Solid-State Characterization of Two Polymorphs of Aspartame Hemihydrate

Abstract

From the known crystal structure of aspartame hemihydrate, designated form 1, the theoretical powder X-ray diffraction (PXRD) pattern was calculated. This PXRD pattern differs significantly from that of the commercially available aspartame hemihydrate, which is therefore a different polymorph, designated form II. Form II transforms to form I during ball-milling or on heating for 30 min at 160 degrees C in the presence of steam. The two polymorphs were compared by PXRD, differential scanning calorimetry, thermogravimetric analysis, Karl Fischer titrimetry, Fourier transform infrared (FTIR) absorption spectroscopy, 13C solid-state nuclear magnetic resonance (SSNMR) spectroscopy, scanning electron microscopy, particle size analysis, and measurements of true density and intrinsic dissolution rate. Comparison of the 13C SSNMR and FTIR spectra of the two polymorphs suggests that the crystal structure of form II is less symmetric, with the side chains located in multiple environments. Although both hemihydrate polymorphs on heating in the absence of moisture dehydrate to a crystalline anhydrate, form I does so at a lower temperature, suggesting weaker interactions of water with aspartame molecules. At higher temperatures the anhydrate from both hemihydrate polymorphs yields 3-(carboxymethyl)-6-benzyl-2,5-dioxopiperazine (DKP) by a cyclization reaction for which the temperature, reaction enthalpy, and activation energy are very similar. Both hemihydrate forms, when in contact with liquid water, yield the 2.5-hydrate.

Identification of Phase Boundaries in Anhydrate/Hydrate Systems

“…7,8 Under isothermal conditions, hydrates may convert to higher hydrated states with an increase in relative humidity. 9 Hydrates are susceptible to dehydration during routine drying and storage conditions, which may lead to the formation of a lower hydrated state, dehydrated hydrate, amorphous material, and/or an anhydrous form. 10 Additionally, the transformation between anhydrous and hydrous crystal forms has been detected during crystallization, wet granulation, development of liquid formulations, and on long-term storage.…”

“…Methods have been previously reported in the literature that can be used to determine the stability relationship of anhydrous and hydrated crystal forms, which include the use of water sorption/desorption isotherms, 9,17 isothermal dehydration measurements, 5,18,19 water activity studies in binary aqueous solutions, 20,21 solubility as a function of temperature, 22,23 and intrinsic dissolution rate. 9 In general, these methods are valuable in assessing the physical stability of these crystalline phases but lack the ability to determine both the thermodynamic phase boundary and the kinetics of the anhydrate/hydrate transformation in the solid state.…”

“…9 In general, these methods are valuable in assessing the physical stability of these crystalline phases but lack the ability to determine both the thermodynamic phase boundary and the kinetics of the anhydrate/hydrate transformation in the solid state. An understanding of both thermodynamic and kinetic properties is required to (a) select the development crystal form, (b) assess the shelf-life of metastable crystal forms, and (c) select appropriate manufacturing and storage conditions for an API.…”

Dehydration kinetics of neotame monohydrate

“…6 Neotame also exists as solvates, such as a methanol solvate. 7 The related dipeptide, aspartame, exists as two crystalline polymorphic hemihydrates and as a crystalline bishemihydrate whose thermodynamic properties, including hydration, 8 dehydration, 8 polymorphic behavior, 9 and solid-state stability 10 have been studied extensively.…”

Solid State 13C NMR Investigation of Impact of Annealing in Lyophilized Glasses

“…47 The peak at 50 ppm assigned to the C3 and C14 carbon of aspartame was used for T 1 and T 1r measurement to characterize the molecular mobility of aspartame. 48 For sucrose 49 and trehalose 50 the peak at 75 ppm belonging to the methylene carbons was used for T 1 and T 1r measurement because of its high sensitivity. The chemical shifts were externally referenced to the -CH 2 peak of adamantane (38.2 ppm).…”