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Crystal forms of LY334370 HCl: isolation, solid-state characterization, and physicochemical properties
Susan M Reutzel-Edens1, Rita L Kleemann, Peggy L Lewellen
1Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA. reutzel-edens_susan_m@lilly.com
Journal of Pharmaceutical Sciences
|May 23, 2003
Summary
Five crystal forms of LY334370 HCl, a migraine treatment, were identified. Anhydrous Form I, though most stable, dissolves slower than the dihydrate, impacting development.
Area of Science:
- Pharmaceutical Sciences
- Solid-State Chemistry
- Drug Development
Background:
- LY334370 HCl is a 5HT1f agonist explored for migraine treatment.
- Understanding crystal forms is crucial for drug development and bioavailability.
Purpose of the Study:
- To identify and characterize the different crystal forms of LY334370 HCl.
- To evaluate the physical properties of viable crystal forms for commercial development.
Main Methods:
- Optical microscopy, differential scanning calorimetry, thermogravimetric analysis, moisture sorption analysis, solid-state NMR, and X-ray crystallography were used.
- Physical properties including hygroscopicity, solubility, and dissolution rate were assessed.
Main Results:
- Five crystal forms were identified: three anhydrates (I-III), a dihydrate, and an acetic acid solvate.
- Anhydrous Form I was the most thermodynamically stable in water.
- Form I dissolved six times slower than the dihydrate, correlating with aqueous solubility differences.
Conclusions:
- Anhydrous Form I is the most stable but exhibits slower dissolution compared to the dihydrate.
- These findings are critical for selecting the optimal crystal form for LY334370 HCl commercialization.
- The differing dissolution rates highlight the importance of solid-state characterization in drug development.