Inhibition of surface crystallisation of amorphous indomethacin particles in physical drug–polymer mixtures

• Published in: International journal of pharmaceutics 2013-11, Vol.456 (2), p.301-306
• Main Authors: Priemel, Petra A., Laitinen, Riikka, Barthold, Sarah, Grohganz, Holger, Lehto, Vesa-Pekka, Rades, Thomas, Strachan, Clare J.
• Format: Article
• Language: English
• Subjects: Amorphous; crystallites; Crystallization; differential scanning calorimetry; Excipients; Indomethacin; Indomethacin - chemistry; Particle Size; polymers; Polymers - chemistry; scanning electron microscopy; Spatial separation; Surface crystallisation; Surface Properties; Technology, Pharmaceutical - methods; thermogravimetry; water uptake; X-radiation; X-Ray Diffraction - methods
• ISSN: 0378-5173; 1873-3476
• DOI: 10.1016/j.ijpharm.2013.08.046

Surface coverage may affect the crystallisation behaviour of amorphous materials. This study investigates crystallisation inhibition in powder mixtures of amorphous drug and pharmaceutical excipients. Pure amorphous indomethacin (IMC) powder and physical mixtures thereof with Eudragit® E or Soluplus® in 3:1, 1:1 and 1:3 (w/w) ratios were stored at 30°C and 23 or 42% RH. Samples were analysed during storage by X-ray powder diffraction, thermogravimetric analysis, differential scanning calorimetry, and scanning electron microscopy (SEM). IMC Eudragit® mixtures showed higher physical stability than pure IMC whereas IMC Soluplus® mixtures did not. Water uptake was higher for mixtures containing Soluplus® than for amorphous IMC or IMC Eudragit® mixtures. However, the Tg of amorphous IMC was unaffected by the presence (and nature) of polymer. SEM revealed that Eudragit® particles aggregated on the surface of IMC particles, whereas Soluplus® particles did not. The drug particles developed multiple crystallites at their surface with subsequent crystal growth. The intimate contact between the surface agglomerated Eudragit® particles and drug is believed to inhibit crystallisation through reduced IMC surface molecular mobility. Polymer particles may also mechanically hinder crystal growth outwards from the surface. This work highlights the importance of microparticulate surface coverage of amorphous drug particles on their stability.