Self-shaping of oil droplets via the formation of intermediate rotator phases upon cooling.

Revealing the chemical and physical mechanisms underlying symmetry breaking and shape transformations is key to understanding morphogenesis. If we are to synthesize artificial structures with similar control and complexity to biological systems, we need energy- and material-efficient bottom-up processes to create building blocks of various shapes that can further assemble into hierarchical structures. Lithographic top-down processing allows a high level of structural control in microparticle production but at the expense of limited productivity. Conversely, bottom-up particle syntheses have higher material and energy efficiency, but are more limited in the shapes achievable. Linear hydrocarbons are known to pass through a series of metastable plastic rotator phases before freezing. Here we show that by using appropriate cooling protocols, we can harness these phase transitions to control the deformation of liquid hydrocarbon droplets and then freeze them into solid particles, permanently preserving their shape. Upon cooling, the droplets spontaneously break their shape symmetry several times, morphing through a series of complex regular shapes owing to the internal phase-transition processes. In this way we produce particles including micrometre-sized octahedra, various polygonal platelets, O-shapes, and fibres of submicrometre diameter, which can be selectively frozen into the corresponding solid particles. This mechanism offers insights into achieving complex morphogenesis from a system with a minimal number of molecular components.European Research Council (Grant ID: EMATTER 280078), European networks COST MP 1106 and 1305 and the capacity building project BeyondEverest of the European Commission (Grant ID: 286205)This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/nature1618

Mechanisms of Drug Solubilization by Polar Lipids in Biorelevant Media

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.<br /

Solubilization of Itraconazole by Surfactants and Phospholipid-Surfactant Mixtures: Interplay of Amphiphile Structure, pH and Electrostatic Interactions

Although surfactants are frequently used in enabling formulations of poorly water-soluble drugs, the link between their structure and drug solubilization capacity is still unclear. We studied the solubilization of the “brick-dust” molecule itraconazole by 16 surfactants and 3 phospholipid:surfactant mixtures. NMR spectroscopy was used to study in more details the drug-surfactant interactions. Very high solubility of itraconazole (up to 3.6 g/L) was measured in anionic surfactant micelles at pH = 3, due to electrostatic attraction between the oppositely charged (at this pH) drug and surfactant molecules. 1H NMR spectroscopy showed that itraconazole is ionized at two sites (2+ charge) at these conditions: in the phenoxy-linked piperazine nitrogen and in the dioxolane-linked triazole ring. The increase of amphiphile hydrophobic chain length had a markedly different effect, depending on the amphiphile type: the solubilization capacity of single-chain surfactants increased, whereas a decrease was observed for double-chained surfactants (phosphatidylglycerols). The excellent correlation between the chain melting temperatures of phosphatidylglycerols and itraconazole solubilization illustrated the importance of hydrophobic chain mobility. This study provides rules for selection of itraconazole solubilizers among classical single-chain surfactants and phospholipids. The basic physics underpinning the described effects suggests that these rules should be transferrable to other “brick-dust” molecules

Albendazole solution formulation via vesicle-to-micelle transition of phospholipid-surfactant aggregates

<p><b>Objective:</b> To reveal the physicochemical mechanisms governing the solubilization of albendazole in surfactant and phospholipid-surfactant solutions and, on this basis, to formulate clinically relevant dose of albendazole in solution suitable for parenteral delivery.</p> <p><b>Significance:</b> (1) A new drug delivery system for parenteral delivery of albendazole is proposed, offering high drug solubility and low toxicity of the materials used; (2) New insights on the role of surface curvature on albendazole solubilization in surfactant and surfactant-phospholipid aggregates are provided.</p> <p><b>Methods:</b> The effect of 17 surfactants and 6 surfactant-phospholipid mixtures on albendazole solubility was studied. The size of the colloidal aggregates was determined by light-scattering. The dilution stability of the proposed formulation was assessed by experiments with model human serum.</p> <p><b>Results:</b> Anionic surfactants increased very strongly drug solubility at pH = 3 (up to 4 mg/mL) due to strong electrostatic attraction between the oppositely charged (at this pH) drug and surfactant molecules. This effect was observed with all anionic surfactants studied, including sodium dodecyl sulfate, double chain sodium dioctylsulfosuccinate (AOT), and the bile salt sodium taurodeoxycholate. The phospholipid-surfactant mixture of 40% sodium dipalmitoyl-phosphatidylglycerol +60% AOT provided highest albendazole solubilization (4.4 mg/mL), smallest colloidal aggregate size (11 nm) and was stable to dilution with model human serum at (and above) 1:12 ratio.</p> <p><b>Conclusions:</b> A new albendazole delivery system with high drug load and low toxicity of the materials used was developed. The high solubility of albendazole was explained with vesicle-to-micelle transition due to the larger interfacial curvature preferred for albendazole solubilization locus.</p