[learn_more caption=”Balázs Démuth”] Balázs Démuth^a,b,

Zsombor K. Nagy^a,

Johny Bertels^b,

Jurgen Mensch^b,

Ivo Van Assche^b,

Geert Verreck^b,

György Marosi^a

^a Budapest University of Technology and Economics, 1111 Budapest, Hungary

^b Janssen Pharmaceutica N.V., 2340 Beerse, Belgium [/learn_more]

 

 

Purpose

The purpose of the present work was to assess the particular properties of the downstream processing of the electrospun, itraconazole-PVPVA64 solid dispersion. As the main part of the work, a design of experiments was planned in order to systematically study the compression behavior of electrospun material (EM) while it was intended to produce fast disintegrating tablets, to optimize the formulation and the tableting process.

Methods

Tablets were compressed on a Huxley Bertram compaction simulator (Cambridge, UK). A 3² design of experiments was carried out (dependent variables: tensile strength, disintegration time). Results were evaluated with Statistica software (Tulsa, USA).

Results

The residual solvent content of solid dispersion prepared by high speed electrospinning could be pressed under the limitations before further application (300 ppm for dichloromethane and 700 ppm for ethanol) by simple drying on a tray.

Tableting blends: based on particle size measurements (sieve method and laser diffraction method) the EM is prone to aggregate though these aggregates were disrupted during mixing with excipients. Based on scanning electron microscope images MCC particles were covered by the EM due to their structured surface. This was confirmed later by Raman mapping of the subsequent tablets.

Design of experiments: tensile strength was almost only dependent on compression force; hence a linear model would be adequate. For disintegration time, fillers ratio was also significant along with interactions (quadratic effects). A saddle point was found at 76.25% fillers ratio. Tensile strength and disintegration times were in the pharmaceutically useful range. At low fillers ratio disintegration time increased very quickly due to the formation of a gelling polymer network. According to Raman maps in a tablet where fillers:EM ratio was 1:1, EM occupied a lot of space in the tablet, and in addition, high concentration of it was detected on MCC particles.

Dissolution behavior: it was found that magnesium stearate increases the wetting time of EM which can recrystallize during the dissolution test due to the elevated temperature and high humidity. Therefore the lubricant was changed to sodium stearyl fumarate with which total dissolution was achievable.

High speed tableting: preliminary experiments were carried out for high speed tableting of the EM on the compaction simulator which showed that this process seems feasible. The flowability and the tablet weight deviation remained the only questions. Therefore tablets were compressed on an 8-station rotary tablet press. Deviation was kept at low values, while tablet properties were satisfying, even at high speed.

Conclusions

During the formulation of an electrospun material important ascertainments were made. Design of experiments seemed an effective method to survey the tableting of an electrospun solid dispersion. With this and the optimization of the tableting an industrially acceptable formulation and process were realizable.