Solubilization of itraconazole by surfactants and phospholipid-surfactant mixtures: interplay of amphiphile structure, pH and electrostatic interactions

Vinarov, Zahari; Gancheva, Gabriela; Burdzhiev, Nikola

doi:10.1016/j.jddst.2020.101688

Cited by 19 publications

(7 citation statements)

References 62 publications

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“…Specific drug-solubilizer interactions can have a significant impact on drug solubilization: for example, we have recently demonstrated that electrostatic attraction between oppositely charged phospholipids and drugs (albendazole and itraconazole) can significantly enhance solubilization. 54,61 Ion-dipole interactions can also promote the increase of the solubilization capacity, as shown for ionic surfactants and progesterone. 62 Thus, an expanded range of carefully selected drugs needs to be studied in order to clarify the effect of drug structure on solubilization by polar lipids.…”

Section: Effect Of Drug Structurementioning

confidence: 98%

“…The impact of the chain melting temperature for drug solubilization was highlighted also in our recent study on itraconazole solubilization in mixed PL-surfactant solutions. 54 Discrepancy is observed for the compounds with C16:0 chains (DPPC, DPPG and palmitic acid), as they all have critical transition temperatures near T = 37 °C, see Table 4. The increase from C14:0 to C16:0 increases the solubilization capacity in the case of choline PL, whereas a significant drop in solubilization was observed for glycerol PL and FA.…”

Section: Phospholipidsmentioning

confidence: 99%

“…This effect has been widely documented for drug solubilization by classical surfactants in aqueous media and is explained by the decreased CMC and the bigger volume available for solubilization in colloidal aggregates. 54,[57][58][59][60][61][62] Let us now focus on the mechanisms that drive the very strong drug solubilization in presence of the unsaturated polar lipids. The set of C18 FA homologues with varying degree of saturation (Figure 2A) provides useful data for such analysis.…”

Section: Phospholipidsmentioning

confidence: 99%

“…Indeed, Figure 9 shows that a reasonable correlation is obtained between these two parameters, confirming the impact of packing in the colloidal aggregates for drug solubilization. 54 However, other factors might also be responsible for the observed effects: π-π interactions between the double bonds in the FA and the aromatic structure of FEN, could also play a role in the improved drug solubilization. For example, the solubilization of clofazimine, which contains multiple aromatic rings in its structure, was also found to increase with the increasing number of double bonds in the chain of C18 FA.…”

Section: Phospholipidsmentioning

confidence: 99%

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Mechanisms of drug solubilization by polar lipids in biorelevant media

Katev

Vinarov

2021

European Journal of Pharmaceutical Sciences

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Despite the widespread use of lipid excipients in both academic research and oral formulation development, rational selection guidelines are still missing. In the current study, we aimed to establish a link between the molecular structure of commonly used polar lipids and drug solubilization in biorelevant media. We studied the effect of 26 polar lipids of the fatty acid, phospholipid or monoglyceride type on the solubilization of fenofibrate in a two-stage in vitro GI tract model. The main trends were checked also with progesterone and danazol. Based on their fenofibrate solubilization efficiency, the polar lipids can be grouped in 3 main classes. Class 1 substances (n = 5) provide biggest enhancement of drug solubilization (>10-fold) and are composed only by unsaturated compounds. Class 2 materials (n = 10) have an intermediate effect (3-10 fold increase) and are composed primarily (80 %) of saturated compounds. Class 3 materials (n = 11) have very low or no effect on drug solubilization and are entirely composed of saturated compounds. The observed behaviour of the polar lipids was rationalized by using two classical physicochemical parameters: the acyl chain phase transition temperature (Tm) and the critical micellar concentration (CMC). Hence, the superior performance of class 1 polar lipids was explained by the double bonds in their acyl chains, which: (1) significantly decrease Tm, allowing these C18 lipids to form colloidal aggregates and (2) prevent tight packing of the molecules in the aggregates, resulting in bigger volume available for drug solubilization. Long-chain (C18) saturated polar lipids had no significant effect on drug solubilization because their Tm was much higher than the temperature of the experiment (T = 37 C) and, therefore, their association in colloidal aggregates was limited. On the other end of the spectrum, the short chain octanoic acid manifested a high CMC (50 mM), which had to be exceeded in order to enhance drug solubilization. When these two parameters were satisfied (C > CMC, Tm < Texp), the increase of the polar lipid chain length increased the drug solubilization capacity (similarly to classical surfactants), due to the decreased CMC and bigger volume available for solubilization. The hydrophilic head group also has a dramatic impact on the drug solubilization enhancement, with polar lipids performance decreasing in the order: choline phospholipids > monoglycerides > fatty acids. As both the acyl chain length and the head group type are structural features of the polar lipids, and not of the solubilized drugs, the impact of Tm and CMC on solubilization by polar lipids should hold true for a wide variety of hydrophobic molecules. The obtained mechanistic insights can guide rational drug formulation development and thus support modern drug discovery pipelines.

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Section: Effect Of Drug Structurementioning

confidence: 98%

Section: Phospholipidsmentioning

confidence: 99%

Section: Phospholipidsmentioning

confidence: 99%

Section: Phospholipidsmentioning

confidence: 99%

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Mechanisms of drug solubilization by polar lipids in biorelevant media

Katev

Vinarov

2021

European Journal of Pharmaceutical Sciences

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“…The impact of the chain melting temperature for drug solubilization was highlighted also in our recent study on itraconazole solubilization in mixed PL-surfactant solutions. 54 Figure 8. Fenofibrate solubilization ratio (S/Sbile), as a function of the saturated acyl chain length for phospholipids (red), fatty acids (blue) and monoglycerides (green).…”

Section: Phospholipidsmentioning

confidence: 99%

Mechanisms of Drug Solubilization by Polar Lipids in Biorelevant Media

Katev¹,

Vinarov²

2020

Preprint

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Despite the widespread use of lipid excipients in both academic research and oral formulation development, rational selection guidelines are still missing. In the current study, we aimed to establish a link between the molecular structure of commonly used polar lipids and drug solubilization in biorelevant media. We studied the effect of 26 polar lipids of the fatty acid, phospholipid or monoglyceride type on the solubilization of fenofibrate in a two-stage in vitro GI tract model. The main trends were checked also with progesterone and danazol. Based on their fenofibrate solubilization efficiency, the polar lipids can be grouped in 3 main classes. Class 1 substances (n = 5) provide biggest enhancement of drug solubilization (>10-fold) and are composed only by unsaturated compounds. Class 2 materials (n = 10) have an intermediate effect (3-10 fold increase) and are composed primarily (80 %) of saturated compounds. Class 3 materials (n = 11) have very low or no effect on drug solubilization and are entirely composed of saturated compounds. The observed behaviour of the polar lipids was rationalized by using two classical physicochemical parameters: the acyl chain phase transition temperature (Tm) and the critical micellar concentration (CMC). Hence, the superior performance of class 1 polar lipids was explained by the double bonds in their acyl chains, which: (1) significantly decrease Tm, allowing these C18 lipids to form colloidal aggregates and (2) prevent tight packing of the molecules in the aggregates, resulting in bigger volume available for drug solubilization. Long-chain (C18) saturated polar lipids had no significant effect on drug solubilization because their Tm was much higher than the temperature of the experiment (T = 37 C) and, therefore, their association in colloidal aggregates was limited. On the other end of the spectrum, the short chain octanoic acid manifested a high CMC (50 mM), which had to be exceeded in order to enhance drug solubilization. When these two parameters were satisfied (C > CMC, Tm < Texp), the increase of the polar lipid chain length increased the drug solubilization capacity (similarly to classical surfactants), due to the decreased CMC and bigger volume available for solubilization. The hydrophilic head group also has a dramatic impact on the drug solubilization enhancement, with polar lipids performance decreasing in the order: choline phospholipids > monoglycerides > fatty acids. As both the acyl chain length and the head group type are structural features of the polar lipids, and not of the solubilized drugs, the impact of Tm and CMC on solubilization by polar lipids should hold true for a wide variety of hydrophobic molecules. The obtained mechanistic insights can guide rational drug formulation development and thus support modern drug discovery pipelines.

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Nanocrystals and nanosuspensions: an exploration from classic formulations to advanced drug delivery systems

Rossier,

Jordan,

Allémann

et al. 2024

Drug Deliv. and Transl. Res.

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Nanocrystals and nanosuspensions have become realistic approaches to overcome the formulation challenges of poorly water-soluble drugs. They also represent a less-known but versatile platform for multiple therapeutic applications. They can be integrated into a broad spectrum of drug delivery systems including tablets, hydrogels, microneedles, microparticles, or even functionalized liposomes. The recent progresses, challenges, and opportunities in this field are gathered originally together with an informative case study concerning an itraconazole nanosuspension-in-hydrogel formulation. The translational aspects, historical and current clinical perspectives are also critically reviewed here to shed light on the incoming generation of nanocrystal formulations.

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Solubilization of itraconazole by surfactants and phospholipid-surfactant mixtures: interplay of amphiphile structure, pH and electrostatic interactions

Cited by 19 publications

References 62 publications

Mechanisms of drug solubilization by polar lipids in biorelevant media

Mechanisms of drug solubilization by polar lipids in biorelevant media

Mechanisms of Drug Solubilization by Polar Lipids in Biorelevant Media

Nanocrystals and nanosuspensions: an exploration from classic formulations to advanced drug delivery systems

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