Increasing the Dissolution Rate of a Low-Solubility Drug Through a Crystalline- Amorphous Transition: A Case Study with Indomethicin

This article may be used for research, teaching and private study purposes. Any substantial or systematic reproduction, redistribution , reselling , loan or sub-licensing, systematic supply or distribution in any form to anyone is expressly forbidden. The publisher does not give any warranty express or implied or make any representation that the contents will be complete or accurate or up to date. The accuracy of any instructions, formulae and drug doses should be independently verified with primary sources. The publisher shall not be liable for any loss, actions, claims, proceedings, demand or costs or damages whatsoever or howsoever caused arising directly or indirectly in connection with or arising out of the use of this material. The purpose of this research is to further the understanding of the crystalline to amorphous phase transition (amorphization) that occurs when some crystalline drugs are dry blended with porous adsorbents. Indomethacin (IMC) and three grades of silica gel (SGs) were used in the study. Amorphization of crystalline IMC occurs rapidly during dry mixing with SG and was independent of mixing intensity and time. Extent of amorphization increases with lower ratios of IMC:SG and with decreased IMC and SG particle size. Blocking H-bonding silanol groups on SG by chemical modification reduced the extent of amorphization. IMC-SG mixtures showed improved dissolution rates over crystalline IMC, the improvement being directly related to the extent of amorphization. To preserve the improved dissolution rate, mixtures should be protected from moisture and heat. This approach holds promise as a mean of improving the dissolution rate of sparingly soluble drugs such as IMC. INTRODUCTION For poorly water-soluble drugs, improving dissolution is key to achieving the desired bioavailability. Most active pharmaceutical ingredients in products are in their stable form (crystalline form) for physical and chemical stability considerations. In more recent years, the use of high energy state materials, namely the amorphous materials, to improve the dissolution and hence the