Crystallization solvate pseudopolymorphs

An understanding of crystallization is important for the systematic development of crystal engineering, but it is not a simple phenomenon and many would agree that it is still far too difficult to study in a rigorous way, either experimentally or theoretically. However, indirect approaches to the study of crystallization are evolving. Three possible types of crystals that may be pertinent to this endeavor are (1) polymorphs - these represent cases of alternative crystallization, (2) pseudosymmetric structures with multiple molecules in the asymmetric unit - these could represent cases of incomplete crystallization, and (3) solvated crystals or pseudopolymorphs -these may represent cases of interrupted crystallization. These three scenarios are now sketched very briefly and the treatment given is necessarily selective. 

The most common crystalline forms are polymorphs, hydrates, and solvates (pseudopolymorphs). Polymorphs are formed when a substance crystallizes in two or more crystal structures. Polymorphism significantly impacts on physicochemical properties of materials, such as stability, density, melting point, solubility, bioavailability, and so on. Hence the characterization of all possible polymorphs, identifying the stable (thermodynamic) polymorph, and design of reliable processes for consistent production are critical in modem day drug development. 

The phenomenon of pseudopolymorphism is also observed, i.e., compounds can crystallize with one or more molecules of solvent in the crystal lattice. Conversion from solvated to nonsolvated, or hydrate to anhydrous, and vice versa, can lead to changes in solid-state properties. For example, a moisture-mediated phase transformation of carbamazepine to the dihydrate has been reported to be responsible for whisker growth on the surface of tablets. The effect can be retarded by the inclusion of Polyoxamer 184 in the tablet formulation [61]. 

The importance of polymorphism in pharmaceuticals cannot be overemphasized. Some crystal structures contain molecules of water or solvents, known as hydrates or solvates, respectively, and they are also called as pseudopolymorphs. Identifying all relevant polymorphs and solvates at an early stage of development for new chemical entities has become a well-accepted concept in pharmaceutical industry. For poorly soluble compounds, understanding their polymorphic behavior is even more important since solubility, crystal shape, dissolution rate, and bioavailability may vary with the polymorphic form. Conversion of a drug substance to a more thermodynamically stable form in the formulation can signiLcantly increase the development cost or even result in product failure. 

Single crystal x-ray analysis can often be used to localize the solvent molecules in the crystal lattice, which may be present in stoichiometric ratios or nonstoichiometrically. Byrn (1982) has clas-siLed solvates as polymorphic (desolvate to a newXRD pattern) or pseudopolymorphic (desolvate to a similar x-ray powder pattern). Nonstoichiometric solvates that desolvate to the same x-ray powder pattern are often caused by the presence of channels in the crystal that can take up varying amounts of water based on the vapor pressure. SQ33600 (Brittain et al., 1995) and cromolyn sodium (Cox et al., 1971) are examples of this type of solvate. 

Solid Form Selection A drug can exist in multiple forms in the solid state. If the two forms have the same molecular structure but different crystal packing, then they are polymorphs. Pseudopolymorphs (or solvatomorphs) differ in the level of hydration/solvation between forms. Polymorphs and pseudopolymorphs in principle will have a different solubility, melting point, dissolution rate, etc. While less thermodynamically stable, polymorphs have higher solubilities they also have the potential to convert to the more thermodynamically stable form. This form conversion can lead to reduced solubility for the formulated product. One example is ritonavir, a protease inhibitor compound used to treat acquired immune deficiency syndrome (AIDS). Marketed by Abbott Labs as Norvir, this compound began production in a semisolid form and an oral liquid form. In July 1998, dissolution tests of several new batches of the product failed. The problem was traced to the appearance of a previously unknown polymorph (Form II) of the compound. This form is thermodynamically more stable than Form I and therefore is less soluble. In this case, the solubility is at least a factor of 2 below that of Form I.12 The discovery of this new polymorph ultimately led to a temporary withdrawal of the solid form of Norvir from the market and a search for a new formulation. 

Polymorphism, as applied to the sohd state, can be defined as the ability of the same chemical substance to exist in different crystalline structures (Findlay et al. 1951) (regular, repeating arrangement of atoms or molecules in the solid state). The different structures are generally referred to as polymorphs, polymorphic modifications, crystal forms, or forms (Verma and Krishna 1966). Strict adherence to this definition of polymorphism excludes solvates and hydrates (specific water solvate) as polymorphs because they correspond to different chemical substances. Solvates and hydrates are sometimes referred to as pseudopolymorphs. Molecule A is a different chemical substance than molecule A coordinated with a solvent. 

Polymorphs are crystalline solids that have the same chemical composition, yet adopt different molecular arrangements in the crystal lattice (Grant, 1999 Byrn et al., 1999 Vippagunta et al., 2001 Bernstein, 2002). Crystalline solids may also incorporate solvent into the lattice during crystallization to form a solvate, or a hydrate in the case of water, an occurrence that is commonly referred to as pseudopolymorphism (Bym et al., 1999 Nangia and Desiraju, 1999). Adequate control over the crystallization of solid forms is of utmost importance, as each form can exhibit different pharmaceutically relevant properties including solubility, dissolution rate, bioavailability, physical and chemical stability, and mechanical properties (Grant, 1999 Bernstein, 2002). 

The phenomenon whereby solvent or water is incorporated in the crystal lattice or in interstitial voids, for example, has been termed pseudopolymorphism. When incorporated into a crystal lattice, the solvent usually has a space-filling role, especially where solvent molecules do not show strong interactions. If the crystal has large empty channels or holes, their nature will determine which solvent will be included and the structure of the resulting solvate. Although solvates can show higher solubilities and dissolution rates compared to non-solvated species (e.g., Stoltz et al. 1988 Suleiman and Najib 1989), solvates cannot normally be used in the pharmaceutical arena. Residual solvents have been classified the ICH into three classes ... 

When a material can crystallize into a different polymorph, the chemical nature of the species remains identical, however, the physical properties of the material can be different. For example, properties such as density, heat capacity, melting point, thermal conductivity, and optical activity can vary from one polymorph to another. Table 2.3 lists common materials that exhibit polymorphism. Looking at Table 2.3 we can see that density varies significantly for the same materials when the crystal structure has changed. In addition, the change in the crystal structure often means a change in the external shape of the crystal, which is often an important parameter in industrial crystallization that has to be controlled. Many substances crystallize into structure in which the solvent is present as part of the crystal lattice. These crystals are known as solvates (or hydrates when the solvent is water). A substance can have multiple solvates with different crystal structures as well as a solvent free crystal form with a unique crystal structure. The solvates are often referred to as pseudopolymorphs. They are not true polymorphs because of the addition of the solvent molecule(s) to the crystal lattice. Conformational polymorphism refers to the situation where the molecular conformation of the molecules of a given substance are different in each polymorph. 

This report describes some recent developments in the understanding of the thermodynamic, kinetic and structural aspects of organic crystal polymorphism with an emphasis on the application of newer methodology used for its study, since this is one of the areas in which significant progress has been made in recent years. Numerous examples of polymorphic systems are described to illustrate the applications of both older and newer techniques for their investigation. These include studies of pseudopolymorphism manifested by hydrates and solvates of the parent organic molecule. Finally, the crucial question of... 

This type of behaviour is not confined to polymorphs but may extend to pseudopolymorphic forms such as hydrates and solvates. A recent case of solvent-mediated phase transformation involved polymorphic and pseudopolymorphic forms of thiazole carboxylic acid [55], where the transformation is again sensitive to the composition of the mixed solvent. Three forms of the compound are known, an anhydrous form, a 0.5 hydrate, and a 1.5 hydrate. In 50-80% solutions (% = vol.% MeOH-H20), transformation of the 1.5 hydrate to the 0.5 hydrate was observed while transformation to the anhydrous form occurred in 85-100% solutions. No transformation occurred in 0-30% solutions. Detailed study of a solvent-mediated polymorphic transition has also been carried out for the antiulcerative agent cimetidine [56] for which seven polymorphic forms are known. An important feature of this study was the systematic use of seed crystals to induce crystallization at different supersaturation ratios. 

The choice of analytical and physicochemical methods for the characterization of polymorphs is dictated by the need to measure properties which ultimately depend on the different internal arrangements of the same molecules in these phases. When pseudopolymorphs are also considered, the range of suitable analytical techniques is significantly broadened owing to the presence in the crystal of the solvating molecule and the possibility of analysing the physical and chemical changes which may accompany both formation and decomposition of pseudopolymorphs. 

Cortisone in the form of the acetate ester, administrated as an anti-inflammatory agent, exists in polymorphic and pseudopolymorphic forms (solvate crystals). Six crystalline forms were distinctly found by the analysis of solid-state C NMR spectra of nine various samples [36]. Crystal structures were known for three forms and, therefore some correlation between NMR and XRD results could be made. Larger chemical shifts of C3=0 are related with the presence of hydrogen bonding other chemical shift differences between solid forms appear in the side chain and the conformations of ring A. 

Many pharmaceutical compounds exist as distinct polymorphs, which are defined as crystalline solids with the same chemical composition but with different arrangements and/or conformations of the molecules in the crystal lattice. A compound may also form solvates (sometimes known as pseudopolymorphs), which are crystals that contain the solvent of crystallization as part of the crystal structure [18]. Different polymorphs exhibit significantly different physicochemical properties, owing to differences in... 

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