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Vol 2 | Issue 3 | Jul – Apr 2023                                                                          Indian J Pharm Drug Studies | 107  

Review Article 

An overview of solvent-free and solvent/s-involved phosphorylation to 

synthesize Zoledronic acid 

Sanjay Sukumar Saralaya 

From, Assistant Professor, Department of Chemistry, Sri Dharmasthala Manjunatheshwara Institute of Technology (SDM IT), 

[affiliated to Visvesvaraya Technological University (VTU), Belagavi], Ujire, Dakshina Kannada, Karnataka, India.  

ABSTRACT 

This work provides a complete overview of solvent-free and solvent-involved phosphorylation strategies employed to synthe- 

size the renowned biphosphonate drug, Zoledronic acid. In this regard, all the disclosed patents and journal publications were 

considered and reviewed as per the yearly chronology towards the use of solvent/s or in the absence of it for the 

phosphorylation. Interestingly, a prolonged reaction time, sticky lump formation, exothermicity, enormous HCl release, tedious 

workup, etc had allowed the researchers to venture various synthetic and isolation approaches to overcome the process-specific 

setbacks. In line to this context, various solvent/s were used alone or in combination with another solvent to synthesize Zole- 

dronic acid in varied yields. A few attempts were also reported under solvent-free conditions in reasonably good yields. More- 

over, along with the above variations, a few different p-reagent/s are also reported towards the synthesis of Zoledronic acid.  

Key words: Biphosphonates, Zoledronic acid, Phosphorylation, P-reagents, Hydrolysis, Green-solvent. 

ynthesis of Zoledronic acid Z involves the reaction 

of an acid derivative (2) or its salt (3) with selective 

p-reagent/s {phosphoric acid (H3PO4), phosphorous 

acid (H3PO3), phosphorous trichloride (PCl3), phosphorous 

oxychloride (POCl3), triphosgene, mesyl chloride, etc} in 

the presence of suitable solvent/s or in the absence of 

solvent at a suitable temperature. After the 

phosphorylation, the reaction mixture was hydrolyzed by 

refluxing in water or HCl solution and further workup 

processes will lead to the isolation of Z (Scheme 1).  

Numerous synthetic strategies were adopted by various 

researchers and are reported in various publications 

(patents/journals). The present review attempt will provide 

a distinct sectorial overview of the solvent-free or 

solvent/s-involved phosphorylation approaches disclosed 

in patents and journal publications to synthesize Z.  

 

Access this article online 

Received – 13th June 2023 

Initial review –  17th June 2023 

Accepted –  26th June 2023 
Quick Response Code 

N

N

OH

O

OH

PO3H2

PO3H2

N
N

Z

N

N

H

(1)

(2)

N

N

OH

O

(3)

(OR)
1. solvent/s or no solvent,  p-reagent/s, heating

2. hydrolysis by water or HCl solution, heating

3. anti-solvent addition, cooling, filtration, drying

HCl

optional
recrystallization optional

Scheme 1. A renowned pathway to synthesize Zoledronic 

acid via phosphorylation and hydrolysis of (2) or (3). 

Details gathered from patent publications 

Numerous patents were published/filed comprising a lot of 

information on the synthesis and biological activities of Z.  

_______________________________________ 

Correspondence to: Dr. Sanjay Sukumar Saralaya, 

Assistant Professor, Department of Chemistry, SDM IT, 

Opposite to Siddhavana Gurukula, Dharmasthala Road,  

Ujire, Belthangady TQ, DK, Karnataka, India- 574 240 

Email: sanjayss@sdmit.in  

S 

mailto:sanjayss@sdmit.in


Sanjay S S                                                                        A sectorial overview on the synthesis of Zoledronic acid 

Vol 2 | Issue 3 | Jul – Apr 2023                                                                          Indian J Pharm Drug Studies | 108  

To the context, a critical examination of disclosed 

processes was done to identify the solvent-free and 

solvent/s-based strategies employed to isolate Z. Jaeggi 

KA & Widler L., in 1989, had reported the 

phosphorylation of key starting material 1-H-imidazol-1-

ylacetic acid hydrochloride (3) by the renowned p-reagents 

like H3PO4 (85%) and PCl3 in the presence of 

chlorobenzene to isolate Z (yield: 41.0%) [1]. Hu W., et al, 

in 2002, had illustrated the condensation of key starting 

material 1-H-imidazole (1) with ethyl-chloroacetate (4) 

and then hydrolyzed to isolate (3). Phosphorylation of (3) 

using the p-reagents like H3PO3 and PCl3 in chlorobenzene 

to get Z (yield: 48.1%) [2]. De FL., et al, in 2002, had 

reported the use of tributyl ammonium chloride (TBAC) as 

the solvent instead of hydrocarbon-based solvents. 

Phosphorylation of 1-H-imidazol-1-ylacetic acid (2) was 

done by using H3PO3 and PCl3 in the TBAC medium to get 

Z (yield: 25.95%) [3]. Lidor HR., et al, in 2003, had 

illustrated the phosphorylation of key starting material 

(2)/(3) in silicon oil alone or with toluene using the p-

reagents H3PO3 and phosphorous oxychloride (POCl3) to 

isolate Z (yield: 38.0-79.0%) [4].  

Aronhime J & Lifshitz LR., in 2004, had disclosed the 

phosphorylation of (2)/(3) in solvents like silicon oil, 

chlorobenzene, toluene, and PEG-400 in distinct 

experiments using H3PO3 and POCl3 to get Z (yield: 13.4-

100%). Interestingly, the use of chlorobenzene or silicon 

oil for phosphorylation gave a better yield compared to 

other solvents [5]. Patel VM., et al, in 2004, had reported 

the phosphorylation of (2) in sulfolane using H3PO3 and 

PCl3 to isolate Z (yield: 70.7%). A similar attempt was 

done using 1, 2-dimethoxyethane as the solvent to isolate 

Z (yield: not mentioned) [6]. Patel VM., et al, in 2004, had 

disclosed the condensation of (1) with chloroacetyl 

chloride (5) and benzyl alcohol (6) to isolate the 

intermediate benzyl-1-H-imidazol-1-ylacetate (7). It was 

then reduced by Pd/C or hydrolyzed by 10% HCl to isolate 

(2). It was subjected to phosphorylation using H3PO3 and 

PCl3 in sulfolane to get Z (yield: 70.7%) [7].  

Pulla RM., et al, in 2004, had illustrated the 

condensation of (1) with methyl chloroacetate (8) to get 

(2), it was then converted to (3) by the treatment with 

isopropanol-HCl. Phosphorylation of (3) using H3PO4 and 

PCl3 in the presence of various solvents like ethylene 

dichloride, cyclohexane, and chlorobenzene gave Z (crude 

yield: 79.0-85.0%). A better yield was obtained in an 

experiment performed using ethylene dichloride as the 

diluent for phosphorylation [8]. Grassi S & Volante A,. et 

al, in 2004, had reported the phosphorylation of (3) using 

H3PO3 and POCl3 in the absence of solvent to isolate Z 

(yield: 62.0%) [9]. Cai WZ., in 2005, had illustrated a one-

step process to condense (1) with (4) in 1, 4-dioxane using 

60% sodium hydride (NaH), and an in situ 

phosphorylation was done using H3PO4 and PCl3 to get Z 

(yield: 32.0%). Similarly, (1) was reacted with 

chloroacetonitrile (9) in 1, 4-dioxane using potassium 

carbonate (K2CO3) and phosphorylation was done using 

H3PO4 and PCl3 to isolate Z (yield: 29.9%) [10].  

Pandey SC., et al, in 2005, had disclosed the 

phosphorylation of (2) in n-octane using H3PO3 and PCl3 

to get Z (yield: 64.89%). A similar attempt of 

phosphorylation in 1, 4-dioxane for (2) gave Z (yield: 

51.91%) [11]. Vecchioli A., et al, in 2006, had illustrated 

the phosphorylation of (2) in methanesulfonic acid (MSA) 

using PCl3 to isolate Z (crude yield: 83.0%). The process 

efficiently avoids the use of H3PO4 or H3PO3 for the 

reaction [12]. Deshpande PB & Luthra PK., in 2006, had 

reported an efficient phosphorylation of (2) in diphenyl 

ether (DPE) using H3PO3 and PCl3 to isolate Z (crude 

yield: 75.0%) [13].  

Yadav RP., et al, in 2006, had disclosed the 

condensation of (1) with (8) to isolate the intermediate 

methyl 1-H-imidazol-1-ylacetate (10). It was hydrolyzed 

to (2) and then subjected to phosphorylation in the absence 

of solvent using H3PO3 and PCl3 or POCl3 to isolate Z 

(crude yield: 74.62-78.79%) [14]. Samsel EG & Wu TC., 

in 2007, had illustrated the condensation of (1) with t-butyl 

chloroacetate (11) to get (2). It was then phosphorylated in 

the presence of diglyme using H3PO4 and PCl3 to isolate Z 

(crude yield: 28.0%). An experiment was also conducted 

in PEG-400 instead of diglyme to isolate Z (yield: 7.0%) 

[15]. Baptista J & Mendes Z., in 2007, had reported the 

phosphorylation of (2) in the presence of an aprotic polar 

solvent N, N’-dimethylethyleneurea (DMEU) using H3PO3 

and PCl3 to obtain Z (crude yield: 85.6%) [16]. Liu Y & 

Delaup AJ., in 2008, illustrated the phosphorylation of (2) 

in sulfolane using H3PO3 and the PCl3 to isolate Z (crude 

yield: 53.0-64.0%). The experiments were done by the 

modulated mode of addition of p-reagents (co-

addition/alternate addition etc) [17].  

Nazarenko AB & Fedorov VE., in 2009, had 

demonstrated the phosphorylation of 1-H-imidazol-1-

ylacetonitrile (12) in MSA using alone PCl3 to isolate Z 

(yield: 85.0-92.0%). A few experiments were conducted 

using different equivalents (1.25, 2.5, and 3.0) of MSA for 

phosphorylation [18]. Dembkowski L., et al, in 2009, 

disclosed the conversion of (2) to (3) by the addition of 

HCl solution and immediate phosphorylation in the 

absence of solvents/diluents using PCl3 alone to isolate Z 

(crude yield: 41.0-49.0%). Initially added water itself will 

act as the diluent for the process. Moreover, it avoids the 



Sanjay S S                                                                        A sectorial overview on the synthesis of Zoledronic acid 

Vol 2 | Issue 3 | Jul – Apr 2023                                                                          Indian J Pharm Drug Studies | 109  

use of H3PO4 or H3PO3 for phosphorylation [19]. Kas M., 

et al, in 2009, had reported a few pathways to convert (1) 

to (2) by the condensation with (8). Moreover, (2) was 

phosphorylated in a PEG-400 medium using H3PO3, PCl3, 

or POCl3 to isolate Z (yield: 31.3-32.9%). Instead of PEG-

400, diethyl carbonate (DEC) was used to convert (2) to Z 

(yield: 59.0%). Interestingly, the combination of diluents 

like PEG-400 and DEC for phosphorylation gave a better 

atom economy of Z (crude yield: 75.0-84.0%). 

Furthermore, propylene carbonate (PC) was used along 

with PEG-400 / PEG-600 / PEG-1000 as the solvent 

combination in distinct experiments to isolate Z (crude 

yield: 97.0-99.0%) [20].  

Hu Y., et al, in 2010, had disclosed a one-pot synthetic 

strategy to condense (1) with (4) using 1, 4-dioxane or 

tetrahydrofuran (THF) and the in situ phosphorylation 

using H3PO3 and PCl3 to isolate Z (crude yield: 55.0-

58.3%) [21]. Lanxiang S., et al, in 2011, had disclosed the 

phase transfer reagent mediated condensation of (1) with 

(4) and its further hydrolysis to isolate (3). It was 

phosphorylated in trifluoroacetic acid (TFA) or sulfuric 

acid (H2SO4) using H3PO4 and PCl3 to get Z (crude yield: 

57.0-58.8%) [22]. Yinchuan Z., et al. in 2011, had reported 

the phosphorylation of (2) or (3) in liquid paraffin medium 

using H3PO4 and PCl3 to get Z (crude yield: 56.6-81.1%) 

[23]. Keglevich G., et al, in 2012, had reported the 

phosphorylation of (2) in an MSA medium using a 

different set of p-reagents like triphosgene, mesyl chloride, 

PCl3, etc to get Z (crude yield: 59.0-74.0%). The process 

avoids the use of routine p-reagents like H3PO4 or H3PO3 

for phosphorylation [24]. Kai S., et al, in 2012, had 

illustrated the phosphorylation of (2) in commercially 

affordable aliphatic hydrocarbon-based solvents like n-

hexane, n-decane, n-tetradecane along with water using 

PCl3 alone to isolate Z (crude yield: 81.0-91.0%) [25].  

N

N

OH

O

N

N
PO3H2

OH
PO3H2

Z

N

N

H

N

N

OH

O

HCl

(1) (2) (3)

O

O

Cl

(4)

Cl
O

Cl

(5)

OH

(6)

N

N

O

O

(7)

O

O

Cl

(8)

Cl

N

(9)

N

N

O

O

(10)

O

O

Cl

(11)

N

N

N

(12)

N

N

O
O

(13)
 

Figure 1. List of various key reactants and intermediates featuring in different synthetic strategies of Zoledronic acid 

Hao E., et al, in 2015, had illustrated the condensation 

of (1) with (3) in the presence of ionic liquid ([bmim]BF4)  

to get (3). Phosphorylation of (3) in the presence of ionic 

liquid ([bmim]BF4) using H3PO4 (85%) and PCl3 gave the 

sodium salt of Z monohydrate (yield: 60.0%). Numerous 

experiments were done to optimize the process using 

different ionic liquids, variations in reaction temperature, 

and changes in PCl3 addition duration. Different ionic 

liquid {N-ethylpyridine tetrafluoroborate [EPy][BF4], 

[bmim][PF6], LOH, LCN, LOOH} was used in distinct 

experiments to obtain Z (yield: 90.0-92.0%). Meanwhile, 

the ionic liquid facilitated the phosphorylation as an 

effective reaction mixture diluent [26]. Wu Y., et al, in 

2016, had disclosed the phosphorylation of (2) in 

chlorobenzene and also in sulfolane using H3PO3 along 

with PCl3 in high scale to isolate Z (crude yield: 78.1% 

and 65.0% respectively). A few experiments were also 

done by conducting the phosphorylation of (2) in the 

absence of solvent using H3PO3 along with PCl3 or POCl3 

to isolate Z (crude yield: 83.7-87.3%) [27].  

Details gathered from journal publications  

Many researchers had reported their work on Z in 

numerous national/international journals.. In all those, the 

synthetic method part was examined critically to tabulate 

the disclosures about solvent-free and solvent/s-based 

strategies to isolate Z.  

Widler L., et al, in 2002, had reported the phosphorylation 

of (2) in chlorobenzene using H3PO4 (85%) and PCl3 to 

isolate Z (yield: 67.0%) [28]. Srinivasa RDVN., et al, in 



Sanjay S S                                                                        A sectorial overview on the synthesis of Zoledronic acid 

Vol 2 | Issue 3 | Jul – Apr 2023                                                                          Indian J Pharm Drug Studies | 110  

2007, had reported the phosphorylation of (2) in p-cresol 

using H3PO3 along with PCl3 to get Z (crude yield: 80.0%) 

[29]. Keglevich G., et al, in 2011 and 2012, had illustrated 

and explained the mechanistic aspects behind the 

phosphorylation of (2) in MSA using PCl3 and 

with/without H3PO3 to obtain Z (crude yield: 0-71.0%). 

The work proved that, in the presence of MSA as the 

medium for reaction, alone PCl3 can induce the 

phosphorylation and hence there is no requirement of 

H3PO3 to obtain Z (crude yield: 23.0-71.0%) [30, 31]. 

Mustafa DA., et al, in 2011, had disclosed the 

phosphorylation of (2) in sulfolane medium using H3PO3 

along with PCl3 under the assistance of microwave 

irradiation (3-4 min) to isolate Z (yield: 70.0%). 

Interestingly, the same experiment when conducted in a 

conventional pathway resulted in the formation of Z (yield: 

67.0%) with not much deviation in outcome. But the 

conventional process takes more reaction time than the 

microwave irradiation pathway [32]. Lenin R., et al, in 

2013, had reported the phosphorylation of (2) using H3PO3 

and PCl3 in the presence of silica gel under microwave 

irradiation (3-4 min) to isolate sodium salt of Z (yield: 

80.0%) [33]. Kovács R., et al, in 2014, had reported a 

review article regarding the use of greener solvent MSA 

for the phosphorylation of (2) requiring alone PCl3 [34]. 

Ratrout SS., et al, in 2015, had reported the 

phosphorylation of t-butyl-imidazol-1-yl acetate (13) in the 

presence of MSA and chlorobenzene using H3PO4 and 

POCl3 to isolate sodium salt of Z (yield: 85.0%). It was 

later converted to Z (yield: 79.0%) by the treatment with 

concentrated HCl (37.0%). The work also disclosed the 

route of synthesis of (13) by condensation of (1) with (11) 

in acetonitrile using NaH [35]. 

Keglevich G., et al, in 2015, had disclosed the 

phosphorylation of (2) in MSA using PCl3 to isolate 

sodium salt of Z and then to Z (yield: 49.0%) using 1 N 

HCl solution [36]. Nagy DI., et al, in 2016, had reported a 

review article regarding the use of different solvents for 

the synthesis of hydroxymethylenebisphosphonic acids. 

The work covers the synthesis of Z (yield: 31.0-53.0%) 

using MSA to phosphorylate (2) using PCl3 and 

with/without H3PO3. Similarly, the use of chlorobenzene in 

various disclosures using H3PO4 or H3PO3 and PCl3 gave Z 

(yield: 41.0-100%). Furthermore, the use of sulfolane for 

phosphorylation gave Z (yield: 67.0-71.0%). Attempts of 

solvent-free conditions for phosphorylation of (2) using 

H3PO3 and PCl3 / POCl3 gave Z (yield: 61.0-81.0%). Use 

of different ionic liquids as the diluent also gave Z or its 

sodium salt (yield: 26.0-92.0%). Similarly, the use of p-

cresol as the solvent gave Z (yield: 80.0%). Additionally, 

phosphorylation of (2) in n-octane gave Z (yield: 65.0%). 

The work covers the use of other solvents like 

cyclohexane, 1, 4- dioxane, diphenyl ether, propylene 

carbonate, a mixture of propylene carbonate and PEG 600, 

PEG 400, dimethoxymethane, dimethoxyethane, diglyme, 

1, 2-dichloroethane, N, N-dimethylurea, and silicon oil [37].  

Nagy DI., et al, in 2017, had reported a review article 

covering the vital role of PCl3 and H3PO3 in specific molar 

equivalents for the formation of hydroxymethy lenebisp 

hosphonic acids from the corresponding carboxylic acids. 

The work disclosed the impact of p-reagent/s for the 

phosphorylation of (2) in MSA or sulfolane medium to 

isolate Z [38]. Nagy DI., et al, in 2018, had illustrated the 

phosphorylation of (2) in sulfolane using H3PO3 and PCl3 

to isolate Z dihydrate (yield: 74.0%). The use of ionic 

liquid [bmim][BF4] as the reaction medium gave Z 

dihydrate (yield: 75.0%). Similarly, the use of sulfolane 

and  [bmim][BF4] for phosphorylation resulted in the 

formation of Z dihydrate (yield: 93.0%) [39]. Nagy DI., et 

al, in 2018, had emphasized the phosphorylation of (2) in 

MSA using the p-reagent PCl3 alone to isolate Z (yield: 

53.0%) [40]. Grün A., et al, in 2019, had reported the 

phosphorylation of (2) in sulfolane, or the presence of an 

ionic liquid, or both together as the medium for the 

reaction using PCl3 and H3PO3 to obtain Z (yield: 74.0-

93.0%). The combination of solvent sulfolane and the 

ionic liquid [bmim][BF4] gave a promising output of Z 

(yield: 93.0%) [41].  

Ábrányi BP., et al, in 2021, had reported a review 

article covering the phosphorylation of (2) using only PCl3 

using MSA to isolate Z (yield: 46.0-53.0%). Similarly, the 

use of H3PO3 and PCl3 in sulfolane gave Z (yield: 63.0-

74.0%) [42]. Grün A., et al, in 2021, had disclosed the 

phosphorylation of (2) using different equivalents of 

H3PO3 and PCl3 in diethyl carbonate (DEC) as a green 

solvent medium to isolate Z (0-61.0%). The work extends 

to cover the use of MSA and DEC, alone or in different 

combination ratios to synthesize Z (yield: 0-53.0%). This 

approach was observed to be less efficient as compared to 

the use of sulfolane for phosphorylation. But, found 

reasonably better as compared to the use of MSA for 

phosphorylation to isolate Z. [43]. Sanjay SS., in 2023, had 

reported a review article regarding the synthesis and 

purification of Z. It covers the disclosures provided in 

various patents regarding the till date adopted synthetic 

strategies in detail to isolate Z and its few forms [44]. 

Summary 

As per the prior arts, phosphorylation in MSA medium 

requires only PCl3. If the same was performed in solvents 

other than MSA, then both PCl3 and H3PO3 are required in 



Sanjay S S                                                                        A sectorial overview on the synthesis of Zoledronic acid 

Vol 2 | Issue 3 | Jul – Apr 2023                                                                          Indian J Pharm Drug Studies | 111  

optimum equivalents. Numerous solvents are being used 

for the phosphorylation to isolate Z and its salt, all those 

were tabulated in Table 1.  

Table 1 List of solvent-free and solvent-based strategies 

employed for the phosphorylation to synthesize Z. 

Solvent/s based synthetic strategies 

Solvent/s for phosphorylation References 

Chlorobenzene [1], [2], [5], [8], 

[27], [28], [35] 

Tributylammoniumchloride [3] 

Silicon oil [4], [5] 

Toluene [5] 

PEG-400 [5], [15], [20] 

Sulfolane [6], [7], [17], [27], 

[32], [39], [41] 

1, 2-Dimethoxyethane [6] 

Cyclohexane [8] 

Ethylene dichloride [8] 

1, 4-Dioxane [10], [21] 

n-Octane [11] 

Methanesulfonic acid [12], [18], [24], 

[30], [31], [34], 

[35], [36], [40], [43] 

Diphenyl ether [13] 

Diglyme [15] 

N, N’-dimethylethyleneurea [16] 

Diethyl carbonate [20],  [43] 

Diethyl carbonate & PEG-400 [20] 

Propylene carbonate & PEG-400 [20] 

Propylene carbonate & PEG-600 [20] 

Propylene carbonate & PEG-1000 [20] 

Tetrahydrofuran [21] 

Trifluoroacetic acid [22] 

Sulfuric acid [22] 

Liquid paraffin [23] 

n-Hexane [25] 

n-Decane [25] 

n-Tetradecane [25] 

Ionic liquid/s [26], [39], [41] 

p-Cresol [29] 

Silica gel [33] 

Sulfolane & Ionic liquid [39], [41] 

Methanesulfonic acid & Diethyl 

carbonate 

[43] 

Solvent-free synthetic strategies 

Phosphorylation in the absence of 

solvent/s 

[9], [14], [19], [27] 

CONCLUSION 

An exceptionally complex phosphorylation forms a crucial 

step to synthesize Z. To ensure the scalability and the 

industrial adaptability of phosphorylation, numerous 

reaction optimization experiments were reported by many 

researchers. As a part of it, solvent-free and different 

solvent/s involved phosphorylation reactions were 

demonstrated with varied purity and yields of Z. This work 

primarily focused to give an overview of all the solvents 

used and the solvent-free synthetic strategies adopted for 

the phosphorylation to prepare Z. The supportive details 

were extracted separately from the filed patents and the 

journal publications, comprising the specific illustrations 

towards the synthesis of Z. 

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How to cite this article: Sanjay Sukumar Saralaya. An 

overview of solvent-free and solvent/s-involved 

phosphorylation to synthesize zoledronic acid. Indian J 

Pharm Drug Studies. 2023; 2(3) 107-112. 

Funding: None             Conflict of Interest: None Stated 

 

http://dx.doi.org/10.1021/jm020819i
http://dx.doi.org/10.1080/00397910701578545
http://dx.doi.org/10.1016/j.tetlet.2011.03.093
http://dx.doi.org/10.2174/138955712799829285
http://dx.doi.org/10.1016/j.tetlet.2011.02.058
http://dx.doi.org/10.1007/s00044-012-0153-4
http://dx.doi.org/10.1515/gps-2013-0107
http://dx.doi.org/10.1007/s11094-015-1205-0
http://dx.doi.org/10.1080/10426507.2015.1072194
http://dx.doi.org/10.3390/molecules21081046
http://dx.doi.org/10.2174/1385272821666170417122441
http://dx.doi.org/10.1080/00397911.2017.1410894
http://dx.doi.org/10.1080/10426507.2018.1555537
http://dx.doi.org/10.3390/molecules26247587
http://dx.doi.org/10.2174/1570178617999200730203738
http://dx.doi.org/10.20959/wjpr20239-28454

