Sulfanilamide polymorphism

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. 

Figure 3.2.14 13C CPMAS spectra of various polymorphs of sulfanilamide. Reproduced with permission from Ref. [33].

Conformational differences can result in variations in local electron density and NMR can be an ideal probe for this type of behavior, via the chemical shielding tensor [31, 32]. For example detailed inter- and intramolecular conformations can be described at high resolution. Proton sites and hydrogen bonds, which are usually averaged in solution state NMR and not easily assessed in crystallographic studies, can be directly determined by solid state NMR. In Fig. 3.2.14 is presented a typical example in which the different polymorphs of sulfanilamide can be distinguished by their 13C CPMAS spectra [33],... 

The AAP approach, with some variations, has recently been applied with varying degrees of success to the prediction of several other structures including, in order of increasing molecular complexity, high pressure solid phases of benzene [73], the three polymorphs of sulfanilamide [74], and the low and high temperature phases of poly(p-hydroxybenzoic acid) [75]. 

At any one temperature and pressure, only one crystal (polymorph) form will be stable. Any other polymorph found under these condition is metastable and will eventually convert to the stable form, but the conversion may be very slow (sometime can take years). The metastable form is a higher energy form and usually has a lower melting point, greater solubility, and faster dissolution rate. Examples are chloramphenicol palmitate (Aguir etal. 1967) and sulfameter (Khalil et al. 1972). This sulfanilamide is reported to have six polymorphs. Crystalline form II is about twice as soluble as crystalline form III. Studies in normal subjects showed that the rate and extent of absorption is approximately 40% greater from form II. Table 8.3 provides a few examples of drugs that exhibit polymorphism. 

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. 

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