A Comparative Evaluation of Mono-, Di- and Triglyceride of Medium Chain Fatty Acids by Lipid/Surfactant/Water Phase Diagram, Solubility Determination and Dispersion Testing for Application in Pharmaceutical Dosage Form Development

Purpose To compare physiochemical properties of mono-, diand triglycerides of medium chain fatty acids for development of oral pharmaceutical dosage forms of poorly water-soluble drugs using phase diagrams, drug solubility, and drug dispersion experiments. Methods Phase diagrams were prepared using a monoglyceride (glycerol monocaprylocaprate: Capmul MCM ® EP), a diglyceride (glycerol dicaprylate) and two triglycerides (glycerol tricaprylate

In vitro dispersion test that could serve as a predictive method for assessing performance of lipid-based drug delivery systems

A relatively simple in vitro dispersion test using the USP Dissolution Apparatus II filled with 250 ml of dispersion fluid (0.01M HCl) at 37°C and a rotation speed of 50 RPM was used to assess the performance of lipid-based formulations. Solutions of probucol in mixtures with the surfactant Cremophor® EL with four different medium chain lipids (glyceryl monocaprylocaprate, Capmul® MCM EP; glyceryl dicaprylate; glyceryl tricaprylate, Captex® 8000 EP/NF; caprylic/capric triglyceride, Captex® 355 EP/NF) were formulated and filled into Size 00 hard gelatin capsules (~1 g/capsule) for dispersion testing. Drug concentration in the dispersion fluid and the particle size of the dispersed phase as a function of time were measured with, and without, filtration through 0.45 micron filters. All the lipid/surfactant mixtures dispersed in 80%), indicating suitability for their use in immediate-release formulations. The particle size of the unfiltered samples confirmed whether a microemulsion (1000 nm) was formed. The dispersion test developed here could be used to screen different lipid-based formulations for in vitro performance. Justification for using an in vitro dispersion test to predict in vivo performance of lipid-based drug delivery systems has been provided

Development of solid SEDDS, III: application of Acconon® C-50 and Gelucire® 50/13 as both solidifying and emulsifying agents for medium chain triglycerides

Solid self-emulsifying drug delivery systems (SEDDS) for medium chain triglycerides (Captex® 355, ABITEC) were developed using stearoyl polyoxyl glycerides (Acconon® C-50, ABITEC and Gelucire® 50/13, Gattefosse) as both solidifying and emulsifying agents. Different mixtures of the lipid and each solidifying agent were heated to 65ºC until homogenously mixed clear liquids were formed. Probucol was dissolved as the model drug. The molten mass was then filled into hard gelatin capsules, which upon cooling to room temperature converted to a solid mass inside capsules. The triglyceride could be incorporated into the system to a concentration as high as 80% w/w, still maintaining the solid or semisolid consistency of the system. Powder XRD, DSC, microscopy (cross-polarization and confocal fluorescence techniques), dispersion test and particle size analysis of the solid systems with, and without, drug were conducted to characterize different formulations. The solidifying agents maintained their crystallinity in solid systems, while the lipids were interspersed in between crystalline regions. The drug remained solubilized in the lipid phase. The formulations dispersed almost completely in 2 hours with particle size of the dispersed lipid in the range of 250 to 500 nm when the lipid content in the formulation was up to 50% w/w. Thus, a novel method of developing solid formulations of liquid triglycerides by incorporating lipids in stearoyl polyoxyl glycerides has been developed

Development of Solid SEDDS, II: application of Acconon® C-44 and Gelucire® 44/14 as solidifying agents for self-emulsifying drug delivery systems of medium chain triglyceride.

Self-emulsifying drug delivery systems (SEDDS) are usually isotropic liquids consisting of drugs, lipids, surfactants and/or co-surfactants that spontaneously form fine oil-in-water emulsions in contact with water. Since a solid dosage form has better patient acceptance than a liquid, it was investigated whether liquid SEDDS containing medium-chain lipids (mono- or tri-glycerides) may be converted to solids or semisolids using lauroyl polyoxyl glycerides (Acconon® C-44, ABITEC, and Gelucire® 44/14, Gattefosse) as solidifying agents. Acconon® C-44 and Gelucire® 44/14 were melted at 65EC. The liquid lipids or the liquid lipidsurfactant mixtures, with and without dissolved drug (probucol), were mixed with the melts, and the hot liquid solutions were filled into hard gelatin capsules. The solutions solidified inside the capsules when cooled to room temperature. Acconon® C-44 and Gelucire® 44/14 had a greater propensity for solidifying the triglyceride of medium chain fatty acids (Captex® 355, ABITEC) rather than the monoglyceride. Powder XRD, DSC and microscopic analyses indicated that the lauroyl polyoxyl glycerides crystallized at room temperature, while the lipid or the lipid-surfactant mixtures present in the formulations remained interspersed in between solids as a separate liquid phase. The drug remained dissolved in the liquid phase and there was no crystallization of the drug. Although Acconon® C-44 and Gelucire® 44/14 are themselves surface active, the dispersion testing using the USP apparatus II at 50 rpm and 37EC using 250 ml of 0.01N HCl as the dispersion medium showed that a second surfactant (Cremophor® EL®, BASF) was required in the solid formulation to maximize drug release and dispersion. Formulations containing 1:1 and 3:1 w/w ratios of Captex® 355 and Cremophor® EL produced lipid particles in the range of 200 to 450 nm. Thus, a novel approach of preparing solid SEDDS resulting in submicron emulsions with particle size <500nm is presented

Development of Solid SEDDS, II: application of Acconon® C-44 and Gelucire® 44/14 as solidifying agents for self-emulsifying drug delivery systems of medium chain triglyceride.

Self-emulsifying drug delivery systems (SEDDS) are usually isotropic liquids consisting of drugs, lipids, surfactants and/or co-surfactants that spontaneously form fine oil-in-water emulsions in contact with water. Since a solid dosage form has better patient acceptance than a liquid, it was investigated whether liquid SEDDS containing medium-chain lipids (mono- or tri-glycerides) may be converted to solids or semisolids using lauroyl polyoxyl glycerides (Acconon® C-44, ABITEC, and Gelucire® 44/14, Gattefosse) as solidifying agents. Acconon® C-44 and Gelucire® 44/14 were melted at 65EC. The liquid lipids or the liquid lipidsurfactant mixtures, with and without dissolved drug (probucol), were mixed with the melts, and the hot liquid solutions were filled into hard gelatin capsules. The solutions solidified inside the capsules when cooled to room temperature. Acconon® C-44 and Gelucire® 44/14 had a greater propensity for solidifying the triglyceride of medium chain fatty acids (Captex® 355, ABITEC) rather than the monoglyceride. Powder XRD, DSC and microscopic analyses indicated that the lauroyl polyoxyl glycerides crystallized at room temperature, while the lipid or the lipid-surfactant mixtures present in the formulations remained interspersed in between solids as a separate liquid phase. The drug remained dissolved in the liquid phase and there was no crystallization of the drug. Although Acconon® C-44 and Gelucire® 44/14 are themselves surface active, the dispersion testing using the USP apparatus II at 50 rpm and 37EC using 250 ml of 0.01N HCl as the dispersion medium showed that a second surfactant (Cremophor® EL®, BASF) was required in the solid formulation to maximize drug release and dispersion. Formulations containing 1:1 and 3:1 w/w ratios of Captex® 355 and Cremophor® EL produced lipid particles in the range of 200 to 450 nm. Thus, a novel approach of preparing solid SEDDS resulting in submicron emulsions with particle size <500nm is presented

Effect of Difference in Fatty Acid Chain Lengths of Medium- Chain Lipids on Lipid/Surfactant/Water Phase Diagrams and Drug Solubility

Lipids consisting of medium chain fatty acids are commonly used in the development of lipid-based selfemulsifying and self-microemulsifying drug delivery systems. However, no systematic approach to selecting one lipid over another has been reported in the literature. In this study, propylene glycol (PG) monoester (PG monocaprylate, Capmul PG-8®) and PG diester (PG dicaprylocaprate, Captex 200P®) of C8-fatty acids were compared with PG monoester (PG monolaurate, Capmul PG-12®) and PG diester (PG dilaurate, Capmul PG-2L®) of C12-fatty acids with respect to their phase diagrams, and especially for their ability to form microemulsions in the presence of a common surfactant, Cremophor EL®, and water. The solubility of two model drugs, danazol and probucol, in the lipids and lipid/surfactant mixtures were also compared. The effect of the chain length of medium-chain fatty acids (C8 versus C12) on the phase diagrams of the lipids was minimal. Both shorter and longer chain lipids formed essentially similar microemulsion and emulsion regions in the presence of Cremophor EL® and water, although the C12-fatty acid esters formed larger gel regions in the phase diagrams than the C8-fatty acid esters. When monoesters were mixed with their respective diesters at 1:1 ratios, larger microemulsion regions with lower lipid particle sizes were observed compared to those obtained with individual lipids alone. While the solubility of both danazol and probucol increased greatly in all lipids studied, compared to their aqueous solubility, the solubility in C12-fatty acid esters was found to be lower than in C8-fatty acid esters when the lipids were used alone. This difference in solubility due to the difference in fatty acid chain length, practically disappeared when the lipids were combined with the surfactant

Development of solid SEDDS, III: application of Acconon® C-50 and Gelucire® 50/13 as both solidifying and emulsifying agents for medium chain triglycerides

Solid self-emulsifying drug delivery systems (SEDDS) for medium chain triglycerides (Captex® 355, ABITEC) were developed using stearoyl polyoxyl glycerides (Acconon® C-50, ABITEC and Gelucire® 50/13, Gattefosse) as both solidifying and emulsifying agents. Different mixtures of the lipid and each solidifying agent were heated to 65ºC until homogenously mixed clear liquids were formed. Probucol was dissolved as the model drug. The molten mass was then filled into hard gelatin capsules, which upon cooling to room temperature converted to a solid mass inside capsules. The triglyceride could be incorporated into the system to a concentration as high as 80% w/w, still maintaining the solid or semisolid consistency of the system. Powder XRD, DSC, microscopy (cross-polarization and confocal fluorescence techniques), dispersion test and particle size analysis of the solid systems with, and without, drug were conducted to characterize different formulations. The solidifying agents maintained their crystallinity in solid systems, while the lipids were interspersed in between crystalline regions. The drug remained solubilized in the lipid phase. The formulations dispersed almost completely in 2 hours with particle size of the dispersed lipid in the range of 250 to 500 nm when the lipid content in the formulation was up to 50% w/w. Thus, a novel method of developing solid formulations of liquid triglycerides by incorporating lipids in stearoyl polyoxyl glycerides has been developed

In Vitro Dispersion Test Can Serve as a Predictive Method for Assessing Performance of Lipid-based Drug Delivery Systems

A relatively simple in vitro dispersion test using the USP Dissolution Apparatus II with 250 mL of dispersion fluid (0.01M HCl) at 37°C and the rotation speed 50 RPM was used to assess the performance of lipid-based formulations. Solutions of probucol in mixtures of the surfactant Cremophor EL with four different medium chain lipids (glycerol monocaprylocaprate, Capmul MCM EP; glycerol dicaprylate; glycerol tricaprylate, Captex 8000 EP/NF; caprylic/capric triglyceride, Captex 355 EP/NF) were formulated and filled in Number 00 hard gelatin capsules (~1 g/capsule) for dispersion testing.. Drug concentration in the dispersion fluid and the particle size of the dispersed phase as a function of time were measured without and with filtration through filters of 0.45 micron pore size. All lipid/surfactant mixtures used dispersed (≥80%) in &lt;1 h, indicating their suitability for the development of immediate-release formulations. The particle size of unfiltered samples indicated whether microemulsion (&lt;250 nm), very fine emulsion (250-1000 nm) or emulsion with relative larger sizes (&gt;1000 nm) were formed. The dispersion test developed is capable of screening different lipid-based formulations for in vitro performance. Justification is also provided for using the dispersion test as a predictive method for assessing in vivo performance of such formulations

Effect of Difference in Fatty Acid Chain Lengths of Medium-Chain Lipids on Lipid-Surfactant-Water Phase Diagrams and Drug Solubility

Lipids consisting of medium chain fatty acids are commonly used in the development of lipid-based selfemulsifying and self-microemulsifying drug delivery systems. However, no systematic approach to selecting one lipid over another has been reported in the literature. In this study, propylene glycol (PG) monoester (PG monocaprylate, Capmul PG-8®) and PG diester (PG dicaprylocaprate, Captex 200P®) of C8-fatty acids were compared with PG monoester (PG monolaurate, Capmul PG-12®) and PG diester (PG dilaurate, Capmul PG-2L®) of C12-fatty acids with respect to their phase diagrams, and especially for their ability to form microemulsions in the presence of a common surfactant, Cremophor EL®, and water. The solubility of two model drugs, danazol and probucol, in the lipids and lipid/surfactant mixtures were also compared. The effect of the chain length of medium-chain fatty acids (C8 versus C12) on the phase diagrams of the lipids was minimal. Both shorter and longer chain lipids formed essentially similar microemulsion and emulsion regions in the presence of Cremophor EL® and water, although the C12-fatty acid esters formed larger gel regions in the phase diagrams than the C8-fatty acid esters. When monoesters were mixed with their respective diesters at 1:1 ratios, larger microemulsion regions with lower lipid particle sizes were observed compared to those obtained with individual lipids alone. While the solubility of both danazol and probucol increased greatly in all lipids studied, compared to their aqueous solubility, the solubility in C12-fatty acid esters was found to be lower than in C8-fatty acid esters when the lipids were used alone. This difference in solubility due to the difference in fatty acid chain length, practically disappeared when the lipids were combined with the surfactant