Plastically bendable pregabalin multi-component systems with improved tabletability and compressibility

U. B. Rao Khandavilli *ab, Mustafa Yousuf a, Barbara E. Schaller a, René R. E. Steendam a, Leila Keshavarz a, Patrick McArdle c and Patrick J. Frawley a
aSolid State Pharmaceutical Centre (SSPC), University of Limerick, Limerick, Ireland. E-mail:
bPSC Biotech Limited, Blanchardstown, Dublin 15, Ireland
cSchool of Chemistry, National University of Ireland, Galway H91 TK33, Ireland

Received 15th October 2019 , Accepted 9th December 2019

First published on 10th December 2019

Pregabalin is an anti-convulsant blockbuster chiral drug with the trade name Lyrica in its S-form. Anhydrous pregabalin (SPG) is brittle in nature and herein, we report two novel plastically bendable SPG salts with pharmaceutically acceptable coformers oxalic acid and salicylic acid. These mechanically flexible salts show improved solubility, tabletability and compressibility compared to the marketed anhydrous form.

The majority of pharmaceutical drugs on the market exist in solid oral dosage forms due to ease of handling and administration.1,2 Of late, several solid forms have been found to exhibit poor physicochemical properties including poor solubility, stability, flowability and tabletability, bringing forth manufacturability and medicinal efficacy issues.3–6 It is known that brittle crystals do not flow properly but fracture easily producing cracks in the tablet.7–9 Further, research has shown that the mechanical properties of pharmaceutical compounds have an important role in product performance since they can alter the elasticity, hardness, tensile strength, and fracture toughness of an active pharmaceutical ingredient (API).10–13 Hence, solid form screening towards developing a robust solid form has been integrated into drug R&D programs with multi-component crystallization offering new solutions.14–18 For example, there are a few reports in the literature showing that the powder flow properties of APIs can be resolved and other physicochemical properties can be improved by converting the singular brittle compounds into plastically bendable multi-component systems.19–23 Therefore, plastically bendable dmulti-component systems such as salts, cocrystals and solvates have practical applicability in solving pre- and post-formulation issues. Mechanically flexible compounds have also been proven to be smart materials and have vital applications in the making of future generation electronics and medical devices.23–29 However, it is a daunting task to find mechanically flexible multi-component crystalline materials. There are only a handful of examples in the literature that show mechanical flexibility. In recent years, generation of mechanically flexible crystals (single and multi-component) has taken a subtle shift from serendipitous discovery to strategic design.30–33 The recent 3rd generation crystal engineering principles (supramolecular synthon concepts) can help to predict/recognise patterns to synthesize mechanically flexible compounds.34–39

The mechanism of shear sliding of the crystallographic planes is responsible for plastic bendability in molecular crystals, and these planes interact through weak van der Waals (vdW) interactions to generate low energy slip planes.13,40,41 This plastic bending trait is frequently seen in compounds that interact via weakly interacting functional groups such as halogen interactions. Anisotropic interactions and the combination of weak and strong hydrogen bonds in perpendicular directions can facilitate slip planes in the structure.14,42,43 Amino acids, some APIs and many alkaloids exist in their zwitterionic form. It has come to our attention that even zwitterionic compounds show bendable behavior, as usually, zwitterionic compounds comprise strong ionic interactions and typical intrinsic molecular arrangements. However, our previous work has demonstrated how a brittle zwitterionic compound can become bendable when it takes water in its lattice.44

This time, we tried to understand the mechanical flexibility behaviour of (S)-3-isobutyl-γ-aminobutyric acid also, known as pregabalin (SPG), when it forms multi-component systems. SPG is an antiepileptic drug and SPG anhydrate is marketed under the trade name Lyrica. SPG anhydrate is brittle in nature and in our previous studies, we have also demonstrated how hydration alters the nucleation kinetics and mechanical behavior of this compound.44,45 However, the flexible SPG hydrate was found to be highly unstable which makes further processing a challenge. Based on this investigation, we further proceeded to understand the mechanical nature of flexible crystals by producing tailor-made multi-component stable forms, which are sufficiently stable for pharmaceutical applications. There is one co-crystal of SPG with (S)-mandelic acid reported in the literature; however, the authors did not discuss the mechanical properties of this system.46 To our knowledge, there are no studies on the plastic bendability of zwitterionic multi-component systems in the literature.

In this regard, we have screened SPG with a range of various organic and inorganic compounds (see the ESI). In this screening, we discovered two plastically bendable organic salts with oxalic acid (OX) and salicylic acid (SA) which comprised weak dispersive noncovalent interactions in their crystal structures. Fig. 1 shows the bendability of these crystals when mechanical force is applied with tweezers.

image file: c9ce01625b-f1.tif
Fig. 1 Mechanical flexibility of SPG+–OX and SPG+–SA crystals.

Fig. 2 shows that the reported anhydrous SPG brittle form exists in a propeller conformation that has one-dimensional sheets.47 Each molecule in this structure interacts with four other molecules through R22(8) tetramers along the b-axis and the terminal alkyl groups are locked into each other to form an interdigitated structure.

image file: c9ce01625b-f2.tif
Fig. 2 Interdigitation of planes in the SPG anhydrous form.4

The SPG+–OX salt was formed in a 2[thin space (1/6-em)]:[thin space (1/6-em)]1 stoichiometric ratio and crystallized in the C2 monoclinic space group (Fig. 3). In the crystal structure, each oxygen of the oxalate anion interacts with two SPG molecules via O⋯H–N+ (2.049 Å, 166°, 2.24 Å, 177°), O⋯H–O (1.737 Å, 172°), and O⋯H–N+ (2.257 Å, 139°) hydrogen bonding. In turn, each SPG molecule interacts with four other oxalate molecules. Here, the oxalate molecules act as a bridge to bring two SPG molecules together. These interactions cause close packing, and the alkyl groups are facing each other. Consequently, there is low rugosity of the slip layer along the slip direction.

image file: c9ce01625b-f3.tif
Fig. 3 Slip planes in the SPG+–OX salt along the bc plane (hydrogen atoms were omitted for clarity).

On the other hand, SPG+–SA was crystallized in the P21212 orthorhombic space group with 1[thin space (1/6-em)]:[thin space (1/6-em)]1 stoichiometric ratio. Each salicylate molecule in this structure held three other SPG molecules via O–H⋯O (1.733 Å, 164°), N–H⋯O (1.94 Å, 142°) and N+–H⋯O (2.127 Å, 140°) interactions (Fig. 4). Again, due to the stronger interactions between SA and SPG, tight packing is combined with alkyl groups facing each other leading to the slip planes shown in Fig. 4.

image file: c9ce01625b-f4.tif
Fig. 4 Slip planes in the SPG+–SA salt along the ac plane (hydrogen atoms were omitted for clarity).

The interdigitated structures of SPG are rearranged by strong interactions with OX/SA molecules which act as structural buffers which disperse weak interactions throughout the lattice. In both SPG salts, the counterions (OX or SA) play space filling and tight packing roles which facilitate layer separation and thus enable slip between the layers.

Physicochemical properties like tabletability, compressibility and solubility of SPG+–SA, SPG+–OX and SPG have been studied. The studies have revealed that the salts have improved properties over anhydrous SPG.

To study the tableting performance, sieved bulk powder samples of SPG, SPG+–OX and SPG+–SA were compacted over a pressure range of 75–190 MPa. The compacted powders were tested for their tablet tensile strength which was plotted against the compaction pressure (Fig. 5). Among the three samples, SPG+–OX and SPG+–SA showed the best tableting behaviour, compacting into quite strong tablets under fairly low pressures, indicating good particle packing behaviour compared to SPG.

image file: c9ce01625b-f5.tif
Fig. 5 Tabletability plot comparing the tensile strength–compaction pressure relationship of SPG, SPG+–OX and SPG+–SA.

The solubility of SPG, SPG+–OX and SPG+–SA was determined in 20[thin space (1/6-em)]:[thin space (1/6-em)]80 water and ethanol medium at various temperatures (Fig. 6). The solubility study revealed that the SPG+–SA and SPG+–OX salts show significantly enhanced solubility behavior across different temperatures as compared to the anhydrous SPG.

image file: c9ce01625b-f6.tif
Fig. 6 Solubility curves of SPG, SPG+–OX and SPG+–SA at different temperatures.

In conclusion, two plastically bendable stable salts of a brittle blockbuster drug SPG with two generally recognized as safe compounds SA and OX are reported. In addition to improved solubility, the current study shows that improved tabletability can also be achieved due to the mechanically flexible nature of these two salts compared to brittle SPG. With respect to the crystal structure of these two salts, mono- and ditopic salt formers OX and SA assist in manipulating the internal structures in the SPG crystal lattice to form slip planes for the bendable properties. Our previous work reported two bendable SPG hydrate polymorphs; however, these two hydrate forms were unstable compared to the SPG anhydrous form. In the present work, we report that stable salts of SPG could be formed which have superior physical properties as compared to the SPG anhydrous form. There were no phase changes observed upon going down to 150 K and up again to 300 K for both the crystals.

Conflicts of interest

There are no conflicts to declare.


The authors gratefully acknowledge the financial support from the Science Foundation Ireland (SFI) under the grant number: 12/RC/2275. We have conducted this research as a part of the Synthesis and Solid State Pharmaceutical Centre (SSPC) and the Bernal Institute facilities at the University of Limerick.

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Electronic supplementary information (ESI) available: Experimental procedures, IR and Raman spectra, PXRD and thermograms. CCDC No. 1952993 and 1952994 (300 K) & 1967509 and 1967510 (150 K). For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c9ce01625b

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