In-Silico Evaluation of Drug–Excipient Compatibility of Paracetamol 500 mg Tablet Using Molecular Docking with PyRx.

Abstract

Drug–excipient compatibility is a crucial factor in the development of stable pharmaceutical formulations. In the present study, an in-silico molecular docking approach was employed to evaluate the compatibility of paracetamol with commonly used tablet excipients. We employed computer simulations to explore the compatibility of paracetamol with chemicals typically used in tablet manufacture, such as alpha-lactose and N-vinyl-2-pyrrolidone. The morphologies of paracetamol and these chemicals were obtained from the Human Metabolome Database and the interactions were studied using the PyRx tool with AutoDock Vina. The results showed that paracetamol had negligible interaction with the investigated substances, with interaction energies of -2.2 kcal/mol for lactose and -1.4 kcal/mol for povidone. This implies that paracetamol is compatible with these components, which is advantageous for pharmaceutical formulation. These weak interactions mean that paracetamol works with these excipients when they are used in tablet formulations. The findings demonstrate that molecular docking can serve as a rapid preliminary tool for predicting drug–excipient compatibility during early formulation development

Keywords

Introduction

In order for ensuring the stability, safety, and effectiveness of the finished dosage form, drug-excipient compatibility studies are a crucial component of pharmaceutical formulation development.¹ The quality of pharmaceutical products may be impacted by interactions between drugs and excipients, which are inactive ingredients that help with manufacturing, stability and drug release.²

One of the most popular analgesics and antipyretics is paracetamol, which is typically prepared as tablets.^3,4,5 Excipients like lactose as a diluent and povidone as a binder are commonly found in tablet formulations. To guarantee formulation stability, it is crucial to comprehend how the drug and excipients interact.^6,7

 

 

Fig. No.1 Paracetamol (also known as Acetaminophen).

Conventional compatibility studies use experimental methods that can take a lot of time and money like DSC, FTIR, and X-ray diffraction. Molecular docking is one computational method that has recently become a valuable tool for molecular interaction prediction.⁸

In order to assess the interaction between paracetamol and specific excipients, namely lactose and povidone (represented by N-vinyl-2-pyrrolidone), molecular docking analysis was carried out using PyRx.^9,10 The nature and strength of intermolecular interactions are revealed by the docking results, which may suggest whether these excipients are compatible with paracetamol tablet formulations.

MATERIALS AND METHODOLOGY

Selection of Drug and Excipients:

The drug selected for the study was paracetamol, a widely used analgesic and antipyretic agent. Two commonly used tablet excipients were selected for compatibility analysis Alpha-lactose (tablet diluent), Povidone (binder), modeled using N-vinyl-2-pyrrolidone.

Retrieval of Molecular Structures:

The three-dimensional molecular structures of paracetamol, alpha-lactose, and N-vinyl-2-pyrrolidone were retrieved from the Human Metabolome Database (HMD) in 3D SDF format.¹¹

Molecular Docking Software

Molecular docking studies were performed using PyRx virtual screening software. Docking simulations were carried out using the AutoDock Vina algorithm, which predicts the binding affinity between molecules.

Docking Procedure

The PyRx virtual screening software's Vina Wizard module was used to perform molecular docking studies. First, the chosen molecules' energy-minimized structures were imported into the PyRx workspace. Before docking, the three-dimensional structures of the drug molecule, paracetamol, and the chosen excipients, alpha-lactose and N-vinyl-2-pyrrolidone (which represents povidone), were created. The MMFF94 force field was used to optimize the molecules' geometry in order to produce stable conformations that could be used for docking analysis.

Following setup, the AutoDock Vina docking engine built into PyRx was used to carry out the docking simulations. In the Vina Wizard interface, the drug and excipient molecules were chosen, and the area where molecular interactions might take place was covered by a search space (grid box). In order to find energetically favorable binding interactions, the docking algorithm investigated several potential ligand orientations and conformations within the specified search space. For every drug-excipient pair, multiple binding poses were produced during the docking process. The software determined the binding affinity, which is expressed in kcal/mol and indicates the anticipated strength of interaction between the molecules, for each pose.

The docking results were looked at to find the pose with the binding energy value. This is because the lowest binding energy value means the drug and the excipient have a stable interaction. The binding affinity values were then used to see if paracetamol is compatible, with the selected excipients. This is important to know about paracetamol and the excipients.

The binding affinity values of paracetamol were used to evaluate the compatibility of paracetamol with the excipients that were selected. The goal is to find out if paracetamol can work well with these excipients.

RESULTS & DISCUSSION

Docking Results

i] For Paracetamol & Lactose

 

 

Fig. No.2  Paracetamol & Lactose.

 

 

 

Fig. No.3 Graphical Representation of Binding Affinity of Paracetamol & Lactose.

ii] For Paracetamol & Povidone

 

 

Fig. No.4  Paracetamol &Povidone.

 

 

Ligand	Binding Affinity	rmsd/ub	rmsd/lb
HMDB0255245_(N-Vinyl-2-pyrrolidone)_3D_mmff94_E=9.34_HMDB0001859_(Acetaminophen)_3D_mmff94_E=-11.52	-1.4	0	0
HMDB0255245_(N-Vinyl-2-pyrrolidone)_3D_mmff94_E=9.34_HMDB0001859_(Acetaminophen)_3D_mmff94_E=-11.52	-1.4	1.45	0.12
HMDB0255245_(N-Vinyl-2-pyrrolidone)_3D_mmff94_E=9.34_HMDB0001859_(Acetaminophen)_3D_mmff94_E=-11.52	-1.3	5.711	2.608
HMDB0255245_(N-Vinyl-2-pyrrolidone)_3D_mmff94_E=9.34_HMDB0001859_(Acetaminophen)_3D_mmff94_E=-11.52	-1.2	4.439	3.286
HMDB0255245_(N-Vinyl-2-pyrrolidone)_3D_mmff94_E=9.34_HMDB0001859_(Acetaminophen)_3D_mmff94_E=-11.52	-1.2	3.399	2.452
HMDB0255245_(N-Vinyl-2-pyrrolidone)_3D_mmff94_E=9.34_HMDB0001859_(Acetaminophen)_3D_mmff94_E=-11.52	-1.2	8.879	7.848
HMDB0255245_(N-Vinyl-2-pyrrolidone)_3D_mmff94_E=9.34_HMDB0001859_(Acetaminophen)_3D_mmff94_E=-11.52	-1.2	8.273	7.896
HMDB0255245_(N-Vinyl-2-pyrrolidone)_3D_mmff94_E=9.34_HMDB0001859_(Acetaminophen)_3D_mmff94_E=-11.52	-1.2	3.402	2.466
HMDB0255245_(N-Vinyl-2-pyrrolidone)_3D_mmff94_E=9.34_HMDB0001859_(Acetaminophen)_3D_mmff94_E=-11.52	-1.1	6.041	3.264

 

 

Fig. No.5 Graphical Representation of Binding Affinity of Paracetamol & Povidone.

Interaction Analysis

The docking results revealed weak intermolecular interactions between paracetamol and the selected excipients. The hydroxyl and amide groups of paracetamol showed possible hydrogen bonding interactions with the hydroxyl groups of lactose and the carbonyl group of N-vinyl-2-pyrrolidone.

However, the interaction energies were relatively low, indicating weak binding between the drug and excipients.

CONCLUSION

The present in-silico study evaluated the compatibility of paracetamol with lactose and povidone using molecular docking. The docking results showed weak binding interactions with binding affinities of −2.2 kcal/mol and −1.4 kcal/mol respectively. These findings suggest that both excipients are compatible with paracetamol in tablet formulations. Molecular docking using PyRx provides a useful computational approach for predicting drug–excipient compatibility during early stages of formulation development.

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