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Novel polymorph of ambrisentan: Characterization and stability
Jamshed Haneef1, Renu Chadha1, Vijay Gupta2
1University Institute of Pharmaceutical Sciences, UGC-Centre of Advanced Studies (CAS), Panjab University, Chandigarh 160 014, India.
Journal of Pharmaceutical and Biomedical Analysis
|February 24, 2018
Summary
A new polymorph of ambrisentan (form II) was discovered, exhibiting 1.5-fold higher solubility than the commercial form. However, form II converts to the commercial form under various conditions.
Area of Science:
- Pharmaceutical Sciences
- Solid-State Chemistry
- Drug Development
Background:
- Ambrisentan (AMT) is a selective endothelin type A (ETA) receptor antagonist crucial for treating pulmonary arterial hypertension (PAH).
- Understanding different solid-state forms (polymorphs) of active pharmaceutical ingredients is vital for optimizing drug efficacy and formulation.
Purpose of the Study:
- To identify and characterize a novel polymorph of ambrisentan (AMT).
- To evaluate the physicochemical properties, particularly aqueous solubility, of the new polymorph compared to the commercial form.
- To investigate the solid-state stability and phase transformation behavior of the novel polymorph.
Main Methods:
- Isolation of the novel polymorph (form II) via solution crystallization.
- Characterization using differential scanning calorimetry, powder X-ray diffraction, solution calorimetry, and aqueous solubility studies.
- Single crystal X-ray diffraction to determine crystal structure and space group.
- Phase transformation studies (solution-mediated and stress-induced) and accelerated stability testing.
Main Results:
- A novel monoclinic polymorph of ambrisentan (form II, space group P21/c) was successfully isolated and characterized.
- Form II demonstrated a 1.5-fold higher apparent solubility in 0.1 N HCl (pH 1.2) compared to the commercial form I.
- Both solution-mediated and stress-induced phase transformations showed that form II converts to form I.
- Accelerated stability studies confirmed the conversion of form II to form I within one month at 40°C and 75% RH.
Conclusions:
- A new enantiotropically related polymorph of ambrisentan (form II) was identified with significantly improved aqueous solubility.
- Despite its enhanced solubility, form II is less stable and converts to the commercial form I under various conditions.
- Further research may be needed to stabilize form II or explore its therapeutic potential despite its transformation characteristics.
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