Example crystallization polymorphs

The literature lists numerous examples of polymorphism i.e., the existence of several crystal forms of a given chemical that exhibit different physical properties [7]. The conversion of one polymorph to another may cause a significant change in the physical properties of the drug and in critical quality attributes of drug products. 

A remarkable example of polymorphism has been found recently for Pigment Red 53 2 (Ca-salt). In addition to the a-, y- and 8-crystal modifications [35, 36] twelve more crystal phases were found and characterized by their X-ray powder spectra. The phase transformation could be achieved by heating P.R.53 2 in different organic solvents at 60-200°C [37],... 

Polymorphism is the capability of a substance in exist in more than one crystal form The basic controlling factors appear to be temperature-pressure conditions at the time of formation, which controls the type of atomic packing within die structure, Examples ol polymorphism ate given in Table 2. 

Electron diffraction therefore makes it possible to establish that the structural continuity of the film is ensured. For example, it can differentiate the chiral and the racemic crystal polymorph of a given polymer (it can tell if the selection of helical hands observed in the first layer is still operative in layers deposited subsequently, away from the foreign substrate). As such, electron diffraction probes growth processes taking place in the polymer itself, as opposed to growth on a foreign substrate. Recall that deposition of,... 

Nature of the drug formulation Drug absorption may be altered by factors unrelated to the chemistry of the drug. For example, particle size, salt form, crystal polymorphism, and the presence of excipients (such as binders and dispersing agents) can influence the ease of dissolution and, therefore, alter the rate of absorption. 

Many molecular and ionic systems crystallize out of solutions as solvates. This is often a totally unavoidable event because solvent molecules fill the voids of otherwise less dense crystal packings, or the solid solvate precipitates out for kinetic reasons, as solvate nuclei are likely to be formed first with respect to unsolvated ones. The presence of solvent molecules trapped more or less tightly within the crystal structure may be turned to advantage if the solvent can be removed by low-pressure or high-temperature treatments or by other means. An example of polymorphs obtained via desolvation is provided by the hexagonal form of a C6o polymorph that can be obtained from desolvation of cubic 1 1 solvate Cgo grown from dichloromethane [72]. 

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). 

If we take a value of Ha — 30 MPa (Martmez-Salazar et al, 1988) for the amorphous phase of i-PP and solve eqs. (4.15) and (4.16), values of // = 143 MPa and He = 119 MPa are obtained. The former value of 143 MPa fits well with the ab initio calculation for the a phase (Balta Calleja et al, 1988). In conclusion, the determination of microhardness is shown to be a technique capable of detecting polymorphic changes in polymers. Further examples of polymorphic crystal-crystal transitions induced by external field (stress or strain) are given in Chapter 6. 

A study example concerning the solid structure of a-amino acid, polypeptide and a protein is given to introduce the basis of the chemical shift of proton NMR precisely, and studies to do this have only recently been undertaken. Some interesting work has been done, including the discrimination of amino acid crystal polymorphism, conformational analysis of polypeptides and fibrous proteins, and the determination of the N—H bond length in polypeptides. 

A dramatic example of the impact of crystal polymorphism on a drug formulation is that of ritonavir (Norvir ), used for the treatment of HIV patients. The problem arose in May of 1998, approximately two years after the launch of the drug, when researchers at the Abbott Laboratories became aware that after 240 production batches it was no longer possible to obtain ritonavir in the crystal form (Form I) approved by the FDA and required for the formulation of Norvir because of the sudden and unexpected appearance of a more stable and much less soluble crystal form (Form II, Fig. 3.3.17). The loss of control over the production process forced Abbott to withdraw the drug from the market for approximately one year until they learned how to replace the solid formulation with a gel capsule suspension with greater problems of stability and bioavailability. Subsequent investigations have led to the discovery of four other crystalline forms of ritonavir [33]. 

If the drug is insufficiently soluble to allow delivery of the required dose as a solution (the maximum delivered dose for each nostril is 200 p,L), then a suspension formulation will be required. There are additional issues for suspension products, for example crystal growth, physical stability, resuspension, homogeneity and dose uniformity. Suspension products will also require information on density, particle size distribution, particle morphology, solvates and hydrates, polymorphs, amorphous forms, moisture and/or residual solvent content and microbial quality (sterile filtration of the bulk liquid during manufacture is not feasible). 

The known structures of the lanthanide and actinide metals are indicated in table 5.01, from which it will be seen that the structures characteristic of the true metals, and particularly the hexagonal close-packed arrangement, are common. Polymorphism, however, is of frequent occurrence among these elements, and plutonium, for example, crystallizes in no fewer than six modifications—the A1 and A2 structures indicated and four others of greater complexity. Praseodymium, neodymium and samarium are of interest in that they possess close-packed structures in which the sequence of layers is... 

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