title: A method to evaluate the effect of contact with excipients on the surface crystallization of amorphous drugs.
abstract: Amorphous drugs are used to improve the solubility, dissolution, and bioavailability of drugs. However, these metastable forms of drugs can transform into more stable, less soluble, crystalline counterparts. This study reports a method for evaluating the effect of commonly used excipients on the surface crystallization of amorphous drugs and its application to two model amorphous compounds, nifedipine and indomethacin. In this method, amorphous samples of the drugs were covered by excipients and stored in controlled environments. An inverted light microscope was used to measure in real time the rates of surface crystal nucleation and growth. For nifedipine, vacuum-dried microcrystalline cellulose and lactose monohydrate increased the nucleation rate of the β polymorph from two to five times when samples were stored in a desiccator, while D-mannitol and magnesium stearate increased the nucleation rate 50 times. At 50% relative humidity, the nucleation rates were further increased, suggesting that moisture played an important role in the crystallization caused by the excipients. The effect of excipients on the crystal growth rate was not significant, suggesting that contact with excipients influences the physical stability of amorphous nifedipine mainly through the effect on crystal nucleation. This effect seems to be drug specific because for two polymorphs of indomethacin, no significant change in the nucleation rate was observed under the excipients.
authors.affiliation: School of Pharmacy, University of Wisconsin-Madison, 777 Highland Avenue, Madison, Wisconsin, 53705-2222, USA.
authors.forename: Si-Wei
authors.initials: SW
authors.lastname: Zhang
authors.forename: Lian
authors.initials: L
authors.lastname: Yu
authors.forename: Jun
authors.initials: J
authors.lastname: Huang
authors.forename: Munir A
authors.initials: MA
authors.lastname: Hussain
authors.forename: Lotfi
authors.initials: L
authors.lastname: Derdour
authors.forename: Feng
authors.initials: F
authors.lastname: Qian
authors.forename: Melgardt M
authors.initials: MM
authors.lastname: de Villiers
mesh_terms: D002482:Cellulose / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical; D003460:Crystallization; D005079:Excipients / Q000737:chemistry*; D006813:Humidity; D007213:Indomethacin / Q000737:chemistry*; D007700:Kinetics; D007785:Lactose / Q000737:chemistry*; D008353:Mannitol / Q000737:chemistry*; D009543:Nifedipine / Q000737:chemistry*; D013229:Stearic Acids / Q000737:chemistry*; D013499:Surface Properties; D013607:Tablets; D013678:Technology, Pharmaceutical / Q000379:methods; D014867:Water / Q000737:chemistry
chemical_list: D005079:Excipients; D013229:Stearic Acids; D013607:Tablets; D014867:Water; D008353:Mannitol; C031183:stearic acid; D002482:Cellulose; D009543:Nifedipine; D007785:Lactose; C109691:microcrystalline cellulose; D007213:Indomethacin