Polymorphism, pharmaceutical industry properties

Polymorphism is a characteristic of the solid state and the concept is immensely important in the pharmaceutical industry. Properties such as stability, solubility, bioavailability, manufacturability, tableting, formulation, and even toxicity are a function of the polymorph crystal structure. 

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... 

Practical considerations may also arise. Supramolecular functionality introduced to control crystal architecture must be added without degrading the fundamental molecular properties of primary interest. Co-crystals offer an alternative approach for controlling crystal architecture without necessarily modifying the primary molecule of interest. In addition, we must recognize the role of the solvent from which the crystal grows. The occurrence of solvates and polymorphs, particularly relevant in the pharmaceutical industry, is still a relatively poorly understood aspect of crystal chemistry. The manner in which synthons are modified from normal geometries in non-crystalline organic structures is also yet to be explored fully. 

In an example from the pharmaceutical industry Sudo et a/. (1991) studied the relative nucleation properties of forms A and B of cimetidine, which is reported to have four polymorphic non-solvated forms and three polymorphic monohydrates. Modification A is preferred for pharmaceutical formulations. The waiting time method was used to study the primary nucleation process (Harano and Oota 1978), mainly for competitive crystallization of the A and B modifications. A is a thermodynamically metastable form and is more soluble than B in any solvent. At high supersaturation... 

Polymorphism can influence every aspect of the solid state properties of a drug. Many of the examples given in preceding chapters on the preparation of different crystal modifications, on analytical methods to determine the existence of polymorphs and to characterize them and to study structure/property relations, were taken from the pharmaceutical industry, in part because there is a vast and growing body of literature to provide examples. One of the important aspects of polymorphism in pharmaceuticals is the possibility of interconversion among polymorphic forms, whether by design or happenstance. This topic has also been recently reviewed (Byrn et al. 1999, especially Chapter 13) and will not be covered here. Rather, in this section, we will present some additional examples of the variation of properties relevant to the use, efficacy, stability, etc. of pharmaceutically important compounds that have been shown to vary among different crystal modifications. 

Thermal analysis methods are defined as those techniques in which a property of the analyte is determined as a function of an externally applied temperature. Regardless of the observable parameter measured, the usual practice requires that the physical property and the sample temperature are recorded continually and automatically and that the sample temperature is altered at a predetermined rate. Thermal reactions can be endothermic (melting, boiling, sublimation, vaporization, desolvation, solid-solid phase transitions, chemical degradation, etc.) or exothermic (crystallization, oxidative decomposition, etc.) in nature. Such methodology has found widespread use in the pharmaceutical industry for the characterization of compound purity, polymorphism, solvation, degradation, and excipient compatibility. ... 

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. ... 

Hilfiker R. Blatter F, von Raumer M. Relevance of. solid-state properties for pharmaceutical products. In Hilfiker R, ed. Polymorphism in the Pharmaceutical Industry. Weinheim, Germany Wiley-VCH, 2006 1-19. 

One property of a crystalline compound is its ability to form polymorphs, that is, more than one crystal form for the same molecular entity. The phenomenon of polymorphism plays a critical role in the pharmaceutical industry because it affects every phase of drug development, from initial drug discovery to final clinical evaluation, including patent protection and competition in the market. A critical challenge is the early identification of possible polymorphs. Chapters 2 and 3 will address this key issue. 

The example of the polymorphs (allotropes) of carbon illustrate the key messages of this chapter different crystal forms of a substance can possess very different properties and behave as different materials. This concept has important implications in all fields of chemistry associated with the production and commercialization of molecules in the form of crystalline materials (drugs, pigments, agrochemicals and food additives, explosives, etc). The producer, in fact, needs to know not only the exact nature of the material in the production and marketing process, but also its stability with time, the variability of its chemical and physical properties as a function of the crystal form, etc. In some areas, e.g. the pharmaceutical industry, the search for and characterization of crystal forms of the API has become a crucial step for the choice of the best form for formulation, production, stability and for intellectual property protection. 

Polymorphism is a keyword of considerable importance in the life sciences and especially in the pharmaceutical industry. It abridges the fact that a solid compound can exist in different crystalline forms that can have different physical chemical properties. To ensure no variations in the product to be due to different solid-state properties, care must be taken in selecting the most appropriate solid-state form for the substance and in ensuring a reproducible production of this form. 

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