2.2.13. Dissolution Analysis

### 2.2.13.1. Powder Dissolution of ITR Systems Mixed with Lactose

For this procedure, samples were prepared by weighing an amount of ITR (starting material), freeze dried ITR (FD ITR), ITR–TER, itraconazole-oxalic acid cocrystals (ITR–OXA) and itraconazole-succinic acid cocrystals (ITR–SUC) containing an equivalent of 100 mg of ITR and mixing with lactose monohydrate in a 1:6 *w*/*w* API:excipient ratio to allow wettability and dispersibility in the liquid medium. Sporanox® was used as the reference formulation and the pellets were removed from the capsule before the use in the dissolution experiments. The dissolution analysis was performed using a solution prepared by mixing 33 mM NaCl with 67 mM HCl (artificial gastric juice (AGJ)) containing 0.05% (*v*/*v*) of Tween 20. The pH of this mixture was then adjusted to 1.2 with 0.5 M HCl. The experiments were carried out using a standard USP II dissolution apparatus (Sotax, Aesch, Switzerland) attached to a UV-Vis spectrophotometer Specord 200 Plus (Analytik Jena, Jena, Germany). The powders were added directly to the media (900 mL) kept at 37 ◦C and agitated at 75 rpm for the first 45 min and at 150 rpm for the final 15 min. The aliquots were automatically taken at predefined time points (2, 5, 10, 15, 20, 25, 30, 45, 50 and 60 min) and the ITR concentration was assessed by measuring the absorbance at 255 nm.

### 2.2.13.2. Powder Dissolution of ITR Systems Mixed with Other Excipients

A second dissolution test evaluated the dissolution of the API when physically mixed with the same excipients as those present in Sporanox® (Jassen, Beerse, Belgium). For this purpose, 350 mg of ITR (starting material) and FD ITR or the amount of the ITR–TER, ITR–OXA and ITR–SUC cocrystals containing the equivalent of 350 mg of the API were carefully weighted and mixed with the other excipients in the concentrations listed in Table 1 for 5 min in 200 mL plastic bottles using a Turbula® mixer (WAB group, Muttenz, Switzerland).

The dissolution analysis was carried out as described in Section 2.2.13.1, using 900 mL peak vessels in a dissolution apparatus 708-DS (Agilent, Lexington, MA, USA) coupled to an Agilent UV-Vis spectrophotometer Cary 60.


**Table 1.** Composition of the powders used in the dissolution study.

(\*) Hydroxypropyl methyl cellulose 2910 (5 mPa.s (HPMC)); (\*\*) polyethylene glycol 6000 Da (PEG); (\*\*\*) mass of the powder containing 100 mg of ITR used in the dissolution test.
