In Situ Formation of Steroidal Supramolecular Gels Designed for Drug Release

In this work, a steroidal gelator containing an imine bond was synthesized, and its gelation behavior as well as a sensitivity of its gels towards acids was investigated. It was shown that the gels were acid-responsive, and that the gelator molecules could be prepared either by a conventional synthesis or directly in situ during the gel forming process. The gels prepared by both methods were studied and it was found that they had very similar macro- and microscopic properties. Furthermore, the possibility to use the gels as carriers for aromatic drugs such as 5-chloro-8-hydroxyquinoline, pyrazinecarboxamide, and antipyrine was investigated and the prepared two-component gels were studied with regard to their potential applications in drug delivery, particularly in a pH-controlled drug release.

. Conversion of imine 3 in CDCl 3 over time.  Figure S1. 1 H-NMR study of imine 3 formation in CDCl 3 over time.
Note: Corresponding signals of the spectra of xerogels closely resemble to each other suggesting that imine 3 behaves very similarly in the xerogel state. The samples of the xerogels from propan-1-ol show relatively sharp signals indicating that they are more crystalline in nature than the sample of the xerogel from pentan-1-ol. Moreover, some signals reveal a double resonance pattern which means that the sample is either (i) a mixture of different polymorphic forms; or (ii) composed of a form having two non-equivalent molecules present in an asymmetric unit.

In Situ Gelation Study
Experimental details: Total volume and the amount of imine 3 (experiments in Table S2) or amine 1 (experiments in Table S3) remained constant during the tests.  Table S3. Results of in situ gelation in propan-1-ol.
Note: S -solution upon cooling, P -partly precipitate upon cooling, pG -partial gel, G -gel. Figure S12. Schematic image of slow-release and acid-induced release of a drug.

Experimental details:
The gels of imine 3 and pyrazinecarboxamide (2.8% w/v), prepared in a 1:1 ratio in 0.5 mL of pentan-1-ol (n PC = 0.0195 mmol), were stabilised overnight. Then water (0.5 mL) either without or with p-toluenesulfonic acid (0.0053 mmol) was added. The samples stayed without any shaking or other type of disturbance. Water layers (0.4 mL) were separated off at certain times (after 0.5, 1, 2, 4 and 24 h), and after solvent evaporation in the open air, solid residues were dissolved in D 2 O (0.6 mL) and analysed by NMR with succinic acid (0.0042 mmol) as an internal standard. As control experiments (A and B), pyrazinecarboxamide (0.0195 mmol) was dissolved in pentan-1-ol (0.5 mL), and the samples were treated in the same way as the gel samples (adding of 0.5 mL of water either without or with 0.0053 mmol of p-toluenesulfonic acid, and then analysed by NMR with 0.0085 mmol of succinic acid as an internal standard). To check the drug release under non-calm conditions, the samples were treated by ultrasonic for 10 min and after one hour of standing without any additional disturbance, the water layers were analysed by NMR in the same way like in the other drug release experiments. The percentage of the released drug was calculated from the peak area of drug signals of a sample to the peak area of drug signals of a reference sample which was prepared by dissolving pyrazine-carboxamide (0.0195 mmol) in 0.6 mL of D 2 O with succinic acid (0.0085 mmol) as an internal standard. Results are summarised in Table S4.