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Pharmaceutical Inorganic Chemistry

Pharmaceutical Inorganic Chemistry. Introduction. In 17th century: Discoveries of glycerine , chlorine, manganese, tartaric acid, Iodine and isolation of mineral salts (sodium, calcium, sulphur , phosphorus etc ) were reported.

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Pharmaceutical Inorganic Chemistry

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  1. Pharmaceutical Inorganic Chemistry Introduction

  2. In 17th century: Discoveries of glycerine, chlorine, manganese, tartaric acid, Iodine and isolation of mineral salts (sodium, calcium, sulphur, phosphorus etc) were reported. • More than 100 elements have been discovered till to this date. • Half of these elements are practically less important due to their rare occurrence. • Rest of the elements may be useful in the biological, pharmacological, medical problems & in pharmaceutical applications.

  3. The knowledge of atomic structure of an ATOM (Atomic theory by Dalton in 1807) that represents simplest unit of the mass helps to predict the physical and chemical properties of an element as they differ due to the difference in their electronic configuration. • Frankland in 1853: significant connection between atomic weight & equivalents. Atomic Weight = Equivalent weight x Valency (Valencywas first mentioned by Lothar Meyer in 1864)

  4. This was the foundation that ultimately developed the modern form of the periodic table by Russian chemist Mendeleeff in 1869. • Now! Molecular orbital’s and its related calculations &/or designs are used to predict optimal structures for selective biological/pharmacological/medicinal activity based on certain physical and bio-chemical properties.

  5. Pharmaceutical chemistry deals with the structure, chemical nature, composition, preparation, studies of physical and chemical properties, methods of quality control and conditions of their uses. The subject is further sub-divided into various branches like: • Inorganic chemistry . Biochemistry • Organic chemistry • Analytical chemistry • Physical chemistry • Phytochemistry • Medicinal chemistry

  6. Now a days compounds of various metals like iron, arsenic, lead, mercury & copper were used for medicinal purpose. • Hence, a sound knowledge of chemistry is required for understanding and following the recent developments in medicine and pharmacy. • Pharmaceutical chemistry thus plays an important role in deciding the physiochemical properties, conditions for the storage and dispensing of drugs.

  7. Nomenclature Pattern: IUPAC

  8. PHARMACOPOEIA

  9. The term Pharmacopoeia first appears as a distinct title in a work published in Basel, Switzerland in 1561 by Dr A. Foes. • But does not appear to have come into general use until the beginning of the 17th century. • Today’s pharmacopoeias focus mainly on assurance of quality of products by various tools of analytical sciences.

  10. PHARMACOPOEIA • Pharmacopoeia: the word derives from the ancient Greek “pharmakopoiia” from pharmako- ″drug″, followed by the verb-stem poi- ″make″ and finally the abstract noun ending -ia. • These three elements together can be rendered as ″drug-mak-ing″ or ″to make a drug″.

  11. A pharmacopoeia, pharmacopeia, or pharmacopoea is a legally binding collection (legal document, monograph, official publication/book), prepared by a national or regional authority, of standards and quality specifications for medicines used in that country or region (e.g., IP, BP, USP). quality specification: such as identity strength or amount and purity of medicines

  12. The role of a modern pharmacopoeia is to furnish quality specifications for pharmaceutical starting materials, excipients, intermediates, active pharmaceutical ingredients (APIs), and finished pharmaceutical products (FPPs). • GENERAL requirements on important subjects related to medicines quality, • such as analytical methods microbiological purity dissolution testing Stability etc.

  13. International Pharmacopoeia (Ph. Int.) • Issued by WHO. • aim to provide international standards & to help achieve a potentially global uniformity of quality specifications for selected pharmaceutical products, excipients and dosage forms. History of these approaches goes back to : 1902–1925 - agreements established a ″Unified″ Pharmacopoeia. 1929 - "Brussels Agreement" stipulated the League of Nations to carry out related administrative functions.

  14. 1937 - the 1stmeeting of the ″Technical Commission of Pharmaceutical Experts″ 1948* - First World Health Assembly (WHA) approved the Expert Committee on Unification of Pharmacopoeias One year later in 1949, the WHA renamed it the Expert Committee on International Pharmacopoeia.

  15. In addition to these some other documents prescribing standards are: • British Pharmaceutical Codex (B.P.C.) & National Formulary in America (U.S.N.F.)

  16. Indian Pharmacopoeia (IP) • Drugs & Cosmetic Act 1949 and Rules 1945. • IP is published by the Indian Pharmacopoeia Commission, the Standards Setting Institution for Drugs. • It is an autonomous body under the Ministry of Health & Family Welfare. • To keep pharmacopoeia up-to-date, pharmacopoeial commissions constantly update pharmacopoeia Once in every four years.

  17. History

  18. Pharmacopoeial Monographs • Monograph refers to the study of published matter of a subject. • The medicinal substance are used to cure & prevent diseases • Hence, it is important to give a detailed written study – appears as a monograph in the pharmacopoeia

  19. Monographs provide the following information: • Main title/synonyms • Chemical formula/formula weight • Therapeutic category • Dosage • Description • Solubility • Minimum standards of purity • Identification tests • Tests for purity/limit tests for impurities • Methods of assay • Storage condition • Packaging and labeling

  20. References • Dr. K G Bothara, A Hand Book of Inorganic Pharmaceutical Chemistry; NiraliPrakashan, New Delhi • WHO, Review of Pharamcopoeias;March,2013. • Indian Pharmacopoeia • P C Kamboj, Pharmaceutical Analysis, Vol.1, Vallabh Publications, New Delhi

  21. Sources & Types of Impurities

  22. Since the drug and pharmaceutical products concern with health and life of people and animal The prime consideration behind every formulation is that the product should be: • Pure as much as possible (absolute purity). • Satisfactory clinically. • Homogenecity. • Safety in its use.

  23. Impurities: • A compound is said to be impure if it is having foreign matter i.e., impurities. • Pure chemical compound refer to that compound which is having no foreign matter! • Purification of chemicals is an expensive process, substances should not be purified more than required as it brings about waste of time, material and money. • In such cases, if it is not possible to eliminate out these impurities completely, attempts have to be made to at-least minimise their concentration!

  24. Pharmacopoeia prescribe limits for physiologically harmful compound(s)/impurities present in substances/formulations. Impurities commonly found in Medicinal preparations: 1. Activity depressing impurities. e.g., presence of water in hard soap. 2. Due to colouring or flavouring substances, e.g., Sodium Salicylate is discoloured due to phenolic compounds. 3. Humidity – may cause many substances to oxidize. 4. Decrease shelf life. 5. Physical and chemical properties. 6. Impurities due to which substances become incompatible or unfit for medicinal use. (Physical, Chemical & Therapeutically). 7. Toxic impurities. E.g. Lead and arsenic salts.

  25. SOURCES OF IMPURITIES: Raw, Solvents, Mfgetc 1. Raw Materials Employed in the Manufacturing of the Pharmaceutical Substance: • It is essential to verify the identity of the source (natural e.g. mineral sources, plants, animals, microbes or synthesized from chemicals) of raw materials. • In nature minerals rarely occurs in a reasonably pure from. Almost always mixtures of closely related substances occur together e.g., • Barium and Magnesium impurities are found in calcium minerals. • Magnesium or Iron compounds are found in zinc. • Leadand Heavy metals are found as impurities in many sulphide ores. • Chlorides, bismuth salts contains silver copper and lead as impurities. • Rock salt used for the preparation of sodium chloride is contaminated with small amounts of calcium and magnesium chlorides

  26. SOURCES OF IMPURITIES 2. Method of Manufacture: • Reagents used/employed in the manufacturing process: Calcium carbonate contains ‘soluble alkali’ as impurity which arises from the sodium carbonate (Na2CO3) employed in the process of Calcium carbonate. CaCl2 + Na2CO3 → CaCO3 ↓ + 2 NaCl Soluble Soluble Precipitate Soluble • Anions like chlorides and sulfates are common impurities in many substances because of the use of tap water, hydrochloric acid and sulphuric acid respectively in processing. • Hydrogen peroxide can contaminate the final product with barium ion. (B) Regents used to eliminate other impurities: Barium is used in the preparation of potassium bromide to remove sulphate which in turn - potassium bromide will now be contaminated by traces of barium.

  27. SOURCES OF IMPURITIES 2. Method of Manufacture: (C) Solvents: Water! • Tap water: Containing impurities of Ca2+, Mg2+, Na+, Cl–, CO3–2 and SO4–2 in trace amounts. The use of tap water on large scale will lead to the contamination of the final product with these impurities because the impurities will remain in the product even after washings. • Demineralized water: is free from above ions. It may have pyrogens, bacterias and organic impurities. So, discourage its use on large scale. • Distilled water: It is free from all organic and inorganicimpurities and is therefore the best as a solvent but it is quite expensive. • Softened water: It is almost free from divalent cations (Ca2+, Mg2+ ) but contains more of Na+ and Cl– ions as impurities.

  28. SOURCES OF IMPURITIES D) Reaction vessels: The reaction vessels used/employed in the manufacturing process may be metallic such as: copper, iron, cast iron, galvanized iron, silver, aluminium, nickel, zinc, lead, glass and silica. • Some solvents and reagents used/employed in the process may react with the metals of reaction vessels, leading to their corrosion and passing traces of metal impurities into the solution & contaminating the final product. • Similarly, glass vessels may give traces of alkali to the solvent.

  29. SOURCES OF IMPURITIES (E) Intermediates: Sometimes, an intermediate substance produced during the manufacturing process may contaminate the final product e.g., Sodium bromide is prepared by reaction of sodium hydroxide and bromine in slight excess. 6NaOH + 3Br2 → NaBrO3 + 5NaBr + 3H2O The sodium bromatean intermediate product is reduced to sodium bromide by heating the residue (obtained by evapourating the solution to dryness) with charcoal. NaBrO3 + 3C → NaBr + 3CO Sodium bromate Sodium bromide • If sodium bromate is not completely converted to the sodium bromide then it is likely to be present as an impurity.

  30. SOURCES OF IMPURITIES (F) Atmospheric contamination during the manufacturing process: • Atmosphere may contain: dust of aluminum oxide, sulphur, silica etc. And • some gases like carbon dioxide, sulphur dioxide and hydrogen sulphide etc. These may contaminate the final product. e.g., sodium hydroxide readily absorbs atmospheric carbon dioxide when exposed to atmosphere. 2NaOH + CO2 → Na2CO3 + H2O Calcium hydroxide solutions can absorb carbon dioxide from the atmosphere to form calcium carbonate. Ca(OH)2 + CO2 → CaCO3 + H2O

  31. SOURCES OF IMPURITIES (G) Manufacturing hazards: Contamination from the particulate matter: • from sieves, granulating, tabletting and filling machines and the product container. • From dirty or improperly maintained equipments. • From Cross-contamination of the product. Contamination by microbes: • products intended for parenteral administration and ophthalmic preparations are liable to contamination by microbes from the atmosphere • sterility testing - provides an adequate control for microbial contaminations in such preparations. • Microbial contamination can be controlled by adding suitable antimicrobial and antifungal agents.

  32. SOURCES OF IMPURITIES Errors in the packaging: Similar looking products, such as tablets of the same size, shape and colour, packed in similar containers can result in mislabeling of either or both of the products. Adequate care should be taken to avoid the handling of such products in the close proximity.

  33. Cont..

  34. 3. Instability of the Product • Chemical instability/decomposition: Impurities can also arise during storage when storage conditions are inadequate. • This chemical decomposition is often catalyzed by: Light , traces of acid or alkali, traces of metallic Impurities, air oxidation, carbon dioxide and water Vapours. • It can easily be predicted from the knowledge of chemical properties of the substance. • It can be minimized or avoided by using proper storage procedures & conditions.

  35. The photosensitive substances should be protected from light by storing them in darkened glass (amber glass bottles) or metal containers thereby inhibiting photochemical decomposition. • Materials susceptible to oxidation by air or attack by moisture should be stored in sealed Containers and if necessary the air from the containers can be displaced by an inert gas such as Nitrogen or by adding suitable antioxidants (like in food products ascorbic acid, tocopherol and sodium citrate.

  36. (B) Changes in physical properties: • changes in crystal size and shape, sedimentation, agglomeration and caking of the suspended particles. • Particle size and surface area is a critical factor in determining the bioavailability of the low solubility drug. E.g: under dosage and later to over dosage of the drugs (suspensions). & Injectable emulsions on storage may lead to fat embolism.

  37. (C) Reaction with container material: • e.g., salicylic acid ointment must not be packed in metal tubes. • alkali-sensitive e.g., atropine sulphate injection must be packed in glass ampoules must not be packed in containers made from soda glass. • Plastic containers - plasticizers, particularly in the presence of non-aqueous solvents. • Rubber closures are more susceptible to absorb medicaments • Temperature: The rate of chemical decomposition and physical changes of stored products depends upon the temperature.

  38. Types of Errors or Impurities 1. Determinate Errors (Systematic errors): Definite value and underlying (undisclosed/hidden) cause. • Can measure & account for these errors. Sources: Impurities in the crude material. Excess of reagent used. Salts from the water used when the preparation is carried out in aqueous solutions. Metallic contamination. Contamination from exposure to the atmosphere.

  39. Types of Errors or Impurities 2. Indeterminate errors: • Result from extending a system of measurements to its maximum. • Neither identify the sources of these errors nor predict the magnitudes of individual errors.

  40. The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH)

  41. Permissible Limits of Impurities • Impurities are always present in the Pharmaceutical products. • The following points are considered to permit the impurities in these substances: • A level of harmful substances is to be determined. • A permissible limit, based on the amount to be tolerated of the toxic substances is prescribed. e.g., Heavy metal (Toxic impurities) limits in India • P.T.O

  42. Permissible Limits of Impurities Heavy metal limits

  43. Permissible Limits of Impurities Acceptance criteria for impurities in drug substances: Provided it has been determined that the impurities are not toxic. Higher limits may be set if scientifically justified. Source: Dr Saranjit Singh, National Institute of Pharmaceutical Education and Research , SAS Nagar 160 062 India. e-mail: ssingh@niper.ac.in

  44. Permissible Limits of Impurities Acceptance criteria for degradation products in drug products: Provided it has been determined that the impurities are not toxic. Higher limits may be set if scientifically justified. Source: Dr Saranjit Singh, National Institute of Pharmaceutical Education and Research , SAS Nagar 160 062 India. e-mail: ssingh@niper.ac.in

  45. The limit for harmless impurities are also prescribed depending upon the nature, type and usefulness of the substances.E.g., colouring substances flavouring agentspreservatives are the harmless compounds added to the pharmaceutical preparations. Permissible Limits of Impurities

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