Crystallization from Supersaturated Solutions: Role of Lecithin and Composite Simulated Intestinal Fluid

Indulkar, Anura S.; Gao, Yi; Raina, Shweta A.; Zhang, Geoff G. Z.; Taylor, Lynne S.

doi:10.1007/s11095-018-2441-2

Cited by 40 publications

(44 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Preparation of composite-FaSSIF was performed as described before. 36 Briefly, all six bile salts were weighed, added to buffer-V1, stirred and then allowed to settle for 30 min. Meanwhile, 0.2 mM of lecithin was dissolved in dichloromethane (DCM) and titrated into the aqueous bile salt mixture.…”

Section: Media Selection and Preparationmentioning

confidence: 99%

“…Therefore, all media achieved an equivalent maximum supersaturation for atazanavir. Indulkar et al previously reported an average activity-based supersaturation of 65 36. The activity-based SRmax was found to be ~36 for posaconazole.…”

mentioning

confidence: 93%

“…Theoretically, differences in solubilization capacity between media may impact the perceived supersaturation extent when evaluated based on the total dissolved concentration (Equation 1). 35,36 This could be particularly important when evaluating aspirated fluids following oral dosing to assess the extent to which supersaturation has occurred, as well as using simulated media to predict in vivo supersaturation.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Interplay of Supersaturation and Solubilization: Lack of Correlation between Concentration-Based Supersaturation Measurements and Membrane Transport Rates in Simulated and Aspirated Human Fluids

et al. 2019

Self Cite

View full text Add to dashboard Cite

Supersaturating formulations are increasingly being used to improve the absorption of orally administered poorly water-soluble drugs. To better predict outcomes in vivo, we must be able to accurately determine the degree of supersaturation in complex media designed to provide a surrogate for the gastrointestinal environment. Herein, we demonstrate that relying on measurements based on consideration of the total dissolved concentration, leads to underestimation of supersaturation and consequently membrane transport rates. Crystalline and amorphous solubilities of two compounds, atazanavir and posaconazole, were evaluated in six different media. Concurrently, diffusive flux measurements were performed in a side-byside diffusion cell to determine the activity-based supersaturation by evaluating membrane transport rates at the crystalline and amorphous solubilities. Solubility values were found to vary in each medium due to different solubilization capacities. Concentration-based supersaturation ratios were also found to vary for the different media. Activity-based measurements however, were largely independent of the medium, leading to relatively constant values for the estimated supersaturation. These findings have important consequences for modeling and prediction of supersaturation impact on the absorption rate, as well as for better defining the thermodynamic driving force for crystallization in complex media.

show abstract

Section: Media Selection and Preparationmentioning

confidence: 99%

mentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Interplay of Supersaturation and Solubilization: Lack of Correlation between Concentration-Based Supersaturation Measurements and Membrane Transport Rates in Simulated and Aspirated Human Fluids

et al. 2019

Self Cite

View full text Add to dashboard Cite

show abstract

“…Calcium phosphate can increase the pH at the solid surface of the drug-excipients particles, then increasing DKT solubility, and consequently decreasing the degree of supersaturation, which will, subsequently, prevent or reduce the precipitation gradient [25]. Besides calcium phosphate, FaSSIF-v1 surfactants seem to play a major role in the supersaturation/free acid precipitation balance as it has been reported for other ionizable compounds [26,27,28].…”

Section: Resultsmentioning

confidence: 99%

Exploring Bioequivalence of Dexketoprofen Trometamol Drug Products with the Gastrointestinal Simulator (GIS) and Precipitation Pathways Analyses

et al. 2019

View full text Add to dashboard Cite

The present work aimed to explain the differences in oral performance in fasted humans who were categorized into groups based on the three different drug product formulations of dexketoprofen trometamol (DKT) salt—Using a combination of in vitro techniques and pharmacokinetic analysis. The non-bioequivalence (non-BE) tablet group achieved higher plasma Cmax and area under the curve (AUC) than the reference and BE tablets groups, with only one difference in tablet composition, which was the presence of calcium monohydrogen phosphate, an alkalinizing excipient, in the tablet core of the non-BE formulation. Concentration profiles determined using a gastrointestinal simulator (GIS) apparatus designed with 0.01 N hydrochloric acid and 34 mM sodium chloride as the gastric medium and fasted state simulated intestinal fluids (FaSSIF-v1) as the intestinal medium showed a faster rate and a higher extent of dissolution of the non-BE product compared to the BE and reference products. These in vitro profiles mirrored the fraction doses absorbed in vivo obtained from deconvoluted plasma concentration–time profiles. However, when sodium chloride was not included in the gastric medium and phosphate buffer without bile salts and phospholipids were used as the intestinal medium, the three products exhibited nearly identical concentration profiles. Microscopic examination of DKT salt dissolution in the gastric medium containing sodium chloride identified that when calcium phosphate was present, the DKT dissolved without conversion to the less soluble free acid, which was consistent with the higher drug exposure of the non-BE formulation. In the absence of calcium phosphate, however, dexketoprofen trometamol salt dissolution began with a nano-phase formation that grew to a liquid–liquid phase separation (LLPS) and formed the less soluble free acid crystals. This phenomenon was dependent on the salt/excipient concentrations and the presence of free acid crystals in the salt phase. This work demonstrated the importance of excipients and purity of salt phase on the evolution and rate of salt disproportionation pathways. Moreover, the presented data clearly showed the usefulness of the GIS apparatus as a discriminating tool that could highlight the differences in formulation behavior when utilizing physiologically-relevant media and experimental conditions in combination with microscopy imaging.

show abstract

“…The solubility advantage of an amorphous compared to a crystalline form has been described in several theories [55][56][57][58]. The solubility advantage of the amorphous form has also been referred to as the amorphous solubility [59][60][61], although this is not a thermodynamic stable solubility. In this paper, we refer to the solubility advantage of the amorphous form as the apparent amorphous solubility (aAS).…”

Section: Apparent Amorphous Solubility Of Danazol In Different Sif Media Is Positively Influenced By Increasing Amounts Of Both Bile Saltmentioning

confidence: 99%

Exploring the Impact of Intestinal Fluid Components on the Solubility and Supersaturation of Danazol

Madsen

Plum

Hens

et al. 2021

Journal of Pharmaceutical Sciences

View full text Add to dashboard Cite

Eleven simulated intestinal fluids (SIF) were designed using a Design of Experiment (DoE) approach.The DoE SIF covered a range of compositions of fasted state human intestinal fluid (FaHIF) with regard to pH, bile salt (BS), and phospholipid (PL). Using the model compound danazol, the apparent crystalline (aCS) and amorphous solubility (aAS), as well as the supersaturation propensity was determined in the DoE SIF media. The aCS of danazol was dependent on the composition of the SIF, with PL as the main factor, and a small effect from BS and an interaction between BS and PL. From the DoE solubility data a model was derived, which could predict aCS in a commercially available SIF (FaSSIF-V1 and -V2) and in a range of FaHIF. The aAS of danazol was differently affected by the SIF composition than the aCS; PL was again the main factor influencing the aAS, but interactions between BS and pH, as well as pH and PL were also important. The supersaturation propensities of danazol in the DoE SIF media were affected by the same factors as the aCS. Hence, the supersaturation behaviour and aCS of danazol, were found to be closely related. Abbreviations aAS Apparent amorphous solubility aCS Apparent crystalline solubility BCS Biopharmaceutics classification system BS Bile salt CSS Concentration of supersaturation CSS,X% Concentration of supersaturation, compared to the concentration where a briefly stable supersaturation is observed, followed by precipitation. DMSO Dimethyl sulfoxide DoE Design of experiments aDS Apparent degree of supersaturation, e.g. CSS/aCS FaHIF Fasted state human intestinal fluid HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid HIF Human intestinal fluid LLPS Liquid-liquid phase separation MES 2-(N-morpholino)ethanesulfonic acid PL Phospholipid PBBM Physiologically Based Biopharmaceutics Modeling SDDS Supersaturating drug delivery system SIF Simulated intestinal fluid SSPM Standardized supersaturation and precipitation model

show abstract

Crystallization from Supersaturated Solutions: Role of Lecithin and Composite Simulated Intestinal Fluid

Abstract: This study shows that variations in the composition of SIF can lead to differences in the solubility and crystallization tendency of drug molecules, both of which are critical when evaluating supersaturating systems.

Cited by 40 publications

References 58 publications

Interplay of Supersaturation and Solubilization: Lack of Correlation between Concentration-Based Supersaturation Measurements and Membrane Transport Rates in Simulated and Aspirated Human Fluids

Interplay of Supersaturation and Solubilization: Lack of Correlation between Concentration-Based Supersaturation Measurements and Membrane Transport Rates in Simulated and Aspirated Human Fluids

Exploring Bioequivalence of Dexketoprofen Trometamol Drug Products with the Gastrointestinal Simulator (GIS) and Precipitation Pathways Analyses

Exploring the Impact of Intestinal Fluid Components on the Solubility and Supersaturation of Danazol

Contact Info

Product

Resources

About