Mini-review Pharmaceutical salts and cocrystals involving amino acids: A brief structural overview of the state-of-art Anaëlle Tilborg * , Bernadette Norberg, Johan Wouters Unité de Chimie Physique Théorique et Structurale, Dept. Chemistry, University of Namur, 61, Rue de Bruxelles, B-5000 Namur, Belgium article info Article history: Received 24 May 2013 Received in revised form 22 November 2013 Accepted 27 November 2013 Available online 18 January 2014 Keywords: Therapeutic salt Pharmaceutical cocrystal Amino acids Active pharmaceutical ingredient (API) Drug substance Coformer Patent rights abstract Salification of new drug substances in order to improve physico-chemical or solid-state properties (e.g. dissolution rate or solubility, appropriate workup process, storage for further industrial and marketing development) is a well-accepted procedure. Amino acids, like aspartic acid, lysine or arginine take a great part in this process and are implicated in several different formulations of therapeutic agent families, including antibiotics (amoxicillin from beta lactam class or cephalexin from cephalosporin class), NSAIDs (ketoprofen, ibuprofen and naproxen from profen family, acetylsalicylic acid) or antiarrhythmic agents (e.g. ajmaline). Even if more than a half of known pharmaceutical molecules possess a salifiable moiety, what can be done for new potential drug entity that cannot be improved by transformation into a salt? In this context, after a brief review of pharmaceutical salts on the market and the implication of amino acids in these formulations, we focus on the advantage of using amino acids even when the target compound is not salifiable by exploiting their zwitterionic potentialities for cocrystal edification. We summarize here a series of new examples coming from literature to support the advantages of broadening the application of amino acids in formulation for new drug substances improvement research for non- salifiable molecules. Ó 2013 Elsevier Masson SAS. All rights reserved. 1. Salts 1.1. Why using salt forms in drugs substances? Since modern medication research has produced valuable drug compounds, the problem of appropriate administration of these molecules has been posed. In fact, even if the compound is considered as biologically efficient after a series of molecular tests, its physico-chemical and solid-state lacks of performance can break the preformulation development. Since a while, the main pathway for more than an estimated half of all concerned potential thera- peutic molecules (i.e. those possessing a (de)protonation center) has been to turn them into a properly-administrated salt with a convenient salt agent [1e3]. Salt formulation offers great convenience for drug administra- tion, essentially by providing for concerned molecules an improved physico-chemical fitted pattern for further application. If one looks carefully through this improvement, the main constituent of the promotion lies in the increase of dissolution rate and solubility in water. In fact, it seems legit that an ionizable species like a salt will be more soluble in water and thus afford a better chance of reaching the biological target place, regardless of the required administra- tion pathway (e.g. intravenous, oral, .) [1,4,5]. But other objectives can also be achieved by forming a salt. First, pure solid-state considerations are to be taken into account: more reliable products, chemically stable and easy to recrystallize and purify formulations can be obtained by this way [1]. Polymorphism issues for some compounds can be avoided. In the synthetic devel- opment process, working with salts can be an economic means to separate an intermediate from side products. Similarly like for solu- bility properties, compatibility with selected excipients, biological performance and safety concerns can also be modified by salification. By all these modifications, a new salt formulation certainly opens a new field of therapeutic applications. Moreover, it can valuably ap- peal for an extension of patent rights: approval will be simplified because of the already stating knowledge of the effects of the newly drug form, with background coming from the early product [3e5]. 1.2. Which salt agent can be selected to form a reliable pharmaceutical salt? A lot of aspects have to be considered when a salt formation is envisaged for a drug development. In fact, so many additional costs will be engaged if the salt agent proves to be non-suitable for the * Corresponding author. E-mail addresses: anaelle.tilborg@unamur.be (A. Tilborg), bernadette.norberg@ unamur.be (B. Norberg), johan.wouters@unamur.be (J. Wouters). Contents lists available at ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech 0223-5234/$ e see front matter Ó 2013 Elsevier Masson SAS. All rights reserved. http://dx.doi.org/10.1016/j.ejmech.2013.11.045 European Journal of Medicinal Chemistry 74 (2014) 411e426