Solubility Enhancement of Dicofenac Sodium by Mixed Solvency Method: A Novel Approach

The concentration of the solute in a saturated solution at a specific temperature is the quantitative definition of solubility. A drug's solubility is a major factor in its bioavailability.  Convenience, safety, and preventing contamination are among benefits of using the co-solvent approach to improve drug solubility in a based formulation.  No dosage form formulation is required because a number of techniques have been used to enhance the solubilization of poorly soluble drugs, as well as to enhance their bioavailability. These techniques include complexation, pH adjustment, chemical modification, and micro-ionization. [1]

A non-steroidal anti-inflammatory drug with analgesic, anti-inflammatory, and antipyretic properties is diclofenac sodium.  Several co-solvents, including urea, sodium benzoate, sodium acetate, and sodium citrate, are employed to increase solubility.  Enhancing water solubility was found to be the most beneficial usage of PEG 200. [2]

It has been noted that hydrotropes, co-solvents, and water soluble solutes improve the aqueous solubility of medications that are not very water soluble.  It has been shown that the mixed solvency idea can produce a synergistic impact. [3]

A solubilization process known as hydrotropy occurs when a significant amount of a second solute is added, increasing the solute's water solubility.  Alkali metal salts of different organic acids make up the solute.  Hydrotropy is a novel and unheard-of method of solubilization whereby specific chemical components known as hydrotropes can be employed to boost the solubility of sparingly soluble solutes by many times under typical conditions.[6]                              

General information about Diclofenac sodium:

Molecular Formula:  C₁₄H₁₀CL₂NNaO₂

Molecular Weight:   318.1

Category:   Analgesic and Anti-Inflammatory

Description: A white to slightly yellowish crystalline powder, slightly hygroscopic.                      

Dose:  Orally or by intramuscular injection, 25-75mg.

Structure:

Solubility enhancement methods:

The solubility enhancement methods are as follow:

1. Particle size reduction
2. PH adjustment
3. Super critical fluid process
4. Pastillation
5. Micro emulsion
6. Solid dispersion
7. Hydrotropy
8. Complexation
9. Mixed co-solvency

Particle size reduction:

Introduction:

The drug particles have a intrinsic relationship with bioavailability dimensions. Particle size was decreased by increasing surface area which enhances the properties of dissolution. Size of particles reduction, which is accomplished through the use of jet mill milling techniques. Colloid mills, rotor stator, etc. It is not suitable for drugs with high dosage numbers since it does not change the drug's saturation solubility.  Each technique uses a different piece of equipment to lower the particle size.  The solubility and particle size of a drug are often related when it is micronized.  By reducing the particle size, the increased surface area improves the drug's dissolving properties.  Using milling techniques like jet mills, rotor stator colloid mills, etc., drugs are micronized.  Micronization is inappropriate for drugs with large dosage numbers since it does not change the drug's saturation solubility.  Nanosuspension is an additional technique that involves dispersing pure medicine particles in a sub-micron colloidal form stabilized by surfactants.

Among the drugs that have been utilized using the nanosuspension approach are paclitaxel, bupravaquon, amphotericin B, atovaquone, and tarazepide.  A greater rate of dissolution due to the exposed surface area and the absence of Ostwald ripening due to the uniform and restricted particle size range that eliminates the concentration gradient effect are two advantages of nanosuspension.  Nanosuspensions are made via the homogenization and wet milling procedures.[2]

Procedure:

A. Ball Milling:

1. Load diclofenac sodium into the ball mill chamber.

2. Add grinding media (e.g., zirconia balls).

3. Add a stabilizer solution (like 1–2% PVP or HPMC in water).

4. Mill the suspension at a defined speed (e.g., 300–500 rpm) for a set duration (2–24 hours).

5. Monitor temperature to avoid thermal degradation.

6. Collect and filter the suspension if required.

7. Dry the final product using a freeze dryer or spray dryer

B. Jet Milling:

1. Feed dry diclofenac sodium powder into the jet mill.

2. Use compressed air or inert gas as the milling medium.

3. Collect the fine powder after milling.

4. Store in a desiccator or appropriate container.

Advantages:

• It is possible to quickly generate liquid forms for pre-clinical testing, which can then be transformed into solids for clinical development.
• Generally, modest ratios of excipient to medication are needed.
• As long as powerful surfactants are not needed for stabilization, formulations are usually well tolerated.
• In general, amorphous particles are less stable both chemically and physically than crystal forms.
• For obstinate chemicals that defy prior efforts to improve solubility, there is a technique to think about.
• Disadvantages:
•  There is a strong tendency for particles to aggregate because of the high surface charge on individual tiny particles.
• It could be technically difficult to create a solid dosage form with a large payload without promoting agglomeration.
• The creation of sterile intravenous formulations is technically even more difficult.

pH adjustment:

Introduction:

Drugs that are insoluble in water can become soluble by altering the pH.  When using this technique to achieve solubility, consideration must be given to the buffer's capacity and pH tolerance.  As a result, weakly acidic drugs may become more soluble when alkalizing excipients are used, while weakly basic medications may become more soluble when pH is lowered.  It can also be used with lipophilic and weakly soluble crystalline materials.  Theoretically, both parenteral and oral delivery systems might use pH variations.  After intravenous administration, the poorly soluble medication may precipitate because blood, which has a pH of 7.2 to 7.4, is a powerful buffer. [5]

Procedure:

1. Preparation of Drug Solution:

Weigh a known quantity of diclofenac sodium.

Add it to a measured volume of distilled water in a beaker or volumetric flask.

2. Stirring:

Stir the mixture using a magnetic stirrer to help dissolve the drug.

The initial pH of the solution may be around neutral (pH ~7) or slightly basic.

3. pH Monitoring:

Use a calibrated pH meter to monitor the pH of the solution.

4. pH Adjustment:

If the pH is too low and the drug is not dissolving well, gradually add NaOH solution dropwise to raise the pH.

If the solution is too basic and precipitation occurs, adjust by adding HCl solution dropwise to lower the pH.

The optimal solubility for diclofenac sodium is typically achieved in alkaline pH range (~7.5 to 9.0), where it remains in ionized form and shows better solubility.

Advantages:

• Easy to create and evaluate.
• Easy to produce and speed up.

• uses few chemicals, it can be used for high-throughput testing.

Disadvantages:

• Precipitation danger arises when a substance is diluted in an aqueous medium whose pH is lower than its solubility.
• Intravenous emboli and oral variations could arise from this.
• Extreme pH and non-physiological pH are linked to tolerance and toxicity (local and systemic).

Super critical fluid process:

Introduction:

The supercritical fluid process  Super Critical Fluids (SCFs), which can dissolve nonvolatile solvents, contain carbon dioxide as their critical point.  A SCF exists as a single phase above its critical temperature and pressure.  SCFs have characteristics that are useful for product processing since they are a transition between pure liquids and gases.  Furthermore, density, transport characteristics like viscosity and diffusivity, and other physical qualities like dielectric constant and polarity are all significantly impacted by even small changes in operating temperature, pressure, or both near the critical points. The most common supercritical solvents include n-pentane, ethylene, propylene, nitrous oxide, water, ethanol, and ammonia.  Techniques have been developed to address various aspects of these problems, including aerosol-based SCF processing, impregnation or infusion of polymers with bioactive materials, precipitation with compressed antisolvents (PCA), solution enhanced dispersion by supercritical fluid (SEDS), compressed fluid anti-cosolvent, and rapid expansion of supercritical solutions. [5]

Procedure: Supercritical Anti-Solvent (SAS) Method

1. Preparation of Drug Solution:

Dissolve diclofenac sodium in an appropriate organic solvent (e.g., ethanol  or  methanol) to form a drug solution.

2. Setup of SAS System:

Load the solution into a high-pressure chamber.

Preheat the CO? and bring it to supercritical conditions (temperature > 31.1°C, pressure > 73.8 bar).

3. Injection:

Inject supercritical CO? into the chamber containing the drug solution.

The CO? acts as an anti-solvent, reducing the solubility of diclofenac sodium in the solvent and causing it to precipitate.

4. Particle Formation:

Fine particles of diclofenac sodium are formed due to rapid precipitation.

These particles typically exhibit reduced particle size, improved surface area, and better solubility.

5. Separation and Drying:

After precipitation, depressurize the system slowly.

Collect the dried, micronized diclofenac sodium particles from the chamber.

Advantages:

• Drug particles can be micronized within specified particle size ranges, often to sub-micron levels, thanks to the accuracy and flexibility offered by SCF methods.
• The drug particles can be recrystallized with much lower particle sizes after they have been dissolved in the SCF.

Pastillation :

Introduction:

For improved handling and solidification, the chemical industry frequently uses the pastillation process.  Pastilles are distinct, hardened objects that originate directly from the melt mixture.  However, this pastillation technique has not yet been used to study the drug delivery mechanism.  According to published research, it is a new, simple, and efficient way to increase solubility and dissolving rate.  Kolliphor HS 15, a polymer chosen following solubility testing, was used to create the Diclofenac Sodium pastilles.  The yield percentage, medication content, solubility analysis, and dissolving test were assessed following FT-IR confirmation of the pastilles' manufacture. Pastillation may therefore be a quick and simple way to improve the solubility, rate of dissolution, and bioavailability of medications with good permeability but poor water solubility. [6]

Procedure:

1. Preparation of the Molten Mass:

The drug is melted alone or with solubilizing excipients (e.g., PEG, surfactants).

Temperature is controlled carefully to avoid degradation.

2. Droplet Formation:

The molten material is allowed to form uniform droplets using a drop former (e.g., rotary drum with perforations or nozzles).

Droplets are typically deposited on a cooling surface like a steel belt or drum.

3. Solidification:

As the droplets contact the cooled surface, they solidify quickly into pastilles.

Rapid cooling may trap the drug in an amorphous or metastable crystalline state, which has higher solubility and dissolution rate than its stable crystalline form.

4. Collection and Packaging:

The pastilles are collected at the end of the belt.

They can be directly packaged or milled into powders for formulation.

Micro emulsion:

 Introduction:

Micro emulsions' improved bioavailability and controlled drug release make them more important as drug delivery systems.  Micro emulsions are transparent in terms of optics.  These are low viscosity, thermodynamically stable oil and water dispersions stabilised by surfactants, usually employed in combination with a co-surfactant.  There are three types of micro emulsions: oil-in-water, water-in-oil, and bicontinuous.  In addition to including proteins for oral, parenteral, and percutaneous/transdermal delivery, micro emulsions have been utilised to increase the solubility of certain medications that are essentially insoluble in water. A micro emulsion, which is an optically transparent pre-concentrate, dissolves a drug that is poorly soluble in water by combining hydrophilic solvent, oil, and hydrophilic surfactant.  When the formulations come into contact with water, they "self emulsify," or scatter, creating a highly transparent emulsion of uniformly small oil droplets that contain the weakly soluble solubilised medication.  Micro emulsions are transparent (or translucent) systems of oil, water, and surfactant that are isotropic, thermodynamically stable, and commonly combined with a co-surfactant.  Typically, their droplet sizes range from 20 to 200 nm. [7]

Procedure:

1. Preformulation Studies

Conduct solubility studies of diclofenac sodium ( various oils, surfactants, and co-surfactants.)

Select components with highest solubility.

2. Construction of Pseudoternary Phase Diagrams

Prepare mixtures of selected oil, surfactant, and co-surfactant.

Titrate with water to identify micro emulsion regions.

3. Preparation of Drug-Loaded Microemulsion

Incorporate diclofenac sodium into the selected phase.

Mix with water to form a clear, stable micro-emulsion.

4. Characterization of Microemulsion

Evaluate the conductivity, pH, zeta potential, droplet size, and polydispersity index (PDI).  Conduct tests for thermodynamic stability using centrifugation and freeze-thaw cycles.

 5. In-Vitro Drug Release Studies

 Evaluate drug release profile using appropriate methods (e.g., dialysis bag diffusion).

 6. Stability Studies

  Store formulations at various  temperatures.

  Monitor physical appearance, droplet size, and drug content over time.

Advantages:

• Manufacturing the pre-concentrates is rather simple.
• Drug release from well-developed micro emulsion pre-concentrates is often independent of digestion.  Thus, without concurrent food administration, excellent bioavailability and repeatability can likewise be anticipated (i.e. the fasting state).

Disadvantages:

• The hydrophilic solvent's dilution impact may increase the drug's precipitation tendency upon dilution.
• When long-term chronic administration is the goal, formulations containing substantial amounts of synthetic surfactants may not be as tolerable.  

Solid dispersion:

Introduction:

For the solute to dissolve uniformly in an appropriate solvent and provide the necessary pharmacological response, solubility is a crucial factor in reaching the intended concentration in a systemic circulation. Only 50–60% of the new chemical entities (NCEs) generated in industry are soluble in water; the rest are relatively insoluble. This is the primary issue with drug formulation development.  Improving the solubility and bioavailability of medications that are not very soluble in water is one of the most challenging aspects of drug research.  A member of the phenylacetic acid class, diclofenac is a non-steroidal anti-inflammatory drug (NSAID) that has analgesic, anti-inflammatory, and antipyretic effects.  It was first presented in 1973 and is a member of BCS class II. It has poor solubility and high permeability. Different diclofenac formulations have been created to improve patient adherence and effectiveness. In order to improve the safety profile, patient adherence, and one-daily dose regimen for patients with chronic pain, a controlled release formulation of diclofenac sodium was created. It is slightly insoluble in chloroform, toluene, and ether; it is soluble in ethanol and easily soluble in glacial acetic acid, water, and acetic acid. [8]

Procedure: Preparation of Solid Dispersion

1. Solubility Studies:

Determine the solubility of diclofenac sodium in various carriers to select the most suitable one.

2. Weighing:

Accurately weigh diclofenac sodium and the selected carrier in a specific ratio (e.g., 1:1, 1:2, or 1:3 w/w).

3. Dissolution:

Dissolve both the drug in minimum amount of solvent (e.g., methanol) under continuous stirring to form a clear solution.

4. Solvent Evaporation:

Remove the solvent by:

Using a rotary evaporator under reduced pressure, or Heating on a water bath at a temperature below the melting point of the drug and carrier with constant stirring.

5. Drying:

Allow the resultant solid mass to dry completely in a desiccator over silica gel or in a vacuum oven to remove residual solvent.

6. Pulverization:

Grind the dried mass gently using a mortar and pestle.

7. Sieving:

Pass the pulverized mass through a 60-mesh sieve to obtain uniform particle size.

Hydrotropy

The scientist Neuberg initially proposed the idea of hydrotropism in 1916. He described hydrotropy as an increase in a substance's solubility when alkali metal salts of different organic acids are present in large concentrations. Two groups make up a typical Neuberg's hydrotropic salt. The first is an anionic group, which gives it its great solubility in water. The mechanism of hydrotropic solubilization is attributed to a hydrophobic ring structure. The type of metal ion or anion has a slight impact on solubilization.

Hydrotropic agent:

Freely soluble organic chemicals known as hydrotropic agents significantly boost the water solubility of organic molecules that are otherwise nearly insoluble at concentrations high enough to cause a stack- type aggregation. These substances could be neutral, cationic, or anionic molecules. Since many different chemicals have been employed as hydrotropes, it is challenging to categorize them. Chemical structure has been used to categorize them.

Mechanism of hydrotropic solubilization:

A hydrotrope dissolves substances in aqueous solutions that are insoluble or poorly soluble in water.  Its hydrophilic and hydrophobic constituents are insufficient to cause the spontaneous self-aggregation observed in surfactants.  Changes in the solution's solubility, surface tension, conductivity, or viscosity are often signs of the minimum hydrotrope concentration (MHC), which is the concentration at which self-association begins.  Hydrotrope molecules initially associate pairwise, in contrast to micellar association.  This initial association is followed by subsequent stages to generate trimers, tetramers, and so forth. The entropy contribution from water molecules released from the structural shell surrounding the negative ions was found to be the association's main free energy component, and it was estimated to be the relationship's primary free energy component.  Nicotinamide is a well-studied hydrotropic material that demonstrates stacking-type complexation.  The solubilizing activity of hydrotropes and aromatic planar structures is believed to be primarily caused by their predilection for aromatic ring stacking in an aqueous environment. The degree of aromaticity of the hydrotropic agent influences its dissolution rate.  Nicotinamide forms 1:1 complexes with medication molecules at low dosages and 1:2 complexes with drug molecules at higher levels.  Ionic organic salts, such as urea, sodium benzoate, and sodium citrate, are hydrotropic substances.  are used as additives that can alter the solubility of a solute in a specific solvent.  A phenomenon called "hydrotropism" happens when certain salts that have large anions or cations that dissolve well in water cause non-electrolytes to "salt in."[10]

• Advantages: -

Hydrotropy is superior to other solubilization methods including miscibility, micellar solubilization, co-solvency, and salting since its solvent characteristic is pH-independent.  The hydrotrope and medicine are simply dissolved in water.  Since organic solvents are not used, it is advantageous for the environment.  There is no need to prepare the emulsion system.  The hydrotropes are known to self-assemble in solution.

• Disadvantages:-

 Overuse of hydrotropic compounds might result in issues linked to toxicity.  The relatively high doses required to reach the MHC limit the commercial application of hydrotropes.  It is possible for medications and hydrotropic substances to interact weakly.  Complete water removal is impossible because water is utilized as a solvent.

Complexation:

Introduction: Increased aqueous solubility and medication stability are the results of complexation with cyclodextrins.  Pharmaceutically significant cyclodextrins consist of six, seven, or eight dextrose molecules (α, β, or γ-cyclodextrin), which are joined in a 1,4-form to create rings with different diameters.  By creating non-covalent inclusion complexes in the ring's lipophilic core and hydrophilic outside, organic molecules of the proper size can improve the ring's aqueous solubility and chemical stability.  The most often utilised β-cyclodextrin derivatives in pharmaceutical formulations are those that are more soluble in water, such as hydroxypropyl-β-cyclodextrin.  It has been demonstrated that cyclodextrin complexes improve the wettability, solubility, and stability of the lipophilic insect repellant N-diethyl-m-toluamide in addition to the stability and photostability of sunscreens. 58, 59  Given their 1000Da molecular weights, it makes natural that cyclodextrins would have trouble penetrating the skin.  Numerous studies have demonstrated that complexation with cyclodextrins can both promote and prevent skin penetration.  62–64  Loftsson and Masson reviewed the evidence and came to the conclusion that skin penetration might be affected by the cyclodextrin content.  They found that low cyclodextrin concentrations resulted in greater flux, while comparatively high cyclodextrin concentrations generally showed lower flux.[2]

Procedure:

1. Weighing:

Accurately weigh diclofenac sodium and β-cyclodextrin in a 1:1 molar ratio. Adjust weights based on the molecular weights of the compounds.

2. Dissolution:

Dissolve the weighed β-cyclodextrin in a minimal volume of distilled water.

Heat the solution to 70°C with continuous stirring to facilitate dissolution.

Once β-cyclodextrin is completely dissolved, add diclofenac sodium to the solution.

Continue stirring at 70°C until a clear solution is obtained, indicating the formation of the inclusion complex.

3. Cooling:

Allow the solution to cool slowly to room temperature over approximately 12 hours.

This slow cooling facilitates the crystallization of the inclusion complex.

4. Crystallization:

Let the solution stand undisturbed for several days to allow complete crystallization of the complex.

Crystals of the inclusion complex will form as fine, colorless needles with a hexagonal cross-section.

5. Filtration and Drying:

Filter the crystals using appropriate filtration techniques to separate them from the mother liquor.

Dry the collected crystals in a drying oven at 40°C or use a lyophilizer to remove residual moisture.

Mixed co-solvency:

High concentrations of a single solubilizer, like a hydrotrope, are typically the most popular methods for increasing solubility.  A practical method for achieving an additive or even cooperative rise in drug solubility is mixed co-solvency, which involves combining these compounds at lower individual concentrations.  However, using PEG200, 300, 400, urea, and sodium benzoate in high concentrations can cause formulation issues.  Mixed co-solvency has several advantages, including better formulations, reduced toxicity, and enhanced solubility.  Several analytical techniques use the co-solvency notion to evaluate solubility. [9]

• MATERIAL AND METHOD:

Every chemical and solvent that was used was of analytical quality.  The solubilizer solutions were made with distilled water.  For quantitative analysis, a Shimadzo UV-1900i spectrophotometer was employed.

UV Spectroscopy:

Introduction: UV-Vis, or ultraviolet visible, spectroscopy is widely used to give information on the characteristics of different materials.  UV-visible spectroscopy can be used to identify inorganic or organic, solid or liquid groups, including organic compounds and functional groups.  It can also be used to evaluate reflectance for dissolution kinetics, paints, coatings, textiles, biochemical studies, and band gap measurements.  The UV-Vis gives these facts based on the various reactions of samples and the degree of transmission or absorption of a particular beam light wavelength.

Electromagnetic spectrum:

Ultraviolet visible, or UV-Vis, spectroscopy is frequently used to provide details about the properties of various materials.  Inorganic or organic, solid or liquid groups, including organic molecules and functional groups, can be identified using UV-visible spectroscopy.  Additionally, it can be used to assess reflectance for band gap measurements, biochemical research, paints, coatings, textiles, and dissolution kinetics.  Based on the different reactions of samples and the degree of transmission or absorption of a specific beam light wavelength, the UV-Vis provides these facts. [11]

Principle:

According to the Beer-Lambert equation, a solution's absorbance (A) is inversely related to its route length (b), absorbing species concentration (c), and near-infrared ranges.  Accoring to the Beer-Lambert equation, a solution's absorbance (A) is inversely related to its route length (b), absorbing species concentration (c), and near-infrared ranges.  I0 and I, respectively, represent the incident and transmitted radiation intensity. 

Absorbance  A = molar absorptivity constant x concentration x cell length.

A= abc

C= A/ab 

where A stands for molar absorptivity,

 b for path length, and

 c for concentration in the absorbance equation. [12]

Method:

After carefully weighing 40 mg of diclofenac sodium, it was added to a 50 ml volumetric flask.  Forty millilitres of distilled water were combined with this.  The drug was dissolved by shaking the flask, and then distilled water was added to bring the volume up to the right level.  Distilled water was used to dilute the stock solution, resulting in concentrations ranging from 10 to 60 µg/ml.  The calibration curve was created by comparing the absorbance at 276 nm to a blank.  Diclofenac sodium's solubility in pure water was noted and demonstrated. [13]

Fig. No 1:  Solubility of diclofenac sodium in purified water.

Table No 1: Solubility of diclofenac sodium in purified water.

Blends of solubilizers were made with varying solvent concentrations (50%w/v constant).  Blend 1 contains urea, sodium lauryl sulphate, sodium citrate, and sodium acetate.  In Blend 2, urea, sodium benzoate, PEG200, and sodium acetate are present; in Blend 3, urea, PEG200, sodium citrate, and sodium acetate are present; and in Blend 4, urea, sodium citrate, sodium benzoate, and sodium acetate are present (Table 2)

Table No. 2: Content of blends

Fig No 2: Preparation of blends.

Fig No 3: Solutions of diluted blends

Solution was achieved, the mixture was agitated forcefully for a predetermined amount of time at regular intervals.  The mix was used to dilute the resultant solution up to 500 milliliters.  Take one milliliter of the diluted solution and dilute it once more using one hundred milliliters of distilled water.  Next, this solution's absorbance was measured at 276 nm in comparison to the solvent blend.  The absorbance was measured at the same wavelength for the other blends, blends 2, 3, and 4, correspondingly, using the same process.  By comparing the drug's solubility in water, the improved solubility was determined. The matching concentration provides the drug's solubility. [13]

Fig.No.4: Determination of absorbance of different blends.

• RESULTS AND DISCUSSION:

Table No. 3:  Solubility of diclofenac sodium in different blends.