Solubility

Introduction
Effect of bonding on solubility
Importance of Solubility
Types of Solutions
Factor affecting Solubility
Phase Solubility Analysis
Need for solubility enhancement
Technique for solubility enhancement
Reference

1. SOLUBILITY Prepared By: Dolly Sadrani Department of Pharmaceutics I st Sem M.Pharma 1

2. Introduction Effect of bonding on solubility Importance of Solubility Types of Solutions Factor affecting Solubility Phase Solubility Analysis Need for solubility enhancement Technique for solubility enhancement Reference 2 CONTENTS:

3. Solubility Qualitative term : Solubility is defined as, “the spontaneous interactions of two or more substances to form a homogeneous molecular dispersion”. Quantitative term : Solubility is defined as, “the concentration of a solute in a saturated solution at a constant temperature”. 3 ( 1,2) INTRODUCTION:

4. As Per USP and IP (2014) 4 Sr no. Descriptive Term Parts of Solvent required For 1 Part Of Solubility 1 Very Soluble < 1 2 Freely Soluble 1 to 10 3 Soluble 10 to 30 4 Sparingly Soluble 30 to 100 5 Slightly Soluble 100 to 1000 6 Very Slightly Soluble 1000 to 10,000 7 Practically insoluble > 10,000

5. As per IP 1996, 5 Sr no. Descriptive Term Approximate volume of solvent in milliliters per gram of solute 1 Very Soluble < 1 2 Freely Soluble 1 to 10 3 Soluble 10 to 30 4 Sparingly Soluble 30 to 100 5 Slightly Soluble 100 to 1000 6 Very Slightly Soluble 1000 to 10,000 7 Practically insoluble > 10,000

6. Solvent: Holes open in the solvent Solute: Molecules of the solid break away from the bulk Solution: The solid molecule is integrated into the hole in the solvent 6 SOLUBILITY PROCESS:

7. When the solute molecules are dispersed, the bonds or attraction holding the particles are replaced by interactions between solvent and solute. Example Clofibrate is sparingly soluble in aqueous solvent due to C-C bonds are much stronger than the possible interaction between carbon atoms and water molecules. When Clofibrate is dissolved in water a chemical reaction must takes place in which multiple covalent bonds are broken. By this we conclude that the stronger the interaction between the solute particles, less favourable for the water solubility. The stronger the interaction between solute and solvent molecules, solubility will increases. 7 (11) EFFECT OF BONDING ON SOLUBILITY:

8. For Increasing the Bioavailability. Achieve desired concentration of drug in systemic circulation. Currently only 8 % of new drug candidates have both high solubility and permeability. Nearly 40% of the new chemical entities discovered as poorly water soluble. Selection of solvent for dosage form. Selection of dosage form. Information about the structure, Inter molecular forces. Selection of dissolution medium. Separation of mixtures. 8 (5) IMPORTANCE OF SOLUBILITY:

9. Separation of optical isomers. Detection of impurities. Preparation of reference substances. Determination of physicochemical properties. 9

10. Under saturated: It is a state of a solution that contain less of a solute than could be a dissolved by that quantity of solvent under normal circumstances. Saturated: Solvent holds as much solute as is possible at that temperature. Dissolved solute is in dynamic equilibrium with solid solute particles. Unsaturated: Less than the amount of the solute for that temperature is dissolved in the solvent. Supersaturated: Solvent holds more solute than is normally possible at that temperature. 10 TYPES OF SOLUBILITY:

11. 11

12. 1. The nature of the Solute and Solvent: When two substances are similar they can dissolve in each other. Polar solute is dissolve in polar solvent. Non polar solute is dissolve in non polar solvent. “ LIKE DISSOLVES LIKE ” Two liquids dissolve in each other because their molecule are a like in polarity. 2. Temperature: Raising the temperature will increases the solubility. 12 ( 8) FACTORS AFFECTING ON SOLUBILITY:

13. 3. Pressure: When the pressure is increased over the solvent, the solubility of the gas is increased. Henry’s Law: “ Solubility of gas is directly proportional to the partial pressure of the gas above the liquid.” 4. Surface area: The greater the surface area per unit mass, the quicker it will dissolve. 13

14. PSA is the quantitative determination of purity of a substance through the application of precise solubility measurement. variability of solubility indicates the presence of an impurity or impurities. Steps to determine the solubility: Control temperature and pressure. Add a quantity of solid to the solvent in the excess of what will dissolve. Let the system come to the equilibrium. Use the specific assay to determine how much of the substance (Concentration) in solution. 14 (3,4,12) PHASE SOLUBILITY ANALYSIS:

15. Solvent Selection: Sufficient Volatility Boiling point in between 60-150℃ Not react with test substance Don’t form solvates, salt Pure in nature The test compound has solubility about 10-20mg/ml in the solvents system. 15

16. Mixing, in series of separate systems, increasing quantities of material and fixed amount of solvents Establishment of equilibrium at identical constant temperature and pressure Separation of solid phase from solution Determination of concentration of the material Plotting the conc. Of the dissolved materials per unit of solvent (Y) against the weight of material per unit of solvent (X) 16 The standard solubility method consists of several distinct steps:

17. Temperature bath - Contain Horizontal shaft (25rpm) - Clam - Vibrator (100-120/Sec) Ampoule Solubility Flask 17 For the method described below the test substance should be soluble to the extent of not less than 4 mg/g and not more than 50 mg/g in the solvent chosen. A solubility of 10-20 mg/g is optimal. Apparatus:

18. Use the constant temperature bath that is capable of maintaining the temperature within ±0.1 and that is equipped with horizontal shaft capable of rotating at approximately 25 rpm. The shaft is equipped with clamps to hold the ampoules. The bath contain suitable vibrator, capable of agitating the ampoules at 100 to 200 vibrations per second, and equipped with the shaft and suitable clamps hold the ampoules. Ampoules: Use 15 ml ampoules. Ampoules and Solubility flask used in phase solubility analysis. 18 Constant Temperature Bath:

19. 19 Apparatus:

20. Mixing of material with Solvent. Establishment of equilibrium. Separation of solid phase from Solution. Determination of concentration of material dissolved per unit of Solvent. Determination of weight of material unit of Solvent. Plotting graph, Extrapolation and calculation. 20 Standard Method:

21. Increased amount of Sample + 5 ml Solvent Cool in dry acetone Double jet air gas burner Weigh all Ampoules 21 System Composition:

22. Calculate the system composition, in mg per g, for each ampoules by the formula: C system (mg/ml)= 1000×(W 2 - W 1 ) / (W 3 – W 2 ) Where, W 1 = Weight of the ampoule plus test substance W 2 = Weight of the empty ampoule W 3 = Weight of the ampoule plus test substance, solvent and separated glass 22

23. Equilibrium is obtained more rapidly by the vibration method (1-7 days) than the rotational method (7-14 days). Determine whether equilibration has been effected 1 ampoule, the next to the last in the series Warmed to 40 ℃ to produce a supersaturated solution. Equilibration is ensured if the solubility obtained on the supersaturated solution falls in line with the test specimens that approach equilibrium from an under saturated solution. 23 Equilibration:

24. Ampoule Water bath Content Settles Open Ampoule 2 ml Aliquot Solubility flask Cool Evaporate vacuum Dry residue 24 Solution Composition:

25. System composition in mg/ gm for each ampoule: 1000(W 2 - W 1 ) / (W 3 - W 2 ) Solution composition in mg/gm for each ampoule: 1000(F 3 –F 1 ) / (F 2 – F 3 ) Where F3: weight of the flask plus residue F1: weight of the solubility flask F2: weight of the flask plus solution 25 Calculations:

26. Percentage Purity=100-100S Where, S= graphically 26

27. BC- Saturate with one component CD- Saturate with 2 components AE- Major Components EF- Minor Components 27

28. Test Specimen + Non Reactive Solvent So that about 10% of the material is dissolved at equilibrium. Sealed and shaken at room temperature until equilibrium is attained Mother liquor is then drawn off and evaporated to dryness. Mother liquor contained impurities that were present in the specimen The residue has been concentrated with respect to the impurities roughly in proportion to the ratio of the weight of specimen taken to the weight of solids dissolved in the volume of solvent used. The undissolved crystals remaining after withdrawal of the mother liquor are usually sufficiently pure to be used as a reference standard after appropriate rinsing and drying. 28 Purification Technique:

29. There are variety of new drugs and derivatives are available. But less than 40% of lipophilic drugs candidates fail to reach market due to poor bioavailability, even these drugs might exhibit pharmacodynamic activities. The lipophilic drugs that reaches market requires a high dose to attain proper pharmacological action. 29 NEED FOR SOLUBILITY ENHANCEMENT:

30. 1. Physical Modification A. Particle Size reduction - Micronization - Sonocrystalisation - Nanosuspension - Supercritical Fluid Process B. Modification of crystal habits - Polymorphs - Pseudopolymorphs C. Drug Dispersion Carriers - Eutectic Mixture - Solid Dispersion D. Lyophilisation 30 (1,7) TECHNIQUE FOR SOLUBILITY ENHANCEMENT :

31. 2. Chemical Modification - Change in pH - Complexation - Salt formation 3. Other Method - Co Crystallisation - Co Solvency - Solubilizing agent - Solvent disposition - Selective Adsorption on insoluble carriers - Using Soluble Prodrug 31

32. Particle Size reduction can be achieved by: Micronization: Micronization increases the dissolution rate of drug through increased surface area. Example: Fenofibrate Nanosuspension: It is a biphasic system consist of nano size drug particles stabilized by surfactant for either oral and topical use or parenteral and pulmonary administration. Example : Azithromycin 32 A. Particle Size Reduction:

33. Sonocrysallisation: In these utilization of ultrasound power for introducing crystallisation. Example: Rosiglitazone Super Critical Fluid Process: A SCF can be define as, “ dense non condensable fluid.” B. Modification of crystal habit: Polymorphs: Polymorphs exist in 2 form (I) Stable form: Shows low aqueous solubility. (II) Metastable form: Shows high aqueous Solubility. Example: Polymorphic form III of riboflavin is 20 times more water soluble than form I. 33

34. Pseudopolymorphs: (Hydrates & Solvates) The anhydrous form of drug has greater aqueous solubility than the hydrates, because of the hydrates are already in interaction with water and therefore have less energy for crystal breakup in comparison to the anhydrous for further interaction with water. Example: Chloroform solvates of griseofulvin more water soluble than their non solvates form. C. Drug dispersion: Eutectic mixture: When these mixture is exposed to water the soluble carrier dissolves leaving the drug in a microcrystalline state which solubilize rapidly. 34

35. Example: Mixture of paracetamol and Urea Solid dispersion: Prepared by solvent or co precipitation method. Guest solute + solid carrier solvent Dissolved in common volatile liquid solvent (Alcohol) The liquid solvent is removed by evaporation under reduced pressure or by freeze drying which results in amorphous precipitation of guest in crystalline carrier which solubilizes rapidly. Example: Amorphous sulfathiazole in crystalline urea. 35

36. Amorphous powder with high degree of interaction between drug and carrier like cyclodextrine. It get in to porous – solubilizes rapidly. Example: Indomethacin having low solubility in water increased by lyophilisation. Change of pH: This can be achieved in two ways (I) In situ salt formation (II) Addition of buffers to formulation Example: Buffered Aspirin tablet. 36 D. Lyophilisation:

37. Complexation: The beta and gamma cyclodextrin having ability to form molecular inclusion complexes with hydrophilic drug having poor aqueous solubility. Example: Barbiturates , Benzodiazepines. Salt formation: Salts have improve solubility in comparison to the original drug. Example,: - Alkali metal salts of acidic drug like penicillin -Strong acid salt of basic drug like atropine are water soluble than parent drugs. 37

38. Co crystallization: It is a define as “ a crystalline material that consist of two or more molecular species held together by non covalent bond. Co solvency: The solubilization of drug in co solvent. Solubilizing agent: Adding various solubilizing material. Solvent disposition: In that poorly water soluble drugs like nifedipine is dissolved in an organic solvent like Alcohol and deposited on an inert, hydrophilic, solid matrix such as starch or MCC and evaporation of solvent is done. 38

39. Selective adsorption on insoluble carriers: A highly active adsorbent like inorganic clays, bentonite can enhance the dissolution rate by maintaining the concentration gradient at its maximum. Use of soluble prodrug: It involves incorporation of polar or ionizable moiety into the parent compound to improve water solubility of corticosteroids, Benzodiazepines. 39

40. 1. International journal of pharma professional’s research review solubility enhancement techniques volume 1, issue 1, July 2010. 2. Journal of Global Pharma Technology Techniques To Solubility of poorly Soluble Drugs Review. 3. The International Pharmacopoeia Eight edition, 2018. 4. The United States Pharmacopeia Volume III. 5. Remington The science and practice of pharmacy 19 th edition Page no. 194-200. 6. World research journal of pharmaceutical Research volume 1, issue 1, 2013. 40 References:

41. 7. International journal of pharma professional’s research review article solubility enhancement techniques volume 1, issue 1, July 2010. 8. https://www.researchgate.net/publication/325686980 9. Journal of pharmaceutical Sciences volume61, issue 7, July 1972, Page no 1069-1075. 10. Phase solubility analysis William J. Madar & Takeru Higuchi Pages 193- 215 Published online 18 Feb 2008. 11. https://chem.libretexts.org 12. Ansel Book of Pharmaceutics Page no. 214 41

42. Thank you For Your Attention! 42