INTRODUCTION:

Safinamide Mesylate is a third-generation reversible MAO-B inhibitor, is a recently developed medicine to treat Parkinson's disease (PD). Parkinson's disease (PD) is the second most common chronic progressive neurological condition among the elderly, after Alzheimer’s disease. Parkinson's disease is a progressive neurodegenerative disorder affecting about 1 person every 1000 in the fifth decade and 19 every 1000 above 80 years to every person¹. (S)-2-[[4-[(3-fluorophenyl) methoxy] phenyl] methyl] aminopropanamide methanesulfonate, Safinamide is a novel chemical licensed by the European Economic Area (EEA), EMA, and FDA as an add-on therapy to stable dose L-DOPA, alone or in combination with other PD therapies in mid-to late-stage-fluctuating PD patients². Safinamide has been described as a multimodal medication, combining dopaminergic and nondopaminergic activities, although it remains unclear how the nondopaminergic properties contribute to its overall effect³. Safinamide is a water-soluble enantiomeric a-aminoamide derivative that acts on both dopaminergic and non-dopaminergic systems. It was created as anti-epileptic drug^4-6.

Newron developed Safinamide (Xadago) Mesylate (SAF), an oral derivative of aminoamides with many mechanisms of action, including inhibition of MAO-B and Dopamine reuptake, for the treatment of epilepsy and Parkinson's disease^7,8,9. MAO-B inhibitors, such as selegiline and rasa giline, are less usually associated with such safety risks, which is one of the reasons for their widespread usage in the treatment of Parkinson's disease¹⁰. The drug was approved in February 2015 and in the US on March 21, 2017. Safinamide Mesylate is an alpha- aminoamide (chemical formula C17H19FN2O2 CH4O3S) with multiple mechanisms of action. Safinamide Mesylate (SAF)(S1), also known as (S)-2-(4-((3-Fluorobenzyl) oxy) benzyl) amino) propanamide methane sulfonate, which also blocks sodium voltage-sensitive channels and modulates stimulated release of glutamate¹¹. Safinamide is an orally available derivative of the chemical class of α -aminoamides, has numerous modes of action and experimental indications of symptomatic and neuroprotective potential¹². Safinamide Mesylate, chemically named (S)-2-[[4-[(3-fluorophenyl) methoxy] phenyl] methyl] ami-nopropanamide methane sulfonate, is a novel drug that acts on dopaminergic and non- dopaminergic receptors¹³. Safinamide's potency, broad spectrum of activity, and safety profile prompted researchers to study its use in the treatment of epilepsy and Parkinson's disease. Safinamide inhibits MAO-B and DA reuptake¹⁴, leading to relief of Parkinson's symptoms. Safinamide at dosages of 50-200 mg/day is safe and well tolerated, with minimal occurrences of adverse events compared to placebo. However, the concomitant consumption of Safinamide has been associated with: (i) increased risk of fractures and Falls occur when: used with anxiolytics and antihypertensive drugs; (ii) increased risk of psychoses with amantadine use; and (iii) Increased risk of neuropsychiatric AEs in patients taking DAAs¹⁵. Furthermore, it shares a comparable efficacy with entacapone in decreasing motor fluctuations, but with greater tolerability, including reduced nausea, vomiting, shortness of breath, urine abnormalities, other symptoms include dizziness¹⁶.

Thus, although safinamide differs from the existing MAO-B inhibitors rasagiline and selegiline because of its reversible mode of MAO-B inhibition, the therapeutic implications of this distinction is still unclear¹⁷. Furthermore, safinamide blocks voltage-dependent sodium channels, modifies calcium channels, and inhibits glutamate release caused by aberrant neuronal activity, all of which may increase cognition and neuroprotective characteristics¹⁸. Various analytical methods, such as HPLC^19-21, HPTLC, UV-S pectrophotometric, spectrofluorimetric method and potentiometric and voltammetric methods can detect SAF alone or in combination with other drug. In fact, studies have suggested this safinamide exhibits potent, highly selective, and reversible MAO-inhibition (with full inhibition in human platelets at 0.6 mg/kg orally)²².

Mechanism of Action:

The mechanism of the drug action operates through the inhibition of monoamino oxidase-B, an enzyme responsible for the breakdown of dopamine. As a result, an increase of the dopamine level in the brain for subsequent dopaminergic activity in PD patients is observed. Moreover, safinamide shows nondopaminergic actions such as sodium channel blocking and inhibition of glutamate release. Additionally, safinamide is chemically and metabolically stable, is well tolerated in patients, and has not exhibited serious adverse effects even upon treatment at higher dosage ranges²³.

Physical and Chemical property:

The IUPAC name for Safinamide Mesylate is (S)-2-[[4-[(3-fluorophenyl) methoxy] phenyl] methyl] ami-nopropanamide methane sulfonate. The chemical formula for Safinamide Mesylate is C17H19FN2O2. CH4SO3. The molecular weight is 398.5 g/mol. Safinamide Mesylate is freely soluble in water, methanol and dimethyl sulfoxide and sparingly soluble in ethanol. The active pharmaceutical ingredient (API) of Xadago is Safinamide Mesylate (SM) salt (molecular structure shown schematically in Figure 1)²⁴.

Fig. 1: Chemical structure of Safinamide Mesylate

Pharmacokinetics of Safinamide:

Orally administered safinamide has favorable pharmacokinetic qualities that are proportionate to the dosage²⁵. Food has little effect on absorption, which is complete and consistent. The absolute bioavailability is excellent, at 95 percent. The pharmacokinetics are dose-proportional across the therapeutic dosage range, with minimal inter subject variability. In a study on the pharmacokinetics of safinamide, a single dose of 400 mg [14C] safinamide methanesulfonate was supplied to healthy volunteers. The maximal concentration was attained at 1 hour for the parent drug, 7 hours for plasma, and 1.5 hours for whole-blood [14C] radioactivity²⁶. Its extravascular distribution is broad, indicating a high lipophilicity. The plasma protein binding (92%) appears lower than the extravascular tissue binding²⁷. Safinamide reaches high concentrations in the CNS. Safinamide has proven to be both safe and well tolerated. There were no significant differences in vital signs or biochemical examination of blood and urine when compared to placebo²⁸.

Pharmacodynamics of Safinamide:

The exact mechanism by which safinamide improves Parkinson's disease symptoms is unknown (see Figure 1 for the impact of safinamide on PD). Safinamide works through both dopaminergic and non-dopaminergic mechanisms, inhibiting MAO-B selectively and reversibly, as well as activity-dependent sodium channel antagonism and inhibiting glutamate release in vitro. The dopaminergic method of action involves selectively inhibiting MAO-B, which increases brain dopamine levels²⁹. Safinamide's strong selectivity for MAO-B eliminates the need for any dietary restrictions. In vitro tests have showed reversibility caused by noncovalent binding to the enzyme's core. The reversibility of safinamide avoids potential drug interactions³⁰. Safinamide's selectivity for MAO-B is 1000 times greater than placebo. The selectivity of MAO-B over MAO-A is larger than that of selegiline and rasagiline.

Analytical Method Development:

Analytic technique development is the process of creating an accurate assay to determine the composition of formulations. Developing an analytical methodology involves establishing its suitability for laboratory application. Analytical techniques must follow GMP and GLP protocols and meet approval criteria outlined in ICH guidelines Q2 (R1)³¹.

Validation:

The idea of validation was created in the US in 1978. Over time, the idea of validation has expanded to encompass a wide range of tasks, such as clinical trials, process management, labelling, and analytical procedures to ensure medicinal substance and product quality. Validation has a crucial role in cGMP. Validation is the process of showing efficacy or assessing validity. Validation involves collaboration among plant disciplines. The "process of establishing documented evidence," known as "method Validation," ensures that analytical equipment or products meet their intended purposes³².

Parameters (components) of method validation:

1. Accuracy

2. Precision

3. Linearity

4. Limit of detection

5. Limit of quantitation

6. Specificity

7. Range

8. Robustness³³.

1. Accuracy: Accuracy is defined as the closeness of the test results to the true value.

2. Precision: Precision is defined as the level of agreement between numerous measurements on the same sample.

The precision is expressed as the relative standard deviation.

%RSD = Standard deviation/Mean ×100.

3. Linearity: Linearity refers to an analytical process producing a response proportional to the concentration of the analyte in the sample. Linearity is defined as the confidence limit around the slope of a regression line.

4. Limit of detection: LOD refers to the lowest concentration of an analyte in a sample that can be detected or identified but not measured. LOD is defined as a concentration at a specific signal: noise ratio, usually 3:1.

LOD =3.3 × S/ SD

5. Limit of quantitation: LOQ refers to the smallest amount of analyte that can be quantified. The ICH recommends the following signal for LOQ: noise ratio 10:1.

LOQ = 10 × S/SD

6. Specificity: Specificity refers to an analytical method's capacity to accurately measure one analyte despite the presence of additional components. This term has the following implications.

7. Range: The method's range refers to the top and lower levels of an analyte determined with acceptable accuracy, precision, and linearity. The response curve might be linear or nonlinear, and it is stated in the same unit as the test findings.

8. Robustness: Robustness is defined as the ability of an analytical procedure to remain unaffected by minor variations in method parameters.

Chromatographic Technique:

1. UV-VIS spectroscopy:

UV-VIS spectroscopy measures the amount of light absorbed at different wavelengths of the electromagnetic spectrum, including UV and visible. Absorption spectroscopy uses electromagnetic radiation from 200 nm to 800nm, separated into UV (200-400 nm) and visible (400-800nm) areas³⁴.

UV-VIS spectroscopy involves the absorption of UV-VIS lights by a sample or chemical compound, resulting in various spectra. When a molecule absorbs UV radiation, its electron are excited and move from lower to a higher electronic energy level, resulting in ultraviolet emission spectrum³⁵.

2. High-Performance Liquid Chromatography:

HPLC can separate, identify and quantify the compounds present in any sample which can be dissolved in liquid. Adsorption is the primary principle of liquid chromatography. It is a chromatographic method in which the mobile phase is liquid. The sample is in the form of a liquid solution. The sample is injected into a column composed of a porous substance (stationary phase) and a liquid phase (mobile phase). The sample moves through the column with the mobile phase under high pressure provided by a pump. Sample components move according to their affinity for the stationary phase moves slower. The component with less attraction for the immobile phase moves quicker. The components are separated from one another³⁶.

3. High-Performance Thin Layer Chromatography:

High-performance thin layer chromatography is an enhanced instrumental approach that takes advantage of the capabilities of thin layer chromatography. For chromatographic information of complex mixtures of phamaceuticals, natural products, clinical samples, food items, and so forth, it ia a powerful analytical tool because of its advantages in automation, scanning, full optimization, selective detection principle, minimum sample preparation, hyphenation, and so on³⁷.

4. Gas Chromatography:

Gas Chromatography refers to a set of analytical separation procedures used to evaluate volatile substances in the gas phase. Gas Chromatography divides a sample into two phases- a stationary phase and a mobile phase- by dissolving its constituent parts in a solvent and vaporizing them to separate the analytes. The analyte molecules are carried through the heated column by the mobile phase, a chemically inert gas. Gas Chromatography is one of the few chromatography methods that does not interact with the analyte via the mobile phase. Gas-solid chromatography (GSC) utilizes a solid adsorbent as the stationary phase, whereas gas-liquid chromatography (GLC) employs a liquid on an inert support³⁸.

5. Ultra-Performance Liquid Chromatography:

In the early 2000s, Ultra-performance liquid chromatography (UPLC) was introduced, marking another significant milestone. This technology uses sub-2- μm particles and operates at pressures above 6000 psi, providing extraordinary advances in resolution, speed, and sensitivity³⁹. UPLC was developed to meet the increasing demand for faster analytical times without sacrificing separation quality. Technological breakthroughoughs have led to substantial improvements in column chemistry, such as hybrid organic particles, monolithic columns, and superficially porous particles. Modern software, automated sample handling, and detection technologies⁴⁰.

Reported Method for Safinamide Mesylate:

Safinamide Mesylate is a widely used as third-generation reversible MAO-B inhibitor, which also blocks sodium voltage-sensitive channels and modulates stimulated release of glutamate. The development of reliable analytical methods is crucial to ensuring its efficacy, safety, and quality in pharmaceutical application. Numerous studies have explored and reported various analytical technique for safinamide quantification in recent years, focusing on both biological matrices and pharmaceutical formulations. These methodologies include UV-spectrophotometry, high performance liquid chromatography (HPLC), and mass spectrometry each contributing to advancement in Safinamide Mesylate analysis.

1. Dusakanti Akhila and her co-workers published this research in 2024. For the objective of developing and validating an RP-HPLC analytical method for estimating safinamide in bulk and pharmaceutical dose form. Chromatography was performed using a Symmetry C18 column (4.6 x 150 mm, 5 µm) with a mobile phase of methanol and water (45:55% v/v) at a flow rate of 0.8 ml/min. The detection wavelength was 260 nm. Safinamide's retention time was 2.379±0.02 minutes. The technique produces linear responses in the Safinamide concentration range of 24-120 mg/ml. The method precision for determining assay was less than 2.0% RSD. The method was validated for accuracy, precision, linearity, robustness, ruggedness, and the LOD and LOQ of the standard solution.⁴¹

Parameters	Description
Column Name	Symmetry C18 column (4.6 x 150 mm, 5 µm)
Mobile Phase	Methanol and water (45:55% v/v)
Flow Rate	0.8 ml/min.
Detection	260 nm
Retention Time	2.379±0.02 minutes
Precision	2.0% RSD

2. In order to develop and Validate Stability Indicating RP-HPLC Method for Estimation of Safinamide in Bulk Drug and Dosage Form. Gayatri R. Amrutkar and her co-workers published the paper in the year 2022. This research article emphasizes on this research, a novel, sensitive, convenient, clear, accurate, and robust reverse-phase high-performance liquid chromatography (RP-HPLC) method was developed and validated for the determination of safinamide in drug and tablet formulation. HPLC with UV detector, Open Lab EZchrome workstation, and Kromasil C18 (250mm × 4.6 mm i.d.) 5μm were used for separation. Methanol: 0.025% TFAA (45:55) was pumped at 1.0mL/min and measured at 226nm.⁴²

Parameters	Description
Column Name	EZchrome workstation, and Kromasil C18 (250 mm X 4.6 mm i.d.) 5 μm
Detector	HPLC with UV detector
Mobile Phase	Methanol: 0.025% TFAA (45:55)
Flow Rate	1.0 mL/min
Detection	226 nm
Retention Time	3.96 min

3. In order to develop and Validate Stability Indicating RP- UPLC Method for Quantitative Estimation of Safinamide Mesylate in Bulk and its Tablet Dosage Form. Madhu Medabalimi and her colleagues published the paper in the year 2022. The chromatographic separation was obtained by using an ACQUITY BEH C18 column (50 mm × 2.1 mm, 1.7 μm; Waters), with an isocratic elution of 0.02 M diammonium hydrogen phosphate buffer pH 9.0 and acetonitrile (80:20 v/v), at a flow rate of 0.25 ml/min, with UV detection at 272nm. Linearity studies were carried out in the range of 10 - 60 μg/ml and the linear response (r2) was found to be 0.9999 with limits of detection and quantification being 0.081 and 0.271μg, respectively. Linearity studies were carried out in the range of 10 - 60 μg/ml and the linear response (r2) was found to be 0.9999 with limits of detection and quantification being 0.081 and 0.271μg, respectively⁴³.

Parameters	Description
Column Name	ACQUITY BEH C18 column (50 mm × 2.1 mm, 1.7 μm; Waters)
Mobile Phase	Isocratic elution of 0.02 M diammonium hydrogen phosphate buffer pH 9.0 and acetonitrile (80:20 v/v),
Flow Rate	0.25 ml/min
Retention Time	0.285 at 272 nm
Linearity Study	10 - 60 μg/ml
Detection	272nm

4. Rehman Ayesha and her colleagues published the paper in the year 2022. In order to develop and validate a quick and highly sensitive high performance liquid chromatographic technique (HPLC) has been developed for determining Safinamide Mesylate in bulk and tablet form. Safinamide mesylate was eluted from an XBridge C18 (250mm × 4.6mm) reversed-phase column using a mobile phase of ammonium acetate buffer pH 5.8 and acetonitrile in a 55:45 (v/v) ratio at a flow rate of 1 ml/min with a UV detection wavelength of 26 nm. The retention time for Safinamide mesylate was 3.8 minutes. The linear response (r2 = 0.997) was seen in the range of 10-60 μg/ml. The limits of detection (LOD) and quantification (LOQ) were 2.85 and 9.5 μg/ml, respectively⁴⁴.

Parameters	Description
Column Name	XBridge C18 (250 mm x 4.6 mm)
Mobile Phase	Ammonium acetate buffer pH 5.8 and acetonitrile in a 55:45 (v/v) ratio
Flow Rate	1 ml/min
Detection	26nm
Retention Time	3.8 minutes
Linear Response	10-60 μg/ml

5. In 2021, the study was published by Ayesha Rehman and her co-workers for the purpose of method for determining Safinamide mesylate in bulk and tablet dosage form using both RP-HPLC and HPTLC. Safinamide mesylate was eluted from a NEOSPHERE RP C18 reversed-phase column using a mobile phase of methanol and water (80:20, v/v) at a flow rate of 1 ml/min. UV detection was performed at 226nm. The retention time for Safinamide mesylate was 5.2 minutes. A high-performance thin layer chromatography technique has been developed for estimating Safinamaide mesylate in bulk and tablet form. The detection was conducted densitometrically at 226nm. The Rf value of the medication was determined to be 0.54±0.02. The medication Safinamide mesylate may be approximated using both RP-HPLC and HPTLC methods, based on the available information and data⁴⁵.

Parameters	Description
Column Name	NEOSPHERE RP C18
Mobile Phase	Methanol and water (80:20, v/v)
Flow Rate	1 ml/min
Detection	226nm
Retention Time	5.2 minutes

6. In 2021, the study was published by V. Shirisha and her colleagues. A simple, precise, rapid and accurate RP-HPLC method was developed for the simultaneous estimation of Safinamide in bulk form and the pharmaceutical dosage form. The column of Symmetry ODS RP C18, 5 µm, 15 mm x 4.6 mm i.d., with a mobile phase of 80:20 v/v methanol and acetonitrile. The flow rate was maintained at 1.0 ml/min, and effluents were measured at 282 nm. The retention time for Safinamide was 2.545 ± 0.3 minutes. The detection concentration of Safinamide was linear from 0 to 14 μg/ml. The regression equations for Safinamide were y = 61767x + 8995.1, with a regression coefficient of 0.9993.⁴⁶

Parameters	Description
Column Name	ODS RP C18, 5 µm, 15 mm x 4.6 mm
Mobile Phase	80:20 v/v methanol and acetonitrile
Flow Rate	1.0 ml/min
Retention Time	2.545 ± 0.3 minutes
Detection	282 nm

7. The research was published by Amira M El-Kosasy and her co-workers in the year 2020. In order to develop a simple, precise, quick, and accurate reversed-phase high- performance liquid chromatography (RP-HPLC) method for Quantification of Safinamide Mesylate in Presence of Its Basic Degradate, Levodopa and Ondansetron: Application to Human Plasma. The mobile phase consisted of acetonitrile and 20mM potassium dihydrogen orthophosphate buffer with a pH of 5 (40:60 v/v). Quantification was achieved using an ultraviolet detector at 226nm. The linear range was 0.5- 10 μg/mL, with an average recovery of 99.72 ± 1.59. The peak purity of SAF in pharmaceutical preparation spiked with its degradation, and co-administered medicines demonstrated a symmetry factor (999.8) within the estimated threshold (>998.1)⁴⁷.

Parameters	Description
Mobile Phase	Acetonitrile and 20 mM Potassium dihydrogen orthophosphate buffer with a pH of 5 (40:60 v/v).
Detector	Ultraviolet
Linear Range	0.5- 10 μg/mL
Detection	226 nm
Retention Time	3.87 min

8. In 2020, Vaibhav s. Adhao and his colleagues released this paper. For the Development and Validation of Stability Indicating RP- HPLC Method for Determination of Safinamide Mesylate. The effective isolation of the drug from degradation products generated under stress conditions was accomplished utilizing a Hypersil BDS C18 column (250 mm × 4.6 mm, 5.0μ particle size). The mobile phase comprised Methanol and Phosphate Buffer at pH 6.8 in a ratio of 80:20 % v/v, with a flow rate set at 1.0mL/min, and the column temperature was regulated at 40˚C. Increased degradation was observed under acidic, alkaline, oxidative, and photolytic conditions. Lesser degradation was observed at thermal conditions. The achievement of quantification and linearity was observed at 226nm across the concentration spectrum of 40 - 180μg/mL for Safinamide Mesylate⁴⁸.

Parameters	Description
Column Name	Hypersil BDS C18 column (250 mm × 4.6 mm, 5.0 μ particle size)
Mobile Phase	Methanol and Phosphate Buffer at pH 6.8 in a ratio of 80:20 % v/v
Flow Rate	1.0 mL/min
Detection	226 nm
Column Temperature	40˚C.
Retention Time	4.57 min

9. In order to develop and validate a simple, specific, and precise high-performance thin-layer chromatographic (HPTLC) method for estimation of Safinamide Mesylate as bulk and in tablet dosage form. Vivekkumar K. Redasani and his colleagues released this study in the year 2012. Toluene, Methanol, and Triethylamine (4: 1:0.5 v/v) were used as the mobile phase for chromatographic development on silica gel 60 F254-coated metal plates. We carried out the detection densitometrically at 226nm. The RF value for the medication was 0.54±0.02. The approach was verified based on linearity, accuracy, precision, and robustness. The calibration curve was linear throughout a range of 400-2400 ng μL⁻¹. The percentage assay (mean ±standard deviation) was 100.27±0.72. The method's accuracy was 99.77±0.71%, as shown by percentage recovery analysis⁴⁹.

Parameters	Description
Column Name	silica gel 60 F254-coated metal plates
Mobile Phase	Toluene, Methanol, and Triethylamine (4: 1: 0.5 v/v)
Detection	226 nm.
Accuracy was 99.77±0.71%,	99.77±0.71%
RF Value	0.54 ± 0.02

CONCLUSION:

This review gathers and appraises earlier published analytical techniques for the quantification of safinamide mesylate in different pharmaceutical and biological matrices. HPLC, more so RP-HPLC, remains the most employed technique for the determination of safinamide mesylate due to its accuracy, precision, robustness, etc. Many studies have developed and validated the methods of determination of safinamide mesylate in bulk drug and formulations. Other techniques such as spectrophotometry, gas chromatography, also have been investigated.

This study makes an important contribution by systematically synthesizing previous work on the development of safinamide mesylate methodologies. It will be useful for researchers and pharmaceutical analysts looking for dependable analytical approaches to quality control and pharmacokinetic investigations.

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Received on 23.03.2025 Revised on 08.04.2025

Accepted on 21.04.2025 Published on 06.05.2025

Available online from May 10, 2025

Asian Journal of Pharmaceutical Analysis. 2025; 15(2):153-159.

DOI: 10.52711/2231-5675.2025.00024

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