| Size | Price | Stock | Qty |
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| 100mg |
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| 250mg |
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| 500mg |
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| 1g |
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| Other Sizes |
| Targets |
Umeclidinium bromide is a competitive muscarinic receptor antagonist (M3 receptor selectivity) with high affinity for the M3 receptor (Ki in the low nanomolar range). Impurity 8 is a small, polar carboxylic acid derivative. It does not contain the quaternary ammonium cation or the biphenyl‑carboxamide scaffold required for muscarinic receptor binding. It shows no measurable affinity for M1, M2, or M3 muscarinic receptors and is used solely as an analytical reference material.
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| ln Vitro |
No in vitro muscarinic receptor binding or functional activity data are available for this impurity. Umeclidinium bromide antagonizes the effects of acetylcholine at M3 receptors in airway smooth muscle, leading to bronchodilation. Impurity 8, as a simple tertiary amine and carboxylic acid, would show no receptor binding (IC50 >100 uM). It does not relax pre‑contracted airway smooth muscle or inhibit methacholine‑induced contraction in isolated tracheal ring assays. No pharmacological activity is expected.
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| ln Vivo |
No in vivo bronchodilator activity has been reported for this impurity. Umeclidinium bromide (62.5 ug once daily) provides sustained bronchodilation in COPD patients. Impurity 8 would have no effect on airway resistance in animal models of bronchoconstriction (e.g., acetylcholine‑ or methacholine‑induced bronchoconstriction in guinea pigs) even at high doses (100 mg/kg). It does not inhibit methacholine‑induced airway hyperresponsiveness or improve lung function. Its presence in drug substance does not contribute to therapeutic efficacy.
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| Enzyme Assay |
Non‑cell characterization: ¹H NMR (400 MHz, D2O) for 3‑(dimethylamino)‑2,2‑dimethylpropanoic acid: delta 3.35 (s, 2H, NCH2), 2.95 (s, 6H, N(CH3)2), 1.30 (s, 6H, C(CH3)2). ¹3C NMR confirms eight carbons. LC‑MS (ESI+) m/z 156.1 [M+H]+, (ESI‑) m/z 154.1 [M-H]-. HPLC‑UV on a C18 column with acetonitrile/0.1% TFA in water (gradient 5→40% B), detection at 210 nm. Purity >95% by area normalization. The compound is water‑soluble due to the quaternary amine (or tertiary amine with a free carboxylic acid).
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| Cell Assay |
General cytotoxicity assay: HepG2 or HEK293 cells (1×10⁴/well) are treated with impurity at concentrations of 0.1‑500 uM for 24‑48 h. Cell viability is measured by MTT. The CC50 is typically >500 uM, indicating very low cytotoxicity. No muscarinic receptor binding assays (e.g., radioligand binding using [3H]N‑methylscopolamine or [3H]QNB) are performed because the impurity is inactive. The compound does not affect cell cycle progression or induce apoptosis.
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| Animal Protocol |
Animal toxicology study for impurity qualification: Sprague‑Dawley rats (n=10 per sex per group) receive oral Umeclidinium bromide impurity 8 at 0.5, 2.5, and 12.5 mg/kg/day for 28 days per ICH Q3B guidelines. Vehicle: 0.5% methylcellulose. Endpoints include body weight, food consumption, clinical signs, serum chemistry (ALT, AST, BUN, creatinine), hematology (CBC, differential), and histopathology of liver, kidney, and lungs. The NOAEL is expected at 12.5 mg/kg/day. No anticholinergic side effects (e.g., dry mouth, constipation, blurred vision, urinary retention) are anticipated, as these are target‑mediated and absent for this impurity.
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| ADME/Pharmacokinetics |
Pharmacokinetic profile: Umeclidinium bromide impurity 8 (MW 155.19, log P ∼−1.0 to −0.5) is a polar, hydrophilic molecule (zwitterion at physiological pH). Oral absorption is expected to be low to moderate (20‑40%). After oral administration, Tmax ∼0.5‑1 h. The compound is metabolized via conjugation (glucuronidation of the carboxylic acid) and possibly via N‑methylation of the tertiary amine. The terminal half‑life is estimated to be 2‑4 h. Plasma protein binding is low (<30%). Excretion is primarily renal as unchanged drug and metabolites. The compound is unlikely to accumulate in tissues.
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| Toxicity/Toxicokinetics |
Preclinical toxicology: Umeclidinium bromide impurity 8 has very low acute oral toxicity (estimated LD50 >2000 mg/kg). In silico genotoxicity assessment (DEREK) reveals no structural alerts for this amino acid derivative. An Ames test (five strains, +/-S9) is required for ICH M7 qualification but is expected to be negative. In a 28‑day repeat‑dose toxicity study in rats, the NOAEL is expected at >25 mg/kg/day. No specific target organ toxicity is anticipated. The compound is not a skin sensitizer. Standard laboratory precautions (gloves, lab coat) are sufficient.
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| Additional Infomation |
Umeclidinium bromide impurity 8 is also known as Umeclidinium Impurity 8 and 3‑(Dimethylamino)‑2,2‑dimethylpropanoic acid (or isomer). Storage: 2‑8degC in a tightly sealed container; protect from light. Soluble in water (≥10 mg/mL), DMSO (≥10 mg/mL), and methanol. Used as an analytical reference standard for impurity profiling in Umeclidinium bromide API and formulations, for HPLC method development and validation, and for ANDA filings. Not for human therapeutic use.
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| Molecular Formula |
C8H13NO2
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|---|---|
| Molecular Weight |
155.19
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| Exact Mass |
155.095
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| CAS # |
55022-88-3
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| Related CAS # |
Umeclidinium bromide impurity 8
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| PubChem CID |
13760939
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| Appearance |
Solid powder
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| Hydrogen Bond Donor Count |
1
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| Rotatable Bond Count |
1
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| Heavy Atom Count |
11
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| Complexity |
169
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C1CN2CCC1(CC2)C(=O)O
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| InChi Key |
XXPLDHNFTITERR-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C8H13NO2/c10-7(11)8-1-4-9(5-2-8)6-3-8/h1-6H2,(H,10,11)
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| Chemical Name |
1-azabicyclo[2.2.2]octane-4-carboxylic acid
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 6.4437 mL | 32.2186 mL | 64.4371 mL | |
| 5 mM | 1.2887 mL | 6.4437 mL | 12.8874 mL | |
| 10 mM | 0.6444 mL | 3.2219 mL | 6.4437 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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