Crystals pseudopolymorphism

The use of white-light microscopy to identify differently coloured polymorphs was mentioned above. Colour polymorphism may be quantified using UV/vis electronic spectroscopy (diffuse reflectance, fluorescence methods). Colour differences for polymorphs of the same compound may originate from differences in charge transfer interactions or different molecular conformations in the crystals. Pseudopolymorphs may also be distinguished using fluorescence spectroscopy since they may display characteristic absorption maxima as well as fluorescence intensities. Systems which exhibit colour polymorphism have been reviewed [27]. 

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 utilization of IR spectroscopy is very important in the characterization of pseudopolymorphic systems, especially hydrates. It has been used to study the pseudopolymorphic systems SQ-33600 [36], mefloquine hydrochloride [37], ranitidine HC1 [38], carbovir [39], and paroxetine hydrochloride [40]. In the case of SQ-33600 [36], humidity-dependent changes in the crystal properties of the disodium salt of this new HMG-CoA reductase inhibitor were characterized by a combination of physical analytical techniques. Three crystalline solid hydrates were identified, each having a definite stability over a range of humidity. Diffuse reflectance IR spectra were acquired on SQ-33600 material exposed to different relative humidity (RH) conditions. A sharp absorption band at 3640 cm-1 was indicative of the OH stretching mode associated with either strongly bound or crystalline water (Fig. 5A). The sharpness of the band is evidence of a bound species even at the lowest levels of moisture content. The bound nature of this water contained in low-moisture samples was confirmed by variable-temperature (VT) diffuse reflectance studies. As shown in Fig. 5B, the 3640 cm-1 peak progressively decreased in intensity upon thermal... 

Olesen and Szabo obtained crystals from ethanol and acetone53. They found the crystals to have different solubility, melting point and x-ray diffraction patterns. Since acetone is retained in the crystalline lattice, it was indicated that the forms are 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 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. 

Nangia, A., Desiraju, G. R., Pseudopolymorphism occurrences of hydrogen bonding organic solvents in molecular crystals. Chem. Commun. 1999, 605-606. 

A cp/mas VACP 13C-NMR study was made of these three pseudopolymorphic crystals (19, 21, and 22).29 The prefix pseudo is affixed to polymorph to describe this series of nefopam methohalide crystals since the anions therein are different. The results of this solid-state 13C-NMR study are presented in Table 3 along with the solution-state 13C chemical shifts. The cp/mas 13C-NMR spectra of crystalline 19, 21, and 22 are illustrated in Fig. 5. It is seen that the C(4) peak (<5 58.51) in the cp/mas 13C-NMR spectrum of the methochloride (22) is sharp due to the sole presence of the immobile BB conformation quaternary ammonium cation in the crystal. However, the C(4) peak (V) 59.42) in the methobromide (21) spectrum was markedly lower in intensity and broad, and in the methiodide (19) spectrum it was just a broad shoulder at 5 62.29 Therefore, as the C(4) nucleus becomes more site-disordered in the crystal due to conformational interconversion, its cp/mas peaks show lower intensities and greater line-broadening. 

If the chemical contents of a polymorph are different than other forms, it is designated as a pseudopolymorph.Most often this occurs due to the presence of differing amounts of solvent, and may alter physical properties of the crystals such as melting points and solubilities. Polymorphism and pseudopolymorphism may be observed when different experimental conditions are used for synthesis. For example, if crystals are grown by sublimation, changing the temperature will often yield different crystal structures, possibly even metastable phases that are kinetically favored. 

McCrone (1965) also noted that second-order phase transitions have been termed as pseudopolymorphic. Such transitions are difficult to detect by optical methods, because of the small structural changes that occur hence, the origin of the prefix pseudo sometimes used to describe them. However, the birefringence of the crystals changes during such phase changes (see Section 4.2), so the use of crossed polarizers makes the phase change readily detectable. 

McCrone (1957, 1965) has also given detailed descriptions of the microscopic examinations and phenomena that can be used to distinguish polymorphism from other phenomena that sometimes have been mistakenly labelled as pseudopolymorphism mesomorphism (i.e. liquid crystals), grain growth (boundary migration and recrystallization), and lattice strain. 

M. Tominaga, K. Katagiri, 1. Azumaya, Pseudopolymorph and charge-transfer co-crystal of disubstituted adamantane containing dimethoxyphenol moieties, Cryst. Growth Des. 9 (2009) 3692-3696. 

Hydrates normally form crystal structures (pseudopolymorphs) that differ from the anhydrous form. Different powder XRD patterns of ampicillin in the anhydrous and trihydrate forms are shown in Fig. 16. Although moisture contents often present values that are close to being stoichiometric, X-ray confirmation of the differing crystal structure should be a requisite for designation as a hydrate. 

Each polymorph contains the same chemical contents of the respective unit cells. If the chemical contents differ, for example by the presence of different amounts of solvent, they are called pseudopolymorphs. Polymorphs may differ with respect to physical properties such as melting points, or solubilities, as also may pseudopolymorphs. Their existence often presents a serious problem in the pharmaceutical industries since physical properties of crystals are often used as criteria for quality control and thereby the effectivity of a given preparation. Polymorphs and pseudopolymorphs are usually obtained when crystals are grown under different conditions. For example, metastable crystals of the 7T-donor acceptor complex between biphenylene and pyromellitic dianhydride were obtained when crystals were grown by sublimation at high temperatures, whereas a different polymorph, stable at room temperature, was grown by the same method at a lower temperature. ... 

An analysis of the crystal structures of pseudopolymorphs can also lead to a better understanding of interrelationships between structure... 

Polymorphism is the existence of more than one crystalline form of the same chemical substance. If there are only two forms, the phenomenon is dimorphism if the materials are elements, it is allotropy if the forms differ by solvent of crystallization, they are called pseudopolymorphs. Different polymorphs have different relative stabilities, but these may be varied by changing temperature, pressure, and other conditions. 

Pseudopolymorphs Polymorphs that differ by solvent of crystallization. 

Two pseudopolymorphic crystalline forms of 235 (235y and 235o) were isolated and characterized by X-ray diffraction.105 The first (yellow crystals)... 

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. 

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