The application of porous adsorbents to increase the dissolution rate of low solubility drugs.

摘要

The purpose of this research was to further the understanding of the crystalline to amorphous phase transitions that occur when some crystalline drugs are physically mixed with porous adsorbents. This phenomenon may provide a convenient means of enhancing the bioavailability of some poorly soluble drugs that exhibit dissolution-rate limited absorption. Indomethacin (IMC), a high permeability and low solubility drug, was used as a model drug. Three different grades of silica gel (SG) having different pore sizes and surface areas were used as the porous adsorbent. DSC and XRPD analysis showed that the loss in IMC crystallinity, or amorphization of IMC occurs rapidly during the mixing process and was found to occur within 5 minutes. Amorphization was also found to be independent of mixing intensity and time under the experimental conditions studied. The extent of amorphization is dependent upon the IMC/SG ratio, the particle size of IMC and SG and the amount of moisture in SG. The extent of amorphization in the mixtures increased as the ratio of IMC to SG decreased and as the IMC particle size decreased. The extent of amorphization was not highly dependent on the SG surface area or pore size since the bulk of the SG surface area is contained within the pore structure, and is only partially available to crystalline IMC. Blocking the H-bonding silanol groups on SG by chemical modification significantly reduced the extent of amorphization of crystalline IMC. This indicated that the amorphization of crystalline IMC in mixtures with SG occurs as a result of H-bonding between IMC and the silanol groups on the surface of SG. IMC/SG mixtures showed improved dissolution compared to pure crystalline IMC. The improvement in dissolution was directly related to the amount of amorphous IMC in the mixture. IMC/SG mixtures stored at room temperature and under desiccation are physically and chemically stable up to 4 months. To maintain the physical/chemical stability and improved dissolution performance, IMC/SG mixtures should be stored protected from heat, humidity and light. This work has demonstrated the potential of using SG as a means to induce amorphization of crystalline, sparingly soluble drugs such as IMC and to improve in-vitro dissolution.