Meglumine (DB09415): A Comprehensive Monograph on its Dichotomous Role as a Benign Excipient and a Component of Potent APIs

Executive Summary

Meglumine is a glucose-derived amino sugar with a fundamentally dichotomous identity in medicine and pharmacology. On one hand, it is globally recognized and widely employed as a benign pharmaceutical excipient, valued for its exceptional ability to enhance the aqueous solubility and stability of Active Pharmaceutical Ingredients (APIs).[1] Its physicochemical properties, stemming from a polyol backbone and a basic amino group, make it an ideal solubilizer, pH modifier, and counterion for forming stable, bioavailable salts with poorly soluble drug candidates. In this capacity, it is generally considered pharmacologically inert and possesses a very low toxicity profile.

On the other hand, meglumine serves as an integral component of potent therapeutic and diagnostic agents, where the overall formulation exhibits significant pharmacological activity and, in some cases, severe toxicity. This is most evident in its use in the antiprotozoal drug meglumine antimoniate—a first-line treatment for leishmaniasis—and in a vast array of iodinated and gadolinium-based radiological contrast media.[5] This report establishes a central thesis: the pharmacological and toxicological profile of any meglumine-containing product is dictated not by meglumine itself, but almost exclusively by the API or counterion with which it is paired. The safety of "meglumine" is therefore a meaningless concept without specifying its chemical and clinical context.

Furthermore, this monograph examines emerging preclinical evidence suggesting that meglumine, when administered at high doses, may possess intrinsic biological activity, particularly anti-inflammatory and metabolism-modulating effects.[9] This challenges its traditional classification as a purely inert substance and opens new avenues for research, including its potential repurposing as a therapeutic agent. This report provides a comprehensive analysis of meglumine's chemical properties, its dual roles in formulation and therapy, its pharmacology, safety, and regulatory status, offering a nuanced perspective for pharmaceutical scientists, clinicians, and regulatory professionals.

Section 1: Chemical Identity and Physicochemical Properties

A thorough understanding of meglumine's behavior in pharmaceutical systems begins with its fundamental chemical and physical characteristics. Its structure and properties are well-defined and consistently documented across global chemical and regulatory databases, reflecting its long-standing use in the industry.

1.1 Nomenclature and Identification Codes

Meglumine is known by several names and is cataloged under numerous international identifiers, which ensures unambiguous identification in research, manufacturing, and regulatory documentation.

• Primary Name: Meglumine.[11]
• Systematic IUPAC Name: (2R,3R,4R,5S)-6-(methylamino)hexane-1,2,3,4,5-pentol.[8]
• Synonyms and Alternate Names: The most common synonym is N-Methyl-D-glucamine. Other widely used names include 1-deoxy-1-methylaminosorbitol, N-Methylglucamine, Meglumina, Méglumine, and Megluminum.[11]
• Key Database Identifiers: Its identity is firmly established through a series of unique codes in major databases:
• CAS Number: 6284-40-8. This is the primary Chemical Abstracts Service registry number. Several deprecated CAS numbers also exist in historical records, which is important to note for comprehensive literature reviews.[15]
• DrugBank ID: DB09415.[11]
• UNII (Unique Ingredient Identifier): 6HG8UB2MUY. This code is used by the FDA for substance registration.[15]
• Other Identifiers: Further characterization is provided by codes such as ChEBI ID (CHEBI:59732), PubChem CID (8567), European Community (EC) Number (228-506-9), and National Cancer Institute (NCI) numbers (NSC-52907, NSC-7391).[12]

The extensive and consistent cross-database identification of meglumine underscores its established and non-controversial status in chemical and pharmaceutical registries. This uniformity, which is not always present for less-studied molecules, simplifies regulatory filings and material sourcing for pharmaceutical manufacturers. Its "grandfathered" status as an excipient is a direct result of this long, well-documented history of use.[9]

1.2 Molecular Structure and Chemical Formula

Meglumine is classified as a small molecule amino sugar.[11]

• Chemical Formula: .[8]
• Molecular Weight: The average molecular weight is consistently reported as 195.21 g/mol to 195.22 g/mol. The monoisotopic mass is 195.110672651 Da.[11]
• Chemical Classification: Meglumine is a hexosamine derived from D-glucitol (more commonly known as sorbitol). Structurally, the hydroxyl group at the C1 position of sorbitol is substituted by a methylamino group ().[5] This places it within the chemical class of hexoses and allows for further classification as a polyol (due to multiple hydroxyl groups), a secondary amino compound, and an aminoalcohol.[11]
• Structural Representations: For computational and database purposes, its structure is defined by the following codes:
• SMILES: .[12]
• InChI Key: .[8]

1.3 Physical and Chemical Properties

The specific physicochemical properties of meglumine are directly responsible for its utility in pharmaceutical formulations.

• Appearance: It is a white to almost white crystalline powder.[8]
• Melting Point: The melting point ranges from 129.0 °C to 132.0 °C.[14]
• Solubility: It exhibits high solubility in water, with reported values of 0.1 g/mL and 1000 g/L.[14] This property is the cornerstone of its function as a solubilizing agent.
• Acidity/Basicity (pKa): With a pKa value of approximately 9.60, meglumine is a crystalline base.[2] This basicity allows it to act as a pH modifier and to form salts with acidic APIs.
• Optical Activity: Its specific rotation, , is between -16.0° and -17.0° (c=2, H2O), confirming its distinct D-glucitol-derived stereochemistry.[14]
• Purity: For pharmaceutical applications, meglumine is available at very high purity, typically ≥99.0%.[13]

The chemical structure of meglumine is the direct origin of its primary pharmaceutical functions. The molecule's polyol backbone contains multiple polar hydroxyl (–OH) groups, which readily form hydrogen bonds with water, explaining its excellent aqueous solubility.[11] This high solubility allows it to serve as a hydrophilic carrier when paired with poorly soluble (lipophilic) APIs, thereby functioning as a solubilizing agent.[1] Concurrently, the structure contains a basic secondary amino group, which can accept a proton to form a cation. This enables the formation of an ionic bond, or salt, with an acidic API, a common and effective mechanism for enhancing both solubility and stability.[2] Thus, the combination of its polyol nature and basic amino group directly facilitates its dual function as a solubilizer and salt-forming counterion.

Property	Value	Source(s)
IUPAC Name	(2R,3R,4R,5S)-6-(methylamino)hexane-1,2,3,4,5-pentol	8
CAS Number	6284-40-8	13
DrugBank ID	DB09415	11
UNII	6HG8UB2MUY	15
Chemical Formula		11
Average Molecular Weight	195.21 - 195.22 g/mol	11
Appearance	White to almost white crystalline powder	8
Melting Point	129.0 - 132.0 °C	14
Water Solubility	High (e.g., 1000 g/L)	14
pKa (Strongest Basic)	9.11 - 9.60	2
Specific Rotation	-16.0 to -17.0 deg (c=2, H2O)	14

Section 2: The Role of Meglumine in Pharmaceutical Formulation

Meglumine's primary role in the pharmaceutical industry is that of a functional excipient. Its unique chemical properties are leveraged to overcome common challenges in drug development, particularly those related to the solubility, stability, and bioavailability of active pharmaceutical ingredients.

2.1 Mechanism as a Solubilizer and Bioavailability Enhancer

A significant portion of new drug candidates are poorly soluble in water, which severely limits their absorption in the body and, consequently, their therapeutic effectiveness. Meglumine is employed as a critical solubilizing agent to address this issue.[1] By increasing the aqueous solubility of a drug, meglumine helps to improve its dissolution rate in the gastrointestinal tract or in parenteral formulations, which is often a prerequisite for absorption and achieving therapeutic bioavailability.[1] The primary mechanism involves either forming a more soluble salt with the API or generally increasing the hydrophilicity of the formulation matrix.[2]

2.2 Function as a pH Modifier and Stabilizing Agent

With a pKa of approximately 9.6, meglumine is an effective organic base.[2] This property allows it to function as a buffering agent or alkalizer within a pharmaceutical formulation.[1] By maintaining the pH in a desired range, meglumine can prevent the degradation of pH-sensitive APIs, thereby enhancing the stability and shelf-life of the final drug product.[2] This function is not limited to pharmaceuticals; its buffering capacity is also utilized in industrial applications, such as the removal of boron from aqueous solutions.[17]

Furthermore, meglumine's utility extends beyond simple formulation to actively solving specific chemical challenges in drug stability. Research has shown that common excipients like lactose can degrade over time to generate formaldehyde, a reactive impurity that can compromise drug safety and efficacy. Meglumine has been demonstrated to be uniquely effective among certain amines at scavenging and neutralizing this formaldehyde by reacting with it to form a stable 1,3-oxazinane skeleton.[18] This represents a sophisticated, active chemical protection mechanism, positioning meglumine not just as a passive solubilizer but as a strategic stabilizing agent to mitigate degradation pathways caused by other components in the formulation.

2.3 The Counterion Concept: Forming Salts to Optimize APIs

One of the most important applications of meglumine is its use as a counterion to form salts with acidic APIs. This is a key strategy in drug development known as salt formation, which can dramatically improve an API's physicochemical properties, including solubility, stability, and manufacturability. Meglumine is particularly suitable for forming salts with acidic drugs that have a pKa of 6 or lower.[2] The resulting meglumine salt is a new chemical entity with distinct properties from the original acidic drug. Prominent examples include the veterinary non-steroidal anti-inflammatory drug (NSAID) flunixin meglumine and the transthyretin stabilizer tafamidis meglumine.[8]

2.4 Regulatory Considerations for Meglumine as an Excipient

Meglumine has a long history of safe use and is recognized as a benign excipient by major regulatory bodies, including the U.S. Food and Drug Administration (FDA).[10] It is listed in all major pharmacopeias—USP, Ph. Eur., JP, and ChP—which standardizes its quality and facilitates its use in products intended for global markets.[2]

However, the regulatory classification of meglumine is context-dependent, creating a critical distinction for manufacturing and compliance. While it is broadly considered an excipient, guidance from both the FDA and the European Medicines Agency (EMA) stipulates that when meglumine is used as a counterion to form a distinct salt of a drug, it is legally considered to be part of the API.[2] This reclassification has profound consequences. It mandates that the meglumine itself must be manufactured in an API-grade facility under the stringent International Council for Harmonisation (ICH) Q7 Good Manufacturing Practice (GMP) guidelines. This is a much higher and more costly quality standard than that required for typical excipients. This distinction is vital for any company developing a meglumine salt, as it directly impacts supplier selection, cost of goods, and the entire regulatory submission strategy. It also explains why certain manufacturers heavily promote their "API-grade" meglumine, which is produced to meet these exacting regulatory demands.[2]

Section 3: Pharmacology and Mechanisms of Action

The pharmacological profile of meglumine is multifaceted and, like its regulatory status, is entirely dependent on its context of use. In most of its applications, it is considered pharmacologically inert, serving only as a vehicle. However, in the case of meglumine antimoniate, it is paired with a highly active moiety, and emerging research suggests meglumine itself may not be entirely devoid of biological activity.

3.1 Pharmacological Profile of Meglumine-Containing Formulations

In the vast majority of its applications, such as in iodinated contrast media (e.g., diatrizoate meglumine) and NSAIDs (e.g., flunixin meglumine), the pharmacological and diagnostic effects are attributed exclusively to the active moiety (diatrizoate, flunixin).[5] In these contexts, meglumine's role is to optimize the delivery, solubility, and stability of this active component.

A fundamental dichotomy exists, however, between this perceived "inert" nature of meglumine as an excipient and its potential for direct, dose-dependent biological activity. Compelling preclinical research has begun to challenge the paradigm of meglumine as a simple, benign carrier. Studies have shown that high-dose oral meglumine can exert intrinsic anti-inflammatory and metabolic benefits, such as limiting the secretion of proinflammatory cytokines and showing potential in animal models to treat conditions like diabetes, obesity, and nonalcoholic fatty liver disease (NAFLD/NASH).[9] The proposed mechanism for these effects involves the stimulation of Sucrose Non-Fermenting AMPK-Related Kinase (SNARK) expression in muscle cells, a protein kinase involved in cellular energy sensing and glucose uptake.[10] This suggests a concentration-dependent effect: at the low molar ratios used for salt formation, any intrinsic activity is likely negligible, but when administered at high oral doses, meglumine itself may function as an API. This finding opens the possibility of repurposing meglumine as a low-cost therapy for metabolic conditions, though it also necessitates careful toxicological assessment if it is to be used in high-concentration formulations.

3.2 The Antiprotozoal Mechanism of Meglumine Antimoniate

Meglumine antimoniate is a cornerstone therapy for leishmaniasis, a parasitic disease caused by protozoa of the genus Leishmania. It is recommended by the World Health Organization (WHO) as a first-choice drug for all forms of the disease.[6] It is critical to understand that the potent antiprotozoal activity of this drug stems entirely from the antimony component; meglumine serves as the solubilizing counterion that enables its administration.[7] The mechanism of action is complex and multifactorial, targeting both the parasite directly and modulating the host's immune response.

3.2.1 Prodrug Activation and Induction of Oxidative Stress

The pentavalent antimonial () in meglumine antimoniate is widely considered to be a prodrug. Within the host's macrophages, where the Leishmania parasites reside, it is metabolized and reduced to its more toxic trivalent form ().[26] This active form exerts its primary leishmanicidal effect by inducing massive oxidative stress within the parasite. It promotes the generation of reactive oxygen species (ROS), which are highly damaging to cellular components, leading to the peroxidation of lipids, oxidation of proteins, and damage to nucleic acids, ultimately causing parasite cell death.[27]

3.2.2 Inhibition of Parasitic Metabolic Pathways

In addition to inducing oxidative damage, the active antimonial component directly interferes with the parasite's essential energy metabolism. It has been shown to inhibit key enzymes in the glycolytic pathway and fatty acid β-oxidation.[26] This disruption of bioenergetic processes leads to a severe depletion of intracellular adenosine triphosphate (ATP), starving the parasite of the energy required for survival, growth, and replication.[27]

3.2.3 Modulation of Host Immune Response and Parasitic Defenses

The mechanism of meglumine antimoniate represents a sophisticated dual-pronged attack, targeting the parasite directly while also co-opting the host's own defense mechanisms. The drug enhances the activation of host macrophages, leading to increased production of pro-inflammatory cytokines and nitric oxide (NO), both of which are potent leishmanicidal agents.[27] Simultaneously, it weakens the parasite's defenses against this onslaught. The active  disrupts the parasite's crucial thiol-redox balance by inhibiting the enzyme trypanothione reductase, which is essential for the parasite to neutralize ROS and maintain its intracellular environment.[26] This dual mechanism is highly effective but also helps to explain the drug's significant toxicity profile. The same oxidative burst and inflammatory response that kill the parasite can cause collateral damage to host cells, as evidenced by findings of DNA damage in mammalian cells following treatment.[24] This directly links the drug's therapeutic efficacy to its inherent toxicity.

Section 4: Pharmacokinetic Profile

A comprehensive pharmacokinetic profile for meglumine alone in humans is not available in the provided research. The existing data is derived exclusively from studies of flunixin meglumine, an NSAID used in veterinary species. Therefore, the following analysis must be interpreted with the strong caveat that these findings relate to the disposition of the flunixin salt in animals and cannot be directly extrapolated to meglumine alone or to human subjects.

4.1 Analysis of Available Data: A Focus on Flunixin Meglumine

The available pharmacokinetic data comes from studies conducted in dogs, horses, and cattle treated with flunixin meglumine.[30] These studies provide valuable insights into how a meglumine salt behaves in a biological system and how its disposition is affected by the route of administration.

4.2 Absorption, Distribution, and Bioavailability

The route of administration significantly influences the absorption and bioavailability of flunixin meglumine.

• Intravenous (IV) administration provides immediate and complete (100%) bioavailability by definition.[30] In dogs, after IV administration, the drug's disposition was best described by a two-compartment model, with a rapid distribution half-life of 0.55 hours.[32]
• Intramuscular (IM) and Subcutaneous (SC) administration in cattle resulted in high bioavailability (84.5% and 104.2%, respectively) but with a delayed absorption phase compared to the IV route.[30]
• Transdermal administration in horses showed much slower absorption, with the time to reach maximum plasma concentration (Tmax) occurring at a mean of 8.67 hours.[31]

4.3 Metabolism and Excretion

The elimination of flunixin from the body is also highly dependent on the administration route.

• The terminal elimination half-life () in cattle was 3.42 hours following IV administration but was prolonged after IM (4.48 hours) and SC (5.39 hours) administration.[30]
• Transdermal administration in horses resulted in a markedly long terminal half-life of 22.4 hours, indicating very slow clearance from the body following this route.[31]
• The primary metabolite of flunixin identified in the milk of dairy cattle is 5-hydroxy flunixin (5OH).[30]
• In patients with severe renal impairment, the body utilizes alternate pathways for excretion. For diatrizoate salts, including diatrizoate meglumine, the liver and small intestine become the major routes of excretion under such conditions.[33]

The pharmacokinetic data from flunixin meglumine, while indirect, strongly suggests a critical principle: meglumine's role as a counterion creates a drug entity whose disposition is highly dependent on the administration route. The consistent observation that extravascular routes like IM and SC prolong the drug's half-life points to a "depot effect," where the drug is absorbed more slowly from the tissue site compared to direct entry into the bloodstream.[30] The practical consequence, as highlighted in the veterinary context, is that unapproved IM or SC administration of flunixin meglumine leads to violative drug residues in milk because the drug is not cleared within the withdrawal time established for IV use.[30] This is a crucial lesson for drug developers: formulation and delivery route decisions for any meglumine salt will fundamentally alter its pharmacokinetics and directly impact its efficacy, safety, and regulatory compliance.

Species	Route of Administration	Key Parameter	Value	Source(s)
Cattle	IV	Elimination Half-life ()	3.42 hours	30
Cattle	IM	Elimination Half-life ()	4.48 hours	30
Cattle	IM	Bioavailability	84.5%	30
Cattle	SC	Elimination Half-life ()	5.39 hours	30
Cattle	SC	Bioavailability	104.2%	30
Horse	Transdermal	Time to Max Concentration (Tmax)	8.67 hours	31
Horse	Transdermal	Max Concentration (Cmax)	515.6 ng/mL	31
Horse	Transdermal	Elimination Half-life ()	22.4 hours	31
Dog	IV	Distribution Half-life	0.55 hours	32
Dog	IV	Elimination Half-life	3.7 hours	32

Section 5: Clinical and Investigational Applications

The applications of meglumine in medicine are exceptionally broad, spanning diagnostics, established therapeutics, and emerging investigational treatments. These uses fall into two distinct functional categories: a "delivery vehicle" for diagnostic agents and a "formulation partner" for therapeutic drugs.

5.1 Diagnostic Imaging: A Cornerstone of Contrast Media

Meglumine is a ubiquitous component of injectable contrast media, where its function is to act as the solubilizing counterion for the diagnostically active but poorly soluble radiopaque or paramagnetic molecule.[5] In this role, it is functionally a "delivery vehicle," enabling the safe intravenous administration of the agent.

5.1.1 Iodinated Contrast Agents

These agents are used to enhance the visibility of vascular structures and organs during X-ray and computed tomography (CT) procedures.

• Diatrizoate Meglumine: Often used in combination with diatrizoate sodium in products like UROGRAFIN and Hypaque for excretory urography, angiography, and other vascular procedures.[5]
• Iothalamate Meglumine: Marketed under brand names such as CONRAY and CYSTO-CONRAY, it is used for a wide range of applications including cerebral angiography, peripheral arteriography, urography, and contrast enhancement of CT images.[5]
• Iodipamide Meglumine: Specifically used for cholangiography to visualize the gallbladder and biliary ducts, with a common brand name being Cholografin Meglumine.[5]

5.1.2 Gadolinium-Based Contrast Agents (GBCAs)

These agents are used in magnetic resonance imaging (MRI) to enhance the signal from tissues, particularly for visualizing areas with a disrupted blood-brain barrier or other pathologies.

• Gadoterate Meglumine: A macrocyclic GBCA (e.g., Dotarem) indicated for MRI of the brain (intracranial), spine, and associated tissues in both adult and pediatric patients.[39]

5.2 Established Therapeutic Uses

In therapeutic applications, meglumine acts as a "formulation partner," forming a specific salt that defines the final drug product and influences its stability and pharmacokinetic properties.

• Treatment of Leishmaniasis (Meglumine Antimoniate): As an antiprotozoal, meglumine antimoniate is used to treat visceral, mucocutaneous, and cutaneous forms of leishmaniasis.[6] It came into medical use in 1946 and remains on the WHO's List of Essential Medicines, highlighting its critical role in global health despite its toxicity profile.[7]
• Veterinary Anti-inflammatory Applications (Flunixin Meglumine): Marketed as BANAMINE and other generic forms, flunixin meglumine is a potent NSAID widely used in horses and cattle. It provides analgesic, antipyretic, and anti-inflammatory effects for treating conditions such as colic, endotoxemia, bovine respiratory disease, and mastitis.[23]

5.3 Emerging and Investigational Indications

The presence of meglumine in multiple, diverse investigational drugs for complex diseases indicates its enduring value as a "go-to" formulating agent for difficult-to-develop APIs. Its combination of high solubilizing power, excellent safety profile as an excipient, and well-understood chemistry makes it a reliable choice for overcoming the common development hurdle of poor API solubility.

• Ischemic Stroke: A completed clinical trial (NCT05169450) evaluated the efficacy of Diterpene Ginkgolides Meglumine Injection for treating ischemic stroke in elderly patients.[41]
• Cognitive Dysfunction: Meglumine is a component of the multi-ingredient formulation Cytoflavin®, which was studied in a completed Phase 3 trial (NCT03849664) for its ability to prevent postoperative cognitive decline.[43]
• Intrahepatic Cholestasis: It is also a component of REMAXOL®, an infusion solution that was investigated in a completed Phase 2 trial (NCT06183242) for treating intrahepatic cholestasis.[44]

Section 6: Comprehensive Safety, Toxicology, and Risk Management

The safety profile of meglumine is critically dependent on its formulation context. While meglumine itself demonstrates very low toxicity, the products in which it is formulated can range from exceptionally safe to highly toxic. Therefore, a nuanced, product-class-specific analysis is essential to avoid dangerous overgeneralizations.

6.1 Preclinical Toxicology Profile

Studies on meglumine as a standalone substance support its classification as a benign compound.

• Acute Toxicity: Meglumine exhibits very low acute oral toxicity. The median lethal dose (LD50) in both rats and rabbits is greater than 5,000 mg/kg, indicating that massive doses are required to produce acute lethal effects.[45]
• Irritation: In its pure, undiluted powder form, it may cause skin, eye, and respiratory irritation upon direct contact.[45]
• Mutagenicity and Carcinogenicity: There is no evidence to suggest that meglumine itself is mutagenic or carcinogenic. The International Agency for Research on Cancer (IARC) does not classify it as a probable, possible, or confirmed human carcinogen.[45] However, a theoretical risk exists for the formation of carcinogenic nitrosamines if the substance comes into contact with nitrites or nitrous acid under certain conditions.[46]
• Reproductive Toxicity: Data on the reproductive toxicity of meglumine alone is not available.[45]

6.2 Clinical Safety and Adverse Drug Reactions (ADRs)

The clinical safety profile of "meglumine" is a meaningless concept without specifying the active moiety it is paired with. The observed clinical toxicity of a meglumine-containing product is a direct result of the API's pharmacology, not meglumine's. This is the single most important principle for clinicians and regulators to understand.

6.2.1 Profile of Meglumine in Gadolinium-Based Contrast Agents (GBCAs)

• General Safety: Macrocyclic GBCAs like gadoterate meglumine have an excellent safety profile. In a large observational study of nearly 35,500 patients, the overall rate of adverse events was only 0.12%, with most being mild and transient.[47] The most common adverse drug reactions (ADRs) include nausea, headache, injection site pain or coldness, and rash.[48]
• Nephrogenic Systemic Fibrosis (NSF): This is the most significant risk associated with the gadolinium class of agents. NSF is a rare but debilitating and potentially fatal fibrosing disease affecting the skin, muscles, and internal organs.[48] The risk is almost exclusively confined to patients with impaired drug elimination, particularly those with severe chronic kidney disease (glomerular filtration rate < 30 mL/min/1.73m²) or acute kidney injury.[48] Notably, no unconfounded cases of NSF have been associated with the use of the macrocyclic agent gadoterate meglumine, which is considered to be in a lower-risk category.[51]
• Acute Kidney Injury (AKI): In patients with pre-existing chronic renal impairment, GBCAs can precipitate an episode of AKI, which may require dialysis.[49]
• Hypersensitivity Reactions: Anaphylactic and anaphylactoid reactions are uncommon but can be severe and life-threatening, requiring immediate medical intervention.[49]

6.2.2 Profile of Meglumine in Iodinated Contrast Agents

• Common ADRs: These are often related to the high osmolality of the solutions and the speed of injection. They include a transient sensation of warmth or flushing, a metallic taste, nausea, and vomiting.[52]
• Hypersensitivity Reactions: Allergic-type reactions are a known risk, ranging from mild urticaria (hives) and rash to severe, life-threatening anaphylaxis.[52] Patients with a history of asthma, food allergies, or a prior reaction to a contrast agent are at a significantly higher risk.[53]
• Contrast-Induced Nephropathy (CIN): Hypertonic solutions like diatrizoate meglumine can cause osmotic diuresis and fluid shifts, leading to dehydration and an increased risk of acute kidney injury. This risk is elevated in patients who are dehydrated, elderly, diabetic, or have pre-existing renal insufficiency.[54]

6.2.3 Toxicity Profile of Meglumine Antimoniate

This drug has a significant and severe toxicity profile that necessitates careful patient monitoring.

• Cardiotoxicity: This is a major concern. The drug can cause electrocardiogram (ECG) abnormalities, including QT interval prolongation and T-wave inversion, which can progress to severe and potentially fatal cardiac arrhythmias.[6]
• Hepatotoxicity and Pancreatitis: Liver toxicity, indicated by elevated liver enzymes and jaundice, is a known risk. Acute pancreatitis, which can be severe and fatal, has also been frequently reported, particularly in HIV-co-infected patients.[6]
• Renal Toxicity: The drug is nephrotoxic and can cause acute renal failure.[6]
• Genotoxicity/Mutagenicity: The mutagenic potential of meglumine antimoniate in host cells reveals a critical trade-off in treating severe infections. Preclinical studies have definitively shown that the drug induces oxidative stress-derived DNA damage and increases the frequency of micronucleated cells (a marker of mutagenicity) in the host's mammalian cells.[24] This means the very mechanism that kills the parasite—oxidative stress—is also damaging the patient's own DNA. This represents a profound clinical dilemma, where the immediate benefit of treating a life-threatening infection must be weighed against the potential long-term risk of genotoxicity-induced secondary effects.
• Other Common ADRs: A wide range of other side effects are common, including fever, nausea, vomiting, loss of appetite, muscle pain (myalgia), joint pain (arthralgia), headache, and a decrease in white blood cells (leukopenia).[6]

6.3 Contraindications, Warnings, and Precautions

• General: A history of hypersensitivity to meglumine or any component of a specific formulation is a universal contraindication.[54]
• Contrast Media: All injectable contrast media are strictly contraindicated for intrathecal (spinal) administration, as this can lead to severe neurological events, including death and seizures.[33] They must be used with extreme caution in patients with severe renal impairment, dehydration, multiple myeloma, hyperthyroidism, or pheochromocytoma due to the risk of exacerbating these conditions or causing acute renal failure.[33]
• Meglumine Antimoniate: This drug should not be used in patients with significant pre-existing heart, liver, or kidney disease, as it can worsen these conditions.[6]

Adverse Event Class	Gadoterate Meglumine (GBCA)	Diatrizoate Meglumine (Iodinated)	Meglumine Antimoniate (Antiprotozoal)
Acute Hypersensitivity	Uncommon; can range from mild rash to severe anaphylaxis.49	Known risk, higher in patients with history of allergy/asthma. Can be severe.53	Reported, including anaphylactic shock.56
Renal Toxicity	NSF: Risk in severe renal impairment (GFR < 30) or AKI. No unconfounded cases with this agent. AKI: Can occur in patients with pre-existing renal disease.49	CIN: Risk in dehydrated, elderly, diabetic, or renally-impaired patients due to hypertonicity.54	High risk of acute renal failure. Requires monitoring.6
Cardiotoxicity	Not a primary concern.	Tachyarrhythmia reported.54	Major, life-threatening risk. Causes QT prolongation and severe arrhythmias.6
Hepatotoxicity/Pancreatitis	Not a primary concern.	Not a primary concern.	High risk. Can cause severe liver damage and fatal acute pancreatitis.6
Genotoxicity	Not a known risk.	Not a known risk.	Confirmed mutagenic potential in host mammalian cells via oxidative stress-derived DNA damage.24
Common Mild ADRs	Nausea, headache, injection site pain/coldness, rash.47	Sensation of warmth/flushing, metallic taste, nausea, vomiting.52	Fever, myalgia, arthralgia, headache, nausea, anorexia.6

Section 7: Manufacturing and Regulatory Status

The production and regulatory oversight of meglumine reflect its established role in the global pharmaceutical industry. Manufacturing processes are well-defined, and its regulatory status is harmonized across major international markets.

7.1 Chemical Synthesis and Commercial Production

The primary commercial synthesis route for meglumine is a two-step chemical process.

1. Condensation (Imination): The process begins with the condensation reaction between D-glucose and monomethylamine, typically in an alcoholic solvent. This reaction forms an intermediate known as a Schiff's base (or imine).[61]
2. Catalytic Hydrogenation: The Schiff's base intermediate is then reduced via catalytic hydrogenation. This step converts the imine group to a secondary amine and the aldehyde group of the glucose precursor to a primary alcohol, yielding the final meglumine product. Raney nickel or a more advanced skeleton nickel catalyst is commonly used for this reduction.[61] Patents describe various process optimizations, such as the use of specific aluminum-nickel-chromium-rhodium alloy catalysts to improve reaction efficiency and yield.[62]

Interestingly, in addition to being a product of chemical synthesis, meglumine itself has been investigated as a green, efficient, and reusable catalyst for certain multi-component organic synthesis reactions.[64]

7.2 Global Regulatory Landscape and Pharmacopeial Standards

Meglumine is a globally accepted pharmaceutical substance with a well-established regulatory framework.

• FDA Approval: It is an FDA-approved excipient for use in pharmaceutical formulations.[21] As previously noted, when used as a salt-forming counterion, it is regulated more stringently as part of the API under ICH Q7 guidelines.[2]
• EMA and Other Agencies: Meglumine is compliant with European Pharmacopoeia (EP) standards and is a component of numerous products approved by the EMA.[66] The EMA provides specific guidelines on the control of excipients and potential impurities (e.g., nitrosamines) that are relevant to meglumine manufacturing and formulation.[68]
• TGA (Australia): While specific TGA approval documents for meglumine as a standalone excipient were not detailed in the source material, its inclusion as a counterion in TGA-approved products, such as tafamidis meglumine (Vyndaqel), confirms its acceptance for use in Australia.[20]
• Pharmacopeial Monographs: Meglumine is a multi-compendial product. Its quality standards are defined in monographs in the world's major pharmacopeias, including the United States Pharmacopeia (USP), European Pharmacopoeia (Ph. Eur.), Japanese Pharmacopoeia (JP), and Chinese Pharmacopoeia (ChP). This harmonization ensures consistent quality and facilitates its use in pharmaceutical products intended for global distribution.[2]

7.3 Major Manufacturers and Suppliers

Meglumine is produced and supplied by numerous chemical and pharmaceutical companies worldwide, with significant manufacturing presence in China, the United States, India, and Europe.[71] A notable production site is the FDA-audited facility operated by Merck in Mollet del Vallès, Spain, which is described as the only facility in Europe solely dedicated to the manufacture of API-grade meglumine, designed to meet the stringent regulatory requirements for its use as a counterion.[2] Other suppliers include Actylis, Spectrum Chemical, and a large number of manufacturers based in Asia.[71]

Section 8: Expert Analysis and Future Perspectives

A comprehensive review of meglumine reveals a molecule of profound contrasts. Its utility is undeniable, yet its identity is fluid, shifting from a benign formulating aid to a component of highly toxic, life-saving drugs. This final analysis synthesizes the report's findings and explores future trajectories for this versatile compound.

8.1 The Dichotomy of Meglumine: Reconciling its Benign and Toxic Roles

The central conclusion of this monograph is that meglumine's safety and pharmacological profile are entirely dictated by the chemical context in which it is used. The molecule itself exhibits very low intrinsic toxicity. However, it is frequently associated with products that have severe adverse effects. This creates a dichotomy that must be carefully understood by clinicians, researchers, and regulators. Referring to "meglumine toxicity" is often a misnomer for the toxicity of the API it is formulated with, be it antimony, gadolinium, or an iodinated compound. Meglumine's primary contribution to the safety profile is by enabling the administration of these active—and sometimes toxic—agents. Therefore, risk assessment must always be performed on the final drug product as a whole, never on the excipient in isolation.

8.2 Unraveling Potential Intrinsic Biological Activity

The most intriguing recent development in meglumine research is the preclinical evidence suggesting it possesses intrinsic biological activity at high doses.[9] The findings that it can modulate inflammatory pathways and stimulate SNARK, a key regulator of cellular metabolism, are significant. This challenges the long-held assumption of its complete pharmacological inertness and raises several critical questions for future investigation. Could meglumine be repurposed as a low-cost therapeutic agent for metabolic syndrome or type 2 diabetes? What is the therapeutic window for these effects, and what are the potential toxicities associated with the high doses required to elicit them? Furthermore, does this potential for biological activity have any bearing on its use as an excipient, particularly in high-concentration parenteral formulations where local tissue concentrations could be substantial? These questions merit further study to fully understand the molecule's capabilities and limitations.

8.3 Future Research and Development Trajectories

Based on the analysis presented, several future research directions can be proposed:

• Formulation Science: Head-to-head studies comparing the solubilizing efficacy and stability enhancement of meglumine against newer, more complex excipients for challenging new chemical entities would be valuable. Further investigation into its formaldehyde-scavenging properties could lead to its strategic use in designing more stable and safer drug products.
• Clinical Pharmacology: The promising preclinical data on meglumine's metabolic effects warrants follow-up. Well-designed clinical trials are needed to explore the therapeutic potential of high-dose oral meglumine for conditions like metabolic syndrome, prediabetes, or NAFLD.
• Infectious Disease Therapeutics: The severe toxicity of meglumine antimoniate, particularly its demonstrated genotoxic risk to the host, underscores the urgent and ongoing need for the development of safer, more targeted, and equally effective alternative treatments for all forms of leishmaniasis.

In conclusion, meglumine is a foundational molecule in pharmaceutical science whose apparent simplicity belies a complex and context-dependent identity. While its role as a reliable excipient is secure, future research may yet unlock new therapeutic applications, further expanding the utility of this versatile amino sugar.

Section 9: Appendices

Appendix A: Compendium of Pharmaceutical Products Containing Meglumine

The following table provides a non-exhaustive list of pharmaceutical and diagnostic products that contain meglumine, illustrating the breadth of its applications.

Product/Brand Name(s)	Other Active Ingredient(s)	Product Class	Primary Application	Source(s)
Meglumine Antimoniate	Pentavalent Antimony	Antiprotozoal API	Treatment of leishmaniasis	6
Flunixin Meglumine (e.g., BANAMINE)	Flunixin	Veterinary NSAID	Anti-inflammatory, analgesic, antipyretic in livestock	30
Tafamidis Meglumine (Vyndaqel)	Tafamidis	Transthyretin Stabilizer	Treatment of transthyretin amyloid cardiomyopathy	19
Gadoterate Meglumine (e.g., Dotarem)	Gadoteric acid	Gadolinium-Based Contrast Agent (GBCA)	MRI contrast agent for CNS imaging	34
Diatrizoate Meglumine (e.g., Hypaque, UROGRAFIN)	Diatrizoate Sodium	Iodinated Contrast Agent	X-ray/CT contrast for urography and angiography	11
Iothalamate Meglumine (e.g., CONRAY, CYSTO-CONRAY)	Iothalamic acid	Iodinated Contrast Agent	X-ray/CT contrast for angiography, urography, etc.	35
Iodipamide Meglumine (Cholografin Meglumine)	Iodipamide	Iodinated Contrast Agent	X-ray contrast for cholangiography (gallbladder imaging)	38
Diterpene Ginkgolides Meglumine Injection	Diterpene Ginkgolides	Investigational	Treatment of ischemic stroke	41
Cytoflavin®	Succinic acid, Inosine, Nicotinamide, Riboflavin	Investigational	Prevention of postoperative cognitive decline	43
REMAXOL®	Succinic acid, Inosine, Nicotinamide, Methionine	Investigational	Treatment of intrahepatic cholestasis	44

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