Solvent-free polymorphs

Terazosin hydrochloride is an alpha-1-selective adrenoceptor blocking agent marketed by Abbott Labs under the name Hytrin. The molecular structure of this compound is shown in Figure 4.10. This pharmaceutical is used to treat benign prostatic hyperplasia and high blood pressure. Like many modern pharmaceuticals, the compound is found to exist in several polymorphic forms as well as solvates. Four solvent-free polymorphs have been isolated directly and one solvent-free form has been isolated indirectly by desolvation of a methanol solvate. In addition to the methanol solvate, a dihydrate has also been found.These forms all exist at room temperature and their relative stabilities have been determined experimentally. 

The situation may be further complicated by the presence of different polymorphs for tris(l-pyrrolidine-dithiocarbamato)iron(III) two solvent-free modifications could be characterised. The first one has been crystallised from an ethanol/chloroform solution [14], whereas the second has been isolated from a chloroform/toluene mixture [16]. Both compounds differ in their structural parameters determined at room temperature, where they are both high spin. At lower temperatures the ethanol/chloroform product displays a gradual spin transition [14], whereas the chloroform/toluene form remains high spin down to very low temperature [33]. 

Drug products are frequently isolated as polymorphs or solvates. One solvent-free crystalline form and three solvates were noted for aztreonam [16]. Dirithromycin has been crystallized as two anhydrous polymorphs, nine solvates [17], and forms solvates with nearly all of the pharmaceutically acceptable solvents [18]. Lorazepam forms multiple polymorphs and solvates [19]. At least 14 polymorphs and solvates were found for an organic dye complex, and the more effort put into preferentially growing a crystal form, the more polymorphs and psuedopolymorphs were uncovered [13]. A second polymorph of natamycin was observed 35 years after the discovery of this natural product [20]. As more batches of an intermediate or final product are prepared, the greater the chances that a new polymorph or solvate will be formed. Crystallization conditions must be... 

In addition to showing that solvent-free melt and sublimation crystallization conditions offer an attractive route to new polymorphs, a CSD survey of these methods of crystallization and the frequency of Z was performed (Table 3-5). There is a dramatic increase in the occurrence of Z > 3 crystal structures when melt or sublimation crystallization conditions are used [20]. The occurrence of high Z in melt crystallization and sublimation methods is ascribed to the rapid cooling of the hot liquid or vapor (100-300° C) in the open flask or on the cold finger (kinetic phase), conditions under which hydrogen-bonded clusters are likely to condense in a pseudo-symmetric crystalline arrangement. On the other hand, the slower nucleation process of solution crystallization gives the frequent situation of Z < 1 (88% hits). 

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. 

Thus, solid 1 exists as at least four forms differing in both crystalline and molecular structure two yellow crystalline 1 1 solvates with toluene and THF (lb and Ic), and two solvent-free forms orange crystals (la) and a yellow powder (Id). Bernstein [10] uses a term conformational polymorphism for this phenomenon, that is, existence of several forms of a conformationally flexible molecule (with energy difference between the conformers less then 2 kcal/mol) depending on crystallization conditions. Our experience with a step-by-step serendipitous finding of new conformational polymorphs of 1 ([1, 4-6] and this paper) closely resembles the classical story about analogous forms of dimethylbenzylideneaniline, described vividly in [10]. 

Pseudopolymorph—pseudo meaning false is often and mistakenly/incorrectly associated with the term polymorph when it is used to describe solvated or hydrated forms of compounds. Solvated and solvent-free phases are distinct and should therefore not be referred to as polymorphs of one another. ... 

Even though solution crystallization is always the method of choice, it has limited applicability in cases where the molecules have a strong tendency to form solvates. Solvent-free techniques such as melt crystallization and sublimation are suitable for certain compounds. For example. Das and Barbour obtained four polymorphs of a hexa-host, hexakis(4-cyanophenyloxy)benzene, upon melt crystallization, which otherwise forms a series of solvates with the solvent of crystallization. Sublimation is yet... 

R Alexandridis, U. Olsson, P, Linse, B. Lindman, Structural polymorphism of amphiphilic block copolymers in mixtures with water and oil Comparison with solvent-free block copolymers and surfactant systems. In Amphiphilic Block Copolymers. Self-Assembly and Applications, Ed. P. Alexandridis, U. Olsson, B. Lindman, p. 169, Elsevier, Amsterdam (2000) (overview over the phase behavior of PEO-PPO block copolymers). 

The effect of polymorphism becomes especially critical on solubility since the rate of compound dissolution must also be dictated by the balance of attractive and disruptive forces existing at the crystal-solvent interface. A solid having a higher lattice free energy (i.e., a less stable polymorph) will tend to dissolve faster, since the release of a higher amount of stored lattice free energy will... 

In some instances, distinct polymorphic forms can be isolated that do not interconvert when suspended in a solvent system, but that also do not exhibit differences in intrinsic dissolution rates. One such example is enalapril maleate, which exists in two bioequivalent polymorphic forms of equal dissolution rate [139], and therefore of equal free energy. When solution calorimetry was used to study the system, it was found that the enthalpy difference between the two forms was very small. The difference in heats of solution of the two polymorphic forms obtained in methanol was found to be 0.51 kcal/mol, while the analogous difference obtained in acetone was 0.69 kcal/mol. These results obtained in two different solvent systems are probably equal to within experimental error. It may be concluded that the small difference in lattice enthalpies (AH) between the two forms is compensated by an almost equal and opposite small difference in the entropy term (-T AS), so that the difference in free energy (AG) is not sufficient to lead to observable differences in either dissolution rate or equilibrium solubility. The bioequivalence of the two polymorphs of enalapril maleate is therefore easily explained thermodynamically. 

DHPLC (C2, L3, U1) uses a proprietary matched ion polynucleotide chromatography column devised by Transgenomics, Inc., in combination with an organic solvent and thermal denaturation (rather than an electrophoretic gel) to resolve heteroduplexes containing a suspected polymorphism from a polymorphism-free homoduplex. Homo- and heteroduplexes are visualized through UV absorbance readings of the eluent as it leaves the column. 

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