Effect of carrier type and Tween® 80 concentration on the release of silymarin from amorphous solid dispersions

Silymarin is a mixture of flavonolignans obtained from the seeds of milk thistle (Silybum marianum L. Gaertner). Silymarin behaves as a weak acid and is categorised as a class IV drug substance in accordance with biopharmaceutics drug disposition classification system, possessing low solubility, as well as low bioavailability. The scope of this study was to identify possible formulation strategies of silymarin. Then, the main aim was to manufacture silymarin solid dispersions using a solvent evaporation approach and to characterise the physicochemical and drug release properties of the two formulations containing two different porous carriers, namely Avicel (R) PH-102 and Syloid (R) XDP 3150, and different concentrations of Tween (R) 80. Silymarin Log P was determined to be 1.6 (+/- 0.14) negating the possibility of bypassing first pass metabolism via lymphatic transport. Utilising alkaline titration, the apparent pKa of silymarin was found to be similar to that of the silybin pKa (5.68). The crystallinity of raw silymarin was confirmed using powder X-ray diffraction and differential scanning calorimetry, and its thermal degradation was observed at a temperature higher than 220 degrees C (thermogravimetric analysis). Avicel(R)(R) PH-102 and Syloid(R)(R) XDP 3150 were characterised in terms of morphology using scanning electron microscopy, particle size distribution (laser diffraction spectroscopy), pore size distribution and intra-particle porosity using mercury intrusion porosimetry. Solid dispersions were manufactured using an organic solvent method incorporating silymarin, the carrier and optionally Tween (R) 80. The amorphous state of silymarin in all prepared formulations was confirmed using differential scanning calorimetry and powder X-ray diffraction. Silymarin dissolution kinetics were faster for Syloid (R) XDP 3150 versus Avicel (R) PH-102 and explained through carrier properties. The addition of Tween (R) 80 and increasing the concentration from 0.3 to 1.6% (w/w) significantly increased the drug release kinetics of Avicel (R) PH-102 formulations but had no effect on Syloid (R) XDP 3150 formulations. Drug release from prepared formulations was compared with Legalon (R) 70 using the similarity factor (F2). Syloid (R) XDP 3150-based formulations showed F2>50%. Tween (R) 80 had a negligible effect on the silymarin release from Syloid (R) XDP 3150-based formulations. Interestingly, the ability of Tween (R) 80 to inhibit gut wall efflux is well known. Thus, the inclusion of this excipient offers an opportunity to modulate the silymarin bioavailability without changing the drug release profile. A six-month stability study (at room temperature and 40% RH) confirmed that solid dispersions were still powder X-ray diffraction and differential scanning calorimetry amorphous. Acetone was used for both silymarin extraction and preparation of solid dispersions. Thus, there is an opportunity to use a single step to both load silymarin and form solid dispersions within a single-step.