B Pharmacy Sem 1: Pharmaceutical Inorganic Chemistry

Subject 4. Pharmaceutical Inorganic Chemistry

1. 1. General Inorganic Chemistry & Water
   2. Acid–Base Balance & Buffers
   3. Heavy Metals & Their Estimations
   4. Radiopharmaceuticals
   5. Inorganic Pharmaceutical Substances
   6. Quality Control Tests for Inorganic Drugs

Unit 1: General Inorganic Chemistry & Water

This unit covers basic principles of inorganic chemistry relevant to pharmacy and the critical role of water in preparing and testing inorganic drugs. You’ll learn types of water used in pharmaceutical processes, how they’re produced, their properties, and quality standards.

1.1 Scope of Inorganic Chemistry in Pharmacy

• Studies the chemistry of non‑carbon elements and their compounds used as drugs, excipients, reagents, and equipment materials.

• Emphasizes reaction mechanisms, solubility, coordination chemistry (complexes), and analysis methods for inorganic substances.

1.2 Importance of Water in Pharmaceutics

• Universal solvent for formulation of injections, oral liquids, and topical preparations.

• Medium for chemical reactions in manufacturing and quality control tests.

• Source of injectable and laboratory-grade water must be free from harmful ions, microorganisms, and pyrogens.

1.3 Types of Pharmaceutical Waters

1.4 Physical & Chemical Properties of Water

• Polarity & Hydrogen Bonding: High dielectric constant, excellent solvent for ionic substances.

• Boiling & Freezing Points: 100 °C and 0 °C at 1 atm; used in distillation and storage guidelines.

• pH: Neutral 7.0 at 25 °C; must be adjusted in some formulations to maintain stability.

• Conductivity & Resistivity: Indicators of ionic impurities; Purified Water: ≤ 1.3 µS/cm at 25 °C; WFI: ≤ 1.1 µS/cm.

1.5 Production Methods

1. Distillation

   • Vaporize water; condense pure steam; removes most organics, microbes, and inorganic ions.

   • Single‑pass vs. multi‑pass systems; multi‑pass gives higher purity.

2. Ion Exchange (Deionization)

   • Cation and anion exchange resins remove dissolved salts.

   • Requires pretreatment to remove organics; not effective against organics or microbes alone.

3. Membrane Filtration

   • Reverse Osmosis (RO): Semi‑permeable membrane excludes ions, particles, and most organics.

   • Nanofiltration/Ultrafiltration: Removes larger molecules, bacteria, and pyrogens.

4. Combination Systems

   • Often combine RO + deionization + UV oxidation + ultrafiltration to meet WFI standards.

1.6 Impurities in Water & Their Effects

• Inorganic Ions (Na⁺, Cl⁻, Ca²⁺, SO₄²⁻): May cause precipitation, affect drug stability, interfere in assays.

• Microbial Contaminants: Bacteria and endotoxins (pyrogens) can cause infections or fever if injected.

• Organic Compounds: TOC from plastics or organics leached from resin; affects chromatography and stability.

• Particulates: Dust and rust; can clog filters, cause dosing errors, or damage equipment.

1.7 Quality Standards & Tests

1.8 Storage & Distribution

• Closed Loop Systems: Stainless steel or sanitized piping, no dead‑legs to prevent microbial growth.

• Temperature Control: WFI stored at ≥ 70 °C to maintain microbial control; Purified Water at ambient with periodic sanitation.

• Recirculation: Continuous flow to minimize stagnation and biofilm formation.

• Routine Monitoring: Daily conductivity, TOC, microbial sampling, and sanitization cycles.

1.9 Key Points for Exams

• Distinguish Purified Water vs. Water for Injection and their production methods.

• Memorize critical water quality tests (conductivity, TOC, microbial limits).

• Understand how water properties (polarity, pH, conductivity) affect formulations.

• Know common impurities and why they must be controlled.

• Recall storage/distribution requirements to maintain water quality.

Unit 2: Acid–Base Balance & Buffers

This unit explains how acids and bases behave in solution, how pH is controlled in pharmaceutical preparations, and how buffer solutions are designed, prepared, and tested to maintain stable pH.

2.1 Acid–Base Concepts

• Arrhenius Definitions

  • Acid: produces H⁺ in water (e.g., HCl → H⁺ + Cl⁻)

  • Base: produces OH⁻ in water (e.g., NaOH → Na⁺ + OH⁻)

• Brønsted–Lowry Definitions

  • Acid: proton donor

  • Base: proton acceptor

• Conjugate Pairs

  • Acid (HA) ⇌ H⁺ + A⁻, where A⁻ is the conjugate base

  • Base (B) + H⁺ ⇌ BH⁺, where BH⁺ is the conjugate acid

2.2 pH and pKa

• pH

  • Measure of H⁺ concentration: pH = –log₁₀[H⁺]

  • pH 7 is neutral; below 7 acidic; above 7 basic

• pKa

  • pKa = –log₁₀Ka where Ka is the acid dissociation constant

  • Lower pKa = stronger acid; pKa indicates the pH at which acid is 50% dissociated

2.3 Henderson–Hasselbalch Equation

• Relates pH, pKa, and ratio of conjugate base to acid:

  pH = pKa + log₁₀([A⁻] / [HA])

• Used to calculate:

  • pH of buffer when concentrations are known

  • Ratio of salt/acid needed to achieve desired pH

2.4 Buffer Capacity and Range

• Buffer Capacity (β)

  • Ability of buffer to resist pH change on addition of acid or base

  • Maximum at pH = pKa

• Effective Buffering Range

  • pKa ± 1 pH unit (≈ 10:1 to 1:10 ratio of [A⁻]:[HA])

2.5 Common Pharmaceutical Buffers

2.6 Preparation of Buffer Solutions

1. Select appropriate acid–base pair based on target pH and compatibility.

2. Calculate ratio of salt (conjugate base) to acid using Henderson–Hasselbalch.

3. Weigh components, dissolve in purified water, adjust volume.

4. Fine‑tune pH with small amounts of strong acid (HCl) or base (NaOH).

5. Validate pH using a calibrated pH meter at 25 °C.

2.7 Quality Control of Buffers

• pH Accuracy: ± 0.05 pH units of target

• Ionic Strength: Consistent to avoid shifts in pH upon dilution

• Sterility (if required): Filtration through 0.22 µm filter for parenterals or ophthalmics

• Preservative Content (if multi‑dose): Confirm correct concentration

2.8 Biological Acid–Base Balance

• Physiological Buffers:

  • Blood: bicarbonate (HCO₃⁻)/carbonic acid (H₂CO₃) system; pKa ≈ 6.1; blood pH ~7.4

  • Intracellular: phosphate buffers, proteins

• Homeostasis: Lungs regulate CO₂ (respiratory), kidneys handle HCO₃⁻ (metabolic)

2.9 Examples & Calculations

1. Making 0.1 M Phosphate Buffer at pH 7.4

   • pKa = 7.2; Henderson–Hasselbalch → ratio [HPO₄²⁻]/[H₂PO₄⁻] = 10^(7.4–7.2) ≈ 1.58

   • For 100 mL, total phosphate = 0.1 mol → split into 0.061 mol HPO₄²⁻ and 0.039 mol H₂PO₄⁻

2. Adjusting pH of an Acetate Buffer

   • Initial mix gives pH 5.0; target pH 4.8 → add dilute HCl dropwise while stirring, monitor pH.

Key Points for Exams

• Be clear on Arrhenius vs. Brønsted–Lowry definitions.

• Use Henderson–Hasselbalch to design buffers and calculate ratios.

• Know effective buffering ranges for common systems.

• Remember physiological relevance of bicarbonate buffer in blood.

• Practice preparing buffers and verifying pH and sterility.

Unit 3: Heavy Metals & Their Estimations

This unit examines the significance of heavy metal impurities in pharmaceuticals, the health risks they pose, official “limit tests” to detect them, and detailed analytical methods used to quantify or confirm their absence.

3.1 Why Heavy Metals Matter

• Definition: Metals with high atomic weight and density (e.g., lead, mercury, arsenic, cadmium) that can accumulate in body tissues.

• Toxicity: Even trace amounts may cause organ damage, neurological disorders, or carcinogenic effects.

• Sources in Pharmaceuticals: Raw materials, water, catalysts, glassware, packaging, or environmental contamination during manufacturing.

3.2 Common Heavy Metals and Their Hazards

3.3 Official Limit Tests (USP/BP)

• Purpose: Qualitative detection of “heavy metals” as a group, ensuring they do not exceed pharmacopeial limits (typically 10 ppm).

• Lead Acetate Test

  1. Acidify sample with dilute HCl.

  2. Add lead acetate solution: converts all heavy metals to sulfides.

  3. Add dilute H₂S: heavy metal sulfides precipitate.

  4. Compare turbidity or precipitate amount against standard (e.g., 10 µg Pb²⁺ per mL).

• Limit Test Interpretation: Cloudiness in the test solution indicates heavy metals above permissible levels.

3.4 Preparation of Sample Solutions

• Digestion

  • Dissolve organic matrices by wet ashing (nitric + sulfuric acid) or dry ashing (muffle furnace) to leave inorganic residue.

  • Dissolve residue in dilute acid.

• Filtration and Dilution

  • Filter to remove insoluble matter.

  • Dilute to known volume ensuring pH and acidity compatible with test reagents.

3.5 Quantitative Estimation Methods

3.5.1 Gravimetric Analysis

• Principle: Convert metal into insoluble salt, filter, dry/ignite, and weigh.

• Example: Precipitation of lead as PbSO₄ or AgCl for silver estimation.

• Advantages: Simple, no sophisticated equipment.

• Limitations: Time‑consuming, low sensitivity (mg level).

3.5.2 Volumetric (Titrimetric) Methods

• EDTA Titration

  • Forms stable complexes with many divalent and trivalent metals.

  • Use buffer (pH 10) and indicator (e.g., Eriochrome Black T) to detect endpoint.

• Iodometric Titration

  • For mercury: Hg²⁺ oxidizes iodide to iodine, titrate liberated I₂ with sodium thiosulfate.

• Advantages: Moderate sensitivity; relatively fast.

• Limitations: Requires careful pH control and standardization.

3.5.3 Colorimetric Methods

• Metal forms colored complex with specific reagent.

• Measure absorbance in a colorimeter or spectrophotometer.

• Examples:

  • Copper with biquinoline (green complex) at 480 nm

  • Iron with thiocyanate (red complex) at 480 nm

• Advantages: Good sensitivity (ppm level), relatively simple instrumentation.

• Limitations: Potential interferences by other colored species.

3.5.4 Instrumental Techniques

• Atomic Absorption Spectroscopy (AAS)

  • Measures absorption of light by ground‐state metal atoms in a flame or graphite furnace.

  • Detection limits in ppb range.

• Inductively Coupled Plasma Optical Emission Spectroscopy (ICP‑OES)

  • Excites atoms/ions in plasma; measures emitted light wavelengths.

  • Multi‐element capability, high throughput.

• Inductively Coupled Plasma Mass Spectrometry (ICP‑MS)

  • Ionizes sample in plasma and separates by mass; ultra‑trace detection (ppt).

• Advantages: High sensitivity and specificity, simultaneous multi‐element analysis.

• Limitations: Expensive equipment and maintenance.

3.6 Avoiding Interferences

• Masking Agents: EDTA or cyanide binds interfering ions selectively.

• pH Control: Adjust sample pH to favor target metal complexation or precipitation.

• Sample Cleanup: Use ion‑exchange resins or solvent extraction to remove matrix components.

3.7 Quality Standards & Acceptance Criteria

• USP/BP Heavy Metals Test: No more turbidity than standard (10 ppm Pb).

• Individual Metal Limits: Some metals (e.g., arsenic, mercury) may have stricter limits based on ICH Q3D guidelines.

• Reporting: Quantitative results reported as mg/kg or µg/mL; must comply with pharmacopeial monographs.

3.8 Key Points for Exams

• Understand why detection of heavy metals is critical for patient safety.

• Be able to describe the lead acetate limit test step by step.

• Know sample digestion methods for organic matrices.

• Compare gravimetric, titrimetric, colorimetric, and instrumental techniques in terms of sensitivity, speed, and complexity.

• Recall methods to minimize interferences and the rationale for masking and pH adjustment.

Unit 4: Radiopharmaceuticals

This unit covers drugs that contain radioactive isotopes for diagnosis or therapy. You’ll learn what radiopharmaceuticals are, the isotopes used, how they’re produced and labeled, how kits are prepared, and the critical quality‑control and safety measures required.

4.1 What Radiopharmaceuticals Are

Radiopharmaceuticals are sterile preparations that include a radionuclide—an unstable isotope that emits gamma rays, beta particles, or positrons—either alone or bound to a carrier molecule. They localize in specific organs or tissues, allowing imaging (diagnostic) or delivering cytotoxic radiation (therapeutic).

4.2 Commonly Used Radionuclides

4.3 Production of Radionuclides

• Nuclear Reactors

  • Neutron bombardment of targets (e.g., ⁹⁸Mo → ⁹⁹Mo → ⁹⁹ᵐTc generator).

  • Produces high‑activity batches, but limited access and complex waste disposal.

• Cyclotrons

  • Proton or deuteron bombardment of enriched targets (e.g., ¹⁸O‑water → ¹⁸F).

  • Ideal for short‑lived PET isotopes; on‑site or nearby production.

• Generator Systems

  • Parent–daughter systems (e.g., ⁹⁹Mo/⁹⁹ᵐTc) where the parent decays to the desired radionuclide, which is “eluted” as needed.

4.4 Labeling and Formulation Techniques

• Direct Labeling

  • Radionuclide binds directly to the active molecule (e.g., radioiodination of proteins).

• Chelation

  • Use of chelating agents (DTPA, DOTA) to stably bind radiometals (e.g., ⁶⁸Ga‑DOTA‑peptides).

• Kit-Based Preparations

  • Freeze‑dried vial containing ligand, buffer, and stabilizers.

  • Add sterile radionuclide solution, incubate for labeling, then dilute for injection.

4.5 Kit Preparation and Reconstitution

1. Kit Composition

   • Lyophilized mixture of chelator/ligand, buffer, and antioxidants.

2. Radiolabeling Procedure

   • Aseptically add measured activity of radionuclide solution to the kit vial.

   • Incubate at specified temperature/time (e.g., 10 min at room temperature).

   • Dilute with sterile saline to final volume.

3. Storage

   • Keep kits refrigerated (2–8 °C) until use; protect from light if necessary.

   • Labeled product used promptly to minimize decay losses.

4.6 Quality Control Tests

4.7 Radiation Safety and Handling

• Shielding: Use lead or tungsten containers for storage and transport.

• Time–Distance–Shielding: Minimize exposure time, maximize distance, and use appropriate shields.

• Contamination Control: Work in designated hot labs, use disposable trays, gloves, and absorbent pads.

• Monitoring: Survey work surfaces and personnel with Geiger–Müller counters; wear dosimeters.

• Waste Management: Segregate radioactive waste by half‑life; store until decay before disposal as non‑hazardous.

4.8 Regulatory and Documentation

• Licensing: Facilities and personnel must be authorized by local regulatory bodies (e.g., AERB in India).

• Batch Records: Document radionuclide activity, labeling procedure, QC results, and release criteria.

• Transport: Comply with IAEA and national regulations for packaging, labeling, and paperwork.

4.9 Clinical Applications

• Diagnostic

  • SPECT (⁹⁹ᵐTc agents) for cardiac perfusion, bone scans, renal function.

  • PET (¹⁸F‑FDG) for oncology staging, neurology, and cardiology.

• Therapeutic

  • ¹³¹I for thyroid cancer and hyperthyroidism.

  • ¹⁷⁷Lu‑DOTATATE for neuroendocrine tumors.

  • ⁸⁹Sr or ⁹⁰Y for bone pain palliation.

4.10 Key Points for Exams

• Understand how radionuclides are produced (reactor vs. cyclotron vs. generator).

• Be able to outline kit labeling steps and critical QC tests (RCP, sterility, apyrogenicity).

• Recall the half‑lives and uses of major radionuclides.

• Know basic radiation safety principles: shielding, time–distance, contamination control.

• Recognize major diagnostic and therapeutic applications of radiopharmaceuticals.

Unit 5: Inorganic Pharmaceutical Substances

This unit reviews commonly used inorganic compounds in pharmacy, their therapeutic roles, formulation requirements, quality‑control tests, and storage considerations.

5.1 Role of Inorganic Substances

Inorganic drugs and excipients serve many purposes: correcting electrolyte imbalances, neutralizing gastric acid, acting as disinfectants, providing essential ions, or serving as diagnostic gases. Their purity and correct formulation are critical for safety and efficacy.

5.2 Major Classes and Examples

5.3 Antacids

• Mechanism: Neutralize excess hydrochloric acid to raise gastric pH.

• Key Agents:

  • Aluminum hydroxide (Al(OH)₃): Slow onset, constipating.

  • Magnesium hydroxide (Mg(OH)₂): Fast onset, laxative.

  • Calcium carbonate (CaCO₃): Rapid action, may cause belching.

• Formulations: Powders, suspensions, chewable tablets.

• QC Tests: Assay (titration to pH endpoint), pH of slurry, loss on ignition (for carbonate content), absence of heavy metals.

5.4 Electrolytes and Saline Solutions

• Purpose: Restore fluid and ionic balance in IV therapy or oral rehydration.

• Normal Saline (0.9% NaCl)

  • Osmolarity ≈ 308 mOsm/L; isotonic with plasma.

  • QC: Chloride assay (argentometric titration), pH (4.5–7.0), sterility, endotoxin.

• Ringer’s Lactate

  • Contains Na⁺, K⁺, Ca²⁺, and lactate buffer.

  • QC: Individual ion assays (ion‑selective electrodes), pH (6.0–7.5), sterility.

• Calcium Gluconate

  • Used in hypocalcemia; supplied as 10% w/v solution.

  • QC: Calcium content (complexometric titration), pH, sterility.

5.5 Acidifiers

• Dilute Hydrochloric Acid

  • Used to acidify gastric contents in hypochlorhydria.

  • QC: Strength by acid‑base titration, specific gravity, absence of metals.

• Citric Acid Solutions

  • Used to adjust pH of suspensions or solutions for stability.

  • QC: Assay (titration), pH, clarity.

5.6 Adsorbents

• Activated Charcoal

  • Porous carbon that adsorbs toxins and gases in overdose or flatulence.

  • QC: Surface area (BET method), moisture content, ash value.

• Kaolin

  • Clay that adsorbs bacterial toxins; gentle astringent.

  • QC: Assay (loss on ignition), fineness (sieve analysis), pH.

5.7 Disinfectants & Antiseptics

• Boric Acid

  • Mild antiseptic for eyes and skin.

  • QC: Assay (titration), pH (5.0–7.0), sterility for ophthalmic use.

• Silver Nitrate

  • Astringent and antiseptic for wounds and ophthalmia neonatorum prophylaxis.

  • QC: Silver content (gravimetric), pH, loss on drying.

5.8 Therapeutic Gases

• Oxygen

  • ≥ 99% purity medical grade; used in hypoxia therapy.

  • QC: Purity (gas chromatography), moisture content, absence of contaminants.

• Nitrous Oxide (N₂O)

  • Analgesic gas; supplied in 50:50 mixture with O₂ or alone.

  • QC: Purity, pressure, absence of oil or water vapor.

5.9 Formulation & Storage Considerations

• Stability: Protect moisture‑sensitive salts in airtight, desiccated containers.

• Compatibility: Avoid mixing reactive inorganics (e.g., alkaline with acidifiers).

• Labeling: Include chemical name, concentration, pH range, storage conditions.

• Storage: Controlled room temperature (15–25 °C) for most; refrigerate dilute acids if specified.

5.10 Key Points for Exams

• Be able to classify inorganic substances by therapeutic use.

• Recall mechanisms, examples, and QC tests for antacids and electrolytes.

• Understand assay methods for salts (titrations, electrode methods).

• Know key storage and compatibility issues for inorganic formulations.

• Memorize purity standards for therapeutic gases.

Unit 6: Quality Control Tests for Inorganic Drugs

This unit details the laboratory tests and specifications used to ensure inorganic pharmaceutical substances meet safety, purity, potency, and performance standards before release.

6.1 Purpose of Quality Control

• Verify Identity: Confirm that raw materials and finished products are the correct chemical entity.

• Assess Purity: Detect and quantify impurities (heavy metals, anions, cations, organics).

• Determine Potency: Measure active ingredient concentration or strength.

• Ensure Performance: Check physical properties (pH, specific gravity) and microbial safety.

• Comply with Regulations: Meet USP/BP/ICH and national pharmacopeial monographs.

6.2 Identification Tests

6.3 Assay Methods

6.3.1 Titrimetric (Volumetric) Assays

• Acid–Base Titrations

  • For carbonates (antacids), acidify sample and titrate released CO₂ or HCl with NaOH using phenolphthalein indicator.

• Complexometric Titrations

  • Use EDTA to assay Ca²⁺ (calcium gluconate) or Mg²⁺; endpoint detected with Eriochrome Black T at pH 10.

• Redox Titrations

  • Iodometric for Cu²⁺, Fe²⁺; permanganometric for iron in ferrous salts.

6.3.2 Gravimetric Assays

• Precipitate and weigh insoluble salts (e.g., BaSO₄ for sulfate content). Useful for sulfate and phosphate determinations.

6.4 Limit Tests for Impurities

6.5 Physical & Physicochemical Tests

• pH: Measure with calibrated meter; critical for stability and compatibility (e.g., saline pH 4.5–7.0).

• Specific Gravity/S.G.: Determine with pycnometer for liquids (e.g., dilute acids).

• Loss on Drying: Heat sample to remove water; calculate weight loss to assess moisture content.

• Residue on Ignition: Burn sample to ash; residue indicates non‑volatile inorganic content.

• Clarity & Color: Visual inspection against white/black backgrounds for solutions or suspensions.

6.6 Microbial and Pyrogen Tests

• Microbial Limit Tests

  • Plate count for total aerobic microbes; ≤ 10 CFU/mL for parenterals, ≤ 100 CFU/mL for non‑sterile liquids.

  • Tests for specific pathogens (E. coli, S. aureus).

• Sterility Testing

  • Membrane filtration or direct inoculation; no growth after 14 days in fluid thioglycollate and soybean‑casein media.

• Pyrogen (Endotoxin) Test

  • Limulus amebocyte lysate (LAL) assay or Rabbit pyrogen test; limits depend on dose and route (e.g., < 0.25 EU/mL for injectables).

6.7 Packaging & Storage Verification

• Container Integrity: Check closures and seals prevent moisture or gas ingress (e.g., hermetic seals for salts).

• Label Accuracy: Verify labels include name, strength, batch number, expiry, storage conditions.

• Stability Sampling: Store samples under accelerated (40 °C/75% RH) and long‑term (25 °C/60% RH) conditions; test at intervals for potency, appearance, and pH.

6.8 Documentation & Release

• Certificate of Analysis (CoA): Summarizes all QC results against specifications.

• Batch Manufacturing Record (BMR): Documents entire manufacturing process, in‑process checks, and deviations.

• Product Release: Only after CoA confirms compliance with all tests is the batch approved for distribution.

Key Points for Exams

• Be able to list and describe identification, assay, and limit tests for common inorganic substances.

• Know titrimetric procedures for antacids, electrolytes, and complexometric assays.

• Understand microbial, sterility, and pyrogen testing requirements for parenteral inorganics.

• Recall storage and stability testing parameters relevant to inorganic drugs.