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Aripiprazole
ABILIFY · ARIPIPRAZOLE-D8 · Aripirazole · Arpiprazole · Aripiprazole CRS · OPC 31 · ABILITAT · OPC 14597
Identifikatoren & physikalische Daten
| CAS No. | 129722-12-9 |
|---|---|
| Summenformel | C23H27Cl2N3O2 |
| Durchschnittliche Molmasse | 448,4 g/mol |
| Monoisotopische Masse | 447,14803246 g/mol |
| SMILES | O=C1CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1 |
| InChIKey | CEUORZQYGODEFX-UHFFFAOYSA-N |
| PubChem CID | 60795 |
| ChEMBL | CHEMBL1112 |
| ChEBI | CHEBI:31236 |
| EC No. | 603-355-5 |
| DTXSID | DTXSID3046083 |
Chemische & physikalische Eigenschaften
| XLogP | 4,6 |
|---|---|
| Polarare Oberfläche (TPSA) | 44,8 |
| H-Brücken-Donoren | 1 |
| H-Brücken-Akzeptoren | 4 |
| Frei drehbare Bindungen | 7 |
| Schwere Atome | 30 |
| Formalladung | 0 |
| Komplexität | 559 |
| Arzneimittel | Pharmaceuticals -> Listed in ZINC15Pharmaceuticals -> Antipsychotics |
| Color/Form | Colorless, flake crystals from ethanol |
| Löslichkeit | 0.00001%<0.3 [ug/mL] (The mean of the results at pH 7.4)DMSO: soluble5mg/mL, clear (warmed) |
| Human Drugs | Breast FeedingLactationMilk, HumanAntipsychotic AgentsFDA approved drugs -> Active ingredientEMA approved medicines: Human medicine |
| Siedepunkt | 139.0-139.5 °C646.2±55.0 °C(Predicted) |
| Schmelzpunkt | 137-140139°C |
| Physical Description | Solid |
| Stability/Shelf Life | Stable under recommended storage conditions. |
| Ionization Efficiency | Positive4.392067472.7Thermo LTQElectrospray ionizationformic acid (5.3nM) |
| Dissociation Constants | 7.6 |
| Collision Cross Section | 205.8 Ų [M+H]+ [CCS Type: TWMethod: Major Mix IMS/Tof Calibration Kit (Waters)]203.5 Ų [M+H]+ [CCS Type: TWMethod: calibrated with polyalanine and drug standards]202.75 Ų [M+H]+ [CCS Type: TW |
| Dichte | 1.263±0.06 g/cm3(Predicted) |
| Lagerbedingungen | 2-8°C |
| pKa (Säurekonstante) | 14.42±0.20(Predicted) |
| Aggregatzustand | powder |
| Farbe | white to beige |
| Merck | 14,785 |
| Henry-Konstante | 9.9×1011 mol/(m3Pa) at 25℃, HSDB (2015) |
| BCS Class | 2 |
| Stabilität | Stable for 2 years from date of purchase as supplied. Solutions in DMSO or ethanol may be stored at -20° for up to 3 months. |
| InChI | InChI=1S/C23H27Cl2N3O2/c24-19-4-3-5-21(23(19)25)28-13-11-27(12-14-28)10-1-2-15-30-18-8-6-17-7-9-22(29)26-20(17)16-18/h3-6,8,16H,1-2,7,9-15H2,(H,26,29) |
| InChIKey | CEUORZQYGODEFX-UHFFFAOYSA-N |
| SMILES | N1C2=C(C=CC(OCCCCN3CCN(C4=CC=CC(Cl)=C4Cl)CC3)=C2)CCC1=O |
| CAS Datenbank | 129722-12-9(CAS DataBase Reference) |
Sicherheit & Vorschriften
| GHS-Einstufung | DangerH301 (62.7%): Toxic if swallowed [Danger Acute toxicity, oral]P203, P264, P270, P273, P280, P301+P316, P301+P317, P318, P321, P330, P405, and P501 (click each P-code to see the statement)Aggregated GHS information provided per 51 reports by companies from 20 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.H226: Flammable liquid and vapor [Warning Flammable liquids] |
|---|---|
| FDA-Anforderungen | The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including aripiprazole, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. |
| Special Reports | Swainston Harrison T, Perry CMAripiprazole: A Review of its Use in Schizophrenia and Schizoaffective disorderDrugs 64 (15): 1715-36 (2004).[] |
| Toxic Combustion Products | Special hazards arising from the substance or mixture: Carbon oxides, Hydrogen chloride gas |
| Hazard Classes and Categories | Acute Tox. 3 (62.7%) |
| Hazardous Reactivities and Incompatibilities | Incompatible materials: Strong oxidizing agents |
| Brandbekämpfungsverfahren | Advice for firefighters: Wear self-contained breathing apparatus for firefighting if necessary. Use water spray to cool unopened containers.Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide. |
| Lagerbedingungen | Conditions for safe storage, including any incompatibilities: Keep container tightly closed in a dry and well-ventilated place. Containers which are opened must be carefully resealed and kept upright to prevent leakage. Storage class (TRGS 510): Flammable liquids |
| Reinigungsverfahren | ACCIDENTAL RELEASE MEASURES. Personal precautions, protective equipment and emergency procedures: Wear respiratory protection. Avoid breathing vapours, mist or gas. Ensure adequate ventilation. Remove all sources of ignition. Evacuate personnel to safe areas. Beware of vapours accumulating to form explosive concentrations. Vapours can accumulate in low areas.Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains.Methods and materials for containment and cleaning up: Contain spillage, and then collect with an electrically protected vacuum cleaner or by wet-brushing and place in container for disposal according to local regulations. |
| Entsorgungsverfahren | SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash.SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator. |
| Preventive Measures | Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands.Appropriate engineering controls: Avoid contact with skin, eyes and clothing. Wash hands before breaks and immediately after handling the product.Precautions for safe handling: Avoid contact with skin and eyes. Avoid inhalation of vapour or mist. Keep away from sources of ignition - No smoking.Take measures to prevent the build up of electrostatic charge. |
| Personal Protective Equipment (PPE) | Respiratory protection: Where risk assessment shows air-purifying respirators are appropriate use a full-face respirator with multipurpose combination (US) or type ABEK (EN 14387) respirator cartridges as a backup to engineering controls. If the respirator is the sole means of protection, use a full-face supplied air respirator. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU).Body Protection: Complete suit protecting against chemicals, Flame retardant antistatic protective clothing., The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace.Skin protection: Handle with gloves.Eye/face protection: Face shield and safety glasses Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU). |
| Treatment | No specific information is available on the treatment of overdose with aripiprazole. An electrocardiogram should be obtained in case of overdosage and if QT interval prolongation is present, cardiac monitoring should be instituted. Otherwise, management of overdose should concentrate on supportive therapy, maintaining an adequate airway, oxygenation and ventilation, and management of symptoms. Close medical supervision and monitoring should continue until the patient recovers. Consider charcoal and hemodialysis. (A308) |
| Wechselwirkungen | Substrates of Hepatic Microsomal Enzymes: Substrates of CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4pharmacokinetic interaction unlikely.Hypotensive Agents: Potential pharmacologic interaction (additive hypotensive effects)Famotidine: Coadministration of aripiprazole (given in a single dose of 15 mg) with a 40-mg single dose of the H2 antagonist famotidine, a potent gastric acid blocker, decreased the solubility of aripiprazole and, hence, its rate of absorption, reducing by 37% and 21% the Cmax of aripiprazole and dehydro-aripiprazole, respectively, and by 13% and 15%, respectively, the extent of absorption (AUC). No dosage adjustment of aripiprazole is required when administered concomitantly with famotidine.Valproate: When valproate (500-1500 mg/day) and aripiprazole (30 mg/day) were coadministered at steady state, the C max and AUC of aripiprazole were decreased by 25%. No dosage adjustment of aripiprazole is required when administered concomitantly with valproate.For more Interactions (Complete) data for ARIPIPRAZOLE (12 total), please visit the HSDB record page. |
| Gesundheitliche Auswirkungen | Health effetcs include hyperpyrexia,muscle rigidity,altered mental status,and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Other effects may include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology (RxList, A308). |
| Hepatotoxicity | Liver test abnormalities have not been reported to occur in patients on long term therapy with aripiprazole, but most studies have not provided information on serum enzyme results. Despite its widescale use, aripiprazole has been implicated in only rare and isolated cases of clinically apparent liver injury in the literature. All reported cases have been hepatocellular arising after 1 to 3 months of therapy and with accelerated onset in one instance upon re-exposure. Immunoallergic and autoimmune features were not present. Most cases have been anicteric, and none were fatal or resulted in chronic injury. Aripiprazole has not been reported among agents implicated in large case series of drug induced liver injury. The product label for aripiprazole mentions that hepatitis and jaundice have been reported, but no specific details were provided. Thus, clinically apparent liver injury from aripiprazole must be very rare. |
| Umweltverhalten | TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 2.5X10+4(SRC), determined from a structure estimation method(2), indicates that aripiprazole is expected to be immobilein soil(SRC). The estimated pKa1 of aripiprazole is 7.46(3), indicating that this compound will exist partially in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Volatilization of the neutral species of aripiprazole from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 7.7X10-17 atm-cu m/mole(SRC), using a fragment constant estimation method(5). Aripiprazole is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 3.2X10-13 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). Biodegradation data in soil were not available(SRC, 2015).AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 2.5X10+4(SRC), determined from a structure estimation method(2), indicates that aripiprazole is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 7.7X10-17 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 1500(SRC), from an estimated log Kow of 5.30(2) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is very high(SRC). Biodegradation data in water were not available(SRC, 2015).ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), aripiprazole, which has an estimated vapor pressure of 3.2X10-13 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase. Particulate-phase aripiprazole may be removed from the air by wet and dry deposition(SRC). Aripiprazole contains chromophores that absorb at wavelengths >290 nm(4) and, therefore, may be susceptible to direct photolysis by sunlight(SRC). |
| Unerwünschte Wirkungen | Although the side effects of aripiprazole are similar to those found in typical and atypical antipsychotics, the degree of extrapyramidal symptoms (EPS) and metabolic syndromes is less due to receptor specificity. EPS, such as akathisia, Parkinsonian features such as resting tremor and shuffling gait, acute dystonic reactions, oculogyric crises, opisthotonos, and tardive dyskinesia, are manageable with benztropine or sodium benzoate. Aripiprazole is associated with lower incidences of weight gain, hypercholesterolemia, glucose dysregulation, cardiovascular abnormalities, and hyperprolactinemia. Hyperprolactinemia may manifest as galactorrhea, gynecomastia in men, sexual dysfunction, amenorrhea, or off-cycle bleeding. Other possible side effects of aripiprazole include somnolence, nausea, vomiting, akathisia, and lightheadedness. Antipsychotics agent use requires caution in older adults because it can cause or exacerbate the syndrome of inappropriate antidiuretic hormone secretion (SIADH) or hyponatremiathus, it is crucial to monitor sodium during initiation and dosage adjustment. Children and adolescents are more susceptible than older patients to experience EPS, weight gain, and other metabolic side effects. The FDA also recently identified an association between aripiprazole use and compulsive or uncontrollable urges to engage in sex, gamble, binge eat, and shop. |
| Expositionspfade | Oral |
| Milk Concentrations | Aripiprazole is excreted in human breast milk. A decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. |
| Toxizitätsübersicht | IDENTIFICATION AND USE: Aripiprazole is used IM for the acute management of agitation associated with schizophrenia or bipolar disorder, mixed or manic, in adults for whom treatment with aripiprazole is appropriate and who require an IM antipsychotic agent for rapid control of behaviors that interfere with diagnosis and care (e.g., threatening behaviors, escalating or urgently distressing behavior, self-exhausting behavior). Aripiprazole is used orally for the acute treatment of irritability associated with autistic disorder. Aripiprazole is used orally as an adjunct to antidepressants for the acute treatment of major depressive disorder in adults. Aripiprazole is used orally as monotherapy or as an adjunct to either lithium or valproate for the acute treatment of manic or mixed episodes associated with bipolar I disorder with or without psychotic features in adults and pediatric patients 10-17 years of age. The drug also is used orally as monotherapy or as adjunctive therapy with lithium or valproate for the maintenance treatment of bipolar I disorder in adults and pediatric patients 10-17 years of age. Aripiprazole is used orally for the acute and maintenance treatment of schizophrenia in adults and adolescents 13-17 years of age. HUMAN EXPOSURE AND TOXICITY: A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs, including aripiprazole. Two possible cases of NMS occurred during aripiprazole treatment in the premarketing worldwide clinical database. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. ANIMAL STUDIES: In female mice, the incidences of pituitary gland adenomas and mammary gland adenocarcinomas and adenoacanthomas were increased at dietary dose of 3 to 30 mg/kg/day. Female rats were treated with oral doses of 2, 6, and 20 mg/kg/day of aripiprazole from 2 weeks prior to mating through day 7 of gestation. Estrus cycle irregularities and increased corpora lutea were seen at all doses, but no impairment of fertility was seen. Increased pre-implantation loss was seen at 6 and 20 mg/kg, and decreased fetal weight was seen at 20 mg/kg. Pregnant rabbits were treated with oral doses of 10, 30, and 100 mg/kg/day of aripiprazole during the period of organogenesis. Decreased maternal food consumption and increased abortions were seen at 100 mg/kg. Treatment caused increased fetal mortality (100 mg/kg), decreased fetal weight (30 and 100 mg/kg), increased incidence of a skeletal abnormality (fused sternebrae at 30 and 100 mg/kg) and minor skeletal variations (100 mg/kg). Aripiprazole and a metabolite (2,3-DCPP) were clastogenic in the in vitro chromosomal aberration assay in CHL cells with and without metabolic activation. The metabolite, 2,3-DCPP, produced increase in numerical aberrations in the in vitro assay in CHL cells in the absence of metabolic activation. A positive response was obtained in the in vivo micronucleus assay in mice, however,the response was shown to be due to a mechanism not considered relevant to humans.According to FDA reports, there have been 76 cases of aripiprazole overdose. These include instances of both deliberate and accidental overdose in combination with other substances. There is currently no known antidote for aripiprazole overdose. However, early charcoal administration partially prevents the absorption of the drug if it is ingested orally, e.g., a tablet. Management of aripiprazole overdose should focus on supportive therapy. The clinician should obtain an EKG to identify any cardiac arrhythmias, such as QTc prolongation.Aripiprazole's antipsychotic activity is likely due to a combination of antagonism at D2 receptors in the mesolimbic pathway and 5HT2A receptors in the frontal cortex. Antagonism at D2 receptors relieves positive symptoms while antagonism at 5HT2A receptors relieves negative symptoms of schizophrenia. Aripiprazole exhibits high affinity for dopamine D2 and D3, serotonin 5-HT1A and 5- HT2A receptors, moderate affinity for dopamine D4, serotonin 5-HT2C and 5-HT7, alpha1-adrenergic and histamine H1 receptors and moderate affinity for the serotonin reuptake pump. Aripiprazole has no appreciable affinity for cholinergic muscarinic receptors. Aripiprazole functions as a partial agonist at the dopamine D2 and the serotonin 5-HT1A receptors, and as an antagonist at serotonin 5-HT2A receptor. |
| Soil Adsorption/Mobility | Using a structure estimation method based on molecular connectivity indices(1), the Koc of aripiprazole can be estimated to be 2.5X10+4(SRC). According to a classification scheme(2), this estimated Koc value suggests that aripiprazole is expected to be immobile in soil. The estimated pKa of aripiprazole is 7.46(3), indicating that this compound will exist partially in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). |
| Human Toxicity Excerpts | /SIGNS AND SYMPTOMS/ A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs, including aripiprazole. Two possible cases of NMS occurred during aripiprazole treatment in the premarketing worldwide clinical database. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure./SIGNS AND SYMPTOMS/ Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome requiring immediate discontinuance of the drug and intensive symptomatic treatment, has been reported in patients receiving antipsychotic agents, including rare cases associated with aripiprazole therapy./SIGNS AND SYMPTOMS/ A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) may occur with administration of antipsychotic drugs, including aripiprazole. Rare cases of NMS occurred during aripiprazole treatment in the worldwide clinical database. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to exclude cases where the clinical presentation includes both serious medical illness (eg, pneumonia, systemic infection) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology./SIGNS AND SYMPTOMS/ A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown. The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses.For more Human Toxicity Excerpts (Complete) data for ARIPIPRAZOLE (7 total), please visit the HSDB record page. |
| Artificial Pollution Sources | Aripiprazole's production and administration as a medication(1) may result in its release to the environment through various waste streams(SRC). |
| Wassergefährdungsklasse (WGK) | 3 |
| UN-Transportnummer | UN 1993C 3 / PGIII |
| Zollcode | 29349990 |
| RTECS-Nr. | VC8275950 |
| R-Sätze (R) | 11-20/21/22-36 |
| Toxizität | TDLo ivn-dog: 0.03 mg/kg/10M TXAPA9 173,120,2001 |
| Gefahrensymbole | F,Xn |
| Sicherheitshinweise (S) | 16-36/37 |
| Lagerklasse | 11 - Combustible Solids |
| Gefahrstoffdaten | 129722-12-9(Hazardous Substances Data) |
| Gefahrenklasse | Acute Tox. 4 Oral |
Anwendungen & Verwendung
Verwenden
A deuterated version of Aripiprazole, a selective dopamine D2-receptor antagonist with dopamine autoreceptor agonist activity. Please note that users have reported separation of this compound and aripiprazole under normal-phase and reverse-phase