Glycyrrhizin (1405-86-3) Physical and Chemical Properties
Glycyrrhizin
A high‑molecular‑weight triterpenoid saponin extracted from licorice root, used in formulation and R&D for its surfactant and sweetening properties and as an analytical reference material.
| CAS Number | 1405-86-3 |
| Family | Triterpenoid saponins |
| Typical Form | Crystalline powder / plates |
| Common Grades | BP, EP, USP |
Glycyrrhizin (glycyrrhizic acid) is a high–molecular-weight triterpenoid saponin: a pentacyclic triterpene aglycone (glycyrrhetinic-type) conjugated to a disaccharide comprised of two glucuronic acid residues. Structurally it is a glucopyranosiduronic acid ester of a noroleanane-type triterpenoid; the molecule contains multiple secondary and tertiary stereocenters and extensive oxygenation in both the aglycone and carbohydrate portions. The combined hydrophobic pentacyclic core and highly polar, polyacidic sugar domain produce amphiphilic behaviour typical of saponins.
Electronically the molecule is neutral in its protonation state as listed (formal charge 0) but presents a high density of hydrogen-bond donors and acceptors (numerous hydroxyl and carboxylate groups). The topological polar surface area and multiple ionizable carboxyl groups confer strong aqueous interactions and propensity to form salts (e.g., ammonium, potassium, sodium, dipotassium glycyrrhizinates) for improved solubility. Acid–base behaviour is dominated by the glucuronic acid moieties (acidic, readily ionized under physiological and neutral pH), while the aglycone portion is nonpolar and chemically similar in shape to steroidal scaffolds.
Functionally and industrially, glycyrrhizin is the principal sweet constituent of licorice root and is used as a flavouring and humectant; pharmacologically it is a bioactive natural product with multiple reported activities (anti-inflammatory, antiviral, hepatoprotective) that are mediated largely by its intestinal hydrolysis product glycyrrhetinic acid and subsequent systemic metabolites. Common commercial grades reported for this substance include: BP, EP, USP.
Molecular Overview
Molecular Weight and Composition
- Molecular formula: C42H62O16
- Molecular weight: 822.9 (reported value) — use units \(822.9\,\mathrm{g}\,\mathrm{mol}^{-1}\).
- Exact/monoisotopic mass: 822.40378589 (reported as ExactMass/MonoisotopicMass).
- Heavy atom count: 58.
- Defined atom stereocenter count: 19.
The large molecular weight and the intense stereochemical complexity reflect the fused pentacyclic triterpenoid core attached to a di‑glucuronic acid residue. This size and polyfunctionality limit membrane permeability of the intact glycoside and complicate conformer generation for small-molecule modelling.
Charge, Polarity, and LogP
- Formal charge: 0.
- Hydrogen-bond donors: 8.
- Hydrogen-bond acceptors: 16.
- Rotatable bond count: 7.
- Topological polar surface area (TPSA): 267 \(\text{Å}^2\).
- Computed XLogP3-AA: 3.7 (computed descriptor).
- Experimental/log Kow: 2.8 (reported as log Kow = 2.80).
The molecule is amphiphilic: a relatively nonpolar aglycone domain raises computed lipophilicity metrics, while the di‑glucuronic acid moiety elevates polarity and TPSA. The discrepancy between computed XLogP (3.7) and reported experimental log Kow (2.8) is consistent with strong ionization and extensive hydrogen bonding of the sugar/carboxylate portion in aqueous/partitioning assays. High TPSA and multiple polar functional groups predict low passive diffusion across biological membranes for the intact glycoside; systemic exposure after oral administration is mainly via microbial hydrolysis to the more lipophilic aglycone glycyrrhetinic acid.
Biochemical Classification
Glycyrrhizin is classed as:
- A triterpenoid saponin (pentacyclic triterpene glycoside).
- A glucosiduronic acid derivative (two glucuronic acid residues).
- Functionally described as a plant natural product and flavoring agent with pharmacological activity (listed liver therapy agent in some classification systems).
As a saponin, it exhibits surfactant-like amphiphilicity and tends to produce foaming in aqueous systems; salt forms (ammonium, potassium) are used commercially to enhance water solubility and formulation handling.
Chemical Behavior
Stability and Degradation
- Physical description: solid, crystalline plates or prisms; intensely sweet taste.
- Melting point: 220 (reported value) — noted as \(220\,^\circ\mathrm{C}\) with decomposition.
- Boiling/decomposition point: decomposes at \(200\,^\circ\mathrm{C}\) (reported).
- Additional decomposition range noted: needles from 75% aqueous ethanol decompose at 212–217 \(^{\circ}\mathrm{C}\).
Glycyrrhizin is thermally unstable at elevated temperatures and decomposes rather than boiling. The carbohydrate esters and the conjugated aglycone carbonyls are potential loci for thermal degradation. Crystalline solid form and hydrated/ammoniated salts show slightly different thermal behaviour; processing should avoid sustained heating above the indicated decomposition thresholds.
Hydrolysis and Transformations
- Hydrolysis: on hydrolysis it yields glycyrrhetinic acid plus two moles of glucuronic acid (reported).
- Salt and formulation chemistry: ammoniated or ammonium salt forms (ammonium glycyrrhizinate, monoammonium glycyrrhizinate) are employed to improve aqueous solubility; commercial glycyrrhizin is commonly supplied as the ammonium salt.
- Incompatibility: sweetness is lost in acidic foods due to hydrolysis to non‑sweet constituents (reported).
The glycosidic linkages to glucuronic acid are labile under acidic or enzymatic conditions; microbial β‑glucuronidase activity in the gut converts glycyrrhizin to the active aglycone glycyrrhetinic acid and glucuronic acid. The aglycone is more lipophilic and undergoes further phase II conjugation (glucuronidation/sulfation) before biliary excretion and enterohepatic recirculation.
Biological Role
Functional Role and Pathways
Glycyrrhizin acts as a bioactive saponin with multiple mechanistic actions:
- Enzyme modulation: reported inhibitor of thrombin (EC \(3.4.21.5\)) and of 11‑beta‑hydroxysteroid dehydrogenase (leading to effects on corticosteroid metabolism).
- Anti-inflammatory and immunomodulatory effects: suppression of TNF‑α, inhibition of NF‑κB translocation, downregulation of pro‑inflammatory mediators and caspase‑3 activity.
- Antiviral and cytoprotective actions: reported inhibition of replication or cytopathic effects for several viral types in cell culture.
- Metabolic effects: modulation of glucose tolerance parameters and potential effects on lipid metabolism via enzyme induction or inhibition.
Most systemic pharmacology arises after presystemic hydrolysis to glycyrrhetinic acid, which is the primary active metabolite entering circulation.
Physiological and Cellular Context
- Absorption and presystemic metabolism: orally administered glycyrrhizin is largely hydrolyzed by intestinal bacteria to glycyrrhetinic acid; after a \(100\,\mathrm{mg}\) oral dose the major metabolite appears in plasma at approximately \(200\,\mathrm{ng}\,\mathrm{mL}^{-1}\) while intact glycyrrhizin is usually undetectable.
- Elimination and kinetics: biliary excretion and enterohepatic cycling dominate elimination. Reported apparent volumes of distribution are in the ranges \(37\text{–}64\,\mathrm{ml}\,\mathrm{kg}^{-1}\) (central) and \(59\text{–}98\,\mathrm{ml}\,\mathrm{kg}^{-1}\) (steady state). Total body clearance reported in the context of reabsorption is approximately \(16\text{–}25\,\mathrm{ml}\,\mathrm{kg}^{-1}\,\mathrm{h}^{-1}\) (reported range). The terminal elimination half-life for glycyrrhizic acid can show a biphasic profile with a reported second elimination phase half-life of about 3.5 hours for glycyrrhizic acid and between 10–30 hours for glycyrrhetinic acid depending on dose and conjugation/recycling.
- Protein binding: intact glycyrrhizic acid shows minimal systemic protein binding because it is poorly absorbed; its aglycone metabolite glycyrrhetinic acid binds extensively to serum proteins (e.g., albumin).
These properties drive the clinical and toxicological profile: enterohepatic recirculation and metabolite reabsorption prolong systemic exposure and underlie delayed effects such as electrolyte disturbances in susceptible individuals.
Identifiers and Synonyms
Registry Numbers and Codes
- CAS number: 1405-86-3
- EC number: 215-785-7
- UNII: 6FO62043WK
- ChEBI: CHEBI:15939
- ChEMBL: CHEMBL441687
- DrugBank: DB13751
- InChIKey: LPLVUJXQOOQHMX-QWBHMCJMSA-N
- InChI: InChI=1S/C42H62O16/c1-37(2)21-8-11-42(7)31(20(43)16-18-19-17-39(4,36(53)54)13-12-38(19,3)14-15-41(18,42)6)40(21,5)10-9-22(37)55-35-30(26(47)25(46)29(57-35)33(51)52)58-34-27(48)23(44)24(45)28(56-34)32(49)50/h16,19,21-31,34-35,44-48H,8-15,17H2,1-7H3,(H,49,50)(H,51,52)(H,53,54)/t19-,21-,22-,23-,24-,25-,26-,27+,28-,29-,30+,31+,34-,35-,38+,39-,40-,41+,42+/m0/s1
- SMILES: C[C@]12CCC@(C)C(=O)O
(Identifiers above are presented as reported for cross‑referencing and analytical use.)
Synonyms and Biological Names
Key synonyms and names reported include:
- Glycyrrhizic acid; Glycyrrhizin; Glycyrrhizinic acid
- Glycyrrhizate; Glycyrrhizinate (salt forms)
- Beta‑Glycyrrhizin; 18‑beta‑Glycyrrhizic acid
- Ammonium glycyrrhizinate; Dipotassium glycyrrhizinate; Trisodium glycyrrhizate (associated salts)
- (Descriptive IUPAC and systematic names recorded in computed descriptors)
These synonyms cover the free acid, its various salt forms used in formulations, and legacy/trade synonyms that appear in chemical inventories and pharmacopoeial contexts.
Safety and Handling Overview
Handling and Storage of Biochemical Materials
- Hazard classification: reported as "Not Classified" under standard hazard criteria in multiple supplier notifications, but biological and clinical toxicity manifestations are well documented under conditions of significant exposure.
- Primary human adverse effects: sustained or high intake has been associated with pseudohyperaldosteronism — sodium retention, potassium loss (hypokalemia), edema, and increased blood pressure — mediated by inhibition of 11‑beta‑hydroxysteroid dehydrogenase and altered corticosteroid metabolism. Data indicate that an intake of about 100 mg/day is unlikely to cause adverse effects in the majority of adults but susceptible individuals may experience physiological effects at lower intakes.
- Acute handling: treat as a bioactive natural product. Standard laboratory PPE (gloves, eye protection, lab coat) is recommended to avoid ingestion and contact. Avoid conditions that promote hydrolysis (strong acids, prolonged heating) if retention of the glycoside is required. Use ammonium or other salt forms when formulating for aqueous systems to improve solubility and handling.
- Storage: store the solid material protected from prolonged moisture and excessive heat; use appropriate containers to avoid contamination. For formulations, control pH to minimize unintended hydrolysis.
- Regulatory and transport: do not infer transport classifications from this summary; for product‑specific hazard, transport and regulatory information consult the product Safety Data Sheet (SDS) and applicable local regulations.
Laboratory and industrial users should exercise standard precautions for biologically active natural products and account for potential systemic effects after repeated dermal exposure or accidental ingestion. For detailed hazard, transport and regulatory information, users should refer to the product‑specific Safety Data Sheet (SDS) and local legislation.
Handling and Storage of Biochemical Materials
(Section focused on operational guidance)
- Use closed handling systems or local exhaust for dust and powders when processing bulk material to limit inhalation exposure.
- Avoid formulation into strongly acidic media if sweetness or intact glycoside is required, because acid hydrolysis reduces sweetness and converts the glycoside to non‑sweet constituents.
- When aqueous dissolution is needed, consider using the commercially available ammonium or alkali metal salts (ammonium glycyrrhizinate, dipotassium glycyrrhizinate) to achieve higher solubility and improved handling characteristics.
- Segregate from strong oxidizers and incompatible reactive chemicals; ensure secondary containment for bulk storage.
- Dispose of process residues and waste in accordance with local environmental and waste regulations; confirm acceptable disposal routes with environmental authorities prior to land application or landfill disposition.
(Refer to product SDS for concentration‑dependent and product‑specific recommendations; this section provides general class‑level guidance only.)
