Crystal structure of Brinzolamide: a carbonic anhydrase inhibitor

In the crystal structure of Brinzolamide, the various hydrogen bonds present lead to the formation of a bilayer structure. The absolute configuration of the asymmetric C atom was determined to be R by resonant scattering.


Chemical context
The crystal structures of organic solids are dominated mainly by hydrogen-bonding interactions (Steiner, 2002). Hydrogen bonding plays a crucial role in polymorphism of active pharmaceutical ingredients (Vippagunta et al., 2001). Brinzolamide (Conrow et al., 1999), is a carbonic anhydrase inhibitor used for the treatment of open-angle glaucoma or ocular hypertension (March & Ochsner, 2000). Herein,we report on the crystal structure of Brinzolamide and the hydrogen-bonding interactions present in the crystal packing.

Supramolecular features
There are three kinds of hydrogen-bonding interactions in the crystal of Brinzolamide (Table 1 and Figs. 2 and 3). The sulfonamide group is involved in hydrogen bonding [N1Á Á ÁN3 = 2.886 (2) Å , Table 1] with the secondary amine, forming a C(8) chain along the b-axis direction. The sulfonamide group is also involved in hydrogen bonding with the methoxy group [N1Á Á ÁO5 = 2.841 (2) Å , Table 1], linking the chains to form sheets parallel to the bc plane ( Fig. 2 and Table 1). There also exists another hydrogen bond between the sulfonamide and the secondary amine [N3Á Á ÁO1 = 3.042 (2) Å , Table 1], linking the sheets to form a unique bilayer structure (Fig. 3).

Figure 1
The molecular structure of the title compound, showing the atom labelling and 30% displacement ellipsoids. Table 1 Hydrogen-bond geometry (Å , ). in the case of BUXDEE, fused to the N-C bond. The thiazine ring in BUFQIE has a distorted twist-boat conformation, while in BUFQIE all four independent molecules have halfchair conformations. This is in contrast to the situation in the title compound where the thiazine ring has an envelope conformation with the N atom as the flap.

Synthesis and crystallization
The enantioselective synthesis of Brinzolamide has been reported by Conrow et al., (1999). It is marketed under the trade name of Azopt by Alcon Laboratories, Inc., Fort Worth, Texas 76134, USA. Colourless prismatic crystals of Brinzolamide (383 mg, 1 mmol) were obtained by slow evaporation of a solution in chloroform (15 ml).

Special details
Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes. Refinement. Refinement of F 2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F 2 , conventional R-factors R are based on F, with F set to zero for negative F 2 . The threshold expression of F 2 > 2sigma(F 2 ) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F 2 are statistically about twice as large as those based on F, and R-factors based on ALL data will be even larger.