Solvent crystallization, role polymorphism

Threlfall T. Crystallization of Polymorphs Thermodynamic Insight into the Role of Solvent. Org Process Res Dev WOO, 4 384—390. 

The general considerations above highlight the importance of nucleation and the role of environmental conditions (e.g. solvent, temperature) in the crystallization of polymorphs as well as their interconversions. These areas continue to be the subject of intense interest especially in the context of polymorphic control in crystallization. 

The choice of solvent plays an important role in the crystallization of any substance. Properties of the solvent such as hydrogen-bonding capability, polarity, dipole moment, boiling point, dielectric constant, viscosity, density, and so on influence the crystallization of polymorphs. Fnrthermore,... 

Practical considerations may also arise. Supramolecular functionality introduced to control crystal architecture must be added without degrading the fundamental molecular properties of primary interest. Co-crystals offer an alternative approach for controlling crystal architecture without necessarily modifying the primary molecule of interest. In addition, we must recognize the role of the solvent from which the crystal grows. The occurrence of solvates and polymorphs, particularly relevant in the pharmaceutical industry, is still a relatively poorly understood aspect of crystal chemistry. The manner in which synthons are modified from normal geometries in non-crystalline organic structures is also yet to be explored fully. 

Crystal solvates exhibit a wide range of behaviour depending on the interaction between the solvent and the crystal stmcture. With some solvates the solvent plays a key role in holding the crystal together for example, it may he part of a hydrogen-honded network within the crystal stmcture. These solvates are very stable and are difficult to desolvate. When these crystals lose their solvent they collapse and recrystallise in a new crystal form. We can think of these as polymorphic solvates. In other solvates, the solvent is not part of the crystal bonding and merely occupies... 

When some dmgs crystallise they may entrap solvent in their crystals and so form different crystal solvates. In some solvates the solvent plays an important role in holding the crystal together. These solvates, called polymorphic solvates, are very stable, and when they lose their solvent they recrystallise in a different crystal form. In other solvates, referred to as pseudopoly-morphic solvates, the solvent is not part of the crystal bonding and merely occupies voids in the crystal. These solvates can lose their solvent more readily and desolvation does not alter the crystal lattice. Solvated and anhydrous forms of a drug differ in... 

Crystallization plays an important role in the synthesis, scale-up, processing, formulation, and stability of active pharmaceutical ingredients (API) (Rodriguez-Hornedo and Murphy, 1999 Shekunov and York, 2000 Rodriguez-Hornedo and Sinclair, 2002). Crystallization from solvent is a particularly important process, as this is the primary means of purihcation during the intermediate and hnal stages of drug synthesis. Moreover, solution crystallization determines the hnal solid-state modihcation of the API namely polymorphs, solvates, and hydrates. 

The rate and mechanisms by which crystallization occurs are determined by numerous thermodynamic, kinetic, and molecular recognition factors. (Nyvlt et al., 1985 Sohnel and Garside, 1992 Mersmann, 1995 Mullin, 2001 Myerson, 2002) These factors are summarized in Figure 1. The solvent plays a key role in crystallization as many of the factors depend directly on the solvent (Davey, 1982). Therefore, the intricate balance between thermodynamic, kinetic, and molecular recognition must be considered when designing experiments for polymorph screening, selection, and isolation. 

In this chapter, the effects of these thermodynamic, kinetic, and molecular recognition phenomena on crystallization and the role of solvent in these processes will be described. The role of solvent on crystallization, polymorphic outcome, and phase transformations will also be discussed. Experimental approaches for polymorph screening will be presented with an emphasis on the important considerations and strategies for solvent selection. 

Theoretical and experimental studies of the role of solvent on polymorphic crystallization and phase transformations abound in the literature of the last few years and some pertinent examples are described here. For solvent-mediated transformations, the driving force is the difference in solubility between different polymorphs. An important earlier paper on the kinetics of such phase transformations [51 ] described a model featuring two kinetic processes in sohd to solid phase changes via a solution phase, namely dissolution of the metastable phase and growth of the stable one. 

In other instances, it is the solvent of crystallization which plays a decisive role in orienting the crystallization toward one or the other polymorph. Such solvent dependant crystallization is well documented in the case of amylose (7) where minute changes in solvent/precipitant ratio have a dramatic effe ct on shifting the recrystallized amylose among three polymorps amylose A,B and V. 

The phenomenon of polymorphism demonstrates that metastable erystal struetures are observed, and it is not always obvious that sueh crystal structures are metastable. The energy differences between different polymorphs crystallized out of different solvent are small, and those between concomitant polymorphs presumably are very small. Kinetics must play a major role in determining which of the approximately equi-energetic hypothetical crystal structures are actually observed. How do the kinetics of nucleation and growth, and the variations with crystallization conditions, affect which thermodynamically feasible crystal structures are actually seen How can this be incorporated in the crystal structure prediction model to produce a polymorph prediction model ... 

Crystallization experiments from solution, using several techniques (e.g., (i), (ii), (iii), and (v) in Table 5.1) with a variety of solvents and solvent mixtures. Due to the practical relevance of hydrates, water and water/solvent mixtures should always be included. Suspension equilibration and slow coohng experiments play a particular role in finding the thermodynamically stable form, which is often the most important aim of a polymorph screen. 

Syndiotactic poly(styrene) displays a complex polymorphic behavior that reflects the specific role played by solvents. Four crystalline forms have been reported.(289,290) The a and p forms can be obtained from the melt (or glass), depending on the crystallization conditions.(291) Both structures comprise planar zigzag chains that have the same identity period of 5.1 A. The a form has a trigonal unit cell while the p form is orthorhombic. The P form can also be produced by crys-taflization from solution.(292,293) The y and 8 structures develop after interaction with solvent. In contrast to the all trans bond orientation of the a and p structures, the chains in the y and 8 crystals adopt a ttggttgg sequence of bond orientation. Thus a helical ordered structure evolves. This structure is similar to the crystalline chain conformation of syndiotactic poly(propylene).(294) The difference between the y and the 8 polymorphs is that in the former the sample is completely dried, while the solvent is included in the 8 form. It therefore represents a clathrate type structure. The formation of these structures is, thus, solvent specific.(292,293,295,296) The... 

Role of the nature and the quality of solvent on crystallization Most of the drugs on the market are obtained as a defined crystalline structure and formulated as solid dosage forms. It is well known that a molecule can crystallize to give different crystalline structures displaying what is called polymorphism. The crystal structures may be anhydrous or may contain a stoichiometric number of solvent molecules leading to the formation of solvates (hydrates in case of water molecules). Pseudopolymorphism is the term used to describe this phenomenon. 

---