Published: May 23, 2011 r2011 American Chemical Society 774 dx.doi.org/10.1021/op100294f | Org. Process Res. Dev. 2011, 15, 774–782 ARTICLE pubs.acs.org/OPRD Towards the Determination of the Solubilities of the Two Enantiotropically Related Crystallographic Forms of Etiracetam in Methanol Christelle Herman,* ,† Benoît Haut, † V  eronique Halloin, † Val  erie Vermylen, ‡ and Tom Leyssens § † Universit  e Libre de Bruxelles, Transfers, Interfaces and Processes Department, Chemical Engineering Unit, 50 Avenue Franklin D-Roosevelt, CP 165/67, 1050 Bruxelles, Belgium ‡ UCB Pharma, 60 All  ee de la Recherche, 1070 Braine l’Alleud, Belgium § Universit  e Catholique de Louvain, Institute of Condensed Matter and Nanosciences, 1 Place Louis Pasteur, 1348 Louvain-La-Neuve, Belgium b S Supporting Information ABSTRACT: This contribution focuses on the presentation and the comparison of five experimental methods for the determination of the solubilities of the two enantiotropically related crystallographic forms of etiracetam (racemic intermediate to the synthesis of leviteracetam, Keppra, UCB Pharma) in methanol. The five experimental methods can be divided into two sets of methods, depending on whether the method is isothermal or whether the temperature varies during the experiment. The results show that the most accurate and reliable determination of the solubility curves of the two crystallographic forms is obtained when combining the different methods. Using a single method limits the amount of information gained, does not allow for a verification of the obtained data, and can even limit the range for which solubility data can be experimentally determined. The results allow distinguishing the solubilities of the stable and the metastable forms and hence confirming the enantiotropic relationship of the two crystallographic forms. The transition temperature is determined to be equal to 30 °C, which confirms previous findings. 1. INTRODUCTION Crystallization by cooling followed by the separation of the crystals from the resulting suspension is the most frequent method used to achieve the required purity of active pharma- ceutical ingredients (API). 1,2 However, this unit operation is still poorly understood, leading to a lack of strategies for its design, optimization and control. Moreover, depending on the pharma- ceutical compound and the crystallization process applied, different crystallographic forms may appear in the suspension. 3 Some of these forms may be undesirable from a pharmaceutical point of view. New crystallization methodologies and online control techniques are therefore developed to ensure that the solid form of interest is isolated. 4,5 The determination of the physicochemical characteristics of all the crystallographic forms possibly present in suspension is thus crucial for the crystal- lization process control and its optimization. One such property is the solubility in a given solvent, which forms the basis for the development of a robust crystallization process. The solubility of the compound A in the solvent B at the temperature T is defined as the concentration of the dissolved compound A in the liquid phase, composed of the solvent B in which the compound A is dissolved, when this liquid phase is in equilibrium with macroscopic crystals of the compound A, at the temperature T. Hereafter, the compound A dissolved is called the solute, the crystals of A are called the solid phase and the liquid mixture of A and B is called the solution. In this paper, the solubility is expressed in grams of solute per gram of solution: g/g sol . The solubility is also called the saturation concentration. The solubility can generally be determined by the measurement of the maximum mass of macroscopic crystals that can be dissolved in a given mass of solvent at the temperature T. 2 Over recent years, several experimental methods for the determination of the solubility have been described in the literature. 6À9 The choice of one method over another depends on many factors: the soluteÀsolvent system studied, the available technical and ana- lytical devices, the operator’s expertise, the available time, or the accuracy and precision required. 10 When a pure compound can crystallize in several crystal- lographic forms, only one of these is stable at a given temperature unless the solid forms are enantiotropically related, in which case a transition temperature, a temperature at which both forms are stable, exists. Thermodynamically, only the solubility of the stable crystallographic form, hereafter referred to as thermody- namic solubility, can be defined and determined. However, the solubility of metastable crystallographic forms, hereafter referred to as metastable solubility, can also be experimentally determined if the experiment duration is long enough for a metastable equilibrium state to be established between the solid and the liquid phases and short enough to avoid a polymorphic transition from the metastable form towards the more stable one. 7,11 Both the time needed for equilibrium to be reached and the time required for the polymorphic transition to occur are not only temperature dependent but also dependent on external Received: November 5, 2010