Solid State Characterization of E2101, A Novel Antispastic Drug

doi:10.1002/jps.10211

Journal of Pharmaceutical Sciences

Volume 91, Issue 10, October 2002, Pages 2193-2202

https://doi.org/10.1002/jps.10211 Get rights and content

Abstract

E2101, a novel antispastic drug, was found to exist in at least two polymorphs that were confirmed by X‐ray powder diffraction (XRD). These two species are designated forms I and II. The physicochemical and thermodynamic properties of these polymorphs were characterized by variable temperature XRD, thermal analysis, hygroscopicity measurements, and dissolution studies. The transition temperature was also estimated from the solubilities determined at various temperatures. The E2101 polymorphs were anhydrous and adsorbed little moisture under high humidity conditions. The melting onsets and heats of fusion for form I were 148.1 ± 0.2°C and 38.2 ± 1.0 kJ/mol, respectively, and for form II were 139.8 ± 0.4°C and 35.2 ± 0.5 kJ/mol, respectively. The intrinsic dissolution rate of form II in JP 2 medium was 1.5‐fold faster than that of form I, corresponding to the rank order of the aqueous solubility and the enthalpy of fusion. Accordingly, form I was thought to be thermodynamically more stable than form II and thus suitable for further development. According to the thermal analysis and variable temperature XRD results, the recrystallization of form I occurred at ∼145°C after form II melted, however, no crystal transition behavior was observed below the lower melting point. The DSC thermograms at various heating rates and van't Hoff plots from the solubility studies indicated that the polymorphic pair would be monotropic. © 2002 Wiley‐Liss Inc. and the American Pharmaceutical Association J Pharm Sci 91: 2193–2202, 2002

Section snippets

INTRODUCTION

Understanding the polymorphism of a drug candidate can be critical to the drug development because polymorphs and hydrates have different physical and chemical properties, such as solubility and stability. These properties can impact on the rational design of a pharmaceutical dosage form, the optimization of a manufacturing process,¹,² and the bioavailability of the drug.3, 4, 5 Therefore, polymorphism of pharmaceutical molecules,6, 7, 8, 9, 10 including excipients such as D‐mannitol,¹¹ has

Materials

E2101, N‐methyl‐[1‐[1‐(2‐fluorophenethyl)piperidin‐4‐yl]‐1H‐indol‐6‐yl]acetamide, was synthesized at Tsukuba Research Laboratories for Drug Discovery, Eisai Company, Ltd. The solvents used in the present study were either HPLC grade or special grade. All other chemicals were of analytical grade, and the water used was filtered through a Mill‐Q Water Purification System (Millipore, Bedford, MA) prior to use.

Preparation of Polymorphs

Form I crystals were prepared by dissolving excess E2101 in ethyl acetate at ∼80°C. The

Effect of Crystallization from Various Solvents

E2101 was crystallized from seven solvent systems with wide‐ranging polarity. The nature of the crystallizing solvent is a known factor in the isolation of various polymorphs of organic compounds.⁴ After excess E2101 was completely dissolved at around the boiling point, the solution was spontaneously cooled to room temperature in an oil bath. No significant differences were observed in the HPLC impurities of seven crystallized materials, which were <0.1%. Six lots of them showed the same XRD

CONCLUSIONS

E2101 was found to exist in at least two polymorphs, form I and form II, with a single endothermic peak that resulted from the melting at 148.1 ± 0.2 and 139.8 ± 0.4°C, respectively. Form I showed a higher heat of fusion and a lower aqueous solubility. Although the recrystallization of form I occurred at ∼145°C after form II melted, neither of them showed any crystal transition until their melting points in the thermal analysis and variable temperature XRD results. The enthalpy/temperature

Acknowledgements

The authors thank Kaoru Murata and Takako Yoshiba for their technical assistance as well as helpful suggestions.

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Research ArticlesSolid State Characterization of E2101, A Novel Antispastic Drug

Abstract

Section snippets

INTRODUCTION

Materials

Preparation of Polymorphs

Effect of Crystallization from Various Solvents

CONCLUSIONS

Acknowledgements

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Research Articles
Solid State Characterization of E2101, A Novel Antispastic Drug