Formoterol, (+/−)N-[2-hydroxy-5-[1-hydroxy-2-[[2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl]phenyl]formamide, is a highly potent and β2-selective adrenoceptor agonist having a long lasting bronchodilating effect when inhaled. It is represented by the following structural formula:

Formoterol was first disclosed in Japanese patent application 13121 (equivalent to U.S. Pat. No. 3,994,974), wherein formoterol is synthesised by N-alkylation using a phenacyl bromide.
Formoterol has two chiral centres, each of which can exist in two different configurations. This results in four different combinations: (R,R), (S,S), (S,R) and (R,S). Formoterol is commercially available as a racemic mixture of 2 enantiomers (R,R) and (S,S) in a 1:1 ratio. The generic name formoterol always refers to its racemic mixture. Trofast et al. (Chirality, 1, 443, 1991) reported on the potency of these isomers, showing a decrease in the order of (R,R)>(R,S)≧(S,R)>(S,S). The (R,R) isomer, also known as arformoterol, being 1000 fold more potent than the (S,S) isomer.
Arformoterol is commercialised by Sepracor as a tartrate salt under the brand name Brovana®. The chemical name for arformoterol tartrate is N-[2-hydroxy-5-[(1R)-1-hydroxy-2-[[(1R)-2(4-methoxyphenyl)-1-methylethyl]amino]ethyl]phenyl]formamide, (2R,3R)-2,3-dihydroxybutanedioate (1:1 salt), and it is represented by the following structural formula:

Various processes for the preparation of formoterol, its enantiomers, related compounds, and their pharmaceutically acceptable salts are disclosed in U.S. Pat. Nos. 3,994,974; 5,434,304; 6,268,533 and 6,472,563; Chem. Pharm. Bull. 26, 1123-1129 (1978); Chirality 3, 443-450 (1991); Drugs of the Future 2006, 31(11), 944-952; and WO 2008/035380A2. U.S. Pat. No. 6,268,533 describes salts of arformoterol and a method to produce them; amongst these salts L-tartrate was used to produce R,R-formoterol L-tartrate (hereinafter referred to as arformoterol tartrate). U.S. Pat. No. 6,268,533 further discloses polymorphic forms of arformoterol tartrate referred to as P1 and P2, characterized by Differential Scanning calorimetry (DSC). Polymorph P1 in pure form exhibits a peak at about 193° C. on DSC and a solubility in water at 25° C. to the extent of 15.4 mg/mL. Polymorph P2 in pure form exhibits a transition peak at about 179° C. on DSC and a solubility in water at 25° C. to the extent of 26.7 mg/mL.
U.S. Pat. No. 6,472,563 discloses a further crystalline polymorph of arformoterol tartrate, designated as “polymorph C”, and which is reported to be useful for the preparation of highly pure “form A” of arformoterol. U.S. Pat. No. 6,472,563 renamed the polymorphs P1 and P2 of U.S. Pat. No. 6,268,533 as “polymorph A” (i.e. form A) and “polymorph B”, respectively. The XRPD peaks and the FTIR spectrum for the polymorphic forms A, B and C are also disclosed in U.S. Pat. No. 6,472,563.
Polymorphs are different crystalline forms of the same pure substance in which the molecules have different spatial configurations relative to each other in the solid state. In accordance with regulatory requirements of the U.S. and other countries, e.g. the FDA's Good Manufacturing Practice (“GMP”) requirements, when preparing pharmaceutical compositions containing active ingredients for administration to mammals, there is a need to produce crystalline forms, or polymorphs, which are as pure and as stable as possible. Differences in the chemical and physical properties of polymorphic forms of an active ingredient such as melting point, chemical reactivity and apparent solubility can have a direct effect on the ability to process and/or manufacture the active ingredient and its pharmaceutical compositions, as well as on its stability, dissolution and bioavailability.
Arformoterol tartrate is commercialised as a sterile, clear and colourless aqueous solution for inhalation. Therefore, it is desirable to develop a pure and stable polymorphic form of arformoterol tartrate, which shows reproducibly uniform crystalline form and high solubility, which results in better properties for use in pharmaceutical preparations, particularly in the preparation of liquid pharmaceutical compositions. The preparation of new polymorphic forms and solvates of pharmaceutically useful compounds also provides a new opportunity to improve the performance characteristics of pharmaceutical products and enlarges the repertoire of materials that formulation scientists have available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic.