Crystal Structure and Solid-State Properties of 3,4-Diaminopyridine Dihydrogen Phosphate and Their Comparison with Other Diaminopyridine Salts Nathalie Mahe ́ , † Be ́ atrice Nicolaï, † Hassan Allouchi, ‡ Maria Barrio, § Bernard Do, ∥,⊥ Rene ́ Ce ́ olin, †,§ Josep-Lluis Tamarit, § and Ivo B. Rietveld* ,† † EAD Physico-chimie Industrielle du Me ́ dicament (EA4066), Faculte ́ de Pharmacie, Universite ́ Paris Descartes, 4, Avenue de l’Observatoire, 75006 Paris, France ‡ Recherche et Innovation en Chimie Me ́ dicinale (RICM, ISP-UMR 1282), Faculte ́ de Pharmacie, Universite ́ Franç ois Rabelais, 31 Avenue Monge, 37200 Tours, France § Grup de Caracterització de Materials (GCM), Departament de Fisica i Enginyeria Nuclear, Universitat Polite ́ cnica de Catalunya, ETSEIB, Diagonal 647, 08028 Barcelona, Spain ∥ Etablissement Pharmaceutique de l'Assistance Publique-Hô pitaux de Paris, Agence Ge ́ ne ́ rale des Equipements et Produits de Sante ́ , 7, rue du Fer a ́ Moulin, 75005 Paris, France ⊥ Chimie Analytique, Faculte ́ de Pharmacie, Universite ́ Paris Descartes, 4, Avenue de l’Observatoire, 75006 Paris, France * S Supporting Information ABSTRACT: 3,4-Diaminopyridine is an active pharmaceutical ingredient for the treatment of Lambert−Eaton myasthenic syndrome (LEMS). It is 3,4-diaminopyridine dihydrogen phosphate that has become the active ingredient of choice. As part of a larger study for the development of this drug, solid-state studies have been carried out. At room temperature, the crystals are monoclinic (C2/c). Dihydrogen phosphate anions H 2 PO 4 − form infinite chains parallel to the b axis, and these chains can be considered as macroanions (H 2 PO 4 )∞. The organic cations form hydrogen bonds with the macroanions bridging them together. A negative thermal expansion is observed along the [103] direction in the crystal, which coincides with the direction of chains of interchanging anions and cations. The crystal packing shows similarities with the hydrogen tartrate salt as illustrated by a Hirshfeld surface analysis. This phosphate and this tartrate salt are also the two diaminopyridine salts that have been selected for therapeutic use because of their appropriate physical properties. ■ INTRODUCTION 3,4-Diaminopyridine (C 5 H 7 N 3 , cf. Figure 1; from here on, 3,4- DAP) is an efficient drug to treat muscular weakness caused by the Lambert−Eaton myasthenic syndrome (LEMS) first described by Lambert, Eaton, and Rooke in 1956. 1−7 It has been shown to block the voltage-dependent K-channels; 5,8 however, the molecule is too unstable for commercializa- tion. 6,7,9 Six 3,4-DAP salts have been produced with counter- ions in accordance with FDA regulations (hydrogen chloride, hydrogen bromide, sulfate, dihydrogen phosphate, tartrate, and benzoate). 7,8 These salts are more stable than the molecule itself; the involvement of the lone electron pair on the pyridine nitrogen in a charge-assisted hydrogen bond reduces the possibility of oxidation for 3,4-DAP. 7,9 Among the six salts, only two (dihydrogen phosphate and hydrogen tartrate) have been selected for medical use because they appear physically and chemically stable in time, possess little hygroscopicity, have excellent solubility in water, and have an acceptable pH in saturated solution. 7 Physical−chemical stability and bioavailability are strongly influenced by the crystalline form of a substance. 10 A survey of the literature demonstrated that a number of crystal structures of 3,4-DAP salts have been determined together with the structure of the free base. 11 Crystal structures involving the cation 3,4-DAPH + (Figure 1) include dinitrosalicylate, 12 hydrogen squarate, 13 hydrogen succinate, 14 4-nitro-benzoate- Received: September 28, 2012 Revised: December 13, 2012 Published: December 21, 2012 Article pubs.acs.org/crystal © 2012 American Chemical Society 708 dx.doi.org/10.1021/cg3014249 | Cryst. Growth Des. 2013, 13, 708−715