GABA-Controlled Synthesis of the Metastable Polymorphic Form and Crystallization Behavior with a Chiral Malic Acid

Lamkowski, Laura; Komisarek, Daniel; Merz, Klaus

doi:10.1021/acs.cgd.1c00991

Cited by 3 publications

(5 citation statements)

References 40 publications

(88 reference statements)

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“…Now, if lattice energies were the only indicator of phase stability, II - 1 and IV - 2 should easily undergo phase transitions to I - 1 and II - 2 , respectively. Indeed, a monotropic phase transition partially occurs by sublimation of I -GABA [ 43 ], but crystallization of this form from an aqueous solution with acetic acid or by liquid-assisted grinding with acetic acid leads to a stable II - 1 product [ 42 , 45 ]. The 2 polymorphs can be obtained from different solvents, but influences such as temperature treatment or mechanical stress can also induce an enantiotropic solid–solid phase transition [ 61 , 62 , 63 ].…”

Section: Resultsmentioning

confidence: 99%

“…Interestingly, Vasceq et al showed polymorphs of GABA to perform different permeabilities in crossing the blood−brain barrier, where the metastable II -GABA modification exhibits higher bioactivity [ 43 ]. 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 ].…”

Section: Introductionmentioning

confidence: 99%

“…However, gabapentin readily converts to its hydrate modification ( I -gabapentin) when water is present during the crystallization process. To sum up, previous factors like crystallization conditions and molecular conformations, as well as energetic contributions on a molecular level, were taken into consideration to describe phase stability for GABA and gabapentin, mainly in solution or in a gas phase [ 24 , 42 , 43 , 44 , 45 , 61 , 63 , 64 , 65 , 66 , 71 , 72 ].…”

Section: Introductionmentioning

confidence: 99%

“…The respective phases are polymorphic modifications I-1 and II-1 (P2 1 /c and I4 1 cd), II-2 and IV-2 (P2 1 /c and C2/c), a gabapentin monohydrate (I-gabapentin), as well as five salts and a co-crystal: GABA fumarate (2:1, 1-3), two gabapentin fumarates (2:1, 2-3a) and (1:1, 2-3b), two GABA succinates (2:1, 1-4a) and (1:1, 1-4b) and a gabapentin:succinic acid co-crystal (2)(3)(4). The nomenclature for GABA and gabapentin single phases is based on the works by Liu et al and Lamkowski et al and their respective 2022 publications [45,71].…”

Section: Introductionmentioning

confidence: 99%

“…Pharmaceutics 2023, 15,2299 3 of 20 on a molecular level, were taken into consideration to describe phase stability for GABA and gabapentin, mainly in solution or in a gas phase [24,42,43,44,45,61,63,64,65,66,71,72].…”

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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