Properties of Solutions and Solubility Manipulation (Part I) - Marshall School of Pharmacy PDF

UNIVERSITY SCHOOL OF PHARMACY Properties of solutions and Marshall solubility manipulation TM Part I...

UNIVERSITY SCHOOL OF PHARMACY Properties of solutions and Marshall solubility manipulation TM Part I School of Pharmacy Biopharmaceutics I Cynthia B. Jones, Ph.D. ©  Marshall Learning Outcomes – Part I School of Pharmacy https://www.sparknotes.com/chemistry/solutions/ https://socratic.org/questions/how-do-solutes-affect-the- https://www.istockphoto.com/vector/tonicity-and-osmosis- boiling-point cell-membrane-and-aquaporin-gm601362806-103401103 https://www.medline.com/product/Large-Volume- colligative/section1/page/2/ Parenteral-Ringers-Injection-USP-by-ICU-Medical/Z05- Define and PF61701 Describe Explain and Compare and colligative explain contrast E osmotic calculate properties of tonicity Value and USP pressure, solutions osmolarity, and Volume osmolality Cynthia B. Jones, Ph.D. © 10/28/2024  Marshall Importance of Solubility School of Pharmacy o Solutions: Molecular dispersions (solid particles less than 1 nm) o Many pharmaceutical dosage forms are solutions: o Syrups o Elixirs o Solutions for the eye, ear, nose, respiratory tract or skin o **Parenteral solutions o Dosage forms that are not solutions must dissolve in aqueous body fluids before they can move across membrane barriers Cynthia B. Jones, Ph.D. © 10/28/2024  Marshall Colligative Properties of Solutions School of Pharmacy o Particles interact with solvent, which Nonelectrolytes Strong Electrolyte influences the properties of the solvent o The degree of solute influence on solvent depends on the type of solute o Nonelectrolytes = Do not ionize in water o Electrolytes = dissociate into ions in solution o Strong electrolytes completely dissociated in solutions o Weak electrolytes partially dissociate in water Cynthia B. Jones, Ph.D. © 10/28/2024  Marshall Colligative Properties of Solutions School of Pharmacy o The alteration of the properties of solvents by solutes depends on the concentration of dissolved particles and not the molar concentration. o Colligative properties (solvent alterations) o Vapor pressure lowering o Boiling point elevation o Freezing point depression o Production of osmotic pressure o Colligative properties are tied together, meaning the effect of a solute on one colligative property can be used to predict the effect of other colligative properties https://chem.libretexts.org/Bookshelves/General_Chemistry/Book%3A_Chem1_(Lower)/08%3A_Solution_Chemistry/ Cynthia B. Jones, Ph.D. © 8.4%3A_Colligative_Properties%3A_Boiling_Point_Elevation_and_Freezing_Point_Depression 10/28/2024  Marshall Osmotic Pressure School of Pharmacy o Osmosis (created by particles in solution) is the movement of water from low concentration to a higher concentration. o Changes in particle concentration of dissolved particles will change each colligative property in a predictable way. o E.g. as concentration of dissolved particles increases, the freezing point will be more depressed and the osmotic pressure of the https://www.quizover.com/chemistry/course/11-4-colligative-properties-solutions-and- colloids-by-openstax?page=7 solution will be increased o The effect of electrolytes on colligative properties of solutions is related to the number of ions rather Cynthia B. Jones, Ph.D. © than the number of moles dissolved in 10/28/2024 solution  Marshall Osmotic Pressure School of Pharmacy o One mole of nonelectrolyte in water produces one mole of dissolved particles o The contributions of different solutes to altering colligative properties are additive o E.g. a solution of sodium, chloride, proteins, and glucose will all contribute to the osmotic pressure of a solution https://byjus.com/chemistry/colligative-properties/ Cynthia B. Jones, Ph.D. © 10/28/2024  Marshall Osmotic Pressure of Drug Solutions School of Pharmacy o Pharmaceutical scientist use freezing point depression and osmotic pressure of aqueous solutions to develop systems to adjust the osmotic pressure of drug solutions that are injected or applied to mucous membranes o The van’t Hoff equation is the basis for these calculations ΔTf = iKfm o where ΔTf is the freezing point depression of water caused by the solution, i is the deviation from ideal Cynthia B. Jones, Ph.D. © behavior created by solute interactions Kf (van’t 10/28/2024 Hoff factor) is 1.86 and m is the concentration of  Marshall Solute structure & Number of Dissolved Particles School of Pharmacy o Van’t Hoff recognized the effect of electrolytes on colligative properties was related to number of ions rather than the number of moles dissolved in solution o E.g. 1 mol/kg solution of NaCl has about 2x the freezing point lowering capability of 1 mol/kg solution of dextrose o i factor for NaCl is not 2 because osmotic activity of the two ions is decreased by interactions with other ions in solutions o i factor corrects for the deviation from ideal behavior that is observed in solutions of pharmaceutical interests o For weak electrolytes, the i factor is reduced significantly as the concentration increases Cynthia B. Jones, Ph.D. © 10/28/2024  Marshall Molality School of Pharmacy o Molality is a property of solutions. Defined by moles of solute per kilogram solvent (molal) o Useful in the measurement of a solution which will be frozen (freezing will change volume) o Molarity (moles of solute per liter of solution) is the preferred concentration https://chemicproject.wordpress.com/2014/04/17/solutions-and-solubility/ convention for solutions at room temperature o Molality can be converted to molarity using the density of the solution https://viziscience.com/chemistry-mole-concept/molarity-change- temperature/ 10/28/2024 Cynthia B. Jones, Ph.D. ©  Marshall Osmolality School of Pharmacy o The USP designates the units for expressing the osmotic pressure of a solution across a semipermeable membrane as osmoles per kg or mosmoles per kg of water (osmolality) o One osmole = 1 mole of dissolved particles; e.g. for a nonelectrolyte, 1 mole equals 1 osmole and by definition would lower the freezing point of water by 1.86°C o The Osmolality of blood and other body fluids is between 285 and 310 mosmol/kg o Drug solutions typically have osmotic https://pediaa.com/difference-between-osmolarity-and-osmolality/ concentrations in the millisomolal range Cynthia B. Jones, Ph.D. © 10/28/2024  Marshall Osmolarity School of Pharmacy o Osmolarity is the number of osmoles or miliosmoles per liter of solution is calculated and cannot be directly measured o The USP provides the following equation to calculate theoretical osmolar concentration of multicomponent drug solutions ΣiiCi Where ii is the van’t Hoff factor of each https://pediaa.com/difference-between-osmolarity-and-osmolality/ component and Ci is the molar concentration Cynthia B. Jones, Ph.D. © 10/28/2024  Marshall Tonicity & Isotonicity School of Pharmacy o Tonicity is used to describe the osmotic pressure exerted across a membrane in the body o Isotonic exerts the same pressure as body fluids; dissolved particles equal o Hypertonic solutions have more dissolved particles than body fluids o Hypotonic solutions have fewer dissolved particles than body fluids o Hyper/Hypotonic ophthalmic or nasal preparations cause tearing or nasal discharge, which flushes away applied drug and reduces medicinal action o Ophthalmic concentrations can have a sodium chloride equivalent between 0.6 to 2% without significant discomfort to the patient Cynthia B. Jones, Ph.D. © 10/28/2024 https://www.quora.com/What-happens-when-you-place-a-cell-in-a-hypotonic- solution  Marshall Tonicity and E-Value School of Pharmacy o Tonicity is calculated using the E-value o The E-value system was developed to facilitate the addition of tonicity agent (an ingredient that increases the osmotic pressure of a solution) measured by weight of a solid o The USP volume method was developed to facilitate the addition of a tonicity agent as an isotonic solution o E-value is defined as the weight of NaCl equivalent to 1 gram of drug or other solute E= Where FW is the formula weight of the substance in grams, i the van’t Hoff factor and Kf =1.86 Cynthia B. Jones, Ph.D. © 10/28/2024  Marshall USP Volume School of Pharmacy o The USP volume is defined as the volume in ml of an isotonic solution that can be prepared by adding water to 1 gram of drug o This equation can be used when you add a tonicity agent as an isotonic solution o Can be calculated from the E-value using the White-Vincent equation: Volume of water = W x E x 111.1 Where, W = weight of drug E = NaCl equivalent of the drug Cynthia B. Jones, Ph.D. 111.1 = represents isotonicity (100/0.9) 10/28/2024 ©  Marshall Review Learning Outcomes – Part I School of Pharmacy 6.1 Describe the concept of solubilization 6.2 Describe colligative properties of solutions 6.3 Define and explain osmotic pressure, osmolarity, and osmolality 6.4 Explain and calculate tonicity 6.5 Compare and contrast E Value and USP Volume Cynthia B. Jones, Ph.D. © 10/28/2024  UNIVERSITY SCHOOL OF PHARMACY Properties of solutions and Marshall solubility manipulation Part TM II School of Pharmacy Biopharmaceutics I Cynthia B. Jones, Ph.D. ©  Marshall Learning Outcomes – Part II School of Pharmacy https://medical-dictionary.thefreedictionary.com/ https://www.dharidasandco.com/ https://www.scientificamerican.com/article/solubility- ionization+path NewProdDetails.aspx?prodid=161&v=PH+Solutions science-how-much-is-too-much/ Explain Describe and Predict the pH Apply drug approaches to interpret the of solutions ionization to manipulate ionization of absorption and drug solubility drugs in solubility solution Cynthia B. Jones, Ph.D. © 10/28/2024  Marshall Manipulation of Solubility School of Pharmacy Drug solubility can be manipulated by serval means: pH (use of strong acids, bases or buffers) Cosolvents Solid State manipulation Solubilizing agents: surfactants, cyclodextrins Drug derivatization Cynthia B. Jones, Ph.D. © 10/28/2024  Marshall Solubility and pH School of Pharmacy Approximately 75% of drugs are weak organic bases and 20% are weak acids. Acidic and basic drugs will dissociate into ions when exposed to solutions (in dosage form or in the body) The extent of ionization depends on the pH in the dosage form or body fluid pH If we manipulate pH to increase the dependent ionization, we can increase the solubility of the drug Cynthia B. Jones, Ph.D. © https://www.slideshare.net/jahidbmc/drug-absorption-27588186 10/28/2024  Marshall pKa and pH School of Pharmacy Understanding the pKa of a compound and pH of a solution can help us: Predict the relative amounts of ionized/unionized forms of a drug at a given pH Choose vehicles to enhance drug solubility Calculate the pH of a drug solution Predict advisability of mixing drug solutions with acidic and basic pHs Predict drug accumulation in body compartments that have different pHs from that of serum Cynthia B. Jones, Ph.D. © https://www.sciencedirect.com/science/article/pii/B9780128144237000034  Marshall Acidic v/s Basic Drug Molecules School of Pharmacy  The terms "acidic" and "basic" in the context of drug molecules refer to their properties as they relate to pH and their ability to donate or accept protons (H+ ions).  These properties are important because they can affect how a drug is absorbed, distributed, metabolized, and excreted in the body, which in turn can influence its efficacy and safety. Cynthia B. Jones, Ph.D. ©  Marshall Acidic Drug Molecules School of Pharmacy  Acidic drug molecules tend to donate protons (H+ ions) to their surroundings.  They are more likely to be positively charged (cationic) when the surrounding environment is acidic.  In physiological conditions, where the pH is around 7.4, acidic drug molecules tend to be in their neutral (uncharged) form.  They may interact with negatively charged components in the body, such as proteins and cell membranes. Cynthia B. Jones, Ph.D. ©  Marshall Basic Drug Molecules School of Pharmacy  Basic drug molecules tend to accept protons (H+ ions) from their surroundings.  They are more likely to be negatively charged (anionic) when the surrounding environment is acidic.  In physiological conditions, basic drug molecules tend to be in their protonated (charged) form because the body's pH is higher than the pKa of the basic group.  They may interact with positively charged components in the body, such as proteins and cell membranes. Cynthia B. Jones, Ph.D. ©  Marshall pH of the Environment School of Pharmacy The pH at the site of drug action or absorption can significantly impact the behavior of acidic and basic drug molecules. In some cases, the ionization state of the drug can affect its solubility, permeability, and ability to bind to its target receptor or enzyme. Understanding the acidic or basic properties of a drug is crucial in pharmacy to optimize drug formulation, absorption, and therapeutic effect. It helps ensure that the drug is in the right form for its intended site of action in the body and that it can reach its target with the desired pharmacological activity. Cynthia B. Jones, Ph.D. ©  Marshall Weakly Basic Drugs School of Pharmacy Amines are included in drugs that are weak bases Unionized form dissolved in water yields: B: + H2O B:H+ + -OH https://www.chegg.com/homework-help/questions-and-answers/structure-non-selective- Ionized form (a salt or conjugate acid) dissolved beta-receptor-antagonist-propranolol-analyze-structural-modificati-q27245369 in water yields: B:H+ + H2O B: + H3O+ Kb tells us the extent of ionization (or dissociation) of the base form of the drug Ka tells us the extent of the ionization (or dissociation) of the acid form of the drug Cynthia B. Jones, Ph.D. 10/28/2024 ©  Marshall Weakly Acidic Drugs School of Pharmacy Carboxylic acids, imides, sulfonamides, phenols, Warfarin thiols and enols are included in drugs that are weak acids Unionized form dissolved in water yields: HA + H2O H3O+ + -A https://en.wikipedia.org/wiki/Warfarin Ionized form (a salt or conjugate base) dissolved in water yields: A- + H2O HA + -OH Ka tells us the extent of the ionization of the acid form of the drug Kb tells us the extent of ionization of the base form of the drug 10/28/2024 Cynthia B. Jones, Ph.D. ©  Drug solution acid or basic Marshall predictions School of Pharmacy The extent of ionization of weak acids and bases is pH dependent For a drug that is a weak base, the unionized form in water will form hydroxide ions and make the solution more basic For a drug that is a weak acid the unionized form in water donates protons and makes the solution acidic A reaction can be pushed to a more soluble ionic form by changing the pH with strong acid or base The extent of ionization of weak electrolytes in water determines the pH of the solution A weak electrolyte in a vehicle with a pH determined by a buffer or a strong acid or base, the pH of the vehicle determines the ionization Cynthia B. Jones, Ph.D. ©  Drug Solution Predictions. Acidic or Marshall Basic? School of Pharmacy We can push this reaction towards the more soluble, ionic form by changing the pH with strong acid or base B:+H2O B:H+ + -OH drive to completion by adding a strong acid B:+ HCl → B:H+ + Cl- When the ionized form (the salt or conjugate acid form) is dissolved in water, it donates protons and makes the solution acidic: B:H+ + H2O B: + H3O+ HA + H2O → A- +H3O+ drive to completion by adding a strong base HA + NaOH → Na+ A− + H2 O When the ionized form (the salt or conjugate base form) is dissolved in water, it forms hydroxyl ion and makes the solution basic: A- + H2O HA + -OH Cynthia B. Jones, Ph.D. © 10/28/2024  Marshall Pharmaceutical Example School of Pharmacy Penicillin G Penicillin G Conjugate base The pKa is 2.76 The Ka is −log Ka = 1.74 × 10−3 Let HA represent penicillin G Let A− represent its conjugate base HA + H2O → A- +H3O+ https://www.sigmaaldrich.com/catalog/product/sigma/ https://en.wikipedia.org/wiki/Benzylpenicillin p7794?lang=en&region=US If Ka is 1.74 × 10−3 we can tell there is more HA in the solution than A− when penicillin G is dissolved in water from the equation for equilibrium constant: Because the Ka is a fraction, there are more reactants, in other words, there is more HA in the solution. If we wanted the ionization of the acid to go to completion, we can use strong base such as sodium or potassium hydroxide for: HA + KOH ⇒ K+A− +H2O which will give K+A− + H2O → HA + K+OH− And we Cynthia B. can Jones, Ph.D. predict a basic pH © 10/28/2024  Drug Solubility Prediction at a given Marshall pH School of Pharmacy Using the Henderson-Hasslebach equation allows us to calculate the degree of ionization of a weak acid at a given pH At pHs below pKa for an acid, HA predominates, which will move through membranes but is less soluble in water Example: Aspirin pKa = 3.5 Cynthia B. Jones, Ph.D. © https://www.memorangapp.com/flashcards/125830/ 10/28/2024 Drug+Absorption+and+Distribution/  Drug Solubility Prediction at a given Marshall pH School of Pharmacy Using the Henderson-Hasslebach equation allows us to calculate the degree of ionization of a weak base at a given pH At pHs below pKa for a base B:H+ predominates and does not move through lipid membranes but is more soluble in water Example: Codeine pKa = 8.2 https://www.memorangapp.com/flashcards/125830/ 10/28/2024 Cynthia B. Jones, Ph.D. © Drug+Absorption+and+Distribution/  Drug Form Prediction at pH in the Marshall Body School of Pharmacy Ion Trapping – body fluids with pH different from blood result in ionized fraction of drug being greater on one side Acidic Drugs accumulate on more basic side of membrane, and basic drugs on acidic side Body Fluids Potential for drug ion trapping include: Breast Milk, Stomach Contents Small Intestinal Contents Urine https://slideplayer.com/slide/ 10834345/ Cynthia B. Jones, Ph.D. 10/28/2024 ©  Drug Form Prediction at pH in the Marshall Body School of Pharmacy Drug HA is a weak acid with pKa 4.4 Its equilibrium concentration is much higher in the plasma (pH = 7.4, total conc. 1001) than in the stomach (pH = 1.4, total conc. 1.001) The ionized form (incapable of diffusion) accumulates in the plasma because of the higher pH which promotes dissociation https://slideplayer.com/slide/ 10834345/ The concentration of HA (capable of diffusion) is equal on both sides of the membrane Cynthia B. Jones, Ph.D. 10/28/2024 ©  Marshall Review Learning Outcomes – Part II School of Pharmacy 6.6 Explain approaches to manipulate drug solubility 6.7 Describe and interpret the ionization of drugs in solution 6.8 Calculate pH of solutions 6.9 Predict drug water or membrane solubility at given pH Cynthia B. Jones, Ph.D. © January 24, 2017  UNIVERSITY SCHOOL OF PHARMACY Properties of solutions and Marshall solubility manipulation TM Part III School of Pharmacy Biopharmaceutics I Cynthia B. Jones, Ph.D. ©  Marshall Learning Outcomes – Part III School of Pharmacy https://www.quora.com/What-are-buffer-solutions http://www1.lsbu.ac.uk/water/cyclodextrin.html Describe Buffer Describe how to manipulate Systems and solubility by cosolvents, solid buffer capacity state, solubilizing agents, cyclodextrins and derivatization Cynthia B. Jones, Ph.D. © 10/28/2024  Marshall Buffers School of Pharmacy Buffers are solutions of weak acids and their conjugate bases that resist changes in pH. (Weak bases are also used, but are less common) Buffers resist changes in pH at pHs where there are substantial amounts of both acid form and conjugate base forms to consume an H+ or OH- ions added to the solution Uses of Buffers: Maximize drug stability Maximize drug solubility Improve patient comfort Improve drug absorption 10/28/2024 Cynthia B. Jones, Ph.D. © http://www.biopharminternational.com/behind-scenes-buffers  Marshall Buffers School of Pharmacy Buffer’s pH is determined by the pKa and the ratio of weak acid and conjugate base. The buffer’s capacity depends on the concentration of buffer components. Buffer concentration should be sufficient to maintain the pH of the dosage form without affecting the pH of the body when the dosage https://www.chegg.com/homework-help/questions-and-answers/show-complete- calculations-buffering-capacity-0500-m-0100-m-acetate-buffers-ch3cooh-aq-rig- form is administered q15104897 10/28/2024 Cynthia B. Jones, Ph.D. ©  Marshall Buffer Selection School of Pharmacy Pharmaceutical buffers are usually used in concentrations between 0.05 and 0.5 molar. The route of administration must be considered when selecting buffers Boric acid are toxic if used parenterally, and can only be used in the eye Buffers made from amines have a disagreeable odor and cannot be used in oral products The buffer pair should have a pKa approximately equal (±1 pH unit of the pKa) to the pH required for the dosage form 10/28/2024 Cynthia B. Jones, Ph.D. ©  Marshall Use of Cosolvents School of Pharmacy A cosolvent is any solvent that is miscible with water Usually mixed with water to produce a blend that is less polar than water and is capable of dissolving a hydrophobic drug at the required concentration Occasionally not used with water to produce a solution dosage form that is miscible with body fluids Blends with water are preferred because undiluted cosolvent is generally not palatable by mouth, uncomfortable by injection, and too viscous for needles 10/28/2024 Cynthia B. Jones, Ph.D. ©  Co-Solvents Influence on Marshall Solubility School of Pharmacy  Frequently, a solute is more soluble in a mixture of solvents (cosolvents) than in one solvent alone (cosolvency).  For example, 1gram of phenobarbital is 1.5% w/v soluble in the following individual phenobarbital solvents: soluble in  100 ml water 22% alcohol,  10 ml alcohol 40% glycerin and 38% water  40 ml chloroform solution  15 ml ether  The solubility of phenobarbital is enhanced in a co-solvent system Cynthia B. Jones, Ph.D. ©  Marshall Solid State Manipulation School of Pharmacy Reduction of the strong attractive forces in a solid by preparation of a lower melting polymorph improves solubility, dissolution rate, and bioavailability Amorphous polymorphs are least orderly and therefore most easily melted and dissolved form of a drug Methods used to prepare amorphous solids do not allow the molecule of a drug enough time to form orderly arrays. Methods include: Rapid precipitation from solvent Rapid cooling of a melt of the drug Spray drying Freeze drying 10/28/2024 Cynthia B. Jones, Ph.D. © https://www.westpharma.com/en/blog/2018/March/emergence-of-plastic-caps  Marshall Solubilizing Agents School of Pharmacy Cyclodextrins are cyclic oligosaccharides derived from starch containing six or more alpha-1,4 linked alpha- D-glucopyranose units Cyclodextrin’s hydroxyl groups are oriented to the exterior of the cone, while carbons and ether oxygens line the interior. The apparent solubility of a lipophilic drug in the cylclodextrin cavity is increased, increasing its dissolution rate and bioavailability. Cyclodextrin-drug complexes may be more stable to hydrolysis, oxidation, and photolysis, and demonstrate lower mucous membrane irritation as a result of lower concentration of free drug. Drugs are released from the complex when they are Cynthia B. Jones, Ph.D. © diluted by body fluids 10/28/2024  Marshall Drug Derivatization School of Pharmacy Drug derivatization can be used to make drug molecules more water soluble and more readily absorbed or less water soluble to achieve sustained release Solubility of drug molecules may be altered by covalently attaching a functional group (usually amides and esters) with the desired solubility properties Derivatized drug molecules are prodrugs because they are not active until the additional functional group is removed in vivo Occasionally a drug molecule is derivatized so that it does not begin to dissolve in the mouth where its bitter taste would be detected Drugs that are unstable in water may be derivatized to reduce the amount of susceptible drug in solution and thus prolong the shelf life in liquid form 10/28/2024 Cynthia B. Jones, Ph.D. ©  Marshall Review Learning Outcomes – Part III School of Pharmacy 6.10 Describe Buffer Systems and buffer capacity 6.11 Describe how to manipulate solubility by cosolvents, solid state, solubilizing agents, cyclodextrins and derivatization Cynthia B. Jones, Ph.D. © January 24, 2017