Pharmaceutical Analytical Chemistry (I) 2024-2025 PDF

‫المحاضرة الرابعة‬ ‫المستوى األول برنامج الصيدلة اإلكلينيكية‬ Pharmaceutical Analytical Chemistry (I) Associate Prof. Mohamed Oraby 2024-2025 4. Biphasic Titrations: water-soluble salts its acid is water-insoluble (soluble in other immiscible solvents). Sodium...

‫المحاضرة الرابعة‬ ‫المستوى األول برنامج الصيدلة اإلكلينيكية‬ Pharmaceutical Analytical Chemistry (I) Associate Prof. Mohamed Oraby 2024-2025 4. Biphasic Titrations: water-soluble salts its acid is water-insoluble (soluble in other immiscible solvents). Sodium salicylate Sample, Titrant: HCl, Indicator: Bromophenol blue. COO Na COO H OH OH + HCl + N aC l The liberated salicylic acid solubility in ether (250 times greater than in water). A separating funnel using bromophenol blue: blue to pale green. 56  Back or Residual Titration Methods 1. Volatile substance as ammonia or formic acid. 2. Substance, which require heating with standard reagent. 3. Insoluble substance as ZnO, CaO, and BaCO3. 4. Substance needed excess reagent for rapid quantitative reaction (lactic acid). 57 Blank Determinations: The sample is replaced by simulated matrix under the same experimental conditions. 1. The standard is unstable or its strength changes on standing (I2 solution). 2. In cases of assays which require heating. 3. To minimize errors due to impurities of reagents. 58  Determination of insoluble oxides and carbonates (ZnO , CaO & CaCO3) A known exces HCl is added to the weight of ZnO and the excess HCl is back titrated with NaOH (M.R.). Determination of mixture of CaO and CaCO3: ✓ Total: Adding known excess st. HCl and back titration with NaOH (M.O.). ✓ CaO: Adding 10% neutral sucrose, alcohol (to prevent lumps formation), st. acid (M.O.).. 64 2. Determination of Inorganic Ammonium Salts NH4Cl + NaOH → NaCl + H2O + NH3 – NH4Cl is boiled with a known excess NaOH (until no more NH3 is evolved), the excess NaOH is titrated with acid (M.R.). – NH4Cl is treated with NaOH solution and the mixture is distilled; NH3 is absorbed in an excess acid. The excess standard acid is back titrated with standard NaOH (M.R.). – Formol Titration: 4NH4Cl + 6HCHO → (CH2)6N4 + 4HCl + 6H2O The produced acid is titrated with NaOH (M.O. or ph.ph.). Hexamethylenetetramine is a very weak base. 59 3. Determination of Organic Nitrogenous Compounds: (Kjeldahl’s Method): Example: amino acids of proteins H2SO4 / Na2SO4 / CuSO4 Organic nitrogen NH3 as (NH4)2SO4 H2SO4: Digestion of amino acids of proteins. Na2SO4: Raises the poiling point of the mixture. CuSO4: Catalyst. (NH4)2SO4 + 2NaOH → Na2SO4 + 2H2O + 2NH3 60 4. Determination of Aldehydes & Ketones: Reaction with hydroxylamine HCl and the liberated HCl (equivalent to the aldehyde or ketone) is titrated with standard NaOH (M.O.). RCHO + H2NOH. HCl → RCH=NOH + HCl + H2O RCOR + H2NOH. HCl → R2C=NOH + HCl + H2O 61 5. Determination of Mercuric oxide: When HgO is dissolved in KI, KOH is produced. The liberated KOH is titrated with HCl (M.O. or ph. ph.) HgO + 4Kl + H2O → K2Hgl4 + 2KOH 6. Determination of Ammoniated Mercury (NH2HgCl): NH2HgCl is dissolved in KI, NH4OH and KOH are produced which can be titrated with acid. NH2HgCl + 4KI + 2H2O → K2Hgl4 + KOH + NH4OH + KCl To  loss of NH3, about 80% of the expected acid required is added before the addition of KI. 62 7. Determination of Esters (acetylsalicylic acid): A known weight of the ester is refluxed with a known excess of NaOH. The excess NaOH is back titrated with acid (Ph.Ph.). Reflux / Heat R—COOR + NaOH R—COONa + ROH 8. Determination of Formaldehyde Solution: HCHO + H2O2 → HCOOH + H2O HCOOH + NaOH → HCOONa + H2O NaOH + HCl → NaCl + H2O (Ph.Ph.) 69 9. Determination of Persulfate: Decomposition / Ag+ 2S2O82- + 2H2O 4H2SO4 + O2 The produced acid can be titrated with standard NaOH (M.O.). 10. Determination of Free Fatty Acids (Acid Value): Dissolving a known weight of the oil or fat in a mixture of chloroform and ethanol followed by titration with NaOH (Ph.Ph.). 70 ACID-BASE TITRATIONS (Neutralization Reactions) Non-Aqueous Medium 71  Uses and Theory of Non-Aqueous Titrations: Too weak bases. Weak acids. Many water-insoluble acidic or basic organic compounds of analytical interest. H+ + H2O H3O+ + NH3 H2O + NH4+ H+ + CH3COOH CH3COOH2+ + NH3 CH3COOH+ NH4+ 72  Glacial HOAC is a much more acidic than H2O. NH3 is more basic in glacial HOAC than it is in H2O because CH3COOH2+ is a much better proton donor than H3O+. A solvent that is more acidic than H2O (HOAC) will enhance the strength of weak bases. A solvent that is more basic than H2O (pyridine, ether) will enhance the strength of a weak acid. 73  Solvents for Non-Aqueous Titrations ✓ Amphiprotic Solvents: Accept or donate protons (bases or acids): water, acetic acid and alcohol. ✓ Protophillic Solvents: Accept protons (basic): acetone and pyridine. They behave as differentiating solvents for weak acids. ✓ Protogenic Solvents: Donate protons (acidic): sulphonyl chloride. ✓ Aprotic solvents: Neither accept nor donate protons (inert): chloroform and benzene. They act as a medium for the titrations. 74  Leveling and Differentiating Effect of Solvents Leveling effect. The inability to distinguish the difference between the strength of two acid as HClO4 and HCl acids: Both acids are much stronger acids than H3O+ (or H2O is a stronger base than either HCIO4 or HCl). HClO4 + H2O ClO4— + H3O+ HCl + H2O Cl— + H3O+ 75  Leveling and Differentiating Effect of Solvents Differentiating effect. The ability to differentiate between the strength of two acids. CH3COOH2+ is a stronger acid than H3O+ (or acetic acid is a much weaker base than water). HClO4 + CH3COOH ClO4- + CH3COOH2+ HCl + CH3COOH Cl- + CH3COOH2+ HClO4 in acetic acid, shows a stronger acidity than HCl in acetic acid. 76  Applications of Non-Aqueous Titrations 1.Determination of Bases: Titrated with HClO4 in HOAC. (CV: Violet → green) a. Titration of Weak Bases (Aniline): Sample: AR—NH2 + CH3COOH AR—NH3+ + CH3COO— (1) Titrant: HClO4 + CH3COOH ClO4— + CH3COOH2+ (2) Reaction: CH3COO — + CH3COOH2+ 2 CH3COOH (3) Overall: AR—NH2 + HClO4 AR—NH3+ + ClO4— (4) 77 b. Titration of Salts of Halogen Acids (Aniline HCl): Sample: 2AR—NH2. HCl 2AR—NH3+ + 2Cl- MAc: (CH3COO)2Hg + 2Cl— HgCl2 (unionized) + 2CH3COO- Titrant: 2HClO4 + 2CH3COOH 2ClO4- + 2CH3COOH2+ Reaction: 2CH3COO- + 2CH3COOH2+ 4CH3COOH Overall: 2AR—NH2. HCl + 2HClO4 2AR—NH3+ + 2ClO4- + 2Cl— 78 2. Determination of Acids (Benzoic acid): Titrated with lithium methoxide in n-butyl amine ( Thymol Blue: Violet → Blue). C6H5COOH + CH3(CH2)3NH2 CH3(CH2)3N+H3 + C6H5COO- CH3(CH2)N+H3 + CH3O- CH3(CH2)3NH2 + CH3OH C6H5COOH + CH3O- C6H5COO- + CH3OH 3. Mixture of sulphanilamide & sulphathiazole: 1. Solvent (DMF) + sample, titrant lithium methoxide [sulphathiazole (V1)]. 2. Solvent (n-butylamine) + sample, titrant lithium methoxide equivalent to total (V2). Sulphanilamide= V2 – V1 79