Determination the solubility of drug at room temperature
Aim: To determine the solubility of a drug at room temperature.
Requirements:
Chemicals: 0.01N sodium hydroxide, phenolphthalein indicator, Benzoic Acid, Distilled water
Apparatus: Beaker (250ml)-2, conical flask (100ml)-2, burette, stand, clamp, tile, tripod stand, wire gauze, bulb pipette (5ml), rubber bulb, thermometer, funnel, filter paper.
Principle:
The solubility and dissolution properties of drugs perform a valuable role in the process of formulation development.
Solubility: Solubility is defined in quantitative terms as the concentration of solute in a saturated solution at a certain temperature. Qualitatively, it is defined as the spontaneous interaction of two or more substances to form a homogeneous molecular dispersion. Solubility is commonly expressed as a concentration; for example, as g of solute per kg of solvent, g per dL(100mL) of solvent, molarity, molality, mole fraction, etc. The maximum equilibrium amount of solute that can dissolve per amount of solvent is the solubility of that solute in that solvent under the specified conditions.
Saturated Solution of Drug: It means one in which the drug (solute) is in equilibrium with the solid phase.
Unsaturated Solution of Drug: It means one containing dissolved drug (solute) in concentration below the saturated solution at a specific temperature.
Supersaturated Solution of Drug: It means one that contains more dissolved drug (solute) than necessary for the preparation of the saturated solution at a specific temperature.
Factors Affecting Solubility: 1. Particle size. 2. Temperature. 4. Nature of the solute and solvent. 5. Molecular size. 6. Polarity. 7. Polymorphs.
Importance of Solubility Determination: Drug absorption requires that molecules be in solution at the absorption site. Dissolution of solid dosage forms in gastrointestinal fluids is a prerequisite for the passage of a drug to the systemic circulation following oral administration. The improvement in oral bioavailability is achieved by increasing solubility. Solubility determination is important in the formulation of dosage forms and in deciding the dose of the drug.
Steps involved in solubility determination:
- 1. Preparation of saturated solution of drug
- 2. Filtration
- 3. Analysis for determination of dissolved amount
Techniques of Solubility Improvement: As solubility and permeability are the deciding factors for the in-vivo absorption of the drug, these can be altered or modified by techniques like (A) Physical Modification (B) Chemical Modifications
Procedure:
- Take 50 ml of distilled water in a suitable beaker.
- Add 200mg benzoic acid to the beaker containing water to stir well for 10mins.
- Note the temperature and heat the solution till the temperature increases by 10 degrees from initial temperature.
- Stop heating and cool to room temperature and filter the solution
- Weigh empty conical flask (w1) and transfer 5 ml of the filtered solution to it.
- Take weight of filled conical flask (w2) and titrate against the 0.01N NaOH using Phenolphthalein indicator. End point is colourless to pink.
- Repeat the steps mentioned in 6 and 7 and consider mean of two readings in calculation.
Precautions:
- Determine end point of the titration accurately.
- Use dry filter paper and funnel for filtration.
- Collect filtrate in clean and dry glassware.
Additional Content to Complement the Original Experiment
1. Theoretical Background: The Science Behind Solubility
Solubility is governed by thermodynamic and kinetic factors:
- Gibbs Free Energy (ΔG): Determines spontaneity (ΔG = ΔH – TΔS).
- Hildebrand Solubility Parameter (δ): Predicts miscibility based on cohesive energy density.
- Noyes-Whitney Equation: Explains dissolution rate:
[
\frac{dC}{dt} = \frac{DA}{h} (C_s – C)
]
Where: - (D) = Diffusion coefficient
- (A) = Surface area
- (h) = Diffusion layer thickness
- (C_s) = Saturation solubility
- (C) = Bulk concentration
2. Beyond Benzoic Acid: Testing Different Drugs
- Hydrophilic Drugs (e.g., Ascorbic Acid): Highly water-soluble due to polar groups.
- Lipophilic Drugs (e.g., Ibuprofen): Require surfactants or cosolvents.
- pH-Dependent Solubility (e.g., Weak Acids/Bases):
- Henderson-Hasselbalch Equation:
[
\text{pH} = \text{pKa} + \log \left( \frac{[\text{A}^-]}{[\text{HA}]} \right)
]
3. Alternative Solubility Determination Methods
| Method | Principle | Application |
|---|---|---|
| Shake Flask Method | Equilibrium saturation + HPLC/UV analysis | Broad-spectrum drugs |
| UV-Spectrophotometry | Measures absorbance of saturated solution | Fast, non-destructive |
| HPLC (High-Performance Liquid Chromatography) | Quantifies solute concentration | High precision |
| Thermodynamic Solubility | Uses calorimetry | Research-based studies |
4. Regulatory Perspectives on Solubility
- ICH Q6A Guidelines: Specifications for solubility in pharmacopeias.
- Biopharmaceutics Classification System (BCS):
- Class I (High Solubility, High Permeability): Ideal for oral delivery.
- Class II (Low Solubility, High Permeability): Need solubility enhancement.
- Class III (High Solubility, Low Permeability): Require permeation enhancers.
- Class IV (Low Solubility, Low Permeability): Poor bioavailability.
5. Case Study: Improving Poorly Soluble Drugs
Problem: Ritonavir (Antiretroviral) had low solubility, leading to erratic absorption.
Solution:
- Hot Melt Extrusion (HME) → Amorphous solid dispersion.
- Nanocrystal Technology → Increased surface area.
Result: 10x higher bioavailability.
6. Troubleshooting Common Solubility Issues
| Issue | Possible Cause | Solution |
|---|---|---|
| Precipitation | Rapid cooling/solvent change | Controlled crystallization |
| Poor Dissolution | Large particle size | Micronization/Nanonization |
| pH-Dependent Instability | Degradation at extreme pH | Buffer optimization |
7. Emerging Trends in Solubility Enhancement
- Nanotechnology: Liposomes, polymeric nanoparticles.
- Cocrystals: Improve solubility without chemical modification.
- Supercritical Fluid Technology (SCF): Eco-friendly particle engineering.
Interactive Learning Section
Quiz for Self-Assessment
- What is the role of phenolphthalein in this experiment?
a) Buffer agent
b) pH indicator
c) Solubilizer - Which equation describes dissolution kinetics?
a) Arrhenius
b) Noyes-Whitney
c) Michaelis-Menten - True or False: Smaller particle size decreases solubility.
Answer: False (Increases surface area → Faster dissolution)
Final Takeaways for Pharmacy Students
- Solubility is a multidisciplinary concept (pharmaceutics, physical chemistry, biopharmaceutics).
- Experimental accuracy is crucial for formulation development.
- Innovative techniques (nanotech, cocrystals) are revolutionizing drug delivery.
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