Characterization of a diflunisal polyethylene glycol solid dispersion system

doi:10.1016/0378-5173(89)90195-6

International Journal of Pharmaceutics

Volume 51, Issue 3, 1 May 1989, Pages 225-232

https://doi.org/10.1016/0378-5173(89)90195-6 Get rights and content

Abstract

This work involves the study of the nature of a possible interaction of diflunisal and polyethylene glylol (PEG) in solution and the solid state. Dynamic and equilibrium solubility studies, solvent power calculation and heat of solution determination were used to elucidate the mechanism of interaction in solution. Differential scanning calorimetric studies, infrared spectroscopy and hot stage microscopy were used to elucidate the mechanism of interaction in the solid state. From these studies it was concluded that no chemical interaction takes place between diflunisal and PEG neither in solution nor in the solid state. The increased solubility of diflunisal when dispersed in PEG could be attributed to one or more of several factors such as local solubilization action, reduction in particle size of the drug, alteration of the surface characteristics of the drug particles, increased thermodynamic activity and the high affinity of the drug to the polymer solution.

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Supramolecular nano-engineered lipidic carriers based on diflunisal-phospholipid complex for transdermal delivery: QbD based optimization, characterization and preclinical investigations for management of rheumatoid arthritis
2017, International Journal of Pharmaceutics
Citation Excerpt :
Hence, there is a practical need to enhance the solubility of DIF before the formulation development. In literature reports, various techniques of solubility enhancement of DIF like polyethylene glycol solid dispersion (Najib and Suleiman, 1989), solid dispersion with Eudragit RS100 and RL 100 (Pignatello et al., 2001), co-precipitates of DIF with polyvinylpyrrolidine; PVP K30 (Rodriguez-Espinosa et al., 1998), β-cyclodextrin inclusion complex (Zugasti et al., 2009), DIF-pyrazinamide cocrystal (Évora et al., 2011) and DIF-nictotinamide cocrystal (Wang et al., 2013) were reported. This is the very first report of DIF-phospholipid complex (DIF-PL) to improve the solubility of DIF.
Diflunisal (DIF) is used for treatment of rheumatoid arthritis, osteoarthritis etc. DIF-phospholipid complex (DIF-PL complex) was prepared by solvent-evaporation method and characterized by molecular docking studies, SEM, FTIR, DSC, PXRD studies. Further, the DIF-PL complex was incorporated into supramolecular nano-engineered lipidic carriers (SNLCs) for transdermal delivery. The optimization exercise was done using Face centered cubic design (FCCD) after screening of variables by L8 Taguchi orthogonal array design. The optimized SNLC formulation depicted average particle size (188.1 nm), degree of entrapment (86.77 ± 3.33%), permeation flux (5.47 ± 0.48 μg/cm²/h) and skin retention (17.72 ± 0.68 μg/cm²). The dermatokinetic studies revealed the higher concentration of DIF in dermis. The Confocal laser scanning microscopy (CSLM) studies revealed penetration of SNLCs into the deeper layers of skin. The results of mice ear edema depicted significant inhibition of ear edema (76.37 ± 12.52%; p < 0.05). In CFA induced rheumatoid arthritis model, the inhibition of paw edema was significantly higher (73.85 ± 14.5%). The levels of TNF-α were reduced in synovial fluid (146.74 ± 1.69 pg/mL) and serum (132.43 ± 2.70 pg/mL). Furthermore, the licking and biting time was reduced in formalin induced hyperalgesia model. Hence, it can be concluded that dual formulation strategy based SNLCs were promising in treatment of pain and inflammation associated with rheumatoid arthritis.
Gelatine enhances drug dispersion in alginate bilayer film via the formation of crystalline microaggregates
2013, International Journal of Pharmaceutics
Citation Excerpt :
The shift in peaks may result from polymer–ibuprofen interactions, which caused by the formation of crystalline microaggregates of drug and the considerable dispersion of microaggregates within the amorphous polymeric matrix. However, the strong interaction between the drug and the polymers does not necessarily indicate drug–polymer incompatibility (Najib and Suleiman, 1989; Bettinetti et al., 1991; Bettinetti and Mura, 1994). There was no significant difference (p > 0.05) in the endotherms of the SA and SA/G films.
In our previous study, a novel alginate-based bilayer film for slow-release wound dressings was successfully developed. We found that alginate alone yielded poor films; however, the addition of gelatine had significantly enhanced the drug dispersion as well as the physical properties. Here, an investigation of the drug–polymer interactions in the bilayer films was carried out. Drug content uniformity test and microscopy observation revealed that the addition of gelatine generated bilayer films with a homogenous drug distribution within the matrix. The FTIR and XRD data showed an increase in film crystallinity which might infer the presence of drug–polymer crystalline microaggregates in the films. DSC confirmed the drug–polymer interaction and indicated that the gelatine has no effect on the thermal behaviour of the microaggregates, suggesting the compatibility of the drug and excipients in the bilayer films. In conclusion, the addition of gelatine can promote homogenous dispersion of hydrophobic drugs in alginate films possibly through the formation of crystalline microaggregates.
Properties of solid dispersion of piroxicam in Pluronic F-98
2004, Journal of Drug Delivery Science and Technology
A solid dispersion approach (SD) has been developed to enhance the dissolution properties of insoluble drugs by improving their aqueous solubility. An insoluble drug, piroxicam (PXM), was dispersed in a water-soluble carrier, Pluronic F-98 (Pl. F-98). Different methods were employed to prepare such dispersion, namely: the solvent method (SM), the melting method (MM), the melting-solvent method (MSM), the co- grinding method (GM) and the kneading method (KM). Solid dispersion obtained using the solvent method was prepared using different solvents, namely: methylene chloride, acetone and chloroform. Different tools were used, to characterize the prepared solid dispersion, such as the infrared spectroscopy (IR), the powder X-ray diffractometry (XRD), differential scanning calorimetry (DSC) and scanning electron microscopy (SEM). The dissolution rate from the prepared SDs was determined in simulated gastric fluid and was found in the following order: KM > MM > GM > PM (physical mixture) > SM > MSM > PXM. Solubility of the free and of the dispersed drug was determined at different temperatures and solution heats were calculated. The results revealed that solubility of the dispersed drug was markedly enhanced by the rise in temperature. From this study, the increased dissolution rate in systems containing Pl. F-98 was probably the result of increased wettability and dispersibility, as well as particle size reduction of PXM and decrease in the crystalline fraction of the drug, since no interaction could be demonstrated between PXM and Pl. F-98.
Ternary naproxen:β-cyclodextrin:polyethylene glycol complex formation
2003, International Journal of Pharmaceutics
The aim of this study was to investigate the effect of the presence of the water-soluble polymer polyethylene glycol (PEG)—MW=35000 g/mol—on the complexation of the phototoxic anti-inflammatory drug naproxen, in its sodium salt form, with β-cyclodextrin (β-CD). The data revealed that the polymer does not interact with the uncomplexed naproxen whereas it does with the β-CD.
The presence of different proportions of PEG, in the 0–1% (w/w) range, systematically lowers K_app of the formation of the naproxen:β-CD inclusion complex. The reason for the decrease in the complexed drug is the presence of other competing equilibria, the first one is an interaction of the polymer with the β-CD, which in turn reduces the amount of free CD available for including the naproxen, and the second is the formation of a naproxen:β-CD:PEG ternary complex with lower affinity than the binary complex. The binding constant of these processes are K₂=(4.5±1.0)×10⁵ M⁻¹ and K₃=870±19 M⁻¹, respectively.
In addition the presence of the PEG produces an important change in the driving force of the complex formation. In this case the process is enthalpically unfavoured and entropically favoured; these are typical characteristics of processes governed by hydrophobic interactions.
The effect of spray drying solutions of bendroflumethiazide/polyethylene glycol on the physicochemical properties of the resultant materials
2003, International Journal of Pharmaceutics
The physicochemical properties of co-spray dried bendroflumethiazide (BFMT)/polyethylene glycol (PEG) 4000 composites were investigated. The co-spray dried composites produced from all BFMT/polymer solutions were amorphous. BFMT/PEG 4000 10 and 20% systems consisted of smooth spherical particles approximately 0.5–4 mm in diameter. Spray drying resulted in no significant production of the main BFMT degradant, 5-trifluoromethyl-2,4-disulphamoylaniline (TFSA), and for composites consisting of 90% PEG 4000 by weight of total solids, spray drying appeared a superior method of production than the melt method which resulted in significant BFMT degradation. All BFMT/PEG compressed discs showed initial increased release of BFMT compared to discs of micronised BFMT alone, with the spray dried BFMT/PEG 4000 10% system showing initial rates two to three times that of BFMT alone. The physical stability of amorphous BFMT was reduced on inclusion of PEG 4000, recrystallisation occurring more quickly with increasing amount of PEG 4000 in the composites. PEG in the co-spray dried systems appeared to degrade on storage and recrystallised samples failed to show the presence of PEG by differential scanning calorimetry (DSC), X-ray powder diffraction (XRD) or GPC. DSC results were consistent with BFMT/PEG forming a eutectic combination rather than a monotectic system.
Development and characterization of naproxen-chitosan solid systems with improved drug dissolution properties
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The solubilizing and amorphizing properties toward naproxen (a poorly water-soluble antiinflammatory drug) of chitosan, an emerging pharmaceutical biopolymer, have been investigated. Solid binary systems at different drug/polymer ratios have been prepared according to different techniques (mixing, cogrinding, kneading, coevaporation) using chitosan at low (CS-L_w) and medium (CS-M_w) molecular weight, and tested for dissolution properties. Drug-carrier interactions were investigated in both the liquid and solid state, by phase solubility analysis, differential scanning calorimetry, X-ray powder diffractometry, FT-IR spectroscopy, and scanning electron microscopy. Drug dissolution parameters improved with increasing the polymer amount in the mixture, reaching the highest values at the 1:9 (w/w) drug/polymer ratio, and CS-L_w was more efficacious than CS-M_w. Cogrinding was the most effective technique, showing the strongest amorphizing effect toward the drug and enabling an increase of more than ten times its relative dissolution rate. Coground mixtures at 3:7 (w/w) drug/polymer ratio were able to give directly compressed tablets which maintained unchanged the improved drug dissolution properties. Enhancer dissolution properties combined with its direct compression feasibility and antiulcerogenic action make CS-L_w an optimal carrier for developing fast-release oral solid dosage forms of naproxen.

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Characterization of a diflunisal polyethylene glycol solid dispersion system

Abstract

J. Pharm. Sci.

J. Pharm. Sci.

J. Pharm. Sci.

J. Pharm. Sci.

In. J. Pharm.

J. Pharm. Sci.

J. Pharm. Sci.

Solid dispersions of testosterone with reduced presystemic inactivation

J. Pharm. Sci.