Neotame anhydrate polymorphs. II: Quantitation and relative physical stability

Area of Science:

• Solid-state chemistry
• Physical chemistry
• Materials science

Background:

• Neotame exists in multiple anhydrous polymorphic forms (A, D, F, G).
• Understanding polymorph stability is crucial for drug formulation and manufacturing.
• Polymorphism can significantly impact a compound's physical and chemical properties.

Purpose of the Study:

• To determine the relative thermodynamic and kinetic stabilities of neotame anhydrate polymorphs A, D, F, and G.
• To establish a quantitative powder X-ray diffractometry (PXRD) method for analyzing polymorphic mixtures of neotame forms A and G.

Main Methods:

• Thermodynamic analysis using melting points, heats of fusion, and densities.
• Estimation of phase transition temperature for forms A and G via heats of solution and intrinsic dissolution rates.
• Development and application of PXRD for quantitative analysis of polymorphic mixtures.
• Monitoring polymorphic composition changes under varying temperature and humidity conditions.

Main Results:

• The endothermic enthalpy of solution ranked polymorphs as G > A > D > F.
• Neotame polymorph G demonstrated the highest relative thermodynamic stability.
• The phase transition temperature between neotame forms A and G was determined to be between 35-70°C.
• Powder X-ray diffractometry (PXRD) proved effective for quantitative analysis of neotame polymorphic mixtures.

Conclusions:

• Powder X-ray diffractometry (PXRD) is a reliable method for quantifying neotame polymorphic mixtures (A and G).
• Neotame polymorphs A-G and A-D are enantiotropic pairs.
• Neotame polymorphs D-F, D-G, and F-G are monotropic pairs.
• Neotame polymorph G exhibits the highest thermodynamic stability among the studied forms.