Solubility and Methods of Solubilization - PDF

Lab.1 Solubility and methods of solubilization Introduction: One of the primary physicochemical considerations in preparing pharmaceutical solutions is the solubility of the drug in a suitable solvent. The solubility of a solute is a physical property referring to its ability to...

Lab.1 Solubility and methods of solubilization Introduction: One of the primary physicochemical considerations in preparing pharmaceutical solutions is the solubility of the drug in a suitable solvent. The solubility of a solute is a physical property referring to its ability to dissolve in a solvent. Studying solubility has many applications in pharmacy, which includes: ▪ Solubility of substance serve as standard test for purity. ▪ The solubility of drug in GI fluid (dissolution)is important step for better absorption. ▪ Side effect of drug are representative of poor aqueous solubility. ▪ Extraction & re-crystalization process Definitions: Solubility may be defined: ▪ In qualitative terms, as the spontaneous interaction of two or more substances to form a homogenous molecular dispersion. ▪ In quantitative terms, as the concentration of a solute in a saturated solution at a certain temperature and pressure. Expressing solubility: The solubility of a substance may be described in a variety of ways as follows: A. Using approximate expressions: in pharmacopeial tests, when it has not been possible (or is undesirable) to indicate exact solubility, one of the following descriptive terms of solubility may be used: Descriptive Term Part of solvent required for 1 part of solute Very soluble Less than 1 part Freely soluble 1-10 parts Soluble 10-30 parts Sparingly soluble 30-100 parts Slightly soluble 100-1000 parts Very slightly soluble 1000-10,000 parts Practically Insoluble More than 10,000 parts 1  B. Using accurate expressions: when quantitative data are available, solubility may be expressed as: g/mL or g/100 mL: here the number of grams of solute dissolved in 1 or 100 mL of solvent at a specified temperature is specified. This is mostly the method used to express solubility in the USP/NF. The number of grams of solute present in grams of saturated solution (for example: 400 gm of saturated solution contains 100 gm of solute and 300 gm of solvent, so the solubility will be 100: 300) Concentration expression: e.g, Molarity (moles of solute in 1 L of saturated solution), normality, mole fraction, percentage, etc. Types of Solutions A. According to nature of solute -Solids in liquids: e.g., glucose & water, most drug solutions -Liquids in liquids: e.g., volatile oils & water (aromatic waters), volatile oils & alcohols (spirits) -Gases in liquids: e.g., ammonia water, pressurized effervescent preparations containing CO2 B. According to saturation state -Unsaturated solutions: solution containing the dissolved solute in a concentration below that necessary for complete saturation at a definite temperature. -Saturated solutions: solution containing the dissolved solute in an amount more of than that it will normally contain at a definite temperature. Saturated solutions are used during the study of solubility of compounds -Supersaturated solutions: Contains more than the usual maximum amount of dissolved solid. Supersaturated solutions are not at equilibrium, they are very unstable, and the excess dissolved solute will crystallize easily. The recrystallization can be initiated by the addition of a piece of dust or a small crystal of the solute (called a seed crystal). Once crystals start to form, their surface area will increase till the solution stabilizes and no more crystals can form. Supersaturated solutions are generally prepared by dissolving more solute at a given temperature than is needed to form a saturated solution in heated water. Usually on cooling of such solutions, the excess solute comes out of solution, leaving the solution saturated at the lower temperature. But sometimes the excess solute does not separate and forms a “supersaturated solution”. 2 Example: Factors affecting solubility: 3 Techniques of Solubility Enhancement (Methods of solubilization) Solubilization is a process of bringing into solution substances that are otherwise insoluble in a given solvent. There are various techniques available to improve the solubility of poorly soluble drugs as shown in the figure below, but only some of these methods will be discussed here. 4 1. Solubilization by Solvent combination (co-solvency): The relationship between polarity and solubility may be used in practice to alter the solubility of a drug in a pharmaceutical solution. This is done by either changing the polarity of the solute or the polarity of the solvent (changing dielectric constant of the solvent); this is done by mixing of solvents of different polarities to form a solvent system of optimum polarity to dissolve the solute. This method is referred to as solvent blending or co-solvency. The solvent used to increase solubility is known as cosolvent. Note: Keep in mind that a cosolvent must be miscible with the initial solvent, available and non- toxic. Experimental work: Objective: To increase water solubility of salicylic acid (weak organic acid which is slightly soluble in water) by solvent combinations, using ethanol as cosolvent. Principle: Mixing solvents of different polarities forms a solvent system of optimum polarity to dissolve SA. Ethanol will be used as a cosolvent with water to solubilize salicylic acid. It makes water less polar and therefore more suitable to dissolve SA. Apparatus and Materials Chemicals: Ethanol, distilled water, salicylic acid (0.1 gm for each group) Glass-ware and equipment: 10 mL pipette, conical flask, glass stirrer, burette with stand, washing bottle containing DW. (For each group) Instruments: Balance (for class) Properties of SA Salicylic acid (SA) is a white crystalline powder, with fine needle or fluffy appearance. It is a weak organic acid, which has polar groups: -COOH and -OH with interacts with H2O but also has intra-molecular H-bonding and benzene ring which can make it “slightly soluble in water”. Solubility in water: 1g/460 mL (at 25 °C) 5 Procedure 1. Weigh 0.1 gm of salicylic acid (SA) and put in a conical flask. 2. Add 10 mL of D.W to it and shake the flask to see the solubility of SA. 3. From a burette, add drop-by-drop absolute ethanol with continuous shaking until the crystals of SA dissolve. Measure the volume of the ethanol used (suppose it is x). 4. Calculate the % of ethanol in the final mixture. 5. Express the solubility as 1 part of SA is soluble in (x) part of y % of alcohol. Results and Calculations 6 2. Solubilization by changing the pH of the system (Salt formation) Solubilization can be achieved by shifting the solute between its molecular (undissociated) state and its ionic (dissociated) state. Such shifts may be produced by altering the pH of the solution. A shift toward the ionic form of a solute improves solubility of the solute in water and other polar solvents. A shift toward the molecular form of a solute improves solute solubility in non- polar solvents. For ionizable organic solutes, or weak electrolytes (i.e, weak acids or weak bases), changing the pH of the system to give a salt form of the weak acid or base (ionized, soluble form) is one of the simplest and most effective means of increasing aqueous solubility. An alkaloid base is, generally, slightly soluble in water, but if the pH of medium is reduced by addition of acid, and the solubility of the base is increased as the pH continues to be reduced. The reason for this increase in solubility is that the base is converted to a salt, which is relatively soluble in water. Likewise, the solubility of slightly soluble acid increases as the pH is increased by addition of alkali, the reason being that a salt is formed. Compounds that do not react with either acids or bases (non-ionizable, hydrophobic organic substances) are not influenced in their aqueous solubility by variations of pH. Experimental work: Objective: To increase the solubility of salicylic acid by salt formation using Na2CO3. Principle: For ionizable organic solutes a shift toward the ionized form of a solute by changing the pH of system improves the solubility of the solute. However, a compromise must be reached during formulation to ensure solubility and stability. SA being a weak acid can be changed to a more water- soluble salt form by addition of a base. Apparatus and Materials Chemicals: Distilled water, salicylic acid (0.1 gm for each group), sodium carbonate (0.1 gm for each group), 10% HCl acid (dilute HCl). Glass-ware and equipment: 10 mL pipette, conical flask, glass stirrer, washing bottle containing DW. (For each group) Instruments: Balance (for class) 7 Procedure: 1. Weigh 0.1 gm of salicylic acid (SA) and put in a conical flask. 2. Add 10 mL of D.W to it and shake the flask to see the solubility of SA. 3. Add 0.1 gm of Na2CO3 to the flask with shaking and observe the result. 4. Add 5 mL of 10% HCl acid (dilute HCl) slowly. Observe the result. 5. Develop an equation to account for your observations in steps 3 and 4. Results and Conclusions: 8 Lab. 2 Solubilization by Complexation Introduction Complexes are species of definite intermolecular associations of substrate (S) and ligand (L) molecules or ions (also called complexing agent) that are kept together in an equilibrium process (in solution, and also may exist in the solid state) by somewhat strong coordinate covalent bonds or by relatively weak non-covalent forces such as hydrogen bonds, van der Waals forces, electrostatic interactions, dipole forces or hydrophobic interactions. The formation of a complex by adding a complexing agent increases the solubility of a compound. Complexation method of solubilization can be used to solubilize both organic and inorganic compounds with low water solubility. Related terminology ❑ Complexing agents (ligands) = molecules or ions that increase the solubility of a compound with low water solubility by forming soluble complexes. Keep in mind, a complexing agent is always water soluble. ❑ Complexation= a term describing the process of covalent or non-covalent interactions between two or more compounds that are capable of independent existence. Types of Complexes 9 1. Metal complexes: Are formed when ionic substrates (Lewis acids) such as transition metal ions (e.g., Fe2+, Fe3+, Co2+, Co3+, Cu2+, Zn2+, Ag+ and Pt4+) bind via coordinate covalent bonds with ligands (Lewis bases) that are neutral molecules or anions. The ligand donates both electrons forming the covalent bond with the substrate. Examples: Water soluble potassium tri-iodide complex (KI3) where Iodine (I2) donates both electrons forming a covalent bond between I2 and K ion. Water-soluble silver-ammonia complex ([Ag (NH3)2] +) where ammonia donates both electrons forming a covalent bond between Ag+ and NH3 2. Organic molecular complexes: are formed when substrates are non-covalently with ligands. These are linked by very weak non-covalent bonds such as hydrogen bonds, hydrophobic bonds, electrostatic interactions, and in aqueous solutions molecules bound within the complexes are frequently in dynamic equilibrium with unbound substrate and ligand molecules Example: Aspirin-TSC complex 3. Inclusion complexes: Are complexes where the ligand (i.e. the host) forms a cavity in which the substrate (i.e. the guest) is located. No covalent bonds are formed between guest and host molecules and the driving forces for the complex formation are usually electrostatic interactions, van der Waals forces, hydrogen bonding, release of conformational strain and charge-transfer interactions. Example: Cyclodextrin and many drugs 10 Experimental work: Objective: To increase the solubility of acetyl salicylic acid (aspirin) by formation of water-soluble complex. Principle: The solubility of slightly soluble organic compound (aspirin) can be increased by addition of water-soluble complexing agent (TSC), which leads to formation of water soluble organic molecular complex of (aspirin-TSC). Apparatus and Materials Chemicals: Distilled water, aspirin (1 gm for each group), trisodium citrate (TSC) (different amounts for each group), phenolphthalein indicator, 0.1 N NaOH solution. Glass-ware and equipment: 10 mL pipette, 50 mL volumetric flask, 2 conical flasks, glass stirrer, funnel, filter paper, washing bottle containing DW, burette with stand and clamp. (For each group) Instruments: Balance (for class) Properties of Chemicals used Aspirin: (also known as acetyl salicylic acid) is odorless colorless-to-white crystals or crystalline powder with a slightly bitter taste which develops the vinegar-like odor of acetic acid on contact with moisture, and is weakly acidic substance. It is slightly soluble in water, which is 1 g per 300 mL water at 25 °C. Trisodium citrate (TSC): White crystalline powder, freely soluble in water (77 gm/100 ml). It is either anhydrous or hydrous (contains 2 molecules of water). It is used in food preservation, blood-collection tubes and for the preservation of blood. The citrate ion chelates calcium ions in the blood by forming calcium citrate complexes, disrupting the blood clotting mechanism. or Anhydrous Trisodium citrate Trisodium citrate dihydrate 11 Procedure 1. Each group will weigh 1 gm of aspirin and put it in a conical flask. 2. Add different weights of TSC to conical flask for each group (0, 0.25, 0.5, 1, 1.5, 2, 4 gm, respectively) 3. Measure exactly 50 mL of DW (use volumetric flask of 50 mL) and add it to the conical flask containing the powders. 4. Shake the flask for 5-10 minutes, observe your result 5. Filter (to get rid of undissolved aspirin), rinse the flask with the first portion of the filtrate, complete the filtration. 6. Take 10 mL of the filtrate from the conical flask and place it in a new conical flask 7. Analyze for aspirin content. This is done after the addition of 1-2 drops of phenolphthalein as indicator and titrating against (0.1 N) NaOH solution. The end point is when the color changes from colorless to pink. Record the end point. 8. Plot percent of aspirin dissolved versus grams tri sodium citrate used. Reaction of Aspirin with TSC 12 Analysis of Aspirin Content Calculations: The reaction between aspirin (acetyl salicylic acid) and sodium hydroxide solution is: 13 ❑ To find out the weight (gm) of aspirin dissolved: Suppose the EP = 2 ml EP x Chemical factor = weight of Aspirin dissolved (present in 10 ml filtrate, since we used only 10 ml filtrate) SO: 2 x 0.018 = 0.036 gm aspirin dissolved by (x) gm TSC (present in 10 ml filtrate) ❑ To find out % aspirin dissolved: Suppose we have 0.036 gm aspirin dissolved, then: X = 0.36 % aspirin is dissolved by (x) gm TSC Tabulation of results and graphical representation After completing the calculations for all the groups, arrange them in the table as follows: Group number TSC (gm) EP (mL) % aspirin dissolved 1 0 2 0.25 3 0.5 4 1 5 1.5 6 2 7 4 14 By plotting your resuls you will have the following figure: Explanation: This occurs when the amount of TSC used is more than that required to solubilize aspirin. The excess will dissociate to citrate and sodium ions. The sodium ions in water will form NaOH solution ( in situ formation of NaOH) which when present in the flask with aspirin will affect on the accuracy of end point obtained during titration (i.e., there are 2 sources of NaOH: one from burette (measurable), the other in the conical flask from TSC hydrolysis (not measurable). This will make EP appear at faster than real EP, and eventually will lead to false calculations in % of aspirin dissolved. 15 Take home questions 1. What happens exactly when you reach the end point? 2. How can you explain the color change when you reach the end point? 3. Which group will have the higher value of EP? Why? 16