Polymorphic forms

HMX, the highest density and highest energy soHd explosive produced on a large scale, primarily for military use, exists in four polymorphic forms. The beta form is the least sensitive, most stable, and the type requited for military use. The mole fraction products of detonation of HMX in a calorimetric bomb are 3.68 N2, 3.18 H2, 1.92 CO2, 1.06 CO, 0.97 C, 0.395 NH3, and 0.30 H2. 

Absorption of x-rays by a powdered sample of soHd fat has been a useful method for determination of polymorphic character as discussed eadier. The a, and P forms may be distinguished however, interpretation is made more difficult because subsets of the P and P forms have often been encountered. Also, a fat may contain mixtures of polymorphic forms and properties may therefore be difficult to relate to the spectra. 

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. 

Bioavailability, Bioequivalence, and Pharmacokinetics. Bioavailabihty can be defined as the amount and rate of absorption of a dmg into the body from an adrninistered dmg product. It is affected by the excipient ingredients in the product, the manufacturing technologies employed, and physical and chemical properties of the dmg itself, eg, particle size and polymorphic form. Two dmg products of the same type, eg, compressed tablets, that contain the same amount of the same dmg are pharmaceutical equivalents, but may have different degrees of bioavailabihty. These are chemical equivalents but are not necessarily bioequivalents. For two pharmaceutically equivalent dmg products to be bioequivalent, they must achieve the same plasma concentration in the same amount of time, ie, have equivalent bioavadabihties. 

The tertiary metal phosphates are of the general formula MPO where M is B, Al, Ga, Fe, Mn, etc. The metal—oxygen bonds of these materials have considerable covalent character. The anhydrous salts are continuous three-dimensional networks analogous to the various polymorphic forms of siHca. Of limited commercial interest are the alurninum, boron, and iron phosphates. Boron phosphate [13308-51 -5] BPO, is produced by heating the reaction product of boric acid and phosphoric acid or by a dding H BO to H PO at room temperature, foUowed by crystallization from a solution containing >48% P205- Boron phosphate has limited use as a catalyst support, in ceramics, and in refractories. 

Crystalline Structures. Crystal shape of amino acids varies widely, for example, monoclinic prisms in glycine and orthorhombic needles in L-alanine. X-ray crystallographic analyses of 23 amino acids have been described (31). L-Glutamic acid crystallizes in two polymorphic forms (a and P) (32), and the a-form is mote facdely handled in industrial processes. The crystal stmeture has been determined (33) and is shown in Figure 1. 

The primary phases all contain impurities. In fact these impurities stabilize the stmctures formed at high temperatures so that decomposition or transformations do not occur during cooling, as occurs with the pure compounds. For example, pure C S exists in at least six polymorphic forms each having a sharply defined temperature range of stability, whereas alite exists in three stabilized forms at room temperature depending on the impurities. Some properties of the more common phases in Portland clinkers are given in Table 2. 

Tempering. The state, or physical stmcture, of the fat base in which sugar, cocoa, and milk soHds are suspended is critical to the overall quaHty and stabiHty of chocolate. Production of a stable fat base is compHcated because the cocoa butter in soHdified chocolate exists in several polymorphic forms. Tempering is the process of inducing satisfactory crystal nucleation of the Hquid fat in chocolate. 

Control of the polymorphic forms in cocoa butter is further compHcated by the presence of other fats such as milk fat. The fat in a chocolate can be likened to the mortar between the bricks in a mason s wall. The soHd particles in a weU-conched chocolate bed down better than the soHds in a coarsely refined and poorly mixed one (30). 

For (Z)-cinnamic acid [102-94-3], three distinct polymorphic forms have been characteri2ed. The most stable form, referred to as aHocinnamic acid, has a melting point of 68°C, and the two metastable forms, isocinnamic acids, have melting points of 58°C and 42°C, respectively. (E)-Cinnamic acid can be converted to the (Z)-isomer photochemicaHy through kradiation of a solution with ultraviolet light. 

Transitions from one polymorphic form to another may be accompanied by changes in specific volume, which may lead to destmction of the crystal and containers in which the substance is stored. 

A specific polymorph may be absolutely essential for a crystalline product, for example, one polymorph may have a more desirable color or greater hardness or disperse in water more easily than another polymorph. Often, one polymorphic form is more stable than another (for example, at 80°C the orthorhombic I form of ammonium nitrate is more stable than the trigonal form) at conditions to which a product is exposed. An interesting approach to... 

Titanium Dioxide. The recrystallization of titanium dioxide in a cover-coat glass is very important to the development of thin, highly opaque finish coats. Titania, Ti02, is the primary opacifying agent for white finish coats. Two polymorphic forms of titania, anatase and mtile, may be present in... 

Of course, freezing of a liquid - or its inverse - are themselves phase transformations, but the scientific study of freezing and melting was not developed until well into the 20th century (Section 9.1.1). Polymorphism also links with metastability thus aragonite, one polymorphic form of calcium carbonate, is under most circumstances metastable to the more familiar form, calcite. 

Likewise for 4-aminopyrazoles 46 and 5-aminopyrazoles 47 (Scheme 28), the most stable tautomer possesses either the amino structure 46a [76AHC(S1), pp. 425, 445 98H(49)157]-or 47a [76AHC(S1), pp. 420, 444 84CHEC-I(5)167 96CHEC-II(3)1], X-Ray structural analysis revealed that the parent 4-aminopyrazole exists in the solid state in two polymorphic forms of amino tautomer 46a these forms differ only by the conformation of the NH2 group [98H(49)157j. 

The geometric data reported for 3,4-bis(p-chlorophenyl)furoxan (71TL2907) seem to be in error. A reinvestigation has shown that there are at least two polymorphic forms of this compound (monoclinic and orthorombic), which are both disordered T. Traulsen, C. Nather, and W. Friedrichsen, unpublished results. 

Polymorphic forms of I and II of 3- 2-[4-(6-fluorobenzo[r/ isoxazol-3-yl)-3,6-dihydro-2//-pyridin-l-yl]ethyl -2-methyl-6,7,8,9-tetrahydro-4//-pyrido [1,2-n]pyrimidin-4-one was characterized by IR spectroscopy (99MIP1). 

Two polymorphic forms of 3- 2-[4-(6-fluorobenzisoxazol-3-yl)-l,2,3,6-tetrahydropyridin-l-yl]ethyl -2-methyl-6,7,8,9-tetrahydro-4//-pyrido[l,2-n] pyrimidin-4-one (137 R = H) were prepared (99MIP1). Racemic 9-hydroxy-2-methyl-3- 2-[4-(6-fluorobenzo[r/ isoxazol-3-yl)-l,2,3,6-tetrahydro-l-pyridyl] ethyl -6,7,8,9-tetrahydro-4//-pyrido[l, 2-n]pyrimidin-4-one was resolved into its (R)- and (5)-isomers (OOMIPIO). 

Process validation should be extended to those steps determined to be critical to the quality and purity of the enantiopure drug. Establishing impurity profiles is an important aspect of process validation. One should consider chemical purity, enantiomeric excess by quantitative assays for impurity profiles, physical characteristics such as particle size, polymorphic forms, moisture and solvent content, and homogeneity. In principle, the SMB process validation should provide conclusive evidence that the levels of contaminants (chemical impurities, enantioenrichment of unwanted enantiomer) is reduced as processing proceeds during the purification process. 

Although vitreous silica is nominally a homogeneous isotropic amorphous material, and should normally remain so during its service life, it is in fact in a metastable condition. The tendency to revert to crystalline forms with attendant deterioration in mechanical durability places severe limitations on the range of applications. Figure 18.2 illustrates the polymorphic forms of silica, and the dimensional changes accompanying each transition. 

If two or more crystalline forms of a substance exist, they are called polymorphic forms if the substance is an element (C, S, P) they are called allotropic forms. The Thomson equation obviously applies to this case ... 

The following section deals with the crystallization and interconversion of polymorphic forms of polymers, presenting some thermodynamic and kinetic considerations together with a description of some experimental conditions for the occurrence of solid-solid phase transitions. 

Some relevant effects of the polymorphism on the properties of polymeric materials are shown in the final section. In particular, it is shown that, while the occurrence of transitions between polymorphic forms can be detrimental for some systems, a precise knowledge of the polymorphic behavior and of the physical properties of the single forms can be used advantageously to improve the in use properties as well as the processing conditions of some polymeric materials,... 

Polymorphic forms characterized by widely different conformations are observed in several cases. 

In other cases, polymorphic forms are characterized by slightly different conformations. In other words, while the chain conformations packed in the different polymorphs are different, they correspond, however, to small variations in the sequences of the dihedral angles along the main chain. 

The different chain conformations observed in different polymorphic forms of a polymer are generally associated to nearly equivalent minima in the conformational energy maps, calculated for isolated chain models [2, 3],... 

A special case of polymorphic forms can be considered the clathrates, that is forms in which polymer molecules interact with solvents in the crystalline state and form inclusion compounds. 

Several bands of the FTIR spectra are conformationally sensitive. For this reason by this technique it is, in general, easy to distinguish between polymorphic forms presenting different chain conformations. 

It is hence easy to detect by this technique different polymorphic forms having different chain conformations. For instance, the a or p forms of s-PS (tram-planar chain conformations) present only a single methylene resonance at 48.1 ppm (vs.TMS), while the y form (helical conformation) presents two methylene resonances at 37.3 and 47.3 ppm (Fig. 20) [114]. 

This occurs, for instance, when a molded manufact tends to have a transition between polymorphic forms in conditions of use. In fact solid-solid transitions can generate problems of dimensional instability of the manufacts. 

A precise knowledge of the physical properties (mechanical, thermal, electrical, solvent resistance, etc.) of the different polymorphic forms of a given polymeric material can be advantageously used for possible applications. 

It is also well known that different polymorphic forms can present largely different crystallite moduli along the chain axis (both observed and calculated). These differences can be large if large variations in the chain conformations are involved, and can have a significant influence on the bulk properties... 

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