Solubility, Polymorphism, Crystallinity, Crystal Habit, and Drying Scheme of (R, S)-(±)-Sodium Ibuprofen Dihydrate - Pharmaceutical Technology

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Solubility, Polymorphism, Crystallinity, Crystal Habit, and Drying Scheme of (R, S)-(±)-Sodium Ibuprofen Dihydrate
The racemic compound (R, S)-()-ibuprofen is a popular and well understood active pharmaceutical ingredient, but it has several disadvantageous formulation properties such as poor solubility, low melting point, and potential esterification with excipients containing an hydroxyl group. The authors investigate the use of an (R, S)-()-ibuprofen salt to evaluate these problems using various analytical methods to determine the polymorphism, crystallinity, and drying scheme.

Pharmaceutical Technology

Figure 9
An endothermic solid–solid transformation with structural editing from a racemic compound to an anhydrous racemic conglomerate started to take place as indicated by the many small peaks from 100–190 C because the enthalpies of fusion of SS or RR interactions (10.49 kcal/mol) were higher than those of RS interactions (8.71 kcal/mol) (24). As the temperature increased, the anhydrous (R, S)-()-sodium ibuprofen eventually melted into liquid around 200 C . The sandwiched layer of water in the racemic (R, S)-()-sodium ibuprofen dihydrate also was completely removed by vacuum-drying either at 40 C for 4 h or at 90 C for 2 h (see Figure 7) (24). The DSC scan of an anhydrous sodium ibuprofen obtained by vacuum-drying either at 40 C for 4 h or at 90 C for 2 h exhibited a hump from 50–90 C (see Figure 7), indicating an endothermic, ongoing diffusive restructuring of the RS packing to form a higher energy state of the SS or RR packing that had not been completely finished during the annealing period at 40 C for 4 h or 90 C for 2 h under vacuum.

Figure 10
A typical PXRD diffractograph of (R, S)-()-ibuprofen dihydrate solids grown from water and oven-dried at 40 C for 4 h in air is shown in Figure 8. A SEM micrograph (see Figure 9) showed when the water molecules of racemic (R, S)-()-sodium ibuprofen dihydrate partially were removed under the high vacuum inside the SEM chamber, the R-layer and the S-layer stacked in the [001] direction were unzipped like a zipper in the [100] direction as seen in Figure 10, which was redrawn (12) by computer software (Diamond 3.1, Crystal Impact GbR, Brandenberg Germany). The authors believe the tiny elongated pores of the anhydrous sodium ibuprofen gave rise to its hygroscopic nature.

Crystallinity of all crystals harvested from solvent screening was approximated using the following relationship (13, 25):

Figure 11
All of the DSC endotherms (melting peaks) for racemic (R, S)-()-sodium ibuprofen dihydrate crystals produced from seven of nine good solvents and oven-dried at 40 C for 4 h in air were compared with the DSC endotherm for racemic (R, S)-()-sodium ibuprofen dihydrate crystals grown from methanol with the highest heat of melting of 54.95 J/g near 200 C as a standard. These results are summarized in Table IV.


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