A Lection in Humbleness: Crystallization of Chiral and Zwitterionic APIs Baclofen and Phenibut

Herbst, Marco; Komisarek, Daniel; Strothmann, Till; Vasylyeva, Vera

doi:10.3390/cryst12101393

Cited by 6 publications

(8 citation statements)

References 55 publications

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“…However, mechanochemically prepared systems may have higher amorphicity, more crystalline defects, or morphology changes that can affect product properties [ 61 , 62 , 63 ]. Our group observed similar findings for Baclofen and Phenibut, where multicomponent forms received through grinding or solvent-based methods showed different thermal properties in some cases [ 57 ]. Over the years, various theories on crystallization mechanisms during grinding have been proposed.…”

Section: Introductionsupporting

confidence: 57%

“…Thus, it appears that an additional crystallization product forms here that are not yet characterized by single-crystal diffraction. Past works have shown that 4 tends to form non-pure phases more commonly, which is likely due to comparatively high lattice energy that makes the formation of multicomponent phases unfavorable [ 56 , 57 ].…”

Section: Resultsmentioning

confidence: 99%

“…This establishes maleic acid as a promising candidate for reliable salt production with pharmaceutically active GABA derivatives, distinguishing it from other GRAS-list co-formers like tartaric or malic acid. These acids tend to produce unreliable phase mixtures with Baclofen and Phenibut, and malic acid forms potentially viscous residues with Pregabalin [ 56 , 57 ]. Other factors in crystal phase production, such as time and waste reduction, are also important.…”

Section: Introductionmentioning

confidence: 99%

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Maleic Acid as a Co-Former for Pharmaceutically Active GABA Derivatives: Mechanochemistry or Solvent Crystallization?

2023

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In this study, we compare the mechanochemical and classical solvent crystallization methods for forming maleates of GABA and its pharmaceutically active derivatives: Pregabalin, Gabapentin, Phenibut, and Baclofen. Common characterization techniques, like powder and single crystal X-ray diffraction, IR-spectroscopy, differential scanning calorimetry, thermogravimetric analysis and 1H-NMR spectroscopy, are used for the evaluation of structural and physicochemical properties. Our work shows that maleate formation is possible with all investigated target compounds. Large increases in solubility can be achieved, especially for Pregabalin, where up to twentyfold higher solubility in its maleate compared to the pure form can be reached. We furthermore compare the mechanochemical and solvent crystallization regarding quickness, reliability of phase production, and overall product quality. A synthetic route is shown to have an impact on certain properties such as melting point or solubility of the same obtained products, e.g., for Gabapentin and Pregabalin, or lead to the formation of hydrates vs. anhydrous forms. For the GABA and Baclofen maleates, the method of crystallization is not important, and similarly, good results can be obtained by either route. In contrast, Phenibut maleate cannot be obtained pure and single-phase by either method. Our work aims to elucidate promising candidates for the multicomponent crystal formation of blockbuster GABA pharmaceuticals and highlight the usefulness of mechanochemical production routes.

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Section: Introductionsupporting

confidence: 57%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Maleic Acid as a Co-Former for Pharmaceutically Active GABA Derivatives: Mechanochemistry or Solvent Crystallization?

2023

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“…However, 2 behaves rather different than 1 in two key aspects: firstly, 2 does not form a stable hydrate as racemic 1 does. 85,86 Contrary to the latter, 2 -hydrate transitions to anhydrous 2 quickly, suggesting a preferable form in the anhydrous species. Furthermore, experimental observations conducted in the presented work suggest a higher stability of 2 as compared to 2 : 3 .…”

Section: Resultsmentioning

confidence: 92%

Co-crystals of zwitterionic GABA API's pregabalin and phenibut: properties and application

2022

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“…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%

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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A Lection in Humbleness: Crystallization of Chiral and Zwitterionic APIs Baclofen and Phenibut

Cited by 6 publications

References 55 publications

Maleic Acid as a Co-Former for Pharmaceutically Active GABA Derivatives: Mechanochemistry or Solvent Crystallization?

Maleic Acid as a Co-Former for Pharmaceutically Active GABA Derivatives: Mechanochemistry or Solvent Crystallization?

Co-crystals of zwitterionic GABA API's pregabalin and phenibut: properties and application

Polymorphism and Multi-Component Crystal Formation of GABA and Gabapentin

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