Pioglitazone Hydrochloride (24-16-7) Physical and Chemical Properties
Pioglitazone Hydrochloride
Hydrochloride salt of a thiazolidinedione small molecule API used in formulations that modulate insulin sensitivity via PPARγ activation; commonly handled in pharmaceutical R&D and manufacturing contexts.
| CAS Number | 24-16-7 |
| Family | Thiazolidinediones |
| Typical Form | Powder or crystalline solid |
| Common Grades | BP, EP, JP, USP |
Pioglitazone hydrochloride is a small-molecule thiazolidinedione class compound present as the monohydrochloride salt of a substituted thiazolidine-2,4-dione. Structurally it contains a 2,4-thiazolidinedione core appended to a benzyl–ether–pyridinyl side chain; the presence of a basic pyridinyl nitrogen and the stoichiometric chloride counter‑ion define the hydrochloride salt form. The molecular formula is \(\ce{C19H21ClN2O3S}\); the salt form increases solid-state ionicity relative to the neutral parent and modifies aqueous solubility, dissolution kinetics and solid stability compared with the free base.
Electronically, the molecule contains multiple polarized carbonyl and heteroatom centers (oxygen, nitrogen, sulfur) that contribute to hydrogen-bonding (hydrogen-bond donor count = 2; acceptor count = 5) and a moderately polar surface (topological polar surface area = 93.6). The tertiary aromatic and aliphatic regions impart significant lipophilic character; consequently the compound shows limited aqueous solubility at neutral pH and strong binding to lipophilic matrices and biological membranes. Metabolic clearance is hepatic and the molecule is a PPAR‑gamma agonist pharmacologically; oxidative metabolism and phase II conjugation are dominant biotransformation pathways in vivo.
As a pharmaceutical hydrochloride salt, the material is handled and formulated as an orally dosed active ingredient in solid oral forms (tablets, often as monotherapy or in combination products). Common commercial grades reported for this substance include: BP, EP, JP, USP.
Basic Physicochemical Properties
Density and Solid-State Form
Pioglitazone hydrochloride is supplied and handled as a crystalline hydrochloride salt (monohydrochloride association of the active moiety with chloride). The salt character increases ionic interactions in the crystal lattice relative to the neutral parent and commonly yields a defined crystalline form used for manufacture and QC. No experimentally established bulk density value for this property is available in the current data context.
Melting Point
No experimentally established value for this property is available in the current data context.
Solubility and Dissolution Behavior
An experimental aqueous solubility measurement is reported as 1.8 \(\mathrm{\mu g}\,\mathrm{mL}^{-1}\) (the mean of the results at \(\mathrm{pH}\) 7.4). This very low solubility at near‑physiological pH is consistent with a molecule that combines lipophilic aromatic domains with localized polar and ionizable functionality; the hydrochloride salt provides improved solubility versus the free base under acidic conditions but can still show limited dissolution at neutral pH. In formulation development, pH adjustment, salt selection, particle-size reduction, solid dispersions or use of solubilizing excipients are typical strategies to address low aqueous solubility for oral delivery.
Chemical Properties
Acid–Base Behavior and Qualitative pKa
Pioglitazone hydrochloride exists as a protonated salt in the solid state; the protonation site is the pyridinyl nitrogen of the side chain, which confers the hydrochloride counter‑ion. No numerical \(\mathrm{p}K_a\) value is available in the current data context. Qualitatively, the compound is a weak base (heteroaromatic basic site) presented as a stable salt for pharmaceutical use; protonation state strongly influences aqueous solubility and ion-pair interactions in formulation matrices.
Reactivity and Stability
The thiazolidinedione core is generally stable under ambient conditions encountered in typical pharmaceutical manufacture and storage, but carbonyl-bearing heterocycles can be sensitive to strong nucleophiles or prolonged exposure to strongly basic hydrolytic conditions. The substance is metabolically transformed in the liver (hepatic metabolism reported) via oxidative pathways; oxidative degradation should be considered in forced‑degradation studies. Standard solid‑state stability controls (controlled temperature, low humidity, protection from strong oxidants) and routine stability-indicating assays are appropriate for quality control.
Molecular Parameters
Molecular Weight and Formula
- Molecular formula: \(\ce{C19H21ClN2O3S}\)
- Molecular weight: 392.9
Other computed composition parameters available: exact mass 392.0961414; monoisotopic mass 392.0961414.
LogP and Structural Features
No experimentally measured LogP/logD value is available in the current data context. Structural descriptors relevant to formulation and ADME: hydrogen-bond donor count = 2; hydrogen-bond acceptor count = 5; rotatable bond count = 7; topological polar surface area = 93.6; heavy atom count = 26; complexity = 466. These descriptors reflect a balance of polar functionality (carbonyls, heteroatoms) and lipophilic aromatic/alkyl fragments, compatible with moderate permeability but low intrinsic aqueous solubility.
Structural Identifiers (SMILES, InChI)
- SMILES:
CCC1=CN=C(C=C1)CCOC2=CC=C(C=C2)CC3C(=O)NC(=O)S3.Cl - InChI:
InChI=1S/C19H20N2O3S.ClH/c1-2-13-3-6-15(20-12-13)9-10-24-16-7-4-14(5-8-16)11-17-18(22)21-19(23)25-17;/h3-8,12,17H,2,9-11H2,1H3,(H,21,22,23);1H - InChIKey: GHUUBYQTCDQWRA-UHFFFAOYSA-N
Identifiers and Synonyms
Registry Numbers and Codes
- CAS number (as presented in the document header): 24-16-7
- Additional CAS identifiers appearing in supplier and registry strings: 112529-15-4 (primary CAS shown in associated identifiers); deprecated CAS: 127676-30-6
- EC number: 629-731-9
- UNII: JQT35NPK6C
Synonyms and Brand-Independent Names
Reported names and synonyms include (selection of common, non‑proprietary variants): Pioglitazone Hydrochloride; pioglitazone hydrochloride; Pioglitazone HCl; Pioglitazone (as hydrochloride); Pioglitazone (hydrochloride); IUPAC: 5-[[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione;hydrochloride. Several pharmacopeial and registry descriptors (BP/EP/JP/USP reference standards) and legacy synonyms are reported in vendor and regulatory listings.
Industrial and Pharmaceutical Applications
Role as Active Ingredient or Intermediate
Pioglitazone hydrochloride is used as an active pharmaceutical ingredient (API) in oral antidiabetic therapies. It is a selective agonist of peroxisome proliferator-activated receptor gamma (PPAR‑gamma), used in the management of type 2 diabetes mellitus to improve insulin sensitivity and modulate transcription of insulin‑responsive genes. The substance appears in monotherapy and combination oral tablet products; marketed formulations and regulatory listings indicate its primary role as an API rather than a synthetic intermediate for other APIs.
Formulation and Development Contexts
The hydrochloride salt is employed to provide a discrete, manufacturable crystalline form for tablet formulation. Route and dosage form data indicate TABLET; ORAL usage in marketed products. Formulation and development considerations center on low intrinsic aqueous solubility (measured 1.8 \(\mathrm{\mu g}\,\mathrm{mL}^{-1}\) at \(\mathrm{pH}\) 7.4), hepatic metabolism, and the need to achieve consistent dissolution and bioavailability in oral solid dosage forms; co‑formulation with metformin or other oral antidiabetics is a common clinical practice.
Specifications and Grades
Typical Grade Types (Pharmaceutical, Analytical, Technical)
Typical grade concepts applicable to this API include pharmaceutical (pharmacopeial) grade for use in finished dosage forms, analytical/reference standards for QC and method validation, and technical grades for non‑clinical research. Pharmacopeial reference standards and certified reference materials are reported for the hydrochloride salt, consistent with regulated manufacture and release testing.
General Quality Attributes (Qualitative Description)
Key quality attributes for pioglitazone hydrochloride batches include identity (structural confirmation by spectroscopic and chromatographic methods), assay/potency, residual solvents, impurity profile (related substances), particle size distribution (affecting dissolution), polymorphic/crystalline form, and moisture content. When BP/EP/JP/USP grades are specified, compliance with monograph requirements and validated analytical procedures is expected; batch release is governed by stability data and validated impurity limits.
The following commercial grades are reported for this substance: BP, EP, JP, USP.
Safety and Handling Overview
Toxicological Profile and Exposure Considerations
Pharmacology: the compound is a PPAR‑gamma agonist; clinically it reduces insulin resistance by modulating transcription of insulin‑sensitive genes in liver, adipose tissue and muscle. Toxicology classifications reported include suspected reproductive toxicity (GHS hazard code H361) and a carcinogenicity classification of 2A (probably carcinogenic to humans) in some notifications. Aggregated hazard notifications include Acute Tox. 4, Eye Irrit. 2A and Repr. 2 in certain supplier reports; specific GHS statements reported (aggregate notification frequencies) are H302 (harmful if swallowed), H319 (causes serious eye irritation) and H361 (suspected of damaging fertility or the unborn child). Hypoglycemia is a pharmacological adverse effect of clinical relevance. Oral absorption characteristics: measurable in serum within 30 minutes after dosing with peak concentrations within approximately 2 hours in the fasting state (food delays time‑to‑peak but not extent of absorption). Hepatic metabolism is the primary biotransformation route.
Exposure control: avoid ingestion, inhalation of dust and contact with eyes. Use appropriate protective equipment (gloves, eye protection, lab coat); engineering controls and dust suppression for powder handling are 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 the solid API in a cool, dry, well‑sealed container away from strong oxidizing agents and excessive humidity; control of temperature and protection from light are standard for long‑term stability. Use appropriate containment to minimize dust generation during transfer and formulation. Spills should be confined and cleaned up with methods that avoid dust dispersion and permit recovery for disposal following local regulations. For detailed hazard, transport and regulatory information, users should refer to the product‑specific Safety Data Sheet (SDS) and local legislation.
