title: Polymorphic control of inhalation microparticles prepared by crystallization.
abstract: Milling processes are known to cause polymorphic transition in enantiotropic systems and the micronization process employed to produce microparticles for inhalation formulations has been reported to result in solid-state damage. The aim of the current work was to investigate the polymorphism of salmeterol xinafoate (SX) following antisolvent micronization from poly(ethylene glycol) (PEG) solvents and compare this to the properties of SX conventionally crystallized and micronized. Powder X-ray diffraction revealed that SX crystallized predominantly as the SX form I polymorph following rapid precipitation from PEG solvents and cooling crystallization from propan-2-ol. Thermo-kinetic analysis using a modified Avrami-Erofe'ev equation was applied to differential scanning calorimetric thermographs of crystallized and micronized SX. The kinetic analysis revealed that SX crystallized from PEG solvents underwent significantly less or no re-crystallization of SX form II from the melt. A polymorphic transition was identified upon heating ball-milled SX, although the untreated material was resistant to such transformation. The thermal behaviour of SX crystallized from PEG solvents was consistent with a lower degree of crystal lattice disorder and higher enantiotropic purity than SX crystallized from propan-2-ol; the same was also true when comparing SX before and after micronization.
authors.affiliation: King's College London, Drug Delivery Research Group, Pharmaceutical Science Division, 150 Stamford Street, London SE1 9NH, United Kingdom.
authors.forename: Darragh
authors.initials: D
authors.lastname: Murnane
authors.forename: Christopher
authors.initials: C
authors.lastname: Marriott
authors.forename: Gary P
authors.initials: GP
authors.lastname: Martin
mesh_terms: D019840:2-Propanol / Q000737:chemistry; D000280:Administration, Inhalation; D000420:Albuterol / Q000031:analogs & derivatives* / Q000737:chemistry; D001993:Bronchodilator Agents / Q000737:chemistry*; D002152:Calorimetry, Differential Scanning; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003460:Crystallization; D008863:Microspheres; D010316:Particle Size; D011092:Polyethylene Glycols / Q000737:chemistry; D033362:Powder Diffraction; D000068299:Salmeterol Xinafoate; D012997:Solvents / Q000737:chemistry
chemical_list: D001993:Bronchodilator Agents; D012997:Solvents; D011092:Polyethylene Glycols; D000068299:Salmeterol Xinafoate; D019840:2-Propanol; D000420:Albuterol