Elsevier

Drug Discovery Today

Volume 26, Issue 2, February 2021, Pages 384-398
Drug Discovery Today

Keynote (green)
Recent developments in pharmaceutical salts: FDA approvals from 2015 to 2019

https://doi.org/10.1016/j.drudis.2020.11.016Get rights and content

Highlights

  • Around half of the new molecular entities approved by the US Food and Drug Administration are pharmaceutical salts.

  • The drug-approval database contains 61 pharmaceutical salts with diverse counterions.

  • Salts in each class are categorized according to their therapeutic indication and approval date.

  • The counterion selection and its technical superiority over the free base is discussed.

  • Around half of the FDA approved new molecular entities are pharmaceutical salts.

  • Drug approval database contains 61 pharmaceutical salts comprising diverse counterions.

  • Salts under each class categorized as per the therapeutic indication and approval date.

  • Selection of counterion and its technical superiority over the free base is discussed.

Around half of the new molecular entities approved by the US Food and Drug Administration (FDA) are pharmaceutical salts. The pharmaceutical salts have been on a continuous growth trajectory since the approval of the first salt form in 1939. This review aims to provide updates on pharmaceutical salts approved by the FDA between 2015 and 2019. The five-year drug-approval database contains 61 pharmaceutical salts, featuring a diverse range of counterions; however, hydrochlorides are the most abundant. The chemical structures of all pharmaceutical salts in each class are presented here, along with their therapeutic indications and date of approval. The reason behind the selection of a particular counterion and the technical superiority achieved by the salt form over the free active pharmaceutical ingredient base are also discussed.

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

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    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.

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