An Alternate Crystal Form of Gabapentin: A Cocrystal with Oxalic Acid

Abstract

A cocrystal of gabapentin and oxalic acid has been prepared employing a strategy based on a hydrogen-bonded synthon described by the graph set notation R4 2(8). High throughput techniques and solvent drop grinding were used along with traditional crystallization methods, including crystallization in aqueous solutions at various pH. A number of new solid forms have been detected. The cocrystal of gabapentin and oxalic acid was fully characterized including single crystal structure analysis, which revealed the R4 2(8) synthon.

Novel Challenges in Crystal Engineering: Polymorphs and New Crystal Forms of Active Pharmaceutical Ingredients

“…The thermogram of 4 ( Figure 12.a) is characterized by an endothermic peak at 150ºC, corresponding to the melting of the compound. The melting peak is found at a lower temperature than any of the reported polymorphic forms of gabapentin 32 and within the range obtained for other multicomponent forms 33,34 . This peak encloses the cyclisation/ lactamization of gabapentin 32 implying water release that is observed on HSM experiments ( Figure 13) and detected in TGA.…”

“…An extensive pH stability of gabapentin has been disclosed where an ester derivative obtained at low pH was reported 83 . Multicomponent crystal forms (co-crystals and molecular salts) involving GBP with different carboxylic acids were also recently disclosed 1,[32][33][34] .…”

“…A wide range of studies have been performed in the last few years, here we will focus on some of those we have been recently engaged. Several studies with gabapentin, a neuroleptic drug, have been reported [31][32][33][34] and a few multicomponent crystal forms with carboxylic acids have been exploited and will be deeply discussed in this chapter. With the antibiotic 4-aminosalicylic acid (4ASA) some new crystal forms were disclosed, solvates, and molecular salt 35 , showing a clear tendency of this API to form multicomponent crystallines with lone-pair containing heterocycles, such as dioxane, morpholine and piperazine, disrupting the typical R 8 homosynthon in 4ASA ( Figure 1 Gabapentin (1-(aminomethyl)cyclohexane acetic acid, GBP) is an analogue of gammaaminobutyric acid (GABA) and exhibits anticonvulsant properties.…”

Characterisation, solubility and intrinsic dissolution behaviour of benzamide: dibenzyl sulfoxide cocrystal

“…A number of cocrystals of APIs with different co-formers formed by different methods have been reported and it was shown that the solid-state interactions between the two compounds are mainly based on hydrogen bonds Childs et al, 2004;Lu and Rohani, 2009;Padrela et al, 2009;Paluch et al, 2011;Trask et al, 2005;Wenger and Bernstein, 2008). We have previously shown that the sulfoxide (S=O) functionality, common in a significant number of APIs, is a potent hydrogen bonding acceptor and forms cocrystals in association with a wide variety of amino (NH) functional groups (Eccles et al, 2010).…”

Investigating Gabapentin Polymorphism Using Solid-State NMR Spectroscopy

“…Form III is metastable while form IV has not been well-characterized. Co-crystals of gabapentin, with numerous carboxylic acid coformers, have been reported (3,4). A number of studies used Fourier transform infrared spectroscopy (FTIR) to investigate the effect of various processing methods on the polymorphism of gabapentin (2,5).…”