Pseudopolymorph

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]. 

In this IR sampling technique, a thermogravimetric (TG) analyzer is interfaced to an IR spectrophotometer so that the evolved gas from the sample/TG furnace is directed to an IR gas cell. This IR sampling technique lends itself to the identification and quantitation of residual solvent content for a pharmaceutical solid [17], and also to the investigation of pharmaceutical pseudopolymorphs. 

The topics of polymorphism and pseudopolymorphism dominate the majority of publications that deal with utilizing infrared spectroscopy for the physical characterization of pharmaceutical solids. Typically, in each of the publications, IR spectroscopy is only one technique used to characterize the various physical forms. It is important to realize that a multidisciplinary approach must be taken for the complete physical characterization of a pharmaceutical solid. Besides polymorphism, mid- and near-IR have been utilized for identity testing at the bulk and formulated product level, contaminant analysis, and drug-excipient interactions. A number of these applications will be highlighted within the next few sections. 

Infrared spectroscopy has been widely used for the qualitative and quantitative characterization of polymorphic and pseudopolymorphic compounds of pharmaceutical interest. Since solid state IR can be used to probe the nature of (pseudo)polymorphism on the molecular level, this method is particularly useful in instances where full crystallographic characterization of (pseudo)poly-morphism was not found to be possible. Recently, a significant number of publications have appeared that discuss where a multidisciplinary, spectroscopic... 

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... 

The most widely used application of solid state NMR in the pharmaceutical industry is in the area of polymorphism, or pseudopolymorphism, and this will be the focus of this section. 

Quantitative solid state 13C CP/MAS NMR has been used to determine the relative amounts of carbamazepine anhydrate and carbamazepine dihydrate in mixtures [59]. The 13C NMR spectra for the two forms did not appear different, although sufficient S/N for the spectrum of the anhydrous form required long accumulation times. This was determined to be due to the slow proton relaxation rate for this form. Utilizing the fact that different proton spin-lattice relaxation times exist for the two different pseudopolymorphic forms, a quantitative method was developed. The dihydrate form displayed a relatively short relaxation time, permitting interpulse delay times of only 10 seconds to obtain full-intensity spectra of the dihydrate form while displaying no signal due to the anhydrous... 

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. 

Pseudomonas fluorescens, 1 732 11 4 Pseudomonas putida, 11 4 Pseudomonas testosteroni alcohol dehydrogenase, 3 672 Pseudopelletierine, 2 81-82 Pseudoplastic flow, 7 280t Pseudoplastic fluids, 11 768 Pseudoplasticity, 10 679 Pseudoplastic with yield stress flow, 7 280t Pseudopolymorphism, 8 69... 

A.M. Amado, M.M. Nolasco and P.J.A. Ribeiro-Claro, Probing pseudopolymorphic transitions in pharmaceutical solids using Raman spectroscopy Hydration and dehydration of theophylline, J. Pharm. Sci., 96, 1366-1379 (2007). 

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. 

Everz, L. and Mielck, J. (1992). V feter-induced physical transformation of a crystalline drug in a uidized bed pseudopolymorphism-polymorphism of carbamazepiBa/ J. Pharm. Biopharm., 38 28S. 

Rasanen, E. Rantanen, J. Jorgensen, A. etal., Novel identification of pseudopolymorphic changes of theophylline during wet granulation using near infrared spectroscopy J. Pharm. 

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

Figure 9.19 (a) transformations between different polymorphs or pseudopolymorphs of 9.4, (b) TGA... 

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