1. INTRODUCTION:

Functional (primary) and secondary constipation are the two main types into which chronic constipation falls. The Rome III diagnostic criteria define functional constipation¹. It can also be further separated into defecation problems, delayed transit constipation, and normal transit constipation². Conditions and drug use such diabetes mellitus, hypothyroidism, depression, opioids, antidepressants, and calcium channel blockers can result in secondary constipation^3,4. Both gastrointestinal doctors and gastrointestinal surgeons find the management pathway to be understandably convoluted, much like the definition of functional and secondary constipation. The majority of constipation experts recommend a variety of strategies to treat chronic constipation. The first is a change in lifestyle; if this is not successful, osmotic laxatives (lactulose), bulk-forming laxatives (ispaghula husk), and stimulant laxatives (senna) are used. Furthermore, before using relatively novel medications, it was also usual practice to utilise macrogol, sodium phosphate, bisacodyl or glycerol suppository, and arachis oil enema.^5-15.

Prucalopride, the fourth novel agent, is a 5-HT4 agonist and a novel enterokinetic therapy that has been shown to be equally successful. It is the only medication that the National Institute for Health Care Excellence (NICE) recommends for women with persistent constipation. Prucalopride's significance in treating chronic constipation is highlighted in this article using data from published randomised, controlled trials as reported by the Cochrane Collaboration, in accordance with the criteria of meta-analysis.^{16, 17, 18.}

A derivative of dihydrobenzofurancarboxamide, prucalopride is a highly selective agonist of the 5-HT4 receptor. According to in vitro research, prucalopride differs structurally from previous serotonergic prokinetic agents. This differences not only give prucalopride a high affinity for the 5-HT4 receptor but also prevent it from interacting with other receptors at therapeutic doses, including the 5-HT3, 5-HT1B/D, motilin and cholecystokinin (CCK) receptors, or hERG K+ channels. It has no anticholinesterase or anticholinergic properties¹⁹. By binding to 5-HT4 receptors found all over the gastrointestinal tract and causing cholinergic neurones to release acetylcholine, prucalopride promotes gut motility^20,21. Considering the previously mentioned effects of prucalopride on colonic transit and motility.^22,23.

1.1 5-HT4 receptor agonists in CC:

The colon and other parts of the gastrointestinal system have 5-HT4 receptors, which are mostly found on enterochromaffin cells, smooth muscle cells, and the myenteric plexus. When serotonin agonists are administered to the 5-HT4 receptor, a G-protein coupled receptor, the generation of cyclic adenosine monophosphate (cAMP) is increased. Acetylcholine, the primary excitatory neurotransmitter in the gastrointestinal system, is boosted in release as a result of this, along with the modulation of other neurotransmitters.^24.

It has been demonstrated that the highly selective serotonin 5-HT4 receptor agonist prucalopride increases gastrointestinal motility both in vitro and in vivo²⁵. Prucalopride enhanced colonic and whole gut transit but not gastric emptying or small bowel transit in healthy individuals, according to scintigraphic investigations.²⁶

However, using the same scintigraphic method, the same authors discovered that prucalopride at doses of 2 or 4 mg per day increased the transit of the whole gut, stomach, small intestine, and colon in patients who were constipated.²⁷

1. Mechanism of Action:

Compared to other members of its class, prucalopride is a prokinetic drug that acts as an agonist at the 5-hydroxytryptamine receptor 4 (5-HT4) with decreased proarrhythmic risk and increased receptor selectivity. Because prucalopride can both increase the number of synchronous contractions in the large intestine and decrease the frequency of solitary contractions in the proximal colon, it is thought to help alleviate constipation. It causes the colon to contract in massive migratory contractions, which may be the root cause of CIC. Increasing gastrointestinal motility is particularly helpful for chronic constipation patients who do not have these high amplitude propagating contractions (HAPS). Not just the big bowel is affected by these prokinetic effects. Small bowel transit and stomach emptying are also accelerated by it ^[28]

2. Physical and Chemical Property:

Table.no 1. Physical and chemical property of prucalopride

Drug name	Prucalopride
Category	Serotonin receptor agonist
Molecular formula	C18H26CIN3O3
Molecular weight	367.87 g/mol
Chemical name	4-amino-5-chloro-N-[1-(3-methoxypropyl) piperidin-4-yl]-2,3-dihydrobenzofuran-7-carboxamide
description	Prucalopride is a member of benzamides. To treat (CIC)
Melting point	99 – 101 ^oC
Solubility	In ethanol and DMSO is approximately 10 mg/ml and approximately 20mg/ml DMF

Fig. 1: Chemical structure of prucalopride

3. Pharmacodynamics:

Additionally, a loosening in stool consistency and a rise in stool frequency were noted²⁹. When the medication was stopped, there was no rebound effect on bowel function³⁰. In a study that included an equal number of male and female healthy volunteers, propralopride's effects on bowel function and gastrointestinal transit in healthy men were similar to those seen in healthy women³¹. For patients with persistent constipation, prucalopride-induced acceleration of colonic transit was also linked to loosening of stool consistency and higher frequency of bowel movements^32,33. Prucalopride's effects on bowel and gastrointestinal transit were dosage responsive ³⁴.

4. Pharmacokinetics:

After taking prucalopride orally, it is quickly and widely absorbed from the digestive system. The mean plasma concentration of 4.34 ng/mL was reached in 14 healthy adult volunteers 2.1 hours after a single 2 mg dosage. Prucalopride has a 93% absolute oral bioavailability that is unaffected by food consumption. Prucalopride has linear pharmacokinetics with drug exposure, rising proportionately as dosage is increased across a range of 1–20 mg per day. Low plasma protein binding occurs between 28% and 33%. With a steady state volume of distribution of 567 L, extensive spread is evident³⁵. The human body has a restricted capacity to metabolise prucalopride. Less than 4% of the dose is made up of the main metabolite, and only trace levels of its metabolites are detected in the urine and faeces.

Following the administration of a radiolabeled medication in an oral dosage study, approximately 85% of the plasma radioactivity is attributed to unchanged prucalopride. The medication is eliminated mostly unaltered; almost 60% of the dose is eliminated through active secretion and passive filtration in the urine, and over 6% is eliminated in the faeces. Once daily dose is supported by prucalopride's elimination half-life of 24 to 30 hours³⁶.

5. Pharmaceutical Analysis:

The process of creating a precise test to determine a formulation's composition is called analytical technique development. Assessing an analytical approach's suitability for usage in a lab is a necessary step in its development. Analytical techniques must meet ICH guidelines' approval requirements and follow GMP and GLP processes³⁷.

6. Specific technologies used in pharmaceutical analysis:

6.1 UV Spectrophotometry:

UV Spectrophotometry: UV spectroscopy is the absorption or reflectance spectroscopy of the electrical spectrum's ultraviolet and near-visible regions. It is also known as UV-visible spectrophotometry, commonly abbreviated as UV-Vis or UV/Vis. This methodology's inexpensive cost and ease of implementation make it widely used in many fundamental and practical applications. For the sample to be recognised as a chromophore, it only needs to absorb in the UV-Vis range. In addition to fluorescence spectroscopy, absorption spectroscopy is used. Absorbance (A), reflectance (%R), transmittance (%T), and their time-varying characteristics are of significance in addition to wavelength.³⁸.

6.2 High-performance liquid chromatography

Any material that can dissolve in liquid can have its chemicals separated, identified, and quantified using HPLC. The fundamental idea behind liquid chromatography is adsorption. This chromatographic technique uses a liquid as the mobile phase. A liquid solution is the sample's shape. A column made up of a liquid phase (mobile phase) and a porous material (stationary phase) is filled with the sample. A pump provides high pressure as the sample and mobile phase pass through the column. The components of the sample migrate in accordance with their affinity for the stationary phase, which moves more slowly. In the immobility phase, the component that is less attracted moves more quickly. The parts are isolated from each other³⁹.

6.3 Ultra-High Performance Liquid Chromatography (UHPLC):

UPLC stands for Ultra Performance Liquid Chromatography. It improves in three areas: sensitivity analysis, speed, and chromatographic resolution. It uses fine particles, uses less solvent, and saves time. The source of UPLC is HPLC. With HPLC, the packing materials needed to create the separation have changed. A basic HPLC principle is that when column packing particle size reduces, efficiency and, in turn, resolution increase. The conventional Van Demeter equation states that efficiency does not decrease at increasing linear velocities or flow rates, but rather increases dramatically when particle size decreases to less than 2.5µm⁴⁰.

6.4 Reverse Phase High Performance Liquid Chromatography (RP-HPLC):

Reversed phase liquid chromatography (RPLC) is the technology of choice for pharmaceutical ingredient analysis for several reasons, including as its high consistency and repeatability, compatibility with a wide range of detection devices, and suitability for both organic and aqueous solutions. In both the pharmaceutical and bioanalytical sectors, the adoption of stationary phases that generate symmetrical and useful peaks is necessary for sensitive and accurate RPLC analysis. There is a large selection of reversed phase stationary phase options available as a result of stationary phase manufacturers continuously creating and introducing new RPLC products. The requirement for standardisation and the internationalisation of pharmaceutical companies necessitate that the techniques be translated with the same column brands or their equivalents from one region to another. This has led to a comprehensive categorisation or description of the diverse spectrum of stationary phases in recent years^41-42.

7.4.1 Emerging Trends in RP HPLC Method Development:

The quality-by-design (QBD) method is a rigorous process for developing procedures that concentrate on identifying and controlling the causes of variability in order to guarantee accurate and high-quality outputs. As a way to provide reliable procedures, this technology is growing in popularity in the development of RP HPLC methods⁴³.

7.4.2 Important attributes about QBD:

1. The Quality Target Product Profile (QTPP) serves as the foundation for the design of the product and is primarily concerned with safety and efficacy. It may take into account factors such as intended use in a clinical setting, the route of administration, dosage forms, and livery systems.

2. Critical Quality Attributes (CQAs): A CQA is a physical, chemical, biological, or microbiological property that must fall within a certain limit, range, or distribution in order to ensure the desired product.

3. Risk Assessment: This important science-based procedure in quality risk management can help determine which process variables and material characteristics may have an impact on product CQAs. Risk assessment is usually carried out at the beginning of the pharmaceutical development process and is repeated as new data and insights become available.

4. The Design Space provides a description of the link between Critical Quality qualities and the process inputs, which include material qualities and process parameters. Engaging in design work is not regarded as a shift. It is deemed a change when someone leaves the design space, and this usually starts a regulatory post-approval change process.

5. Control strategy: This can involve: • Controlling input material attributes based on knowledge of how they affect processability or product quality, such as drug substance, excipients, primary packaging materials, etc. • Product specification(s).

6. Life cycle management: Under the QBD paradigm, process modifications in the design space won't need to be reviewed or approved, so process improvements in terms of process consistency and throughput could occur during the product life cycle with fewer post-approval submissions.⁴⁴

8 Reported Method for Prucalopride:

1. A novel validated UPLC method for the determination of Prucalopride Succinate in solid dosage form was the goal of a publication published in 2024 by Dr. G. Abirami and her colleagues. Prucalopride succinate may be estimated in bulk and tablet form using a new and practical UPLC approach presented in this work. Using a C18 column (50 mm × 3 mm × 1.7µ) and a mobile phase made up of methanol and potassium dihydrogen ortho phosphate in a 60:40 %w/w ratio at room temperature, the procedure was made to be easy, quick, accurate, repeatable, and selective.⁴⁵

Table.no 2. Summary of above literature no.1

Parameters	Description
Column Name	Phenomenex C18 (50x3.0) mm
Mobile Phase	2.72g of potassium di hydrogen ortho phosphate
Flow Rate	Flow Rate was 0.8ml/min, injection volume 2 µl
Detection	225nm.
Retention Time	0.61 minutes.
Linear Response	50-150µg/ ml

2. The paper was released in 2023 by Ms. Priya Chidrewar and her colleagues. In order to develop and validate a stability-indicating reversed-phase high-performance liquid chromatography (RP-HPLC) method for the assay of the drug substance prucalopride. In this work, a novel technique (RP-HPLC) for determining the amount of prucalopride in tablet formulations is presented. With a far lower retention period of 1.5 minutes as opposed to the prior 4.73 minutes, the procedure is straightforward, accurate, dependable, and reproducible. 30% Orthophosphoric acid and 70% Methanol (v/v) make up the mobile phase, which has a flow rate of 1 mL/min and UV detection at 225 nm.⁴⁶

Table.no 3. Summary of above literature no.2

Parameters	Description
Column Name	C18 (150mm × 4.6mm, 5μ)
Mobile Phase	30% Orthophosphoric acid and 70% methanol (v/v)
Flow Rate	1 ml/min. 20 μL were injected.
Detection	225 nm.
Retention Time	1.5 minutes
Linear Response	25-150μg/ml

3. The Kumudini In 2023, Rahul Pawar and her colleagues released the study. for the development's sake. and verification of the HPLC-UV method for quantifying prucalopride succinate in biological samples. This work created and verified an HPLC-UV technique to measure the amount of the medication Prucalopride Succinate, which is used to treat gastrointestinal issues, in human plasma. In order to promote the use of Prucalopride Succinate in clinical and pharmaceutical research, this validated method is essential for studies of its bioavailability, bioequivalence, pharmacokinetics, and toxicokinetics in human plasma.⁴⁷

Table.no 4. Summary of above literature no.3

Parameters	Description
Column Name	BDS Hypersil C8 Column (250 × 4.6 mm, 5 μ)
Mobile Phase	Methanol: 0.1 % Formic Acid (80:20 v/v)
Flow Rate	1.0 mL/min.
Detection	276 nm
Retention Time	3.692 ± 0.05
Linear Response	(0.05- 0.5μg/ml)

4. In 2022, Chandanam Sreedha and her colleagues released the paper. for the development and validation of a novel analytical RP-HPLC method for the estimation of prucalopride in pharmaceutical dosage form and bulk. This work created a brand-new RP-HPLC technique that offers a much shorter retention time for measuring prucalopride in pharmaceutical dosage forms and bulk. With a flow rate of 1 mL/min and a detection wavelength of 225 nm, the technique employed a mobile phase consisting of 0.1% orthophosphoric acid and methanol (30:70 v/v). Prucalopride had a retention period of one and a half minutes. The technique performed well in terms of precision, accuracy, linearity, and robustness when validated by ICH recommendations. Prucalopride may be quickly and accurately quantified using this RP-HPLC technology, which makes it appropriate for routine quality control and analysis in pharmaceutical settings.⁴⁸

Table.no 5. Summary of above literature no.4

Parameters	Description
Column Name	Water’s X Bridge 5 µ C18(2) 100A, 250 X 4.6 mm)
Mobile Phase	0.1% orthophosphoric acid: methanol in ratio of 30:70 v/v
Flow Rate	1 mL/min
Detection	225 nm.
Retention Time	1.5 min
Linear Response	5-30 μg/mL

5. In 2021, A.C. Bhosale and her colleagues published a paper titled "Analytical Method Development And Validation Of Prucalopride Succinate In Bulk And Formulation By UV-Visible Spectrophotometry." This study developed and validated a UV-Visible Spectrophotometric method for quantifying Prucalopride Succinate in bulk and tablet formulations, adhering to ICH guidelines and being simple, rapid, and reproducible. Methanol was used as the solvent, and drug estimation was carried out at a wavelength of 243 nm. The method showed good linearity (2–10 µg/ml), with accuracy ranging from 97.2% to 98.3%, as determined by recovery studies. It was successfully applied for routine analysis of Prucalopride Succinate, making it appropriate for both pharmaceutical development and manufacturing.⁴⁹

Table.no 6. Summary of above literature no.5

Parameters	Description
Column Name	JASCO model V-530 UV-Visible
Mobile Phase	10ml of methanol to forms 1000ug/ml
Detection	243nm
Linear Response	2-10μg/ml

6. For the objective of implementing a quality-by-design approach for the development and validation of analytical methods for the estimation of prucalopride succinate in bulk and solid dosage form, Ashwini S. Chawathe and her colleagues released a paper in 2020. Developing and validating a reliable RP-HPLC method for quantifying Prucalopride succinate using the (QBD) approach is the aim of this work. Important parameters including buffer pH, acetonitrile %, and flow rate were improved using the Box-Behnken design. These factors affected attributes like retention duration and symmetry factor. With an Inertsil ODS C18 column and a mobile phase consisting of acetonitrile (77:23) and ammonium formate buffer (pH 5.0), the enhanced method showed good linearity (r2 = 0.9987), accuracy, and sensitivity (LOD: 0.2 µg/mL; LOQ: 0.8 µg/mL). Acidic, basic, and thermal degradation were all avoided in stability tests, although oxidative and photolytic conditions were vulnerable (8.2% and 10.6%, respectively). With an assay accuracy of 98.05%, the validated method is appropriate for routine analysis of prucalopride succinate in bulk and tablet formulations in compliance with ICH guidelines.⁵⁰

Table.no 7. Summary of above literature no.6

Parameters	Description
Column Name	over Inertsil ODS C18, 250 mm x 4.6mm x 5μmcolumn
Mobile Phase	0.01M ammonium formate with pH 5.0 and acetonitrile 77:23 v/v
Flow Rate	1.0 mL/min
Detection	226nm
Retention Time	Rt–5.8 minutes)
Linear Response	0.2 μg/ml and 0.8 μg/ml

7. In 2020, G. Abirami and her colleagues released the paper. ln order to develop and validate the RP-HPLC method for the dosage form of prucalopride succinate in both bulk and tablet form. In order to quantify Prucalopride Succinate in bulk and tablet dosage forms, this study created a sensitive and selective HPLC method. Potassium dihydrogen orthophosphate and methanol (60:40% v/v) were employed as the mobile phase in a C18 column (KROMASIL 150) at room temperature. The injection volume was 20 µl, the run time was 3.24 minutes, and the flow rate was 1 ml/min. At 225 nm, detection was made. The outcomes validated the method's applicability for regular quality control and Prucalopride Succinate drug assay.⁵¹

Table.no 8. Summary of above literature no.7

Parameters	Description
Column Name	C18 column (KROMASIL 150)
Mobile Phase	Potassium dihydrogen ortho phosphate: Methanol 60:40 % v/v.ll.
Flow Rate	1 ml/min
Detection	225 nm
Retention Time	3.24 min.
Linear Response	50 – 150 μg/mL

8. In 2020, Vaibhavi N. Akhani and her colleagues released the study. in order to develop and validate the RP-HPLC method for estimating the amount of prucalopride succinate in pharmaceutical dosage forms. For the estimation of Prucalopride Succinate in tablet dosage forms, a precise and accurate RP-HPLC method was created and verified. The technique demonstrated a linear response in the concentration range of 10–50 μg/mL using a Waters C18 column (150 × 4.6 mm, 5μ). Methanol and water (70:30 v/v) made up the mobile phase, which was detected at 226 nm. The retention period was 2.9 minutes, and the flow rate was set at 1 mL/min. This approach, which was validated in accordance with ICH recommendations, worked well for routine analysis of tablet formulations containing prucalopride succinate.⁵²

Table.no 9. Summary of above literature no.8

Parameters	Description
Column Name	C18 water (150 × 4.6 mm, 5μ)
Mobile Phase	Methanol: Water (70:30)
Flow Rate	1 mL/min
Detection	226 nm
Retention Time	2.9 min.
Linear Response	10 – 50 μg/mL

9. In 2020, a study was released by Sangameshwar B. Kanthale and her colleagues with the aim of developing and validating a stability-indicating RP-HPLC method for determining the amount of prucalopride succinate in tablets and bulk. Prucalopride succinate (PRU) was estimated using an HPLC method devised in the study utilising a Grace C18 column (150 mm × 4.6 mm, 5 μm). Using a mobile phase of acetonitrile: 0.02 M potassium dihydrogen phosphate (20:80 v/v), the solute was eluted in a 10-minute isocratic mode at a flow rate of 1 mL/min and 30°C, with a 277 nm readout. The duration of retention was 5.416 minutes. For accurate measurement of prucalopride succinate in pharmaceutical applications, this proven method is appropriate.⁵³

Table.no 10. Summary of above literature no.9

Parameters	Description
Column Name	Grace C18 column of dimension 150 mm × 4.6 mm
Mobile Phase	Acetonitrile: 0.02 m potassium dihydrogen phosphate in the ratio of 20:80 v/v
Flow Rate	1 mL/min
Detection	277 nm
Retention Time	5.416 minutes
Linear Response	2-12 μg/mL

SUMMARY:

Prucalopride, a highly selective serotonin 5-HT4 receptor agonist, has gained significant attention for its role in the management of chronic idiopathic constipation (CIC). Unlike earlier serotonergic agents, prucalopride enhances colonic motility while minimizing adverse effects. This review article provides an in-depth analysis of various analytical methods utilized for prucalopride quantification in pharmaceutical and biological matrices. The discussed techniques include UV spectrophotometry, high-performance liquid chromatography (HPLC), ultra-high-performance liquid chromatography (UHPLC), and gas chromatography (GC). Each method’s principles, advantages, and limitations are examined, with a particular focus on method validation parameters such as sensitivity, accuracy, precision, and specificity. Furthermore, emerging analytical trends, including Quality by Design (QbD) and stability-indicating methods, are highlighted to emphasize advancements in pharmaceutical analysis.

CONCLUSION:

The review highlights the importance of robust and validated analytical techniques for the accurate estimation of prucalopride, ensuring its efficacy and safety in clinical and pharmaceutical applications. Among the discussed methods, UHPLC and RP-HPLC emerge as highly efficient techniques due to their superior resolution, reduced analysis time, and improved sensitivity. The adoption of QbD principles further enhances the reliability of these methods. Given the increasing clinical use of prucalopride, continuous advancements in analytical techniques are essential for optimizing drug monitoring, quality control, and regulatory compliance. This review serves as a valuable resource for researchers and industry professionals in selecting appropriate analytical methodologies for prucalopride determination.

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Received on 24.03.2025 Revised on 03.05.2025

Accepted on 07.06.2025 Published on 12.07.2025

Available online from July 21, 2025

Asian Journal of Pharmaceutical Analysis. 2025; 15(3):229-235.

DOI: 10.52711/2231-5675.2025.00036

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