishehkar, H.,
Mesgari-Abbasi, M., Ezzati Nazhad Dolatabadi, J., de la Guardia, M., 2019.
Ethambutol-loaded solid lipid nanoparticles as dry powder inhalable formulation for
tuberculosis therapy. AAPS PharmSciTech 20, 120.
Ngilirabanga, J.B., Aucamp, M., Pires Rosa, P., Samsodien, H., 2020. Mechanochemical
Synthesis and Physicochemical Characterization of Isoniazid and Pyrazinamide Co-
crystals With Glutaric Acid, Frontiers. Chemistry 8.
Olayanju, O., Esmail, A., Limberis, J., Gina, P., Dheda, K., 2019. Linezolid interruption in
patients with fluoroquinolone-resistant tuberculosis receiving a bedaquiline-based
treatment regimen. Int. J. Infect. Dis. 85, 74–79.
Onorato, L., Gentile, V., Russo, A., Di Caprio, G., Alessio, L., Chiodini, P., Coppola, N.,
2021. Standard versus high dose of rifampicin in the treatment of pulmonary
tuberculosis: a systematic review and meta-analysis. Clin. Microbiol. Infect. 27,
830–837.
Organization, W.H., 2000. The use of essential drugs: ninth report of the WHO expert
committee (including the revised Model list of essential drugs). World Health
Organization.
Panchagnula, R., Bedi, S., Yasvanth, A., 2006. Rifampicin Dissolution: Polymorphism or
Crystal Defects. Clin. Res. Regulat. Affairs 23, 71–83.
Papich, M.G., 2016. Isoniazid. In: Papich, M.G. (Ed.), Saunders Handbook of Veterinary
Drugs (Fourth Edition). W.B. Saunders, St. Louis, pp. 412–413.
Para-aminosalicylic acid, Tuberculosis, 88 (2008) 137-138.
Pham, D.-D., Fattal, E., Ghermani, N., Guiblin, N., Tsapis, N., 2013. Formulation of
pyrazinamide-loaded large porous particles for the pulmonary route: Avoiding
crystal growth using excipients. Int. J. Pharm. 454, 668–677.
Pinto Vitorino, G., Sperandeo, N., Caira, M., Mazzieri, M., 2013. A Supramolecular
Assembly Formed by Heteroassociation of Ciprofloxacin and Norfloxacin in the Solid
State: Co-Crystal Synthesis and Characterization. Cryst. Growth Des. 13, 1050–1058.
Pranger, A.D., Alffenaar, J.W.C., Aarnoutse, R.E., 2011. Fluoroquinolones, the
cornerstone of treatment of drug-resistant tuberculosis: a pharmacokinetic and
pharmacodynamic approach. Curr. Pharm. Des. 17, 2900–2930.
Ràfols, C., Fael, H., Fuguet, E., Outhwaite, B., Lee, S., Ruiz, R., 2018. Dissolution rate of
ciprofloxacin and its cocrystal with resorcinol. ADMET and DMPK 6, 61.
T. Rajbongshi, K. Kumar Sarmah, R. Ganduri, S. Cherukuvada, M. Arhangelskis, R.
Thakuria, Mechanosynthesis of Eutectics of Anti-Inflammatory Drug Ethenzamide –
A Comparison with Analogous Cocrystals, Chemistry–Methods, n/a.
Rajbongshi, T., Sarmah, K.K., Sarkar, A., Ganduri, R., Cherukuvada, S., Thakur, T.S.,
Thakuria, R., 2018. Preparation of Pyrazinamide Eutectics versus Cocrystals Based
on Supramolecular Synthon Variations. Cryst. Growth Des. 18, 6640–6651.
Rao, A., Nayak, G., Kumari, S., Prabhu, A.D., Khandige, N., Kalthur, S.G., Mutalik, S.,
Kalthur, G., Adiga, S.K., 2016. Ethambutol induces testicular damage and decreases
the sperm functional competence in Swiss albino mice. Environ. Toxicol. Pharmacol.
47, 28–37.
Rosa, J., Machado, T.C., da Silva, A.K., Kuminek, G., Bortolluzzi, A.J., Caon, T.,
Cardoso, S.G., 2019. Isoniazid-Resveratrol Cocrystal: A Novel Alternative for Topical
Treatment of Cutaneous Tuberculosis. Cryst. Growth Des. 19, 5029–5036.
Rubin-Preminger, J.M., Bernstein, J., Harris, R.K., Evans, I.R., Ghi, P.Y., 2004. Variable
Temperature Studies of a Polymorphic System Comprising Two Pairs of
Enantiotropically Related Forms: [S, S]-Ethambutol Dihydrochloride. Cryst. Growth
Des. 4, 431–439.
Salem F.G.A., Sz Pál S., Széchenyi A. 2019. Nano-sized anti-tuberculosis multi-drug co-
crystals. In: 6th Nano Today, Lisbon, Portugal.
Salem, A., Takácsi-Nagy, A., Nagy, S., Hagymási, A., Gősi, F., Vörös-Horváth, B., Balić, T.,
Pál, S., Széchenyi, A., 2021. Synthesis and Characterization of Nano-Sized 4-Ami­
nosalicylic Acid-Sulfamethazine Cocrystals. Pharmaceutics 13, 277.
Salem, A., Hagymási, A., Vörös-Horváth, B., Šafarik, T., Balić, T., Szabó, P., Gősi, F.,
Nagy, S., Pál, S., Kunsági-Máté, S., Széchenyi, A., 2021. Solvent dependent 4-
A. Salem et al.
aminosalicylic acid-sulfamethazine co-crystal polymorph control. Eur. J. Pharm. Sci.
156, 105599.
Saraf, G., Akshata, J.S., Kuruthukulangara, S., Thippeswamy, H., Reddy, S.K., Buggi, S.,
Chaturvedi, S.K., 2015. Cycloserine induced delirium during treatment of multi-drug
resistant tuberculosis (MDR-TB). Egypt. J. Chest Dis. Tubercul. 64, 449–451.
Sarcevica, I., Orola, L., Veidis, M.V., Podjava, A., Belyakov, S., 2013. Crystal and
Molecular Structure and Stability of Isoniazid Cocrystals with Selected Carboxylic
Acids. Cryst. Growth Des. 13, 1082–1090.
Sarcevica, I., Orola, L., Belyakov, S., Veidis, M.V., 2013. Spontaneous cocrystal hydrate
formation in the solid state: crystal structure aspects and kinetics. New J. Chem. 37,
2978–2982.
Sarceviča, I., Orola, L.N., Nartowski, K.P., Khimyak, Y.Z., Round, A.N., Fábián, L., 2015.
Mechanistic and kinetic insight into spontaneous cocrystallization of isoniazid and
benzoic acid. Mol. Pharm. 12, 2981–2992.
Sarmah, K.K., Rajbongshi, T., Bhowmick, S., Thakuria, R., 2017. First-line
antituberculosis drug, pyrazinamide, its pharmaceutically relevant cocrystals and a
salt. Acta Crystallographica Section B 73, 1007–1016.
Sathisaran, I., Dalvi, S.V., 2019. Cocrystallization of carbamazepine with amides:
Cocrystal and eutectic phases with improved dissolution. J. Mol. Struct. 1193,
398–415.
Sbarbaro, J.A., Iseman, M.D., Crowle, A.J., 1996. Combined effect of pyrazinamide and
ofloxacin within the human macrophage. Tuber. Lung Dis. 77, 491–495.
Seddon, J.A., Hesseling, A.C., Marais, B.J., McIlleron, H., Peloquin, C.A., Donald, P.R.,
Schaaf, H.S., 2012. Paediatric use of second-line anti-tuberculosis agents: A review.
Tuberculosis 92, 9–17.
Self, T.H., Chrisman, C.R., Baciewicz, A.M., Bronze, M.S., 1999. Isoniazid Drug and Food
Interactions. Am. J. Med. Sci. 317, 304–311.
Serrano, D.R., O’Connell, P., Paluch, K.J., Walsh, D., Healy, A.M., 2016. Cocrystal habit
engineering to improve drug dissolution and alter derived powder properties.
J. Pharm. Pharmacol. 68, 665–677.
Serrano, D.R., Persoons, T., D’Arcy, D.M., Galiana, C., Dea-Ayuela, M.A., Healy, A.M.,
2016. Modelling and shadowgraph imaging of cocrystal dissolution and assessment
of in vitro antimicrobial activity for sulfadimidine/4-aminosalicylic acid cocrystals.
Eur. J. Pharm. Sci. 89, 125–136.
Serrano, D.R., Walsh, D., O’Connell, P., Mugheirbi, N.A., Worku, Z.A., Bolas-
Fernandez, F., Galiana, C., Dea-Ayuela, M.A., Healy, A.M., 2018. Optimising the in
vitro and in vivo performance of oral cocrystal formulations via spray coating. Eur. J.
Pharm. Biopharm. 124, 13–27.
Shaikh, R., Singh, R., Walker, G.M., Croker, D.M., 2018. Pharmaceutical cocrystal drug
products: an outlook on product development. Trends Pharmacol. Sci. 39,
1033–1048.
Sheena Mary, Y., Shyma Mary, Y., Yadav, R., Celik, I., Rad, A.S., Sarala, S., 2021. MD,
DFT Investigations and Inhibition of the Novel SARS- CoV-2 Mainprotease in Three
Cocrystals of Hydrochloro- thiazide, Analytical. Chem. Lett. 11, 450–468.
Shiehzadeh, F., Hadizadeh, F., Mohammadpour, A., Aryan, E., Gholami, L.,
Tafaghodi, M., 2019. Streptomycin sulfate dry powder inhalers for the new
tuberculosis treatment schedule. J. Drug Delivery Sci. Technol. 52, 957–967.
Shinozaki, T., Ono, M., Higashi, K., Moribe, K., 2019. A Novel Drug-Drug Cocrystal of
Levofloxacin and Metacetamol: Reduced Hygroscopicity and Improved
Photostability of Levofloxacin. J. Pharm. Sci. 108, 2383–2390.
Shrestha, D., Maharjan, B., Thida Oo, N.A., Isoda, N., Nakajima, C., Suzuki, Y., 2020.
Molecular analysis of streptomycin-resistance associating genes in Mycobacterium
tuberculosis isolates from Nepal. Tuberculosis 125, 101985.
Sibum, I., Hagedoorn, P., Kluitman, M.P.G., Kloezen, M., Frijlink, H.W., Grasmeijer, F.,
2020. Dispersibility and Storage Stability Optimization of High Dose Isoniazid Dry
Powder Inhalation Formulations with L-Leucine or Trileucine. Pharmaceutics 12, 24.
Singh, H., Jindal, S., Singh, M., Sharma, G., Kaur, I.P., 2015. Nano-formulation of
rifampicin with enhanced bioavailability: Development, characterization and in-vivo
safety. Int. J. Pharm. 485, 138–151.
Singh, S., Mariappan, T.T., Shankar, R., Sarda, N., Singh, B., 2001. A critical review of
the probable reasons for the poor variable bioavailability of rifampicin from anti-
tubercular fixed-dose combination (FDC) products, and the likely solutions to the
problem. Int. J. Pharm. 228, 5–17.
Singh, M., Schiavone, N., Papucci, L., Maan, P., Kaur, J., Singh, G., Nandi, U., Nosi, D.,
Tani, A., Khuller, G.K., Priya, M., Singh, R., Kaur, I.P., 2021. Streptomycin sulphate
loaded solid lipid nanoparticles show enhanced uptake in macrophage, lower MIC in
Mycobacterium and improved oral bioavailability. Eur. J. Pharm. Biopharm. 160,
100–124.
Streptomycin, Tuberculosis, 88 (2008) 162-163.
Sung, J.C., Padilla, D.J., Garcia-Contreras, L., VerBerkmoes, J.L., Durbin, D., Peloquin, C.
A., Elbert, K.J., Hickey, A.J., Edwards, D.A., 2009. Formulation and
Pharmacokinetics of Self-Assembled Rifampicin Nanoparticle Systems for Pulmonary
Delivery. Pharm. Res. 26, 1847–1855.
Surendran, V., 2013. Development and validation of isoniazid and paraamino salicylic
acid simultaneously in prepared cocrystal formulation by uv spectrophotometry.
J. Sci. Technol.
Suresh, A., Gonde, S., Mondal, P.K., Sahoo, J., Chopra, D., 2020. Improving solubility and
intrinsic dissolution rate of ofloxacin API through salt formation via
mechanochemical synthesis with diphenic acid. J. Mol. Struct. 1221, 128806.
Swapna, B., Maddileti, D., Nangia, A., 2014. Cocrystals of the Tuberculosis Drug
Isoniazid: Polymorphism, Isostructurality, and Stability. Cryst. Growth Des. 14,
5991–6005.
Swapna, B., Mannava, M.K.C., Nangia, A., 2018. Improved Stability of TB Drug Fixed
Dose Combination Using Isoniazid-Caffeic acid and Vanillic acid Cocrystal. J. Pharm.
Sci.
15
International Journal of Pharmaceutics 623 (2022) 121924
Tewes, F., Brillault, J., Couet, W., Olivier, J.-C., 2008. Formulation of
rifampicin–cyclodextrin complexes for lung nebulization. J. Control. Release 129,
93–99.
Thee, S., Garcia-Prats, A.J., Donald, P.R., Hesseling, A.C., Schaaf, H.S., 2015.
Fluoroquinolones for the treatment of tuberculosis in children. Tuberculosis 95,
229–245.
Thee, S., Garcia-Prats, A.J., Donald, P.R., Hesseling, A.C., Schaaf, H.S., 2016. A review of
the use of ethionamide and prothionamide in childhood tuberculosis. Tuberculosis
97, 126–136.
Thipparaboina, R., Thumuri, D., Chavan, R., Naidu, V.G.M., Shastri, N.R., 2017. Fast
dissolving drug-drug eutectics with improved compressibility and synergistic effects.
Eur. J. Pharm. Sci. 104, 82–89.
Thorat, S.H., Sahu, S.K., Gonnade, R.G., 2015. Crystal structures of the pyrazinamide–p-
aminobenzoic acid (1/1) cocrystal and the transamidation reaction product 4-
(pyrazine-2-carboxamido)benzoic acid in the molten state. Acta Crystallographica
Section C 71, 1010–1016.
Tomioka, H., Sato, K., Shimizu, T., Sano, C., 2002. Anti- Mycobacterium tuberculosis
Activities of New Fluoroquinolones in Combination with Other Antituberculous
Drugs. J. Infect. 44, 160–165.
Torquetti, C., Ferreira, P.O., de Almeida, A.C., Fernandes, R.P., Caires, F.J., 2021.
Thermal study and characterization of new cocrystals of ciprofloxacin with picolinic
acid. J. Therm. Anal. Calorim.
Unissa, A.N., Subbian, S., Hanna, L.E., Selvakumar, N., 2016. Overview on mechanisms
of isoniazid action and resistance in Mycobacterium tuberculosis. Infect. Genet. Evol.
45, 474–492.
Varma, J.N.R., Kumar, T.S., Prasanthi, B., Ratna, J.V., 2015. Formulation and
characterization of pyrazinamide polymeric nanoparticles for pulmonary
tuberculosis: efficiency for alveolar macrophage targeting. Ind. J. Pharm. Sci. 77,
258–266.
Vasilev, N.A., Surov, A.O., Voronin, A.P., Drozd, K.V., Perlovich, G.L., 2021. Novel
cocrystals of itraconazole: Insights from phase diagrams, formation thermodynamics
and solubility. Int. J. Pharm. 599, 120441.
Velaga, S.P., Basavoju, S., Boström, D., 2008. Norfloxacin saccharinate–saccharin
dihydrate cocrystal – A new pharmaceutical cocrystal with an organic counter ion.
J. Mol. Struct. 889, 150–153.
Walsh, D., Serrano, D.R., Worku, Z.A., Norris, B.A., Healy, A.M., 2018. Production of
cocrystals in an excipient matrix by spray drying. Int. J. Pharm. 536, 467–477.
Wan, C.-J., Zhang, Y., Liu, C.-X., Yang, Z.-C., 2022. Cinnamic aldehyde, isolated from
Cinnamomum cassia, alone and in combination with pyrazinamide against
Mycobacterium tuberculosis in vitro and in vivo. S. Afr. J. Bot. 144, 200–205.
Wang, Q., Xue J., Hong, Z., Du, Y. 2019. Pharmaceutical cocrystal formation of
pyrazinamide with 3-hydroxybenzoic acid: a terahertz and Raman vibrational
spectroscopies study, Molecules, 24, 488.
Wang, X., Du, S., Zhang, R., Jia, X., Yang, T., Zhang, X., 2021. Drug-drug cocrystals:
Opportunities and challenges. Asian J. Pharm. Sci. 16, 307–317.
Wang, W.-X., Liu, F., Li, J.-Y., Xue, J., Li, Y.-T., Liu, R.-M., 2021. A cocrystal for
effectively reducing the hepatotoxicity of ethionamide. J. Mol. Struct. 1243, 130729.
Wang, J.-R., Ye, C., Mei, X., 2014. Structural and physicochemical aspects of
hydrochlorothiazide co-crystals. CrystEngComm 16, 6996–7003.
Wang, J.-R., Ye, C., Zhu, B., Zhou, C., Mei, X., 2015. Pharmaceutical cocrystals of the
anti-tuberculosis drug pyrazinamide with dicarboxylic and tricarboxylic acids.
CrystEngComm 17, 747–752.
Whitfield, M.G., Soeters, H.M., Warren, R.M., York, T., Sampson, S.L., Streicher, E.M.,
Van Helden, P.D., Van Rie, A., 2015. A global perspective on pyrazinamide
resistance: systematic review and meta-analysis. PLoS One 10, e0133869.
WHO, Groups at risk: WHO report on the tuberculosis epidemic 1996, in, World Health
Organization, Geneva, 1996.
WHO, Global tuberculosis report 2018, in, World Health Organization, 2018.
W.H.O. (WHO), Global tuberculosis report, in, WHO, Geneva, Switzerland, 2020.
Wiens, T., Redelmeier, T., Av-Gay, Y., 2004. Development of a Liposome Formulation of
Ethambutol. Antimicrob. Agents Chemother. 48, 1887–1888.
Wong, S.N., Weng, J., Ip, I., Chen, R., Lakerveld, R., Telford, R., Blagden, N., Scowen, I.J.,
Chow, S.F., 2022. Rational Development of a Carrier-Free Dry Powder Inhalation
Formulation for Respiratory Viral Infections via Quality by Design: A Drug-Drug
Cocrystal of Favipiravir and Theophylline. Pharmaceutics 14, 300.
Wu, X., Wang, Y., Xue, J., Liu, J., Qin, J., Hong, Z., Du, Y., 2020. Solid phase drug-drug
pharmaceutical co-crystal formed between pyrazinamide and diflunisal: Structural
characterization based on terahertz/Raman spectroscopy combining with DFT
calculation. Spectrochim. Acta Part A Mol. Biomol. Spectrosc. 234, 118265.
Yadav, B., Gunnam, A., Thipparaboina, R., Nangia, A.K., Shastri, N.R., 2019.
Hepatoprotective Cocrystals of Isoniazid: Synthesis, Solid State Characterization,
and Hepatotoxicity Studies. Cryst. Growth Des. 19, 5161–5172.
Yang, X., Zhu, J., Chen, Z., Chen, B., Jin, S., Liu, B., Wang, D., 2022. Seven cocrystals of
pyrazinamide and organic acids by H-bonds and some noncovalent associations.
J. Mol. Struct. 1250, 131770.
Žegarac, M., Lekšić, E., Šket, P., Plavec, J., Devčić Bogdanović, M., Bučar, D.-K.,
Dumić, M., Meštrović, E., 2014. A sildenafil cocrystal based on acetylsalicylic acid
exhibits an enhanced intrinsic dissolution rate. CrystEngComm 16, 32–35.
Zhang, Z., Fang, J., Bo, Y., Xue, J., Liu, J., Hong, Z., Du, Y., 2021. Terahertz and Raman
Spectroscopic Investigation of Anti-tuberculosis Drug-Drug Cocrystallization
Involving 4-aminosalicylic Acid and Pyrazinamide. J. Mol. Struct. 1227, 129547.
A. Salem et al.
Zhang, K., Shen, H., Xu, S., Zhang, H., Zhu, M., Shi, P., Fu, X., Yang, Y., Gong, J., 2017.
Thermodynamic study of solubility for pyrazinamide in ten solvents from T=(283.15
to 323.15) K. J. Chem. Thermodyn. 112, 204–212.
Zhang, Z.-H., Zhang, Q., Zhang, Q.-Q., Chen, C., He, M.-Y., Chen, Q., Song, G.-Q.,
Xuan, X.-P., Huang, X.-F., 2015. From a binary salt to salt co-crystals of antibacterial
16
International Journal of Pharmaceutics 623 (2022) 121924
agent lomefloxacin with improved solubility and bioavailability. Acta
Crystallographica Section B 71, 437–446.
Zheng, J., Rubin, E.J., Bifani, P., Mathys, V., Lim, V., Au, M., Jang, J., Nam, J., Dick, T.,
Walker, J.R., Pethe, K., Camacho, L.R., 2013. para-Aminosalicylic Acid Is a Prodrug
Targeting Dihydrofolate Reductase in Mycobacterium tuberculosis◆. J. Biol. Chem.
288, 23447–23456.