Solvatomorphs

Several of the chapters in the current volume are comprehensive in nature, but others are more specialized. Volume 32 also contains a methodology review article on the validation of chromatographic methods of analysis. New to the series are annual reviews, and volume 32 contains a summary of the publications appearing during 2004 that dealt with polymorphism and solvatomorphism. It is anticipated that future volumes in the Profiles series will contain similar methodology reviews, as well as other types of review articles that summarize the current state in a particular field of pharmaceutics. As always, I welcome communications from anyone in the pharmaceutical community who might want to provide an opinion or a contribution. 

United States polymorph and solvatomorph patents issued during 2005 276... 

Over the past two decades, the pharmaceutical community has become acutely aware that many substances of interest can be obtained in more than one crystal form, and that the properties of these solids may often be quite different. Polymorphism is the term used to denote crystal systems where a substance can exist in different crystal packing arrangements, but all of which are characterized by exactly the same elemental composition. Other crystal variations are known where a given substance exists in different crystal packing arrangements, but each of which exhibits a different elemental composition. Since this latter phenomenon usually involves the inclusion of one or more solvent molecules in the crystal, the term solvatomorphism has been coined to replace the inconsistent nomenclature used over the years. These and related phenomena have been the focus of several recent monographs [1-3],... 

The pharmaceutical industry has taken great interest of late in the study of polymorphism and solvatomorphism in its materials, since a strong interest in the phenomena has developed now that regulatory authorities understand that the nature of the structure adopted by a given compound upon crystallization can exert a profound effect on its solid-state properties. For a given material, the heat capacity, conductivity, volume, density, viscosity, surface tension, diffusivity, crystal... 

As might be expected, the literature associated with studies of polymorphism and solvatomorphism has grown in proportion to the interest in the field. As a result, an annual review of the area has been initiated, and will be continued in succeeding volumes in the Profiles series. The citations in this article are drawn primarily from the major pharmaceutical and crystallographic journals, and therefore are not represented to be comprehensive. However, they should represent the bulk of work that was conducted with pharmaceutical interest in mind. 

Fluconazole was shown to be crystallizable in the form of a monohydrate and as a 1/4 ethyl acetate solvate, as well as a new nonsolvated form [56], In the hydrate phase the water molecules were established as isolated sites, while the ethyl acetate molecules occupied constricted channels in its phase. In all of the structures, the fluconazole molecule adopted a common overall conformation, but one that was capable of some degree of flexibility. Hydrogen-bonding effects were deduced to be dominant in determining the structure of the different solvatomorphs. 

The crystal structures of the 2 1 solvates formed by phenylbutazone with benzene, cyclohexane, 1,4-dioxane, tetrahydrofuran, and tetrachloromethane were found to be isostructural, while the structure of the chloroform solvate differed [57]. In all of the solvatomorphs, the solvent molecules were found to be located in channels along the (0 1 0) direction, and their inclusion served to increase the length of the unit cell along the n-axis. The solvent inclusion was also found to alter the //-angle. 

The effect of relative humidity and temperature on the physical and structural properties of the 1 1 isopropanol solvatomorph of warfarin has been studied [58], Below the critical relative humidity of 60-68% the solid is not hygroscopic, but becomes deliquescent at higher values of relative humidity without exchange of water for isopropanol. Storage of the solvate-morph at elevated temperatures causes formation of an amorphous solid owing to loss of isopropanol, which may proceed through an intermediate crystalline phase. 

The physical properties of the anhydrate form and two polymorphic monohydrates of niclosamide have been reported [61], The anhydrate form exhibited the highest solubility in water and the fastest intrinsic dissolution rate, while the two monohydrates exhibited significantly lower aqueous solubilities. In a subsequent study, the 1 1 solvates of niclosamide with methanol, diethyl ether, dimethyl sulfoxide, N,/V -dimethyl formamide, and tetrahydrofuran, and the 2 1 solvate with tetraethylene glycol, were studied [62], The relative stability of the different solvatomorphs was established using desolvation activation energies, solution calorimetry, and aqueous solubilities. It was found that although the nonaqueous solvates exhibited higher solubilities and dissolution rates, they were unstable in aqueous media and rapidly transformed to one of the monohydrates. 

Methoxypurine was found to crystallize as a hemihydrate from /V,/V -dimethyl formamide, and as a trihydrate from water [63]. Thermal treatment of the trihydrate could be used to obtain the hemihydrate. Zafirlukast was obtained in the form of monohydrate, methanol, and ethanol solvatomorphs, with the drug substance adopting a similar conformation in all three structures [64], In the isostructural methanol and ethanol solvates, the solvent molecules are hydrogen-bonded to two zafirlukast molecules, while in the monohydrate, the water molecules are hydrogen-bonded to three zafirlukast molecules. The structures of the acetone and isopropanol solvatomorphs of brucine have been reported, where the solvent controlled the self-assembly of brucine on the basis of common donor-acceptor properties [65],... 

The structure of the 1 1 methanol solvate of olanzapine has been reported, where pairs of olanzapine molecules form a centrosymmetric dimer by means of C—H—-7t interactions [66]. The solvent molecule was linked to the drug substance through O—H-N, N—H O, and C—interactions. In a new polymorph of the 1 1 dioxane solvatomorph of (+)-pinoresinol, the structure was stabilized by O—H O hydrogen bonds between the compound and the solvent [67], Two new polymorphs of 2-cyano-3-[4-(/Y,jV-diethylamino)-phenyl]prop-2-enethioamide and its acetonitrile solvatomorph have been characterized [68], Although crystallization of the title compound was conducted out of a number of solvents, only the acetonitrile solvatomorph could be formed. 

The phase transformation relationships for the solvatomorphs of naproxen sodium have been reported [71], The dihydrate phase is obtained upon crystallization from water, and a monohydrate phase could be prepared by the dehydration of the dihydrate phase in a desiccator (RH = 0%) for two days. The anhydrate phase could be obtained from either the monohydrate or dihydrate by drying the substance in an oven at 120 °C for two hours. Thermal analysis data was used to demonstrate the existence of two types of water in the dihydrate phase, and that each could be removed at a characteristic temperature. 

The formation of niclosamide hydrates, and the effect of relative humidity on the solvatomorphs obtained from acetone and ethyl acetate has been studied [79], The acetone and ethyl acetate solvatomorphs could be desolvated, and exposure to elevated humidity resulted in the formation of two hydrate structures. Each hydrate could be dehydrated into a different anhydrate phase, but only the hydrate formed from the acetone desolvate could be rehydrated to form a hydrate phase. Dynamic vapor sorption has been used to develop a method for determining the onset relative humidity of a glass transition and associated crystallization process [80]. 

Polymorphism and solvatomorphism are not, of course, limited to small molecules, and such phenomena can be observed in protein crystals as well. Two polymorphic forms of aprotinin have been identified, and the solubility of these studied in a variety of aqueous media [84], The needle polymorph was found to exhibit increased solubility with increased temperature (i.e., an endothermic heat of solution), while the solubility of the bipyramid form decreased by with increasing temperature (i.e., an exothermic heat of solution). The solubility curves crossed at 25 °C for a pH of 4.75, and hence one could obtain the desired crystal form through a judicious selection of crystallization temperature. 

The chemical and physical stability of aqueous and nonaqueous suspensions of a number of solvatomorphs of niclosamide has been evaluated in an effort to develop pharmaceutically acceptable suspension formulations [90]. Studied in this work was the anhydrate, two polymorphic monohydrates, the 1 1, Y, A"-dimethyI I ormam ide solvatomorph, the 1 1 dimethyl sulfoxide solvatomorph, the 1 1 methanol solvato-morph, and the 2 1 tetraethylene glycol hemisolvate. All of the solvatomorphs were found to convert initially to one of the polymorphic monohydrates, and over time converted to the more stable monohydrate phase. The various solvatomorphs could be readily desolvated into isomorphic desolvates, but these were unstable and became re-hydrated or re-solvated upon exposure to the appropriate solvent. 

UNITED STATES POLYMORPH AND SOLVATOMORPH PATENTS ISSUED DURING 2005... 

The listing of patents published by the United States Patent Office was searched for polymorph and solvatomorph patents using the keywords polymorph(s), polymorphic, solvate(s), hydrate(s), crystal form(s), and crystal modification, and the following patents issued during 2005 were returned using these keywords. 

Fig. 4.21. Thermogravimetric analysis of a compound capable of being isolated as an anhydrate crystal form (solid trace), and as the monohydrate (dashed trace) and dihydrate (dotted trace) solvatomorphs.

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