TY - JOUR

T1 - The influence of thermal and mechanical preparative techniques on the amorphous state of four poorly soluble compounds

AU - Patterson, James E

AU - James, Michael B

AU - Forster, Angus H

AU - Lancaster, Robert W

AU - Butler, James M

AU - Rades, Thomas

PY - 2005

Y1 - 2005

N2 - A number of studies in the literature have reported on the use of different preparative techniques to convert crystalline pharmaceutical compounds into the amorphous form. However, very few direct comparisons of different preparative techniques using the same drugs are available. The purpose of this study was to determine the influence of two techniques: quench cooling and ball milling on four structurally diverse pharmaceutical drugs. Dipyridamole, carbamazepine, glibenclamide, and indomethacin were converted to the amorphous form by (a) quench cooling of the drug melt and (b) ball milling. The chemical purity and physical form of the products was determined using diffractometric, spectroscopic, and thermal analytical techniques. Products were analysed immediately post preparation and after storage under different stability conditions. Quench cooling of the melt resulted in amorphous conversion of all four compounds. However with glibenclamide, quench cooling resulted in unacceptable chemical degradation whereas ball milling of glibenclamide resulted in a change in the keto-enol tautomerism at the aryl amide moiety of this drug. Ball milling resulted in predominantly amorphous products for all compounds except carbamazepine. Ball milling of carbamazepine resulted in a polymorphic transition of the starting material to form III. Physical stability studies showed that irrespective of preparative technique and storage conditions all samples showed at least partial reversion to the crystalline state after storage. Quench cooling of drug melts may be of use as a preparative technique however it can result in chemical degradation. Ball milling may also be of use as a preparative technique however its effectiveness is dependent on the unit cell structure of the compound.

AB - A number of studies in the literature have reported on the use of different preparative techniques to convert crystalline pharmaceutical compounds into the amorphous form. However, very few direct comparisons of different preparative techniques using the same drugs are available. The purpose of this study was to determine the influence of two techniques: quench cooling and ball milling on four structurally diverse pharmaceutical drugs. Dipyridamole, carbamazepine, glibenclamide, and indomethacin were converted to the amorphous form by (a) quench cooling of the drug melt and (b) ball milling. The chemical purity and physical form of the products was determined using diffractometric, spectroscopic, and thermal analytical techniques. Products were analysed immediately post preparation and after storage under different stability conditions. Quench cooling of the melt resulted in amorphous conversion of all four compounds. However with glibenclamide, quench cooling resulted in unacceptable chemical degradation whereas ball milling of glibenclamide resulted in a change in the keto-enol tautomerism at the aryl amide moiety of this drug. Ball milling resulted in predominantly amorphous products for all compounds except carbamazepine. Ball milling of carbamazepine resulted in a polymorphic transition of the starting material to form III. Physical stability studies showed that irrespective of preparative technique and storage conditions all samples showed at least partial reversion to the crystalline state after storage. Quench cooling of drug melts may be of use as a preparative technique however it can result in chemical degradation. Ball milling may also be of use as a preparative technique however its effectiveness is dependent on the unit cell structure of the compound.

KW - Carbamazepine

KW - Chemistry, Pharmaceutical

KW - Crystallization

KW - Dipyridamole

KW - Drug Stability

KW - Glyburide

KW - Indomethacin

KW - Powder Diffraction

KW - Solubility

KW - Spectroscopy, Fourier Transform Infrared

KW - Technology, Pharmaceutical

KW - Temperature

KW - Thermogravimetry

KW - X-Ray Diffraction

U2 - 10.1002/jps.20424

DO - 10.1002/jps.20424

M3 - Journal article

C2 - 16052554

VL - 94

SP - 1998

EP - 2012

JO - Journal of Pharmaceutical Sciences

JF - Journal of Pharmaceutical Sciences

SN - 0022-3549

IS - 9

ER -