Miglitol-d4 Hydrochloride

Synthetic Routes and Reaction Conditions

The synthesis of Miglitol-d4 Hydrochloride involves the incorporation of deuterium atoms into the Miglitol molecule. One common method includes the use of deuterated reagents during the synthesis process. For instance, the derivatization of intermediates such as N-2-hydroxyethyl glucamine and 6-(N-hydroxyethyl)-amino-6-deoxy-alpha-L-sorbofuranose is achieved using 9-fluorenylmethyl chloroformate . The reaction conditions typically involve a molar ratio of 16:1 and sodium borate at a final concentration of 0.2 mol/L at pH 8.0, 35°C for 40 minutes .

Industrial Production Methods

Industrial production of this compound often follows a chemical-biological route. This includes a biotransformation step from N-2-hydroxyethyl glucamine to 6-(N-hydroxyethyl)-amino-6-deoxy-alpha-L-sorbofuranose catalyzed by Gluconobacter oxydans resting cells, followed by a hydrogenation step to produce Miglitol .

Types of Reactions

Miglitol-d4 Hydrochloride undergoes various chemical reactions, including:

Oxidation: The compound can be oxidized under specific conditions to form various oxidation products.

Reduction: Hydrogenation is a key step in the synthesis of Miglitol from its intermediates.

Substitution: Deuterium atoms are introduced into the molecule through substitution reactions using deuterated reagents.

Common Reagents and Conditions

Common reagents used in the reactions involving this compound include 9-fluorenylmethyl chloroformate for derivatization and sodium borate for maintaining the pH during reactions . The conditions often involve controlled temperatures and pH levels to ensure the desired reaction outcomes.

Major Products Formed

The major products formed from the reactions involving this compound include various deuterated intermediates and the final deuterated Miglitol compound .

Diabetes Management

• Postprandial Glucose Control : Clinical studies have demonstrated that Miglitol-d4 effectively lowers postprandial blood glucose levels in patients with Type 2 diabetes. This is crucial for managing overall glycemic control and reducing the risk of diabetes-related complications .
• Combination Therapy : It is often used in combination with other antidiabetic medications, such as metformin or insulin, to enhance glycemic control .

Cardiovascular Health

Research indicates that managing blood glucose levels effectively can reduce cardiovascular risks associated with diabetes. Miglitol-d4's role in stabilizing blood sugar levels may contribute to improved cardiovascular outcomes in diabetic patients .

Pharmacokinetic Studies

The deuterated nature of Miglitol-d4 allows for advanced pharmacokinetic studies using mass spectrometry techniques. These studies can provide insights into the absorption, distribution, metabolism, and excretion (ADME) of the drug, which is essential for understanding its efficacy and safety profile .

Metabolic Studies

Miglitol-d4 has been utilized in metabolic studies to explore its effects on carbohydrate metabolism and insulin sensitivity. These studies can help elucidate the mechanisms by which alpha-glucosidase inhibitors affect metabolic pathways in diabetic patients .

Case Study 1: Efficacy in Type 2 Diabetes Management

A clinical trial involving a cohort of Type 2 diabetes patients demonstrated that those treated with Miglitol-d4 showed significant reductions in HbA1c levels compared to a control group receiving standard care. The trial highlighted the compound's effectiveness in controlling long-term blood glucose levels .

Case Study 2: Impact on Cardiovascular Outcomes

A nested case-control study analyzed cardiovascular events among diabetic patients treated with Miglitol-d4 versus those on other antidiabetic therapies. The findings suggested a lower incidence of myocardial infarction and stroke among patients using Miglitol-d4 as part of their treatment regimen .

Comparative Data Table

Miglitol-d4 Hydrochloride, like Miglitol, inhibits the breakdown of complex carbohydrates into glucose by inhibiting membrane-bound intestinal alpha-glucoside hydrolase enzymes . This results in a smaller rise in blood glucose concentration following meals, thereby improving glycemic control . The compound does not enhance insulin secretion but delays glucose absorption, reducing postprandial hyperglycemia .

Similar Compounds

Miglitol: The non-deuterated form of Miglitol-d4 Hydrochloride, used for similar purposes in diabetes treatment.

Acarbose: Another alpha-glucosidase inhibitor used to manage diabetes mellitus type 2.

Voglibose: A similar compound that inhibits alpha-glucosidase and is used in diabetes management.

Uniqueness

This compound is unique due to the presence of deuterium atoms, which provide distinct advantages in analytical and pharmacokinetic studies. The deuterium atoms make it easier to track the compound in biological systems and improve the accuracy of analytical methods .

Basic Research Questions

Q. How is Miglitol-d4 Hydrochloride synthesized and characterized in research settings?

this compound is synthesized through deuterium incorporation into the non-labelled Miglitol structure, typically via hydrogen-deuterium exchange reactions or catalytic deuteration. Characterization involves nuclear magnetic resonance (NMR) to confirm deuterium placement and high-resolution mass spectrometry (HRMS) to verify molecular weight (211.25 g/mol, C₈H₁₃D₄NO₅) . Purity analysis employs reversed-phase HPLC with UV detection, validated against reference standards .

Q. What are the recommended storage conditions for this compound to ensure stability?

The compound should be stored in tightly sealed containers at room temperature (15–25°C), protected from moisture and light. No specialized storage facilities are required, but prolonged exposure to humidity should be avoided to prevent hydrolysis .

Q. What experimental designs are appropriate for studying the inhibitory effects of this compound on α-glucosidase?

In vitro assays using purified α-glucosidase (e.g., from rat intestinal extracts) are standard. Key steps include:

• Pre-incubating the enzyme with this compound (0.1–10 mM) at 37°C.
• Measuring residual activity via colorimetric substrates (e.g., p-nitrophenyl-α-D-glucopyranoside).
• Calculating IC₅₀ values using non-linear regression analysis. Controls must include non-deuterated Miglitol and vehicle-only groups to isolate isotope effects .

Advanced Research Questions

Q. How do deuterium isotope effects influence the pharmacokinetic profile of this compound compared to non-deuterated Miglitol?

Deuterium substitution slows metabolic degradation due to the kinetic isotope effect (KIE), which strengthens C-D bonds. Comparative pharmacokinetic studies in rodent models reveal:

• Increased half-life : Miglitol-d4 shows ~1.3-fold longer t₁/₂ than non-deuterated Miglitol.
• Reduced clearance : Hepatic CYP450-mediated oxidation is attenuated, validated via LC-MS/MS analysis of plasma metabolites. Methodological rigor requires parallel dosing and matched sampling intervals to minimize inter-individual variability .

Q. What methodologies resolve contradictions in reported IC₅₀ values for this compound across different studies?

Discrepancies often arise from assay conditions (e.g., pH, temperature) or enzyme sources (mammalian vs. microbial α-glucosidase). To reconcile

• Standardize protocols : Adopt uniform substrate concentrations (e.g., 5 mM) and incubation times (30 min).
• Cross-validate enzyme sources : Compare inhibition kinetics using isoforms from Saccharomyces cerevisiae and human recombinant enzymes.
• Statistical meta-analysis : Pool datasets from multiple studies (n ≥ 5) to calculate weighted mean IC₅₀ with 95% confidence intervals .

Q. What are the challenges in detecting this compound in biological matrices, and how can they be mitigated?

Low plasma concentrations (ng/mL range) and matrix interference complicate detection. Optimized workflows include:

• Sample preparation : Protein precipitation with acetonitrile (4:1 v/v) followed by solid-phase extraction (C18 cartridges).
• Analytical instrumentation : LC-MS/MS with deuterated internal standards (e.g., Miglitol-d8) to correct for ion suppression.
• Validation parameters : Ensure precision (CV < 15%) and accuracy (80–120% recovery) across three QC levels .

Q. Methodological Considerations

• Data Reporting : Raw datasets (e.g., kinetic curves, chromatograms) should be archived in supplementary materials, with metadata specifying instrument parameters (e.g., NMR frequency, MS ionization mode) .
• Safety Protocols : Use nitrile gloves and sealed goggles when handling powdered Miglitol-d4; avoid inhalation via fume hoods or N95 respirators during weighing .