ASE 136
Dirithromycin
CAS: 62013-04-1
Molecular Formula: C42H78N2O14
ASE 136 - Names and Identifiers
ASE 136 - Physico-chemical Properties
| Molecular Formula | C42H78N2O14 |
| Molar Mass | 835.07 |
| Density | 1.19±0.1 g/cm3(Predicted) |
| Melting Point | 186-189° (dec) (Counter) |
| Boling Point | 871.8±65.0 °C(Predicted) |
| Flash Point | 481°C |
| Solubility | DMSO 11 mg/mL Water <1 mg/mL Ethanol 100 mg/mL |
| Vapor Presure | 1.72E-35mmHg at 25°C |
| Appearance | solid |
| Color | white to off-white |
| pKa | 9.0 in 66% aq dimethyl fluoride |
| Storage Condition | Sealed in dry,2-8°C |
| Refractive Index | 1.533 |
| MDL | MFCD00865041 |
| Physical and Chemical Properties | Crystallization from ethanol-water, melting point 186~189 °c (decomposition). pKa9.0(66% dimethyl fluoride in water). Acute toxicity LD50 mice (g/kg):>1 subcutaneous injection,>1 oral. |
| Use | A class of semi-synthetic macrolide antibiotics |
ASE 136 - Risk and Safety
| Risk Codes | R42/43 - May cause sensitization by inhalation and skin contact. R36/37/38 - Irritating to eyes, respiratory system and skin. |
| Safety Description | S36 - Wear suitable protective clothing. S26 - In case of contact with eyes, rinse immediately with plenty of water and seek medical advice. |
| WGK Germany | 3 |
| HS Code | 29419000 |
| Toxicity | LD50 in mice (g/kg): >1 s.c.; >1 orally (Maier) |
ASE 136 - Upstream Downstream Industry
| Raw Materials | hydrazine hydrate |
ASE 136 - Standard
Authoritative Data Verified Data
This product is (9s, 16R)-9,ll-dideoxy-9, 11-[imino [(1R)-2-(2-methoxyethoxy) ethylidene] oxy] erythromycin. Dirithromycin-containing (C42H78N2014) should be between 96.0% and 102.0%, calculated as anhydrous.
Last Update：2024-01-02 23:10:35
ASE 136 - Trait
Authoritative Data Verified Data
- This product is white or off-white crystalline powder; Odorless.
- This product is soluble in methanol and dichloromethane, slightly soluble in N ,N-dimethylformamide, slightly soluble in acetonitrile, almost insoluble in water.
specific rotation
take an appropriate amount of this product, weigh it accurately, add methanol to dissolve and quantitatively dilute to make a solution containing about 20mg per lml, and determine it according to law (General rule 0621), the specific rotation is from one to 83 ° to one to 87 °.
Last Update：2022-01-01 11:43:27
ASE 136 - Introduction
DirithromyCln is a macrolide glycopeptide antibiotic that inhibits peptide translocation by binding to the 50S subunit of the bacterial 70S ribosome
Last Update：2022-10-16 17:27:17
ASE 136 - Differential diagnosis
Authoritative Data Verified Data
- in the chromatogram recorded under the content determination item, the retention time of the main peak of the test solution should be consistent with the retention time of the main peak of the reference solution.
- The infrared absorption spectrum of this product should be consistent with that of the reference substance of dirithromycin (General rule 0402). If not, take about 20mg each of this product and dirithromycin reference, add 3ml of absolute ethanol to dissolve, water bath to dry, put phosphorus pentoxide dryer under reduced pressure to dry overnight, and then measure.
Last Update：2022-01-01 11:43:27
ASE 136 - Exam
Authoritative Data Verified Data
isomer
The Peak area of 16s-dirithromycin isomer shall not be greater than the main peak area of the control solution (1.0%) as determined by the method under the item of related substances.
Related substances
new system for clinical use. Take an appropriate amount of this product, precision weighing, add acetonitrile-methanol (70:30) dissolved and quantitatively diluted into a solution containing about 10 mg per lml, as a test solution; take 1ml in precision, put it in a 100ml measuring flask, dilute it to the scale with acetonitrile-methanol (70:30), shake it well, and use it as a control solution, set in a 10mi measuring flask, dilute to the scale with acetonitrile-methanol (70:30), shake, as a sensitivity solution. According to the chromatographic conditions under the content determination item, take the sensitivity solution 20 u1, inject the human liquid chromatograph, record the chromatogram, and the signal-to-noise ratio of the peak height of the principal component chromatogram should be greater than 10. 20 u1 of the test solution and the control solution were respectively injected into the human liquid chromatograph, and the chromatogram was recorded to 3 times of the retention time of the main component peak. If there are impurity peaks in the chromatogram of the test solution, except for the 16s-dirithromycin isomer peak, 9-(S)-The Peak area of erythromycylamine shall not be greater than the main peak area of the control solution. The Peak area of other individual impurities shall not be greater than the main peak area of the control solution (1.0% ) , the sum of each impurity peak area shall not be greater than 3 times (3.0%) of the main peak area of the control solution. The peaks in the chromatogram of the test solution which are smaller than the main peak area of the sensitivity solution are ignored.
residual solvent
take about 0.2g of this product, weigh it accurately, put it in a 10ml measuring flask, Add 10ml of N,N-dimethylformamide to dissolve and dilute to the scale, shake it well, and use it as a test solution; accurately take the appropriate amount of methanol, dichloromethane, ethanol and acetonitrile, and quantitatively dilute with N,N dimethylformamide to make a mixed solution containing about 0.06mg of methanol, 0.012mg of dichloromethane, 0.1 mg of ethanol and 0.008mg of acetonitrile per 1 ml, as a control solution. 2ml of the test solution and the reference solution were accurately measured, placed in the top empty bottle, sealed, and determined according to the residual solvent determination method (General 0861 second method), with polyethylene glycol (PEG-20M) (Or similar to the polarity) the capillary column for the stationary liquid column; The initial temperature is 40°C, maintained for 15 minutes, at a rate of 30°C per minute to 240°C, maintained for 10 minutes; the inlet temperature was 200°C; The detector temperature was 250°C. The Headspace bottle equilibration temperature was 90°C and the equilibration time was 20 minutes. Take the reference solution into the headspace, the separation degree between the peaks of each component shall meet the requirements. Then the test solution and the reference solution are injected in the headspace respectively, and the chromatogram is recorded. The residual amount of methanol, dichloromethane, ethanol and acetonitrile shall be calculated by the peak area according to the external standard method.
moisture
take this product, according to the moisture determination method (General 0832 first method 1), the water content shall not exceed 1.0%.
ignition residue
take l.Og of this product and check it according to law (General rule 0841). The residue left shall not exceed 0.1%.
Heavy metals
The residue left under the item of taking the ignition residue shall not contain more than 20 parts per million of heavy metal when examined by law (General rule 0821, Law II).
Last Update：2022-01-01 11:43:28
ASE 136 - Content determination
Authoritative Data Verified Data
measured by high performance liquid chromatography (General 0512).
chromatographic conditions and system suitability test
with eighteen alkyl silane bonded silica gel as filler (4.6mm X 250mm, 5um or performance equivalent column); Phosphate buffer (take potassium dihydrogen phosphate 6.91g and potassium dihydrogen phosphate g, 1000ml of water was added to dissolve)-acetonitrile-methanol (37:44:19) as a mobile phase; The detection wavelength was 205mn. The appropriate amount of dirithromycin control was taken, dissolved and diluted with mobile phase to make a solution containing about 2.5mg per 1 ml, and left at room temperature for at least 24 hours as a system-suitable solution. 20ul was injected into the liquid chromatograph and the chromatogram was recorded. The relative retention time of the peak of 9-(S)-erythromycylamine was about 0.6, the relative retention time of 16s-dirithromycin isomer peak was about 1.1. The resolution between the peak and 16s-dirithromycin isomer peak should be more than 2.0; the separation degree between dirithromycin Peak and other impurity peaks shall meet the requirements.
assay
new system for clinical use. Take an appropriate amount of this product, precision weighing, add acetonitrile-methanol (70:30) to dissolve and quantitatively dilute to prepare a solution containing about 2mg per 1 ml as a test solution, 20u1 was injected into the liquid chromatograph accurately, and the chromatogram was recorded. An appropriate amount of dirithromycin reference substance was taken, dissolved and quantitatively diluted with acetonitrile-toluene (70:30) to prepare a solution containing about 2mg per 1 ml, same method determination. According to the external standard method to calculate the peak area, that is.
Last Update：2022-01-01 11:43:29
ASE 136 - Category
Authoritative Data Verified Data
macrolide antibiotics.
Last Update：2022-01-01 11:43:29
ASE 136 - Storage
Authoritative Data Verified Data
sealed and stored in a cool and dry place.
Last Update：2022-01-01 11:43:29
ASE 136 - Reference Information
| Background and overview | dirithromycin is a second-generation erythromycin macrocyclic (fourteen-membered) lactone, by 2-methoxyethoxyacetaldehyde and erythromycylamine in C9, C11 synthesis of oxazine ring and the formation of similar structure and erythromycin. In vivo non-enzymatic hydrolysis to the red mold cyclic Amine, by binding to the 50S ribosomal subunit of sensitive pathogenic microorganisms to hinder the bacterial peptide transfer process, inhibiting protein synthesis and antibacterial. compared with erythromycin and other new macrolide antibiotics, the drug has the following characteristics:(1) Antibacterial effect: in addition to retaining the antibacterial effect of dirithromycin on G 10 bacteria, on a variety of G bacteria, anaerobic bacteria and other pathogens, such as Mycoplasma, chlamydia and spirochetes still have a strong antibacterial effect. The antibacterial effect of dirithromycin on Staphylococcus aureus and Staphylococcus epidermidis was stronger or equivalent to that of erythromycin. (2) Pharmacokinetics: compared with other macrocyclic antibiotics, the half-life of dirithromycin is longer, the plasma elimination of tl/2 is greater than 24h, and the tissue permeability is strong, can be administered once a day. Therefore, in the market, it will also be different from other antibiotics to show the characteristics of competitive. The product of U. S. Poly Company was listed in Spain in September 1993. It was approved by FDA in 1996 and listed in U. S. Pharmacopeia USP 23, and was listed in China in 2005. At present, there are a number of domestic research and development of the Erythromycin Enteric-coated Tablets and enteric capsules approved for production and clinical use. |
| synthesis | Route 1: erythromycin hydrazone (2) was prepared by reacting erythromycin with hydrazine hydrate, erythromycin amine (3) was synthesized with erythromycin hydrazone, and dirithromycin (1) was finally synthesized with 2-methoxyethoxyacetaldehyde (5), as shown in the figure: Route 2: erythromycin is reacted with hydroxylamine hydrochloride to obtain erythromycin oxime, which is reduced to erythromycin amine and then reacted with 2-(2-methoxyethoxy) dirithromycin (DRM) is formed by condensation of acetaldehyde glycol acetal. The specific reaction route is as follows: |
| pharmacological action | dirithromycin has an antibacterial spectrum similar to erythromycin. It has a strong inhibitory effect on chlamydia and Mycoplasma. For most Gram-positive bacilli, the activity of dirithromycin is 2~4 times lower than that of erythromycin. To Bordetella pertussis, the activity of dirithromycin was 4 times stronger than that of erythromycin. The in vitro anti-staphylococcal activity of dirithromycin is similar to or less than that of erythromycin. Dirithromycin in less than or equal to 0.03~0.12g/ml can inhibit Streptococcus pyogenes, Pneumonia Streptococcus. Group B streptococci were also inhibited at the same concentration. Pneumonia Streptococcus and Listeria were inhibited at 0.12 μg/ml and 0.5 μg/ml, respectively. Group A Streptococcus, Listeria, and Enterococcus, which are resistant to antibiotics, are also resistant to dirithromycin. The erythromycin-sensitive and drug-resistant staphylococci MIC90 was 0.5 μg/ml and 8 μg/ml. Dirithromycin did not inhibit aerobic Gram-positive bacteria. In general, dirithromycin is 2-4 times more active than erythromycin. The activity of dirithromycin against Staphylococci and streptococci is not reduced by the addition of human serum. This class of macrolides is 1 to 4 times more active at pH 8.0 than at pH 6.0. Dirithromycin has bacteriostatic action on Staphylococcus aureus and slow bactericidal action on Haemophilus influenzae. Dirithromycin is resistant to enterococci and most methicillin-resistant Staphylococcus aureus, and has a close cross-resistance relationship with other macrolides. Figure 1 is the structural formula of dirithromycin |
| pharmacokinetics | absorption: after oral administration, conversion to the biologically active substance erythromycylamine by non-enzymatic hydrolysis has an absolute bioavailability of about 10%. Healthy volunteers (19-59 years, single dose: 500mg; Multiple doses: 500mg/day, 10 days). Distribution: erythromycylamine is rapidly and widely distributed into tissues, and its intracellular concentration is higher than the tissue concentration, while the tissue concentration is significantly higher than the plasma concentration. The protein binding rate was 15-30%, and the average apparent volume of distribution (VDSS) was 800L(540-1041L). Metabolism and excretion of the steady-state tissue concentration of erythromycylamine (500mg/time once a day): erythromycylamine is almost not metabolized by the liver, 81-97% of the drug is eliminated by the biliary pathway, about 2% of the drug is eliminated by the kidneys. In patients with normal renal function, the average plasma half-life is about 8 hours, the average elimination half-life is about 44 hours, and the average apparent clearance is about 23L/h. Effects of food: the product can be taken with food or within 1 hour after a meal. The study showed a 33% decrease in Cmax and a 31% decrease in AUC 1 hour before meals. The level of fat in food has little effect on bioavailability. |
| clinical evaluation | 3299 patients received oral administration of the drug (0.5g/day) for 7-14 days, no toxicity-related death or disability was found. Eighty-seven patients (2.6%) discontinued medication due to adverse reactions, of which 35 (40%) were due to discontinuation Nausea and Abdominal Pain. Another clinical trial (oral administration of the drug 0.5g/day, 5 days of treatment) showed that 35 patients (3.8%) due to adverse reactions to medication, of which 15 cases (43%) it was due to drug discontinuation in Nausea and Abdominal Pain. The adverse reactions related to the drug treatment were as follows: Head Pain (7.7%), Abdominal Pain (7.1%), Diarrhea (6.7%), Nausea (5.9%), dyspepsia (2.6%), dizziness/dizziness (2.1%), rash (1.4%), Vomit (1.1%). Platelet count increased (3.8%), potassium increased (2.6%), bicarbonate decreased (1.4%), CPK increased (1.2%), eosinophils increased (1.2%), neutrophils increased (1.2%), leukocytosis (0.8%), etc. |
| indications | for patients over 12 years of age, for the treatment of mild to moderate infections caused by the following sensitive bacteria: 1. Acute exacerbation of chronic bronchitis: caused by Haemophilus influenzae, Moraxella catarrhalis, Pneumonia streptococci. 2. Acute bronchitis: caused by Moraxella catarrhalis, Pneumonia Streptococcus. 3. Community Acquired Pneumonia: caused by Legionella pneumophila, Mycoplasma pneumoniae, Streptococcus pneumoniae. 4. Pharyngitis and tonsillitis: caused by Streptococcus pyogenes. Simple skin and soft tissue infections: caused by Staphylococcus aureus (methicillin-sensitive strains), Streptococcus pyogenes. |
| specification | tablet: 125mg/tablet, 250mg/tablet; Capsule: 125mg/tablet, 250mg/tablet. |
| usage and dosage | , MG each time, once a day, taken while eating, the course of treatment is 7~14 days according to the disease. Elderly people do not need to change the dose. Dose adjustment is also not necessary for patients with mild hepatic insufficiency and chronic renal failure. |
| adverse reactions | 1. Adverse reactions mainly for the digestive system, such as Abdominal Pain, Nausea, Diarrhea, Vomit, indigestion, constipation, loose stools, dry mouth, oral ulcers, taste changes; Other Head Pain, dizziness, cough: The patient presented with aggravation, rash and pruritus. 2. Laboratory tests showed increased platelets; ALT, AST bilirubin, creatinine increased. |
| drug interaction | terfenadine: This product does not affect the metabolism of terfenadine, in vitro experiments demonstrated that the two drugs do not interact, but interact with erythromycin. theophylline: Under normal circumstances, is taking theophylline in patients receiving this product treatment, do not need to adjust the theophylline dose or blood concentration monitoring. When it is necessary to maintain a high plasma concentration of theophylline, the plasma concentration should be detected and the dose should be adjusted. antacids or H2 receptor antagonists: After taking antacids or H2 receptor antagonists, taking this product immediately can increase the absorption of dirithromycin. The interaction between erythromycin and the following drugs is clear, but the interaction with dirithromycin is not clear, therefore, the combination should be careful. triazolam: can reduce the clearance of triazolam, increase its pharmacological effects. digoxin: can increase the blood concentration of digoxin. Anticoagulants: can increase the role of anticoagulants, especially in the elderly. ergotamine: produces toxic symptoms such as peripheral vasospasm and dysesthesia. other drugs: interactions between erythromycin and the following drugs have been reported, such as: cyclosporine, cyclohexobarbital, carbamazepine, alfentanil, probamide, phenytoin, bromocriptin. Valproate, asimazole, lovastatin. |
| precautions | hepatic insufficiency: In patients with mild hepatic impairment, the mean Cmax. The AUC and volume of distribution increased slightly with increasing doses, but dose adjustment was not necessary. Renal insufficiency: the mean Cmax.AUC tends to increase with a decrease in creatinine clearance, but dose adjustment is not necessary in patients with renal impairment (including dialysis). Pseudomembranous colitis has been reported to occur with virtually all broad-spectrum antibiotic agents, including dirithromycin. Therefore, it is important to take this diagnosis into account if Diarrhea of patients using antibiotics occur. The degree of this colitis varies from mild to life-threatening. For mild cases of pseudomembranous colitis, it is usually effective simply by stopping the drug. For moderate to severe cases, appropriate treatment should be taken. |
| contraindicated | is contraindicated in patients with hypersensitivity to dirithromycin, erythromycin and other macrolides. should not be used in patients with suspected or potential bacteremia (as they do not provide effective drug concentrations to the site of treatment). |
| pregnant and lactating women | pregnant women: reproductive studies in rats, the dose was 21 times higher than the human dose (calculated in terms of mg/m2) and 4 times the study dose for rabbits. The results showed that this product had no damage to fertility and fetus. Reproductive studies were performed on mice at doses 8 times higher than the human dose. The results show that the product can significantly reduce the fetal weight. However, there are no properly controlled clinical studies in pregnant women. Therefore, pregnant women using this product should weigh the pros and cons. delivery: the impact on delivery is unknown. Lactation: it is not clear whether this product is contained in breast milk of lactating women, but other macrolide antibiotics are found in breast milk, and this product is also contained in breast milk of rodents. Therefore, lactating women should be used with caution. |
| Children | the safety and efficacy of this product in children under 12 years of age have not been determined. |
| use in elderly patients | Cmax.AUC tended to increase with age, but there was no statistically or clinically significant difference. Therefore, elderly patients do not need to adjust the dose. |
| Main reference material | [1] Li Lin et al. Preparation and in vitro release of dirithromycin enteric-coated pellets. Chinese Journal of Hospital Pharmacy, 2011, 31(19):1591-1595. [2] Yang Changhua et al. Determination of the degree of release of Erythromycin Enteric-coated Tablets. Journal of Hunan Normal University. 2014,11(4): 86-89. [3] Zhang Yudi et al. A long-acting safe macrolide antibiotic, dirithromycin. Chinese Journal of Clinical Pharmacology. 2011,27(6):467-471. [4] dirithromycin. Medical Encyclopedia. [5] Liang Yiheng. Synthesis of dirithromycin. Chinese Journal of Pharmaceutical industry. 2002,33(6):269-270. [6] Liao Liang. Study on synthesis of a new generation of macrolide antibiotic dirithromycin. Thesis of Dalian University of Technology. 1999. [7] place Erythromycin Enteric-coated Tablets description. |
| Usage | erythromycin antibiotics. A semisynthetic macrolide antibiotic |
| production method | the following compounds and 2-(2-methoxyethoxy) acetaldehyde, stirring in ethanol at room temperature for 24h; Alternatively and methylal or Acetal of 2-(2-methoxyethoxy) acetaldehyde in dioxane-water in the presence of Dowex 50W, dirithromycin was obtained by stirring for 6h at room temperature. |
Last Update：2024-04-09 21:01:54
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CAS: 62013-04-1
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CAS: 62013-04-1
Tel: 18301782025
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Raw Materials for ASE 136