LP 13a MONOPHASIC Liquid Dosage Forms PDF

Liquid Dosage Forms Volkmar Weissig, Sc.D., Ph.D. Professor of Pharmaceutical Sciences Professor of Pharmacology and Biomedical Sciences Department of Pharmaceutical Sciences 1  Liquid dosage forms (Overview) For internal use (swallo...

Liquid Dosage Forms Volkmar Weissig, Sc.D., Ph.D. Professor of Pharmaceutical Sciences Professor of Pharmacology and Biomedical Sciences Department of Pharmaceutical Sciences 1  Liquid dosage forms (Overview) For internal use (swallowed) For use in the oral cavity For use on body surface (not swallowed) Single-phase systems Single-phase systems Solutions Single-phase systems Solutions Syrups Mouthwashes Tinctures Elixirs Gargles Collodions Tinctures Throat sprays Multi-phase systems Multi-phase systems Suspensions Suspensions Emulsions (lotions) Emulsions 2  Liquid dosage forms: Role and responsibilities of the pharmacist Dispensing: Attach appropriate label to pre-filled container Repackaging: Pour correct amount into prescription bottle, label and dispense Reconstitution: Add solvent, shake, label and dispense Compounding: Prepare, label and dispense Technical challenges: Issues related to stability, solubility & taste3 Administration of liquid Dosage Forms (DF) Points to consider Requires patients to measure the dose which reduces dosing convenience and accuracy. But allows for greater dosing flexibility. Requires an accurate measuring device. Few drops to several 100 mL’s, 5 to 15 mL most common Biphasic systems must be shaken well to ensure uniformity 4 All drugs, regardless of their route of administration, must exhibit at least limited aqueous solubility for therapeutic efficiency Drugs are either hydrophilic, hydrophobic or amphiphilic Hydrophilic: “water-loving” › Compatible with water; incompatible with oil Hydrophobic: “water-fearing” or Lipophilic: “fat-loving” › Incompatible with water; compatible with oil Amphiphilic: “both-loving” › Compatible with both water and oil 5 Solute A substance undergoing dissolution Solvent A liquid capable of dissolving other substances (solutes) Solubility Maximum amount of solute that can be dissolved. Depends on nature of solute, solvent and temperature. Solution Homogenous mixture of solute and solvent 6 Depending on size of the solute, they are classified as: True solutions: solute < 1 nm Colloidal solutions: solute 1-1000 nm Suspension: solute (particle) > 1000nm 7  Visualizing one nanometer 1 nm / second 100,000 nm 100 nm diameter Stack up 1000 liposomes on top of each other 8 Colloid solution display the “Tyndall effect” = Light scattering by particles 9 A saturated solution is a solution that contains the maximum amount of solute that can be dissolved under the condition at which the solution exists. An unsaturated solution is a solution that contains the dissolved solute in a concentration below that necessary for complete saturation at a given temperature A supersaturated solution contains more dissolved solute than required for preparing a saturated solution and can be prepared by heating a saturated solution, adding more solute, and then cooling it gently. 10  Supersaturated solutions are unstable Shaking or adding a “seed crystal” leads to spontaneous precipitation or crystallization of excess of solute yielding a precipitate and saturated solution Supersaturated Shaking or adding seed crystal 11  Expressing Solubility If solubility is not definitely known, the following descriptive terms may be used: Descriptive Terms Parts of Solvent for 1 Part of Solute Very soluble Less than 1 Freely soluble From 1 to 10 Soluble From 10 to 30 Sparingly soluble From 30 to 100 Slightly soluble From 100 to 1000 Very slightly soluble From 1000 to 10,000 Practically insoluble, or More than 10,000 insoluble > 10,000 ml (10L) to dissolve 1 mg of substance “Very slightly soluble” is closer to insoluble than it is to soluble! 12  Expressing Solubility The solubility of a solute is reported as 1gram of solute per x milliliters of solvent Example: 1 g of NaCl in 2.8 mL of water @ RT Based upon this solubility of NaCl in H2O can we prepare a 45% (w/v) NaCl solution in water? ?? g/ml %w/v (1 𝑔)/(2.8 𝑚𝐿) x 100 mL = 36 g that is 36%w/v Therefore the answer is “No” 13  Expressing Solubility › Solubility is expressed as: – Molarity (M = moles/L of solution) – Molality (m = moles/kg of solvent) – Mole Fraction ( = moles of solute/Total moles) – Percentage (%w/w, %w/v, %v/v) – Parts (ppm, ppb) – Milliequivalents (mEq) and normal (N) solutions 14  Expressing Solubility in USP/NF Lists solubility of drugs as the volume of solvent which will dissolve 1 gram of solute – Must identify solvent! Example: 1 g of boric acid will dissolve in: 18 mL of water 18 mL of ethyl alcohol 4 mL of glycerin USP/NF: Combination of the United States Pharmacopeia (USP) + National Formulary (NF). 15  Solubility versus Dissolution Solubility is the maximum concentration of a solute that can dissolve in a solvent at a given temperature. How long it takes to get to saturation does not matter Dissolution is the process where a solute dissolves in a solvent to form a solution (“Rate of dissolution”) It is all about how long it takes to get to saturation A solute can be very soluble, yet require a large amount of time to arrive at the final, saturation concentration. A solute may have poor solubility in a solvent, yet its dissolution rate may be rapid. 16 Dissolution rate is expressed with the Noyes-Whitney equation S D m CS Cb h M = solid mass (drug particle) [kg] … just “arrived” in GI tract S = surface area of drug particle [m2] D = diffusion coefficient [m/second]… largely related to viscosity of solvent h = thickness of surface saturation phase Cs = drug particle surface (saturation) concentration [kg/L] Cb = drug concentration in bulk solvent (GI tract) [kg/L] 17  dM/dt = drug dissolution rate [kg/sec] dM S D = (Cs -Cb) t = time [sec] dt h Four major conclusions from the Noyes-Whitney equation: 1) “D” decreases with increasing viscosity. The larger viscosity the smaller D and the smaller dissolution rate. 2) The smaller “h” (thickness surface saturation phase), the larger dissolution rate. Stirring increases dissolution rate 18 3) The larger “S” the larger dissolution rate. The smaller the drug particle the higher dissolution rate. Nanoparticles! 4) If drug is absorbed immediately after dissolution: “Sink condition” Cb extremely small, therefore dissolution rate high 19  Main rules and factors for predicting and/or modifying solubility and/or dissolution 20 Classification of solvents 21 Polarity correlates with “Dielectric Constant” = Property of solvent which is related to the amount of energy required to separate two oppositely charged bodies in the solvent as compared to the energy required to separate the same bodies in vacuum. For water = 78.5 at 18C: It takes 78.5 times more energy to separate opposite charged bodies in vacuum versus in water 22  Dielectric constants of some common pharmaceutical solvents at 25 °C Solvent Dielectric constant (no unit, dimensionless) Water 78.5 Glycerine 40.1 Methanol 31.5 Ethanol 24.3 Acetone 19.1 Benzyl alcohol 13.1 Phenol 9.7 Ether 4.3 Ethyl acetate 3.0 23  Dipole moment (electrical polarity of charges) = Basis for the Dielectric Constant Any molecules that can interact with that dipole will be water-soluble: Ions Examples Dipoles next slide Some induced dipoles 24  https://www.flickr.com/photos/121935927@N06/16304482797 Ion - water Dipole – Water https://www.khanacademy.org/ Induced dipole – Water Water – Water Benjah-bmm27 https://commons.wikimedia.org/wiki/File:Hydrogen-bonding- in-water-2D.png 25 In summary: Any molecule having functional groups able to interact with the dipole of water will be water-soluble Hydroxyl group Forms hydrogen bonding CH3-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2- But: Solubility in water decreases as number of carbons increases. Increases MW without increasing polarity 26  Water-solubility increases with polarity of the solute Compound Formula Water Solubility Benzene C6H6 1 g/1430 mL polarity Increased Benzoic acid C6H5COOH 1 g/275 mL Benzyl alcohol C6H5CH2OH 1 g/25 mL Phenol C6H5OH 1 g/15 mL Pyrocatechol C6H4(OH)2 1 g/2.3 mL Pyrogallol C6H3(OH)3 1 g/1.7 mL Increased polarity Benzene Phenol Pyrocatechol Pyrogallol 27  Solubility rule in layman terms: Oil and water “Like dissolves like” don’t mix Polar solutes dissolve in polar solvents Water is a good solvent for: Salts Sugars Non-polar solutes dissolve in non-polar solvents Mineral oil (mixtures of higher alkane), benzene, ether, etc. are good solvents for: Fixed oils (nonvolatile oil of animal or plant origin) Fats Petrolatum (derived from petroleum) Paraffin (hydrocarbon molecules containing 20…40 carbon atoms) 28 Other factors that affect solubility / dissolution 1. pH OVERVIEW 2. Complexation Details to follow 3. Salt and ester formation 4. Influence of foreign substances (salts) 5. Surfactants 6. Polymorphism 7. Temperature 8. Cosolvents 29 Factors Affecting Solubility: pH Solubility of weak acids and bases strongly influenced by the pH of the solution A weak acid is one that does not dissociate completely in solution, while a weak base does not ionize fully in an aqueous solution Weak acids: What happens when we decrease pH? Total solubility decreases as pH decreases (drug becomes charge neutral) Decreasing pH means increasing H+ concentration. CH3COOH CH3COO- + H+ “Adding H+” Weak base: Total solubility increases as pH decreases Causes shift in dissociation (drug becomes ionized) equilibrium NH3 + H+ NH4+ 30 Factors Affecting Solubility: Complexation › The interaction between two solutes (in solution) to form a third compound which has different physical properties than either of the original two › Complexes are sometime used to increase or decrease solubility Hydroquinone / digoxin complexes increase solubility and absorption rate Tetracycline / calcium complexes decrease solubility and absorption rate, and lead to decreased dose absorbed by patient 31  Factors Affecting Solubility: Salts and Esters Solubility can increase or decrease greatly when drug is modified into a salt or ester. Insoluble forms used to formulate a suspension or to increase duration of drug action Compound Aqueous solubility Erythromycin: Erythromycin estolate practically insoluble Erythromycin stearate practically insoluble Erythromycin base slightly soluble Erythromycin ethylsuccinate slightly soluble Erythromycin lactobionate freely soluble Macrolide antibiotic 32  Factors Affecting Solubility: Salts and Esters Penicillin G solution: Freely soluble in water. Immediate action after i.v. Bicillin® (penicillin G benzathine) suspension: Very low solubility. Prolonged action for days after injection. Chlordiazepoxide Solubility (mg/mL H2O) salt Base 2.0 Acetate 4.1 Benzoate 6.0 Tartrate 17.9 Maleate 57.1 Hydrochloride 0 → Ka → finite The less dissociated a weak acid the larger [HA] the smaller Ka 55 Acid-base theory (Brønsted-Lowry) Typical weakly acidic functional groups in drugs https://quizlet.com/223910561/phm-6110-acid-base-equilibria-flash-cards/ 56 Acid-base theory (Brønsted-Lowry) Bases “B” accept protons B + H2O → BH+ + OH- [𝑩𝑯+ ][𝑶𝑯− ] Equilibrium: 𝑲𝒃 = [𝑩] 𝑲𝒃 = base dissociation constant “Strong” base; 𝑲𝒃 is infinite ([B] = zero) “Weak” base; 𝑲𝒃 is finite Weak bases dissociate only partially in water Exist in solution in two forms: Uncharged, un-ionized species Positively charged ions 57 Acid-base theory (Brønsted-Lowry) Typical weakly basic functional groups Aliphatic amines Aromatic amines N-heterocycles Pyridine Imidazole 58 Acid-base theory (Brønsted-Lowry) Relationship between Ka and Kb for conjugated acid-base pairs Ka x Kb= Kw = 10-14 pKW = -log10Kw = 14 pKA = -log10KA pKB = -log10KB pKA + pKB = pKW = 14 59  Test Question Ammonia has a KB = 1.74 x 10-5 at 25oC. Calculate KA for its conjugate acid, NH4+ KA = KW/KB = 1.0 x 10-14 / 1.74 x 10-5 = 5.75 x 10-10 pKA = -log10 (5.75 x 10-10) = 9.26 60 Acid-base theory (Brønsted-Lowry) Note: Quaternary ammonium salts are not weak bases. – Permanently positively charged (accompanied by negative counter- ion like Cl-) – Dissociate completely in water – Behave as strong electrolytes, neither acidic or basic Nitrogen is not protonated 4 Alkyl/Aryl Residues 61 Summary: Weak Acids and Bases Weak Acids and Bases Dissociate partially in water (only a fraction dissociates) Rest remains un-ionized Weak Acids Weak Bases ↓ solution pH when added to water ↑ solution pH when added to water Exists in solution as negative ions and Exists in solution as positive ions and un-ionized molecules un-ionized molecules 62 There are acidic and basic salts, changing pH when dissolved in water Acidic Salt Basic Salt Explanations to follow 63 Acid-base theory (Brønsted-Lowry) Salts of weak bases Example: Morphine sulfate Example: Ammonium chloride 64 Salts formed by weak base and a strong acid = “Acidic salts” Why is ammonium chloride an acidic salt? NH3 + H2O NH4OH NH4+ + OH- Equilibrium shifted to the left: Ammonia dissolved in water slightly increases [OH-] = Weak base Formation of salt: HCl + NH4OH NH4Cl + H2O Strong acid + Weak Base NH4Cl strong electrolyte: NH4Cl → NH4+ + Cl- NH4+ NH3 + H+ Equilibrium on the left, hence NH4+ slightly increases [H+] Therefore it is an acidic salt 65 Acid-base theory (Brønsted-Lowry) Salts of weak acids Example: Sodium acetate Example: Sodium sulfathiazole 66 Salts formed by strong base and a weak acid = “Basic salts” Why is sodium acetate an basic salt? Strong electrolyte: CH3COO-Na+ → CH3COO- + Na+ CH3COO- + H2O CH3COOH + OH- No matter where the equilibrium lies, the presence of acetate anions always causes the formation of acetic acid and OH- Hence, sodium acetate is a “basic salt” 67 Salts formed by strong base and a strong or salts formed by weak base and weak acid are “neutral salts” HCl + NaOH → NaCl + H2O → Na+ + Cl- + H2O Strong acid + strong base Remain dissociated CH3COOH + NH4OH → NH4+CH3COO- → NH4+ + CH3COO- Weak acid + weak base Do not remain dissociated NH4+ H2O NH3 + H3O+ CH3COO- + H2O CH3COOH + OH- No increase of H+ over OH- and vise versa 68 Self Ionization of Water https://chem.libretexts.org/Courses/Mount_Royal_University In pure water at 250C: [H3O+] = 1 x 10-7 mol/L [OH-] = 1 x 10-7 mol/L 69  Concentration of water: How many moles of water in 1L of water? 1L water = 1000g. MW water = 18g 18/1000 = 55.55 mol 55.55 x 55.55 = Huge number in comparison to H+ and OH- concentration. Hardly changes and can be considered as a constant Keq x [H2O] = Kw Introducing -log 70  More about pKa 𝑝𝐾𝑎 = − log 𝐾𝑎 1) pKa is a number that shows how weak or strong an acid is. A very strong acid will have a pKa of less than zero. 71  HA + H + A - KA = [H+] [A-] / [HA] The larger [H+], the smaller [HA], the larger KA The larger KA, the smaller the negative log10 Ka Just as an log 0.5 = - 0.30 -log 0.5 = 0.30 log 5 = 0.69 -log 5 = - 0.69 example: log 50 000 = 4.69 -log 50 000 = - 4.69 72 2) Cannot tell if drug is a weak acid or base from the pKa Phenytoin (acid) + NaOH → Sodium phenytoin Morphine (base) + H2SO4 → Morphine sulfate Phenytoin (acid): pKa 8.3 Morphine (base): pKa 8.0 Look at structure to determine (more in med chem IS sequence) The listed pKA for a base is always the pKA for the conjugate acid. Listed pKA values always refers to the proton donor from that molecule “This is confusing to students, pharmacists, clinicians and experienced scientists” (Wilson and Gisvold’s 10th edition) 73 Ionization and pH: Henderson-Hasselbalch equation › Degree of ionization of weak acids and bases depends on: [𝑏𝑎𝑠𝑒] – pKa 𝑝𝐻 = 𝑝𝐾𝑎 + log See 3 following slides [𝑎𝑐𝑖𝑑] – pH – Used to determine fraction of drug in acidic or basic form in various pH environments State of drug ionization (ionized vs. un-ionized) impacts: ADME (Absorption, Distribution, Metabolism, Elimination) PD (Pharmacodynamic): Interaction with drug receptor 74 Ionization and pH: Henderson-Hasselbalch equation 𝑢𝑛𝑝𝑟𝑜𝑡𝑜𝑛𝑎𝑡𝑒𝑑 General form: 𝑝𝐻 = 𝑝𝐾𝑎 + 𝑙𝑜𝑔 𝑝𝑟𝑜𝑡𝑜𝑛𝑎𝑡𝑒𝑑 Weak acid versions: 𝑠𝑎𝑙𝑡 𝑝𝐻 = 𝑝𝐾𝑎 + 𝑙𝑜𝑔 OR 𝑎𝑐𝑖𝑑 𝐴− 𝐼𝑜𝑛𝑖𝑧𝑒𝑑 𝑝𝐻 = 𝑝𝐾𝑎 + 𝑙𝑜𝑔 OR 𝑝𝐻 = 𝑝𝐾𝑎 + 𝑙𝑜𝑔 𝐴𝐻 𝑈𝑛𝑖𝑜𝑛𝑖𝑧𝑒𝑑 Weak base versions: 𝑏𝑎𝑠𝑒 𝑝𝐻 = 𝑝𝐾𝑎 + 𝑙𝑜𝑔 OR 𝑠𝑎𝑙𝑡 𝐵 𝑈𝑛𝑖𝑜𝑛𝑖𝑧𝑒𝑑 𝑝𝐻 = 𝑝𝐾𝑎 + 𝑙𝑜𝑔 OR 𝑝𝐻 = 𝑝𝐾𝑎 + 𝑙𝑜𝑔 𝐵𝐻 + 𝐼𝑜𝑛𝑖𝑧𝑒𝑑 75  https://study.com/academy/answer/explanation-1-look-up-the-chemical-name-of-aspirin-and-then-its-conjugate-base-as-the-sodium-salt- and-provide-those-names-here-2-the-manufacturer-s-label-for-the-aspirin-lists-aspirin-as-the-acti.html 76 Ionization and pH: Henderson-Hasselbalch equation Conjugated acid / base pairs Ionization and pH: Henderson-Hasselbalch equation “… yet another form” 𝒄𝒐𝒏𝒋𝒖𝒈𝒂𝒕𝒆𝒅 𝑩𝒂𝒔𝒆 Weak acids: 𝑝𝐻 = 𝑝𝐾𝑎 + log 𝑨𝒄𝒊𝒅 𝑩𝒂𝒔𝒆 Weak bases: 𝑝𝐻 = 𝑝𝐾𝑎 + log 𝒄𝒐𝒏𝒋𝒖𝒈𝒂𝒕𝒆𝒅 𝑨𝒄𝒊𝒅 𝑩 Always CONJUGATED Simplified to: 𝑝𝐻 = 𝑝𝐾𝑎 + log 𝑨 acid/base pairs! 77 For weak acids 78 For weak base The listed pKA for a base is always the pKA for the conjugate acid. Listed pKA values always refers to the proton donor from that molecule 79 Practice Problem › Assume – pH in stomach = 1 – pH in intestine = 6 › Aspirin is a weak acid with a pKa of 3.5 › What percent (or fraction) of aspirin is un-ionized in the stomach (pH = 1)? Round the percentage to one decimal place. 80 Practice Problem What percentage of aspirin in un-ionized in the stomach? 𝑠𝑎𝑙𝑡 𝟎. 𝟎𝟎𝟑 𝑼 = 𝑰 𝑝𝐻 = 𝑝𝐾𝑎 + log 𝑎𝑐𝑖𝑑 We know 𝑈 + 𝐼 = 1 Salt = “Ionized” 𝐼 𝑈 = 1 − [𝑰] 1 = 3.5 + log Acid = “Unionized” 𝑈 𝑈 = 1 − 𝟎. 𝟎𝟎𝟑 𝑼 𝐼 −2.5 = log 0.003 𝑈 + 𝑈 = 1 𝑈 STOP here, if you are [U ] (0.003 + 1) = 1 asked to give your −2.5 𝐼 10 = 1.003 𝑈 = 1 answer as a fraction 𝑈 1 𝐼 𝑈 = = 0.997 0.003 = 1.003 𝑈 Fraction un-ionized = 0.997 0.003 𝑈 = 𝐼 % 𝑈 = 0.997 𝑥 100 = 99.7% un-ionized 81  pH … pKA relationship Typical weak acid: CH3COOH Typical weak base: NH3 Decrease pH: Add large amounts of H+ CH3COOH can not accept more protons… stays un-ionized NH3 accepts proton… becomes ionized Increase pH: Remove large amounts of H+ CH3COOH becomes ionized NH3 stays un-ionized 82 pH … pKA relationship in “general terms” Weak acids Almost completely un-ionized when the pH is 2 units below pKa Almost completely ionized when the pH is 2 units above pKa Weak bases Almost completely un-ionized when the pH is 2 units above pKa Almost completely ionized when the pH is 2 units below pKa Acid Base pH < pKa More un-ionized More ionized pH = pKa Equal Equal pH > pKa More ionized More un-ionized 83 Drugs as salts of weak acids and bases › Why salt form might be preferred? – Usually easier to form into stable crystals that are easier to use in manufacturing – Dissolve faster in aqueous solutions – More stable on storage – Easier to handle during processing 84 Drugs as salts of weak acids and bases › Why salt form might be preferred? – Amines › Weak bases › Volatile and unstable › Short shelf life as solids › Shelf life dramatically improves if formulated as the hydrochloride salt 85 Drugs as salts of weak acids and bases › How is salt form selected? – Different salts of the same active drug are distinct products › Chemical and biological properties vary – Example: › Calcium supplements vary in absorption and possible efficacy: – Carbonate – Citrate – Gluconate – Lactate 86 Practice problem › Determine the “fraction and percentage” of the ionized and un-ionized form of Morphine Sulfate in blood (pH=7.4) › Morphine sulfate, pka = 8 𝑼𝒏𝒊𝒐𝒏𝒊𝒛𝒆𝒅 Weak base: 𝒑𝑯 = 𝒑𝑲𝒂 + 𝒍𝒐𝒈 𝑰𝒐𝒏𝒊𝒛𝒆𝒅 87 88 Practice problem › What is the pH of a buffer solution containing 0.05 M boric acid and 0.5 M sodium borate? The Ka value of boric acid is 6.4x10-10 at 25°C. Round your final answer to the nearest hundredth. 89  “Answer Key” pH of a buffer solution containing 0.05 M boric acid and 0.5 M sodium borate? 𝑝𝐾𝑎 = − log 𝐾𝑎 𝑝𝐾𝑎 = − log(6.4 × 10−10 ) 𝑝𝐾𝑎 = 9.19 𝑠𝑎𝑙𝑡 𝑝𝐻 = 𝑝𝐾𝑎 + 𝑙𝑜𝑔 𝑎𝑐𝑖𝑑 0.5 𝑝𝐻 = 9.19 + 𝑙𝑜𝑔 0.05 𝑝𝐻 = 9.19 + 1 𝑝𝐻 = 10.19 90 Determination of pH › [H+] and [OH-] can vary over a wide range (1 - 1x10-14); and therefore, are expressed as pH (-log [H+]) and pOH (-log [OH-]) › Variation over wide range also true for Ka and Kb For water: pH = (-log [H+]) pOH = (-log [OH-]) pKw = -log kw = pH + pOH = 14 General for pKa = -log ka conjugated pKb = -log kb acid/base pair: pKw = pKa + pKb 91 pH of strong acids Example: pH of 0.15 M HCl? › Ca= molar acid concentration › Complete ionization equilibrium › HCl ↔ H+ + Cl- › [H+] = Ca › pH = -log [H+] › pH = -log Ca › pH = -log [0.15] › pH = 0.82 92 pH of weak acids Some times (other teachers) use Ca instead of [HA] + [𝑯 ] = 𝑲𝒂𝑪𝒂 𝒑𝑯 = −𝒍𝒐𝒈 𝑲𝒂𝑪𝒂 93 pH of weak bases − › [𝑶𝑯 ] = 𝑲𝒃𝑪𝒃 › 𝒑𝑶𝑯 = −𝒍𝒐𝒈 𝑲𝒃𝑪𝒃 › 𝒑𝑯 = 𝒑𝑲𝒘 − 𝒑𝑶𝑯 › 𝒑𝑯 = 𝟏𝟒 − 𝒑𝑶𝑯 [B] = Cb = Concentration of base 94 Practice problem Calculate the pH of … 1) a 0.26 M solution of ammonia 2) a 0.05 M solution of ammonium chloride pKb for ammonia is 4.76 95  Answer Key The key is to choose the correct equation from all previously shown slides Ammonia NH3 + H2O NH4OH NH4+ + OH- See previous slide about “pH of weak bases” Ammonium chloride NH4+ NH3 + H+ See previous slide about “pH of weak acids” 96  Answer Key For ammonia For ammonium chloride › 𝒑𝑶𝑯 = −𝒍𝒐𝒈 𝑲𝒃𝑪𝒃 › 𝒑𝑶𝑯 = −𝒍𝒐𝒈 𝑲𝒃𝟎. 𝟐𝟔 𝒑𝑯 = −𝒍𝒐𝒈 𝑲𝒂𝑪𝒂 › 𝒑𝑲𝒃 = − 𝐥𝐨𝐠 𝑲𝒃 𝒑𝑯 = −𝒍𝒐𝒈 𝑲𝒂𝟎. 𝟎𝟓 𝑲𝒘 = 𝑲𝒂 𝑲𝒃 › 𝟒. 𝟕𝟔 = − 𝐥𝐨𝐠 𝑲𝒃 𝑲𝒘 𝑲𝒂 = › 𝑲𝒃 = 𝟏. 𝟕𝟓 𝒙 𝟏𝟎−𝟓 𝑲𝒃 › 𝒑𝑶𝑯 = −𝒍𝒐𝒈 𝟏. 𝟕𝟓𝒙 𝟏𝟎−𝟓 𝒙𝟎. 𝟐𝟔 𝟏𝒙𝟏𝟎−𝟏𝟒 𝑲𝒂 = › 𝒑𝑶𝑯 = 𝟐. 𝟔𝟕 𝟏. 𝟕𝟓𝒙𝟏𝟎−𝟓 › 𝒑𝑯 + 𝒑𝑶𝑯 = 𝟏𝟒 𝑲𝒂 = 𝟓. 𝟕𝟓𝒙 𝟏𝟎−𝟏𝟎 𝒑𝑯 = −𝒍𝒐𝒈 𝑲𝒂𝟎. 𝟎𝟓 › 𝒑𝑯 = 𝟏𝟒 − 𝟐. 𝟔𝟕 𝒑𝑯 = −𝒍𝒐𝒈 𝟓. 𝟕𝟓𝒙𝟏𝟎−𝟏𝟎 𝒙𝟎. 𝟎𝟓 › 𝒑𝑯 = 𝟏𝟏. 𝟑 𝒑𝑯 = 𝟓. 𝟐𝟕 97 Buffers › Consist of a mixture of weak acids and their conjugate bases (in salt form), or weak bases and conjugate acids (in salt form): › Example - acetic acid/sodium acetate buffer CH3COOH + H2O → CH3COO- + H3O+ Strong electrolyte: CH3COO-Na+ → CH3COO-+ Na+ CH3COO- + H2O → CH3COOH + OH- Buffer effect in “simple terms”: Catches (“buffers”) added OH- CH3COOH by forming water and acetate anion pH remains Catches (“buffers”) added H3O+ unchanged CH3COO- by forming acetic acid 98 Buffers Such solutions are resistant to changes in pH; and therefore, may be used to ensure drug solubility / stability: Adding an acid or a base to the buffer will cause the reactions involving the weak acid and the conjugate base to shift in order to maintain equilibrium As a result, the concentrations of weak acid and conjugate base change, but the concentrations of H3O+ and OH- remain relatively constant (i.e. constant pH) 99 Calculating pH of a buffer solution Use Henderson-Hasselbalch equation [𝑨− ] Conjugated base (salt) 𝒑𝑯 = 𝒑𝑲𝒂 + 𝒍𝒐𝒈 [𝑯𝑨] Weak acid [𝐵] Weak base 𝒑𝑯 = 𝒑𝑲𝒂 + 𝒍𝒐𝒈 [𝑩𝑯+] Conjugated acid (salt) [𝑨− ] [𝐵] pH dependent on pKa and 𝒍𝒐𝒈 or 𝒍𝒐𝒈 [𝑯𝑨] [𝑩𝑯+] respectively; Ratio! Not amount! 100  Acetic acid & conjugate base: CH3COOH & CH3COO– Examples of Formic acid & conjugate base: HCHO2 & CHO2– buffer solutions Pyridine & conjugate acid: C5H5N & C5H5H+ Ammonia & conjugate acid: NH3 & NH4+ Methylamine & conjugate acid: CH3NH2 & CH3NH3+ Acetic acid buffer solution: Mix equal volumes of 0.2M acetic acid and 0.6 M sodium acetate Ammonia buffer solution: Dissolve 67.5 g of ammonium chloride in about 200 ml of water, add 570 ml of 10M ammonia solution and dilute with water to 1000 ml 101 Buffered pH always “around” pKa of the buffer BB 102 Buffer capacity › The ability of a buffer to resist changes in pH is an indicator of buffer effectiveness › Buffer capacity depends upon – 1) buffer concentration – 2) the pKa of the buffer relative to the desired pH Greater concentrations of weak acid and conjugate base (or weak base and conjugate acid) will be able to neutralize greater amounts of added acid or base The pH : pKa ratio indicates the relative quantity of weak acid to conjugate base (or weak base to conjugate acid) in the buffer, which determines the buffer capacity towards the addition of either acid or base (see next slide) 103 Buffer capacity 𝑩 › 𝑝𝐻 = 𝑝𝐾𝑎 + log CH3COO- (conjugated base) NH3 (base) 𝑨 CH3COOH (acid) NH4+ (conjugated Acid) If 𝑝𝐻 = 𝑝𝐾𝑎 then 𝑩 = 𝑨 ; equal capacity towards added acids and bases If 𝑝𝐻 < 𝑝𝐾𝑎 then 𝑩 < 𝑨 ; increased capacity towards added bases If 𝑝𝐻 > 𝑝𝐾𝑎 then 𝑩 > 𝑨 ; increased capacity towards added acids B>A: log B/A = Positive log 1 = 0 B20 g sorbitol/day for adults, less for children) – Contraindicated in animals (Xylitol) 137 Artifical Sweeteners: Non-caloric Saccharin (Sweet’N Low®) Aspartame (Nutrasweet™, Equal®) Sucrolose (Splenda™) Acesulfame Potassium (Ace-K) Stevia/Stevioside (Truvia®) Monkfruit Can be used in conjunction with other sweeteners to enhance sweetness. Used on their own in formulations for patients who must restrict their intake of sugar or calories in general Viscosity enhancers such as methylcellulose are frequently added, as these sweeteners do not increase solution viscosity as sucrose or sugar alcohols do Disadvantage: Tendency to impart a bitter or metallic aftertaste 138 Aspartame is contraindicated in patients with phenylketonuria (PKU) Flavoring Agents › Improves palatability of bland substances › Improves patient adherence › Used to mask unpleasant-tasting medicines – Some flavors mask certain tastes better than others Not useful if intended patient dislikes that flavor Especially important with children and pets Many pharmacies have flavor programs that allow the pharmacist to change the flavor of a manufactured product by masking the original flavor and replacing it with one more acceptable to the patient or caregiver 139 Flavoring Agents › Personal preferences for flavors and perfumes often vary with age › In general: – Children prefer sweet flavors (bubblegum, butterscotch, fruit) – Adults often prefer flowery odors and acid or bitter flavors (licorice, chocolate, coffee, spice) 140 Flavoring Agents: Natural flavorants Aromatic oils (e.g., peppermint, anise and lemon), herbs – Widely used in extemporaneous compounding of products – Available as concentrated extracts, alcoholic or aqueous solutions https://pharmaeducation.net/flavoring-agents-in-pharmaceutical-formulations/ 141 Flavoring Agents: Artificial flavorants – Tend to be cheaper – More readily available – Less variable in chemical composition – More stable than natural flavorants – Flavors frequently less complex; some patients can detect a difference 142 Flavors: Suitable masking flavors for various product tastes – Salty: – Sweet: – Bitter: – Acid/Sour: › Apricot › Vanilla › Anise › Citrus › Butterscotc › Fruit › Chocolate fruits h › Berry › Coffee › Licorice › Licorice › Bubblegum › Mint › Raspberry › Peach › Wild › Cherry › Vanilla cherry › Raspberry › Passion fruit 143 Flavoring techniques used to formulate more appealing solutions Blending: Use of a flavor that blends with the drug taste Examples: › Drugs with sour or acidic taste can be blended with citrus fruit flavors and a sweetener › Bitter tastes can be improved by adding a salty, sweet, or sour flavor Overshadowing (or masking): Use of a flavor with a stronger intensity and longer residence time in the mouth Examples: Oil of wintergreen (methyl salicylate) Glycyrrhiza (licorice) 144 Colorants Used to improve patient acceptance and compliance (i.e. pharmaceutical elegance/aesthetic appeal ) – Natural colors: mineral pigments – ex. titanium dioxide; plant pigments – ex. indigo – Synthetic colors: certified by the FDA as FD&C or FD dyes – ex. FD&C Yellow #5 (tartrazine; possible allergic reaction) Amount also determined by trial and error Typically, 0.1% is sufficient for pastel colors Many colors are influenced by pH or are sensitive to light degradation 145 Colorants It is not always necessary to color a product Some patients may be allergic or sensitive to artificial colorants – Dye-free formulations sometimes available, or product may be extemporaneously compounded for patient Color should generally correlate with the flavor employed Mint with green or blue Cherry with red 146 Thickeners (Viscosity-inducing agents) › Improve mouth feel › Provide “physical concealment” of the drug – Keep most of the dissolved drug from making contact with the taste buds › Form solutions that are stable over a wide pH range Examples: Celluloses Methylcellulose, sodium carboxymethylcellulose (SCMC) Natural polymers Acacia (gum arabic), xanthan gum Some sweeteners Sucrose, sorbitol, glycerin, propylene glycol 147 Solubilizing agents › Surface active agents (surfactants) can solubilize poorly water- soluble drugs (e.g., vitamin K1) › Caused by formation of micelles › The solubilizing agent can be either dispersed in the vehicle before the drug is added, or mixed with the drug and then added to the vehicle › Examples: – Tweens (polysorbates) – Sodium oleate SuperManu https://commons.wikimedia.org/wiki/File:Micelle_scheme-en.svg 148 pH adjusters Acidifying agents: Used in liquid preparations to provide an acidic medium for product stability Examples: Citric acid, Acetic acid, Fumaric acid, Hydrochloric acid, Nitric acid Alkalinizing agents: Used in liquid preparations to provide an alkaline medium for product stability Examples: Ammonia solution, Diethanolamine, triethanolamine, Potassium hydroxide, Sodium bicarbonate 149 pH adjusters Buffer systems: – Compounds or mixtures of compounds that, when present in solution, resist changes in the pH of the solution when small quantities of acid or base are added. – Some solid oral dosage forms also have buffering agents – Examples: › Citric acid buffer (e.g. citric acid/sodium citrate) › Phosphoric acid buffer › Boric acid 150 Tonicity adjusters Tonicity = Measure of the effective osmotic pressure gradient; the water potential of two solutions separated by a partially permeable membrane. Tonicity agents are used to render a solution similar in osmotic pressure to physiological fluids. Most commonly needed in injectable and ophthalmic products. Examples: Sodium chloride, Dextrose, Boric acid, Mannitol Red blood cells in: 151 Single-Phase Liquid Systems Solutions Syrups Elixirs Spirits Tinctures Aromatic waters Fluid Extracts 152 Single-phase liquid systems All single-phase systems are variants of solutions!! Clear liquids A drug is completely dissolved and evenly dispersed throughout the solvent There are no solids or immiscible liquids present 153 Single-phase oral systems › Advantages › Disadvantages – Easy to swallow – Bulkier than solid dosage – Flexible dosing forms – Rapid onset of action – Taste may be an issue › Faster than solid dosage forms – Certain drugs are not stable in – Homogenous solution › Do not have to shake to get – Certain drugs are not soluble uniform dose enough – Storage – Dose accuracy › Spills › Incorrect measuring device 154 Solutions See also all previous slides about “solutions” Liquid preparations that contain one or more drug substances dissolved (i.e., molecularly dispersed) in a suitable solvent or mixture of mutually miscible solvents. Most solutions are unsaturated 155 Solutions › Solutions are administered via various routes of administration, including: – Oral – Topical – Rectal – Vaginal – Ophthalmic – Otic – Pulmonary – Injectable (IV/IM/SC) 156 Solutions: Preparation Simple solution: Drug is already dissolved in a solvent Dry mixtures for solution Appropriate when drug has limited stability in solution Dry powder or granules, for reconstitution Prepare just before dispensing to patient Examples of dry mixtures for reconstitution: Penicillin V Potassium for Oral Solution, USP Cloxacillin Sodium for Oral Solution, USP Oxacillin Sodium for Oral Solution, USP Methylprednisolone sodium succinate for injection, USP 157 Solutions: Preparation by Extraction The separation of medicinally-active portions of plant [or animal] tissues from the inactive or inert components by using selective solvents Extractives do not contain just a single constituent Extraction by percolation See following slides Extraction by maceration Solvent systems used in extraction selected on basis of their capacity to dissolve the max. amount of desired active constituents and the min. amount of undesired constituents Nature (classification) of extract (solution, syrup, elixir, tincture) is determined by solvent(s) chosen 158  Extraction by percolation Soluble components are extracted from solid materials by the slow passage of a suitable solvent through a column of source material Method of choice for moderately coarse powders Another example: https://www.sciencedirect.com/topics/chemistry/percolation “Menstruum” = Solvent used Perked coffee to extract a drug from a plant. Examples: Digitalis extract and Belladonna Tincture 159  Extraction by maceration Latin macerare, meaning “to soak”. A comminuted solid (plant) material is soaked in a suitable solvent until the cellular structure is softened and penetrated and the soluble constituents are dissolved. Method of choice for fine powders Example: Compound Benzoin Tincture USP 160 Percolation versus Maceration https://www.semanticscholar.org/paper/Herbal-extraction-procedures%3A-need-of-the-hour- Saravanabavan-Salwe/d58a7c999e8c36dc41141cc86d503497811523ef 161 Syrups Concentrated aqueous solutions that contain sugar or sugar substitutes, with or without medicinal substances. But: Term “Syrup” no longer preferred. Now referred to officially as a solution containing high concentrations of sucrose or other sugars Sucrose-containing syrups are not suitable for diabetics Sugar-free options are available Frequently used to administer drugs to children: Pleasant and sweet means of masking disagreeable drug taste Contain little or no alcohol 162 Non-medicated syrups › Do not contain medicinal substances › Used to extemporaneously prepare liquid dosage forms › Syrup NF, also referred to as “simple syrup” – 85% (w/v) sucrose – Nearly saturated solution – Self preserving Most contain flavoring agents Examples: Cherry syrup Cocoa syrup Raspberry syrup Ora-Sweet™ and Ora-Sweet SF™ 163 Medicated syrups Contain therapeutically active ingredients › Examples: – Various cough / cold preparations – Celexa® (citalopram hydrobromide) › Antidepressant – Demerol® (meperidine HCl) › Opioid analgesic – Phenergan® (promethazine HCl) › Control of nausea and vomiting, motion sickness, and allergic reactions – Reglan® (metoclopramide) › Relief from gastroesophageal reflux 164 Medicated syrups: Components 1. Active ingredient 2. Sweetener – Antitussive syrups: The thickness and sweetness soothe the throat (demulcent) 3. Preservatives 4. Flavoring and coloring agents 5. Other ingredients (as needed) – Solubilizing agents – Polyhydric alcohols (sugar alcohols): › Retard crystallization › Osmotic effect – Thickeners › Minimize contact of the drug with taste buds 165 Preparation of syrups 1. Solution with heat Syrups are prepared in this method when: › it is desired to prepare the syrup as quickly as possible › the syrup’s components are not damaged or volatilized by heat Heat makes dissolution faster If heat labile or volatile substances (e.g., flavoring oils, alcohol) are to be added, they are incorporated into the syrup after cooling to room temperature Risk of inversion of sucrose to dextrose (glucose) and fructose (levulose); caramelization (polymerization and oxidation products 166 167 Preparation of syrups 2. Agitation without heat – More time consuming – Avoids heat-induced inversion; more stable product – Addition of dissolved components to the syrup 3. Percolation Purified water or an aqueous solution is allowed to pass through a bed of crystalline sucrose. Liquid is re-passed through the percolator to dissolve the sugar completely Process is similar to coffee percolation 168 Elixirs › Transparent, sweetened, hydro-alcoholic solutions intended for oral use – Proportion of alcohol varies widely (3%-40%) – “Iso-alcoholic elixir”: Mixture of low (10%) and high (75%)alcoholic elixirs Always flavored to enhance palatability Most elixirs have colorants Usually less sweet than syrups Less viscous than syrups Less effective than syrups in masking the taste of medicinal substances 169 Elixirs › Some products that no longer contain alcohol continue to use the term “elixir” as part of their marketed name – Most companies are rebranding products to be listed more accurately as solutions or suspensions – If you see the term “elixir”, assume alcohol is present unless you confirm that it is not by reading the ingredient list Disadvantages of using alcohol in elixirs Inebriation Not to be used in instances when patient is receiving medication that causes drowsiness or have Antabuse® (disulfiram)-like activity (Antabuse or disulfiram for treatment of alcoholism. Causes an extremely unpleasant reaction if a person drinks alcohol while taking it) Alcohol can accentuate saline taste of bromides and similar salts. Requires application of flavor masking techniques 170 Common components of elixirs › Active ingredient › Adjunct solvents › Water – Glycerin, propylene glycol › Alcohol › Flavoring agents (always used) › Sweeteners › Coloring agents – If alcohol content is high, usually artificial sweeteners › Preservatives are used, as sucrose is only slightly soluble in alcohol and requires large amounts for equivalent sweetness 171 Elixirs: Preparation and storage › Preparation of elixirs – Alcohol-soluble and water-soluble components are generally dissolved separately in alcohol and in purified water, respectively – Aqueous solution is added to the alcoholic solution – After mixing, completion to volume (qs) with appropriate solvent › Storage – Tight, light-resistant container protected from excessive heat 172 Non-medicated elixirs Used for extemporaneous preparations 1. Dilution of a medicated elixir Alcohol content of non-medicated elixir should be approximately the same as the medicated elixir being diluted Flavor and color should not conflict with the medicated elixir 2. Preparation of an elixir from stock ingredients Proportion of alcohol should be only slightly higher than that required to maintain the drug in solution 173 Non-medicated elixirs: Examples Iso-alcoholic Elixir (iso-elixir) Mixture of low-alcoholic elixir (8%-10% v/v) and high-alcoholic elixir (73%-78% v/v) Alcohol concentration based on solubility of the drug Concentration prepared will depend on the relative proportions of the ingredients Flavored with compound orange spirit 174  Medicated Elixirs: Examples Phenobarbital elixir (phenobarbital oral solution, USP) Alcohol content is 14% (minimum) in order to dissolve phenobarbital Some glycerin is included as a co-solvent Digoxin elixir 10% (v/v) alcohol Used in pediatric populations Packaged with a calibrated dropper to facilitate accurate dose Dexamethasone Elixir, USP 3.8-5.7% (v/v) ethanol Fluphenazine Hydrochloride Elixir, USP Not more than 15% (v/v) ethanol Hyoscyamine Sulfate Elixir, USP 20% (v/v) ethanol 175 Spirits › Alcoholic solutions of volatile substances with – Contain high concentration (62% to 85%) of alcohol – Used medicinally for the therapeutic value of the aromatic solute, and pharmaceutically as flavoring agents Examples: Peppermint Spirit, USP Compound Orange Spirit, USP Aromatic Ammonia Spirit, USP Respiratory stimulant (using vapors when someone fainted) Spirits are prepared by simple solution or extraction Compounding problems: Becomes cloudy when added to aqueous preparation Portion of aromatic material comes out of solution Storage: Tight, light-resistant container protected from excessive heat 176 Tinctures › Alcoholic or hydro-alcoholic solutions of non-volatile substances prepared from vegetable materials or chemical substances – 15%-80% alcohol – No longer in common use for oral preparations (unpleasant taste) – Storage: Often in light-resistant containers › Typical concentration of: – Vegetable drugs: Each 100 mL contains the extracted components of 20 g of plant material – Potent vegetable drugs: Each 100 mL contains the extracted components of 10 g of plant material › Preparation by: Simple solution; Extraction; Maceration; Percolation 177 Tinctures: Examples › Compound benzoin tincture – Antiseptic and protective effect on minor wounds › Opium products – rare, but still available: 1. Laudanum (Opium tincture, or deodorized tincture of opium, DTO) › Analgesic / antiperistaltic › CII › 10 milligram morphine / 1 mL (or 50 mg / 5 mL) › Much higher concentration (25x) than paregoric 2. Paregoric (Camphorated opium tincture) A paregoric tincture is a › Analgesic / antiperistaltic hydroalcoholic solution › CIII prepared from extractions › 2 mg morphine / 5 mL of plant / vegetable material 178 Aromatic waters › Clear, saturated aqueous solutions of volatile oils or other aromatic materials – Very diluted; aromatic substances are not very water-soluble – Used for flavoring / perfuming – The tastes and odors of aromatic waters are similar to those of the drugs and volatile substances from which they are prepared – Examples: › Peppermint water › Orange flower water › Rose water 179 Aromatic waters › Preparation of aromatic waters: Solution process May involve talc (soft mineral composed of Mg, Si) Increases the surface area of the volatile substance that is exposed to the water (talc breaks up aromatic oils into fine particles) Talc also used as a clarification agent to remove excess volatile oil from a solution Talc filtered out before packaging Distillation Volatile substances in vapor Remain in liquid when cooled 180  https://slidetodoc.com/aromatic-water-by-assistant-lect-nora-zawar-assistant/ 181 Aromatic waters: Example Fluidextracts Liquid preparations of vegetable drugs containing alcohol as a solvent, preservative or both › Contain high alcohol content › Each milliliter contains the therapeutic constituents of 1 g of the crude drug that it represents – Too potent to be safely self-administered by the patient – Generally used as the drug source component of other liquid dosage forms such as syrups › Prepared by percolation A vegetable drug (crude drug) is any naturally occurring, unrefined substance derived from organic or inorganic sources such as plant, animal, bacteria, organs or whole organisms intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in humans or other animals. 182 Fluidextracts: Preparation Methods (General) Add the required amount of solid drug & excipients to an appropriately sized conical, graduated cylinder desired concentrations must be below the max. solubility of the drug / excipient in the solvent at the intended storage temperature Conical graduates are more accurate than Rx bottles Also wider at the top to ease prep 183 Fluidextracts: Preparation Methods (General) › Dissolve solutes in a minimal amount of solvent – must dissolve before final volume is reached because volumes may change upon dissolution › Qs to the desired volume with small portions of solvent – unlike with solids, we cannot calculate the exact amount needed Qs: as much as suffices : a sufficient quantity — abbreviation qs —used on medical prescriptions to indicate that the amount is to be determined by the pharmacist (Merriam-Webster) 184 Fluidextracts: Preparation Methods See also earlier slides under: Dissolution rate: Temperature Main rules and factors for predicting and/or modifying solubility and/or dissolution Influences preparation time Applying heat will increase solubility (Cs) and the diffusion coefficient (D); both of which increase dissolution rate However, solubility should not be increased beyond that at the expected storage temperature otherwise will ppt. upon cooling Also, an increase in temperature may increase drug degradation 185 Fluidextracts: Preparation Methods See also earlier slides under: Main rules and factors for predicting and/or modifying solubility Dissolution rate: Agitation and/or dissolution › mixing or stirring will decrease the thickness of the stagnant layer (h) and thus increase dissolution rate › this should be done using a stirring rod / bar not a spatula or thermometer Dissolution rate: Surface area › decreasing particle size will increase total surface area (S) and thus increase dissolution rate › therefore, trituration will generally increase dissolution rate; however, most pharmaceutical powders are already supplied having a relatively small particle size 186 Fluidextracts: Preparation Methods See also earlier slides under: Dissolution rate: Solvent Main rules and factors for predicting and/or modifying solubility and/or dissolution a solvent having a lower viscosity will increase the diffusion coefficient (D) and decrease the thickness of the stagnant layer (h); both of which increase dissolution rate using a solvent in which the drug / excipient has a greater solubility (Cs) produces a larger concentration gradient (Cs-Ct), which increases dissolution rate might require co-solvents 187 Fluidextracts: Preparation Methods Using co-solvents Used to increase drug or excipient solubility (Cs) while balancing other properties such as viscosity or toxicity. An increase in solubility results in an increase in dissolution rate / decrease in preparation time All co-solvents used to prepare a solution must be miscible within each other; this may be verified by consulting various references To ensure the quickest dissolution, the drug or excipient should first be dissolved using the solvent in which it has the greatest solubility; the additional co-solvents should then be added in order of decreasing solubility 188 Reconstitution of a manufactured product › loosen the powder within the container, › add the required amount of solvent in small portions, › shake after each addition of solvent until all powder is dissolved › container oversized for shaking, so may not appear full 189 Measurement of Volume › Graduated cylinders: › Cylindrical (sides parallel to each other) and conical (cone- shaped with a larger circumference at the top) are the most common types › Cylindrical cylinders typically contain metric units; whereas, conical cylinders are usually dual scaled with both metric and apothecary units of volume › Both types are typically prepared using glass or plastic and most commonly range from 5 – 1000 milliliters in capacity 190 Measurement of Volume Graduated cylinders In addition, cylindrical graduates typically result in less error when measuring liquids because of their narrower diameter The optimal capacity is one equal to or just exceeding the volume to be measured Generally, volumes less than 20% of the graduate capacity (i.e. volumes below the minimum measurable quantity (MMQ) cannot be measured with the appropriate accuracy (±5%) Calibrated syringes / pipettes / droppers Typically, used for smaller volumes that cannot be accurately measured using a graduated cylinder Syringes are good for viscous liquid 191 How to handle small quantities? Liquid / liquid aliquot method A method for obtaining small quantities (