Pharmaceutical Chemistry Chapter 1 PDF

PHARMACEUTICAL CHEMISTRY ER20-12T ER20-12T PHARMACEUTICAL CHEMISTRY CHAPTER-01 CONTENT Introduction to Pharmaceutical chemistry: Scope and objectives Sources and types of errors: Accuracy, precision, significant figures Impu...

PHARMACEUTICAL CHEMISTRY ER20-12T ER20-12T PHARMACEUTICAL CHEMISTRY CHAPTER-01 CONTENT Introduction to Pharmaceutical chemistry: Scope and objectives Sources and types of errors: Accuracy, precision, significant figures Impurities in Pharmaceuticals: Source and effect of impurities in Pharmacopoeial substances, the importance of the limit test, Principle and procedures of Limit tests for chlorides, sulfates, iron, heavy metals and arsenic.  PHARMACEUTICAL CHEMISTRY ER20-12T Pharmaceutical Chemistry Pharmaceutical chemistry is a branch of chemistry that focuses on the study of organic molecules and compounds, structural and chemical biology, and pharmacology to develop pharmaceutical drugs and medicines. Scope of Pharmaceutical Chemistry: Drug Development: Involves drug discovery, metabolism, absorption, and delivery, aiming to ​ develop effective medications. Quality Assurance & Quality Control (QA & QC): Ensures the quality of drug compounds ​ through processes and standards. Industry: Pharmaceutical chemists play vital roles in the pharmaceutical industry, working on ​ drug development, quality control, and regulatory compliance. Education: Pharmaceutical chemistry professionals may serve as educators in colleges and ​ institutes, teaching students about drug discovery, analysis, and synthesis. Pharmaceutical chemistry integrates various fields such as drug chemistry, quality assurance, metabolism, pharmacology, and analytical techniques to develop effective cures and remedies for diseases Introduction to Errors, Accuracy, Precision, and Significant Figures Errors in measurements result from internal or external factors affecting the accuracy and precision of results. In pharmaceutical and analytical chemistry, errors arise from defective equipment or methods, impacting the reliability, reproducibility, and precision of material products. Types of Errors: Systematic Errors: Predictable errors that consistently affect measurements. Random Errors: Unpredictable errors that vary with each measurement. Accuracy and Precision: Accuracy: The closeness of measurements to the true value. Precision: The closeness of repeated measurements to each other.  PHARMACEUTICAL CHEMISTRY ER20-12T Significant Figures: Significant figures represent the precision of a measurement and include all reliably known digits plus one uncertain digit. Absolute and Relative Errors: Absolute Errors: The difference between measured and true values, which can be positive or negative. Absolute Error=Measured Value−True Value Where: Measured Value-Measured Value is the value obtained from measurement. True Value-True Value is the actual or accepted value. Relative Errors: The ratio of absolute errors to true values, often expressed as a percentage or parts per thousand. Relative Error=Absolute Error/Actual Value Where: Absolute Error: The absolute difference between the measured value and the actual value. Actual Value: The true or accepted value. Example: Actual caffeine content: 3.50% Measured caffeine content: 3.75% Absolute error: 3.75 - 3.50 = 0.25% Relative error (percentage): (0.25 / 3.50) * 100 = 7.14% Relative error (parts per thousand): (0.25 / 3.50) * 1000 = 71.42 In this example, the absolute error in determining the caffeine content is 0.25%, with a relative error of 7.14% (percentage) and 71.42 (parts per thousand)  PHARMACEUTICAL CHEMISTRY ER20-12T Errors in Measurement: Types and Sources Determinate or Systematic Errors Definition: Systematic errors arise from consistent inaccuracies in measurement procedures or equipment. ​ Control: These errors are under the analyst's control and can often be eliminated or minimized. ​ Sources: Instrumental Errors: Stem from defective or low-quality equipment, affecting the accuracy of analytical procedures. Proportional Errors: Absolute value changes with sample size, maintaining a constant relative error. Common in materials interfering with analytical processes. Personal Errors: Result from carelessness, lack of skill, or ignorance during method handling, also known as operative errors. Chemical/Reagent Errors: Stem from chemical reactivity between used chemicals and reagents, impacting accuracy. Methodology Errors: Arise from faulty analysis methods, such as incomplete reactions or co-precipitation of impurities. Indeterminate or Random Errors Definition: Indeterminate errors are unpredictable and result from successive measurements under identical conditions. ​ Characteristics: Follow a random distribution pattern, making them difficult to identify or eliminate. ​ Mathematical Treatment: Statistical laws like the law of probability are used to analyze and mitigate the impact of random errors on results ​ Indeterminate Errors and the Normal Distribution Curve Definition: Indeterminate errors are represented by the normal frequency distribution curve, also known as the curve of error. ​  PHARMACEUTICAL CHEMISTRY ER20-12T Graph Characteristics: ​ The x-axis represents the magnitude of errors, while the y-axis represents the frequency of deviation. The curve follows a normal distribution pattern or probability curve. Key Observations: ​ Very large errors are unlikely to occur, as they are situated at the tails of the curve. Smaller errors occur more frequently than larger errors, indicating a higher probability of occurrence. Errors on the positive and negative sides of the curve occur with equal probability, reflecting the symmetrical nature of the normal distribution. Significance: The normal distribution curve helps in understanding the nature and frequency ​ of errors in experimental or analytical processes. Applications: Widely used in statistical analysis and quality control to assess the reliability ​ and consistency of data. Graph Representation: Visualizing errors through the normal distribution curve facilitates the ​ identification of trends and patterns in data variability. ​  PHARMACEUTICAL CHEMISTRY ER20-12T Accuracy and Precision in Measurement Accuracy Definition: Accuracy refers to the degree of agreement between a measured value and the true or accepted value of a quantity. ​ Description: In scientific experiments, no measurement is perfectly accurate, so accuracy is within certain limits. It's typically determined by comparing multiple measurements from ​ different sources using various techniques. Relation to Error: Accuracy is inversely proportional to the error; the lower the error, the higher the accuracy. ​ Example: If the true water percentage in milk is 87%, and an analyst obtains measurements of 88.3%, 85.4%, 86.8%, 88.5%, and 87.9%, the accuracy is determined by how close these ​ values are to the true value. Precision Definition: Precision refers to the consistency or reproducibility of measurements when repeated under the same conditions. ​ Description: Precision does not necessarily indicate accuracy but rather the agreement among a set of measurements. It signifies how closely repeated measurements cluster ​ around the same value. Example: In the milk experiment, if the range of measured values is 85.4% to 88.5%, precision is determined by how consistently these values cluster around each other. ​ Accuracy reflects how close measured values are to the true value, while precision indicates the consistency of repeated measurements. Both are essential in evaluating the quality of experimental results, with accuracy focusing on correctness and precision on reproducibility. Significance of Significant Figures Definition: Significant figures are crucial in expressing the precision of measurements. They represent the digits that convey meaningful information about the measured quantity. ​  PHARMACEUTICAL CHEMISTRY ER20-12T Role in Accuracy and Precision: Significant figures ensure that measurements are reported accurately and precisely, reflecting the level of certainty in the measurement. ​ Digit Representation: Each digit in a measurement signifies its quality and contributes to the overall precision of the result. ​ Zeroes in Significance: Zeroes in measurement can denote significant parts, such as denoting the scale (e.g., tens, hundreds) or merely locating the decimal point. ​ Examples: 25.05 and 1350 have four significant figures, where the zeroes are significant. 0.0034 signifies the decimal point but does not add to the significant figures. Application: ​ In instruments like burettes, measurements can be reported using significant figures to indicate precision. ​ Example: Measuring 7.34 mL signifies three significant figures, two of which are certain and one uncertain. Minimizing Errors: ​ Calibration of instruments and apparatus ensures accuracy. Personal care and skilled handling reduce human-induced errors. Selection of suitable materials and elimination of impurities minimize contamination. Thorough chemical evaluation, analysis, and adherence to proper methodology enhance accuracy. Impurities in Pharmaceuticals Definition: Impurities refer to undesired or unexpected materials present during pharmaceutical processes, which can alter the final products. ​ Purity Requirements: Pharmaceuticals must contain substances pure enough to ensure safe use, but achieving absolute purity is challenging. ​ Origin of Impurities: Impurities can arise accidentally during manufacturing, crystallization, or purification processes, depending on various factors and methods involved. ​ Harmful Effects: Many impurities can have detrimental effects on pharmaceutical ​  PHARMACEUTICAL CHEMISTRY ER20-12T preparations, making their removal a critical challenge. Control Measures: Achieving acceptable purity involves controlling various sources or factors ​ contributing to impurities in active pharmaceutical ingredients (APIs) and excipients. Pharmacopoeial Standards: Pharmacopoeias establish limits for impurities in ​ pharmaceutical substances, ensuring the safety and efficacy of medicinal products. Sources of impurities Impurities may enter or form in a drug substance during any of the following three stages--- 1. During manufacturing. 2. During purification and processing. 3. During storage. During Manufacturing: ​ Raw Materials: Impurities present in raw materials, such as heavy metals and chlorides, can contaminate the final product. Reagents: Impurities in manufacturing reagents can find their way into the final product, affecting its purity. Solvents: Contamination from solvents like toluene and n-butanol can occur if their quality is not assured. Reaction Equipment: Reacting vessels can introduce impurities due to corrosion or reaction with solvents and reagents. Intermediate Products: Intermediates formed during manufacturing can carry impurities into the final product. Manufacturing Hazards: Industrial contaminants like dust particles and gases can enter during production, altering product potency. During Purification and Processing: ​ Purifying Reagents: Reagents used for purification can inadvertently introduce impurities. Solvents: Purification solvents, including organic solvents and acids, may contain  PHARMACEUTICAL CHEMISTRY ER20-12T impurities. Equipment Contamination: Vessels and equipment used for purification can introduce impurities if not properly cleaned. During Storage and Packing: ​ Packaging Materials: Substandard packaging materials can lead to impurities in the product. Packaging Process: Faulty packaging processes can cause contamination and impurities. Microbial Contamination: Improper storage conditions or faulty packaging can result in microbial contamination, necessitating sterility testing Effects of Impurities Reduction in Active Strength: Impurities exceeding limits can diminish the potency of the ​ substance and alter its therapeutic effects. Incompatibility and Deterioration: Impurities may cause the original substance to degrade or ​ become incompatible with other substances, leading to deterioration. Chemical Reactivity: Some impurities directly participate in chemical reactions, altering the ​ behavior of the substance. Cumulative Toxicity: Even trace amounts of impurities can accumulate over time, resulting in ​ toxic effects. Microbial Growth Promotion: Certain impurities can encourage microbial growth, leading to ​ substance deterioration. Catalyzing Degradation: Some impurities catalyze the degradation process, reducing the ​ shelf life of the drug substance. Physical Property Changes: Unstable impurities can alter physical properties like ​ appearance, taste, and odor, posing challenges in formulation and use. Limit Test Definition: Quantitative or semi-quantitative tests to identify and control small impurity amounts in a substance.  PHARMACEUTICAL CHEMISTRY ER20-12T Role: Crucial in pharmaceutical analysis for substance clarification and purity determination, particularly for identifying inorganic impurities. Not Numerically Based: Limit tests rely on the comparison of turbidity, opalescence, or color intensity between standard solutions and test samples Importance of Limit Test Solution Compatibility: Limit tests indicate the compatibility of a solution when other substances are present, ensuring its suitability for use. ​ Impurity Quantification: They quantify the amount of impurities present in a solution, aiding in determining its purity. ​ Distinguishing Impurity Types: Limit tests differentiate between avoidable and unavoidable impurities, aiding in the identification and control of impurity sources. ​ Enhanced Purity and Clarity: Overall, limit tests contribute to enhancing the purity and clarity of solutions, ensuring they meet quality standards. ​ Pharmacopeia Standard for Preparation of Test Solution during Limit Test A specified amount of the substance is dissolved in distilled water, making up the volume to 50ml in a Nessler’s cylinder. For alkaline substances like hydroxides and carbonates, they are dissolved in sufficient acid to cease effervescence and ensure the presence of free acid. Insoluble substances like kaolin undergo water extraction, filtration, and use of the filtrate. Salts of organic acids undergo acidification to liberate insoluble organic acids, with the filtrate used for the test. Colored substances are carbonized, and the resulting ash is extracted in water. Reducing substances are oxidized with oxidizing agents, and the solution is then prepared and used. Substances like potassium permanganate are reduced by boiling with alcohol, and the filtrate is utilized Limit Test of Chloride  PHARMACEUTICAL CHEMISTRY ER20-12T The limit test of chloride is a chemical test used to determine the presence and concentration of chloride ions in a given sample. Here's an explanation of the apparatus, chemicals, chemical reaction, and procedure involved: Apparatus: Nessler's Cylinder: Used for holding and measuring liquid samples. ​ Pipette: For accurate measurement and transfer of liquids. ​ Stirring Rod: Used for stirring solutions to ensure uniform mixing. ​ Beaker: Container for holding liquids during the test. ​ Stand: Provides support for apparatus during the procedure. ​ Chemicals: Dilute Nitric Acid (10%): Acid used to acidify the sample and prevent precipitation of other ions. ​ Silver Nitrate (5%): Reagent used for the detection of chloride ions. ​ Test Sample: Substance being tested for the presence of chloride ions. ​ Standard Sample (Sodium Chloride): Known concentration of chloride ions used as a reference for comparison. ​ Chemical Reaction: The principle of the test is based on the reaction between soluble chloride ions in the test sample and silver nitrate in the presence of dilute nitric acid. The reaction results in the formation of insoluble silver chloride precipitate: ​ AgNO3+Cl−→AgCl↓+NO3− Procedure: Test: ​ Dissolve the test sample in water and transfer it to a Nessler's cylinder. Add 1 ml of dilute nitric acid and dilute to 50ml with water.  PHARMACEUTICAL CHEMISTRY ER20-12T Add 1 ml of silver nitrate and stir immediately. Allow the solution to stand for 5 minutes and observe the turbidity. Compare the turbidity with that of the standard sample. Standard: ​ Prepare a standard sample containing a known concentration of chloride ions (e.g., sodium chloride). Follow the same procedure as the test sample and compare the turbidity with the test solution..in If the turbidity observed in the test sample is less than that of the standard sample, the test sample passes the limit test for chloride. This test is essential in various industries, including pharmaceuticals, food, and environmental testing, to ensure compliance with quality standards. Limit Test for Sulphate Apparatus: Nessler's Cylinder: Used for holding the test solution and facilitating easy observation of ​ turbidity. Pipette: To accurately measure and transfer liquids, such as the test sample and reagents. ​ Stirring Rod: To mix the solutions thoroughly during the testing process. ​ Beaker: To prepare and hold the solutions before transferring them to the Nessler's cylinder. ​ Stand: Provide support for the Nessler's cylinder during the testing procedure. ​ Chemicals: Dilute Hydrochloric Acid: Used as a reagent to create the acidic environment necessary for ​ the reaction. Test Sample: Substance or solution under investigation for the presence of sulphate ions. ​ Standard Sample: Contains a known quantity of sulphate ions, often prepared using ​ potassium sulphate. Barium Chloride: Reagent that reacts with sulphate ions to form insoluble barium sulphate. ​  PHARMACEUTICAL CHEMISTRY ER20-12T Chemical Reaction: The reaction involves the interaction between soluble sulphate ions (SO42−) and barium ​ chloride (BaCl2​) in the presence of dilute hydrochloric acid (HCl). This leads to the formation of insoluble barium sulphate (BaSO4​) precipitate. The chemical equation representing the reaction is: BaCl2+SO42−+HCl→BaSO4↓+2HCl+NaCl ​ ​ ​ The appearance of a white precipitate or turbidity indicates the presence of sulphate ions in the test solution. Procedure: Prepare the test solution by dissolving the specified quantity of the test sample in distilled water and transferring it to Nessler's cylinder. Add a measured volume of dilute hydrochloric acid to the test solution to create an acidic environment. Introduce a measured volume of barium chloride reagent to the test solution. Stir the solution thoroughly using the stirring rod and allow it to stand for a few minutes. Observe the formation of turbidity or white precipitate in the solution. Repeat the procedure using a standard sample with a known quantity of sulphate ions for comparison. Compare the turbidity observed in the test solution with that of the standard sample to determine the presence of sulphate ions and assess if the sample passes the limit test. This procedure is essential in qualitative analysis to detect sulphate ions in various substances Limit Test for Iron Apparatus: Test tubes Test tube holder  PHARMACEUTICAL CHEMISTRY ER20-12T Test tube rack Bunsen burner Dropper Chemicals: Hydrochloric acid (HCl) Potassium hexacyanoferrate(III) solution (also known as potassium ferricyanide) (K3[Fe(CN)6]) Distilled water Test sample Standard solution of iron (Fe) Chemical Reaction: Principle: ​ In the limit test for iron, the principle involves the formation of a blue precipitate of ferric hexacyanoferrate(II) complex when iron ions react with potassium hexacyanoferrate(III) solution in an acidic medium. Chemical Reaction: ​ Iron ions (Fe²⁺) react with potassium hexacyanoferrate(III) solution: Fe2++K3[Fe(CN)6]→Fe[Fe(CN)6]↓+3 K+ Procedure: Preparation of Test Solutions: ​ Prepare the test sample solution by dissolving the substance containing iron in dilute hydrochloric acid. Prepare a standard solution of iron with a known concentration. Test: ​  PHARMACEUTICAL CHEMISTRY ER20-12T In separate test tubes, add equal volumes of the test sample solution and potassium hexacyanoferrate(III) solution. Heat the mixture gently in a water bath. Observe for the formation of a blue precipitate. Compare the color and intensity of the precipitate with that of the standard solution. Interpretation: ​ If the color and intensity of the precipitate in the test solution match or are less intense than that of the standard solution, the test is negative for the presence of iron. This procedure is commonly used in qualitative analysis to determine the presence of iron ions in a given sample. Limit Test of Heavy Metals Limit tests for heavy metals are analytical procedures used to detect the presence of certain heavy metals in pharmaceuticals and other substances. Here's an explanation of the required apparatus, chemicals, chemical reaction, and procedure involved: Apparatus: Test Tubes: Used for mixing solutions and conducting reactions. ​ Bunsen Burner: To provide heat for certain reactions if required. ​ Test Tube Holder: For handling hot test tubes safely. ​ Pipettes: For accurate measurement and transfer of liquids. ​ Glass Stirring Rod: To stir solutions uniformly. ​ Filter Paper: To separate precipitates from the solution. ​ Centrifuge: If necessary, to separate solids from liquids. ​ Chemicals: Test Sample: The substance being tested for the presence of heavy metals. ​ Reagents: Specific reagents are used depending on the heavy metal being tested for (e.g., ammonium sulfide for detection of lead, silver nitrate for mercury, etc.). ​  PHARMACEUTICAL CHEMISTRY ER20-12T Solvents: Dilute acids (such as hydrochloric acid) may be used to dissolve the test sample and facilitate reactions. ​ Standard Solutions: Solutions containing known concentrations of heavy metals for comparison. ​ Indicator Solutions: Such as potassium chromate for detecting the endpoint of certain reactions. ​ Chemical Reaction: The chemical reactions involved in limit tests for heavy metals vary depending on the specific metal being tested for. For example: Lead: Lead ions react with ammonium sulfide to form a black precipitate of lead sulfide. Mercury: Mercury ions react with silver nitrate to form a white precipitate of mercury chloride. Procedure: Sample Preparation: Dissolve the test sample in an appropriate solvent. ​ Reaction with Reagents: Mix the sample solution with the specific reagent for the heavy metal being tested. ​ Observation: Observe any color changes or precipitation reactions. ​ Comparison with Standards: Compare the observed results with those obtained from standard solutions of known concentrations. ​ Interpretation: Determine if the observed reaction corresponds to the presence of the heavy metal in the test sample. ​ Documentation: Record observations and results for reporting purposes. ​ These procedures help ensure the safety and quality of pharmaceuticals and other products by detecting potentially harmful levels of heavy metals. Limit Test of Arsenic Apparatus: Test Tubes: To hold and mix the samples and reagents. ​  PHARMACEUTICAL CHEMISTRY ER20-12T Bunsen Burner: For heating purposes. ​ Test Tube Holder: To hold and manipulate test tubes during heating. ​ Filter Paper: For filtration. ​ Glass Rod: For stirring solutions. ​ Beakers: To contain solutions and reagents. ​ Pipettes: For precise measurement of liquids. ​ Measuring Cylinder: For accurate measurement of liquids. ​ Safety Equipment: Gloves, goggles, and lab coats for personal protection. ​ Chemicals: Arsenic Standard Solution: A known concentration of arsenic solution for comparison. ​ Hydrochloric Acid (HCl): To acidify the sample and facilitate the reaction. ​ Stannous Chloride (SnCl₂): Reagent used in the Gutzeit method to generate arsine gas. ​ Sodium Hydroxide (NaOH): To neutralize excess acid after the reaction. ​ Distilled Water: To prepare solutions and dilute reagents. ​ Chemical Reaction: The chemical reaction involved in the limit test of arsenic depends on the method used. One common method is the Gutzeit method, which involves the generation of arsine gas (AsH₃) from arsenic present in the sample. The reaction proceeds as follows: 2As+6HCl+6SnCl2→2AsH3+6SnCl4 Arsenic reacts with hydrochloric acid and stannous chloride to produce arsine gas and stannic chloride. PHARMACEUTICAL CHEMISTRY ER20-12T