Polymorphism and solvatomorphism

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... 

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. 

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. 

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. 

Typical applications of x-ray powder diffraction methodology include the evaluation of polymorphism and solvatomorphism, the study of phase transitions, and evaluation of degrees of crystallinity. More recently, advances have been made in the use of powder diffraction as a means to obtain solved crystal structures. A very useful complement to ordinary powder x-ray diffraction is variable temperature x-ray diffraction. In this method, the sample is contained on a stage that can be heated to any desired temperature. The method is extremely useful for the study of thermally induced phenomena, and can be a vital complement to thermal methods of analysis. 

The substantial research focus on the crystal structures of drug substances that has developed over the past decade [l-5a,b] has led to extensive interest in any modification of the properties of drug substances whose physical properties are less than desirable. Within this context, the advances being made in the areas of polymorphism and solvatomorph-ism have been amply documented [6-9]. 

Aspartame is known to exist in a variety of polymorphs and solvatomorphs, and the x-ray powder patterns for several forms are shown in Figure 3. 

It is essential to determine the range of crystalline forms that are accessible to a potential drug substance and to determine which of the various forms will be the one used in products used in pivotal trials. To answer this question, investigators must conduct whatever studies might be required to evaluate the full range of possible polymorphs and solvatomorphs. The situation can be further complicated by the phenomenon of disappearing polymorphs, where metastable crystal forms become impossible to produce once more stable forms are uncovered. " ... 

In this chapter, the question of small amounts of polymorphic and solvatomorphic impurities in a bulk solid will be addressed. The most useful methods for performing such work will be outlined, and illustrated with appropriate examples. 

There is no doubt that single crystal X-ray diffraction is a powerful technique for the study of polymorphs and solvatomorphs, but it is equally apparent that this methodology is not well suited for the routine evaluation of the crystalline state of powdered solids. It is definitely not a technique that one would want to use in the determination of polymorphic phase impurities in a sample, since by definition only a single crystal is studied at one time. That crystal would certainly be phase-pure, and its quantitative analysis not... 

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