Keynote (green)Recent developments in pharmaceutical salts: FDA approvals from 2015 to 2019
Introduction
Drugs with poor aqueous solubility are liable to have low and variable oral bioavailability 1, 2. A recent estimate states that more than 60% of new molecular entities (NMEs) possess suboptimal aqueous solubility, which might be the reason for their unpredictable clinical response 3, 4. Hence, it is important to identify solubility enhancement strategies for NMEs.
From an analysis of present-day drugs [in the US Food and Drug Administration (FDA) Orange Book], it is evident that ∼43% of the total is represented by pharmaceutical salts [1]. The salification of an active pharmaceutical ingredient (API) is the preferred method for increasing the solubility and thereby the dissolution rate of ionizable drugs [5]. The salt forms of APIs have a long and successful track record of providing first-in-class drugs with improved physicochemical and biopharmaceutical properties in all therapeutic areas [6].
The Compendium of Chemical Terminology (IUPAC Gold Book) defines salt as “a chemical compound consisting of an assembly of cations and anions” [7]. A pharmaceutical salt comprises either a cationic or anionic API and an organic or inorganic counterion (salt former). The FDA Orange Book defines salt as “any of numerous compounds that result from replacement of part or all of the acid hydrogen of an acid by a metal or a radical acting like a metal; an ionic or electrovalent crystalline solid” [8]. However, according to the current regulatory scheme, different salt forms of the same API are considered as different active ingredients. This is because of the ability of different counterions to impart a unique and special advantage to the API over its parent free base form.
Section snippets
The core of this review
This review aims to provide critical analysis of FDA-approved ‘Pharmaceutical Salts’ from 2015 to 2019. Out of the 129 NMEs approved over these five years, 61 (accounting 48%) were pharmaceutical salts. A close look at the distribution of various counterions in these API salt forms indicates that hydrochloride (HCl) is the most predominant (29%), followed by sodium (13%), with 16 different salt-formers in total. To address the central point of this review, the approved salt forms of NMEs are
Distribution of new drug approvals from 2015 to 2019
The FDA's Center for Drug Evaluation and Research (CDER) has approved a total of 219 new drugs in the calendar years 2015–2019. These drugs include 129 NMEs and 90 new therapeutic biologics. The distribution of pharmaceutical salts among these 129 NMEs is analyzed in Fig. 3.
The breakdown of new drugs into NMEs and new biological applications (NBAs) is depicted in Fig. 3a. The highest number of new drugs was approved in the year 2018 (n = 58), whereas the lowest number was approved in the year
FDA-approved pharmaceutical salts from 2015 to 2019
The relative abundance of counterions in the approved salt forms of NMEs is discussed below. Furthermore, the distribution of salts in accordance with their therapeutic indications and year of approval is detailed in subsequent sections.
Hydrochloride salts
The chemical structures of HCl salts approved during 2015–2019 are depicted in Fig. 5. Six APIs were approved in 2015, namely ivabradine, daclatasvir, rolapitant, cariprazine, tipiracil and alectinib. Ivabradine (compound 1 in Fig. 5) is a nitrogen heterocycle belonging to the class of benzo[d]azepin-2(3H)-ones, used for the symptomatic management of angina pectoris and chronic heart failure. To address its physicochemical properties, researchers have prepared its HCl, oxalate and pamoate
Drug designation of salts approved by the FDA between 2015 and 2019
There is a need to accelerate the development and approval of innovative, novel drugs, which can be achieved through drug-designation pathways such as first-in-class, orphan, fast track, breakthrough, priority review, accelerated approval and first cycle. These pathways effectively speed up the development of new drugs by enhancing the interactions between CDER staff and drug developers. The development paths of the pharmaceutical salts that were approved between 2015 and 2019 are discussed in
Conclusion and outlook
In conclusion, this review highlights FDA-approved pharmaceutical salts over the past five years (2015–2019). The physicochemical properties of APIs and NMEs are crucial for their in vivo performance, commercial manufacture and patent protection. Poor physical and material properties are challenging, and partly responsible for decreased productivity in the drug discovery and development process. Pharmaceutical salts are one way to fill this gap, and they can be used to modulate and improve API
Sonali S. Bharate (nee Sonali R. Naikwade) earned her PhD in Pharmaceutics from SNDT Women's University, Mumbai, India, in 2010. She worked for around two years as an Assistant Professor in Pune. In June 2013, she joined CSIR- Indian Institute of Integrative Medicine in Jammu, where she was actively engaged in the pre-formulation and formulation of new chemical entities and phytopharmaceuticals. She was awarded the BioCARe grant in 2017 from the Department of Biotechnology. Currently, she is
References (81)
Pharmaceutical aspects of salt and cocrystal forms of APIs and characterization challenges
Adv. Drug Deliv. Rev.
(2017)Salt formation to improve drug solubility
Adv. Drug Deliv. Rev.
(2007)Use of pharmaceutical salts and cocrystals to address the issue of poor solubility
Int. J. Pharm.
(2013)An integrated approach to the selection of optimal salt form for a new drug candidate
Int. J. Pharm.
(1994)- et al.
Pharmaceutical evaluation of early development candidates ‘the 100 mg-approach’
Int. J. Pharm.
(2004) - et al.
Pharmaceutical salts: a summary on doses of salt formers from the Orange Book
Eur. J. Pharm. Sci.
(2013) Pharmaceutical salts
J. Pharm. Sci.
(1977)Inclusion complexation of ziprasidone mesylate with beta-cyclodextrin sulfobutyl ether
J. Pharm. Sci.
(1998)Enhanced bioavailability of piroxicam via salt formation with ethanolamines
Int. J. Pharm.
(2005)Role of pharmacokinetics in the discovery and development of indinavir
Adv. Drug Deliv. Rev.
(1999)
Properties of FDA-approved small molecule protein kinase inhibitors: a 2020 update
Pharmacol. Res.
Patent review of manufacturing routes to recently approved PARP inhibitors: Olaparib, rucaparib, and niraparib
Org. Process Res. Dev.
Patent review of manufacturing routes to oncology drugs: carfilzomib, osimertinib, and venetoclax
Org. Process Res. Dev.
Drugs as materials: valuing physical form in drug discovery
Nat. Rev. Drug Discov.
Drug delivery strategies for poorly water-soluble drugs
Expert Opin. Drug Deliv.
Supersaturation potential of salt, co-crystal, and amorphous forms of a model weak base
Cryst. Growth Des.
Compendium of Chemical Terminology – Gold Book (Version 2.3.3; 24-02-2014)
Polymorphs, salts, and cocrystals: what's in a name?
Cryst. Growth Des.
Impact of preformulation on drug development
Expert Opin. Drug Deliv.
Salt selection and optimisation procedures for pharmaceutical new chemical entities
Org. Process Res. Dev.
Trends in active pharmaceutical ingredient salt selection based on analysis of the Orange Book database
J. Med. Chem.
Preparation of water-soluble compounds through salt formation
Non-clinical toxicological considerations for pharmaceutical salt selection
Expert Opin. Drug Metab. Toxicol.
Maleate nephrotoxicity: mechanisms of injury and correlates with ischemic/hypoxic tubular cell death
Am. J. Physiol. Renal Physiol.
Clinical and pharmacokinetic comparison of cefuroxime sodium and cefuroxime lysine in the treatment of lower respiratory tract infections
J. Antimicrob. Chemother.
Unexpected side effects of cefuroxime lysine, a new cefuroxime salt
J. Antimicrob. Chemother.
Ziprasidone mesylate (Geodon for injection): the first injectable atypical antipsychotic medication
Proc. (Bayl. Univ. Med. Cent.)
pH-dependent oral absorption of L-735,524, a potent HIV protease inhibitor, in rats and dogs
Drug Metab. Dispos.
Bioinequivalence of erythromycin ethylsuccinate and enteric-coated erythromycin pellets following multiple oral doses
J. Clin. Pharmacol.
Comparative bioavailability evaluation of erythromycin base and its salts and esters I. Erythromycin estolate capsules versus enteric-coated erythromycin base tablets
J. Clin. Pharmacol.
Analysis of relationships between solid-state properties, counterion, and developability of pharmaceutical salts
AAPS PharmSciTech
Crystal structures and thermodynamic properties of new atypical antipsychotic cariprazine and its hydrochloride
Crystallogr. Rep.
Australian Public Assessment Report for Migalastat
Review of eravacycline, a novel fluorocycline antibacterial agent
Drugs
Cited by (57)
Impact of carrier particle surface properties on drug nanoparticle attachment
2024, International Journal of PharmaceuticsElucidating the effect of salt incorporation in tablets on tablet disintegratability
2024, International Journal of PharmaceuticsThe free hydralazine anti-hypertensive drug and new salts with improved solubility
2023, Journal of Molecular StructureHalide counterions in FDA-approved pharmaceutical salts
2023, Journal of Drug Delivery Science and TechnologyNovel drug-drug salts of enoxacin with enhanced antibacterial activity: Insights from solubility and lipid-water partition coefficient
2023, Journal of Molecular Liquids
Sonali S. Bharate (nee Sonali R. Naikwade) earned her PhD in Pharmaceutics from SNDT Women's University, Mumbai, India, in 2010. She worked for around two years as an Assistant Professor in Pune. In June 2013, she joined CSIR- Indian Institute of Integrative Medicine in Jammu, where she was actively engaged in the pre-formulation and formulation of new chemical entities and phytopharmaceuticals. She was awarded the BioCARe grant in 2017 from the Department of Biotechnology. Currently, she is working as an Associate Professor in pharmaceutical sciences at Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM's NMIMS, Mumbai.