Shaanxi BLOOM Tech Co., Ltd. is one of the most experienced manufacturers and suppliers of tadalafil citrate powder cas 171596-29-5 in China. Welcome to wholesale bulk high quality tadalafil citrate powder cas 171596-29-5 for sale here from our factory. Good service and reasonable price are available.
Tadalafil Citrate Powder (core component tadalafil), a gray-white crystalline powder, often has two specifications: tadalafil powder and tadalafil bulk powder. It is a selective and reversible inhibitor of cyclic guanosine monophosphate (CGMP)-specific phosphodiesterase 5 (PDE5). When sexual stimulation leads to local release of nitric oxide, PDE5 is inhibited by tadalafil, which increases the level of cGMP in the penile sponge, which leads to relaxation of smooth muscle, blood flow into the penile tissue, and erection, such as asexual stimulation. The largest market of raw tadalafil powder is mainly UAS.
|
Chemical Formula |
C28H27N3O11 |
|
Exact Mass |
581 |
|
Molecular Weight |
582 |
|
m/z |
581 (100.0%), 582 (30.3%), 583 (2.7%), 583 (2.3%), 583 (1.7%), 582 (1.1%) |
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Elemental Analysis |
C, 57.83; H, 4.68; N, 7.23; O, 30.26 |
|
Morphological |
powder |
|
Color |
white to beige |
|
Melting point |
298-300 ° C |
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Boiling point |
679.1 ± 55.0 °C ( Predicted ) |
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Density |
1.51 ± 0.1 g / cm3 ( Predicted ) |
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Storage conditions |
Sealed in dry, 2 – 8 °C |
|
solubility |
soluble 20 mg / mL |
|
Acidity coefficient ( pKa ) |
16.68 ± 0.40 ( Predicted ) |
|
Flash point |
2 °C |
Optical activity [ α ] / D + 68 to + 78 °, c = 1 in chloroform-d , warning word Danger , Hazard description H225-H302 + H312 + H332-H319-H315-H335 , Hazardous Mark F, Xn , Hazard category code 11-20 / 21 / 22-36 , Safety instructions 16-36 / 37 , WGK Germany 3 , RTECS UQ4431050
We are the supplier of Tadalafil Citrate Powder.
Remark: BLOOM TECH(Since 2008), ACHIEVE CHEM-TECH is the subsidiary of us.
The steps for synthesizing tadalafil from D-tryptophan and compound of formula 1 are as follows:
Firstly
React D-tryptophan and formula 1 with an alkaline reagent (such as a sodium methane solution). This will deprotonate the carboxyl groups in D-tryptophan and generate corresponding negative ions.
Chemical equation: C11H12N2O2+NaCH3 → D tryptophan anion+CH3Na
Next
The generated negative ions of D-tryptophan are reacted with an active electrophilic reagent such as carbene or nitrite chloride. This step is called Cope elimination. In this step, one hydrogen atom in the negative ion will be replaced by an electrophilic reagent, forming an intermediate.
Chemical equation: D tryptophan anion+CH2=C=O → intermediate
Three
Continue to the next step of the reaction, reacting the intermediate with another electrophilic reagent (such as benzyl magnesium bromide) to generate the precursor of the target product.
Chemical equation: Intermediate+CH2PhMgBr → Tadalafil precursor
Finally,
A series of protective/deprotective reactions were performed on the precursor of tadalafil to generate the final tadalafil compound. These steps include the protection of hydroxyl groups (using protective groups such as trimethylsilyl), the protection of amino groups (using protective groups such as p-methoxyphenylmethyl), and the deprotection of carboxyl groups (using alkaline hydrolysis agents).
Finally, after a series of chemical reactions and protection/deprotection steps, D-tryptophan and formula 1 can be converted into tadalafil to obtain the target product.
The source of inorganic impurities in Tadalafil Citrate Powder: the "memory carrier" of the production chain
Tadalafil Citrate Powder is a selective phosphodiesterase 5 (PDE5) inhibitor, and its citrate form (Tadalafil Citrate) is a core drug component for treating erectile dysfunction (ED) and pulmonary arterial hypertension (PAH). However, the potential inorganic impurities in its powder formulation not only affect the purity of the drug, but may also become a blind spot in quality control through the "memory effect" of the production chain.
Raw material procurement: "dual branding" of natural and synthetic raw materials
Mineral pollution of natural raw materials
Some key intermediates in the synthesis of Tadalafil, such as 3,4-methylenedioxybenzoic acid methyl ester, may originate from natural plant extracts. For example, Safrole extracted from pepper plants is a precursor for synthesizing methylenedioxy structures, but natural plants often contain mineral impurities such as calcium, magnesium, and iron. Taking the pepper planting base in Nagpur, India as an example, the soil iron content is as high as 2.5% -3.8%, resulting in a residual iron ion rate of 0.05% -0.1% in the extract. These metal ions may form stable complexes in subsequent synthesis, which are difficult to remove through conventional purification steps.
Catalyst residues in synthetic raw materials
In the chemical synthesis route, the choice of catalyst directly affects the inorganic impurity spectrum. For example, palladium carbon (Pd/C) or Raney nickel (Raney Ni) are often used as hydrogenation catalysts when constructing the pyridine indole ring of Tadalafil core. Batch records from a domestic pharmaceutical company show that Pd/C catalyst (5% loading) has residual palladium content of 0.002% -0.005% after reaction, far exceeding the heavy metal limit for oral formulations in ICH guidelines (Pd ≤ 10 ppm). In addition, aluminum impurities (from the coating on the inner wall of the distillation tower) may be introduced during the solvent recovery process. The aluminum content in a batch of N, N-dimethylformamide (DMF) recovery solution reached 0.3 mg/L.
Synthesis Process: Molecular Footprints of Reaction Pathways
By products of oxidation-reduction reactions
The key steps in the synthesis of Tadalafil include the oxidation of the indole ring and the reduction of the pyridine ring. For example, in the process of converting 3,4-methylenedioxybenzoic acid methyl ester to indolone, the use of manganese dioxide (MnO ₂) as an oxidant may result in the formation of residual low valence oxides of manganese (Mn ∝ O ₄). The synthetic data of a certain laboratory scale shows that when the dosage of MnO ₂ is 1.2 times the theoretical amount, the residual manganese content in the product reaches 0.008%. In addition, in the Raney nickel catalyzed hydrogenation reaction, the wear of nickel particles may introduce nanoscale nickel impurities, and their bioavailability is 3-5 times higher than that of bulk nickel.
Salt residues from condensation reactions
Polyphosphate (PPA) is often used as a condensing agent when constructing the pyrazine indole skeleton of Tadalafil. After the reaction, PPA needs to be removed by water washing, but phosphate ions (PO ₄³ ⁻) may form insoluble phosphate precipitates with calcium and magnesium ions. Data from a pilot batch showed that without optimizing the washing conditions, the residual amount of calcium phosphate in the product reached 0.02%. In addition, when using sodium hydride (NaH) as a base, residual sodium chloride (NaCl) may be generated, and its solubility is significantly affected by temperature, making it easy to encapsulate in the product crystals during low-temperature crystallization steps.
Intermediate control: the "filtering blind spot" of purification process
Impurity Transfer in Recrystallized Solvent
The purification of Tadalafil intermediates is often achieved through recrystallization, but the choice of solvent directly affects the efficiency of inorganic impurity removal. For example, when using ethanol water mixed solvents, chloride ions (Cl ⁻) in the water may come from pipeline corrosion or incomplete regeneration of ion exchange resins. A batch record from a pharmaceutical company shows that when the chlorine content in the water source is not controlled, the residual amount of chloride ions in the recrystallized product reaches 0.05%, far exceeding the pharmacopoeia limit (Cl ⁻ ≤ 0.01%). In addition, silicon impurities (from distillation tower packing) may be introduced during the solvent recovery process, and their residual amount is positively correlated with the number of recoveries.
Packing contamination in column chromatography
Silica gel column chromatography is a commonly used method for purifying Tadalafil intermediates, but silica gel fillers may introduce metal impurities such as aluminum and iron. A study compared the impurity spectra of different brands of silicone gel and found that the aluminum content in a domestic silicone gel reached 50 ppm, resulting in a 0.001% increase in aluminum residue in the product. In addition, the mobile phase used in the chromatography process (such as dichloromethane methanol) may dissolve metal ions on the surface of silica gel, forming soluble impurities.
Preparation processing: synergistic effect of excipients and equipment
Contribution of Inorganic Impurities in Auxiliary Materials
The selection of excipients directly affects the level of inorganic impurities in Tadalafil citrate powder formulations. For example, when using microcrystalline cellulose (MCC) as a filler, the sodium hydroxide (NaOH) used in the MCC production process may retain sodium ions (NaE). The sodium content in MCC products from a certain supplier reached 0.01%, resulting in a 0.002% increase in residual sodium in the formulation. In addition, when magnesium stearate (MgSt) is used as a lubricant, the fluctuation of its magnesium content (standard range 4.0% -5.5%) may introduce magnesium impurities, and the residual magnesium content in a certain batch of formulations can reach 0.005%.
Wear and corrosion of production equipment
The material selection of preparation processing equipment is crucial for controlling inorganic impurities. For example, stainless steel reactors may release chromium and nickel ions under acidic conditions (such as citric acid dissolution). Long term monitoring data from a pharmaceutical company shows that after 5 years of use, the residual chromium content in the product of a 316L stainless steel reactor increased from 0.001% to 0.003%. In addition, the sieve used in the wet granulation process (such as a 30 mesh stainless steel sieve) may generate metal particles due to friction, and the residual amount is positively correlated with the use time of the sieve.
Final testing: methodological limitations and risk of 'false negatives'
Blind spots of traditional detection methods
In the current pharmacopoeia, the detection of inorganic impurities in Tadalafil mainly relies on atomic absorption spectroscopy (AAS) and inductively coupled plasma mass spectrometry (ICP-MS). However, these methods have low sensitivity for detecting nanoscale impurities such as nickel nanoparticles. A study shows that the detection limit of ICP-MS for nickel particles with a particle size<50 nm is 0.1 ppm, while the actual residual amount may be lower than this value. In addition, traditional methods are difficult to distinguish the chemical forms of inorganic impurities (such as free nickel and nickel complexes), leading to bias in risk assessment.
Simulating Impurity Release in Gastric Juice
Tadalafil preparations need to release active ingredients in the gastrointestinal environment, but inorganic impurities may change solubility due to pH changes. For example, calcium phosphate has a lower solubility in gastric acid (pH 1.2), but its solubility significantly increases in intestinal fluid (pH 6.8). A certain in vitro release experiment showed that formulations containing calcium phosphate impurities release 15% faster in intestinal fluid than pure products, which may be due to impurities changing the drug crystal form or surface properties.
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