Characterization, selection, and development of an orally dosed drug polymorph from an enantiotropically related system.
Solid-state characterization methods are used to study a dimorphic pharmaceutical compound and select a form for development. Polymorph screening found that [4-(4-chloro-3-fluorophenyl)-2-[4-(methyloxy)phenyl]-1,3-thiazol-5-yl] acetic acid can crystallize into two non-solvated polymorphs designated Forms 1 and 2. Physical methods including vibrational spectroscopy, X-ray powder diffraction, solid-state NMR (SSNMR), thermal analysis, and gravimetric water vapor sorption are used to fully characterize the two polymorphs. Temperature-dependent competitive ripening experiments and solubility measurements indicated that the polymorphs in this system exhibit enantiotropy with a thermodynamic transition temperature of 35+/-3 degrees C. This complicates the selection of a polymorph to progress in drug development. Both forms had undesirable qualities; however, a particular drawback of Form 1 was found in its tendency to convert to Form 2 upon milling. Combining this effect and the desired formulation approach with physical property results led to a rationale for the choice of Form 2 for further development. Because this form is thermodynamically metastable at room temperature, analytical approaches were developed to ensure its exclusive presence, including a quantitative infrared spectroscopic method for drug substance and (13)C and (19)F solid-state NMR limit tests for the undesired form in drug product at drug loads of 8.3% (w/w).
Katrincic
Lee M
LM
Preclinical Development, GlaxoSmithKline, Research Triangle Park, NC 27709, USA.
Sun
Yan T
YT
Carlton
Robert A
RA
Diederich
Ann M
AM
Mueller
Ronald L
RL
Vogt
Frederick G
FG
D000085:Acetates / Q000737:chemistry*; D000284:Administration, Oral; D003460:Crystallization; D004355:Drug Stability; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D012995:Solubility; D013055:Spectrophotometry, Infrared / Q000379:methods*; D013237:Stereoisomerism; D013696:Temperature; D013816:Thermodynamics; D013844:Thiazoles / Q000737:chemistry*
C534706:(4-(4-chloro-3-fluorophenyl)-2-(4-methoxyphenyl)-1,3-thiazol-5-yl)acetic acid; D000085:Acetates; D013844:Thiazoles