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.

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Table IV: Enthalpy of dehydration, enthalpy of melting, and crystallinity of (R, S)-(6)-sodium ibuprofen dihydrate produced from seven of nine solvents arranged by the total ascending Hildebrand values.
To verify the solubility sphere, the DS–API values of n-propanol and cyclohexane were calculated using Equation 4. They were 18.18 and 35.24 MPa1/2, respectively indicating that n-propanol was inside the solubility sphere (18.18 MPa1/2 < 25.92 MPa1/2 ), but cyclohexane was outside (35.24 MPa1/2 > 25.92 MPa1/2 ). These calculations agreed with the experimental observations that (R, S)-()-sodium ibuprofen dihydrate dissolved well in n-propanol at 25 C with a solubility of 53 mg/mL but dissolved poorly in cyclohexane at 25 C with a solubility < 0.27 mg/mL.

Figure 7
Solids generated from all nine good solvents were isolated and analyzed with DCS, TGA, and PXRD. Solids, however, grown from benzyl alcohol and DMSO (two solvents with high-boiling points) were still wet after oven-drying in air at 40 C for 4 h and formed solvates with ill-defined DSC and TGA results. Only seven of nine solids could be represented by a typical DSC response of solids generated from water (see Figure 6). The wide-base endotherm from 50–100 C as supported by the boiling point of water and an approximately 13% weight loss in Figure 2 was corresponded to the enthalpy of dehydration. The enthalpies of dehydration (ΔHdehydration) of seven solvents are summarized in Table IV. The enthalpies of dehydration were 6.6–12.2 kcal/mol of water loss (23).

Figure 8
Based on the similar DSC response (see Figure 6) and weight-loss pattern (see Figure 2) for all solids grown from THF, n-butyl alcohol, IPA, DMF, ethanol, methanol, and water, only one pseudopolymorph was identified for (R, S)-()-sodium ibuprofen dihydrate. The typical DSC response (see Figure 6) showed that the chemically bonded water molecules sandwiched between a layer of all (R)-()-sodium ibuprofen molecules (R-layer) and a layer of all (S)-(–)-sodium ibuprofen molecules (S-layer) in the racemic (R, S)-()-sodium ibuprofen dihydrate compound were completely removed near 100 C (see Figure 2) (12).


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