INTRODUCTION:

The most practical and widely used method for delivering drugs is the oral route. Because oral drug delivery systems allow for greater dosage form design flexibility than other drug delivery systems, they have drawn greater interest from the pharmaceutical industry. In recent years novel drug delivery systems like nanosuspensions draws a considerable attention in search for improving bioavailability of poorly soluble drugs^1,2.

Low bioavailability is the main issue with poorly soluble medications. For medications that fall within the biopharmaceutical categorization system's BCS class II classification, the issue is much more complicated. The creation of nanosuspensions is a viable solution to these issues. A clean, insufficiently water-soluble medication is suspended in dispersion as a nanosuspension without any matrix ingredient. It is possible to manufacture any drug as a nanosuspension that is insoluble in water^3,4,5. Poor solubility and bioavailability issues are resolved by a nanosuspension, which also modifies the pharmacokinetics of the medication and enhances its safety and effectiveness⁶.

It is predicted that the pharmaceutical business is developing more than one-third of compounds that have low solubility in water. The solvency/disintegration conduct of a medication is key element to its oral bioavailability. An improvement of oral bioavailability of poorly water-dissolving medications stays one of the most difficult errands of medication advancement. To beat poor solubility, many methodologies have been considered. They are for the most part salt arrangement, utilization of surfactant, utilization of prodrugs and micronization. In general, they are micronization, prodrug use, surfactant use, and salt formation. In micronization, the molecule size of a medication powder is decreased to a micron scale size (regularly 2-10 micron), which builds the particular surface region and disintegration rates^9,10.

Since the majority of biological qualities displaying NCEs are poorly water soluble, pharmaceutical businesses are always looking for innovative methods to achieve a good oral bioavailability. Recently, a brand-new and innovative drug delivery technology has emerged with the development of such medications as nanoscale systems. These systems' fast rate of dissolution improves their bioavailability after oral administration. However, the creation of nanoscale systems was spurred by the fact that many novel medications are so poorly soluble that micronization is insufficient. The surface area and associated dissolving rate are significantly increased when the particle size is reduced from the micron to the nanometer range.

Nanosuspensions are sub-micron colloidal scatterings of unadulterated medication particles in an external fluid stage. Nanoparticle designing empowers ineffectively solvent medications to be formed as nanosuspensions alone, or with a mix of drug excipients. Nanosuspensions engineering processes which are presently utilized are precipitation¹¹, high strain homogenization¹², and pearl processing¹³, either in water or in combinations of endlessly water miscible fluids or non-fluid media¹⁴.

Nanoprecipitation strategy presents various benefits, in that it is a direct method, quick and simple to perform. In this strategy, the medication is broken up in a natural dissolvable like (CH₃)₂CO, Acetonitrile, methanol or ethyl acetic acid derivation. The natural dissolvable is vanished either by decreasing the strain or by persistent mixing. The type of stabilizer, stabilizer concentrations, and homogenizer speed were found to have an impact on particle size. To create little molecule size, frequently a high velocity homogenization or ultrasonication might be utilized. The super immersion is additionally highlighted by vanishing of medication dissolvable. This respects the precipitation of the medication. High shear force forestalls core development and Oswald's aging^15,16.

Improvement of water solubility in such case is a significant objective to work on remedial viability. The disintegration rate is a component of the solubility and the surface region of the medication, in this manner, disintegration rate will increase on the off chance that the solvency of the medication is expanded, and it will likewise increase with an expansion in the surface region of the medication¹⁷.

Drug Profile

Diclofenac Sodium:

Figure no. 1: Structure of Diclofenac Sodium

Chemical Formula: C₁₄H₁₀Cl₂NNaO₂

IUPAC Name: sodium 2 {2[(2,6dichlorophenyl) amino]phenyl}Acetate

Category: NSAID (painkiller)

A drug called diclofenac is used to control and treat pain and inflammatory diseases. It belongs to the non-steroidal anti-inflammatory medication (NSAID) subclass. In order for members of the healthcare team to effectively treat and oversee patients with inflammation-related disorders, this activity describes the indications, mechanism of action, administration, side effect profile, contraindications, and other important aspects of diclofenac in the clinical context.

Diclofenac is used to treat and manage both acute and chronic pain brought on by inflammatory diseases, particularly those that affect the musculoskeletal system. These include ankylosing spondylitis, Rheumatoid arthritis and osteoarthritis. It can cure actinic keratosis topically. Additionally, FDA-approved for ophthalmic use, diclofenac is used to treat photophobia, eye discomfort, and cataract extraction.

While it can aid in the management of pain feelings during inflammatory processes, it is unable to prevent or repair the persistent joint damage caused by osteoarthritis and rheumatoid arthritis. The most often prescribed NSAID globally was first synthesized in 1973 and is called diclofenac^18,19,20.

Mechanism of Action:

Diclofenac is an NSAID that belongs to the phenylacetic acid family and works to reduce inflammation in a similar manner to other medications in its class. It also possesses antipyretic and analgesic actions, which are characteristics of other NSAIDs.

Diclofenac works by preventing the formation of prostanoids such prostaglandin-E2 (PGE2), prostacyclins, and thromboxanes, which are crucial elements of the inflammatory and nociceptive response. This inhibits the activities of COX-1 and COX-2. Although evidence suggests that diclofenac has selective COX inhibition, approximately four times the inhibition of COX 1 in in vitro studies, it inhibits COX 1 and COX 2 relatively equally.

Therapeutic Uses:

Pain relief:

Diclofenac sodium is frequently used to treat mild to moderate pain, including gout, ankylosing spondylitis, rheumatoid arthritis, and osteoarthritis.

Anti-inflammatory effects:

It diminishes irritation and enlarging related with different circumstances like joint inflammation, bursitis, and tendonitis.

Menstrual cramps:

Menstrual cramps (dysmenorrhea) pain and discomfort can be alleviated with diclofenac sodium.

Dosage:

The measurements of diclofenac sodium differ relying upon the condition being dealt with, the seriousness of the side effects, and the definition utilized. It is essential to adhere to the instructions given by the healthcare provider or the label of the medication.

Common Complications: Heartburn, stomach pain, upset stomach, nausea, vomiting, diarrhea, constipation, headache, dizziness, skin rash, or itching.

Materials and Equipment’s:

Table no.1: Materials and their Properties

Sr. No.	Materials	Properties
1	Diclofenac Sodium	Active ingredient
2	Diluted Hydrochloric Acid	Precipitating agent
3	Chloroform	solvent
4	Concentrated Hydrochloric Acid	For acid-base balance
5	Methanol	Solvent
6	Sodium Hydroxide	For acid-base balance
7	Hydroxypropyl methylcellulose (HPMC)	Stabilizers
8	Water/ Bi-distilled Water	vehicle

Table no. 2: Equipment and their model

Sr. No.	Equipment	Model
1.	Particle size analyser	Horiba Scientific and SZ-100
2.	Magnetic stirrer	Remi Motors and 2mlh/1mlh
3.	UV spectrometer	Shimadzu and UV 1800
4.	Viscometer	Brookfile and RVDV-11+P
5.	Probe sonicator	PCI Analytics and DPI 120
6.	Homogenizer	Ultra-Turrax and IKA-T10 BASIC
7.	Weighing balance	Shimadzu and AUX 220

EXPERIMENTAL WORK:

A. Formulation of Nanosuspension:

Here, for this formulation preparation was carried out by two very known methods:

1. Precipitation method:

This broad technique is used to create submicron-sized drug particles that are poorly soluble. This approach involves dissolving the drug in a solvent, mixing the solution with a solvent that contains a surfactant, making the drug insoluble. Fast supersaturation of the drug in the solution and the creation of ultrafine amorphous or crystalline drug result from the quick addition of solution to such solvent (usually water)^21,22,23. This process involves the creation of nuclei and the development of crystals, both of which are temperature-dependent. The preparation of a stable suspension with the smallest possible particle size primarily requires a high nucleation rate and a low crystal growth rate^24,25,26.

2. Acid-Base neutralization method:

· Preparation of DFS crystal forms: The crystals of DFS were prepared by precipitation method. Diluted HCl was used to acidify a saturated aqueous solution of diclofenac sodium salt until a white precipitate of diclofenac acid was visible. After filtering, the precipitate was cleaned with bidistilled water and allowed to air dry^27,28.

· Preparation of nanosuspensions: Nanosuspensions of Diclofenac Sodium were prepared using the acid-base neutralisation technique. Dried drug crystals of DFS were added to 1.1ml of concentrated Hydrochloric Acid and 11ml of Methanol (1:10 conc). This is solution 1. Hydroxypropyl methylcellulose (HPMC) was dissolved in 10ml sodium hydroxide solution (0.0375N). And this is solution 2. Then solution 1 was added to the solution 2 dropwise with moderate stirring at 400rpm for 15 minutes^29,30,31,32.

B. Evaluation Parameters:

Determination of melting point:

Melting point of pure Diclofenac sodium was found to be in the range 270-290⁰C as reported in the literature. The melting point of obtained Diclofenac sodium was 273⁰C this indicate that the obtained drug was pure.

Solubility:

Diclofenac Sodium is slightly soluble in water. It is highly soluble in Methanol.

Calibration Curve:

Calibration curves are used to predict the concentration of analyte in a sample. To study the calibration curve UV Visible Spectrophotometer model UV 1800 was used. Samples of concentration 2, 4, 5, 6, 8, 10, 12, 15 microgram were used and there absorbance was noted at 277nm wavelength^33,34.

Particle Size Analysis:

The word "particle sizing" refers to the collection of technical processes or laboratory methods used to calculate the average, mean, and/or size distribution of the particles in a powder. or liquid sample^35,36. The particle size analysis was carried out using Nano Particle size analyzer model SZ-100. Before measurement the samples has to be diluted with Methanol to obtain a suitable Concentration for measurement. The results obtained for particle size distributions were used to confirm the formation of nano-sized particles^37,38.

Viscosity:

Viscosity is the resistance of a fluid (liquid or gas) to a change in shape or movement of neighboring portions relative to one another. Viscosity denotes opposition to flow. Viscosity was carried out using Brookfield Viscometer. One sample each of HPMC and Methyl Cellulose was studied. T spindle was selected and the viscosity was measured at different rpm^39,40.

XRD:

This study is used to study the crystalline phase which is present in material and predicts the chemical composition information. It is one of the non-destructive techniques for characterization of crystalline material. The study was done on the composite mixture^38,41.

RESULT AND DISCUSSION:

Pre Formulation Studies

· Organoleptic Studies:

· Color: White

· Odour: Odourless

· Taste: Bitter

· State: Solid

· Crystallinity: Fine Powder

· Melting Point: 273-278 °C

· pH value: 7.5-8

· Solubility: Soluble in methanol.

· Calibration Curve

Calibration Curve:

Samples of concentration 2, 4, 5, 6, 8, 10, 12, 15 microgram were used and their absorbance was reported and Curve was plotted. Every sample was examined three times, and a calibration curve was created by utilizing linear regression analysis to plot the absorbance against concentration. The R2 value and regression equation was found to be 0.9744 and Y= 0.2248x respectively.

Table no.3: Absorbance value for calibration curve

Concentration	Absorbance
0	0
2	0.2
4	0.4
5	0.7
6	1.7
8	2.2
10	2.4
12	2.6
15	3.3

Figure no. 2: Calibration curve of Diclofenac sodium

Particle Size analysis:

The particle size analysis was carried out using Nano Particle size analyzer model SZ-100. Before measurement the sample has to be diluted with Methanol to obtain a suitable Concentration for measurement. The results obtained for particle size distributions were used to confirm the formation of nano-sized particle.

Diclofenac Sodium:

Diclofenac Sodium + HPMC sample diluted with Water

Figure no.3: Particle Size Analysis of diclofenac sodium

Figure no.4: Particle size of sample diluted with Methanol

Methyl cellulose:

Figure no. 5: Particle size analysis of Diclofenac sodium+methyl Cellulose sample

Viscosity:

Viscosity was carried out using Brookfield Viscometer. One sample each of HPMC and Methyl Cellulose was studied at different rpm by using T shaped spindle.

1. HPMC:

Table no.4: Viscosity of drug + HPMC

Sr. No	RPM	Value
1	5	92500
2	10	47500
3	50	9480
4	100	4735
5	150	2365
6	200	1231

2. Methyl Cellulose:

Table no.5: Viscosity of drug+ Methyl Cellulose

Sr. No	RPM	Value
1	5	94320
2	10	45500
3	50	9380
4	100	3635
5	150	3045
6	200	2244

XRD:

Figure no.6: XRD of the drug + HPMC mixture

SUMMARY:

The most important details in this text are the development of nanosuspension, which are sub-micron colloidal scatterings of unadulterated medication particles in an external fluid stage. Nanotechnology is a new generation of technology with the potential to revolutionize many aspects of daily life, including health and health care, the manufacturing and use of materials and equipment, the environment and protection thereof. It involves research and technology development at the 1 nm – 100 nm range, creating and using structures that have novel properties due to their small size.

This study aims to formulate and evaluate nanosuspension of Diclofenac sodium to improve its bioavailability. The objectives of the study include preformulation studies, screening of excipients for compatibility and efficacy, preformulation study, preparation of nanosuspension drug delivery system, evaluation of formulated product and identification of defects. Nano suspensions are preferred for compounds with high log P value, high melting point, and high dose. Diclofenac is an NSAID that belongs to the phenyl acetic acid family and works to reduce inflammation. Also, the excipients like HPMC, chloroform, HCl, Methanol, sodium hydroxide were used in the present study. Suitable equipments were used for the formulation and evaluation.

Precipitation and acid-base neutralization are two methods used to prepare nanosuspension of Diclofenac Sodium. Precipitation involves dissolving the drug in solvent and mixing it with an insoluble solvent, while acid-base neutralization involves dissolving the drug in hydrochloric acid and Methanol and adding it drop wise with moderate stirring at 400rpm for 15 minutes.

Evaluation parameters such as Organoleptic Studies, Melting Point, pH value, Solubility, Calibration Curve, Particle Size analysis and Viscosity were studied.

CONCLUSION:

The results of the present study demonstrate that Nanoprecipitation technique was employed to produce nanocrystals of Diclofenac Sodium, a poorly water-soluble drug, for the improvement of solubility and oral bioavailability. In this process, the particle size of Diclofenac Sodium can be obtained in the nano-size ranges, by adjusting the operation parameters. The best nanosuspension of Diclofenac Sodium can be obtained by 100mg, 30mg Hydroxypropyl Methylcellulose. Thus, it can be concluded that the dissolution of Diclofenac Sodium is significantly increased when it is nanosized and thus the bioavailability can be increased.

ACKNOWLEDGEMENT:

Authors are thankful to the Department of Pharmaceutics, PES, Modern College of Pharmacy, Nigdi, Pune for providing all laboratory facilities to carry out this research.

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Received on 03.02.2024 Revised on 24.08.2024

Accepted on 28.11.2024 Published on 02.05.2025

Available online from May 07, 2025

Research J. Pharmacy and Technology. 2025;18(5):1983-1988.

DOI: 10.52711/0974-360X.2025.00283

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