Co-crystals as a new approach to multimodal analgesia and the treatment of pain

Figures & data

Figure 1 Potential methods for delivering multimodal drug therapy.

Abbreviations: API, active pharmaceutical ingredient; FDC, fixed-dose combination.

Table 1 Glossary of terms

Term	Definition
API	Active pharmaceutical ingredient
Coformer	Non-volatile component that forms co-crystals with an API.
Enantiomer	An enantiomer is one of two stereoisomers (compounds that have the same molecular formula and differ only in arrangement of their atoms) that are non-superimposable mirror images of each other. Separate enantiomers are optically active compounds; they rotate plane-polarized light in equal amounts but in opposite directions (clockwise direction, dextrorotatory; counterclockwise direction, levorotatory).
Hydrate	Hydrates are multicomponent crystalline solid molecular substances containing both the host molecule (API or excipient) and water in the crystal lattice structure.
Polymorph	Polymorphs are multiple solid forms of a chemical entity that have different crystal structures. Polymorphs occur when a given compound of a specific molecular formula and chemical structure exists in two or more physical phases resulting from differing arrangements of the molecules in the solid state, ie, exhibiting different crystalline lattices. Polymorphs form as a consequence of different stacking arrangements and/or molecular conformations within the crystal lattice. Polymorphs may possess different physical and chemical properties.
Racemate (rac)	A racemate is an equimolar mixture of a pair of enantiomers (levorotatory and dextrorotatory, respectively). A racemate does not exhibit optical activity, meaning that there is no net rotation of plane-polarized light.
Salt	An ionic compound that contains two ions arranged in the crystal lattice predominantly based on ion pairing. Salts are typically formed in an acid–base reaction by proton (H^+) transfer.
Solvate	Solvates are multicomponent solid molecular substances containing both the host molecule and solvents other than water.

Figure 2 Structure of (A) an example API–coformer co-crystal (aprepitant–L-proline monohydrate)⁴² and (B) an example API–API co-crystal (CTC).

Notes: Figure B is reproduced with permission from Almansa C, Mercè R, Tesson N, et al. Co-crystal of tramadol hydrochloride–celecoxib (ctc): a novel API–API co-crystal for the treatment of pain. Cryst Growth Des. 2017;17:1884–1892.⁵⁹ Available from: https://pubs.acs.org/action/doSearch?AllField=10.1021%2Facs.cgd.6b01848. © 2017 American Chemical Society; further permissions related to the material excerpted should be directed to the ACS.
Abbreviations: API, active pharmaceutical ingredient; CTC, co-crystal of tramadol-celecoxib in a 1:1 molecular ratio.

Figure 3 The potential impact of an API–API co-crystal on the physicochemical and clinical properties of the constituent APIs.

Abbreviations: API, active pharmaceutical ingredient; PK, pharmacokinetics.

Figure 4 Mechanisms of action of the constituent APIs within the API–API co-crystal CTC.

Abbreviations: 5-HT, 5-hydroxytryptamine; API, active pharmaceutical ingredient; CTC, co-crystal of tramadol-celecoxib; NET, norepinephrine transporter; PG, prostaglandin; SERT, serotonin transporter.

Figure 5 The anti-nociceptive effects of an API–API co-crystal (a suspension of CTC) in a rat model of acute postsurgical pain (n=8–10 per group). *p<0.05, ***p<0.001 significant difference between the theoretical additive dose and the experimental additive dose (Student’s t-test).

Notes: Isobolographic analysis of the effects of a suspension of CTC in a rat pain model showed supra-additive effects on both mechanical allodynia (A) and thermal hyperalgesia (B) endpoints. Figures A and B are reproduced from Merlos M, Portillo-Salido E, Brenchat A, et al. Administration of a co-crystal of tramadol and celecoxib in a 1:1 molecular ratio produces synergistic antinociceptive effects in a postoperative pain model in rats. Eur J Pharmacol. 2018;833:370–378.⁶⁷ © 2018 The Authors. Published by Elsevier B.V. License available at: https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode. 
Abbreviations: API, active pharmaceutical ingredient; CTC, co-crystal of tramadol-celecoxib in a 1:1 molecular ratio; ip, intraperitoneal.

Figure 6 The clinical pharmacokinetics of tramadol and celecoxib after the administration of the API–API co-crystal CTC, compared with the individual, commercially available, single-entity reference products administered alone or in open combination (n=28 celecoxib alone; n=28 open combination of immediate-release tramadol and celecoxib; n=29 CTC; n=30 immediate-release tramadol alone).⁶⁸.

Notes: The pharmacokinetic profiles of tramadol (A) and (B) and celecoxib (C) and (D) were modified after administration of CTC, compared with administration of the commercially available, single-entity reference products alone or in open combination. Figures A–D are reproduced with minor modifications (minor changes to the size of individual points, axis title fonts, format of units on y-axes, and minor changes to the key) from Videla S, Lahjou M, Vaque A, et al. Pharmacokinetics of multiple doses of co-crystal of tramadol-celecoxib: findings from a 4-way randomized open-label Phase I clinical trial. Br J Clin Pharmacol. 2018;84(1):64–78. © 2017 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society. License available at: https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode.
Abbreviations: API, active pharmaceutical ingredient; CTC, co-crystal of tramadol-celecoxib.

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Almansa C, Mercè R, Tesson N, Farran J, Tomàs J, Plata-Salamán CR. Co-crystal of tramadol hydrochloride–celecoxib (ctc): a novel API–API co-crystal for the treatment of pain. Cryst Growth Des. 2017;17(4):1884–1892. doi:10.1021/acs.cgd.6b01848

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Merlos M, Portillo-Salido E, Brenchat A, et al. Administration of a co-crystal of tramadol and celecoxib in a 1:1 molecular ratio produces synergistic antinociceptive effects in a postoperative pain model in rats. Eur J Pharmacol. 2018;833:370–378. doi:10.1016/j.ejphar.2018.06.02229932927

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Videla S, Lahjou M, Vaque A, et al. Pharmacokinetics of multiple doses of co-crystal of tramadol-celecoxib: findings from a 4-way randomized open-label Phase I clinical trial. Br J Clin Pharmacol. 2018;84(1):64–78. doi:10.1111/bcp.1342828888220

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