Naproxen dissolution

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... 

Mura, P, Bettinetti, G. P, Cirri, M., Maestrelli, F., Sorrenti, M., and Catenacci, L. 2005. Solid-state characterization and dissolution properties of naproxen-arginine-hydroxyptjbtnylelodextrin ternary system. 

Naproxen sodium tablets were used in an in vivo-in vitro evaluation with four different polymeric dispersions, cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), 50 50 CAP/CAT, and methacrylic acid copolymer [64], The study indicated that coating material that dissolves at a more acidic pH in vitro (such as CAT at pH 4.5) will also dissolve at a more acidic pH in vivo (i.e., the coating dissolves higher up in the GI tract). In addition, it was found that aging did not markedly affect dissolution characteristics of CAT or methacrylic acid copolymer-coated tablets. 

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]. 

Hirasawa and coworkers prepared a naproxen solid dispersion by melting, followed by rapid cooling with liquid nitrogen using lactose as a carrier. The dissolution studies of naproxen indicated that the dissolution rate was markedly increased in solid dispersions compared with physical mixtures and pure drugs. 

In wet granulation, the quantity of solvent, usually water, has a definite influence on the tablet properties. Increasing the amount of water as granulation liquid gave naproxen tablets with a significantly higher dissolution rate [534], ace-... 

Usually companies do not investigate other salt-forming species other than those shown in Table 3.8. However, Gu and Strickley (1987) have described the physical properties of the tris-(hydroxymethyl)aminomethane (THAM) salts of four analgesic/antiinflammatory agents with sodium salts and free acids. They concluded that the THAM salts had superior hygroscopicity properties compared to the sodium salts and did not show any loss in aqueous solubility or intrinsic dissolution rate. The one exception to this was the THAM salt of naproxen. Ketoralac is now marketed as the tromethamine or THAM salt. 

Mura, R Faucci, M.T. Manderioli, A. Bramanti, G. Parrini, P. Thermal behavior and dissolution properties of naproxen from binary and ternary solid dispersion. Drug Dev. Ind. Pharm. 1999, 25 (3), 257-264. 

Naproxen, a nonsteroidal anti-inflammatory drug, is practically insoluble in water. F or pharmaceutical application, improvement in the dissolution properties has been expected. Dissolution properties of naproxen in the JP first fluid (pH 1.2) were studied according to the JP paddle method (Fig. 8) [18]. A mixture with CPG 120 showed a dissolution curve similar to that of intact naproxen erystals. It is noteworthy that the dissolution of naproxen was significantly improved in the heated sample with CPG 120, especially in the initial stage of dissolution. In... 

FIG. 8 Dissolution patterns of naproxen in JP first fluid at 37.0"C. (a) Naproxen-CPG 120 system (b) naproxen-CPG 1000 system. ( ) Naproxen crystals (O) fi esh mixture of 10% naproxen crystal and 90% CPG (O) same mixture after heating at 90°C for 3 h. Each point represents the mean value (n = 3). (From Ref 18.)... 

Lobmtmn K, Laitinen R, Grohganz H, Gordon KC, Strachan C, Rades T, (2011) Coamotphous drug systems enhanced physical stability and dissolution rate of indomethacin and naproxen. Mol Pharm 8(5) 1919-1928... 

A similar combination between a poorly soluble NS AID and an antihistaminic drug was investigated by Allesp et al. (2009). Their aim was to prepare co-amorphous blends of naproxen and cimetidine, with molar ratios (and not weight ratios) of 2 1, 1 1, and 1 2 to study potential intermolecular interactions and stability advantages at a molar level. The co-amorphous blends were then compared to the individual drugs with respect to intrinsic dissolution, physical stability, and ease of amorphization. 

Lobmann et al. (2011) prepared co-amorphous binary blends of the two BCS class 2 drugs indomethacin and naproxen with the main aim to further investigate the type of molecular interactions in co-amorphous blends and their influence on recrystallization, dissolution and physicochemical properties. They were able to successfully produce co-amorphous blends at the molar ratios 2 1, 1 1, and 1 2 using quench cooling. Similar to the results obtained by Allespet al. (2009), naproxen showed poor physical stability in its pure amorphous form. However, in combination with indomethacin, stable co-amorphous single-phase systems could be obtained. 

Comparable results were also obtained in the physical stability study and for the intrinsic dissolution rates of co-amorphous indomethacin and naproxen at the 1 1 molar ratio. In spite of an intermediate Tg, this blend remained stable whereas the two other blends (1 2 and 2 1) showed recrystallization events of the excess component. The dissolution smdy revealed an increased dissolution rate, compared to the individual crystalline and amorphous (only indomethacin) dmgs, and a synchronized release of both dmgs in the co-amorphous 1 1 blend (Fig. 21.3). 

Fig. 21.2 Intrinsic dissolution profiles of naproxen (a) and cimetidine (b) showing the dissolution enhancement from the co-amorphous (co-milled) mixture compared to the crystalline and amorphous (only cimetidine) references. (Reprinted from Alles0 et al. 2009, with permission from Elsevier)...

Fig. 21.3 Intrinsic dissolution profiie (nmoi/mL/min) of the co-amorphous 1 1 mixture showing the pair-wise (synchronized) reiease of the heterodimer of indomethacin and naproxen (depicted in the lower right comer), at the same rate. (Reprinted with permission from Lobmann et al. 2011, American Chemical Society)...

Mura P, Maestrelli F, Cirri M (2003) Ternary systems of naproxen with hydroxypropyl-p-cyclodextrin and aminoacids. Int J Pharm 260 293-302 Mura P, Bettinetti GP, Cirri M, Maestrelli F, Sorrenti M, Catenacci L (2(X)5) Solid-state chtirac-terization and dissolution properties of Naproxen-Arginine-Hydroxypropyl-[beta]-cyclodextrin ternary system. Eur J Pharm Biopharm 59 99-106 Newman A, Knipp G, Zografi G (2012) Assessing the performance of amorphous solid dispersions. J Pharm Sci 101 1355-1377... 

G.P. Bettinetti, and P. Mura, Dissolution properties of naproxen in combinations with polyvinylpyrrolidone, Drug Dev. Ind. Pharm., 20,1353-1366,1994. 

Dry granulation via slugging and roller compaction of hydroxypropyhnethyl-cellulose with naproxen, nifedipine, or carbazepine resulted in improvement of their dissolution profiles. The mechanism for dissolution enhancement was believed to be a microenviromnent hydroxypropyhnethylcellulose surfactant effect facilitated by plaeing the hydroxypropyhnethylcellulose in close proximity to the drug as simple mixing did not result in enhanced dissolution (40). Another example was the use of polyethylene 40 hydrogenated castor oil to improve the in vitro release of hydrochlorothiazide (41). The release was dependent on the concentration of surface active... 

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