Solid-state properties polymorphism

A polymorph is a solid crystalline phase of a compound resulting from the possibility of at least two different crystal lattice arrangements of that compound in the solid state [42], Polymorphs of a compound are, however, identical in the liquid and vapor states. They usually melt at different temperatures but give melts of identical composition. Two polymorphs of a compound may be as different in structure and properties as crystals of two different compounds [43,44], Apparent solubility, melting point, density, hardness, crystal shape, optical and electrical properties, vapor pressure, etc. may all vary with the polymorphic form. The polymorphs that are produced depend upon factors such as storage temperature, recrystallization solvent, and rate of cooling. Table 2 suggests the importance of polymorphism in the field of pharmaceutics [45],... 

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... 

X-ray diffraction studies are usually carried out at room temperature under ambient conditions. It is possible, however, to perform variable-temperature XPD, wherein powder patterns are obtained while the sample is heated or cooled. Such studies are invaluable for identifying thermally induced or subambient phase transitions. Variable-temperature XPD was used to study the solid state properties of lactose [20], Fawcett et al. have developed an instrument that permits simultaneous XPD and differential scanning calorimetry on the same sample [21], The instrument was used to characterize a compound that was capable of existing in two polymorphic forms, whose melting points were 146°C (form II) and 150°C (form I). Form II was heated, and x-ray powder patterns were obtained at room temperature, at 145°C (form II had just started to melt), and at 148°C (Fig. 2 one characteristic peak each of form I and form II are identified). The x-ray pattern obtained at 148°C revealed melting of form II but partial recrystallization of form I. When the sample was cooled to 110°C and reheated to 146°C, only crystalline form I was observed. Through these experiments, the authors established that melting of form II was accompanied by recrystallization of form I. 

The solid-state properties like crystallinity, polymorphism (crystal structure), shape (morphology), and particle size of drugs are important in the stability, dissolution, and processibility of drugs. Some commonly used methods in solid-state studies include microscopy, hot stage microscopy with polarized light, x-ray powder diffraction (XRPD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), Fourier transform infrared FTIR/Raman, and solid-state NMR. 

In addition to these compilations of crystal data in which instances of polymorphism may be recorded, a number of texts on the subject of the solid state properties of organic compounds contain many examples of polymorphism. Since these books are based in part, at least, on work by the authors not published elsewhere, they may be considered as primary literature sources. Particularly noteworthy in this regard are the books by Pfeiffer (1922), Kofler and Kofler (1954), and McCrone (1957). 

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. 

Zhang, G.G. Law, D. Schmitt, E.A. Qiu, Y. Bauer, M. Bauer, J. Spanton, S. Henry, R. Quick, J. Dziki, W. Porter, W. Morris, J. Highleyman, L. Phase transformation considerations during process development and manufacture of solid oral dosage forms [Crystallization and solid state properties of molecules of pharmaceutical interest] Ritonavir an extraordinary example of conformational polymorphism Ritonavir manufacturing problems. Adv. Drug. Deliv. Rev. 2004, 56 (3), 371-390. 

Subsequently, workers in pharmaceutically related fields realized that the solid-state property differences derived from the existence of alternate crystal forms could translate into measurable differences in properties of pharmaceutical importance. For instance, it was found that various polymorphs could exhibit different solubilities and dissolution rates, and these differences sometimes led to the existence of nonequivalent bioavailabilities for the different forms. Since then, it has become recognized that an evaluation of the possible polymorphism available to a drug substance must be thoroughly investigated early during the stages of development. In various compilations, it has been reported that polymorphic species are known for most drug substances and that one should be surprised to encounter a compound for which only one structural type can be formed. 

Unfortunately, our understanding of the physics and chemistry of salt formation is not yet at a stage where we can predict a priori the physicochemical properties of a proposed salt. A particular problem in this regard is the formation of a range of salt polymorphs and/or solvates. While qualitative/semiempi-rical guidelines have been developed, the selection process is still largely experiment based. It is to be hoped that developments in computational methods will soon lead to the more accurate prediction of bio-pharmaceutically relevant solid-state properties that will ultimately simplify the task of appropriate salt selection. 

As shown in Fig. and also in the work of Barraclough and Hall, moisture uptake onto sodium chloride as a function of relative humidity is reversible as long as RHq is not attained. This is evidence that actual dissolution of water-soluble crystalline substances does not occur below RHq. This is consistent with the thermodynamic rationale that dissolution below RHq would require a supersaturated solution (i.e., an increased number of species in solution would be necessary to induce dissolution at a relative humidity below that of the saturated solution, RHq). In this regard, one should only need to consider the solid state properties of a purely crystalline material below RHo. As will be described, other considerations may be warranted for a substance that exists in multiple polymorphic forms or contains amorphous material. 

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. 

The solubility is most often experimentally determined from the dmg concentration in the liquid phase after adding excessive amounts of a solid dmg substance to the test medium. This apparent solubility is affected by the solid-state properties of the dmg, for example, polymorphs, solvates, impurities, and amorphous content. An equilibrium with the thermodynamically most stable solid-state form, being the least... 

Solid-state properties (crystalline, not polymorphous, not hygroscopic) that make it a perfect partner for (tablet) compaction. 

Polymorphism is a keyword of considerable importance in the life sciences and especially in the pharmacentical indns-try. 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 prodnct 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. 

A number of other studies can be performed on a candidate drug to determine other important solid-state properties, for example, particle size, powder flow and compression and polymorphism. Therefore, when a sample undergoes initial preformulation testing the following parameters should be noted particle size, true, bulk and tapped density, surface area, compression properties and, powder flow properties. Some of these factors will be discussed in this chapter others, however, are dealt with in more detail in Chapter 11 on Solid Oral Dosage Forms. 

Solid state property differences derived from the existence of alternate crystal forms can lead to extensive differences of pharmaceutical importance, e.g., solubility, dissolution rate, and stability. It is claimed that most drug substances show polymorphism (Borka, 1991). As discussed previously, it is essential to determine which of the various forms should be used in a drug product to assure stable and reproducible formulation. A marked difference between the photostability of various crystal modifications of drug substances has been reported. This can be ascribed to differences in inter- and intramolecular binding, differences in diffusability (crystalline vs. amorphous structure), and differences in water content (crystal water, adsorbed water) (Hiittenrauch et al., 1986). 

Acquisition of potential compounds This could be achieved by chemical synthesis or by extraction from natural resources. This stage includes the development of analytical methods to confirm identity and purity of the compound, and its stability under real-life and stressed storage conditions. Physicochemical properties of the compound are identified, such as the solid-state form (polymorphism, hydrates, and solvates), melting point, solubility, and stability. Synthesis of the molecule is scaled up as the compound progresses in the development pathway. A formulation suitable for human administration and commercialization is identified and scaled-up. 

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