Abstract
Twelve impurities (process-related and degradation) in lisdexamfetamine dimesylate (LDX), a central nervous system (CNS) stimulant drug, were first separated and quantified by high-performance liquid chromatography (HPLC) and then identified by liquid chromatography mass spectrometry (LC-MS). The structures of the twelve impurities were further confirmed and characterized by IR, HRMS and NMR analyses. Based on the characterization data, two previously unknown impurities formed during the process development and forced degradation were proposed to be (2S)-2,6-di-(lysyl)-amino-N-[(1S)-1-methyl-2-phenyl ethyl]hexanamide (Imp-H) and (2S)-2,6-diamino-N-[(1S)-1-methyl-2-(2-hydroxyphenyl)ethyl] hexanamide (Imp-M). Furthermore, these two compounds are new. Probable mechanisms for the formation of the twelve impurities were discussed based on the synthesis route of LDX. Superior separation was achieved on a YMC-Pack ODS-AQ S5 120A silica column (250 × 4.6 mm × 5 μm) using a gradient of a mixture of acetonitrile and 0.1% aqueous methanesulfonic acid solution. The HPLC method was optimized in order to separate, selectively detect, and quantify all the impurities. The full identification and characterization of these impurities should prove useful for quality control in the manufacture of lisdexamfetamine dimesylate.
Highlights
Lisdexamfetamine dimesylate (LDX; formerly NRP-104), (2S)-2,6-diamino-N-[(1S)-1-methyl2-phenylethyl]hexanamide dimethanesulfonate) is a novel, long-acting, central nervous system (CNS) stimulating drug with low toxicity used as an abuse-resistant treatment of attention-deficit/hyperactivity disorder (ADHD)
Impurities in drugs are closely related to their adverse reactions and pharmacological activity
Probable mechanisms for the formation of the process-related and degradation impurities were proposed based on the synthesis route of lisdexamfetamine dimesylate (LDX)
Summary
Lisdexamfetamine dimesylate (LDX; formerly NRP-104), (2S)-2,6-diamino-N-[(1S)-1-methyl2-phenylethyl]hexanamide dimethanesulfonate) is a novel, long-acting, central nervous system (CNS) stimulating drug with low toxicity used as an abuse-resistant treatment of attention-deficit/hyperactivity disorder (ADHD). LDX is a therapeutically inactive amphetamine prodrug, and the pharmacologically active D-amphetamine is gradually released by rate-limited hydrolysis following ingestion [1]. The drug, originally developed by Shire Development Inc. (London, UK) and New River Pharmaceutical Inc. The industrial manufacturing process of LDX was developed by New River Pharmaceutical Inc. Impurities in drugs are closely related to their adverse reactions and pharmacological. Molecules 2018, 23, x FOR PEER REVIEW (Figure 1) [2]. Impurities in drugs are closely related to their adverse reactions and pharmacological activity. Precursors, andand byproducts in drugs can produce fatal
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