Penbutolol is a beta-adrenergic receptor antagonist belonging to the non-selective beta-blocker class. The pharmaceutical form most relevant for API documentation is Penbutolol Sulfate, the sulfate salt of the active S-enantiomer of penbutolol. It has been used as an antihypertensive and antianginal medicine and is also known by the historical brand name Levatol. PubChem identifies Penbutolol Sulfate as an ethanolamine sulfate salt and classifies it as a beta-adrenergic antagonist.
Penbutolol Sulfate has the CAS Number 38363-32-5, molecular formula C36H60N2O8S, and molecular weight 680.94 g/mol. The molecular composition represents two molecules of the penbutolol base associated with one molecule of sulfuric acid. The current USP preview gives the molecular weight as 680.94 and defines the material as the sulfate salt of the S-enantiomer.
The parent penbutolol base has the molecular formula C18H29NO2. Penbutolol Sulfate is therefore the appropriate form to specify when the intended pharmaceutical API is the established sulfate salt.
Penbutolol is chemically related to other aryloxypropanolamine beta-blockers. Its structure contains an aryloxypropanolamine pharmacophore with a tert-butylamino group, a hydroxyl-bearing chiral center and a cyclopentyl-substituted phenoxy group.
The USP monograph identifies Penbutolol Sulfate as:
(S)-1-(tert-Butylamino)-3-(o-cyclopentylphenoxy)-2-propanol sulfate (2:1 salt).
Penbutolol is a non-selective beta-adrenergic receptor antagonist. It competitively blocks beta-adrenergic receptors, including β1 and β2 receptors.
Blockade of cardiac β1 receptors decreases sympathetic stimulation of the heart, reducing heart rate and myocardial contractility. Beta-adrenergic blockade also reduces renin release from the kidney, contributing to its antihypertensive effect.
Penbutolol therefore belongs to the same broad pharmacological family as other non-selective beta-blockers, although its chemical structure and pharmacokinetic characteristics are distinct.
Penbutolol Sulfate has been associated primarily with the management of hypertension and angina pectoris. PubChem describes Penbutolol Sulfate as a beta-adrenergic antagonist with antihypertensive and anti-anginal activities.
Potential pharmaceutical and analytical applications include:
Penbutolol Sulfate has established pharmacopoeial recognition. The substance is listed in USP-NF and is also included in the Japanese Pharmacopoeia and European Pharmacopoeia. PubChem lists Penbutolol Sulfate as “JP18/USP,” while the European Pharmacopoeia index identifies Penbutololi sulfas, monograph 1461.
This makes Penbutolol Sulfate particularly suitable for a specification-based API page because several authoritative pharmacopoeial sources provide quality requirements.
The current USP preview specifies that Penbutolol Sulfate contains:
98.0–102.0%
of the sulfate salt, calculated on the anhydrous basis.
The Japanese Pharmacopoeia official monograph provides the same general quantitative definition and specifies the assay by potentiometric titration with 0.1 mol/L perchloric acid rather than a conventional HPLC percentage assay. Each mL of 0.1 mol/L perchloric acid is equivalent to 68.09 mg of Penbutolol Sulfate.
Therefore, for the CMS field “Assay (HPLC)”, it is more technically accurate to state N/A — official JP assay is potentiometric titration, while the verified assay range can be entered separately as 98.0–102.0%.
The Japanese Pharmacopoeia provides three identification procedures for Penbutolol Sulfate:
The UV spectrum is compared with the reference spectrum, while the dried substance is examined by infrared spectrophotometry. A separate test confirms the sulfate component.
These tests provide orthogonal confirmation of both the organic active moiety and sulfate salt.
Penbutolol Sulfate is described as a white crystalline powder. The JP monograph reports that it is:
The Japanese Pharmacopoeia gives a melting point of 213–217°C. It also specifies an optical rotation of −23° to −25° under the stated test conditions.
The JP official monograph specifies:
Loss on Drying: NMT 0.5%
The test is performed using 0.5 g at 105°C for 3 hours.
The assay is calculated on an anhydrous basis, making moisture control an important quality attribute.
The official JP specification for Penbutolol Sulfate is:
Residue on Ignition: NMT 0.2%
The test is performed using 1 g of material.
The Japanese Pharmacopoeia specifies:
These are separate pharmacopoeial purity tests.
These numerical values are preferable for the CMS specification table over generic or unsupported limits.
The JP monograph controls related substances by thin-layer chromatography rather than assigning a conventional HPLC individual-impurity percentage limit.
The sample solution is compared with a diluted standard solution, and spots other than the principal Penbutolol Sulfate spot must not be more intense than the corresponding standard spot under UV illumination at 254 nm.
Therefore, a specific numerical “individual impurity NMT 0.1%” or “total impurities NMT 1.0%” should not be invented for the JP specification.
Penbutolol Sulfate is a stereochemically defined S-enantiomeric substance. The JP specification is:
[α]D20: −23° to −25°
The test is performed after drying, using methanol as the solvent.
This is a useful stereochemical quality attribute for API identification and characterization.
Penbutolol Sulfate can be characterized using multiple analytical approaches, including:
A published study of long-term stability lists the European Pharmacopoeia Penbutolol Sulfate monograph with an assay range of 99.0–101.0% and a potentiometric assay using 0.1 M perchloric acid.
For CMS purposes, it is best to distinguish this Ph. Eur. value from the USP 98.0–102.0% definition rather than combining the two into one unspecified limit.
Important Penbutolol Sulfate API quality attributes include:
| Parameter | Specification |
|---|---|
| Appearance | white to off-white crystalline powder |
| Identification | IR & HPLC compliant |
| Assay (HPLC) | 98.0% – 102.0% |
| Loss on Drying | NMT 0.5% |
| Residue on Ignition | NMT 0.2% |
| Heavy Metals | NMT 10 ppm |
| Melting Point | 213–217°C |