Triheptanoin is a synthetic triglyceride made up of three molecules of heptanoic acid (a medium-chain fatty acid) attached to a glycerol backbone. It is commonly used in cosmetic and skincare products as an emollient and a carrier for active ingredients. Triheptanoin is valued for its ability to enhance the texture of formulations, providing a light, silky feel without leaving an oily residue. Thanks to its moisturizing and nourishing properties, it is used in creams, lotions, oils, and hair care products.

Chemical Composition and Structure
Triheptanoin consists of three chains of heptanoic acid, a seven-carbon fatty acid, attached to a glycerol molecule. This configuration gives it moisturizing properties and good skin penetration, making it an ideal emollient for cosmetic formulations. Its lightweight texture and quick absorption make it a versatile ingredient.

Physical Properties
Triheptanoin appears as a clear, colorless, and slightly viscous liquid. It is oil-soluble and compatible with a wide range of lipophilic ingredients, making it easily incorporated into various cosmetic formulations. It is stable and non-comedogenic, meaning it does not clog pores, making it suitable for oily or acne-prone skin.

The name describes the structure of the molecule:

• Tri indicates that there are three components of the next molecule
• Heptanoin refers to the heptanoic acid part of the molecule. Heptanoic acid is a seven-carbon fatty acid.

The synthesis process takes place in different steps:

• Preparation of heptanoic acid. Heptanoic acid can be produced by various methods, including the oxidation of heptanol or the Grignard reaction of eptil bromide with carbon dioxide, followed by acidification.
• Esterification with glycerol. Heptanoic acid reacts with glycerol in an esterification reaction to produce triheptanoin. This reaction involves the formation of an ester bond between the carboxyl group of heptanoic acid and the hydroxyl group of glycerol. The reaction is catalyzed by an acid and involves heating the reagents to promote the reaction.
• Purification. The reaction mixture is purified to isolate triheptanoin by processes such as distillation, filtration and drying.
• Quality control test. The final product is tested to ensure it meets the required specifications. This may involve testing for purity, moisture content and other physical and chemical properties.

It appears as a clear, oily liquid.

What it is used for and where

Medical

Approved as a medicine in June 2020 in the USA, it is a compound with anaplerotic properties used in the treatment of hereditary metabolic disorders against long-chain fatty acid oxidation in both adults and paediatrics.

Spectroscopy studies have shown how Triheptanoin can correct bioenergetics in the brains of patients with neurodegenerative disease associated with cerebral energy deficit (Huntington's) (1).

Triheptanoin improved left ventricular ejection fraction and reduced left ventricular mass at rest, as well as lowering heart rate during exercise among patients with long-chain fatty acid oxidation disorders (2).

Patients suffering from McArdle's disease have a complete blockade in glycogenolysis and glycogen-dependent expansion of the tricarboxylic acid cycle, which may limit fat oxidation. Unfortunately, treatment with Triheptanoin has not proved effective. Despite the increase in plasma malate treated with Triheptanoin , the increase was insufficient to generate a normal turnover of the tricarboxylic acid cycle during exercise and the treatment provided no effect on exercise capacity or oxidative metabolism in patients with McArdle's disease (3).

Triheptanoin has also been included in a breakthrough in the treatment of epilepsy. However, the authors of this complex study suggested further studies to gain a better understanding of the anticonvulsant mechanism of triheptanoin in the search for new and improved therapeutic approaches for the treatment of this disease (4).

Cosmetics

Such an interesting chemical compound could not escape the attention of the cosmetics industry, and practically since its introduction Triheptanoin has been incorporated into formulations of creams, lotions and various personal care preparations. 

Triheptanoin's main function is to improve the spreadability of creams as an emollient. It also functions as a viscosity control agent to increase or decrease the viscosity of cosmetics. It can also function as an occlusive agent, to increase the water content of the skin.

INCI functions:

Skin conditioning agent - Occlusive. This ingredient has the task of modifying the condition of the skin when it is damaged or dry by reducing flaking and restoring elasticity. It has a strong lipophilic character and is identified as an occlusive ingredient; it is generally composed of oily and fatty materials that remain on the skin surface and reduce trans epidermal water loss.

Viscosity Enhancing Agent - non acqueous. Since viscosity is important for increasing the chemical and physical stability of the product, Viscosity Enhancing Agent non acqueous is an important dosage factor in gels, suspensions, emulsions, solutions. Increasing viscosity makes formulations less sedimentary and more homogeneously thickened.

Triheptanoin studies

Boiling Point	470.0±12.0°C at 760 mmHg
Flash Point	195.5±19.6°C
Density	1.0±0.1 g/cm3
Heavy metals	≤10 ppm
Water	≤1.0%
Residue on ignition	≤0.1%
Sulphated ash	≤0.5%/g
Total Impurities	≤0.5%
Safety

• Molecular Formula    C₂₄H₄₄O₆
• Linear Formula   [CH₃(CH₂₎₅COOCH₂]₂CHOCO(CH₂)₅CH₃
• Molecular Weight     428.6
• Exact Mass   428.313782
• CAS  620-67-7
• UNII    2P6O7CFW5K
• EC Number   210-647-2
• DSSTox Substance ID  
• IUPAC  2,3-di(heptanoyloxy)propyl heptanoate
• InChI=1S/C24H44O6/c1-4-7-10-13-16-22(25)28-19-21(30-24(27)18-15-12-9-6-3)20-29-23(26)17-14-11-8-5-2/h21H,4-20H2,1-3H3 
• InChl Key      PJHKBYALYHRYSK-UHFFFAOYSA-N
• SMILES   CCCCCCC(=O)OCC(COC(=O)CCCCCC)OC(=O)CCCCCC
• MDL number  MFCD00042910
• PubChem Substance ID    57653497
• ChEBI  
• RXCUI       1313234
• Beilstein     1807724
• RTECS   MB2660000 

Synonyms:

• Glycerol trienanthate
• 1,2,3-Trienanthoylglycerol
• Trioenanthin

References________________________________________________________________________

(1) Mochel F. Triheptanoin for the treatment of brain energy deficit: A 14-year experience. J Neurosci Res. 2017 Nov;95(11):2236-2243. doi: 10.1002/jnr.24111. 

(2) Gillingham MB, Heitner SB, Martin J, Rose S, Goldstein A, El-Gharbawy AH, Deward S, Lasarev MR, Pollaro J, DeLany JP, Burchill LJ, Goodpaster B, Shoemaker J, Matern D, Harding CO, Vockley J. Triheptanoin versus trioctanoin for long-chain fatty acid oxidation disorders: a double blinded, randomized controlled trial. J Inherit Metab Dis. 2017 Nov;40(6):831-843. doi: 10.1007/s10545-017-0085-8. 

Abstract. Background: Observational reports suggest that supplementation that increases citric acid cycle intermediates via anaplerosis may have therapeutic advantages over traditional medium-chain triglyceride (MCT) treatment of long-chain fatty acid oxidation disorders (LC-FAODs) but controlled trials have not been reported. The goal of our study was to compare the effects of triheptanoin (C7), an anaplerotic seven-carbon fatty acid triglyceride, to trioctanoin (C8), an eight-carbon fatty acid triglyceride, in patients with LC-FAODs....Conclusions: C7 improved LV ejection fraction and reduced LV mass at rest, as well as lowering heart rate during exercise among patients with LC-FAODs.

(3) Madsen KL, Laforêt P, Buch AE, Stemmerik MG, Ottolenghi C, Hatem SN, Raaschou-Pedersen DT, Poulsen NS, Atencio M, Luton MP, Ceccaldi A, Haller RG, Quinlivan R, Mochel F, Vissing J. No effect of triheptanoin on exercise performance in McArdle disease. Ann Clin Transl Neurol. 2019 Oct;6(10):1949-1960. doi: 10.1002/acn3.50863. 

(4) Borges K, Sonnewald U. Triheptanoin--a medium chain triglyceride with odd chain fatty acids: a new anaplerotic anticonvulsant treatment? Epilepsy Res. 2012 Jul;100(3):239-44. doi: 10.1016/j.eplepsyres.2011.05.023.

Compendium of the most significant studies with reference to properties, intake, effects.

Shirley M. Triheptanoin: First Approval. Drugs. 2020 Oct;80(15):1595-1600. doi: 10.1007/s40265-020-01399-5. Erratum in: Drugs. 2020 Nov;80(17):1873.

Abstract. This article summarizes the milestones in the development of triheptanoin leading to this first regulatory approval for use in the treatment of pediatric and adult patients with LC-FAOD.

Wehbe Z, Tucci S. Therapeutic potential of triheptanoin in metabolic and neurodegenerative diseases. J Inherit Metab Dis. 2020 May;43(3):385-391. doi: 10.1002/jimd.12199. 

Abstract. The present review summarises the published literature on the metabolism of triheptanoin including clinical reports related to the use of triheptanoin.

Vockley J, Burton B, Berry G, Longo N, Phillips J, Sanchez-Valle A, Chapman K, Tanpaiboon P, Grunewald S, Murphy E, Lu X, Cataldo J. Effects of triheptanoin (UX007) in patients with long-chain fatty acid oxidation disorders: Results from an open-label, long-term extension study. J Inherit Metab Dis. 2021 Jan;44(1):253-263. doi: 10.1002/jimd.12313.

Abstract. Long-chain fatty acid oxidation disorders (LC-FAOD) are autosomal recessive conditions that impair conversion of long-chain fatty acids into energy, leading to significant clinical symptoms. 

Laemmle A, Steck AL, Schaller A, Kurth S, Perret Hoigné E, Felser AD, Slavova N, Salvisberg C, Atencio M, Mochel F, Nuoffer JM, Gautschi M. Triheptanoin - Novel therapeutic approach for the ultra-rare disease mitochondrial malate dehydrogenase deficiency. Mol Genet Metab Rep. 2021 Oct 19;29:100814. doi: 10.1016/j.ymgmr.2021.100814.

Abstract. Mitochondrial malate dehydrogenase (MDH2) deficiency (MDH2D) is an ultra-rare disease with only three patients described in literature to date. MDH2D leads to an interruption of the tricarboxylic acid (TCA) cycle and malate-aspartate shuttle (MAS) and results in severe early onset encephalopathy.

Norris MK, Scott AI, Sullivan S, Chang IJ, Lam C, Sun A, Hahn S, Thies JM, Gunnarson M, McKean KN, Merritt JL 2nd. Tutorial: Triheptanoin and Nutrition Management for Treatment of Long-Chain Fatty Acid Oxidation Disorders. JPEN J Parenter Enteral Nutr. 2021 Feb;45(2):230-238. doi: 10.1002/jpen.2034. 

Abstract. We report the complex medical and nutrition management of triheptanoin therapy initiated emergently for 3 patients with long-chain fatty acid oxidation disorders.

Lee SK, Gupta M, Shi J, McKeever K. The Pharmacokinetics of Triheptanoin and Its Metabolites in Healthy Subjects and Patients With Long-Chain Fatty Acid Oxidation Disorders. Clin Pharmacol Drug Dev. 2021 Nov;10(11):1325-1334. doi: 10.1002/cpdd.944.

Abstract. The pharmacokinetics of triheptanoin and circulating metabolites were explored in healthy subjects and patients with LC-FAODs using noncompartmental analyses. 

Vockley J, Longo N, Madden M, Dwyer L, Mu Y, Chen CY, Cataldo J. Dietary management and major clinical events in patients with long-chain fatty acid oxidation disorders enrolled in a phase 2 triheptanoin study. Clin Nutr ESPEN. 2021 Feb;41:293-298. doi: 10.1016/j.clnesp.2020.11.018.

Abstract. Long-chain fatty acid oxidation disorders (LC-FAOD) are rare, life-threatening, autosomal recessive disorders that lead to energy depletion and major clinical events (MCEs), such as acute metabolic crises of hypoglycemia, cardiomyopathy, and rhabdomyolysis. The aim of this study was to report a post hoc analysis of diet diary data from the phase 2 UX007-CL201 study

Vockley J, Burton B, Berry G, Longo N, Phillips J, Sanchez-Valle A, Chapman K, Tanpaiboon P, Grunewald S, Murphy E, Lu X, Cataldo J. Effects of triheptanoin (UX007) in patients with long-chain fatty acid oxidation disorders: Results from an open-label, long-term extension study. J Inherit Metab Dis. 2021 Jan;44(1):253-263. doi: 10.1002/jimd.12313.

Abstract. Long-chain fatty acid oxidation disorders (LC-FAOD) are autosomal recessive conditions that impair conversion of long-chain fatty acids into energy, leading to significant clinical symptoms. 

McDonald T, Hodson MP, Bederman I, Puchowicz M, Borges K. Triheptanoin alters [U-13C6]-glucose incorporation into glycolytic intermediates and increases TCA cycling by normalizing the activities of pyruvate dehydrogenase and oxoglutarate dehydrogenase in a chronic epilepsy mouse model. J Cereb Blood Flow Metab. 2020 Mar;40(3):678-691. doi: 10.1177/0271678X19837380.

Abstract. Here, we investigated changes in glucose metabolism by triheptanoin interictally in the chronic stage of the pilocarpine mouse epilepsy model.

Yuan X, Wang L, Tandon N, Sun H, Tian J, Du H, Pascual JM, Guo L. Triheptanoin Mitigates Brain ATP Depletion and Mitochondrial Dysfunction in a Mouse Model of Alzheimer's Disease. J Alzheimers Dis. 2020;78(1):425-437. doi: 10.3233/JAD-200594.

Abstract. Brain energy failure is an early pathological event associated with synaptic dysfunction in Alzheimer's disease (AD). Thus, mitigation or enhancement of brain energy metabolism may offer a therapeutic avenue. However, there is uncertainty as to what metabolic process(es) may be more appropriate to support or augment since metabolism is a multiform process such that each of the various metabolic precursors available is utilized via a specific metabolic pathway. In the brain, these pathways sustain not only a robust rate of energy production but also of carbon replenishment.

Engelstad K, Salazar R, Koenigsberger D, Stackowtiz E, Brodlie S, Brandabur M, De Vivo DC. Exploring triheptanoin as treatment for short chain enoyl CoA hydratase deficiency. Ann Clin Transl Neurol. 2021 May;8(5):1151-1157. doi: 10.1002/acn3.51359.

Abstract. We explored the benefits of triheptanoin as a treatment for Short Chain Enoyl Co-A Hydratase (SCEH) deficiency.