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Itraconazole 500mg, CAS 84625-61-6, The molecular formula C35H38Cl2N8O4 appears as a gray white to light yellow crystalline powder at room temperature and pressure, with no odor or a slight special odor. Its flowability is good in powder form, but it is prone to clumping due to moisture absorption, so it needs to be stored in a dry environment. In the production of formulations, the powder form of itraconazole directly affects its mixing uniformity with excipients, thereby affecting the content uniformity of tablets or capsules. For example, in the preparation of oral capsules, it is necessary to control the particle size within a certain range (such as D90<50 μ m) through micronization technology to improve the dissolution rate and bioavailability of the drug.
Additional information of chemical compound:
Our product form
Itraconazole +. COA
The solubility of itraconazole is one of its most critical physical properties, which directly determines the drug's absorption efficiency and formulation design strategy
Solubility
Extremely poor water solubility:
Under neutral pH conditions, the saturated solubility of itraconazole 500mg in aqueous solution is less than 1ng/mL, and it is almost insoluble in water. This characteristic is due to the strong hydrophobic groups in its molecular structure, such as dichlorophenyl, triazole ring, and piperazine ring, which make it difficult for the drug to dissolve and absorb in the gastrointestinal tract.
Organic solvent solubility:
Itraconazole is soluble in organic solvents such as chloroform (50mg/mL), dimethyl sulfoxide (DMSO), and N, N-dimethylformamide (DMF), forming a transparent solution. This characteristic is used in drug analysis to dissolve samples for content determination or structural identification.
PH dependent dissolution:
In strongly acidic environments such as gastric acid, the solubility of itraconazole slightly increases, but it is still insufficient to support its oral absorption. Therefore, cyclodextrin inclusion technology (such as forming a 1:1 inclusion complex with hydroxypropyl - β - cyclodextrin) or nanocrystal technology is often used in formulations to increase drug solubility to 5-10mg/mL, thereby significantly improving bioavailability.
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Melting point and boiling point
Melting point:
The melting point range of itraconazole is 165-169 ℃, which is of great significance in drug purity testing. Itraconazole with higher purity exhibits sharp melting peaks in differential scanning calorimetry (DSC) analysis, while the presence of impurities can lead to a decrease in melting point or a widening of the melting range.
Boiling point:
The predicted boiling point is 850 ± 75 ℃, but in actual research, it is directly measured due to the low risk of decomposition. The high boiling point characteristics indicate that itraconazole is stable under conventional distillation conditions, but care should be taken to avoid oxidative degradation caused by high temperatures.
Density and specific rotation
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Density:
The density of itraconazole is 1.27g/cm ³ (some literature reports it as 1.4g/cm ³), which is used in the tablet compression process to calculate the volume and weight of the tablet and ensure dosage accuracy.
Specific rotation:
In a dichloromethane solution (concentration 10mg/mL, 20 ℃), the specific rotation range of itraconazole is -0.1 ° to+0.1 °, indicating a high symmetry of the chiral center in its molecular structure and a racemic ratio close to 1:1. This characteristic requires strict control of stereoselectivity in drug synthesis to avoid efficacy fluctuations caused by differences in enantiomeric activity.
Itraconazole 500mg is a broad-spectrum triazole antifungal drug, and its synthesis method involves multiple chemical reactions, requiring precise control of reaction conditions to achieve efficient preparation of the target product. The following is a detailed description of its common synthesis methods:
Classic multi-step synthesis method
Starting from m-dichlorobenzene, a core mother core and side chain structure were constructed through multi-step reactions. This method uses modular design to split complex molecules into two parts: the parent nucleus (Ia) and the side chain (Ib), which are synthesized separately and docked to reduce reaction difficulty.
Condensation reaction: m-dichlorobenzene is condensed with 1H-1,2,4-triazole under alkaline conditions (such as catalyzed by potassium carbonate) to form intermediate IIa.
Hydrolysis and deacetylation: IIa is hydrolyzed with sodium hydroxide to remove the acetyl protecting group, resulting in IIIa.
Methanesulfonate esterification: IIIa reacts with methylsulfonyl chloride at low temperature (5 ℃) to form methanesulfonate Ia, which provides active sites for subsequent side chain docking.
Key control points:
The condensation reaction requires strict temperature control (130 ℃) to avoid side reactions;
Methanesulfonic acid esterification requires low-temperature operation to prevent ester bond hydrolysis, and the yield can reach 85%.
Nitration and Reduction: Using 1- (4-methoxyphenyl) piperazine hydrobromide as the raw material, it is condensed with p-chloronitrobenzene to form IIb, which is then reduced to IIIb by hydrogenation catalyzed by active nickel (yield 81.3%).
Chloroformate acylation: IIIb reacts with triphosgene to form chloroformate IVb, which then cyclizes with hydrazine hydrate to form Vb (yield 67.4%).
Alkylation and deprotection: Vb is alkylated with 2-bromobutane to generate VIb, which is then deprotected under hydrobromic acid conditions to obtain side chain Ib (yield 82%).
Key control points:
Nitro reduction requires controlling hydrogen pressure to avoid excessive reduction;
The alkylation reaction requires the addition of alkali and halogenated hydrocarbons in batches to suppress side reactions.
Under alkaline conditions (such as KOH/DMF system), Ia and Ib condense to form crude itraconazole, which is purified by toluene recrystallization to obtain a white powder produts (total yield 22.28%).
Advantages:
Modular design improves reaction controllability;
The yield of each step is stable and suitable for industrial production.
limitations:
Using toxic solvents such as chloroform and dioxane;
Some steps require expensive catalysts (such as triphosgene).
Convergent synthesis optimization method
Adopting the "aggregation strategy" to synchronously prepare the parent core and side chains, shortening the overall reaction cycle. For example:
Mother nucleus synthesis: Using 2,4-dichloroacetophenone as raw material, Ia is generated through 6 steps of reactions (condensation, hydrolysis, esterification, etc.);
Side chain synthesis: Starting from 1- (4-methoxyphenyl) piperazine, Ib is generated through 7 steps of reactions (nitration, reduction, cyclization, etc.).
Optimization point:
Improve the efficiency of nitration reaction through phase transfer catalysis (such as TEBA);
Use DMSO/DMF mixed solvents to reduce the number of solvent changes.
Under alkaline conditions (pH 12-14), Ia and Ib were condensed at 80 ℃ for 5 hours. After removing the solvent by vacuum distillation, the prodcts was extracted with chloroform and purified by recrystallization from toluene (yield 80.3%).
Key improvements:
Introducing phase transfer catalysts (TEBA) to accelerate the reaction;
Adopting a stepwise alkali addition strategy to control the reaction rate.
Alternative toxic solvents: Replace benzene with toluene and dioxane with THF;
Solvent recovery: DMF and DMSO were recovered by vacuum distillation, with a recycling rate of 85%.
Environmental benefits:
Reduce volatile organic compound (VOC) emissions;
Reduce production costs (solvent costs decrease by 30%).
Pharmacokinetics: oral absorption and tissue distribution characteristics
The pharmacokinetic characteristics of Itraconazole 500mg capsules directly affect their efficacy and safety, and understanding their absorption, distribution, metabolism, and excretion processes is of great significance for clinical medication.
Absorb:
Post meal administration: Itraconazole is a fat soluble medication that can be taken immediately after meals to promote bile secretion, increase drug solubility, and absorption rate by utilizing the fat in food. Research has shown that the bioavailability of postprandial medication can reach 55%, while fasting is only less than 30%.
Peak time: After oral administration of 200mg, the blood drug concentration reaches its peak at 4.6 ± 1.3 hours (Cmax is 0.32 ± 0.16 μ g/ml).
Dose dependence: Within the dosage range of 100-400mg, there is a linear relationship between blood drug concentration and dose; When it exceeds 400mg/day, absorption may become saturated, leading to a decrease in bioavailability.
Distribution:
Plasma protein binding rate: up to 99.8%, mainly bound to albumin, with extremely low free drug concentration, but sufficient to exert antifungal effects.
Organizational penetrability: The drug concentration in organs such as the lungs, kidneys, and liver is 2-3 times that of plasma, and the skin concentration is 4 times higher than plasma. The drug concentration in the nail cuticle can be maintained for 6-9 months, making it suitable for treating chronic infections such as onychomycosis.
Special distribution: In vaginal tissue, the drug concentration can last for 2 days after treatment with 0.2g once a day for 3 days; Treating 0.2g twice a day for 1 day can last for 3 days, providing a basis for short-term treatment of vulvovaginal candidiasis.
Metabolism:
Main metabolic enzymes: Metabolized by liver CYP3A4 enzyme to hydroxylated itraconazole, its antifungal activity is equivalent to that of the original drug. The level of antifungal drug measured by biological analysis is about three times that of the original drug analyzed by high-pressure liquid chromatography.
Metabolites: In addition to hydroxylation produts, a small amount of demethylation, oxidation, and binding metabolites are also generated, but the antifungal activity is weak.
Excrete:
Prototype drug excretion: Prototype drugs excreted through feces account for about 3-18% of the dose used, while prototype drugs excreted through kidneys account for less than 0.03%.
Metabolite excretion: About 35% of metabolites are excreted in urine within a week, while the rest are excreted through bile and feces.
Terminal half-life: 23.8 ± 4.7 hours, supports once or twice daily dosing regimen.
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