Journal of Drug Delivery Science and Technology 66 (2021) 102913

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Journal of Drug Delivery Science and Technology

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

Modulation of biopharmaceutical properties of drugs using sulfonate

counterions: A critical analysis of FDA-approved pharmaceutical salts
Sonali S. Bharate
Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM’s NMIMS, V.L. Mehta Road, Vile Parle (W), Mumbai, 400056, India

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

Keywords: The physicochemical and ADMET properties of drugs can be modulated by converting them into a suitable salt
Sulfonic acids form. The detailed analysis of the FDA database over the past 80-years revealed the contribution of 49-counter­
Stable salts ions in pharmaceutical salts with varying ionic charge, dissociation constant, and aqueous solubility. The ‘sul­
FDA
fonate’ is one of the key counterions comprising inorganic sulfate and organic sulfonates. Phentolamine mesylate
Crystal lattice energy
Biopharmaceutical properties
is the first sulfonate salt approved in 1952 as an antihypertensive medication. So far, 69 sulfonate salts are
approved by FDA in the last seven decades comprising sulfate, mesylate, besylate, tosylate, methylsulfate,
camsylate, isethionate, and edisylate salts. Among these sulfonate salts, mesylate (25 drugs) and sulfate (24
drugs) have a major share. This review provides an account of FDA-approved sulfonate salts from 1952 to 2020.
The decade-wise analysis indicates that 2011–2020 contributed a maximum number of sulfonate salts (19) and
least (5) in 1971–1980. The technical advantage of sulfonate salts over other salt forms and the parent drug is
also discussed.

1. Introduction timeline from 1939 to 2020 discloses approval of ~539 API-salts

comprising 49-counterions. Specifically focusing on salts of sulfonic
In early drug development, the molecules with solubility <10 mg/ acids, ~5.2% of drugs approved over a period of 70-years are sulfonate
mL are likely to have bioavailability or absorption issues that may salts. Furthermore, sulfonates share a significant (~13%) fragment in
impact in vivo performance of the dosage form. Thus, the salification of pharmaceutical salts (539 total salts vs. 69 sulfonates). Despite this
active pharmaceutical ingredients is one of the effective handles to considerable presence of sulfonates in the pharmaceutical salt portfolio,
enhance the biopharmaceutical properties. The selection of an appro­ their critical and focused analysis is not reviewed anywhere. Therefore,
priate salt form is likely to improve the chemical stability of active the present review aims at critically analyzing FDA-approved sulfonic
pharmaceutical ingredients (API), and thus it increases the develop­ acid-derived ‘Pharmaceutical Salts’ from its first approval in 1952
ability of a drug molecule. Moreover, the modulation of physicochem­ through 2020. This review unravels the current understanding of sul­
ical properties of drugs via salification also affects the pharmacokinetic fonic acid counterions in approved pharmaceutical salts. Additionally, it
profile of the drug candidate [1–5]. focuses on the advantages offered by sulfonate counterions in the salt
There are few general reviews on salt selection methods, criteria for screening of cationic drugs. The therapeutic benefit provided by sulfo­
salt selection and its solid-state characterization, physicochemical con­ nate salts is also compared over the other counterions.
siderations of API and counterions, etc. [2,4,5]. A detailed analysis of To address the central point of this review, sulfonate counterions are
carboxylates and cationic counterions in FDA (Food and Drug Admin­ categorized as inorganic and organic sulfonates. The chronology of the
istration) approved pharmaceutical salts is reviewed [6,7]. However, discovery of the first API-salt for each sulfonate counterion is discussed.
there is no specific coverage of FDA-approved pharmaceutical salts Additionally, the biopharmaceutical advantage of the specific sulfonate
prepared using sulfonate counterions in any reviews. Hence, the present salt over other salts or the parent molecule is also discussed. The sul­
review focuses on the contribution of sulfonates as counterions in fonate salts are presented class-wise and therapeutic benefits provided
FDA-approved pharmaceutical salts. Thus, herein the analysis of the by them are illustrated using case studies. The first approval of API-salt
orange book was conducted, which revealed that ~40% of first-in-class for each sulfonate counterions and its year of approval is shown in Fig. 1.
drugs approved in the last 80-years are pharmaceutical salts. The Each one of them represents a milestone in the history of the

E-mail addresses: [email protected], [email protected].

https://doi.org/10.1016/j.jddst.2021.102913
Received 16 June 2021; Received in revised form 19 August 2021; Accepted 9 October 2021
Available online 20 October 2021
1773-2247/© 2021 Elsevier B.V. All rights reserved.
S.S. Bharate Journal of Drug Delivery Science and Technology 66 (2021) 102913

development of pharmaceutical salts. The lineage of consequent devel­ is observed that several pharmaceutical salts also exist as hydrates. For
opment of API-salts for each counterion is also presented in the example, HCl salts frequently exist as hydrates which can be problematic
following sections. The databases used for literature search are the FDA for tablet formulation where wet granulation is involved [9]. However,
website, Reaxys, SciFinder, online patent databases, PubMed-NCBI, etc. mesylates (organic sulfonate counterion) do not form hydrates. Sec­
FDA’s Center for Drug Evaluation and Research (CDER) has ondly, the melting point of salt has a direct impact on its physico­
approved ~1372 new drugs during the calendar years 1939–2020. chemical properties. In general, the salts with low melting points exhibit
Fig. 2a depicts the distribution of ~69 FDA-approved sulfonate salts as a plastic deformation during processing and have poor flow properties. It
function of the decade. The highest number of API-sulfonates were may cause caking and aggregation, thus affecting flow and compress­
approved in the 2010s. The number of sulfonate salts approved as first- ibility characteristics [10]. Strong acids such as sulfuric acid and methyl
in-class drugs against decade are ordered as follows: 2020s > 1990s, sulfate usually provide stable salts that are less plastic and are handled
1980s, 1950s > 2000s > 1960s > 1970s. Overall, the number of NMEs better during formulation. Another key aspect is the disproportionation
and sulfonate salts was lowest in the 1960s. The distribution of sulfonic of salt forms, which is less common in sulfonate salts as the byproducts
acids bearing salts currently being used or discontinued is presented in of the resulting reaction are stable and nonvolatile. On the contrary,
Fig. 2b. It is evident that from 69-approved sulfonate salts, 50 are clin­ hydrochloride and dihydrochloride salts may undergo disproportion­
ically used, and 19 salts are discontinued. ation by generating volatile hydrogen chloride gas. The liberated gas
The relative abundance of various sulfonic acid counterions in may react with the formulation or the processing equipment, resulting in
approved salts of new molecular entities (NMEs) is presented in Fig. 2c. destabilization (physical and chemical) of salt form.
Over a period of 70-years, from 1952 to 2020, 69 first-in-class sulfonate The salts with high melting points are stable as the crystal lattice
salts were approved, and further, they are categorized into eight energy is high, making the molecule hard and stable. However, the high
different classes based on their counterion. A detailed breakdown of the melting point has a negative effect on the aqueous solubility of a salt. But
percent distribution of counterions in API-salts is depicted in Fig. 2c. A sulfonate salts are an exception as they exhibit a high melting point and
thorough analysis of Fig. 2c indicates the predominance of mesylate (25 impart relatively high aqueous solubility compared to other counter­
drugs), sulfate (24 drugs), and tosylate (9 drugs) among a total of eight ions. Furthermore, API-salts of sulfonic solid acids such as mesylate,
different sulfonic acid counterions. sulfate, etc., dissolve rapidly owing to their high solubility. Conversely,
this is not the case with HCl salts, wherein due to the common ion effect,
2. Why are sulfonic acids suitable as counterions in salification HCl salts have reduced solubility in the gastric environment. Thus,
sulfonates have an additional advantage over the HCl salt form [11].
The sulfonyl esters can act as DNA-alkylating agents and may exert
genotoxic effects [8]. Thus, the use of alkyl or aryl sulfonic acids raises a 3. Review of sulfonates as pharmaceutical salts addressing
safety concern during drug development. More focused regulatory ADMET issues
attention was given after the product recall of Viracept due to contam­
ination of ethyl methanesulfonate, which is a genotoxic impurity. The systematic analysis of the database of FDA-approved pharma­
However, the reason for this unusual incidence may be a good ceutical salts from 1939 onwards revealed a significant number of sul­
manufacturing practice issue. The contamination of genotoxic alkyl fonate salts approved for clinical use. There are 69 sulfonate salts
sulfonate impurities can be minimized during the synthesis and pro­ approved in the last 80 years that are discussed in the following sections.
cessing of API-salt. These safety issues should not limit the utility of Based on the chemical nature of the counterions employed in approved
sulfonic acids and must be explored owing to their many advantages sulfonate salts, they can be broadly categorized into two major classes
during the salt screening of molecule at its early developmental stage. viz. inorganic sulfonate (comprising hydrogen sulfate) and organic sul­
Sulfonate is one of the key counterion players in the pharmaceutical salt fonates (comprising various alkyl or aryl sulfonates) (Fig. 3). The
portfolio because of its unique properties distinct from other counter­ organic sulfonates that are most frequently used in salification are
ions. Thus, in specific circumstances, their use is preferred for methane sulfonic acid (mesylate), benzenesulfonic acid (besylate), p-
salification. toluene sulfonic acid or tosylic acid (tosylate), mono-methyl ester of
There are certain specific advantages of sulfonates as counterions. It sulfuric acid (methyl sulfate), camphor sulfonic acid (camsylate),

Fig. 1. First pharmaceutical salts of various sulfonic acid counterions. The abbreviations ms, is, cam ed, bs, ts indicates mesylate, isthionate, camsylate, edisylate,
besylate, and tosylate counterions. The structures of counterions are shown in Fig. 3.

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S.S. Bharate Journal of Drug Delivery Science and Technology 66 (2021) 102913

Fig. 2. (a) The distribution of NMEs and sulfonate salts as a function of the decade; (b) Distribution of sulfonic acid pharmaceutical salts: clinically used currently and
discontinued; (c) The percentage distribution of sulfonates in FDA-approved API salt forms (1939–2020: n = 69).

Fig. 3. Sulfonic acid counterions in FDA-approved pharmaceutical salts (1952–2020).

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S.S. Bharate Journal of Drug Delivery Science and Technology 66 (2021) 102913

isethionic acid, or 2-hydroxyethanesulfonic acid (isethionate) and solubility of 0.054 mg/mL. Sulfuric acid is a strong acid (pKa − 3.0, 1.9)
ethanedisulfonic acid (edisylate). Furthermore, besylate, tosylate, and and phosphoric acid is a weak acid (pKa 2.14, 7.2, 12.37). The salifi­
camsylate are aryl sulfonate counterions. cation of HCQ with sulfuric acid results in the formation of water-soluble
The detailed analysis of the FDA database revealed that among 69 HCQS with a solubility of 5 mg/mL at pH 7.2. There is a district dif­
salts, there are 45 (~65%) organic sulfonate salts and 24 (~35%) ference in the melting behavior of both salt forms, namely sulfate and
inorganic sulfonate (sulfate) salts. The aqueous solubilities of sulfonate phosphate (235–240 ◦ C vs. 162–164 ◦ C, respectively). The high melting
counterions are very high, contributing to the high solubility of salts point of HCQS over diphosphate and HCQ free base results in the high
post-salification of APIs. FDA-approved sulfonate salts are discussed in stability of HCQS. The high crystal lattice strength provides stable
this section as per the classification depicted in Fig. 3. molecules like HCQS, and weak lattice energy increases the chance of
forming amorphous forms. Thus, HCQS is the optimum and stable salt of
HCQ free base, which may be the plausible reason for its approval over
3.1. Inorganic sulfonic acid (sulfate) salts
diphosphate salt. Vincristine and vinblastine are vinca alkaloids first
isolated from Madagascar periwinkle Catharanthus roseus in 1961 and
Sulfuric acid is a strong mineral acid used in pharmaceutical and
1958. Structurally, these alkaloids consist of multiple ester groups,
food preparations as an acidifying agent. It is a general observation that
which are labile and make molecules unstable when given orally. Thus,
salification of weakly basic drugs with sulfuric acid yields highly water-
vincristine and vinblastine are not orally bioavailable, and therefore
soluble APIs. Over 80-years, 24 sulfate salts were approved and pre­
sulfate salts of both drugs are intravenously administered in various
sented in Figs. 4–6. These salts are categorized based on the chemical
chemotherapy regimens. Vincristine and vinblastine have pKa of 11.1,
class of API, such as amino-heterocycles, alkylamines, guanidines,
and hence their stable sulfate salts were developed. Vincristine is a
amino sugars, and peptides. Hydroxychloroquine (HCQ) is an amino-
highly lipophilic molecule with Log P 5.749 and water-solubility of
heterocycle class of API synthesized in 1946 by researchers from
0.0001 mg/mL. Salification of vincristine is reported with respective
Albany Medical College, New York. Chloroquine (CQ) was hydroxylated
counterions to yield tartrate, methiodide, and sulfate salts. However, no
to produce HCQ that has reduced toxicity. The acute oral toxicity of CQ
characterization data is reported for tartrate and methiodide salts.
and HCQ in mice was studied, and the LD50 of CQ was evident to
Vincristine sulfate (9) was approved for clinical use due to its high
conclude its toxicity over HCQ by 2 to 3-fold (387 vs. 1880 mg/base/kg)
aqueous solubility (25 mg/mL) administered as an intravenous infusion.
[12]. HCQ was approved for medical use in the United States in 1955. It
In the same way, vinblastine sulfate (10) was developed to address the
is being used as a sulfate salt (3, HCQS) for several indications, including
liabilities of vinblastine, such as Log P 5.922, water-solubility 0.035
malaria, rheumatoid arthritis, and also in the management of COVID-19.
mg/mL. Moreover, sulfate salts of both vinca alkaloids are also used as
The drug is administered by oral route and is slow-acting, requiring ~6
lyophilized powder as they are unstable in solution due to multiple ester
months to achieve steady-state plasma concentrations in arthritic pa­
groups in their chemical structure [14]. Selumetinib is a MEK inhibitor
tients [13]. Two reported salt forms of HCQ are sulfate and diphosphate.
approved for cancer treatment. It is a BCS class IV compound and is
No characterization data on the later one is available. HCQ is a strong
poorly soluble (Log P 3.696, aqueous solubility 0.15 mg/mL) at the
base with pKa 14.76, melting point 87–89 ◦ C, Log P 3.534, and aqueous

Fig. 4. Sulfate salts of amino-heterocycles and other heterocyclic drugs. The year of approval of the salt and its route of administration are shown in the parentheses.
The same pattern is followed in subsequent figures.

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S.S. Bharate Journal of Drug Delivery Science and Technology 66 (2021) 102913

Fig. 5. Sulfate salts of alkylamine class of drugs.

Fig. 6. Sulfate salts of guanidine, amino-sugar, and peptidomimetic class of drugs.

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S.S. Bharate Journal of Drug Delivery Science and Technology 66 (2021) 102913

physiological pH range. During early clinical studies, selumetinib was sulfate salt (18). Penbutolol sulfate has a pKa of 9.26 and exists as a
used in the oral suspension. Later the capsule formulation of positive charge at physiological pH [30]. Isoproterenol (also called
hydrogen-sulfate salt (11) was prepared as the salt exhibited a kinetic isoprenaline) is another amine class drug used for the treatment of
solubility advantage and resulted in improved bioavailability. In the bradycardia. It is clinically used in two salt forms, and the HCl salt was
comparative phase I study, both the free-base oral suspension and approved as an injection [31], whereas the sulfate salt (19) [32] as a
hydrogen-sulfate capsule form showed a similar toxicity profile. How­ powder for oral inhalation. Metaproterenol and terbutaline are also
ever, the hydrogen-sulfate capsule form has shown relatively rapid ab­ phenylethylamine class of drugs approved as their sulfate forms 20–21
sorption with tmax of 90 min and elimination t1/2 of 5–8 h. Furthermore, for clinical use.
the capsule formulation resulted in superior Cmax (1316 vs. 523 ng/ml) Guanethidine [33], guanadrel [34], and bethanidine are guanidine
and AUC0-24 (4454 vs. 2260 ng/ml.h) over the parent drug; thus, the class of antihypertensive drugs approved as sulfate salts. Phenelzine
capsule formulation (sulfate salt) was used in further development and sulfate (25) is a hydrazine class of antidepressant drugs soluble in water
was approved in 2020 [15,16]. Clopidogrel is an antiplatelet drug [35]. Tobramycin is an aminoglycoside antibiotic whose sulfate salt (26)
discovered in 1982 and approved for coronary artery disease in 1997. It is clinically used as an ophthalmic solution. Bleomycin (29) is a glyco­
is practically insoluble in water at neutral pH but freely soluble at pH peptide antibiotic discovered in 1966 by Japanese Scientists from the
1.0. Clopidogrel (clopidogrel base) is unstable, owing to a labile proton cultures of Streptomyces verticillus [36]. It was launched for medical use
in the chiral center, and susceptible to racemization and hydrolysis of in 1969 by Nippon Kayaku, which received FDA approval in 1973 for
the methyl ester group [17,18]. Secondly, the clopidogrel base has low treating Hodgkin’s lymphoma. It is a basic glycopeptide comprising
water solubility, and there is a purification difficulty as it does not form a dimethyl sulfonium that always exists with sulfate counterion. It is a
crystalline solid. Thus, the innovator formulated it as a sulfate salt form highly water-soluble drug with limited stability; therefore, it is available
(12, Plavix, Iscover). This is a crystalline salt form with improved sol­ as a lyophilized powder for injection. Three anti-HIV drugs, namely
ubility over the parent drug. After the innovator’s product patent atazanavir, indinavir, and abacavir, are clinically used as sulfate salts.
expiration, several generic salts emerged, such as besylate, HCl, resinate, Netilmicin and plazomicin are aminoglycoside antibiotics used clini­
and napadisilate [19]. Because of the cost benefits, the clopidogrel base cally as water-soluble sulfate salts, formulated as injectables. Indinavir is
and a few new salt forms have now entered the market. There is limited another anti-HIV drug that is also clinically used as a sulfate salt (30,
bioequivalence data available for generic salt forms; however, some approved in 1996) and formulated as capsules. It is a peptidomimetic
studies are conducted. In clinical trials, the two salt forms besylate and lipophilic drug; however, its sulfate salt has good water solubility. It was
hydrogen sulfate were compared and displayed identical anti-platelet initially developed as a parent drug, but it had poor solubility at neutral
aggregation activity [20,21]. Both these salt forms were also found and alkaline pH and had limited adsorption [37]. Considering the
bioequivalent in a study conducted in 44 Korean make healthy volun­ pH-dependent solubility profile and its stability concern in acidic con­
teers [22]. On May 17, 2012, the FDA approved clopidogrel base ditions, the crystalline sulfate salt was considered for development, with
(generic clopidogrel) tablets in the US market. However, some of the water solubility of 500 mg/ml. However, this salt form is highly hy­
comparative studies noted serious findings, raising concern over generic groscopic; therefore, the manufacturing process involving dry granula­
formulation. The comparative study of clopidogrel base and its tion was used for product manufacturing [38]. In the comparative phase
hydrogen sulfate salt in 1579 patients with coronary artery disease show I clinical trial of sulfate salt and monohydrate form of the parent drug,
that the generic version (i.e., clopidogrel base) has less antiplatelet effect the sulfate salt yielded superior exposure [39]. Atazanavir is an azape­
than the original hydrogen sulfate salt form [23]. Another comparative tide anti-HIV drug approved by FDA in 2003. It is highly lipophilic and
clinical study has noted a more than 2-fold increase in stent thrombosis has poor oral bioavailability associated with its liver metabolism by
with generic clopidogrel [24], thus raising a safety concern over its use. CYP3A5. Therefore, it is co-administered with ritonavir to boosts its
The difference in the physicochemical properties of the clopidogrel base bioavailability [40]. It is clinically used as a sulfate salt (31) with water
and various salt forms is likely impacting the pharmacokinetic profile, solubility of 4–5 mg/ml [41].
thus affecting clinical efficacy. Rimegepant (BMS-927711) is the anti­
migraine drug approved in February 2020 as an orally disintegrating 3.2. Organic sulfonic acid salts
tablet. The approved form of the drug is the sesquihydrate form of
rimegepant hemi-sulfate salt (13) [25]. This indicates that the water 3.2.1. Mesylate salts
molecule stays in the crystal along with the counterion during the Mesylate (methane sulfonic acid) is one of the important organic
crystallization process. In this case, the rimegepant crystal consists of sulfonic counterions used in 24 FDA-approved pharmaceutical salts.
three water molecules and one sulfate per two drug molecules. Rime­ Phentolamine is an antihypertensive drug, and its two salts are reported
gepant sulfate (13) is slightly soluble in water, and on oral administra­ in the literature, namely mesylate (1) and hydrochloride. Phentolamine
tion, it attains tmax of 90 min, and the oral bioavailability is 64% [26]. is insoluble in water, and hence FDA approved its water-soluble mesy­
Isavuconazonium sulfate (15) is a triazole antifungal agent that is late salt in 1952. Both the salt forms viz. HCl and mesylate have aqueous
available as a sterile lyophilized powder for intravenous infusion and as solubility of 20 mg/mL in water. Furthermore, the preferred mode of
a hard gelatin capsule for oral administration. The HCl, iodide, and administration is different for phentolamine mesylate and HCl salt.
sulfate salts were investigated during preclinical development [27]; Mesylate salt is administered parenterally, while phentolamine HCl is
however, the superior physicochemical parameters of sulfate form led to administered orally. Thus, phentolamine mesylate is considered more
its further development in clinical studies. A series of phenylethylamine useful and less toxic than the other [42]. Doxazosin is a quinazoline
class of drugs were emerged from the amphetamine inspired medicinal derivative, patented and launched by Pfizer Corp. [43] in 1978 and
chemistry. Larotrectinib is an orally available tropomyosin receptor ki­ 1988, respectively, as an antihypertensive medication. It belongs to BCS
nase inhibitor approved in 2018 for treatment of cancer. Larotrectinib class II category and is marketed as mesylate salt of doxazosin (38).
sulfate (16) is water-soluble, non-hygroscopic and chemically stable Furthermore, mesylate and HCl salts of doxazosin were investigated to
[28]. improve the aqueous solubility of doxazosin. The solubility of doxazosin
Tranylcypromine is a primary amine discovered in 1946 [29] as an mesylate is significantly higher than the parent drug and HCl salt [44,
analog of amphetamine and clinically used as an antidepressant in 1961. 45]. Delavirdine (PNU-90152T) is an anti-HIV agent approved in 1997.
The parent molecule is liquid, and thus its off-white crystalline The intrinsic solubility of delavirdine in water is 0.86 μg/mL and dem­
powdered sulfate salt (17) was prepared with a 40 mg/ml water solu­ onstrates a pH-dependent solubility profile (higher solubility at acidic
bility. Penbutolol is a lipid-soluble antihypertensive drug rapidly and pH 1.2). Different salts of delavirdine viz. tosylate, HCl, HBr, mesylate,
completely absorbed after oral administration. It is clinically used as a etc., were prepared to improve the solubility of a drug. The equilibrium

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S.S. Bharate Journal of Drug Delivery Science and Technology 66 (2021) 102913

solubility and dissolution rate of delavirdine mesylate (39) is ~250-fold tosylate, glucuronate, isethionate, and maleate. The aqueous equilib­
(>100 mg/mL) higher than the other salt forms. Hence, it was selected rium solubility of prepared salts revealed that nelfinavir mesylate (4.5
for further development and clinical use [46]. Nelfinavir (AG1343) is an mg/mL) had relatively higher solubility than the other salt forms except
HIV-1, and HIV-2 protease inhibitor patented by Agouron Pharmaceu­ for nelfinavir isethionate. The water solubility of alternate salts viz. HCl,
ticals in 1992 and launched for clinical use in 1997 [47]. The parent tosylate, glucuronate, isethionate, and maleate were 1.4, 0.3, 0.7, 4.5,
molecule, nelfinavir, is practically insoluble, and hence to improve its and 2.5 mg/mL, respectively. Based on the other preformulation char­
solubility, various salts were prepared, namely mesylate (41), HCl, acteristics, nelfinavir mesylate received FDA approval [48].

Fig. 7. Mesylate salts 1, 32–55 (Ms indicates the mesylate counterion and H2O indicates the hydrate).

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S.S. Bharate Journal of Drug Delivery Science and Technology 66 (2021) 102913

Trovafloxacin is a fluroquinolone class of antibiotic and has limited commercially available bepotastine besilate. In the patent WO
aqueous solubility at physiological pH; hence it is not suited for IV 2008/123701 Al, bepotastine metal salts viz. sodium, potassium, mag­
infusion. Salification of trovafloxacin is attempted wherein mesylate salt nesium, zinc, calcium were prepared and evaluated [65]. Except for
(43) was chemically stable with high aqueous solubility of 22 mg/mL bepotastine calcium hydrate, the other metal salts were amorphous or
and Log DpH6.5 0.28. Trovafloxacin mesylate received FDA approval in hygroscopic and were further not characterized. Apart from besilate salt,
1997; however, it was withdrawn from market in 2001 due to risk of nicotinate and salicylate salts were studied by a research group from
hepatotoxicity [49,50]. Paroxetine is an antidepressant medication South Korea. The new salts, namely nicotinate and salicylate, were
available in two salt forms, namely HCl and mesylate (48), approved in bioequivalent with the bepotastine besilate [66]. There was no signifi­
1992 and 2003, respectively. Both salt forms of paroxetine are bio­ cant difference between the physicochemical properties and hygro­
equivalent; however, mesylate salt is a generic version of paroxetine scopicity of these salt forms. Despite being bioequivalent, nicotinate and
HCl. The salification process of mesylate salt differs from HCl salt form salicylate salts of bepotastine were not pursued further because of their
and may give rise to potential problems related to efficacy, tolerability, higher toxicity than bepotastine. Therefore, bepotastine besilate was the
and toxicity [51,52]. Rasagiline is a propargylamine derivative optimum salt form in terms of low toxicity, chemical stability and
approved in 2006 for the treatment of Parkinson’s disease. It was first aqueous solubility (~75 mg/mL) [67]. Clopidogrel is an antiplatelet
discovered and patented by Aspro-Nicholas Ltd. in 1970 [53]. The salt medicine used to reduce the risk of heart diseases. The bisulfate salt of
screening of rasagiline was performed to improve solubility, chemical clopidogrel was approved by FDA in 1997. Apart from bisulfate salt,
and storage stability of the parent drug. Various salts, viz. mesylate (49), besylate and hydrochloride salts were also prepared and investigated for
esylate, sulfate, tartrate, etc., were prepared. The characterization their bioequivalence in healthy human subjects. The pharmacokinetic
studies revealed the superiority of salts over the plain molecule [54]. and pharmacodynamic data of clopidogrel bisulfate and besylate was
The major challenge during the production of salts is hygroscopicity that comparable (Cmax = 5.79 vs 7.26 ng/mL and AUC∞ = 9.43 vs 10.83
resulted in the formation of agglomerates during synthesis and thus ng*h/mL, respectively) [31,68]; however, besylate salt has not reached
caused problems during tableting. Direct compression of salts into tab­ to therapeutic use. The structures of besylate salts are shown in Fig. 8.
lets is not recommended for rasagiline salts due to their hygroscopic
nature. Rasagiline mesylate (49) was approved for clinical use due to its 3.2.3. Tosylate salts
excellent stability and high water solubility (>100 mg/mL) [55,56]. Tosylate is a para-toluene sulfonic acid counterion that differs from
Lenvatinib is an anticancer medication and belongs to BCS class II/IV. It besylate only by the presence of an additional para-methyl group on a
has a pH-dependent solubility profile wherein solubility decreases with benzene ring. Tosylate occurs in several recently approved drugs, with
an increase in the pH. Lenvatinib exhibits low solubility than its mesy­ eight drugs in the last decade. Sorafenib (8) is an antitumor agent with a
late salt (51) (1.0 vs. 1.6 mg/mL, respectively), and hence mesylate salt very low pH-dependent aqueous solubility of 1.7, 34, and 13 μg/mL in
was approved in 2015 [57]. Osimertinib is an anticancer agent approved water, pH 1.0 and pH 4.5, respectively. It is a BCS class II drug with log P
in 2015. It is a BCS class III drug discovered (AZD9291) by AstraZeneca. of 3.8 [69]. Various sorafenib salts were attempted to improve its sol­
The physicochemical properties of osimertinib revealed low perme­ ubility, namely HCl, HBr, methanesulfonate, sulfate, and tosylate [70].
ability and pH-dependent solubility, which is maximum under acidic The investigated salts were amorphous except HCl and tosylate forms.
conditions. Biortus Biosciences Co., Ltd. prepared different salts viz. Sorafenib HCl and tosylate are crystalline and chemically stable;
sulfate, tosilate, tartrate, acetate, citrate. However, osimertinib is clini­ furthermore, sorafenib tosylate is the only salt available clinically.
cally used as mesylate salt (52) due to its stable solid form, high solu­ Sorafenib HCl was not investigated further as its solubility was still
bility, and improved PK properties [58,59]. Safinamide is a lower than that of sorafenib tosylate. Niraparib tosylate (60) was
third-generation BCS class II (cLog P = 2.48) molecule approved in approved in 2017 to treat ovarian cancer. Post-approval of tosylate salt,
2017 to treat Parkinson’s disease. It is an α-aminoamide derivative and other salt forms of niraparib viz. HCl, camsylate, mandelate, and
hence displays pH-dependent solubility in aqueous media. It is practi­ camphorate were also studied. Niraparib HCl is highly hygroscopic;
cally insoluble at neutral pH and possesses high acidic solubility. Among however, other salts of niraparib including tosylate demonstrated
the investigated salts (HBr, HCl, and mesylate), mesylate salt (54) is improved solubility and is non-hygroscopic crystalline solid [71]. The
clinically used due to its high water solubility (80 mg/mL) [60,61]. The aqueous solubility of niraparib tosylate is low compared to other salt
chemical structures of mesylate salts are shown in Fig. 7. forms (0.7 vs. 10 mg/mL). Therefore, tosylate salt provided added
therapeutic benefit in reducing unwanted side-effects compared to the
3.2.2. Besylate salts other salt forms of niraparib [72]. Omadacycline is a broad-spectrum
Besylate (benzene sulfonate) is one of the bulkier counterions, not antibiotic belonging to BCS class III. FDA approved omadacycline
commonly used, and hence only four besylate salts are present in the tosylate (63) as it is suitable for intravenous administration due to its
FDA-approved salts portfolio. The aqueous insolubility of amlodipine high aqueous solubility (>2 g/mL) [73]. The improved solubility of salt
led to the discovery of its different salt forms. Maleate salt of amlodipine over the parent drug led to enhanced oral bioavailability and better
was also prepared but dropped out owing to its nephrotoxicity, chemical tolerability. Tosylate salt is favored clinically over HCl as no charac­
instability, and sticky tablet blend [62]. Other salts of amlodipine viz. terization data for omadacycline HCl is available [74]. The solubility of
camsylate, nicotinate, adipate, and orotate were also attempted for talazoparib is very low, with a Log P of 1.6. Extensive salt screening
improving physicochemical properties of API, namely solubility, sta­ experiments identified tosylate (64) as the optimum salt form of tala­
bility, and processability for tablet formulation. The reported salts of zoparib approved in 2018. Furthermore, it possesses desired physico­
amlodipine were comparable with each other in terms of efficacy and chemical properties, namely crystallinity and non-polymorphism,
tolerability. Adipate and besylate salts of amlodipine were bioequivalent chemical stability, non-hygroscopicity, and no special attention during
in healthy male subjects. However, amlodipine besylate (57) demon­ handling, shipping, and storage [14]. Lumateperone is an atypical
strated better solubility, photostability, and reduced toxicity than antipsychotic drug with sticky, oily solid nature having poor solubility
amlodipine adipate [3]. Therefore, amlodipine besylate was marketed [30]. Various salts of lumateperone like HCl, besylate, and tosylate were
first as it was the most stable salt compared with the others [63,64]. prepared to overcome the physicochemical and organoleptic barriers of
Bepotastine besylate (58) is an antihistaminic agent approved in 2009. the parent drug. The HCl and besylate salts were hygroscopic and
The parent drug, bepotastine, is not commercially available due to its demonstrated poor chemical stability [75]. Furthermore, the tosylate
poor aqueous solubility (40 μg/mL), thereby low plasma exposure. To salt of lumateperone (65) has advantageous properties over the other
enhance its aqueous solubility, a nicotinate, salicylate, and calcium salts salt forms. Lumateperone tosylate was approved in 2019 as it was
of bepotastine were prepared, characterized, and compared with the chemically stable, non-hygroscopic, and easy to handle with respect to

8
S.S. Bharate Journal of Drug Delivery Science and Technology 66 (2021) 102913

Fig. 8. Besylate and tosylate salts 6, 8, 56–66 (b and Ts represent besylate and tosylate counterions).

Fig. 9. Camsylate, methyl sulfate, isthionate, and edisylate salts (cam, isth, and ed represent camsylate, isthionate, and edisylate counterions).

9
S.S. Bharate Journal of Drug Delivery Science and Technology 66 (2021) 102913

compressibility during formulation development [76]. The structures of omadacyclidine), improved bioavailability of salt over the parent
tosylate salts are shown in Fig. 8. molecule (e.g., selumetinib, atazanavir) and enhanced manufacturabil­
ity (e.g., amlodipine). Despite the regulatory concern due to the for­
3.2.4. Camsylate and other sulfonate salts mation of genotoxic sulfonate esters (as observed in nelfinavir
Camphor sulfonic acid is an organosulfur compound used as a mesylate), their utility in salification offer advantages such as less for­
counterion in salt screening experiments. It has a high-water solubility mation of polymorphs and hydrated forms compared to HCl. Addition­
of 7.9 mg/mL, and hence the camsylate salts of API have relatively high ally, the greater ionic strength ensures less plastic salt, ultimately
solubility than the salts with other counterions. For instance, careful essential for stability, ease of processing, and high aqueous solubilities.
observation of four FDA-approved camsylate salts (Fig. 9) reveals their The examination of the FDA database revealed that out of 539 salts,
suitability for administration by intravenous route. One plausible reason 69-sulfonates were approved over the last 70-years. This trajectory will
for this could be low crystal lattice energy leading to amorphous salts, continue to grow in the coming years as salification is the most suc­
which possess high aqueous solubility than their parent molecule. cessful approach to tackle the ADMET barriers. The salt screening of lead
Rucaparin is a tricyclic indole class of poly [ADP-ribose] polymerase 1 molecules must be carried during the late stages of preclinical devel­
(PARP-1) inhibitor approved in 2016. Researchers prepared various opment. This will facilitate the identification of optimized drug-form
salts of rucaparib viz. phosphate, maleate, gluconate, and camsylate. which can be clinically investigated and thus may reduce the develop­
Based on the physicochemical properties, namely crystallinity, low hy­ mental time of the drug candidate. The pharmaceutical industry follows
groscopicity, and brittle behavior, only camsylate salt of rucaparib (69) a similar pathway as the change in salt-from at later stages of the
was found suitable for dry granulation manufacturing. The low hygro­ development incur high additional expenses and the loss of valuable
scopicity was advantageous for good compressibility with polymorphic time.
control and retained aqueous solubility [77,78].
Three other sulfonate counterions include methyl sulfate, isthionte, Declaration of competing interest
and edisylate, representing one drug salt for each counterion. Pentam­
idine is an antimicrobial medication for treating leishmaniasis. It dis­ The author declare no known competing financial interests or per­
plays poor oral bioavailability due to two strongly basic amidine sonal relationships that could have appeared to influence the work re­
moieties at the terminal position in the structure. This causes ionization ported in this paper.
of the molecule at gastric pH and thus limits its permeability. Further­
more, it has poor physicochemical properties, namely Log P 2.848 and Abbreviations
water solubility 0.03 mg/mL. All these biopharmaceutical properties
limit its clinical usage as pentamidine. To overcome these liabilities of ADMET Absorption, Distribution, Metabolism, Excretion, and Toxicity
the molecule, salt screening was performed. Various salts of pentami­ AUC Area Under the Curve
dine such as dihydrochloride, nitrate, mesylate, and isethionate are re­ BCS Biopharmaceutical Classification System
ported; however, only pentamidine isethionate (7) is completely CDER Center for Drug Evaluation and Research
characterized, in vitro and in vivo. The water solubility of pentamidine CNS Central Nervous System
isethionate is 100 mg/mL and is suitable for IV and IM injection. The IV COVID-19 Coronavirus disease 2019
route of administration leads to pain at the injection site and causes FDA Food and drug administration
nephrotoxicity due to nucleic acid precipitation [79]. Hence, it is also GIT Gastrointestinal tract
administered as an oral inhalation. A study was conducted in Surinam HCl Hydrochloride
(South America) to identify the drug of choice between pentamidine HCQS Hydroxychloroquine sulfate
mesylate and pentamidine isethionate. Both salts have similar safety, IM Intramuscular
efficacy, and side-effect profiles. However, there is a difference in dose IV Intravenous
and dosing frequency. The treatment involved seven intramuscular in­ NMEs New Molecular Entities
jections of 120 mg daily for pentamidine mesylate, which was much less PO Peroral
for pentamidine isethionate (300 mg IM once a week) [80]. All these SC Subcutaneous
observations could be attributed to the approval of pentamidine isethi­
onate in 1984 by the oral inhalation route. The chemical structures of References
these sulfonate classes of salts are shown in Figs. 8 and 9.
[1] S.S. Bharate, Recent developments in pharmaceutical salts: FDA approvals from
4. Conclusion 2015 to 2019, Drug Discov. Today 26 (2021) 384–398, https://doi.org/10.1016/j.
drudis.2020.11.016.
[2] C. Saal, A. Becker, Pharmaceutical salts: a summary on doses of salt formers from
During early drug development, modulating the biopharmaceutical the Orange Book, Eur. J. Pharmaceut. Sci. 49 (2013) 614–623, https://doi.org/
properties of a molecule ascertains its adequate bioavailability. Salifi­ 10.1016/j.ejps.2013.05.026.
[3] S.M. Berge, L.D. Bighley, D.C. Monkhouse, Pharmaceutical salts, J. Pharmacol. Sci.
cation is one of the widely employed successful approaches among the 66 (1977) 1–19, https://doi.org/10.1002/jps.2600660104.
others like lead optimization, formulation development, etc. A detailed [4] A.T. Serajuddin, Salt formation to improve drug solubility, Adv. Drug Deliv. Rev.
analysis of the orange book revealed that ~40% of approved drugs are in 59 (2007) 603–616, https://doi.org/10.1016/j.addr.2007.05.010.
[5] K.R. Morris, M.G. Fakes, A.B. Thakur, A.W. Newman, A.K. Singh, J.J. Venit, C.
their salt form. The advantages of salification, for instance, enhanced J. Spagnuolo, A.T.M. Serajuddin, An integrated approach to the selection of
aqueous solubility offering a choice of route of administration, relatively optimal salt form for a new drug candidate, Int. J. Pharm. 105 (1994) 209–217,
high plasma exposure compared to the parent drug, improved micro­ https://doi.org/10.1016/0378-5173(94)90104-X.
[6] S.S. Bharate, Carboxylic acid counterions in FDA-approved pharmaceutical salts,
meritics of API that are suitable during formulation development, etc. Pharm. Res. (N. Y.) 38 (2021) 1307–1326, https://doi.org/10.1007/s11095-021-
Specifically focusing on sulfonates as a counterion, sulfate, maleate, 03080-2.
methane sulfate drug salts can be developed as injectables owing to their [7] S.S. Bharate, Modulation of biopharmaceutical properties of acidic drugs using
cationic counterions: a critical analysis of FDA-approved pharmaceutical salts, Int.
high aqueous solubility. The case studies highlighting the biopharma­
J. Pharm. (2021) 120993, https://doi.org/10.1016/j.ijpharm.2021.120993.
ceutical advantage of salt over the parent drug were discussed in this [8] S.S. Bharate, Critical analysis of drug product recalls due to nitrosamine impurities,
review. These include enhanced API stability by salification (e.g., J. Med. Chem. 64 (2021) 2923–2936, https://doi.org/10.1021/acs.
hydroxychloroquine, solifenacin, vincristine, vinblastine, clopidogrel, jmedchem.0c02120.
[9] H. Zhu, J. Xu, P. Varlashkin, S. Long, C. Kidd, Dehydration, hydration behavior,
larotrectinib, trovafloxacin, osimertinib, rasagiline), altering the route and structural analysis of fenoprofen calcium, J. Pharmacol. Sci. 90 (2001)
of administration for API by selecting different salts (e.g., pentamidine, 845–859, https://doi.org/10.1002/jps.1038.

10
S.S. Bharate Journal of Drug Delivery Science and Technology 66 (2021) 102913

[10] R.J. Bastin, M.J. Bowker, B.J. Slater, Salt selection and optimisation procedures for [32] R.L. Talbert, Pharmacokinetics and pharmacodynamics of beta blockers in heart
pharmaceutical new chemical entities, Org. Process Res. Dev. 4 (2000) 427–435. failure, Heart Fail. Rev. 9 (2004) 131–137, https://doi.org/10.1023/B:
[11] D.P. Elder, D.J. Snodin, Drug substances presented as sulfonic acid salts: overview HREV.0000046368.08825.20.
of utility, safety and regulation, J. Pharm. Pharmacol. 61 (2009) 269–278, https:// [33] W.J. Louis, L.G. Howes, Chapter 8. Guanethidine and related compounds, in:
doi.org/10.1211/jpp/61.03.0001. D. Ganten, P.J. Mulrow (Eds.), Pharmacology of Antihypertensive Therapeutics,
[12] E.W. McChesney, Animal toxicity and pharmacokinetics of hydroxychloroquine Springer-Verlag Berlin Heidelberg, 1990, pp. 287–299, https://doi.org/10.1007/
sulfate, Am. J. Med. 75 (1983) 11–18, https://doi.org/10.1016/0002-9343(83) 978-3-642-74209-5_8.
91265-2. [34] J.D. Palmer, C.A. Nugent, Guanadrel sulfate: a postganglionic sympathetic
[13] S.E. Tett, D.J. Cutler, R.O. Day, K.F. Brown, Bioavailability of hydroxychloroquine inhibitor for the treatment of mild to moderate hypertension, Pharmacotherapy 3
tablets in healthy volunteers, Br. J. Clin. Pharmacol. 27 (1989) 771–779, https:// (1983) 220–229, https://doi.org/10.1002/j.1875-9114.1983.tb03257.x.
doi.org/10.1111/j.1365-2125.1989.tb03439.x. [35] R.E. Daly, Phenelzine sulfate, Anal. Profiles Drug Subst. 2 (1973) 383–407, https://
[14] M. Paczkowska, M. Mizera, K. Salat, A. Furgala, P. Popik, J. Knapik-Kowalczuk, doi.org/10.1016/S0099-5428(08)60048-9.
A. Krause, D. Szymanowska-Powalowska, Z. Fojud, M. Kozak, M. Paluch, [36] H. Umezawa, K. Maeda, T. Takeuchi, Y. Okami, New antibiotics, bleomycin A and
J. Cielecka-Piontek, Enhanced pharmacological efficacy of sumatriptan due to B, J. Antibiot. 19 (1966) 200–209, https://doi.org/10.7164/antibiotics.19.200.
modification of its physicochemical properties by inclusion in selected [37] J.H. Lin, D. Ostovic, J.P. Vacca, Chapter 11. The integration of medicinal
cyclodextrins, Sci. Rep. 8 (2018) 16184, https://doi.org/10.1038/s41598-018- chemistry, drug metabolism, and pharmaceutical research and development in
34554-w. drug discovery and development. The story of Crxivan®, an HIV protease inhibitor,
[15] U. Banerji, D.R. Camidge, H.M.W. Verheul, R. Agarwal, D. Sarker, S.B. Kaye, I.M. in: R.T. Borchardt, R.M. Freidinger, T.K. Sawyer, P.L. Smith (Eds.), Integration of
E. Desar, J.N.H. Timmer-Bonte, S.G. Eckhardt, K.D. Lewis, K.H. Brown, M. Pharmaceutical Discovery and Development: Case Studies, Plenum Press, New
V. Cantarini, C. Morris, S.M.A. George, P.D. Smith, C.M.L.v. Herpen, The first-in- York, 1998, https://doi.org/10.1007/0-306-47384-4_11.
human study of the hydrogen sulfate (Hyd-sulfate) capsule of the MEK1/2 inhibitor [38] C.Y. Lui, D. Ostovic, A. Katdare, C. Stemach, Dry Granulation Formulation for an
AZD6244 (ARRY-142886): a phase I open-label multicenter trial in patients with HIV Protease Inhibitor, US Patent 6645961, Merck Sharp and Dohme Corp, 1998
advanced cancer, Clin. Cancer Res. 16 (2010) 1613–1623, https://doi.org/ (March 4, 1998).
10.1158/1078-0432.CCR-09-2483. [39] K.C. Yeh, P.J. Deutsch, H. Haddix, M. Hesney, V. Hoagland, W.D. Ju, S.J. Justice,
[16] G. Metro, R. Chiari, A. Baldi, V.D. Angelis, V. Minotti, L. Crinò, Selumetinib: a B. Osborne, A.T. Sterrett, J.A. Stone, E. Woolf, S. Waldman, Single-dose
promising pharmacologic approach for KRAS-mutant advanced non-small-cell lung pharmacokinetics of indinavir and the effect of food, Antimicrob. Agents
cancer, Future Oncol. 9 (2013) 167–177, https://doi.org/10.2217/fon.12.198. Chemother. 42 (1998) 332–338, https://doi.org/10.1128/AAC.42.2.332.
[17] H. Agrawal, N. Kaul, A.R. Paradkar, K.R. Mahadik, Stability indicating HPTLC [40] K. Fukushima, S. Terasaka, K. Haraya, S. Kodera, Y. Seki, A. Wada, Y. Ito,
determination of clopidogrel bisulphate as bulk drug and in pharmaceutical dosage N. Shibata, N. Sugioka, K. Takada, Pharmaceutical approach to HIV protease
form, Talanta 61 (2003) 581–589, https://doi.org/10.1016/S0039-9140(03) inhibitor atazanavir for bioavailability enhancement based on solid dispersion
00364-3. system, Biol. Pharm. Bull. 30 (2007) 733–738, https://doi.org/10.1248/
[18] M.E. Tsoumani, I.V. Ntalas, J.A. Goudevenos, A.D. Tselepis, Evaluating the bpb.30.733.
bioequivalence of clopidogrel generic formulations, Curr. Med. Res. Opin. 31 [41] A. Sugihara, T. Yasuji, K. Masaki, D. Murayama, Composition for Solid
(2015) 861–864, https://doi.org/10.1185/03007995.2015.1028912. Pharmaceutical Preparation of Solifenacin or Salt Thereof (US 2010-950492),
[19] M.E. Tsoumani, K.I. Kalantzi, I.A. Goudevenos, A.D. Tselepis, Clopidogrel generic Astellas Pharma Inc., 2011. US 20110065746.
formulations in the era of new antiplatelets: a systematic review, Curr. Vasc. [42] A.X. Chen, J. Knowles, E. Weber, Stabilized Formulations of Alpha Adrenergic
Pharmacol. 12 (2014) 766–777, https://doi.org/10.2174/ Receptor Antagonists and Uses Thereof, WO 2004000219, Novalar
15701611113119990135. Pharmaceuticals, Inc., 2003.
[20] B. Borsiczky, Z. Sarszegi, A. Konyi, S. Szabados, B. Gaszner, The effect of [43] S.F. Campbell, Piperazinyl and Homopiperazinyl Quinazolines (US 1978-952317),
clopidogrel besylate and clopidogrel hydrogensulfate on platelet aggregation in 1978.
patients with coronary artery disease: a retrospective study, Thromb. Res. 129 [44] E.V. Gonzaga, S.S. Vieira, J.L.J. Vilaca, M. Guerra, M.G. Evangelista, I.M.L. Rosa,
(2011) 700–703, https://doi.org/10.1016/j.thromres.2011.08.013. M.M. Figueiredo, O.M.M.S. Viana, A.C. Doriguetto, Doxazosin free-base structure
[21] I.V. Ntalas, K.I. Kalantzi, M.E. Tsoumani, A. Bourdakis, C. Charmpas, determination and its equilibrium solubility compared to polymorphic doxazosin
Z. Christogiannis, N. Dimoulis, A. Draganigos, I. Efthimiadis, G. Giannakoulas, mesylate forms A and H, Cryst. Growth Des. 19 (2019) 737–746, https://doi.org/
I. Giatrakos, V. Giogiakas, G. Goumas, G. Hatziathanasiou, E. Kazakos, 10.1021/acs.cgd.8b01323.
N. Kipouridis, S. Konstantinou, H. Milionis, D. Nikolopoulos, L. Peltekis, [45] M. Erceg, M. Vertzoni, H. Ceric, M. Dumic, B. Cetina-Cizmek, C. Reppas, In vitro vs.
N. Prokopakis, I. Sinteles, C. Stroumbis, K. Terzoudi, M. Thoma, K. Tsilias, canine data for assessing early exposure of doxazosin base and its mesylate salt,
I. Vakalis, K. Vardakis, V. Vasilakopoulos, K. Vemmos, M. Voukelatou, I. Xaraktsis, Eur. J. Pharm. Biopharm. 80 (2012) 402–409, https://doi.org/10.1016/j.
D.B. Panagiotakos, J.A. Goudevenos, A.D. Tselepis, Salts of clopidogrel: ejpb.2011.10.004.
investigation to ensure clinical equivalence: a 12-month randomized clinical trial, [46] W.J. Adams, P.A. Aristoff, R.K. Jensen, W. Morozowich, D.L. Romero, W.
J. Cardiovasc. Pharmacol. Therapeut. (2016) 516–525, https://doi.org/10.1177/ C. Schinzer, W.G. Tarpley, R.C. Thomas, Discovery and development of the BHAP
1074248416644343. nonnucleoside reverse transcriptase inhibitor delavirdine mesylate, Pharmaceut.
[22] S.-D. Kim, W. Kang, H.W. Lee, D.J. Park, J.H. Ahn, M.J. Kim, E.Y. Kim, S.W. Kim, Biotechnol. 11 (1998) 285–312, https://doi.org/10.1007/0-306-47384-4_13.
H.S. Nam, H.J. Na, Y.-R. Yoon, Bioequivalence and tolerability of two clopidogrel [47] B.A. Dressman, J.E. Fritz, M. Hammond, W.J. Hornback, S.W. Kaldor, V.J. Kalish,
salt preparations, besylate and bisulfate: a randomized, open-label, crossover study J.E. Munroe, S.H. Reich, J.H. Tatlock, Aromatic and Heterocyclic Amides as HIV
in healthy Korean male subjects, Clin. Therapeut. 31 (2009) 793–803, https://doi. Protease Inhibitors (US 5484926), Agouron Pharmaceuticals, Inc., USA, 1996.
org/10.1016/j.clinthera.2009.04.017. [48] M. Longer, B. Shetty, I. Zamansky, P. Tyle, Preformulation studies of a novel HIV
[23] R. Marcucci, R. Paniccia, A.M. Gori, G.F. Gensini, R. Abbate, Bioequivalence in the protease inhibitor, AG1343, J. Pharmacol. Sci. 84 (1995) 1090–1093, https://doi.
real world is a complex challenge: the case of clopidogrel, J. Am. Coll. Cardiol. 61 org/10.1002/jps.2600840911.
(2013) 594–595, https://doi.org/10.1016/j.jacc.2012.10.020. [49] R. Teng, L.C. Dogolo, S.A. Willavize, H.L. Friedman, J. Vincent, Oral bioavailability
[24] J.C. Kovacic, R. Mehran, J. Sweeny, J.R. Li, P. Moreno, U. Baber, P. Krishnan, J. of trovafloxacin with and without food in healthy volunteers, J. Antimicrob.
J. Badimon, J.-S. Hulot, A. Kini, S.K. Sharma, Clustering of acute and subacute Chemother. 39 (Suppl B) (1997) 87–92, https://doi.org/10.1093/jac/39.suppl_
stent thrombosis related to the introduction of generic clopidogrel, J. Cardiovasc. 2.87.
Pharmacol. Therapeut. 19 (2014) 201–208, https://doi.org/10.1177/ [50] K.E. Brighty, T.D. Gootz, The chemistry and biological profile of trovafloxacin,
1074248413510605. J. Antimicrob. Chemother. 39 (Suppl B) (1997) 1–14, https://doi.org/10.1093/
[25] E.J. Chan, Q. Gao, M. Dabros, Understanding the structure details when drying jac/39.suppl_2.1.
hydrate crystals of pharmaceuticals - interpretations from diffuse scattering and [51] G. Borgheini, The bioequivalence and therapeutic efficacy of generic versus brand-
inter-modulation satellites of a partially dehydrated crystal, Acta Crystallogr B name psychoactive drugs, Clin. Therapeut. 25 (2003) 1578–1592, https://doi.org/
Struct Sci Cryst Eng Mater 70 (2014) 555–567, https://doi.org/10.1107/ 10.1016/s0149-2918(03)80157-1.
S2052520614005125. [52] C.U. Pae, A. Misra, B.J. Ham, C. Han, A.A. Patkar, P.S. Masand, Paroxetine
[26] Anonymous, Nurtec ODT (rimegepant sulfate). https://www.accessdata.fda. mesylate: comparable to paroxetine hydrochloride? Expet Opin. Pharmacother. 11
gov/drugsatfda_docs/label/2020/212728s000lbl.pdf. (Accessed 2 February 2021) (2010) 185–193, https://doi.org/10.1517/14656560903451708.
accessed. [53] J.W. James, L.F. Wiggins, M.W. Gittos, Hypotensive 1-aminoindanes and
[27] R.C. Khunt, M. Rafeeq, A.Y. Merwade, K. Deo, A Process for the Preparation of -tetrahydronaphthalenes (GB 1966-32067), Aspro-Nicholas Ltd., 1970.
Isavuconazonium or its Salt Thereof, WO2016016766A2, Wockhardt Limited., [54] V. Kroselj, M.K. Skube, F. Vrecer, K. Cerpnjak, I. Kolenc, Pharmaceutical
2014. July 26, 2014. Composition Comprising a Pharmaceutically Acceptable Salt of Rasagiline (EP
[28] M.U. Zubair, a. Mahmoud, M.A. Hassan, I.A. Al-Meshat, Caffeine, in: K. Florey 2014-815635), Krka, d.d., Novo Mesto., Slovenia, 2016.
(Ed.), Analytical Profiles of Drug Substances, Academic Press, 1986, pp. 71–150. [55] Y. Jiang, X. Zhang, H. Mu, H. Hua, D. Duan, X. Yan, Y. Wang, Q. Meng, X. Lu,
[29] A. Burger, W.L. Yost, Arylcycloalkylamines. I. 2-Phenylcyclopropylamine, J. Am. A. Wang, W. Liu, Y. Li, K. Sun, Preparation and evaluation of injectable Rasagiline
Chem. Soc. 70 (1948) 2198–2201, https://doi.org/10.1021/ja01186a062. mesylate dual-controlled drug delivery system for the treatment of Parkinson’s
[30] Y.H. Suh, Y.D. Cho, C.S. Lyu, M.Y. Yoon, H.Y. Choi, S.K. Han, Stable disease, Drug Deliv. 25 (2018) 143–152, https://doi.org/10.1080/
Pharmaceutical Composition Comprising Solifenacin, and Method for Preparing 10717544.2017.1419514.
the Same, CJ HealthCare Corporation, South Korea, 2015. [56] J. Bruning, J.W. Bats, M.U. Schmidt, Rasagiline ethanedisulfonate: an inhibitor for
[31] M. Shirley, Ixazomib: first global approval, Drugs 76 (2016) 405–411, https://doi. monoamine oxygenase B (MAO(B)), Acta Crystallogr. C 64 (2008) o613–615,
org/10.1007/s40265-016-0548-5. https://doi.org/10.1107/S0108270108032526.

11
S.S. Bharate Journal of Drug Delivery Science and Technology 66 (2021) 102913

[57] O. Brien Z, M.F. Moghaddam, A systematic analysis of physicochemical and ADME salicylate), J. Toxicol. Environ. Health Part A 77 (2014) 1451–1466, https://doi.
properties of all small molecule kinase inhibitors approved by US FDA from org/10.1080/15287394.2014.955833.
January 2001 to october 2015, Curr. Med. Chem. 24 (2017) 3159–3184, https:// [68] N. Gupta, M.J. Hanley, C. Xia, R. Labotka, R.D. Harvey, K. Venkatakrishnan,
doi.org/10.2174/0929867324666170523124441. Clinical pharmacology of ixazomib: the first oral proteasome inhibitor, Clin.
[58] R.A. Ward, M.R.V. Finlay, Medicinal chemistry case history: osimertinib Pharmacokinet. 58 (2019) 431–449, https://doi.org/10.1007/s40262-018-0702-1.
(AZD9291), Comprehensive Medicinal Chemistry III (8) (2017) 1–32, https://doi. [69] A. Sandberg, B. Abrahamsson, C.G. Regardh, I. Wieselgren, R. Bergstrand,
org/10.1016/j.jtho.2018.05.024. Pharmacokinetic and biopharmaceutic aspects of once daily treatment with
[59] P. Zhou, Y. Liu, H. Tian, H. Zhang, J. Wu, W. Meng, Pharmaceutical Salt of metoprolol CR/ZOK: a review article, J. Clin. Pharmacol. 30 (1990) S2–S16,
AZD9291 as Epidermal Growth Factor Receptor (EGFR) Mutation Inhibitor and its https://doi.org/10.1002/j.1552-4604.1990.tb03490.x.
Crystal Form and Preparation Method, Biortus Biosciences Co., Ltd., Peop. Rep. [70] P. Paoli, P. Rossi, E. Macedi, A. Ienco, L. Chelazzi, G.L. Bartolucci, B. Bruni, Similar
China, 2017. but Different: the Case of Metoprolol Tartrate and Succinate Salts, vol. 16, 2016,
[60] T. Muller, Pharmacokinetic drug evaluation of safinamide mesylate for the pp. 789–799, https://doi.org/10.1021/acs.cgd.5b01383.
treatment of mid-to-late stage Parkinson’s disease, Expet Opin. Drug Metabol. [71] H.J. Tangeman, J.H. Patterson, Extended-release metoprolol succinate in chronic
Toxicol. 13 (2017) 693–699, https://doi.org/10.1080/17425255.2017.1329418. heart failure, Ann. Pharmacother. 37 (2003) 701–710, https://doi.org/10.1345/
[61] R.G. Fariello, Safinamide, Neurotherapeutics 4 (2007) 110–116, https://doi.org/ aph.1C286.
10.1016/j.nurt.2006.11.011. [72] M.J. Kendall, Metoprolol-controlled release, zero order kinetics, J. Clin. Pharm.
[62] C.J. Andres, R.L. Treanor, Patents in drug discovery: case studies, examples, and Therapeut. 14 (1989) 159–179, https://doi.org/10.1111/j.1365-2710.1989.
simple steps medicinal chemists can take to protect hard-won intellectual property, tb00235.x.
in: Annual Reports in Medicinal Chemistry, Elsevier Inc., 2010, pp. 449–463, [73] Anonymous. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/20981
https://doi.org/10.1016/S0065-7743(10)45027-7. 6Orig1s000,209817Orig1s000ChemR.pdf. (Accessed 10 April 2020).
[63] E. Davison, J.I.D. Wells, Amlodipine Besylate for Treatment of Heart Disease and [74] S.K. Tanaka, J. Steenbergen, S. Villano, Discovery, pharmacology, and clinical
Hypertension (EP 1987-302767), Pfizer Ltd., 1990. profile of omadacycline, a novel aminomethylcycline antibiotic, Bioorg. Med.
[64] S.Y. Lee, J.R. Kim, J.A. Jung, W. Huh, M.Y. Bahng, J.W. Ko, Bioequivalence Chem. 24 (2016) 6409–6419, https://doi.org/10.1016/j.bmc.2016.07.029.
evaluation of two amlodipine salts, besylate and orotate, each in a fixed-dose [75] G.G. Fuentes, A.L. Bonde-Larsen, J.D.C. Lopez-Bachiller, C.S. Rodriguez, Y.F. Sainz,
combination with olmesartan in healthy subjects, Drug Des. Dev. Ther. 9 (2015) Preparation of Solifenacin Salts (WO 2011-EP61314), Ragactives, S.L.U., Spain,
2811–2817, https://doi.org/10.2147/DDDT.S82820. 2012.
[65] T.H. Ha, C.H. Park, W.J. Kim, H.S. Oh, S.H. Cho, C.K. Kim, K.H. Suh, G.S. Lee, [76] M.D. Dowle, I.H. Coates, Heterocyclic Compounds and Pharmaceuticals (GB 1983-
Novel Crystalline Bepotastine Metal Salt Hydrate, Method for Preparing Same, and 15564), Ger. Offen, Glaxo Group Ltd., UK, 1983.
Pharmaceutical Composition Comprising Same (WO2008123701A1), Hanmi [77] B.T. Golding, The story of rucaparib (rubraca), in: J. Fischer, C. Klein, W.
Pharm. Co., Ltd., 2008. E. Childers (Eds.), Successful Drug Discovery, Wiley-VCH Verlag GmbH & Co.
[66] K.H. Cho, H.-G. Choi, Development of novel bepotastine salicylate salt KGaA, 2019, pp. 201–223, https://doi.org/10.1002/9783527814695.ch8.
bioequivalent to the commercial bepotastine besilate in beagle dogs, Drug Dev. [78] J. Etter, High Dosage Strength Tablets of Rucaparib (US 9987285 B2), Clovis
Ind. Pharm. 39 (2013) 901–908, https://doi.org/10.3109/ Oncology, Inc., USA, 2018.
03639045.2012.717295. [79] J.M. Andersen, Suspected vein irritation from i.v. pentamidine isethionate, Am. J.
[67] D.S. Lim, Y.S. Youn, S.J. Kwack, H.M. Kwak, S.K. Lim, J.Y. Kim, Y.M. Um, J.D. Lee, Health Syst. Pharm. 53 (1996) 185, https://doi.org/10.1093/ajhp/53.2.185.
J.H. Hyeon, Y.J. Kim, H.S. Kim, B.-M. Lee, Comparative efficacy and [80] A.F.E.J. Lai, M.A. Vrede, R.M. Soetosenojo, A.F.R.F. Lai, Pentamidine, the drug of
bioequivalence of novel H1-antihistamine bepotastine salts (nicotinate and choice for the treatment of cutaneous leishmaniasis in Surinam, Int. J. Dermatol.
41 (2002) 796–800, https://doi.org/10.1046/j.1365-4362.2002.01633.x.

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