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PHARMACEUTICAL ANALYSIS 1 [LEC] ERROR deviation from the absolute value or from DEFINITION OF TERMS the true value/average of a large number...

PHARMACEUTICAL ANALYSIS 1 [LEC] ERROR deviation from the absolute value or from DEFINITION OF TERMS the true value/average of a large number of results QUALITY - combination of attributes compared to a TYPES OF ERROR standard - basis for measuring the uniformity of a Random Error product aka. intermediate error - determines its degree of acceptability - manifest themselves by slight variations in a series of observations made by the SPECIFICATIONS same observer under critical conditions establish the criteria to which a substance - causes are difficult to detect, intangible should conform to be considered and their elimination by the analysts is acceptable for manufacture impossible *e.g. judgment, skill and attitude of the analyst *If the substance meets the acceptance criteria when tested according to the listed analytical Determinate Error procedures, then it conforms to specification. aka. systemic error - recur in a constant manner in each of a QUALITY CONTROL series of determination tool which gives the assurance that a - detectable product conforms to standards and - possible to eliminate or reduce their effect specification through a system of on the final result inspection, analysis and action SOURCES OF ERROR Part of GMP (Good Manufacturing Practice) concerned with sampling, specifications and Instrumental Errors testing ensures that the necessary and relevant caused by non ideal instrument tests are actually carried out and that materials are behavior, by faulty calibrations, or by use not released for use until their quality has been under inappropriate conditions or judged to be satisfactory. apparatus errors *e.g. temperature of uncalibrated hot plate The activity of providing to all concerned, the evidence needed to establish confidence that the Method Errors activities relating to quality are being performed arise from non ideal chemical or adequately. physical behavior of analytical systems *e.g. loss of volatile analyte while heating Totality of the arrangement made with the object of ensuring that pharmaceutical products are of the Personal Errors quality required for their intended use. result from carelessness, inattention, or personal limitations of the experimenter ACCURACY *e.g. improper selection of indicators - denote agreement of an experimental result DEFECT - the agreement of the main value of a - undesirable characteristic of a product series of experimental results with the - failure to conform to specification true value - “nearness to the truth” CLASSIFIC​​ATION OF DEFECTS PRECISION Measurability - measure of reproducibility of data within a) Variable Defect: can be measured a series of results directly by instruments giving dimensions - closeness of the experimental results of length, height, thickness, etc. with each other RIGONAN, R-A.R. | PHA233  b) Attribute Defect: can not be measured SOURCES OF VARIATION (6M) directly by instruments; shows mainly conformance or non-conformance like 1) Materials: variation between batches from based on, odor, taste same supplier or within batch 2) Machines: difference in adjustment of Seriousness or Gravity equipment or aging & improper care a) Critical Defect: may endanger life or 3) Methods: inexact procedures or property and may render the product inadequate procedures non-functional 4) Men: improper working conditions, b) Major Defect: may affect the function of inadequate training and understanding the object and therefore may render the 5) IMproper: improper use of measuring product useless devices & units/conversion c) Minor Defect: does not endanger life or 6) Mother Nature: temperature, relative property nor will it affect the function but humidity, oxygen remains a defect since it is outside the prescribed limits CONTAMINATION - process of making something dirty, Nature polluted, or poisonous by adding a a) Ocular Defect: defect is visible chemical, waste, or infection *e.g. foreign particulate - process of having an impure substance b) Internal Defect: defect is not seen or something is added that must not be although present part of the substance *e.g. sub-potent drug product c) Performance Defect: defect in function TYPES OF CONTAMINATION *e.g. suppository that does not melt in the body Microbial Contamination can occur during manufacturing from TYPES OF DEFECTS water, the environment or packaging Design Defects Particulate Contamination actual design of the product is faulty can come from undissolved residuals in solutions, packaging, seals, etc. Manufacturing Defects only affect certain units or batches of a Cross Contamination product, rather than all products in a line an accidental inclusion of product of another batch or unknown foreign material Labeling Defects into a finished batch, which was not intended or not mentioned on the label VARIATION Mix-up - the extent to which or the range in which a combination of different things, especially thing varies one whose effect is inharmonious - a change or slight difference in *e.g. one blister strip of batch [A] tablet condition, amount, or level, typically within found with another batch [B] certain limit - a different or distinct form or version of something PHARMACOPOEIA According to the World Health Organization, DRUG STANDARDS variation means a post approval change to any - the scientific basis for drugs and drug aspect of a pharmaceutical product, including but products developed, so did the need for not limited to a change to formulation, method uniform standards to ensure quality and site of manufacture, specifications for the - this led to the development and publication finished pharmaceutical product, ingredients, of “pharmacopeias” or “formularies” container and container labeling, and product information. RIGONAN, R-A.R. | PHA233 PHARMACOPEIA PARTS OF USP MONOGRAPH greek. pharmakon - drug; poiein - make - any recipe or formula or other standards a) Official title required to make or prepare drug b) Graphic formula c) Empirical formula and molecular weight - an organized set of monographs d) Established chemical names containing standards about drugs and e) Drug’s Chemical Abstract Service (CAS) drug products f) Registry number HISTORY OF PHARMACOPOEIA OTHER PHARMACOPOEIAS 1800 1) Pharmacopoeia Internationalis or USP First Edition International Pharmacopoeia (IP) Publish Date: December 15, 1820 2) British Pharmacopoeia (BP) Language: English & Latin 3) Japanese Pharmacopoeia (JP) Monographs: 217 drugs 4) Philippine Pharmacopeia (PP) 5) Philippine National Formulary 1900 USP 20 and NF 25 first official combined compendium PHARMACEUTICAL QUANTITATIVE ANALYSIS Date: July 1, 1980 ASSAY *USP Volume contains monographs of all to analyze (something, such as an ore) for therapeutically active drug substances one or more specific components *NF Section contains monographs of all ANALYSIS pharmaceutical agents appeared in this section to determine the presence, absence, or quantity of one or more components USP 23-NF18 became official in 1995 ANALYTICAL CHEMISTRY study of separation, identification and 2000 qualification of the chemical components USP/NF of natural and artificial material became an annual publication in 2002 USP 25 – NF 20 in 2002 2 TYPES OF ANALYSIS USP 26 – NF 21 in 2003 containing approx. 4000 drug monographs Qualitative Analysis (in print and CD-ROM) the determination of non-numerical information about a chemical species, a Note: USP/NF has different release (publication) reaction date and official date (effectivity) *e.g. Year 2023 - Official USP 43 and NF 38 Quantitative Analysis any method used for determining the USP-NF MONOGRAPH amount of a chemical in a sample - adopt standards for drug substances, pharmaceutical ingredients, and dosage Quantitative Pharmaceutical Chemistry is the forms application of the procedures of quantitative - provide suitable tests and assay analytical chemistry to the analysis and procedures for demonstrating compliance determination of: *e.g. Drug Substance: Calcium Citrate, USP a) the purity and quality of drugs and Pharmaceutical Ingredient: Ethyl Alcohol, USP chemicals used in pharmacy especially Dosage Form: Iodine Topical Solution, USP those official in USP and NF b) medicinal agents and their metabolites in biological systems RIGONAN, R-A.R. | PHA233  c) the chemical constituent found in the Precision human body as diagnostic aid in practice Definition: expresses the closeness of of medicine agreement between a series of measurements obtained from different samples from the same General Directions homogeneous sample 1. the reagents used in quantitative analysis must be chemically pure Evaluation: variance, standard deviation, or 2. the purity and strength of chemicals and coefficient of variation (aka relative standard drugs of the USP and NF are usually deviation, %) of a series of measurements. expressed in percent 3. accuracy and precision must be clearly Levels of Precision understood when discussing analytical 1. Repeatability data 2. Intermediate precision 4. analytical balance is used for determining 3. Reproducibility the mass of a substance Specificity VALIDATION Definition: the ability of an analytical method to - comes from the word “valid” which means distinguish analyte from everything else that might “can be justified or legally defined” be in the sample - demonstrating and documenting that something does (or is) what is supposed to *If drug: test for impurities do (or be) *If drug product: Compare pure drug with one containing additions of all possible *Almost all analytical tests require some type of synthetic by-products and intermediates, validation. degradation products and excipients. *The amount and type of validation will depend on the test procedure. Detection Limit (DL) *Validation is necessary before an analytical aka. Limit of Detection (LOD) test can become a test procedure in the QC Definition: Smallest amount of an analyte which laboratory. can be detected by a particular method but not *Validation characteristics for different types of necessarily quantified as an exact value analytical procedures Evaluation: the detection limit is determined by the REVALIDATION analysis of samples with known concentrations of the process of making something officially analyte and by establishing the minimum level at acceptable or approved again which the analyte can be reliably detected WHEN TO USE REVALIDATION Quantification Limit (QL) aka. Limit of Quantification (LOQ) Accuracy Definition: Smallest amount of analyte which can Definition: the closeness of agreement between be quantified reliably the true value and the determined value Evaluation: The quantitation limit is generally Evaluation: Compare the substance being determined by the analysis of samples with known analyzed with a reference standard analyzed by concentrations of analyte and by establishing the the same procedure minimum level at which the analyte can be quantified with acceptable accuracy and Evaluation: % recovery by the assay of the known precision. added amount of analyte in the sample - minimum of 9 determinations over a Linearity minimum of 3 concentration levels (*e.g. 3 Definition: ability to obtain results that are concentrations/ 3 replicates each of the directly proportional to the concentration of the total analytical procedure) sample RIGONAN, R-A.R. | PHA233 Evaluation: square of the coefficient (R2) TITRANT measures how well a calibration curve follows a aka. standard solution straight line, showing that response is proportional aka. volumetric solution to the quantity of analyte the solution of accurately known - the correlation coefficient, y-intercept, concentration slope of the regression line and residual *concentration can either be sum of squares should be submitted NORMALITY (N) or MOLARITY (M) - a plot of the data should be included - minimum of 5 concentrations ANALYTE aka. titrand Range the active constituent in the sample or Definition: interval where it has been used in titrimetry; can also be the sample demonstrated that the analytical procedure has suitable levels of precision, accuracy, and STANDARDIZATION linearity. the process of determining the exact concentration of solution *e.g. R2≥0.995 (linearity), spike recovery of 100 ± 2% (Accuracy) and interlaboratory precision INDICATOR of ± 3% Chemical added which changes color at or very near the point in which equivalent Robustness quantities of analyte and titrant have Definition: “ability of an analytical method to be reacted unaffected by small, deliberate changes in Indicates a desired change in pH has operating parameters” been affected Parameters that can be assessed to determine COMMONLY USED INDICATORS robustness: a) stability of analytical solutions a) Natural indicators: red cabbage, grape b) length of the extraction time juice, curry powder, turnip skin, cherries, c) effect of variations in pH of a solution beets, onions, tomatoes, turmeric d) effect of the temperature indicator, etc. b) Strong acid + strong base: Methyl red (Mr) GENERAL METHODS USED IN OFFICIAL Methyl orange (Mo) PHARMACEUTICAL ANALYSIS Phenolphthalein (Pp) *weak acid + strong base : Pp TITRIMETRIC ANALYSIS *weak base + strong acid : Mr carried out by determining the volume of *weak acid + weak base: Mixed a solution of accurately known concentration which is required to react General Rule: use 3 drops unless indicated quantitatively with a measured volume of a solution of the substance to be Mixed Indicators determined - to sharpen up the color change - should be tested for sensitivity VOLUMETRIC ANALYSIS aka. volumetric titrimetry OTHER WAYS OF DETECTING THE type of titrimetry in which the volume of a EQUIVALENCE POINT IN THE ABSENCE OF AN standard reagent is the measured INDICATOR: quantity Potentiometric Titration TITRATION measures the potential between an indicator process in which a standard reagent is electrode and a reference electrode added to a solution of an analyte until the reaction between the analyte and reagent is judge to be complete RIGONAN, R-A.R. | PHA233 Conductometric Titration 𝑁 = 𝐺𝐸𝑊 measures the change in electrical conductivity 𝐿 𝑀𝑊 of the solution 𝐺𝐸𝑊 = 𝑖 𝑚𝐸𝑞 Amperometric Titration 𝑁 = 𝑚𝐿 measures the current which passes through 𝑀𝑊 𝑚𝐸𝑞 = 𝑖 × 1000 the titration cell between an indicator electrode and a depolarized reference ACID = # H+ ions Spectrophotometric Titration BASE = # OH- ions measures the change in absorbance of the SALT = valence of cation/production solution Primary Standardization EQUIVALENCE POINT aka. stoichiometric point 𝑁 = 1°𝑠𝑡𝑑 𝑤𝑡 𝑖𝑛 𝑔 𝑚𝐿 × 𝑚𝐸𝑞 aka. theoretical point the point in a titration when the amount of 1°𝑠𝑡𝑑 𝑤𝑡 𝑖𝑛 𝑔 added standard reagent is exactly 𝑁 = 𝐿 × 𝐺𝐸𝑊 equivalent to the amount of analyte Calculation Example: Normality ENDPOINT the point in a titration when a physical A primary standard of 0.15 g of sodium carbonate change occurs that is associated with the anhydrous is used to standardize prepared sulfuric condition of chemical equivalence acid. The consumed H2SO4 is 28 mL. What is the normality of the prepared sulfuric acid? TYPES OF STANDARDIZATION 𝑀𝑊 Primary Standardization 𝑚𝐸𝑞 = 𝑖 × 1000 - the solution produced using a primary standard Solution: - *primary standard: a compound of MW of Na2CO3 = 106 g sufficient purity from which a standard ions of Na2CO3 = 2 solution can be prepared by direct weighing of a quality of it, followed by 𝑀𝑊 𝑚𝐸𝑞 𝑜𝑓 𝑁𝑎2𝐶𝑂3 = dilution to give a defined volume of 𝑖 × 1000 solution 𝑀𝑊 𝑚𝐸𝑞 𝑜𝑓 𝑁𝑎2𝐶𝑂3 = 2× 1000 - Type of Titration: Direct 𝑚𝐸𝑞. 𝑤𝑡 𝑜𝑓 𝑁𝑎2𝐶𝑂3 = 0. 053 𝑔 Characteristics of Primary Standardization 1. must be easy to obtain, to purify, to dry Given: and to preserve in a pure state wt.of 1º standard Na2CO3 = 0.15 g 2. should not be hygroscopic, oxidized by vol of H2SO4 = 28 mL air, affected by carbon dioxide mEq of Na2CO3 = 0.053 g 3. substance should be capable of being tested for impurities qualitatively Formula: 4. should have a high molecular mass so 1°𝑠𝑡𝑑 𝑤𝑡 𝑖𝑛 𝑔 that weighing errors may be negligible (not 𝑁 = 𝑚𝐿 × 𝑚𝐸𝑞 exceeding 0.01 to 0.02%) 0.15𝑔 5. the substance should be readily soluble 𝑁 = 28𝑚𝐿 × 0.053𝑔 6. the reaction with the standard solution should be stoichiometric 𝑁 𝑜𝑓 𝐻2𝑆𝑂4 = 0. 1011 𝑁 NORMALITY number of grams equivalent to solute per liter of solution RIGONAN, R-A.R. | PHA233 MOLARITY 𝑁1𝑉1 = 𝑁2𝑉2 number of moles per liter of solution 𝑀1𝑉1 = 𝑀2𝑉2 𝑚𝑜𝑙𝑒 𝑀 = Calculations Example: 𝐿 𝑚𝑜𝑙𝑒 = 𝑀𝑊 𝑚𝑚𝑜𝑙𝑒 If 18.50mL of 0.1173N Sodium hydroxide and 20mL 𝑀 = 𝑚𝐿 of Sulfuric acid were utilized to reach the endpoint 𝑀𝑊 of titration, calculate the normality of the acid 𝑚𝑚𝑜𝑙𝑒 = 1000 Given: Primary Standardization V2 of base = 18.50mL N2 of base = 0.1173 N 𝑀 = 𝑤𝑡 𝑜𝑓 1°𝑠𝑡𝑑 𝑖𝑛 𝑔 V1 of acid = 20 mL 𝑚𝑚𝑜𝑙𝑒 × 𝑚𝐿 N1 of acid = ? 𝑤𝑡 𝑜𝑓 1°𝑠𝑡𝑑 𝑀 = Solution: 𝑀𝑊 × 𝑚𝐿 𝑁1𝑉1 = 𝑁2𝑉2 𝑁2𝑉2 Calculations Example: Molarity 𝑁 = 𝑉1 (0.1173 𝑁) (18.50 𝑚𝐿) Calcium carbonate weighing 200.5 mg is used to 𝑁 = 20 𝑚𝐿 standardize the volumetric solution of EDTA where 19.9 mL of solution is consumed. What is the 𝑁 𝑎𝑐𝑖𝑑 = 0. 1085 𝑁 molarity of EDTA VS? TYPES OF TITRATION Given: Calcium carbonate weight = 200.5 mg Direct Titration EDTA volume = 19.9 mL the treatment of a soluble substance M=? contained in a solution in a suitable vessel CaCO3 MW = 100 g with an appropriate standard solution, the endpoint being determined using Formula: indicators or by instrumentation 𝑤𝑡 𝑜𝑓 1°𝑠𝑡𝑑 𝑀 = 𝑀𝑊 × 𝑚𝐿 𝑉 × 𝑁 × 𝑚𝐸𝑞 %𝑃𝑢𝑟𝑖𝑡𝑦 = 𝑤𝑡 𝑜𝑓 𝑆𝑥 𝑖𝑛 𝑔 × 100 Solution: 𝑉 × 𝑀 × 𝑚𝑚𝑜𝑙 0.2005𝑔 %𝑃𝑢𝑟𝑖𝑡𝑦 = 𝑤𝑡 𝑜𝑓 𝑆𝑥 𝑖𝑛 𝑔 × 100 𝑀 = 100𝑔 × 0.0199𝐿 𝑉 × 𝑁𝐹 × 𝑡𝑖𝑡𝑒𝑟 %𝑃𝑢𝑟𝑖𝑡𝑦 = 𝑤𝑡 𝑜𝑓 𝑆𝑥 𝑖𝑛 𝑚𝑔 × 100 𝑀 𝑜𝑓 𝐸𝐷𝑇𝐴 = 0. 1008𝑀 Where: 𝑎𝑐𝑡𝑢𝑎𝑙 𝑛𝑜𝑟𝑚𝑎𝑙𝑖𝑡𝑦 𝑁𝑜𝑟𝑚𝑎𝑙𝑖𝑡𝑦 𝐹𝑎𝑐𝑡𝑜𝑟 = 𝑡ℎ𝑒𝑜𝑟𝑒𝑡𝑖𝑐𝑎𝑙 𝑛𝑜𝑟𝑚𝑎𝑙𝑖𝑡𝑦 Secondary Standardization - the concentration of dissolved solute has *Titer: the weight (mg) of a substance been determined by titration of a volume chemically equivalent to one mL of the of the solution against a measured standard solution volume of a primary standard solution - *secondary standard: is a substance which may be used for standardization and 𝑇𝑖𝑡𝑒𝑟 = 1 𝑚𝐿 × 𝑁 × 𝑚𝐸𝑞. 𝑤𝑡. whose content of the active substance has been found by comparison against *e.g. primary standard each mL of 1N NaOH is equivalent to - Type of Titration: Residual or Back 75.04mg C4H6O6 each of mL 0.1N silver nitrate is equivalent to 5.844mg of NaCl RIGONAN, R-A.R. | PHA233 Calculation Example: Tablet/Capsule Formula: 𝑉 × 𝑁 × 𝑚𝐸𝑞 𝑉 × 𝑁 × 𝑡𝑖𝑡𝑒𝑟 𝑎𝑚𝑜𝑢𝑛𝑡 𝑚𝑔/𝑡𝑎𝑏 = 𝑤𝑡 𝑜𝑓 𝑆𝑥 𝑖𝑛 𝑔 × 𝐴𝑣𝑒. 𝑤𝑡. 𝑖𝑛 𝑚𝑔 𝑎𝑚𝑜𝑢𝑛𝑡 𝑚𝑔/𝑡𝑎𝑏 = 𝑤𝑡 𝑜𝑓 𝑆𝑥 𝑖𝑛 𝑚𝑔 × 𝐴𝑣𝑒. 𝑤𝑡. 𝑖𝑛 𝑚𝑔 𝑉 × 𝑁 × 𝑡𝑖𝑡𝑒𝑟 𝑎𝑚𝑜𝑢𝑛𝑡 𝑚𝑔/𝑡𝑎𝑏 = 𝑤𝑡 𝑜𝑓 𝑆𝑥 𝑖𝑛 𝑚𝑔 × 𝐴𝑣𝑒. 𝑤𝑡. 𝑖𝑛 𝑚𝑔 %𝐴𝑠𝑠𝑎𝑦 = 𝑚𝑔/𝑡𝑎𝑏 × 100 Solution: 𝑙𝑎𝑏𝑒𝑙𝑒𝑑 𝑐𝑙𝑎𝑖𝑚 0.1065 𝑁 2.2 𝑚𝐿 × 0.1 𝑁 × 50.2 𝑚𝑔 𝑎𝑚𝑜𝑢𝑛𝑡 𝑚𝑔/𝑡𝑎𝑏 = 121.2 𝑚𝑔 × 157. 9 𝑚𝑔 Calculation Examples: Direct Titration 𝑎𝑚𝑜𝑢𝑛𝑡 𝑚𝑔/𝑡𝑎𝑏 = 153. 23 𝑚𝑔/𝑡𝑎𝑏 1. If a 0.2800g sample of sodium bicarbonate is titrated with 3.51 mL of 0.9165N sulfuric Residual / Back Titration acid. What is the % purity of the sample? - carried out by dissolving the substance under examination in an accurately Given: measured quantity of standard solution wt sx of NaHCO3 = 0.2800 g known to be in excess and titrating the V of VS = 3.51 mL excess of the latter with another standard N of VS = 0.9165 N solution meq wt Sx = ? - frequently used when: reaction proceeds % Purity = ? slowly or does not give sharp end point w/ direct titration, a substance is Formula: insoluble, or when a volatile substance 𝑉 × 𝑁 × 𝑚𝐸𝑞 is involved %𝑃𝑢𝑟𝑖𝑡𝑦 = 𝑤𝑡 𝑜𝑓 𝑆𝑥 𝑖𝑛 𝑔 × 100 [(𝑉1𝑁1)]−[𝑉2𝑁2)] 𝑚𝐸𝑞 %𝑃𝑢𝑟𝑖𝑡𝑦 = 𝑤𝑡 𝑜𝑓 𝑆𝑥 𝑖𝑛 𝑔 × 100 Solution: 3.51 𝑚𝐿 × 0.9165 𝑁 × 0.084 %𝑃𝑢𝑟𝑖𝑡𝑦 = 0.2800 × 100 [(𝑉1𝑁1)]−[𝑉2𝑁2)] 𝑡𝑖𝑡𝑒𝑟 %𝑃𝑢𝑟𝑖𝑡𝑦 = 𝑤𝑡 𝑜𝑓 𝑆𝑥 𝑖𝑛 𝑚𝑔 × 100 %𝑃𝑢𝑟𝑖𝑡𝑦 𝑜𝑓 𝑁𝑎𝐻𝐶𝑂3 = 96. 51% 𝑎𝑚𝑜𝑢𝑛𝑡 𝑚𝑔/𝑡𝑎𝑏 = [(𝑉1𝑁1)]−[𝑉2𝑁2)] × 𝑚𝐸𝑞 × 𝐴𝑣𝑒. 𝑤𝑡. 𝑖𝑛 𝑚𝑔 𝑤𝑡 𝑜𝑓 𝑆𝑥 𝑖𝑛 𝑔 [(𝑉1𝑁1)]−[𝑉2𝑁2)] × 𝑡𝑖𝑡𝑒𝑟 𝑎𝑚𝑜𝑢𝑛𝑡 𝑚𝑔/𝑡𝑎𝑏 = × 𝐴𝑣𝑒. 𝑤𝑡. 𝑖𝑛 𝑚𝑔 2. Twenty tablets of Tums ® weigh 3.1575g. 𝑤𝑡 𝑜𝑓 𝑆𝑥 𝑖𝑛 𝑚𝑔 The tablets were dissolved in neutralized alcohol to make 250mL of the solution. Calculation Example: Residual Titration About 9.6mL aliquot portion was titrated with 2.2mL of 0.1065N H2SO4 to bring A 0.3191g sample of sodium chloride was assayed about the endpoint. What is the using 52mL of 0.1095 N AgNO3 and 2.3mL of amount/tab, if each mL of 0.1N H2SO4 is 0.1056N NH4SCN. Calculate the % NaCl in the equivalent to 50.2mg CaCO3? sample. Given: Given: wt sx of NaCl = 0.3191 g wt Sx of 20 tabs = 3.1575 g V of AgNO3 = 52 mL N of AgNO3 = 0.1095N 3.157 𝑔 𝑥 V of NH4SCN = 2.3 mL 250 𝑚𝐿 × 9.6 𝑚𝐿 𝑎𝑙𝑖𝑞𝑢𝑜𝑡 N of NH4SCN = 0.1056N mEq wt NaCl = ? wt of sample (x) = 0.1212g or 121.2 mg % Purity of NaCl = ? Average Sx = 3.1575 g/ 20 tabs = 0.1579 g or 157.9mg Formula: V of VS = 2.2 mL N of VS = 0.1065N [(𝑉1𝑁1)]−[𝑉2𝑁2)] 𝑚𝐸𝑞 %𝑃𝑢𝑟𝑖𝑡𝑦 = × 100 Theoretical N = 0.1N 𝑤𝑡 𝑜𝑓 𝑆𝑥 𝑖𝑛 𝑔 Titer = 50.2mg RIGONAN, R-A.R. | PHA233 Solution: [(52 𝑚𝐿)(0.1095 𝑁)]−[(2.3 𝑚𝐿)(0.1056 𝑁)] 𝑚𝐸𝑞 %𝑃𝑢𝑟𝑖𝑡𝑦 = 0.3191 𝑔 × 100 %𝑁𝑎𝐶𝑙 = 99. 08% Indirect Titration the analyte is treated first with an agent that converts it to an easily measurable substance, which can be easily titrated by a standard solution Example: Assay of Malic Acid (in Cherry Juice) Titrant: KMnO4 C4H6O5 + CaCO3 🡪 CaC4H4O5 + CO2🡩 + H2O Malic acid Calcium Maleate CaC4H4O5 + (NH4)2C2O4 🡪 CaC2O4. H2O🡫+ (NH4)2C4H6O5 Calcium Maleate Calcium Oxalate CaC2O4. H2O + H2SO4 🡪 CaSO4 + H2C2O4 Calcium Oxalate Oxalic Acid *solution with Oxalic acid is then titrated with KMnO4 Solution Blank Titration - to be conducted with the use of the same quantities of the same reagent treated in the same manner as the solution or mixture containing the portions of the substance under assay, but the substance itself is omitted - *purpose: correction/removal of error (𝑉𝑏−𝑉𝑆𝑥) 𝑁 ×𝑚𝐸𝑞 %𝑃𝑢𝑟𝑖𝑡𝑦 = 𝑤𝑡 𝑜𝑓 𝑆𝑥 𝑖𝑛 𝑔 × 100 RIGONAN, R-A.R. | PHA233 PHARMACEUTICAL ANALYSIS 1 [LAB] VOLUMETRIC SOLUTION aka. standard solution TITRATION a homogenous mixture of one or more aka. volumetric analysis substances (solutes) dispersed a process in which a solution of reagent of molecularly in a sufficient quantity of known concentration is added to a solution dissolving medium (solvent) of analyte until the reaction is judged complete CRITERIA FOR PRIMARY STANDARD TYPES OF QUANTITATIVE ANALYSIS 1) highly stable 2) stable in air Volumetric Analysis / Titration 3) easy to measure out determination of volume of solution of 4) pure known concentration required to react with 5) non-toxic a given amount of substance to be 6) high solubility analyzed 7) low hygroscopicity ➔ analyte/sample/titrand: chemical being ACTIVITY NO. 1 analyzed Preparation and Standardization of 1N Sodium ➔ standard solution/titrant: one whose Hydroxide Solution concentration is accurately known ➔ indicator: chemical capable of changing Type of Standardization: Primary color at or very near endpoint. Titrant: Sodium Hydroxide ➔ equivalence/stoichiometric point: Analyte: Potassium Biphthalate theoretical point at which equivalent Primary Standard: Potassium Biphthalate amount of substance has reacted Indicator: Phenolphthalein ➔ endpoint: practical/experimental; can be Endpoint: Permanent Pink seen/shown by the changed of color OTHER PRIMARY STANDARD THAT CAN BE USED FOR ALKALI SOLUTION TYPES OF TITRATION BASED ON THE NO. OF VOLUMETRIC SOLUTION 1) Arsenic trioxide As2O3 2) Potassium bromate KBrO3 DIRECT: uses only 1 volumetric solution 3) Sodium carbonate Na₂CO₃ RESIDUAL: uses 2 volumetric solution 4) Sodium chloride NaCl TYPES OF VOLUMETRIC SOLUTION ACTIVITY NO. 2 Preparation and Standardization of 1N Sulfuric Primary Standard: substance of known Acid Solution concentration and high degree of purity Secondary Standard: solution of known Type of Standardization: Primary concentration; usually standardized by primary Titrant: Sulfuric Acid standard Analyte: Sodium Carbonate Primary Standard: Sodium Carbonate STANDARDIZATION Indicator: Methyl Orange the process of determining the Endpoint: Permanent Pink concentration of the titrant ACTIVITY NO. 3 TEST SOLUTION Assay of Tartaric Acid a solution of a reagent in a specified strength, used in chemical analysis or Type of Titration: Direct Titration testing Titrant: Sodium Hydroxide Analyte: Tartaric Acid Indicator: Phenolphthalein Endpoint: Faint Pink RIGONAN, R-A.R. | PHA233 ACTIVITY NO. 4 Primary Standard: Sodium Chloride Assay of Sodium Bicarbonate Tablet Indicator: Potassium Permanganate Endpoint: Pale Pink Type of Titration: Direct Titration Titrant: Sulfuric Acid ACTIVITY NO. 10 Analyte: Sodium Bicarbonate Assay of Hydrogen Peroxide Topical Indicator: Methyl Orange Solution Endpoint: Yellow Color Type Of Standardization: ACTIVITY NO. 5 Oxidation-Reduction Assay of Zinc Oxide Titrant: Potassium Permanganate VS Type of Titration: Direct Titration Analyte: Hydrogen Peroxide Titrant: Sulfuric Acid Indicator: Potassium Permanganate Analyte: Zinc Oxide Endpoint: Pale Pink Indicator: Methyl Orange Endpoint: Pink Color ACTIVITY NO. 11 Preparation and Standardization Of 0.0 N ACTIVITY NO. 6 Sodium Thiosulfate Solution Assay of Aspirin Type of Standardization: Blank Type of Titration: Residual Titration Determination Titrant: Sulfuric Acid Titrant: Sodium Thiosulfate Solution Analyte: Aspirin Analyte: Potassium Dichromate Indicator: Phenolphthalein Primary Standard: Potassium Dichromate Endpoint: Disappearance of Pink Color Indicator: Starch TS Endpoint: Disappearance of Blue Color ACTIVITY NO. 7 Preparation and Standardization of 0.1N Silver ACTIVITY NO. 12 Nitrate Solution Assay of Iodine In Povidone Iodine Solution Type of Standardization: Precipitation Type of Standardization: Titrant: Silver Nitrate Oxidation-Reduction Analyte: Sodium Chloride Titrant: Iodine Solution Primary Standard: Sodium Chloride Analyte: Arsenic Trioxide Indicator: Eosin Y TS Indicator: Starch TS Endpoint: Formation of Precipitate Endpoint: Permanent Blue Color HCI ACTIVITY NO. 8 aka. muriatic acid, spirits of salt Assay of Sodium Chloride ➔ clear colorless solution ➔ highly corrosive Type of Standardization: Precipitation ➔ strong mineral acid Titrant: Silver Nitrate ➔ contains NLT 36.5% and NMT 38% by wt Analyte: Sodium Chloride ➔ preserved in tight container Indicator: Eosin Y TS ➔ MW = 36.46g/mole Endpoint: Pink ➔ strong monoprotic acid ACTIVITY NO. 9 NaOH Preparation and Standardization of 0.1N aka. caustic soda Potassium Permanganate Solution ➔ highly caustic metallic base ➔ contains NLT 95% and NMT 100.5% of Type of Standardization: total alkali Oxidation-Reduction ➔ MW = 40g/mole Titrant: Potassium Permanganate ➔ preserved in tight container Analyte: Sodium Oxalate ➔ strong base RIGONAN, R-A.R. | PHA233 CH3COOH INDICATOR ACID BASE ➔ colorless liquid ➔ component of vinegar Methyl orange Pink Yellow ➔ weak acid Methyl red Red Yellow ➔ simplest carboxylic acid ➔ contains NLT 36% and NMT 37% by wt Malachite green Yellow Green ➔ MW = 60g/mole Bromothymol blue Yellow Blue ➔ weak acid Phenolphthalein colorless Pink Aspirin Thymol blue Yellow Blue aka. acetylsalicylic acid ➔ contains NLT 99.5% and NMT Phenol red Yellow Red 100.5% of C9H804 ➔ MW = 180g/mole Silver nitrate aka. lunar caustic ➔ organic compound ➔ MW = 169.87g/mole ➔ contains nIt 99.8% and 100.5% of AgNO3. ➔ preserve in a tight, light resistant container NH4SCN ➔ inorganic compound ➔ MW = 76g/mole KMnO4 aka. mineral chameleon aka. condy’s crystal ➔ inorganic chemical compound ➔ gives a deep purple color ➔ MW= 158 ➔ contains NLT 99% and NMT 100.5% ➔ preserve in a well closed container ➔ strong oxidizing acid INDICATORS Phenolphthalein С20Н1404 ➔ often used in titrations, it turns colorless in acidic solutions and pink in basic solutions ➔ Carcinogenic ➔ MW = 318g/mole Methyl orange C14H14N3 NaOS ➔ mutagenic property ➔ acid - red; base - yellow ➔ MW = 327g/mole RIGONAN, R-A.R. | PHA233