Naproxen solubility

Figure 10 Effect of different cosolvents on solid (naproxen) solubility enhancement in SCCO2 at 333 K and 179.3 bar (66).

Fig. 3.2 Solubility profiles log S-pH. The dashed curves, representing uncharged precipitate in equilibrium with solution of the drugs, were calculated by Henderson-Hasselbalch equations. The dotted horizontal lines are estimates of the solubility of the charged form of the drugs, using either actual data (naproxen) or estimates based on the sdiff 3-4 approximation (atenolol and...

Oumada et al. [148] described a new chromatographic method for determining the aqueous pKa of dmg compounds that are sparingly soluble in water. The method uses a rigorous intersolvent pH scale in a mobile phase consisting of a mixture of aqueous buffer and methanol. A glass electrode, previously standardized with common aqueous buffers, was used to measure pH online. The apparent ionization constants were corrected to a zero-cosolvent pH scale. Six sparingly soluble nonsteroidal antiinflammatory weak acids (diclofenac, flurbiprofen, naproxen, ibu-profen, butibufen, fenbufen) were used successfully to illustrate the new technique. 

An interesting paper that attempted to relate dissolution of a poorly soluble acidic drug (naproxen) to simulated gastrointestinal flow in the presence of buffers was published by Chakrabarti and Southard [17]. In addition to showing that buffer type (citrate, phosphate, or acetate) had a significant impact on naproxen dissolution, these authors unexpectedly found that elevating a solid tablet into the flow channel of the flow-between-two-plates apparatus resulted in a substantial... 

The effects of added C02 on mass transfer properties and solubility were assessed in some detail for the catalytic asymmetric hydrogenation of 2-(6 -meth-oxy-2 -naphthyl) acrylic acid to (Sj-naproxen using Ru-(S)-BINAP-type catalysts in methanolic solution. The catalytic studies showed that a higher reaction rate was observed under a total C02/H2 pressure of ca. 100 bar (pH2 = 50bar) than under a pressure of 50 bar H2 alone. Upon further increase of the C02 pressure, the catalyst could be precipitated and solvent and product were removed, at least partly by supercritical extraction. Unfortunately, attempts to re-use the catalyst were hampered by its deactivation during the recycling process [11]. 

Claramonte, M. D. C., A. P. Vialard, and F. G. Vichez. 1993. An application of regularsolution theory inthestudy of the solubility of naproxen in some solvents used in topical preparafalnsL Pharm.94 23-30. 

Faucci, M. T. and P. Mura (2001). Effect of water-soluble polymers on naproxen complexation with natural and chemically modi e0-cyclodextrins.Drug Dev. Ind. Pharm., 27 909-917. 

The effect of various surfactants, the cationics-eetyl trimethyl ammonium bromide (CTAB), and cetyl pyridinium chloride (CPC), the anionic-sodium lauryl sulfate (SLS), and the nonionic-polysorbate 80 (Tween 80), on the solubility and ionization constants of some sparingly soluble weak acids of pharmaceutical interest was studied (Gerakis et al., 1993). Benzoic acid (and its 3-methyl-, 3-nitro-, and 4-tert-butyl-derivatives), acetylsalicylic acid, naproxen, and iopanoic acid were chosen as model drugs. The cationics, CTAB and CPC, were found to considerably increase th< ionization constant of the weak acidS Ka ranged from-0.21 to-3.57), while the anionic, SLS, showed a negligible effect and the nonionic, Tween 80, generally decreased the ionization constants Solubility of the acids increased in aqueous micellar and in acidiLed micellar solutions. 

The solubility and release of naproxen from Pluronic PF-127 micelles were studied as a function of temperature and pH by Suh and Jun (1996). The solubility of the drug at pH 2 was signiLcantly increased as a linear function of PF-127 concentrations for three temperatures. Naproxen was highly entrapped by the micelles as indicated by large partition coefLcient. The micellar solubilization was a spontaneous (AG 0) and exothermic (AH< 0) process that resulted in a less ordered state (AS > 0). In the presence of PF-127, the release of naproxen was sustained at pH 2 and inversely proportional to the surfactant concentration. In contrast, at pH 7, PF-127 had little effect on the membrane transport of naproxen. The release of naproxen from the PF-127 gel into isopropanol myristate was also found to be dependent on the medium pH with the highest release observed at pH 6.3. 

The choline salts of naproxen and tolmetin yielded marked solubility enhancements, even over that of the sodium salts. The aqueous solubility of the choline salt of naproxen was 6700 times the solubility of naproxen and almost twice that of naproxen sodium. The choline salt of tolmetin was almost 8000 times as soluble as the parent drug and almost 5 times as soluble as its sodium salt (Murti, 1993) (Cheenu dissertation, our unpublished results). Table 15.2 shows that the melting points and enthalpies of fusion are both affected by the formation of the choline salt, and in fact, the choline salt proved to be more thermally stable. 

Thermal Properties and Aqueous Solubilities of Naproxen, Tolmetin, and Their Salts3... 

The improved thermal stability of naproxen and tolmetin as a result of formation ofthe choline salt has already been noted. Stability studies of lincomycin as its hydrochloride or cyclamate salt revealed that the cyclamate counterion provided an enhanced thermal stability to the antibiotic without compromising the aqueous solubility (Neville and Ethier, 1971 Neville et al., 1971). 

Ting, S. S. T., S. J. Macnaughtn, D. L. Tomasko, and N. R. Foster. 1993. Solubility of naproxen in supercritical carbon dioxide with and without cosolveitrtisi Eng Chem ReS2 1471-1481. 

The lipase enzyme stereospecifically hydrolyzes the (+) isomer of naproxen ester. The enzyme is immobilized in the wall of an inside-skinned hollow fiber membrane. The racemic d and / naproxen ester mixture, dissolved in methyl isobutyl ketone, is introduced on the shell side of the fiber and an aqueous buffer solution is circulated through the fiber lumen. The lipase enzyme hydrolyzes the d form of naproxen ester, forming ethanol and naproxen d. Naproxen d is a carboxylic acid soluble in aqueous buffer but insoluble in methyl isobutyl ketone. Consequently naproxen d is removed from the reactor with the buffer solution. The naproxen / ester remains in the methyl isobutyl ketone solution. This technique achieves an essentially complete separation of the d and Z forms. In a clever final step... 

The highly water-soluble 2-hydroxypropyl-/i-cyclodextrin (2-HP-/1-CD) is a commercially useful general complexing agent. Inclusion complexes of poorly water-soluble Naproxen with 2-HP-/1-CD were useful to increase its solubility and dissolution rate, and resulted in an enhancement of bio-availability and minimized the gastrointestinal toxicity of the drug [69]. The water solubility of melatonin, which is an indole amide neurohormone, was also enhanced in a complex with 2-HP-/J-CD [70]. 

Figure 6.17 The classification of 42 drugs in the (solubility-dose ratio, apparent permeability) plane of the QBCS. The intersection of the dashed lines drawn at the cutoff points form the region of the borderline drugs. Key 1 acetyl salicylic acid 2 atenolol 3 caffeine 4 carbamazepine 5 chlorpheniramine 6 chlorothiazide 7 cimetidine 8 clonidine 9 corticosterone 10 desipramine 11 dexamethasone 12 diazepam 13 digoxin 14 diltiazem 15 disopyramide 16 furosemide 17 gancidovir 18 glycine 19 grizeofulvin 20 hydrochlorothiazide 21 hydrocortisone 22 ibuprofen 23 indomethacine 24 ketoprofen 25 mannitol 26 metoprolol 27 naproxen 28 panadiplon 29 phenytoin 30 piroxicam 31 propanolol 32 quinidine 33 ranitidine 34 salicylic acid 35 saquinavir 36 scopolamine 37 sulfasalazine 38 sulpiride 39 testosterone 40 theophylline 41 verapamil HC1 42 zidovudine.

Since naproxen is a carboxylic acid, they chose to make the carboxyl ate salt of an enantio-merically pure amine, and found that the most effective was this glucose derivative. Crystals were formed, which consisted of the salt of the amine and (S)-naproxen, the salt of the amine with (f )-naproxen (the diastereoisomer of the crystalline salt) being more soluble and so remaining in solution. These crystals were filtered off and treated with base basic, releasing the amine (which can later be recovered and reused) and allowing the (S)-naproxen to crystallize as its sodium salt. 

This approach was studied for naproxen trifluoroethylthioester [55], feno-profen trifluoroethylthioester [56], naproxen trifluoroethylester [57] and ibupro-fen 2-ethoxyethyl ester [58] (Scheme 6.15). Some of these reactions were not performed in water only, but in biphasic mixtures, due to solubility problems. This is a drawback from a green point of view, but the much higher yield and the fact that no recycling step is needed is a clear indication of the high efficiency of dynamic kinetic resolutions. 

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