Drotaverine (21-10-9) Physical and Chemical Properties
Drotaverine
Drotaverine is a benzylisoquinoline small-molecule antispasmodic that acts as a selective PDE4 inhibitor and is handled commercially as an API for formulation and R&D workflows.
| CAS Number | 21-10-9 |
| Family | Isoquinolines (benzylisoquinoline derivative) |
| Typical Form | Powder or crystalline solid |
| Common Grades | EP |
Drotaverine is a small-molecule benzylisoquinoline derivative belonging to the tetrahydroisoquinoline structural class. The molecule contains a 1,2,3,4‑tetrahydroisoquinoline core substituted at the 1‑position with a benzylidene fragment and carries four ethoxy substituents distributed on both the isoquinoline and benzyl rings. The constitution gives a single basic nitrogen within a partially saturated heterocycle and multiple ether linkages; the calculated topological polar surface area (TPSA) is moderate, while the substituent pattern produces substantial lipophilicity.
Electronic and physicochemical features reflect this mixed profile: the lone pair on the ring nitrogen confers basic character and capacity for salt formation, whereas multiple ethoxy groups increase polarizability and metabolic liability to O‑dealkylation. Overall behaviour is consistent with a weak–moderate base with high lipophilicity and limited aqueous solubility; metabolic clearance is primarily hepatic with phase I O‑dealkylation and phase II conjugation documented. Clinically, drotaverine is employed as an antispasmodic (PDE4 inhibitor) for smooth‑muscle spasm indications in several jurisdictions and has been formulated for oral and intramuscular administration in approved markets.
Common commercial grades reported for this substance include: EP.
Basic Physicochemical Properties
Density and Solid-State Form
Experimental description classifies the substance as a solid. No experimentally established value for density is available in the current data context.
Qualitatively, substituted tetrahydroisoquinoline solids of this type are typically crystalline or microcrystalline and may exhibit polymorphism; handling for processing and formulation should treat the material as a nonvolatile solid with limited hygroscopicity unless otherwise specified by a manufacturer certificate.
Melting Point
A melting point value is reported as \(\mathrm{197^\circ C}\). The relatively high melting point is consistent with a multi‑aromatic, highly substituted rigid core and often correlates with limited aqueous solubility in the neutral free base.
Solubility and Dissolution Behavior
No experimentally established aqueous solubility value is available in the current data context.
Qualitative appraisal: the calculated XLogP (\(5.4\)) and low TPSA (\(49\)) indicate high lipophilicity and therefore low intrinsic aqueous solubility for the free base. Formulation commonly uses salt forms (e.g., the hydrochloride derivative) or solubilizing excipients to increase dissolution rate and oral bioavailability. In practice, poorly soluble neutral bases of this class show enhanced solubility and faster dissolution when converted to a pharmaceutically acceptable salt or formulated with surfactants/co‑solvents.
Chemical Properties
Acid–Base Behavior and Qualitative pKa
No experimentally established value for this property is available in the current data context.
Qualitatively, the compound contains a tertiary/secondary heterocyclic nitrogen in the tetrahydroisoquinoline ring that can be protonated under acidic conditions to form a water‑soluble salt; this is the basis for preparing hydrochloride salts to improve aqueous solubility. Reference to salt forms (hydrochloride) in practical use indicates basicity sufficient for salt formation at pharmaceutically relevant \(\mathrm{pH}\) values.
Reactivity and Stability
The molecule is chemically stable as a solid under typical ambient conditions but shows metabolic and chemical liabilities consistent with its functional groups. Metabolic studies indicate primary biotransformations include O‑dealkylation of ethoxy groups (producing mono‑ and di‑desethyl metabolites) followed by conjugation (e.g., glucuronidation) and biliary excretion. Ether cleavage (O‑dealkylation) and oxidative transformations at benzylic sites are the predominant reactivity pathways under biological oxidative metabolism.
Under forced‑degradation or storage conditions, expect the major chemical risks to be oxidative and hydrolytic pathways affecting ether substituents and potential hydrogenation/reduction at the benzylidene linkage under strong reducing conditions. Standard stability control (protection from strong oxidants, extremes of pH and heat) is recommended until product‑specific stability data are available.
Molecular Parameters
Molecular Weight and Formula
Molecular formula: \(\ce{C24H31NO4}\).
Molecular weight: \(\mathrm{397.5\ g\ mol^{-1}}\). Exact/monoisotopic mass: \(\mathrm{397.22530847}\).
These values reflect a relatively large small molecule for oral drugs, consistent with multiple ethoxy substituents and an aromatic/heterocyclic framework.
LogP and Structural Features
Calculated XLogP3‑AA (lipophilicity): \(\mathrm{5.4}\).
Topological polar surface area (TPSA): \(\mathrm{49}\).
Hydrogen bond donors: 1.
Hydrogen bond acceptors: 5.
Rotatable bond count: 9.
Implications: the high calculated logP and modest TPSA predict high membrane permeability and tissue distribution but limited aqueous solubility. The rotatable bond count indicates moderate molecular flexibility, which can influence oral absorption and entropic components of binding. Observed pharmacokinetic parameters (large apparent volume of distribution) are consistent with a lipophilic distribution profile.
Structural Identifiers (SMILES, InChI)
SMILES: CCOC1=C(C=C(C=C1)/C=C\2/C3=CC(=C(C=C3CCN2)OCC)OCC)OCC
InChI: InChI=1S/C24H31NO4/c1-5-26-21-10-9-17(14-22(21)27-6-2)13-20-19-16-24(29-8-4)23(28-7-3)15-18(19)11-12-25-20/h9-10,13-16,25H,5-8,11-12H2,1-4H3/b20-13-
InChIKey: OMFNSKIUKYOYRG-MOSHPQCFSA-N
Identifiers and Synonyms
Registry Numbers and Codes
CAS (listed for this document): 21-10-9
Other registry and database identifiers reported for this substance include: EC number 604-171-8; UNII 98QS4N58TW; ChEBI CHEBI:135630; ChEMBL CHEMBL551978; DrugBank DB06751; DSSTox DTXSID60161227; HMDB HMDB0015669; KEGG D07088.
Synonyms and Brand-Independent Names
Common nonproprietary and alternative names reported include: drotaverine; drotaverin; dihydroisoperparine; isodihydroperparine. Systematic names include (1Z)-1-[(3,4‑diethoxyphenyl)methylidene]-6,7‑diethoxy‑3,4‑dihydro‑2H‑isoquinoline and 1‑(3,4‑diethoxybenzylidene)‑6,7‑diethoxy‑1,2,3,4‑tetrahydroisoquinoline. The hydrochloride salt appears in clinical formulations and related registries.
Industrial and Pharmaceutical Applications
Role as Active Ingredient or Intermediate
Drotaverine is used as an active pharmaceutical ingredient (API) with spasmolytic (antispasmodic) activity mediated primarily by inhibition of phosphodiesterase‑4 (PDE4), which raises intracellular cAMP and produces smooth‑muscle relaxation. It has been employed for symptomatic relief of gastrointestinal and genitourinary smooth‑muscle spasms and has been formulated for oral tablets and intramuscular injections in certain markets. Investigational uses reported in the literature include applications in dysmenorrhea, labour augmentation, and exploratory antiviral and anticancer research.
Formulation and Development Contexts
Formulation strategies for drotaverine address low aqueous solubility of the free base: conversion to salt forms (e.g., hydrochloride), use of solubilizing excipients, or particulate size reduction are typical approaches. For parenteral use, the hydrochloride salt or appropriately solubilized formulations enable intramuscular administration; oral solid‑dose forms commonly use standard tablet excipients with dissolution enhancers as required to meet bioavailability targets. Pharmacokinetic variability following oral dosing is notable and should be considered in formulation and bioequivalence development.
Specifications and Grades
Typical Grade Types (Pharmaceutical, Analytical, Technical)
Typical commercial grade concepts applicable to drotaverine include pharmaceutical (API) grade for formulation into finished medicinal products, analytical grade for QC and release testing, and technical grade for research or synthesis. If supplied as an API, the material will normally be accompanied by a certificate of analysis describing identity, assay, impurities, and residual solvents consistent with regulatory requirements for the intended market.
Under the "Specifications and Grades" context, the following commercial grade is reported: EP.
General Quality Attributes (Qualitative Description)
Key quality attributes for procurement and QA include chemical identity (structure and stereochemistry), assay/potency, impurity profile (notably related desethyl and other oxidative metabolites/degradation products), residual solvents, water content, and polymorphic form. For parenteral use, additional requirements cover endotoxin limits and sterility assurance in the finished product. Batch certificates and stability data should be reviewed to confirm suitability for the intended application.
Safety and Handling Overview
Toxicological Profile and Exposure Considerations
Human pharmacokinetic data indicate a mean plasma half‑life of approximately \(\mathrm{9.1\ h}\) after oral dosing and primary hepatic metabolism with biliary elimination of conjugated metabolites. Specific protein‑binding data are not available in the current data context. As a pharmacologically active PDE4 inhibitor and antispasmodic, systemic exposure produces intended smooth‑muscle effects; off‑target pharmacology and dose‑dependent adverse effects are possible and are addressed in clinical safety assessments.
General exposure considerations for handling the solid include minimizing dust generation, avoiding ingestion and inhalation, and preventing dermal/ocular contact. Standard laboratory and manufacturing personal protective equipment (PPE) — gloves, eye protection, protective clothing and appropriate respiratory protection where dust or aerosols may be generated — is recommended. For detailed hazard, transport and regulatory information, users should refer to the product‑specific Safety Data Sheet (SDS) and local legislation.
Storage and Handling Guidelines
Store in a cool, dry place in tightly closed containers, protected from strong oxidizing agents and excessive heat. For pharmaceutical API storage, follow manufacturer recommendations on temperature range, humidity control, and light exposure; stability data should guide specific shelf‑life and container/closure system selection. For any concentrated or powdered handling operations, engineering controls (local exhaust ventilation, containment) are advised to limit airborne exposure.
For detailed hazard, transport and regulatory information, users should refer to the product‑specific Safety Data Sheet (SDS) and local legislation.
