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Zoledronic acid | CAS No: 118072-93-8 | GMP-certified suppliers
A medication that treats and prevents bone diseases including osteoporosis, Paget's disease, hypercalcemia of malignancy, multiple myeloma, and bone metastases from solid tumors.
Therapeutic categories
Primary indications
- Zoledronic acid is indicated to treat hypercalcemia of malignancy, multiple myeloma, bone metastases from solid tumors, osteoporosis in men and postmenopausal women, glucocorticoid induced osteoporosis, and Paget's disease of bone in men and women
- Zoledronic acid is also indicated for the prevention of osteoporosis in post menopausal women and glucocorticoid induced osteoporosis
Product Snapshot
- Zoledronic acid is formulated as an injectable solution, including lyophilized powder for reconstitution, intended for intravenous administration
- It is primarily used for the treatment of hypercalcemia of malignancy, multiple myeloma, bone metastases, various forms of osteoporosis, and Paget's disease of bone
- Zoledronic acid is approved for use in key regulatory markets including the United States, European Union, and Canada
Clinical Overview
Pharmacodynamically, zoledronic acid inhibits osteoclast-mediated bone resorption by impairing osteoclast function. It selectively binds to hydroxyapatite in bone, where acidification during osteoclastic resorption facilitates its release and uptake into osteoclasts via fluid-phase endocytosis. Inside osteoclasts, zoledronic acid disrupts the formation of podosomes—actin-rich structures necessary for bone adhesion—by inhibiting vacuolar ATPases, leading to osteoclast detachment and decreased bone resorption.
Mechanistically, zoledronic acid targets the mevalonate pathway by inhibiting farnesyl diphosphate synthase and related isoprenoid intermediates critical for the prenylation of small GTP-binding proteins such as Rap1. This inhibits the post-translational modifications essential for osteoclast viability and function, induces apoptotic pathways via caspase activation, and consequently reduces pathological bone loss.
In terms of ADME, zoledronic acid exhibits poor oral bioavailability and is administered intravenously to ensure systemic availability. It is rapidly distributed to bone and cleared primarily via renal excretion. Its prolonged skeletal retention accounts for an extended duration of action.
Safety considerations include potential risk of renal impairment, hypocalcemia, osteonecrosis of the jaw, atypical femoral fractures, electrolyte imbalances, hepatic impairment, bronchoconstriction, and embryo-fetal toxicity. Monitoring of renal function and serum calcium levels is advised during therapy.
Notable marketed formulations include approved intravenous preparations administered on infrequent dosing schedules for maintenance and treatment. Regulatory approvals date back to 2001 in the United States and globally thereafter.
From an API procurement perspective, zoledronic acid requires stringent control of purity and crystalline form due to its potent pharmacological profile. Manufacturing processes should ensure low levels of impurities, especially related phosphorus-containing byproducts, and robust analytical characterization is essential to meet regulatory standards and ensure consistent clinical safety and efficacy.
Identification & chemistry
| Generic name | Zoledronic acid |
|---|---|
| Molecule type | Small molecule |
| CAS | 118072-93-8 |
| UNII | 70HZ18PH24 |
| DrugBank ID | DB00399 |
Pharmacology
| Summary | Zoledronic acid is a nitrogen-containing bisphosphonate that inhibits osteoclast-mediated bone resorption by binding to hydroxyapatite in bone and disrupting osteoclast function. It inhibits key enzymes in the mevalonate pathway, including farnesyl diphosphate synthase, leading to impaired prenylation of GTP-binding proteins and induction of apoptosis in osteoclasts and certain tumor cells. This mechanism reduces bone turnover and supports the management of conditions characterized by excessive bone resorption. |
|---|---|
| Mechanism of action | Bisphosphonates are taken into the bone where they bind to hydroxyapatite. Bone resorption by osteoclasts causes local acidification, releasing the bisphosphonate, which is taken into the osteoclast by fluid-phase endocytosis. Endocytic vesicles become acidified, releasing bisphosphonates into the cytosol of osteoclasts where they act. Osteoclasts mediate resorption of bone. When osteoclasts bind to bone they form podosomes, ring structures of F-actin. Etidronic acid also inhibits V-ATPases in the osteoclast, though the exact subunits are unknown, preventing F-actin from forming podosomes. Disruption of the podosomes causes osteoclasts to detach from bones, preventing bone resorption. Nitrogen containing bisphosphonates such as zoledronate are known to induce apoptosis of hematopoietic tumor cells by inhibiting the components of the mevalonate pathway farnesyl diphosphate synthase, farnesyl diphosphate, and geranylgeranyl diphosphate. These components are essential for post-translational prenylation of GTP-binding proteins like Rap1. The lack of prenylation of these proteins interferes with their function, and in the case of Rap1, leads to apoptosis. zoledronate also activated caspases which further contribute to apoptosis. |
| Pharmacodynamics | Zoledronic acid is a third generation, nitrogen containing bisphosphonate that inhibits osteoclast function and prevents bone resorption. The therapeutic window is wide as patients are unlikely to suffer severe effects from overdoses and the duration of action is long. Patients should be counselled regarding the risk of electrolyte deficiencies, renal impairment, osteonecrosis of the jaw, atypical femoral fractures, bronchoconstriction, hepatic impairment, hypocalcemia, and embryo-fetal toxicity. |
Targets
| Target | Organism | Actions |
|---|---|---|
| Geranylgeranyl pyrophosphate synthase | Humans | inhibitor |
| Hydroxylapatite | Humans | antagonist, binder |
| Farnesyl pyrophosphate synthase | Humans | inhibitor |
ADME / PK
| Absorption | A 4mg intravenous dose reaches a C<sub>max</sub> of 370±78.5ng/mL, with a T<sub>max</sub> of 0.317±0.014h, and an AUC of 788±181ng\*h/mL. A 5mg intravenous dose reaches a C<sub>max</sub> of 471±76.1ng/mL, with a T<sub>max</sub> of 0.368±0.005h, and an AUC of 917±226ng\*h/mL. |
|---|---|
| Half-life | Zoledronic acid has a terminal elimination half life of 146 hours. |
| Protein binding | Zoledronic acid is 23-53% protein bound in plasma. |
| Metabolism | Zoledronic acid is not metabolized _in vivio_. |
| Route of elimination | Zoledronic acid is 39 ± 16% eliminated in the urine as the unmetabolized parent drug. |
| Clearance | Zoledronic acid has a renal clearance of 3.7 ± 2.0 L/h. |
Formulation & handling
- Zoledronic acid is formulated exclusively for intravenous or parenteral administration and is not indicated for oral use.
- This API is a small molecule bisphosphonate with high water solubility, facilitating aqueous injectable formulations.
- Handling should consider the lyophilized powder forms requiring reconstitution prior to intravenous infusion.
Regulatory status
| Lifecycle | The API is marketed in Canada, the EU, and the US, with key patent protections in North America expiring between 2013 and 2028, indicating a market transitioning from exclusivity toward increased generic competition. |
|---|
| Markets | Canada, EU, US |
|---|
Supply Chain
| Supply chain summary | Zoledronic acid is primarily manufactured and packaged by a single originator company with a strong presence in the US, EU, and Canadian markets. Several branded products are available across these regions, reflecting established market penetration. Patent expirations range up to 2028, indicating that generic competition may emerge in some markets in the coming years. |
|---|
Safety
| Toxicity | Patients experiencing an overdose may present with renal impairment, hypocalcemia, hypophosphatemia, and hypomagnesemia. Overdose should be managed through intravenous administration of the insufficient ions. |
|---|
- Handle with appropriate protective equipment to minimize exposure, as overdose toxicity may involve renal impairment and electrolyte imbalances
- Avoid environmental release
- Ensure proper containment and disposal to prevent contamination and potential systemic toxicity
Zoledronic Acid Maleate is a type of Bisphosphonates
Bisphosphonates are a vital subcategory of pharmaceutical active pharmaceutical ingredients (APIs) widely used in the treatment of various bone-related conditions. These compounds play a crucial role in inhibiting bone resorption, making them particularly effective in managing diseases such as osteoporosis, Paget's disease, and bone metastasis associated with cancer.
The mechanism of action of bisphosphonates involves their binding to hydroxyapatite crystals in bone, leading to the suppression of osteoclast activity. By inhibiting the breakdown of bone tissue, these APIs help to maintain bone density and strength, thereby reducing the risk of fractures and improving overall bone health.
One of the key advantages of bisphosphonates is their high affinity for bone tissue, which allows for targeted treatment. They are administered orally or intravenously, depending on the specific formulation and indication. Commonly prescribed bisphosphonates include alendronate, ibandronate, and zoledronic acid, among others.
Bisphosphonates are generally well-tolerated, although some potential side effects, such as gastrointestinal disturbances or musculoskeletal pain, may occur. These APIs are metabolized in the liver and excreted through the kidneys.
Due to their effectiveness and widespread clinical use, bisphosphonates have gained significant attention in the pharmaceutical industry. Continuous research and development efforts are focused on improving their therapeutic profiles, including enhancing potency and reducing side effects.
In summary, bisphosphonates are a critical subcategory of pharmaceutical APIs employed in the management of bone-related disorders. Their targeted action on bone tissue and ability to inhibit bone resorption make them indispensable in the treatment of conditions like osteoporosis and bone metastasis. Ongoing advancements in this field are expected to further optimize their therapeutic benefits in the future.
Zoledronic Acid Maleate (Bisphosphonates), classified under Metabolic Bone Disease Agents
Metabolic Bone Disease Agents are a category of pharmaceutical active pharmaceutical ingredients (APIs) that are specifically designed to treat and manage conditions related to the bones and their metabolism. These agents play a crucial role in the treatment of various metabolic bone diseases, including osteoporosis, Paget's disease, and rickets.
The primary function of Metabolic Bone Disease Agents is to regulate bone remodeling and maintain bone health. They achieve this by targeting specific pathways involved in bone metabolism, such as osteoclast and osteoblast activity, calcium regulation, and vitamin D metabolism.
These APIs are commonly used in the development of medications, including oral tablets, injectables, and topical formulations, for the effective treatment of metabolic bone diseases. They are carefully formulated to optimize their pharmacokinetic and pharmacodynamic properties, ensuring maximum efficacy and minimal side effects.
Metabolic Bone Disease Agents encompass a range of substances, including bisphosphonates, selective estrogen receptor modulators (SERMs), calcitonin, and vitamin D analogs. These APIs act through different mechanisms to address specific aspects of bone health, such as inhibiting bone resorption, promoting bone formation, or regulating calcium levels.
In conclusion, Metabolic Bone Disease Agents are a vital category of pharmaceutical APIs used in the development of medications for the treatment and management of various metabolic bone diseases. These agents target specific pathways involved in bone metabolism to regulate bone remodeling, enhance bone health, and alleviate the symptoms associated with these conditions.
Zoledronic Acid Maleate API manufacturers & distributors
Compare qualified Zoledronic Acid Maleate API suppliers worldwide. We currently have 19 companies offering Zoledronic Acid Maleate API, with manufacturing taking place in 7 different countries. Use the table below to review supplier type, countries of origin, certifications, product portfolio and GMP audit availability.
| Supplier | Type | Country | Product origin | Certifications | Portfolio |
|---|---|---|---|---|---|
| Apollo Healthcare Resourc... | Distributor | Singapore | Singapore | BSE/TSE, CEP, CoA, EDMF/ASMF, FDA, GMP, ISO9001, JDMF, KDMF, MSDS, USDMF, WC | 200 products |
| Chemi S.p.A. | Producer | Italy | Italy | CoA, JDMF | 18 products |
| Cipla | Producer | India | India | CoA, GMP, USDMF, WC | 164 products |
| Emcure Pharma | Producer | India | India | CoA, GMP, USDMF, WC | 80 products |
| Hetero Labs | Producer | India | India | CoA, GMP, USDMF, WC | 90 products |
| Ipca Labs. | Producer | India | India | CoA, JDMF | 69 products |
| Mac Chem Products | Producer | India | India | CoA, GMP, WC | 25 products |
| Maprimed | Producer | Argentina | Argentina | CoA, USDMF | 6 products |
| Mylan | Producer | India | India | CoA, GMP, USDMF, WC | 201 products |
| Natco Pharma | Producer | India | India | CoA, FDA, GMP, JDMF, USDMF, WC | 40 products |
| Nippon Kayaku | Producer | Japan | Japan | CoA, JDMF | 6 products |
| Okami Chemical Industry | Producer | Japan | Japan | CoA, JDMF | 7 products |
| Sanyo Fine | Producer | Japan | Japan | CoA, JDMF | 4 products |
| Shandong N.T. Pharma | Producer | China | China | CoA, USDMF, WC | 12 products |
| Shilpa Medicare Ltd | Producer | India | India | BSE/TSE, CoA, EDMF/ASMF, GMP, ISO9001, MSDS, USDMF, WC | 54 products |
| Sun Pharma | Producer | India | India | CoA, USDMF | 219 products |
| USV | Producer | India | India | CoA, FDA, GMP, USDMF, WC | 35 products |
| Vamsi Labs | Producer | India | India | BSE/TSE, CoA, FDA, GMP, ISO9001, MSDS, WC, WHO-GMP | 29 products |
| Yung Shin Pharmaceutical | Producer | Taiwan | Taiwan | CoA, USDMF | 7 products |
When sending a request, specify which Zoledronic Acid Maleate API quality you need: for example EP (Ph. Eur.), USP, JP, BP, or another pharmacopoeial standard, as well as the required grade (base, salt, micronised, specific purity, etc.).
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