Polymorphism, of sulfathiazole

In its heyday, DTA analysis was very useful for the study of compound polymorphism and in the characterization of solvate species of drug compounds. It was used to deduce the ability of polymorphs to undergo thermal interconversion, providing information that could be used to deduce whether the system in question was monotropic or enantiotropic in nature. For instance, the enthalpies of fusion and transition were measured for different polymorphs of sulfathiazole and methylprednisolone [24]. The DTA thermograms shown in Fig. 4.5 demonstrate that Form-I is metastable with respect to Form-II, even... 

Platinum complexes, 161 Polarographic studies, 153, 154 of 2-aminothiazoles, 29 of 2-anilinothiazoles, 30 of 2-azothiazoles, 107, 108 Polyacrylonitrile, 105, 163, 164, 167 Polyamines, 156-168 Polycaprolactam, 156-168 Polyesters, 163, 165, 166, 167 Polyhalogenothiazole. reactivity of, 408-409 Polymers, e-caprolactam, butadiene, 438 Polymorphism, of sulfathiazole, 116 Positive colored image, 440 Postemergence activity, 134 Potassium salts, of acetamido thiazoles, 90 Potentiometric measurements, and amido-imido equilibrium, 116 and amino-imino equilibrium, 21 P.P.P. approximation, charge diagrams calculations by, 17... 

Not all polymorphism originates from conformational requirements, and many polymorphic situations exist because of different modes of molecular packing in the solid-state structures. For example, the two polymorphs of enalapril maleate exhibit very similar molecular conformations (as evidenced by the similarity in spectral characteristics), and the observed differences in crystal structure, therefore, are attributed to different modes of crystal packing. Sufficient differences in the solid-state C-NMR spectra of the four polymorphs of sulfathiazole were observed to enable the use of this technique as an analytical tool, but these differences could not be ascribed to differences in molecular conformations among the polymorphs. ... 

In their simplest application, solid-state NMR spectra can be used to differentiate qualitatively between polymorphs or solvates, much in the manner described for vibrational spectroscopy. Such data have been reported for the polymorphs of sulfathiazole [147], cyclopentthiazide [148], and indomethacin [149]. The technique can also be profitably used to differentiate between anhydrate and solvate phases, as has been reported for ampicillin [123], androstanolone [150], and dirithromycin [151]. 

Suitable manipulation of the dissolution medium can sometimes inhibit the conversion of one polymorph to another during the dissolution process, thus permitting the measurement of otherwise unobtainable information. In studies on the polymorphs of sulfathiazole and methylprednisolone, Higuchi, who used various alcohols and additives in the dissolution medium to inhibit phase transformations, first employed this approach [87], Aguiar and Zelmer were able to characterize thermodynamically the polymorphs formed by chloramphenicol palmitate and mefenamic acid by means of dissolution modifiers [88], Furthermore, the use of an aqueous ethanol medium containing 55.4%... 

Solid-state C NMR spectroscopy (SS-NMR) is a powerful and sensitive technique for polymorph characterization and differentiation. Since different polymorphs have different crystal structures, the chemical environment of at least a few of the atoms will differ from one structure to another. This technique also provides valuable crystallographic information, such as the number of crystallo-graphically independent molecules in the crystal structure due to doubled peaks for the same C atom. In addition to C NMR, N CP-MAS NMR (cross-polarized magic-angle spinning) is useful for characterizing polymorphic systems, for example, polymorphs of sulfathiazole, those containing N-heterocycles, and neutral co-crystal versus salt formation. ... 

Chamot, E. M. and Mason, C. W. (1973). Handbook of chemical microscopy. Vol. 1, 3rd edn. Principles and Use of Microscopes and Accessories. Physical Methods for the Study of Chemical Problems, Wiley-Interscience, New York. [22,46,48, 95] Chan, F. C., Anwar, J., Cernik, R., Barnes, R. and Wilson, R. M. (1999). Ab initio structure determination of sulfathiazole polymorph V from synchroton x-ray powder diffraction data. J. Appl Crystallogr, 32,436 1. [111]... 

The supramolecular assembly process can be controlled so that the precursor nuclei in solution adopt a structure that resembles the structure of the desired crystalline modification. " This concept has been used in the design of nucleation inhibitors to prevent growth of the stable polymorph and enhance the growth of the metastable polymorph. Davey and coworkers have explained the solvent dependent polymorph appearance of sulfathiazole by analyzing the intermolecular interactions in the various polymorphic structures, and comparing them with the supramolecular assemblies that could exist in the different solvents. In this case, however, the solvent dependent selective crystallization of a polymorph was not correlated with solubility. 

Figure 14. Proposed supramolecular assembly processes of sulfathiazole polymorphs in w-propanol. Reprinted from Blagden etal. (1998) with permission from The Royal Society of Chemistry.

Hooton JC, German CS, Davies MC, et al. Comparison of morphology and surface energy characteristics of sulfathiazole polymorphs based upon single particle studies. Eur J Pharm Sci 2006 28(4) 315-324. 

Kordikowski A, Shekunov T, York P. Polymorph control of sulfathiazole in supercritical CO2. Pharm Res 2001 18 685-688. 

Kordikowski et al. inferred that SEDS crystallization of sulfathiazole polymorphs from methanol is controlled primarily by thermodynamics, since varying the flow rate of methanol modified the particle size, but not the crystal form of sulfathiazole (38). 

Thermal analysis has been used to identify and characterize polymorphs of chlordiazepoxide hydrochloride, phenobarbital monohydrate, chloramphenicol palmitate, 3 (3-hydroxy-3-methyl-butylamino)-5-methyl-as. triazino ZB,6-b7 indole (SKF 30097), sulfathiazole, and sulfanilamide-d4. Solubility vs. solvent composition diagroms have been useful in the systematic study of pseudopolymorphism in the antibiotics cephaloglycin and cephalexin. This technique is recommended for the detection of solvate farmation when the instability of the compound at elevated temperatures precludes the use of conventional thermal methods, or when poor crystal development limits the use of microscopic methods. 

Raman spectroscopy was also used to probe the nature of a pharmaceutical formulation, in the form of sulfathiazole-povidone coprecipitates (6). Such systems tend to improve dissolution of relatively poorly water-soluble drugs, possibly by the stabilization of a metastable polymorphic form of the drug. The Raman investigation probed the nature of the coprecipitates and concluded that there was no evidence for alteration of the solid-state properties of the drug the experimentally derived increase in drug dissolution resulted from a decrease in the particle size of the therapeutic agent within the drug-polymer formulation. 

Raman spectroscopy has been used to characterize polymorphic forms of griseofulvin [50] and sulfathiazole [51]. In both of these studies, the lattice... 

Sulfathiazole has been found to crystallize in three distinct polymorphic forms, all of which are kinetically stable in the solid state but two of which are unstable in contact with water [130]. As evident in Fig. 20, the initial intrinsic dissolution rates are different, but as forms I and II convert into form III, the dissolved concentrations converge. Only the dissolution rate of form III was constant during the studies, indicating it to be the thermodynamically stable form at room temperature. Aqueous suspensions of forms I or II were all found to convert into form III over time, supporting the finding of the dissolution studies. Interestingly, around the melting points of the three polymorphs, form I exhibited... 

Antipin, M. Y, Timofeeva, T. V., Clark, R. D., Nesterov, V. N., Dolgushin, F. M., Wu, J. and Leyderman, A. (2001). Crystal structures and molecular mechanics calculation of nonlinear optical compounds 2-cyclooctylamino-5-nitropyridine (COANP) and 2-adamantylamino-5-nitropyridine (AANP). New Polymorphic modifcation of AANP and electrooptic effects. /. Mater. Chem., 11, 351-8. [213] Apperley, D. C., Fletton, R. A., Harris, R. K., Lancaster, R. W., Tavener, S. and Threlfall, T. L. (1999). Sulfathiazole polymorphism studied by magic-angle spinning NMR. / Pharm. ScL, 88, 1275-80. [135,139f]... 

Roberts, R.J. Rowe, R.C. Influence of polymorphism on the Young s modulus and yield stress of carbamazepine, sulfathiazole, and sulfanilamide. Int. J. Pharm. 1996,129, 79-94. 

The antibacterial sulfathiazole presents five polymorphic structures. The modification of the operating conditions in a DG antisolvent process allowed control over product composition so that it was possible to produce three of the polymorphic forms separately. 

Examine the five spectra in Fig. 7.14 of five sulfathiazole polymorphs [57]. Not only are the five spectra distinct, but notice that the spectrum of Form I contains several doublets. The doubling of resonance absorptions in not only Form I but also in Forms II and III (e.g. the resonance absorptions for C9) indicates that these crystal forms contain two molecules in the asymmetric crystallographic unit while Forms IV and V each contain only one molecule in the asymmetric crystallographic unit. That is, the fundamental building blocks of Forms I-III... 

Fig. 7.14 Solid-state CP/MAS NMR spectra of five sulfathiazole polymorphs [57],...

The goal of early stage solid-state analysis is the determination of the tendency of a compound to crystallize into different forms. It may have many forms like sulfathiazole with at least four polymorphs [6] or methylestradiol with one anhydrous form, two hydrated forms and at least two solvated forms [4]. This information guides the course of the future studies. If only one pharmaceutically significant form exists, then the subsequent studies should be straightforward and relatively rapid. If many forms exist, choosing the optimal form for development may require extensive time and study. It is useful to operate on the principle that all organic compounds crystallize in different forms and that the only questions are How many and How important McCrone [7] put the matter this way ... 

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