Crystal form identification

Physical and chemical form identification Crystal form identification and/or verification Kinetic and thermodynamic solubility testing Excipient compatibility screening, amorphous content screening and stability analysis... 

A significant advantage of the PLM is in the differentiation and recognition of various forms of the same chemical substance polymorphic forms, eg, brookite, mtile, and anatase, three forms of titanium dioxide calcite, aragonite and vaterite, all forms of calcium carbonate Eorms I, II, III, and IV of HMX (a high explosive), etc. This is an important appHcation because most elements and compounds possess different crystal forms with very different physical properties. PLM is the only instmment mandated by the U.S. Environmental Protection Agency (EPA) for the detection and identification of the six forms of asbestos (qv) and other fibers in bulk samples. 

Syntheses, crystallization, structural identification, and chemical characterization of high nuclearity clusters can be exceedingly difficult. Usually, several different clusters are formed in any given synthetic procedure, and each compound must be extracted and identified. The problem may be compounded by the instabiUty of a particular molecule. In 1962 the stmcture of the first high nuclearity carbide complex formulated as Fe (CO) C [11087-47-1] was characterized (40,41) see stmcture (12). This complex was originally prepared in an extremely low yield of 0.5%. This molecule was the first carbide complex isolated and became the foremnner of a whole family of carbide complexes of square pyramidal stmcture and a total of 74-valence electrons (see also Carbides, survey). 

Although commonly formed from endogenous material, the occurrence of synovial crystals formed following environmental exposure to exogenous agents is indicated by the identification of both aluminium phosphate and aluminium silicate particulates (Netter etal., 1983, 1991). It is noteworthy in this context that arthritic symptoms have been reported following the... 

In this chapter the sequence of observations followed in the microscopic method of identification is outlined. The immersion method for the identification of small separate crystals forms the main subject of this chapter, though some remarks on methods for large aggregates will be found at the end. When the immersion method is to be used aggregates may be crushed or ground carefully. 

In spite of the difficulty in definitely characterizing alkaloids by definition, they do have a surprising number of physical and chemical properties in common. For the most part, the alkaloids are insoluble or sparingly so in water but form salts (by metathesis or addition) that are usually freely soluble. The free alkaloids are usually soluble in ether or chloroform, or other immiscible solvents, in which, however, the alkaloidal salts are insoluble. This permits the isolation and purification of the alkaloids as well as their quantitative estimation. Most of the alkaloids are crystalline solids, although a few are either amorphous (coniine, nicotine, sparteine) or liquid. It is interesting to note that the liquid alkaloids have no oxygen in their molecules. Alkaloidal salts are invariably crystalline, and their crystal form and habit are often useful in their rapid microscopical identification (Sollmann, 1944). 

In addition to characterizing frozen systems intended to be freeze dried, it is important to characterize the freeze-dried product. This includes determination of the physical state of the dried product that is, crystalline, partially crystalline, or amorphous. It may also include identification of the polymorph of a crystallizing component which exhibits polymorphism and determination of whether the crystal form observed is affected by changes in formulation and processing conditions. For amorphous systems, the glass transition temperature of the amorphous solid, as well as the extent to which Ts changes with residual moisture, may be a critical attribute of the product with regard to both physical and chemical stability. 

The plotting of such a phase diagram allows the visualization of saturation varieties, which are regions where one or more components are saturated and can crystallize out of the solution. For example, the region bounded by Ae, ABe, ABCe, ACe, ACDe, ADe, and ABDe in Fig. 11.5(a) is the saturation variety of A, where component A can be crystallized out in a pure form. Identification of this region is useful for determining conditions of a crystallizer for separating A. 

Compounds of divalent samarium, europium, and ytterbium are well-known. In recent years, lower halides of other lanthanides, such as neodymium 48), praseodymium 45, 49, 90), and thulium 4) have been obtained by reducing the trihalide with the metal. The corresponding reaction of thorium tetraiodide with thorium metal has led to the identification of two crystalline forms of Thl2 41, 91) it is unlikely that the Th ", or even Th ", ion is present in Thl2, but like Prl2, which is formulated as Pr " (r)2( ) (2), the compound is probably of the type Th " (r)2(2 ) 41). Certainly one crystal form is diamagnetic 41), suggesting the latter formulation. 

Interfacial angles (angles between crystal faces) are characteristic of the. crystal form being studied and, in certain cases, may aid in identification of the material. When calcite crystals are broken, they form rhombohedra with interfacial angles of 75°. Haiiy discovered this when, to his chagrin, he dropped a valuable Iceland spar (calcite) crystal. He found that the particles into which it broke were always the same type of rhombohedra, with the same shape (but not necessarily the same size). This occurred no matter what external form the original crystal had. 

Infrared spectroscopy Diffuse reflectance analysis eliminates the mechanical stress of preparing a KBr pellet, and may permit identification of more fragile crystal forms.47... 

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 exploration of the crystal form space (polymorph screening) of a substance is the search of the polymorphs and solvates with a twofold purpose (i) identification of the relative thermodynamic stability of the various forms including the existence of enantiotropic crystalline forms (that interconvert as a function of the temperature) or of monotropic forms (that do not interconvert) and of amorphous and solvate forms and (ii) physical characterization of the crystal forms with as many analytical techniques as possible. The relationships between the various phases and commonly used industrial and research laboratory processes are illustrated schematically in Fig. 3.3.3. 

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