Highly purified batches of pharmaceutical grade migalastat and methods of producing the same
Inventors
Sheth, Kamlesh • Tesler, Sergey • Cartwright, James • King, Clive • Cross, Wendy
Assignees
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Publication Number
US-12275703-B2
Publication Date
2025-04-15
Expiration Date
Abstract
Provided are methods of producing Active Pharmaceutical Ingredient (API) grade migalastat hydrochloride, and for purifying intermediate grade migalastat hydrochloride. Further provided are methods of producing [(2R,3S,4R,5S)-1-butyl-2-(hydroxymethyl)piperidine-3,4,5-triol hydrochloride (lucerastat hydrochloride) and other 1-deoxygalactonojirimycin compounds, as well as methods of purifying intermediate grade lucerastat hydrochloride and other 1-deoxygalactonojirimycin compounds.
Core Innovation
The invention relates to a method of purifying intermediate grade migalastat salt or intermediate grade migalastat hydrochloride to produce an active pharmaceutical ingredient (API) grade product. The method includes a first crystallization in a first mixture, isolation of the first crystallized product, a second crystallization in a second mixture, and isolation of the second crystallized product to obtain the API grade material.
The first mixture and/or the second mixture comprise water and a C1 to C4 alcohol. Purification is thus achieved through staged crystallization and isolation steps using water and a C1 to C4 alcohol in one or both crystallization mixtures.
The disclosure also provides impurity-specification context for migalastat hydrochloride manufacturing, including impurity behavior across synthesis stages, impurity standard and specification-limit setting statements based on spiking and purging results, and characterization and release methods using HPLC/HILIC and orthogonal analytics.
Claims Coverage
The independent claims cover a two-step crystallization and isolation purification scheme from intermediate grade to API grade, with water and a C1 to C4 alcohol in one or both crystallization mixtures. Two inventive features are consistently present for each material form.
Two-step crystallization and isolation to purify intermediate grade migalastat salt to API grade
Performing a first crystallization of intermediate grade migalastat salt in a first mixture to give a first crystallized migalastat salt; isolating the first crystallized migalastat salt; performing a second crystallization of the isolated first crystallized migalastat salt in a second mixture to give a second crystallized migalastat salt; and isolating the second crystallized migalastat salt to give an active pharmaceutical ingredient (API) grade migalastat salt.
Water and C1 to C4 alcohol in one or both crystallization mixtures
Wherein one or both of the first mixture and the second mixture comprise water and a C1 to C4 alcohol.
Two-step crystallization and isolation to purify intermediate grade migalastat hydrochloride to API grade
Performing a first crystallization of intermediate grade migalastat hydrochloride in a first mixture to give a first crystallized migalastat hydrochloride; isolating the first crystallized migalastat hydrochloride; performing a second crystallization of the isolated first crystallized migalastat hydrochloride in a second mixture to give a second crystallized migalastat hydrochloride; and isolating the second crystallized migalastat hydrochloride to give an active pharmaceutical ingredient (API) grade migalastat hydrochloride.
Water and C1 to C4 alcohol in one or both crystallization mixtures for hydrochloride
Wherein one or both of the first mixture and the second mixture comprise water and a C1 to C4 alcohol.
Across both independent claims, purification is achieved by sequential crystallization and isolation steps converting intermediate grade migalastat salt or intermediate grade migalastat hydrochloride into API grade material, where one or both crystallization mixtures contain water and a C1 to C4 alcohol.
Stated Advantages
Purifies intermediate grade migalastat salt to provide an API grade migalastat salt.
Purifies intermediate grade migalastat hydrochloride to provide an API grade migalastat hydrochloride.
Provides an impurity control strategy supporting conversion to API grade migalastat salt through impurity tolerance limits after single Stage 4a/4b recrystallization.
Demonstrates purge reduction to below TTC-based limits, including named impurity control outcomes (e.g., Compound X control limit).
Supports CPP/CQA linkage based on monitoring outcomes, including effects of DMSO control on impurity formation and catalyst-related formation patterns for named impurities.
Documented Applications
Purification of intermediate grade migalastat salt to an active pharmaceutical ingredient (API) grade migalastat salt using a two-step crystallization and isolation process with water and a C1 to C4 alcohol in one or both crystallization mixtures.
Purification of intermediate grade migalastat hydrochloride to API grade migalastat hydrochloride using a two-step crystallization and isolation process with water and a C1 to C4 alcohol in one or both crystallization mixtures.
Supports understanding of impurity profiles and quality attributes for intermediate grade migalastat hydrochloride that is later purified to API grade.
Impurity control for intermediate-grade migalastat hydrochloride, including setting impurity specifications using spiking studies and confirming purity/identity of certain compounds via preparatory HPLC/HILIC and NMR/MS/HPLC.
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