title: A Holistic Multi Evidence Approach to Study the Fragmentation Behaviour of Crystalline Mannitol.
abstract: Mannitol is an essential excipient employed in orally disintegrating tablets due to its high palatability. However its fundamental disadvantage is its fragmentation during direct compression, producing mechanically weak tablets. The primary aim of this study was to assess the fracture behaviour of crystalline mannitol in relation to the energy input during direct compression, utilising ball milling as the method of energy input, whilst assessing tablet characteristics of post-milled powders. Results indicated that crystalline mannitol fractured at the hydrophilic (011) plane, as observed through SEM, alongside a reduction in dispersive surface energy. Disintegration times of post-milled tablets were reduced due to the exposure of the hydrophilic plane, whilst more robust tablets were produced. This was shown through higher tablet hardness and increased plastic deformation profiles of the post-milled powders, as observed with a lower yield pressure through an out-of-die Heckel analysis. Evaluation of crystal state using x-ray diffraction/differential scanning calorimetry showed that mannitol predominantly retained the β-polymorph; however x-ray diffraction provided a novel method to calculate energy input into the powders during ball milling. It can be concluded that particle size reduction is a pragmatic strategy to overcome the current limitation of mannitol fragmentation and provide improvements in tablet properties.
authors.affiliation: Aston Pharmacy School, Aston University, Birmingham, B4 7ET, UK.
authors.forename: Jasdip S
authors.initials: JS
authors.lastname: Koner
authors.affiliation: Colorcon® Inc., Harleysville, PA 19438, USA.
authors.forename: Ali
authors.initials: A
authors.lastname: Rajabi-Siahboomi
authors.affiliation: Department of Engineering and Innovation, Open University, Milton Keynes, MK7 6AA, UK.
authors.forename: James
authors.initials: J
authors.lastname: Bowen
authors.affiliation: Aston Pharmacy School, Aston University, Birmingham, B4 7ET, UK.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Perrie
authors.affiliation: Aston Pharmacy School, Aston University, Birmingham, B4 7ET, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Kirby
authors.affiliation: Aston Pharmacy School, Aston University, Birmingham, B4 7ET, UK.
authors.forename: Afzal R
authors.initials: AR
authors.lastname: Mohammed
mesh_terms: D002152:Calorimetry, Differential Scanning; D003460:Crystallization; D004339:Drug Compounding; D006244:Hardness; D057927:Hydrophobic and Hydrophilic Interactions; D008353:Mannitol / Q000737:chemistry*; D018625:Microscopy, Atomic Force; D008855:Microscopy, Electron, Scanning; D010316:Particle Size; D011208:Powders / Q000737:chemistry; D013607:Tablets / Q000737:chemistry*; D014961:X-Ray Diffraction
chemical_list: D011208:Powders; D013607:Tablets; D008353:Mannitol