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Ticarcillin disodium salt, CAS 4697-14-7, molecular formula C15H17N2NaO6S2, is a semi synthetic penicillin antibiotic. Usually white to light yellow to light orange crystalline powder, it is a complex organic compound with multiple functional groups in its structure, such as carboxyl, thienyl, amino, etc. Easy to dissolve in water, the aqueous solution is relatively stable; The solubility in H2O can reach 50mg/mL, and the resulting clear solution has a pH value of 6.0-8.0. The property of being easily soluble in water facilitates its dissolution and absorption in the body, thereby improving the bioavailability of drugs. Water solutions are relatively stable, but acidic solutions are relatively unstable, so attention should be paid to avoiding acidic environments during storage and use. During the heating process, a decomposition reaction occurs, and the specific decomposition temperature and decomposition products depend on the heating conditions and material purity.
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Chemical Formula |
C15H14N2O6S22- |
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Exact Mass |
382.03 |
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Molecular Weight |
382.41 |
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m/z |
191.02 (100.0%), 191.52 (16.2%), 192.01 (9.0%), 191.51 (1.6%), 192.51 (1.5%), 192.02 (1.2%), 192.02 (1.2%) |
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Elemental Analysis |
C, 47.11; H, 3.69; N, 7.33; O, 25.10; S, 16.77 |
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Method 1: Chemical synthesis method
The chemical synthesis of ticarcillin disodium is a complex and intricate process involving multiple steps and chemical reactions.
Synthetic raw materials and intermediates
The synthetic raw materials of ticarcillin disodium mainly include 6-aminopenicillanic acid (6-APA), 3-thiophene malonic acid or its derivatives. Among them, 3-thiophene malonic acid is an important intermediate, and its synthesis process is also relatively complex.
Synthesis steps
1. Synthesis of 3-thiophene malonic acid
3-thiophene malonic acid is a key intermediate for the synthesis of ticarcillin disodium. The synthesis process usually includes the following steps:
(1) Addition reaction of acetylene and chloroacetyl chloride:
Firstly, acetylene and chloroacetyl chloride undergo an addition reaction under the action of a catalyst, producing (E) -1,4-dichloro-3-buten-2-one.
(2) Cronenberg reaction:
Next, (E)-1, 4-Dichloro-3-buten-2-one undergoes the Krebs reaction to generate the corresponding ketone acid.
(3) Hydrolysis and cyclization reaction:
Finally, the ketone acid undergoes hydrolysis and cyclization reaction to obtain 3-thiophene malonic acid.
2. Synthesis of ticarcillin monosodium salt
After obtaining 3-thiophene malonic acid, ticarcillin monosodium salt can be further synthesized. The specific steps are as follows:
(1) Activation of 3-thiophene malonic acid:
Firstly, 3-thiophene malonic acid is activated by esterification reaction to convert it into the corresponding ester compound for subsequent chlorination reaction.
(2) Chlorination reaction:
Activated 3-thiophene malonate reacts with chlorinating agents such as dichlorosulfoxide to generate the corresponding acyl chloride.
(3) Condensation reaction:
Next, the generated acyl chloride is subjected to condensation reaction with 6-APA. This step is usually carried out in the presence of appropriate solvents and catalysts to generate the acid salt of ticarcillin.
(4) Salt formation reaction:
Finally, the acid salt of ticarcillin is reacted with a base such as sodium hydroxide to form a salt, resulting in the formation of ticarcillin monosodium salt.
3. Synthesis of ticarcillin disodium salt
After obtaining ticarcillin monosodium salt, it can be further processed to obtain ticarillin disodium salt. The specific steps are as follows:
(1) Preparation of solution:
Firstly, dissolve ticarcillin monosodium salt in a suitable solvent, such as water or organic solvent.
(2) Adjust pH value:
Next, adjust the pH value of the solution by adding acid or base for subsequent salt formation reactions.
(3) Salting and refining:
Under appropriate temperature and stirring conditions, salt forming agents (such as sodium bicarbonate, sodium acetate, etc.) are added to the solution to convert ticarcillin monosodium salt to ticarillin disodium salt.
Then, the product is refined through steps such as filtration, washing, and drying to obtain high-purity ticarillin disodium salt.
Synthesis Example
The following is a specific example of the synthesis of ticarcillin disodium:
Raw material preparation:
Prepare appropriate amounts of 6-APA, ethyl 3-thiophene malonate, dichlorosulfoxide, sodium hydroxide and other raw materials and reagents.
Synthesis of ethyl 3-thiophene malonate:
Esterify 3-thiophene malonate with ethanol to obtain ethyl 3-thiophene malonate.
Chlorination reaction:
Ethyl 3-thiophene malonate is chlorinated with dichlorosulfoxide to obtain the corresponding acyl chloride.
Condensation reaction:
The generated acyl chloride is condensed with 6-APA in the presence of an appropriate solvent and catalyst to obtain the acid salt of ticarcillin.
Salting reaction:
The acid salt of ticarcillin is reacted with sodium hydroxide to obtain ticarcillin monosodium salt.
Preparation of solution and pH adjustment:
Dissolve ticarcillin monosodium salt in an appropriate amount of water and adjust the pH of the solution by adding acid or base.
Salting and refining:
Adding sodium bicarbonate and other salt forming agents to the solution to convert ticarcillin monosodium salt into ticarillin disodium salt. Then, the product is refined through steps such as filtration, washing, and drying.
Quality testing:
Conduct quality testing on the final obtained ticarillin disodium salt, including purity, content, pH value, and other indicators.
The chemical synthesis of ticarcillin disodium is a complex and intricate process involving multiple steps and chemical reactions. By strictly controlling reaction conditions, selecting appropriate catalysts and solvents, and purifying the product, high-purity and stable quality ticarillin disodium salt can be obtained. This synthesis method has broad application prospects and important clinical significance.
Method 2: Fermentation method
The fermentation production of ticarcillin disodium salt is a complex biochemical process that combines microbial metabolic activity with specific chemical transformation steps. The following is a detailed explanation of the production steps:
Preparation before fermentation
The starting point of fermentation production is to select suitable microbial strains. These strains typically have the ability to produce penicillin compounds and have been screened and optimized to increase the production of ticarcillin.
Before formal fermentation, it is necessary to cultivate and domesticate the bacterial strains to adapt to the environmental conditions during the fermentation process and achieve optimal growth and metabolic status.
Fermentation medium is a mixture of nutrients required for microbial growth and metabolism. For production, fermentation media typically contain carbon sources (such as glucose, sucrose, etc.), nitrogen sources (such as amino acids, urea, etc.), inorganic salts (such as phosphates, magnesium salts, etc.), and growth factors.
The preparation of culture medium requires precise control of the proportions and concentrations of various components to ensure the normal growth and metabolism of microorganisms.
Fermentation equipment is a key device in the production process, including fermentation tanks, mixers, cooling systems, ventilation systems, etc.
Before fermentation, it is necessary to thoroughly clean and disinfect the equipment to prevent bacterial contamination. At the same time, it is necessary to check the operation status of the equipment to ensure that it can work properly.
Fermentation process
(1) Vaccination and cultivation
Inoculate the cultured and domesticated strains into the fermentation medium to begin the fermentation process.
In the early stages of fermentation, it is necessary to control appropriate conditions such as temperature, pH value, and ventilation to promote the growth and metabolism of microorganisms.
(2) Accumulation of metabolites
As microorganisms grow and metabolize, ticarcillin or its precursor substances begin to accumulate in the fermentation broth.
At this point, it is necessary to closely monitor the concentration and proportion of various metabolites in the fermentation broth, as well as the growth status of microorganisms.
(3) Adjustment of fermentation conditions
According to the monitoring results, adjust the fermentation conditions in a timely manner, such as temperature, pH value, aeration rate, stirring speed, etc., to optimize the yield and quality of Tigasilin.
For example, when the production of ticarcillin begins to decrease, the ventilation rate and stirring speed can be appropriately increased to promote microbial metabolic activity.
Processing after fermentation
(1) Collection and treatment of fermentation broth
When the fermentation process reaches the predetermined time or the production of ticarcillin reaches its maximum value, stop fermentation and collect the fermentation broth.
The fermentation broth needs to be filtered, centrifuged, and other steps to remove microbial cells and solid impurities, resulting in a clear fermentation broth.
(2) Extraction and Purification
The ticarcillin or its precursor substances in the fermentation broth need to be separated and purified through appropriate extraction and purification steps.
The extraction steps usually include solvent extraction, ion exchange, membrane separation, etc. The purification steps include crystallization, recrystallization, chromatographic separation, etc.
The purpose of these steps is to remove impurities and by-products from the fermentation broth and improve the purity of ticarcillin.
(3) Salt formation and drying
After extraction and purification, ticarcillin or its precursor substances need to undergo salt formation reaction with appropriate bases to obtain the substance.
The salt formation reaction needs to be carried out under appropriate temperature and pH conditions to ensure stability and yield.
Finally, it will undergo drying treatment to remove moisture and volatile impurities, resulting in the final product.
Quality Control and Testing
(1) Purity testing
Perform purity testing on the final product to ensure that the content meets the predetermined standards.
Purity testing is usually carried out using analytical methods such as chromatography and spectroscopy.
(2) Impurity detection
Perform impurity detection on the final product to ensure that it does not contain harmful impurities and by-products.
Impurity detection is usually carried out using analytical methods such as high-performance liquid chromatography and gas chromatography.
(3) Stability testing
Conduct stability testing on the final product and evaluate its stability under different temperature and humidity conditions.
Stability testing is usually conducted using methods such as accelerated stability testing and long-term stability testing.
Advantages and Challenges
Advantages:
Fermentation production has the advantages of a wide range of raw material sources, relatively low production costs, and environmental friendliness.
Meanwhile, fermentation methods can also utilize the metabolic activities of microorganisms to carry out complex chemical transformations, generating compounds with specific structures and activities.
Challenge:
There are many challenges in the process of fermentation production, such as the selection and optimization of bacterial strains, control and optimization of fermentation conditions, and optimization of extraction and purification steps.
In addition, it is necessary to pay attention to issues such as product quality control, production efficiency improvement, and environmental protection.
In summary, the production of ticarcillin disodium salt is a complex and delicate process that requires strict control of the conditions and operational steps at each stage. Through continuous optimization and improvement, the production and quality of ticarcillin disodium can be increased, meeting market demand and promoting the development of the pharmaceutical industry.
The analytical methods of Ticarcillin Disodium Salt mainly include the following:
High Performance liquid Chromatography (HPLC)
Detection method: HPLC-DAD (Diode Array Detector) or HPLC-ELSD (Evaporative Light Scattering Detector).
Application: It is used to determine the purity, content and related substances of ticacillin disodium salt.
Features: HPLC is characterized by high separation efficiency, fast analysis speed and high sensitivity, and can accurately determine the content and purity of ticacillin disodium salt.
Mass Spectrometry
Application: It is used to confirm the molecular structure of ticacillin disodium salt and for impurity identification.
Feature: Mass spectrometry can provide molecular weight information of compounds, which is of great significance for confirming the structure of compounds and analyzing impurities.
Nuclear magnetic resonance method (NMR)
Application: It is used to further confirm the molecular structure of ticacillin disodium salt, especially its stereochemical structure.
Feature: NMR can provide information on the relative positions of atoms and the chemical environment in compounds, which is very useful for confirming the three-dimensional structure of compounds.
Spectral technology
Including: spectrophotometry, transmission turbidimetry, atomic absorption spectrometry, flame emission spectrometry, molecular fluorescence spectrometry, etc.
Application: It is used for qualitative or quantitative analysis of ticacillin disodium salt, as well as for studying its interaction with other substances.
Features: Spectral technology is characterized by its simplicity, rapidity and high sensitivity, and is suitable for a variety of analytical scenarios.
Separation technology
Including: centrifugation, supercentrifugation, chromatography technology, electrophoresis technology, etc.
Application: It is used for the purification, separation and impurity removal of ticacillin disodium salt.
Feature: The separation technology can effectively separate ticacillin disodium salt from other impurities, improving the purity and quality of the product.
Frequently Asked Questions
1. Why does USP set the ticarcillin content at "80.0%–94.0%" for the bulk salt, but "90.0%–115.0%" for the finished injection? Isn't the salt supposed to be purer?
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This is not about purity, but about calculation basis. For the bulk salt (80–94%), the content is calculated on the anhydrous basis and reflects the intrinsic drug substance specification. For the finished injection (90–115%), it is calculated as is (label claim), allowing for overfill and excipient dilution. The salt is never 100% due to sodium content, residual solvents, and water; USP 29 requires potency ≥800 µg/mg (~84% at 952 µg/mg theoretical).
2. Its major degradation product has its own UNII (0A6CP1X10G). What is this compound and why does it matter for powder handling?
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It is Ticarcilloic Acid – the penicilloic acid formed by hydrolysis of the β-lactam ring . This is the primary degradation pathway. Its existence explains why ticarcillin powder must be stored in tight containers and protected from moisture. USP limits water to ≤6.0% for this exact reason; exposure to humidity triggers ring opening, inactivating the drug.
3. The stability data shows a paradox: it loses 7% in 3 days at 23°C but 14% in 5 days. Why is the degradation rate nonlinear?
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This is autocatalytic hydrolysis. The initial breakdown products (ticarcilloic acid) acidify the microenvironment, accelerating further degradation. The "7% at 3d → 14% at 5d" jump reflects this positive feedback. At 4°C, the loss stays <7% for 21 days, then jumps to 12% at 30 days – same mechanism, simply slowed by cold. This is why "beyond-use" dates are not linear extrapolations.
4. How can ticarcillin powder be simultaneously "feeble inducer" of β-lactamases yet highly susceptible to them? Isn't that contradictory?
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Induction and hydrolysis are distinct properties. Ticarcillin is a poor inducer – it weakly stimulates bacteria to produce more β-lactamase. But once the enzyme is already present (whether constitutive or induced by other drugs), ticarcillin is excellently hydrolyzed by many class I β-lactamases. This is why adding clavulanate (a suicide inhibitor) rescues its activity, and why clavulanate itself can paradoxically antagonize ticarcillin in some Enterobacter strains by inducing more enzyme than it inhibits.
5. The CAS number 4697-14-7 points to ticarcillin disodium, yet the molecular formula is C₁₅H₁₆N₂O₆S₂ (free acid). What is the "invisible" sodium content, and why is it unpredictable?
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The free acid MW is 384.4; the disodium salt MW is 428.4. The sodium content is ~10.3% theoretically, but the USP monograph never states "C₁₅H₁₄N₂Na₂O₆S₂" as the formula. This is deliberate: commercial ticarcillin disodium is not stoichiometrically pure disodium salt – it exists as an equilibrium mixture of mono- and disodium forms depending on pH during lyophilization. The USP potency test (80–94%) accounts for this variability, making the "disodium" label a nominal description, not an exact chemical statement.
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