Ropinirole D3 Hydrochloride

Synthetic Routes and Reaction Conditions

The synthesis of Ropinirole D3 Hydrochloride involves the incorporation of deuterium atoms into the Ropinirole molecule This can be achieved through various methods, including the use of deuterated reagents or solvents during the synthesis processThe final step involves the formation of the hydrochloride salt .

Industrial Production Methods

Industrial production of this compound follows similar steps to the laboratory synthesis but on a larger scale. The process involves the use of high-purity deuterated reagents and solvents to ensure the incorporation of deuterium atoms. The reaction conditions are optimized to maximize yield and purity, and the final product is subjected to rigorous quality control measures to ensure its suitability for pharmaceutical use .

Types of Reactions

Ropinirole D3 Hydrochloride undergoes various chemical reactions, including:

Oxidation: The compound can be oxidized to form various metabolites.

Reduction: Reduction reactions can occur, particularly in the presence of reducing agents.

Substitution: The compound can undergo substitution reactions, particularly at the dipropylaminoethyl side chain.

Common Reagents and Conditions

Oxidation: Common oxidizing agents include hydrogen peroxide and potassium permanganate.

Reduction: Reducing agents such as sodium borohydride and lithium aluminum hydride are commonly used.

Substitution: Substitution reactions often involve the use of halogenating agents or nucleophiles.

Major Products Formed

The major products formed from these reactions include various metabolites and derivatives of this compound, which can have different pharmacological properties .

Ropinirole hydrochloride is a non-ergoline dopamine agonist primarily used to manage Parkinson's disease and Restless Legs Syndrome (RLS) . It can be used as early therapy without concomitant levodopa and as an adjunct to levodopa . While the precise mechanism of action for Parkinson's disease is not fully understood, ropinirole is thought to selectively stimulate dopamine D2 receptors in the caudate-putamen system, a region of the brain affecting body movement . Similarly, its action in RLS is believed to be related to its dopamine receptor stimulation . Ropinirole has a high affinity for D3 receptors, which are concentrated in the limbic areas of the brain and may be responsible for some of the neuropsychiatric effects .

Clinical Applications and Efficacy

Parkinson's Disease: Ropinirole is effective in treating Parkinson's disease, which is characterized by a marked dopamine deficiency in the nigrostriatal system . Ropinirole alleviates this deficiency by stimulating striatal dopamine receptors . Clinical studies have demonstrated the effectiveness of ropinirole in improving locomotor activity and reducing disability in animal models of Parkinson's disease .

Restless Legs Syndrome: Ropinirole is also used to treat Restless Legs Syndrome . RLS is a difficult to define condition that is possibly more prevalent than previously thought .

Amyotrophic Lateral Sclerosis: Ropinirole hydrochloride is being explored as a potential remedy for amyotrophic lateral sclerosis (ALS) . A clinical trial (ROPALS) is underway to assess the safety, tolerability, and efficacy of ropinirole hydrochloride extended-release tablets in patients with ALS . An in vitro model showed that ropinirole hydrochloride had significantly superior anti-ALS therapeutic activity compared with riluzole and edaravone, which are already-approved drugs for ALS .

Dosage and Administration

For Parkinson's disease, ropinirole tablets can be used as early therapy without levodopa or as an adjunct to levodopa . Oral clearance of Ropinirole Tablets is reduced in patients older than 65 years of age, however, the dosing of ropinirole for elderly patients can be titrated in the normal manner .

Ropinirole is available in both immediate-release and prolonged-release formulations . Immediate-release tablets are typically taken three times daily due to ropinirole's short elimination half-life of approximately 6 hours . A low starting dose of 0.75 mg/day is recommended, with a slow initial titration regimen of 0.75 mg weekly over the first four weeks . Prolonged-release tablets allow for once-daily administration, with a higher starting dose of 2 mg/day and a larger up-titration increment of 2 mg weekly .

Adverse Effects

Ropinirole D3 Hydrochloride exerts its effects by stimulating dopamine D2 and D3 receptors in the brain. This leads to an increase in dopamine levels, which helps to regulate motor control and reduce symptoms of Parkinson’s disease and Restless Legs Syndrome. The deuterium atoms in this compound can enhance the stability and bioavailability of the compound, potentially leading to improved therapeutic outcomes .

Pharmacokinetics

• Half-life : 4–6 hours, necessitating multiple daily doses for sustained therapeutic effect .
• Metabolism : Primarily hepatic, via CYP1A2, forming inactive metabolites (oral bioavailability ~50%) .
• Dosage Forms : Available in immediate-release (0.25–5 mg) and extended-release tablets, as well as experimental formulations like buccal and mouth-dissolving films to improve compliance and onset time .

Clinical Applications Approved for PD (monotherapy or adjunct to levodopa) and restless legs syndrome (RLS). Clinical trials demonstrate efficacy in reducing motor symptoms, with a safety profile favoring non-ergot agents due to lower fibrosis risks compared to ergot derivatives like cabergoline .

Receptor Selectivity and Pharmacodynamics

Ropinirole’s D3-preferring profile distinguishes it from other dopamine agonists:

Pharmacokinetic and Formulation Advancements

Key Insight : Ropinirole’s shorter half-life necessitates more frequent dosing than pramipexole, but its extended-release and mucoadhesive formulations address this limitation .

Clinical Efficacy

• Parkinson’s Disease: In trials, ropinirole improved Unified Parkinson’s Disease Rating Scale (UPDRS) scores by ~30% as monotherapy and ~20% as adjunct therapy, comparable to levodopa in early-stage PD .
• Restless Legs Syndrome : Reduces symptom severity by >50% in 70% of patients, with fewer augmentation risks than older agents .

Ropinirole D3 Hydrochloride is a potent non-ergoline dopamine agonist primarily used in the treatment of Parkinson's disease (PD) and restless legs syndrome (RLS). This article delves into its biological activity, mechanisms of action, pharmacokinetics, and relevant clinical findings.

Ropinirole acts predominantly on dopamine D2 and D3 receptors, with a higher affinity for D3 receptors. This selectivity allows it to effectively stimulate postsynaptic dopamine receptors, compensating for the dopamine deficiency characteristic of PD. The mechanism involves the inhibition of adenylyl cyclase and calcium channels while activating potassium channels, leading to enhanced dopaminergic neurotransmission in the striatum and other brain regions involved in motor control .

Pharmacokinetics

• Absorption : Ropinirole is rapidly absorbed after oral administration, reaching peak plasma concentrations within 1 to 2 hours. Its absolute bioavailability ranges from 45% to 55%, indicating significant first-pass metabolism.
• Distribution : The drug exhibits a wide distribution with an apparent volume of distribution of approximately 7.5 L/kg. About 40% of Ropinirole is bound to plasma proteins .
• Metabolism : It is primarily metabolized in the liver via cytochrome P450 enzymes, particularly CYP1A2, producing several metabolites that are also pharmacologically active.
• Elimination : The elimination half-life is approximately 6 hours, allowing for once-daily dosing in many cases .

Parkinson's Disease

In clinical trials assessing Ropinirole's efficacy in PD, significant improvements were noted:

• Unified Parkinson's Disease Rating Scale (UPDRS) : A study showed that after 12 weeks of treatment with an average daily dosage of 7.4 mg, 71% of patients exhibited a clinical response (≥30% improvement in UPDRS motor score) compared to 41% in the placebo group .
• Motor Symptoms : Ropinirole effectively reduced motor symptoms such as tremor and rigidity. In another trial with a mean daily dosage of 15.7 mg, UPDRS scores improved by 22% with Ropinirole versus a decline of 4% with placebo .

Restless Legs Syndrome

Ropinirole has also demonstrated efficacy in treating RLS:

• IRLS Scale : In trials measuring the International Restless Legs Syndrome Study Group rating scale (IRLS), patients receiving Ropinirole showed greater improvements than those on placebo after 12 weeks .
• Quality of Life : Improvements were noted in sleep quality and overall quality-of-life scores among Ropinirole-treated patients compared to controls .

Behavioral Studies

Recent research has highlighted the effects of Ropinirole on cognitive functions such as inhibition:

• A study indicated that acute doses of Ropinirole significantly reduce proactive inhibition without affecting reactive inhibition in healthy participants. This suggests potential implications for impulsivity and decision-making processes influenced by dopaminergic activity .

ROPALS Trial

The ROPALS trial investigated the safety and efficacy of Ropinirole hydrochloride in patients with amyotrophic lateral sclerosis (ALS). Preliminary results indicated that Ropinirole may offer therapeutic benefits beyond its traditional uses, suggesting a broader application for this compound .

Summary Table of Key Findings

Basic Research Questions

Q. What validated analytical methods are recommended for quantifying Ropinirole Hydrochloride in pharmaceutical formulations?

A stability-indicating RP-HPLC method is widely used for quantification. Key parameters include:

• Column : C18 (250 mm × 4.6 mm, 5 µm)
• Mobile phase : Acetonitrile and phosphate buffer (pH 3.0, 30:70 v/v)
• Flow rate : 1.0 mL/min
• Detection : UV at 250 nm Validation metrics include precision (RSD <2%), recovery (98–102%), and linearity (2–10 µg/mL, R² >0.999). This method resolves degradation products (e.g., oxidative byproducts), ensuring specificity .

Q. What is the receptor selectivity profile of Ropinirole Hydrochloride, and how is it determined?

Ropinirole exhibits preferential agonism for D3 > D2 > D4 receptors. Selectivity is quantified via:

• Radioligand binding assays : Ki values (e.g., 29 nM for D2, lower Ki for D3 indicating higher affinity) .
• Functional assays : pEC50 values (e.g., 8.4 for hD3 vs. 7.4 for hD2) using cAMP inhibition in transfected cell lines . No affinity is observed for D1 or 5-HT2 receptors, confirmed via competitive binding studies .

Q. What pharmacokinetic parameters are critical in preclinical studies of Ropinirole Hydrochloride?

Key parameters include:

• Oral bioavailability : ~55% in humans, influenced by first-pass metabolism .
• Half-life : 6 hours, necessitating sustained-release formulations for prolonged efficacy .
• Metabolism : Primarily hepatic via CYP1A2 (70%) and CYP3A4 (10%), requiring drug-drug interaction studies .
• Clearance : 780 mL/min, with renal excretion accounting for <10% of elimination .

Advanced Research Questions

Q. How can researchers design experiments to evaluate Ropinirole’s neuroprotective effects in ALS models?

Methodology :

• iPSC-derived motor neurons : Generate patient-specific motor neurons to model ALS pathology (e.g., TDP-43 aggregation, oxidative stress) .
• Outcome metrics : Neurite length, apoptosis (caspase-3 activation), mitochondrial membrane potential (JC-1 staining), and protein aggregation (immunofluorescence) .
• Dosing : Preclinical studies use 0.05–1.0 mg/kg (subcutaneous) or 1–8 mg/day (oral) in rodent/primate models . Validation : Compare results to positive controls (e.g., riluzole) and assess biomarkers (e.g., plasma TDP-43 levels) .

Q. What methodologies address contradictions in Ropinirole’s receptor activation data across studies?

Discrepancies in receptor efficacy (e.g., D3 vs. D2 activation) may arise from:

• Assay differences : Binding assays (Ki) vs. functional assays (pEC50) .
• Cell type variability : Receptor density in transfected HEK293 cells vs. neuronal models . Resolution strategies :
• Use orthogonal assays (e.g., GTPγS binding for functional activity).
• Normalize data to receptor expression levels (qPCR/Western blot) .

Q. How can dissolution testing for extended-release formulations of Ropinirole Hydrochloride be optimized?

USP-based protocol :

• Apparatus : Paddle (50 rpm) at 37°C in 900 mL pH 6.8 phosphate buffer.
• Sinker use : Improves tablet immersion, reducing RSD from >15% to <5% .
• Sampling intervals : 1, 4, 8, and 24 hours to assess release kinetics. Data analysis : Fit to Higuchi or Korsmeyer-Peppas models to determine release mechanisms (e.g., diffusion vs. erosion) .

Q. What strategies improve buccal film formulations for Ropinirole delivery?

Formulation optimization :

• Polymer selection : HPMC (swelling index >80%) or Carbopol (bioadhesion force >10 N/cm²) .
• Plasticizers : Propylene glycol (10% w/w) enhances flexibility (folding endurance >200 cycles) .
• Evaluation : Measure surface pH (6.5–7.5), drug content uniformity (RSD <5%), and in vitro release (85% over 8 hours using Franz diffusion cells) .

Q. Data Contradiction Analysis

Q. How do researchers reconcile conflicting reports on Ropinirole’s efficacy in Parkinson’s vs. ALS models?

• Mechanistic divergence : In Parkinson’s, efficacy is dopamine-replacement-driven; in ALS, neuroprotection via mitochondrial stabilization and anti-apoptotic effects dominate .
• Dose dependency : ALS models require higher doses (1–8 mg/kg) to mitigate oxidative stress vs. Parkinson’s (0.25–4 mg/day) .
• Biomarker validation : Cross-validate findings using CSF α-synuclein (Parkinson’s) and plasma TDP-43 (ALS) .