Solid-State Overview of R-Baclofen: Relative Stability of Forms A, B and C and Characterization of a New Heterosolvate

Couvrat, Nicolas; Sanselme, Morgane; Poupard, Manon; Bensakoun, Céline; Drouin, Simon H.; Schneider, Jean-Marie; Coquerel, Gérard

doi:10.1016/j.xphs.2021.06.018

Cited by 5 publications

(5 citation statements)

References 32 publications

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“…Whereas, on the DSC curves for samples stored for 90 and 120 days ( Figure 5 e,f), endothermic peaks were observed at 190 °C and around 190–200 °C. Although this study could not clarify the cause of these peaks, Alzoubi et al demonstrated that the solid-state epimerization from a-lactose to b-lactose is triggered by dehydration, and the change in the crystalline form of baclofen was suggested during the storage [ 26 , 27 ]; details of these thermal behaviors will be explained by using DSC-PXRD in a future study.…”

Section: Resultsmentioning

confidence: 94%

Stability Study of Baclofen in an Oral Powder Form Compounded for Pediatric Patients in Japan

et al. 2022

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Baclofen is used as a skeletal muscle relaxant for multiple sclerosis patients and pediatric patients with cerebral palsy and is prescribed to pediatric patients at 0.3 to 1.0 mg/kg/dose. Baclofen tablets, an oral drug, are usually administered as a powder in pediatric wards after a formulation change by the pharmacist. However, there is no information about stability and assurance of quality for compounded products. The purpose of this study was to design a 10 mg/g oral powder of baclofen and to investigate the stability and changes in the physical properties of this compounded product. A 10 mg/g baclofen powder was prepared by adding extra-fine crystal lactose hydrate to crushed and filtrated baclofen tablets and was stored in a polycarbonate amber bottle with desiccant or in a coated paper laminated with cellophane and polyethylene. The stability of baclofen at 25 ± 2 °C/60 ± 5%RH was tested for 120 days in ‘bottle (closed)’, ‘bottle (in use)’, and ‘laminated’ storage conditions. Baclofen concentrations ranged from 90.0% to 110.0% of the initial concentration under all storage conditions. No crystallographic or dissolution changes were observed after storage. This information can help with the management of baclofen compounded powder in pharmacies.

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Section: Resultsmentioning

confidence: 94%

Stability Study of Baclofen in an Oral Powder Form Compounded for Pediatric Patients in Japan

et al. 2022

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“…A dimeric motif built up by N1-H9…O1 and N1-H6…O1 in I - 1 and II - 2 , respectively, connects two molecules via carboxylate and ammonium units ( Figure 2 ). Such a dimeric motif is common for other GABA-related APIs, e.g., pregabalin [ 50 , 56 ], phenibut [ 49 ], or baclofen [ 52 ]. Dimers in I - 1 and II - 2 are further linked via two equal strongest HBs (N1-H8…O1 in I - 1 and N1-H5…O1 in II - 2 ) to give tetrameric aggregates with the overall binding energy of −205.78 kJ mol −1 and -208.42 kJ mol −1 , respectively.…”

Section: Resultsmentioning

confidence: 99%

“…Pharmaceutics 2023, 15, 2299 7 of 20 by N1-H9…O1 and N1-H6…O1 in I-1 and II-2, respectively, connects two molecules via carboxylate and ammonium units (Figure 2). Such a dimeric motif is common for other GABA-related APIs, e.g., pregabalin [50,56], phenibut [49], or baclofen [52]. The described dimeric carboxylate/ammonium motif is noticeably missing in II-1, which could be the reason for its unfavorable formation under normal conditions despite the minute ΔElat value.…”

Section: Compoundmentioning

confidence: 94%

“….O1 in I-1 and II-2, respectively, connects two molecules via carboxylate and ammonium units (Figure 2). Such a dimeric motif is common for other GABA-related APIs, e.g., pregabalin [50,56], phenibut [49], or baclofen [52]. Dimers in I-1 and II-2 are further linked via two equal strongest HBs (N1-H8.…”

Section: Compound Interaction H…a [å] D…a [å] D-h…a [°] Ebond [Kj Molmentioning

confidence: 99%

“…Wang et al reported strategies of additive-induced and liquid-assisted mechanochemical GABA polymorph control [ 42 , 44 ], followed by Lamkowski et al, who discussed the pH influences on the stabilization of II -GABA in 2022 [ 45 ]. A plethora of pharmaceutically active ingredients (APIs) are derived from GABA, such as pregabalin, phenibut, baclofen, and gabapentin, which have all been discussed regarding their crystal structure over time [ 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 ]. Gabapentin stands out as a reliable medication, popularly used for nearly 30 years.…”

Section: Introductionmentioning

confidence: 99%

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Polymorphism and Multi-Component Crystal Formation of GABA and Gabapentin

Komisarek,

Demirbas,

Haj Hassani Sohi

et al. 2023

Pharmaceutics

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This study exploits the polymorphism and multi-component crystal formation of γ-amino butanoic acid (GABA) and its pharmaceutically active derivative, gabapentin. Two polymorphs of GABA and both polymorphs of gabapentin are structurally revisited, together with gabapentin monohydrate. Hereby, GABA form II is only accessible under special conditions using additives, whereas gabapentin converts to the monohydrate even in the presence of trace amounts of water. Different accessibilities and phase stabilities of these phases are still not fully clarified. Thus, indicators of phase stability are discussed involving intermolecular interactions, molecular conformations, and crystallization environment. Calculated lattice energy differences for polymorphs reveal their similar stability. Quantification of the hydrogen bond strengths with the atoms-in-molecules (AIM) model in conjunction with non-covalent interaction (NCI) plots also shows similar hydrogen bond binding energy values for all polymorphs. We demonstrate that differences in the interacting modes, in an interplay with the intermolecular repulsion, allow the formation of the desired phase under different crystallization environments. Salts and co-crystals of GABA and gabapentin with fumaric as well as succinic acid further serve as models to highlight how strongly HBs act as the motif-directing force in the solid-phase GABA-analogs. Six novel multi-component entities were synthesized, and structural and computational analysis was performed: GABA fumarate (2:1); two gabapentin fumarates (2:1) and (1:1); two GABA succinates (2:1) and (1:1); and a gabapentin:succinic acid co-crystal. Energetically highly attractive carboxyl/carboxylate interaction overcomes other factors and dominates the multi-component phase formation. Decisive commonalities in the crystallization behavior of zwitterionic GABA-derivatives are discussed, which show how they can and should be understood as a whole for possible related future products.

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