Crystalline salts polymorphism

As mentioned above, polymorphs may also be related by order-disorder transitions, e.g. the onset of free rotation of a group of atoms, or local tumbling in semi-plastic or plastic phases. This may be due to random orientation of the molecules or ions, but is also diagnostic of the onset of a reorientational motion. Roughly spherical molecules and ions are likely to show order-disorder phase transitions to a plastic state. In the cases of co-crystals or of crystalline salts this process may affect only one of the components, leading to semi-plastic crystals (an example will be discussed below). Order-disorder phase transitions have often... 

Different crystalline forms polymorphs, hydrates, solvates, salts, and co-crystals... 

The observations summarised here show that the high temperature polymorph shows fast Li conductivity and dynamic orientational disorder of the sulfate groups. The coexistence of these two highly unusual properties in a crystalline salt leads to the attractive interpretation that these phenomena are linked. Considerable effort has gone into the examination of a model for correlated motion in this structure and this has led to the description of ionic mobility in the a-Li2S04 structure proceeding via what has become known as the paddle-wheel mechanism. This mechanism describes the sulfate as acting as a rotor which provides a... 

As previously discussed, compound form differs markedly between early discovery and the late discovery/development interface. The early discovery compound is poorly characterized as to its crystalline form - it may be nonsolid, amorphous, or possibly crystalline but uncharacterized as to polymorphic form. The late discovery/development interface compound is crystalline as defined by phase-contract microscopy or powder X-ray diffraction, and its polymorphic and salt form is frequently characterized. This difference has profound implications for the design of a discovery solubility assay. The key question is this Is it better to design an early discovery solubility assay as a separate type of experiment, or is it better to try to automate a traditional thermodynamic solubility assay to handle the very large number of compounds likely to be encountered in early discovery Another way to state this question is this Does it make sense to run a thermodynamic solubility assay on poorly crystalline early discovery compounds This is the type of question about which reasonable people could disagree. However, this author does have a distinct opinion. It is much better to set up a distinctively different solubility assay in early discovery and to maintain a clear distinction between the assay type appropriate in early discovery and the assay type appropriate at the late discovery/ development interface. Two issues are relevant to this opinion One relates to the need for a solubility assay to reflect/predict early discovery stage oral absorption and the other relates to people/chemistry issues. 

US patent 6,677,453, Production of polymorphic forms I and II of finasteride by complexation with group I or II metal salts [97]. Finasteride Form I of was prepared by first forming a substantially insoluble complex of the compound and a Group I or Group II metal salt (such as lithium bromide), and then dissociating the complex by dissolving away the salt component with water to obtain substantially pure crystalline finasteride Form I. 

Crystalline form,—Lithium nitrate crystallizes in rhombohedra (trigonal system).15 P. W. Bridgman observed no new form of lithium nitrate between 20° and 200°, and press, between 1 and 12,000 kgrms. per sp. cm. The older authorities—e.g. P. Kremers—supposed this salt to be trimorphic, but the supposed polymorphism is probably due to their mistaking hydrates for polymers of the anhydrous salt. It is doubtful if lithium nitrate is isomorphous with silver or sodium nitrate, although J. W. Retgers says that sodium and lithium nitrates are isomorphous. 

The physical form of the salt must be taken into account and several issues must be considered (Serajuddin and Pudipeddi, 2002). Forexample, amorphous material might result. Even if crystalline, the salt form might prove to be polymorphic. On crystallization or recrystallization, formation of a hydrate or a solvate might occur, and the effect of temperature and humidity on this form should be investigated. Both the physical and chemical stability of the different candidate salt forms in the solid state will ultimately deLne the optimal form of the drug. 

A systematic study of salting-out precipitation is carried out to obtain the operational limits within which this precipitation method can be applied for the production of fines (mean particle size <10 xm) with acceptable quality and productivity. The model substances glycine and sodium chloride are salted-out from their aqueous solutions by using ethanol as antisolvent. The main operational parameter is the initial supersaturation of the solutions. It is shown that the smallest particles can be produced at the limits of the metastability domain determined by three optional process parameters the initial solution concentration, the equilibrium solubility and the operational time. The product quality (crystallinity, polymorphic states, aggregation) and productivity considerably change with the operational conditions. 

The donor (S, S)-3 forms two different polymorphs when it forms a salt with perchlorate anions, one of which shows a crystalline packing somewhat different to those described above, in which the donors form orthogonally oriented dimers in a sheet (k type packing) [37]. Pseudo-symmetry again prevails here, at the centre of the dimer, despite a slight homochiral twist at the central C = C bond. The salt is weakly metallic. Meanwhile, the compound 2... 

A special type of pseudo-polymorphism is that related to the proton transfer along an X-H Y interaction. The motion may not be associated with a phase transition, but may well imply the transformation of a molecular crystal into a molecular salt. Wilson [34] has discussed, on the basis of an elegant neutron diffraction study, the migration of the proton along an O-H O bond in a co-crystal urea-phosphoric acid (1 1) whereby the proton migrates towards the mid-point of the hydrogen bond as the temperature is increased, becoming essentially centred at T > 300 K. Wiechert and Mootz [35] isolated two crystalline materials composed of pyridine and formic acid of different composition. In the 1 1 co-crystal the formic acid molecule retains its proton and transfer to the basic N-atom on the... 

In spite of the great interest in the phenomenon of polymorphism and of the increased research activity beyond the boundaries of organic solid-state chemistry, it is a fact that only a few molecular compounds possess several crystalline forms, whereas for many other tens of thousands of molecular compounds only one crystalline form is known. In other words, why are there so few molecular crystals polymorphs The often quoted association between number of known forms and the time and energy spent in searching for them put forward by McCrone probably contains the answer to this question. It is probable that if thorough (combinatorial ) crystallization experiments were carried out on any given molecular species or molecular salt, alternative crystalline forms would be found. It is probable but not certain. 

For LZ-105 (28), there is very little observable change in the X-ray spectra before and after treatment. Full retention of crystallinity is evident. However, reduction in intensity for the peak at 20 = 24.4° is noted. Such an intensity change is also very prominent in the spectrum of fluoride silicalite, a silica polymorph synthesized in the presence of a fluoride salt (29). 

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