The poor aqueous solubility and dissolution rate of andrographolide in aqueous gastrointestinal fluids often cause low oral bioavailability. In this work, Andrographis paniculata extract containing 16% andrographolide was coprecipitated with Pluronic F127, Eudragit EPO, and Eudragit L100-55 via solution-enhanced dispersion by supercritical fluids (SEDS) to improve andrographolide dissolution in simulated intestinal fluid (pH 7.4). The SEDS working parameters were set constant as follows: 150 bar, 40 °C, CO2 flow rate 15 L/min (1 bar, 25 °C), liquid feed flow rate 0.5 mL/min, and 25 mg/mL of A. paniculata extract. SEDS coprecipitates formulated with lower Eudragit L100-55:A. paniculata mass ratios exhibited improved andrographolide dissolution in SIF (pH 7.4), while SEDS coprecipitates formulated with either Pluronic F127:A. paniculata or Eudragit EPO:A. paniculata at any mass ratio exhibited poorer andrographolide dissolution (<0.03 mg/mL released in 90 min) than SEDS-precipitated A. paniculata extract powder (0.06 mg/mL released in 90 min). In particular, SEDS coprecipitates formulated with a Eudragit L100-55:A. paniculata mass ratio of 6:25 were found to have the highest andrographolide release and dissolution rate in SIF (pH 7.4) (0.09 mg/mL released in 30 min). SEDS coprecipitation was successful, as indicated by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and Fourier-transform infrared (FTIR) analysis.

The objective of study is to improve aqueous solubility of andrographolide through particle engineering using Solution Enhanced Dispersion by Supercritical Fluids (SEDS) approach. The precipitation pattern of sticky crude Andrographis paniculata extract from CO2-acetone system and CO2-acetone:ethanol (v/v) 1:1 system as well as the aqueous solubility of andrographolide precipitated were first studied at different pressure (100, 150 bar) and temperature (40, 50 °C) combination (full factorial design). The modification of aqueous solubility of andrographolide was then attempted by manipulating its precipitation process from CO2-solvent systems consisting of single solvent and solvent mixture at different proportions (v/v) at the appropriate pressure-temperature combination. A. paniculata powder precipitated from CO2-acetone system at 150 bar, 40 °C was found to be large, irregularly shaped, less crystalline with the highest andrographolide aqueous solubility (twofold increment compared to crude extract) and recovery compared to those precipitated from CO2-ethanol system and other CO2-solvent mixture systems. Complete dissolution of andrographolide from A. paniculata powder precipitated from CO2-acetone system had been achieved within 90 min. For SEDS precipitation under solvent mixture system, with increment of proportion of ethanol from 25% to 75%, larger particles and change of powder morphology from stripes into plates were resulted. Based on the higher aqueous solubility and dissolution of andrographolide, recovery as well as a different morphology observed from the less crystalline A. paniculata powder precipitated from CO2-acetone system, less impurities could have co-precipitated with andrographolide.

The main objective was to evaluate the stability and toxicity of a Solution Enhanced Dispersion by Supercritical Fluids (SEDS) formulated A. paniculata extract that was intended for food applications. The best formulated SEDS A. paniculata extract with improved dissolution of andrographolide (data not shown) was obtained using 25 mg/mL A. paniculata extract (maceration in acetone) and 6 mg/mL Eudragit L100-55 with acetone as feed solvent at the following SEDS co-precipitation conditions: 150 bar, 40 C, 15 L/min CO 2 flow rate (1 bar, 25 C), 0.5 mL/min liquid feed flow. Sticky A. paniculata extract with 16% w/w andrographolide was transformed into SEDS co-precipitates concentrated with 20.4% w/w andrographolide. Only 20-30% of andrographolide was degraded after two-month storage under 5, 30, 45 C at 75% relative humidity (RH). About 30-60% of andrographolide was degraded after addition into drinking water, orange drink, soybean milk for a day. This would imply its unstable nature after being dispersed and wetted in liquid food. SEDS co-precipitate was found to be practically acetone-free (< 0.1 ppm) by Headspace Gas Chromatography-Mass Spectrometry (GC-MS). This showed the capability of the SEDS process in stripping off acetone. Higher cytotoxic potential of SEDS co-precipitates (LC 50 = 46.46 µg/mL) than extract (LC 50 = 150.45 µg/mL) was observed.