Linagliptin (31-12-8) Physical and Chemical Properties
Linagliptin
Small-molecule API: a xanthine-derived DPP‑4 inhibitor supplied for pharmaceutical formulation, analytical development and quality control activities.
| CAS Number | 31-12-8 |
| Family | Xanthines (DPP‑4 inhibitor) |
| Typical Form | Powder or crystalline solid |
| Common Grades | EP, USP |
Linagliptin is a small-molecule, dihydropurinedione (xanthine-like) derivative bearing a substituted quinazoline and an aminopiperidine side chain. Its molecular formula is \(\ce{C25H28N8O2}\) and the structure contains a purine-2,6-dione core substituted at positions that produce a rigid, heteroatom-rich scaffold with a single defined stereocenter (R-enantiomer). Key structural motifs are an N,N-dialkylated xanthine core, a 4-methylquinazolinylmethyl substituent, a but-2-ynyl side chain and a tertiary aminopiperidine; these confer a combination of aromatic and basic heterocycles with a polar tertiary amine and limited flexible linkage count (rotatable bond count = 4).
Electronically and functionally, the molecule is polyheterocyclic and amphoteric in localized regions: the purine-dione unit contributes hydrogen-bond acceptor/donor capacity (hydrogen-bond donor count = 1; hydrogen-bond acceptor count = 7) and the tertiary aminopiperidine gives a basic center with measurable protonation behavior (\(\mathrm{p}K_a\) values reported below). The computed topological polar surface area (TPSA = 113 Ų) together with a measured XLogP of 1.9 indicate moderate overall polarity with sufficient lipophilicity for passive membrane permeation but significant polar surface that can limit solubility in purely aqueous media. The molecule is typically isolated as a crystalline white-to-yellow solid and is slightly hygroscopic.
Pharmacokinetically and industrially relevant attributes include oral bioavailability and a tissue-distribution profile influenced by concentration-dependent protein binding. Clinically it is used as an orally administered DPP‑4 (dipeptidyl peptidase‑4) inhibitor for the management of type 2 diabetes mellitus and is supplied in oral tablet formulations; combination products with metformin and other agents have established regulatory approval. Common commercial grades reported for this substance include: EP, USP.
Basic Physicochemical Properties
Density and Solid-State Form
No experimentally established value for this property is available in the current data context.
The substance is reported as a white to yellow solid and as a crystalline solid; slight hygroscopicity is noted. Crystalline form and particle properties (polymorphism, particle size) are important for downstream formulation and may influence dissolution rate and tablet compression behavior.
Melting Point
Melting point values reported in the data context include 190-196 and 202 \(\mathrm{^\circ C}\). The existence of two reported melting ranges is consistent with measurements on different solid forms or with different measurement protocols; confirmatory DSC or capillary melting-point data should be used for specification.
Solubility and Dissolution Behavior
Aqueous solubility is reported as <1 \(\mathrm{mg}\,\mathrm{mL}^{-1}\), indicating low intrinsic solubility in water at ambient conditions. Solubility in common organic solvents is listed as: soluble in methanol; sparingly soluble in ethanol; very slightly soluble in isopropanol (alcohol). The combination of low aqueous solubility and moderate lipophilicity implies formulation strategies such as salt formation, particle-size reduction, solid dispersions, or the use of solubilizing excipients may be required for immediate-release or controlled-release oral forms. Slight hygroscopicity should be considered when selecting packaging and desiccation measures.
Chemical Properties
Acid–Base Behavior and Qualitative pKa
Dissociation (protonation) constants reported: \(\mathrm{p}K_{a1} = 1.9\); \(\mathrm{p}K_{a2} = 8.6\). The higher \(\mathrm{p}K_a\) (8.6) corresponds to a basic center (tertiary aminopiperidine), which will be substantially protonated at physiological \(\mathrm{pH}\) (7.4), leading to a predominantly cationic form under physiological conditions. The lower \(\mathrm{p}K_a\) (1.9) represents a much weaker acidic/basic site and will be essentially deprotonated at physiological \(\mathrm{pH}\). These protonation states affect aqueous solubility, membrane permeation, protein binding, and environmental speciation.
Reactivity and Stability
Reported stability notes: stable if stored as directed; avoid strong oxidizing agents. Thermal decomposition can release toxic gases such as carbon monoxide, carbon dioxide, and nitrogen oxides. The molecule lacks readily hydrolysable ester or anhydride linkages, so hydrolysis under neutral conditions is unlikely to be a major degradation route; oxidative pathways and oxidative metabolism are the principal chemical liabilities. Slight hygroscopicity implies limited moisture uptake can occur; control of humidity during storage and processing is recommended. For solid‑state stability, standard pharmaceutical stress testing (heat, humidity, light, oxidative atmosphere) is appropriate for identifying degradation pathways and impurity profiles.
Molecular Parameters
Molecular Weight and Formula
- Molecular formula: \(\ce{C25H28N8O2}\)
- Molecular weight: 472.5 (as reported)
- Exact/monoisotopic mass: 472.23352217
- Formal charge: 0
- Heavy atom count: 35
- Complexity: 885
These values define the core mass and composition used for analytical methods, dosing calculations and mass-spectrometric workflows.
LogP and Structural Features
- XLogP (computed): 1.9
- TPSA: 113
- Hydrogen-bond donor count: 1
- Hydrogen-bond acceptor count: 7
- Rotatable bond count: 4
- Defined atom stereocenter count: 1 (single chiral center; clinically used as the R-enantiomer)
The combination of moderate computed logP and significant TPSA supports oral absorption with substantial polar surface; binding to plasma proteins is concentration dependent and can exceed typical values at low concentrations, contributing to a non-linear component of distribution and a long terminal half-life in clinical pharmacokinetic profiles.
Structural Identifiers (SMILES, InChI)
- SMILES:
CC#CCN1C2=C(N=C1N3CCC[C@H](C3)N)N(C(=O)N(C2=O)CC4=NC5=CC=CC=C5C(=N4)C)C - InChI:
InChI=1S/C25H28N8O2/c1-4-5-13-32-21-22(29-24(32)31-12-8-9-17(26)14-31)30(3)25(35)33(23(21)34)15-20-27-16(2)18-10-6-7-11-19(18)28-20/h6-7,10-11,17H,8-9,12-15,26H2,1-3H3/t17-/m1/s1 - InChIKey:
LTXREWYXXSTFRX-QGZVFWFLSA-N
(Identifiers provided verbatim for analytical cross-referencing and method development.)
Identifiers and Synonyms
Registry Numbers and Codes
- CAS (primary identifier field): 31-12-8
- EC (European Community) number: 620-351-9
- UNII: 3X29ZEJ4R2
- ChEBI: CHEBI:68610
- ChEMBL: CHEMBL237500
- DrugBank: DB08882
- DSSTox Substance ID: DTXSID201021653
- KEGG ID: D09566
- InChIKey: LTXREWYXXSTFRX-QGZVFWFLSA-N
These registry identifiers are used for procurement, regulatory filings and analytical traceability.
Synonyms and Brand-Independent Names
Selected synonyms and deposit names appearing in regulatory and chemical nomenclature lists: - Linagliptin - BI‑1356 / BI 1356 - Tradjenta / Trajenta - (R)-8-(3-amino‑piperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione - Linagliptinum - LINAGLIPTIN [INN/USAN/JAN]
Use of any given synonym should be checked against supplier documentation and regulatory dossiers for exact salt/base and form designations.
Industrial and Pharmaceutical Applications
Role as Active Ingredient or Intermediate
Linagliptin is an active pharmaceutical ingredient (API) used clinically as an orally administered dipeptidyl peptidase‑4 (DPP‑4) inhibitor for improving glycemic control in adults with type 2 diabetes mellitus. It is formulated as a 5 mg oral film-coated tablet for monotherapy and as part of combination products with metformin or SGLT2 inhibitors in approved formulations. Its clinical pharmacology includes potent and sustained DPP‑4 inhibition following a 5 mg oral dose.
Formulation and Development Contexts
Key formulation considerations derive from low aqueous solubility (<1 \(\mathrm{mg}\,\mathrm{mL}^{-1}\)), slight hygroscopicity, and moderate lipophilicity (XLogP = 1.9). Typical pharmaceutical forms are immediate‑release film‑coated tablets; combination tablets (e.g., with metformin or empagliflozin) exploit its pharmacokinetic compatibility. The substance exhibits concentration-dependent protein binding and primarily non-renal elimination (major fraction recovered in feces), factors which influence dosing in renal impairment and the design of drug‑drug interaction studies. Solid-state characterization (crystalline form) and control of particle size distribution are relevant for dissolution performance and bioavailability.
Specifications and Grades
Typical Grade Types (Pharmaceutical, Analytical, Technical)
Common pharmaceutical-grade concepts applicable to this API include: - Pharmacopeial grades intended for medicinal manufacture (e.g., EP, USP) - Analytical reagent grades for use in method development and QC - Technical grades for non-clinical research and process development
Under the commercial grades reported for this substance: EP, USP.
General Quality Attributes (Qualitative Description)
Typical quality attributes for specification and procurement include identity (spectroscopic and chromatographic), assay/potency, related substances/impurities profile, residual solvents, water content (hygroscopicity considerations), particle-size distribution, and crystalline form characterization. Batch‑to‑batch consistency in polymorphic form and residual solvent profile are important for regulatory submissions and for reproducible tablet manufacture. Stability testing should address oxidative and thermal degradation pathways and the potential for moisture‑induced changes.
Safety and Handling Overview
Toxicological Profile and Exposure Considerations
Clinical and postmarketing safety data indicate adverse events such as nasopharyngitis (≈7.0%), diarrhea (≈3.3%) and cough (≈2.1%) in pooled trial datasets. Postapproval reports include rare instances of acute pancreatitis (including fatal cases) and serious hypersensitivity reactions (anaphylaxis, angioedema, exfoliative skin conditions). Liver injury has been reported rarely. Animal studies do not indicate a strong carcinogenic signal at clinically relevant exposures, though very high doses in rodents produced effects not relevant to human therapeutic exposure.
Occupational exposure risks during manufacture include inhalation and dermal contact; the compound should be treated as a potent API for which engineering controls and appropriate personal protective equipment (PPE) are required. Protein binding is concentration dependent; in humans the plasma protein binding varies with concentration and can be high at low nanomolar levels.
Storage and Handling Guidelines
- Store in a cool, dry place protected from strong oxidizing agents and excessive humidity; avoid conditions that promote thermal decomposition.
- Use engineering controls to minimize airborne dust; local exhaust ventilation and containment are recommended during weighing and transfer operations.
- PPE: use NIOSH/MSHA‑approved respirator where airborne exposure is possible, chemical‑resistant gloves and safety goggles. For spills, wear full protective clothing and respiratory protection as indicated.
- Firefighting: suitable extinguishing agents include water spray, carbon dioxide, dry chemical powder or foam; thermal decomposition can release carbon monoxide, carbon dioxide and nitrogen oxides—use self‑contained breathing apparatus and protective clothing.
- Waste and disposal: expired or waste pharmaceutical material should be managed per applicable hazardous pharmaceutical waste regulations; do not dispose via sewer systems or regular trash without authorization and appropriate treatment.
For detailed hazard, transport and regulatory information, users should refer to the product‑specific Safety Data Sheet (SDS) and applicable local legislation.
