Inorganic medicinal and pharmaceutical chemistry PDF

‫‪Inorganic medicinal and‬‬ ‫‪pharmaceutical chemistry‬‬ ‫‪by : Block. Roche‬‬ ‫‪lec 1: Atomic and molecular Structure /‬‬ ‫‪complexation‬‬ ‫ﺻ ــﻮروا اﻟ ــﺒﺎرﻛ ــﻮد او اﺿ ــﻐﻄﻮا ﻋ ــﻠﻴﻪ ﻟ ــﻠﻮﺻ ــﻮل اﻟ ــﻰ‬ ‫ﻓـﻴﺪﻳـﻮ ﻳـﻨﻄﻴﻜﻢ ﻓـﻜﺮة ﻋـﺎﻣـﺔ ﻋـﻦ اﻟـﻤﺤﺎ...

‫‪Inorganic medicinal and‬‬ ‫‪pharmaceutical chemistry‬‬ ‫‪by : Block. Roche‬‬ ‫‪lec 1: Atomic and molecular Structure /‬‬ ‫‪complexation‬‬ ‫ﺻ ــﻮروا اﻟ ــﺒﺎرﻛ ــﻮد او اﺿ ــﻐﻄﻮا ﻋ ــﻠﻴﻪ ﻟ ــﻠﻮﺻ ــﻮل اﻟ ــﻰ‬ ‫ﻓـﻴﺪﻳـﻮ ﻳـﻨﻄﻴﻜﻢ ﻓـﻜﺮة ﻋـﺎﻣـﺔ ﻋـﻦ اﻟـﻤﺤﺎﺿـﺮة ﻳﺴﻬـﻞ‬ ‫ﻋﻠﻴﻜﻢ دراﺳﺘﻬﺎ ‪.‬وﻻ ﺗﻨﺴﻮﻧﺎ ﻣﻦ دﻋﺎﺋﻜﻢ 🙏‬  Electronic structure of atoms ATOMS ARE COMPOSED OF A CENTRAL NUCLEUS SURROUNDED BY ELECTRONS WHICH OCCUPY DISCRETE REGIONS OF SPACE. THE NUCLEUS IS CONSIDERED TO CONTAIN TWO TYPES OF STABLE PARTICLES WHICH COMPRISE MOST OF THE MASS OF THE ATOM. 1- NEUTRON: IT IS AN UNCHARGED SPECIES WITH A MASS OF 1.675 X I0-24 2- PROTON: THIS PARTICLE HAS A POSITIVE CHARGE OF ESSENTIALLY ONE ELECTROSTATIC UNIT (E.SU.). ITS MASS IS 1.672 X I0-24. 3- ELECTRON : WHICH HAS A NEGATIVE CHARGE OF ONE E.S.U AND A MASS OF 9.107 X 10-28 THE NUMBER OF PROTONS (EQUAL TO THE NUMBER OF ELECTRONS IN THE NEUTRAL ATOM) AND A PARTICULAR NUMBER OF NEUTRONS. THE SUM OF THE MASSES OF THE PROTONS-AND NEUTRONS ACCOUNTS FOR THE ATOMIC MASS OF THE ELEMENT AND THE NUMBER OF PROTONS IS EQUAL TO THE ATOMIC NUMBER.  ATOMIC ORBITALS Atomic orbital is the volume of space that contain the electrons about the nucleus and they described by a set of 4 quantum no. : 1- The principal quantum no. ( n ) :which state electrons exist in discrete energy levels. The energy associated with electron increases as it locate farther from the nucleus. 2- The suborbital quantum no. ( l ) :which represent the region of greatest probability of finding an electron varies in shape and size , depending upon energy level. l = 0,1,2,3,….(n-1 ) , so when n=1 the l value =0 and when n=2 the l take 2 values = 0,1 l = 0 is s orbital , l=1 is p orbital , l = 2 is d orbital , l = 3 is f orbital 3- The magnetic quantum (m l ) : describes the spatial orientation of the orbital 4- The spin quantum no. (m s) : represent the magnetic moment which is directionally oriented +1/2 , -1/2 , so if 2 electrons occupy the same orbital they must have an opposing spin. - The aufbau principle : is used to determine the electron configuration of an atom, molecule or ion. The principle postulates a hypothetical process in which an atom is "built up" by progressively adding electrons. - The pauli exclusion principle : in any atom , no 2 electron may be described by the same set of values of the quantum no.s. So a maximum of 2 electrons may occupy a single orbital and must be of opposed spin. - Hund’s rules : 1-lower energy orbitals must be filled before higher energy orbitals 2-electrons must enter degenerate orbials singly and with parallel spins and remain unpaired as long as possible.  1s² 2s² 2p⁶ 3s² 3p⁶ 4s² 3d¹⁰ 4p⁶ In certain elements in the transition series where d orbitals are being filled, an ns level will be only half- filled, and the (n — 1)d orbital will be either half-filled or full. These represent more stable configurations than may be achieved by simply filling orbitals. For example, chromium (At. No. 24) has an outer structure of 3d54s1 and copper (At. No. 29) has 3d104s1. It is possible to use the inert gas “core” that precedes the element being considered. For example, sodium (At. No. 11), which has the electronic configuration Na: 1s22s22p63s1, can be written using the neon core for the first ten electrons: Na: [Ne] 3s1. Similarly, manganese (At. No. 25) can be written using the argon core for the first 18 electrons: Mn: [Ar] 3d54s2.  Ionization - Ionization : is The process of losing one or more electrons by chemical or physical means , and the positive ion produced is termed a cation. This process is based in physical reality, and should not be taken as the exact opposite of the process of atom buildup. - It is always the most loosely “held” electrons which are lost first when an atom ionizes. - The electronic structure of the ion may not reveal the level from which the electron was lost. This is particularly true for transition elements. Because Relative orbital energies are subject to change as electrons are “placed” in them. This means that a high energy orbital in one atom may be of lower energy in a neighboring atom where it might be completely filled. Also the possibility of rearrangement of the remaining electrons in an ion to a more stable configuration. - Atoms in the transition series with incompletely filled d orbitals will ionize to leave d ions in which may contain from one to 10 electrons ex: cobalt - This does not necessarily mean that both electrons were lost from the 4s orbital, even though the structure of the ion would seem to indicate that. one or both electrons could have been removed from the 3d orbital followed by rearrangement of all the valence electrons into this orbital. Elements in Groups VIA and VIIA w h i c h h ave l a r g e r n u m b e r s o f electrons in their’ p orbitals tend to ionize by accepting electrons to form anions. These ions have completely filled p orbitals so that the valence shell structure is the same as the inert gas in the same period as the neutral element. Examples of this can be seen in oxygen (At. No. 8) arid bromine (At. No. 35):  Periodic table - The periodic table is a tabular arrangement of the chemical elements, organized on the basis of their atomic numbers, electron configurations, and recurring chemical properties. Elements are presented in order of increasing atomic number. The standard form of the table consists of a grid of elements laid out in 18 columns and 7 rows. - The rows of the table are called periods; the columns are called groups, with some of these having names such as halogens or noble gases. - All elements from atomic numbers 1 (hydrogen) to 118 (ununoctium) have been discovered or reportedly synthesized, with elements 113, 115, 117 and 118 having yet to be confirmed. The first 98 elements exist naturally although some are found only in trace amounts and were initially discovered by synthesis in laboratories. A group :which are eight groups which correspond to the filling of s and p orbitals having principal quantum numbers equal to the number of the period or row of the table. Through Periods 2 and 3 s and p orbitals are filled in normal fashion. These are sometimes referred to as the “typical elements.” In the fourth and successive periods, d orbitals are filled “between” the s and p orbitals, giving rise to the “B groups” intervening between Groups IIA and IIIA. - In Periods 4, b, and 6, toward the center of the table, there is a triad of elements designated Group VIII. These are the “real” transition elements which occur between the group with elements having half- filled d orbitals (VIIB) and the group with elements having full d orbitals (IB). - The separated long periods below the main portion of the table contain the elements known as the lanthanides (atomic numbers 57 to 71) and the actinides (atomic numbers 89 to 103). These elements are formed by the filling of very low-lying f orbitals. - Electronegativity : is the affinity an element has for its electrons and the ability to take on additional electrons which will show that this property increase from left to right across any period and from bottom to top in any group (except VIIIA). The opposite concept is that of electropositivity which varies in directions opposite to those of electronegativity. - The ability to lose electrons increases as we descend in a particular group. This is due to the increased shielding effect of the inner electrons which diminishes the attractive force of the nucleus on the valence electrons.  Electronic structure of molecules - There are three major forces that are involved in the formation of molecules : (1) Coulombic attraction occurs between the negatively charged electrons in the valence orbitals on one atom and the positively charged nucleus of another atom.(2) the number of electrons in the valence shell orbitals, and (3) their orbital distribution. - There are 2 types of bonds : 1- Covalent bond which ranges from an equal sharing of a pair of electrons in homonuclear diatomic molecules (e.g., H2 , Cl2 , I2 , etc.) to a polar or unequal sharing of the electron pair in heteronuclear diatomic molecules (e.g., HCI). 2- Ionic bond which is more of an electrostatic interaction resulting from the transfer of an electron from an electropositive atom to an electronegative atom (e.g., Na+ Cl—). - Orbital hybridization is “mixing” of the atomic orbitals to provide a new set of degenerate (energetically equivalent) orbitals having different spatial orientations and directional properties than the original atomic orbitals. The number of hybrid orbitals produced is equal to the number of atomic orbitals involved in the hybridization, and the electrons contained in the original orbitals occupy the hybrids according to Huad’s rules. - The presumed mechanism allowing elements to increase covalent bonding capacity involves promotion to the valence state, a situation requiring energy.  ‫لحساب نوع التهجني بني الذرات‬ ‫ عدد االرتباطات لهذه الذرة )مجاميع( ناقص واحد يساوي نوع التهجني‬-1 (long pair)‫ املزدوج االلكتروني في الحسابات يعتبر مجموعة كاملة‬-2 There are 3 cases of hybrid orbitals 1- sp orbitals : The two sp orbitals are equivalent (degenerate), symmetrical about the bonding axis, and oriented 180° away from each other. The improved directional characteristics of the hybrid should also be noted. This type of hybridization (sp) is exist in the covalent compounds of Group II elements and the unsaturatedacetylenic compounds of carbon. Linear covalent molecules of gaseous halides of Be, Mg, and Ca, such as MgCI2, and the solid divalent compounds of Cd and Hg are indicative that the bonds are formed through sp hybrids on the Group II element. 2- sp2 orbitals : which involve singly occupied s and two p orbitals combine to form three equivalent sp2 hybrid orbitals. The three hybrids are located in the same plane, and are oriented toward the points of an equilateral triangle, 1200 apart. The monomeric covalent compounds of boron, aluminum , and other Group III elements , unsaturated “ethylenic” compounds of carbon, show sp2 hybridization. 3- sp3 orbitals : which include the tetravalent state of Group IVA elements. When one s and three p orbitals combine, the result is a set of four equivalent sp3 hybrid orbitals pointing to the four corners of a tetrahedron. Therefore, the geometry of a molecule formed through bonding with these orbitals is tetrahedral, and the bond angles are approximately 1090. - Promotion to hybridized states is presumed to occur with doubly occupied orbitals. In other words, it is possible to have a nonbonded pair of electrons in a hybrid orbital. ex H2O. In the ground state electronic structure of oxygen, there are two p orbitals containing one electron each. If the two hydrogen atoms became bonded to the oxygen through these two orbitals, the water molecule would be expected to have an H—O—H bond angle of 1800. - In fact, the bond angle is closer to 1040.The smaller angle cannot be explained on the basis of repulsion between the two polar O—H bonds, It is because that the valence shell orbitals on oxygen achieve a hybridized valence state. orbitals on oxygen achieve a hybridized valence state. Assuming sp3 hybridization, the water molecule would have two lone pairs of electrons in hybridized orbitals. Repulsive forces between these two orbitals will cause the angle between them to enlarge and the orbitals to lose p character. Such a change would in turn cause the H—O—H angle to become smaller, with a corresponding gain in p character for the bonding orbitals. Thus, the two lone pairs of electrons would occupy orbitals which are hybridized somewhere between sp2 and sp3, while the bonding orbitals on the oxygen are between sp3 and pure p orbitals.  Types of bonding interactions 1- Ionic bonding: is the electrostatic force that exists between two chemical entities of opposite charge (The cation : the least electronegative entity loses one or more of its valence electrons) and the negative species (the anion : the more electronegative entity ). It will be found that most stable ions have inert gas valence shell structures. Since the valence shell of all inert gases except helium contain eight electrons, this kind of structure is associated with stability, and has led to the octet theory of chemical bonding. Ionic bonding is usually found in associations between metallic, strongly electropositive elements (Groups IA and IIA) and nonmetallic, strongly electronegative elements (Group VIllA). It is also found in most salts where the anion is complex, such as SO4-2, PO4-3, NO3-. Ionic interactions are also present, in many cases, when polar compounds are dissolved in polar solvents. Hybridization is not involved in the formation of ionic compounds. - Generally speaking, metals lose electrons to form cations, and nonmetals attract electrons to form anions. - In the transition series, the octet theory is less obvious in ion formation. These metals will form variously charged cations , usually with electrons remaining in the d orbital valence shells. The low-lying d orbitals are responsible for the variable valences and electronic structures of these ions. 2- Covalent bonding : is the attractive force that exists between two chemical entities due to their “sharing” a pair of electrons. - The covalent can be either nonpolar or polar , in the nonpolar , the electron pair is shared equally by the two bonded atoms like in homonuclear diatomic molecules such as H2 , Cl2 , N2 , etc. Larger systems of atoms are also covalent with an equal distribution of the bonding electrons, e.g., S8, P4 and diamond carbon. The covalent bonds in saturated hydrocarbons approach an ideal sharing of electrons between the carbon atoms, but the carbon-hydrogen bonds depart from this to some extent. In The polar bond The electron density tends to be shifted toward the more electronegative member of the bond ex, Water which is strongly polar with the more electronegative oxygen taking the largest share of the bonding electron density. this polarity is indicated by noting partial charges. - there is another classification of covalent bond (sigma and pi): in sigma bonds the molecular orbitals (or electron distributions) are symmetrical about the bond axes. - In pi bond (the double and triple bonds) there are two and three pairs of electrons are being shared, respectively, between two atoms. only one of the bonds can be a alpha bond. The other pairs of electrons will occupy molecular orbitals which are distributed on both sides of and perpendicular to a plane passing through the bond axis. Carbon dioxide, CO2, is an illustration of a double covalently bonded molecule. Each C—O bond consists of two pairs of electrons.The sigma bonds are formed by overlapping sp orbitals on the carbon with singly occupied p orbitals on the oxygens. The oxygens can be rotated in turn to bring their p orbitals parallel to one of the carbon p orbitals, Overlapping of parallel porbitals on carbon and oxygen leads to 2 volumes of electron density separated by a nodal plane at the bond axis. The carbon thus forms a pi bond with each oxygen. Similarly, hydrogen cyanide, HCN , will serve as ex. of a triple bonded molecule where two pi bonds are formed between two atoms.The carbon is sp- hybridized as in CO2, but now both p orbitals overlap with two p orbitals on the nitrogen. 3 - Coordinate Covalent Bonding : is a covalent interaction which both electrons in the bond arise from a single orbital on one of the atoms forming the bond. It is found most frequently between complex chemical entities. The entity providing the pair of electrons is called as the donor species. The acceptor species is electron-deficient and has an empty orbital which can overlap with the orbital from the donor. ex; boron-trifluoride etherate complex. - This type of bond formation also occurs in acid-base chemistry, and is frequently the type of bonding one finds between sulfur and oxygen. In particular in the oxyacids, e.g., sulfuric, nitric, phosphoric. 4- Hydrogen bonding: it is a weak secondary interaction between the partial positive hydrogen atom that bonded to more electrongative element (e.g. O,N,F,CL) ,ect, with the nonbonding electrons on the other electronagative atoms in neighboring molecules. Hydrogen bonding is responsible for many of the physical and chemical ptoperties of water. For example, the relatively high boiling point. This type of association can also occur between unlike molecules, and plays an important role in solution formation. Hydrogen bonding is also important in interactions between complex molecules, and in the secondary structure of proteins. It is also a secondary binding force in drug-receptor interactions. 6- Van derwaals(London) Forces: These are very weak electrical dipole forces occur when the electrons in one atomic or molecular species inducing a repulsive distortion in the electron cloud of a neighboring species. The positive end of the dipole, which is essentially produced by protons in the nuclei has an attraction for the oppositely charged electrons in the same or in a neighboring species. Van der Waals forces are virtually the only attractive forces between nonpolar molecules ,The associations between aromatic hydrocarbon molecules such as benzene. These forces also function in the liquefaction and solidification of the inert gases, a process which requires extremely cold temperatures.  Resonance The resonance indicates a tendency for the electrons to be somewhat delocalized. Simple covalent molecules tend to be more localized than more complex systems. For example, the molecules HCL and CO2 , NO2 , benzen are represented by the following canonical (electronic picture) structures. COORDINTION COMPOUNDS AND COMPLEXATION The metallic cation is able to bond with additional anions or neutral molecules after the normal valence requirements have been satisfied. The additional bonding species are termed ligands, and appear to bond directly to the metal cation in accordance with maximum coordination numbers (the secondary valence )(Table below ) :the maximum number of ligands that can be accommodated by a metal ion, and is a property of the metal and its charge. - The metal + associated ligands = coordination compound. Some complexes are stable in crystalline form and decompose in solution, while others are stable only in solution. Ex. : FeCl3, a simple compound of trivalent iron III and chlorine. When FeCl3 dissolved in water and/or HCL the following coordination compounds are formed: - The ligands are arranged around the metallic ion in certain characteristic geometry. PROPERTIES OF LIGANDS 1.– ligand species are generally anions or neutral molecules and not neutral atoms. 2.- all ligands have in common the possession of at least one nonbonded pair of electrons which is used to form a coordinate covalent bond with the metal ion. 3.- The more stable complexes are formed with anionic or molecular ligands involving the elements of Groups VA, VIA, or VIIA. Generally speaking, the order of stability of a ligand in a complex follows the order of basicity of the ligand (lewis base). 4.- ligand species may be classified according to the number of positions on the molecules capable of coordinating with a metal , exe , monodentate , bidentate , ect , …. (table 1-9)  - When polydentate ligands complex a metal ion a ring structure is produced , composed of the metal and the ligand molecule. These ring structures have special significance, and are termed chelates. - The more stable chelates are those where the total number of atoms in the ring including the metal are five, six, or seven. Four and eight-membered rings are usually unstable. - The process of chelation is employed in pharmaceuticals and in drug therapy. The polydentate ligands used for chelate formation are generally referred to as chelating agents. The term sequestering agent is usually applied when a polydentate ligand is used to improve the solubility and/or to stabilize a metal ion by chelation (sequestration).  BONDING IN COMPLEX -It is generally accepted that the (n — 1)d, ns, and np orbitals are close enough in energy to become hybridized into six bonding orbitals which are directed alone the same axes occupied by the ligands. These hybrid orbitals are designated d2sp3 hybrids and are equivalent as long as the six ligands are equivalent. -In the case of the trication of Cr(III) complexing with six CN- , Cr(III) is d3 ion (3 electron occupy d xy , d yz , d xz ), leaving two d orbitals (d x2-y2 , d z2) , one s ,three p orbitals empty to bonding with six cyanato groups to form [ Cr(CN)6] -3 -In the case of metal ions have four or more electrons in their d orbitals, the complexes must alter the ground state configuration and that can be measured experimentally by measuring the magnetic moment -MM-of the complex which is the unpairedness of electrons. -The complex of Fe(III) – 3d5 element – with 6 water units ,the MM is 6 which indicative of 5 unpaired electrons so finding six empty atomic orbitals to overlap with the donor water molecules can be accomplished by assuming that the 4d orbital to hybridize with the 4s and 4p , this type of hybridization-HP- termed outer orbital HP. If water replaced by six CN- the MM is about 2 which indicative of one unpaired electron and that because a cyanato anion has a negative electronic field of sufficient strength to repel the electrons in the 3d orbital (dx2-y2 and dz2) that directly oppose the approaching ligand and force them to paired in the other d orbitals as below :  COMPLEXES AND CHELATING AGENTS. -Complexation plays an important role in analytical chemistry where ,for example, concentrations of metals can be determined by titration with complexing agents. -In some analytical solutions containing metal ions, chelating agents are used to solubilize the metal and to stabilize its oxidation state. Two classical examples are found in solutions employed in the identification of reducing substances (e.g., sugars), Benedict’s solution and Fehling’s solution. Both contain copper(II) ions which are chelated by citric acid in Benedict’s and by tartaric acid in Fehling’s solution. - Chelating agents are also used as preservatives in preparations subject to decomposition due to trace quantities of metals, such as preparations containing hydrogen peroxide  COMPLEXES AND CHELATING AGENTS. - Chelating agents occupy unique place in drug therapy. They essentially the only compounds which have shown much efficacy in the treatment of heavy metal poisonings from such elements as lead, mercury, iron, etc. - They are also being used to treat certain metabolic disorders where metals such as iron and copper are accumulated in abnormal amounts in various tissues. The particular chelating agents that will be discussed include calcium disodium edetate (EDTA), dimercaprol (BAL), penicillamine, and deferoxamnine.  CALCIUM DISODIUM EDETATE, Calcium Disodium Ethylenediaminetetra acetate; Mol. Wt. (anhydrous 374.28), exists as a white crystalline granule. It is odorless, slightly hygroscopic, and has a faint saline taste. It is stable in air, freely soluble in water, and the pH of an aqueous solution is between 6.5 and 8. It is used in the treatment of heavy metal poisoning, primarily that caused by lead (plumbism) by forming insoluble complex excreted by the kidney. EDTA preparations have a strong affinity for calcium; therefore, the disodium calcium form is used to avoid inducing hypocalcemic states (low serum calcium). CALCIUM DISODIUM EDETATE This chelating agent may also be employed in poisonings due to copper, nickel, cadmium, zinc, chromium, and manganese, but it is of no value in the treatment of toxicities produced by mercury, arsenic, or gold. The compound is poorly absorbed from the gastrointestinal tract, so given by I.V. route. Intramuscular (I.M.) administration is employed in diagnosis of metal poisonings. An increase in the excretion of the metal in the urine (500 pg/liter/24 hours or greater for lead) is indicative of toxicity.  DISODIUM EDETATE -This compound is a white crystalline powder which is soluble in water, providing an aqueous solution of pH between 4.0 and 6. It will chelate the same metals as the disodium calcium form. -Its limitation is The chance of hypocalcemia during such therapy. Its primary use of is in conditions related to hypercalcemic states (high serum calcium). The compound may be useful in treating such problems as occlusive vascular disease and cardiac arrhythmias when associated with high blood levels of calcium. -It is apparently of no value in aiding dissolution of urinary calculi (calcium-containing stones in the urinary tract.The usual route of administration is by intravenous injection. The usual route of administration is by intravenous injection. DIMERCAPROL 2,3-Dimercapto- 1-propanol; BAL ,is a colorless or almost colorless liquid having a disagreeable odor. It is soluble in water, alcohol, and benzyl benzoate. Certain heavy metals, such as trivalen arsenic, owe their cellular toxicity to the sulfhydryl (—SH) groups present in enzymes which are responsible for oxidation-reduction reactions in tissues. Presumably, this inactivation involves covalent bond formation between the metal and the sulfhydryl groups.  DIMERCAPROL The introduction of BAL as a competitor with the enzymes for these metals as an effective neutralizing agent in arsenic war gases and other poisoning conditions from other source, poisoning from other sources, and has been extended to the treatment of mercury and gold poisoning. It is contraindicated in poisonings due to iron, cadmium, or selenium because the resulting complexes have greater renal toxicities than do the free metals. Dimercaprol-metal chelates tend to dissociate in acid media; therefore in therapy the urine should be alkalinized (e.g., with sodium bicarbonate) to prevent the release of free metal, producing renal toxicity. The usual route of administration is by intramuscular injection.  PENICILLAMINE 3-mercaptovaline is a white or off-white crystalline powder, having a alight characteristic odor. It is freely soluble in water, and slightly soluble in alcohol. The pH of an aqueous solution is between 4.5 and 5. It is a chelating agent capable of forming soluble complexes with copper, iron, mercury, lead, gold, and other metals. Its use has been reserved for the improvement of copper excretion in patients with Wilson’s disease (degenerative changes in the brain associated with increased levels of copper in the tissues and degeneration of the liver).  PENICILLAMINE -The effectiveness of penicillamine is related to its resistance to metabolic inactivation by amino acid oxydase since it lacks a hydrogen on the beta-carbon atom. -It is used in the treatment of gold dermatitis in patients on chronic gold therapy. -Unlike the other chelating agents Discussed the usual route of administration of penicillamine is oral. Penicillamine Capsules are official in the U.S.P.  DEFEROXAMINE MESYLATE usually available as a white, crystalline, lyophilized powder. It is soluble in water and the aqueous solution is stable at room temperature for two weeks. Deferoxamine is produced naturally by Streptomyces pilosus as a ferric [Fe(III)]complex. After chemical removal of the iron, the chelating agent purified as the methylsulfonate (mesylate) salt. It is a polydentate ligand with a particular affinity for ferric ions with which it forms stable, water soluble, octahedral complexes. It does not have a very strong affinity for ferrous or other divalent metal ions. Deferoxamine is used with other indicated drugs and procedures for the treatment of acute iron toxicity. DEFEROXAMINE MESYLATE The usual route of administration is by intramuscular or intravenous injection. The compound is poorly absorbed from the gastrointestinal tract. Intravenous administration is generally done by slow infusion with isotonic sodium chloride or other electrolyte solution. Inorganic Pharmaceutical Chemistry: Protectives, Adsorbents and Cathartics This group of gastrointestinal agents is commonly used for the treatment of mild diarrhea. Diarrhea is a symptom and not a disease. Very briefly, it results when some factor impairs digestion and/or absorption, thereby increasing the bulk of the intestinal tract. This increased bulk stimulates peristalsis, propelling the intestinal contents to the anus. Diarrhea may be acute or chronic. Acute diarrhea can be caused by bacterial toxins, chemical poisons, drugs, allergy, and disease. The effects of these agents range from tissue damage or irritation to that of causing electrolytes to flow from body fluids into the intestinal tract. Chronic diarrhea can result from gastrointestinal surgery, carcinomas, chronic inflammatory conditions, and various absorptive defects. Frequently the causative factor of acute diarrhea is not found, and the patient shrugs it off as a 24- or 48- hour stomach flu. Diarrhea is a serious condition, particularly for very young or elderly patients. The loss of fluids and electrolytes can quickly lead to dehydration and electrolyte imbalances. The antidiarrheal agents described in this chapter will only treat the symptoms and occasionally the cause, but they will not treat the complications. Most products for the treatment of diarrhea will consist of an adsorbent-protective, an antispasmodic, and possibly an antibacterial agent. The ideal antispasmodic agent should act directly on the smooth muscles of the gut to produce a spasm-like effect which decreases peristalsis and increases segmentation. The antibacterials are only effective if there is an actual infection in the intestinal tract or during epidemics previously shown to be caused by a microorganism. The adsorbent- protectives supposedly adsorb toxins, bacteria, and viruses along with providing a protective coating of the intestinal mucosa. They include bismuth salts, special clays, and activated charcoal. 1 Inorganic Pharmaceutical Chemistry: Protectives, Adsorbents and Cathartics Mechanism of Adsorption Adsorption is a process by which a substance (the adsorbate) adheres to the surface of another substance (the adsorbent). In the case of gastrointestinal protectives and adsorbents, substances like activated charcoal, kaolin, and certain clays (e.g., attapulgite) act as adsorbents by binding toxins, gases, and bacteria in the gut. Types of Adsorption Physical Adsorption: This occurs due to Van der Waals forces, which are weak, non-specific forces that attract molecules to the surface of the absorbent. Physical adsorption is generally reversible and does not involve chemical bonding. Chemical Adsorption: Involves the formation of stronger chemical bonds between the adsorbent and adsorbate. This type of adsorption can be irreversible and involves the exchange or sharing of electrons between the adsorbent and the adsorbate. For example, bismuth compounds can chemically interact with toxins in the gastrointestinal tract, reducing irritation and inflammation. Factors Affecting Adsorption 1. Surface Area and Porosity: Adsorbents like activated charcoal are characterized by high surface areas and porous structures. For instance, one gram of activated charcoal can have a surface area of over 1,000 square meters. This massive surface area allows for a higher amount of substance to be adsorbed. 2. Polarity: Adsorption is affected by the polarity of the molecules. Polar adsorbents, such as certain clays, will more effectively adsorb polar molecules like water and electrolytes, while non-polar adsorbents like activated charcoal will be more effective at binding non-polar substances such as lipophilic drugs and toxins. 2 Inorganic Pharmaceutical Chemistry: Protectives, Adsorbents and Cathartics 3. pH Sensitivity: The pH of the surrounding environment can influence the efficiency of adsorption. For example, the adsorption of bismuth salts can vary based on the pH of the stomach or intestines, as certain compounds become soluble depending on the pH level. Bismuth-Containing Products. The use of bismuth salts as antidiarrheals seems to be supported chiefly by tradition. Bismuth sub carbonate has also found some use as antacid. Although the bismuth salts used as antidiarrheals are water-insoluble, a small amount does go into solution. The soluble bismuth cation supposedly exerts a mild astringent and antiseptic action, but it is doubtful whether this is clinically significant. Intestinal hydrogen sulfide acts upon the bismuth salts to form bismuth sulfide; hence, the black stools resulting from the oral administration of bismuth-containing preparations. These compounds provide a dual action, adsorbing toxins and bacteria while forming a protective barrier in the intestines. 2Bi3+ + 3H2S → Bi2S3 (black precipitate) + 6H+ 1. Bismuth Subnitrate, N.F. XIII (approximate formula: [Bi(OH)2NO3]4·BiO(OH)) Bismuth Subnitrate occurs as a white, slightly hygroscopic powder which gives an acid reaction using blue litmus paper. It is practically insoluble in water and in alcohol but is readily dissolved by hydrochloric or nitric acid. It is assayed in terms of bismuth trioxide (Bi2O3). Bismuth subnitrate has a well-recognized incompatibility with tragacanth, in which tragacanth precipitates as a hard mass in the presence of the salt. 3 Inorganic Pharmaceutical Chemistry: Protectives, Adsorbents and Cathartics An interesting paper in connection with this incompatibility points out that the difficulty may be overcome by the protective action of sodium biphosphate or trisodium phosphate. These authors feel that because tragacanth is a negative colloid, the adsorption of the positive bismuth ion (without corresponding adsorption of the negative nitrate ions) tends to precipitate the colloid. The use of phosphates is based on their supplying the negative ions lacking, which may then be adsorbed by the tragacanth, stabilizing the colloid. Bismuth subnitrate apparently can inhibit pepsin. However, its main use is as a component of Milk of Bismuth, where it probably functions as a mild astringent- protective Milk of Bismuth Milk of Bismuth contains bismuth hydroxide and bismuth sub carbonate in suspension in water. It is made by converting bismuth subnitrate to bismuth nitrate [Bi(NO₃)₃] by the addition of nitric acid. Then, by treatment with ammonium carbonate and ammonia solution, bismuth nitrate is converted to bismuth hydroxide and sub carbonate. Chemical Reactions: NH₂CO₂NH₄·NH₄HCO₃ + NH₄OH ⇌ 2(NH₄)₂CO₃ 3(NH₄)₂CO₃ + 2Bi(NO₃)₃ → Bi₂(CO₃)₃ ↓ + 6NH₄NO₃ 2Bi₂(CO₃)₃ + H₂O → [(BiO)₂CO₃]₂·H₂O + 4CO₂ ↑ Bi(NO₃)₃ + 3NH₄OH → Bi(OH)₃ ↓ + 3NH₄NO₃ It is classified by the National Formulary as an astringent and antacid. 4 Inorganic Pharmaceutical Chemistry: Protectives, Adsorbents and Cathartics 2. Bismuth Sub carbonate, U.S.P. XVIII (approximate formula: [(BiO)₂CO₃]₂·H₂O) Bismuth sub carbonate is a white or pale yellowish white, odorless, tasteless powder, which is stable in air, but is slowly affected by light. It is practically insoluble in water and in alcohol but dissolves completely in nitric acid and in hydrochloric acid, with copious effervescence. Bismuth sub carbonate is assayed in terms of bismuth trioxide (Bi₂O₃). Nonofficial Bismuth Compounds 1. Bismuth Subgallate 2. Bismuth Subsalicylate 3. Bismuth Ammonium Citrate Activated Clays and Other Adsorbents. This group is composed mostly of clays which have excellent adsorbent properties, and most of them are used for that purpose industrially. They appear to have a valid clinical use, at least in mild diarrhea of short duration. 1. Kaolin Kaolin is a native hydrated aluminum silicate, powdered and freed from gritty particles. It occurs as a soft, white, or yellowish white powder, or as lumps. It has an earthy or clay-like taste. Kaolin binds toxins and bacteria through both physical and chemical adsorption. Kaolin is insoluble in water, in cold diluted acids, and in solutions of the alkali hydroxides. It is usually found together with the vegetable carbohydrate, pectin (Kaopectate®, Kao-Con®) and used as an adsorbent. Kaolin- containing products have been reported to interfere materially with the intestinal absorption of lincomycin. 5 Inorganic Pharmaceutical Chemistry: Protectives, Adsorbents and Cathartics 2. Activated Charcoal Activated charcoal has been used as an adsorbent in the treatment of diarrhea. It is now a recommended antidote in certain types of poisoning. It works primarily through physical adsorption. It is highly porous and effective in binding large organic molecules such as bacterial toxins, chemicals, and drugs. SALINE CATHARTICS Saline cathartics (purgatives) are agents that quicken and increase evacuation from the bowels. Laxatives are mild cathartics. Most can be purchased without a prescription and are a group that has been widely used, abused, and often overpromoted by the manufacturer. The 1971 A.M.A. Drug Evaluations states that cathartics are properly used to: (1) ease defecation in patients with painful hemorrhoids or other rectal disorders, and to avoid excessive straining and concurrent increases in abdominal pressure in patients with hernias. (2) avoid potentially hazardous rises in blood pressure during defecation in patients with hypertension, cerebral, coronary, or other arterial diseases. (3) relieve acute constipation. (4) remove solid material from the intestinal tract prior to certain roentgenographic studies. Laxatives should only be used for short-term therapy as prolonged use may lead to loss of spontaneous bowel rhythm upon which normal evacuation depends, causing the patient to become dependent on laxatives, the so-called "laxative habit." Constipation is the infrequent or difficult evacuation of feces. It may be due to a person resisting the natural urge to defecate, causing the fecal material which 6 Inorganic Pharmaceutical Chemistry: Protectives, Adsorbents and Cathartics remains in the colon to lose fluid and to become relatively dry and hard. Constipation can also be caused by intestinal atony (lack of muscle tension), intestinal spasm, emotions, drugs, and diet. Basically, there are four types of laxatives: (1) The stimulant laxatives act by local irritation on the intestinal tract, which increases peristaltic activity. They include phenolphthalein, aloin, cascara extract, rhubarb extract, senna extract, podophyllin, castor oil, 1,8-dihydroxyanthraquinone (danthron), oxyphenisatin, bisacodyl, and calomel (no longer used). (2) The bulk-forming laxatives are made from cellulose and other nondigestible polysaccharides. They swell when wet, with the increased bulk stimulating peristalsis. Included in this group are psyllium seed, methyl cellulose, sodium carboxymethylcellulose, and karaya gum. (3) The emollient laxatives act either as lubricants facilitating the passage of compacted fecal material or as stool softeners. Mineral oil is the main lubricant laxative used, and d-octyl sodium sulfosuccinate, an anionic surface-active agent, is the most used stool softener. (4) The saline cathartics act by increasing the osmotic load of the gastrointestinal tract. They are salts of poorly absorbable anions and sometimes cations. The body relieves the hypertonicity of the gut by secreting additional fluids into the intestinal tract. The resulting increased bulk stimulates peristalsis. Poorly absorbed anions that are used as saline cathartics are biphosphate (H₂PO₄⁻), phosphate (HPO₄²⁻), sulfate, and tartrate. The saline cathartics are water soluble and are taken with large amounts of water. This prevents excessive loss of body fluids and reduces nausea and vomiting if a too hypertonic solution should reach the stomach. 7 Inorganic Pharmaceutical Chemistry: Protectives, Adsorbents and Cathartics The saline cathartics, when taken for brief periods, are relatively free of side effects. Over a longer term, patients on low-sodium diets should not use the sodium-containing saline cathartics (sodium biphosphate, sodium phosphate, sodium sulfate, and potassium sodium tartrate). For those with impaired renal function, the magnesium salts should be restricted, since some magnesium cation is absorbed. Magnesium has a central nervous system depressant effect. Official Saline Cathartics 1. Sodium Biphosphate occurs as colorless crystals or as a white, crystalline powder. It is odorless and is slightly deliquescent. Its solutions are acid to litmus and effervesce with sodium carbonate. When saline cathartics, like sodium biphosphate (NaH₂PO₄) dissolve in water, they dissociate into their respective ions: NaH2PO4 → Na+ + H2PO4− H₂PO₄⁻ + H₂O ⇌ H₃O⁺ + HPO₄²⁻ Although classified by the National Formulary as a urinary acidifier, it is also used as a cathartic (Phospho-Soda, Vacuetts, and Sal Hepatica). 2. Sodium Phosphate occurs as a colorless or white granular salt which effervesces in warm, dry air. Its solutions are alkaline, with a 0.1 M solution having a pH of about 9.5. It is freely soluble in water and very slightly soluble in alcohol. Because of the poor intestinal permeability of the monohydrate phosphate anion, this product is widely used as a saline cathartic (Fleet Enema, Phospho- Soda). 8 Inorganic Pharmaceutical Chemistry: Protectives, Adsorbents and Cathartics Na2HPO4 → 2Na+ + HPO42− 3. Dried Sodium Phosphate is a nearly anhydrous white powder which readily absorbs moisture. It is freely soluble in water and insoluble in alcohol. It is used as a saline cathartic in Effervescent Sodium Phosphate, which is a mixture of sodium bicarbonate, tartaric acid, and citric acid. When dissolved in water, a carbonated solution of sodium phosphate, sodium tartrate, and sodium citrate is obtained. Sodium tartrate is also a saline cathartic, and sodium citrate provides a lemon-like flavor which, along with the carbonation provided by the carbon dioxide, masks the saline taste. NaH2PO4 + NaHCO3 → Na2HPO4 + CO2 + H2O Dried Sodium Phosphate is used because the heptahydrate salt of Sodium Phosphate would cause a premature reaction between the sodium bicarbonate and tartaric and citric acids, yielding a product with a flat, saline flavor. Best of Luck 9 Inorganic Pharmaceutical Chemistry: Topical Agents This chapter discusses the use of topical compounds, which are applied to body surfaces, in contrast to systemic compounds that are absorbed into the bloodstream. Topical drugs primarily act at the surface of application, but in some cases, they may penetrate deeper tissues, leading to both beneficial and potentially harmful systemic effects, such as toxicity or allergic reactions. Some drugs, like antiseptics, can prevent deep infections by penetrating wound tissues, while others (e.g., mercury-based compounds) can be toxic if absorbed in large amounts. Topical compounds are categorized based on their action: (1) protective agents (2) antimicrobial and (3) astringent compounds. Protective Agents Protectives are substances which may be applied to the skin to protect certain areas from irritation, usually of mechanical origin. Those compounds or substances most appropriate for this purpose are insoluble and chemically inert. Insolubility is a desirable property in that this limits the absorption of the compounds through the skin, makes it difficult to wash them off, and diminishes metallic properties on tissue. Compounds which are chemically unreactive are necessary to prevent interactions between the protective substance and the tissue. In other words, ideal protectives are biologically inactive. Many protectives also act as adsorbents, efficiently absorbing moisture from the skin’s surface, which reduces mechanical friction and irritation. The effectiveness of these substances improves with smaller particle size, as finer particles offer a larger surface area for adhesion and better moisture absorption. These protectives are commonly used as powders, ointments, or suspensions, and may also help soothe irritated skin. 1 Inorganic Pharmaceutical Chemistry: Topical Agents 1- Talc (3MgO 4SiO₂ H₂O) Talc is a native, hydrous magnesium silicate, sometimes containing a small proportion of aluminum silicate. The U.S.P. describes it as a very fine, white or grayish white, crystalline powder. It is unctuous, adheres readily to the skin, and is free from grittiness. Talc is a layered silicate and is the softest mineral known. It has a smooth, greasy feeling to the touch, and in its lump form (steatite) it is known as soapstone. Talc is odorless, tasteless, and insoluble in water, dilute acids, and dilute bases. It has very low adsorptive properties. A hydrothermal method can be used to mimic the natural geological conditions under which talc forms. The reaction typically involves reacting magnesium oxide or a magnesium salt with silica in an aqueous solution at elevated temperatures and pressures. MgO + H₂O → Mg(OH)₂ 3Mg(OH)₂ + 4SiO₂ → Mg₃Si₄O₁₀(OH)₂ + H₂O Chemically, talc may consider to be a hydrated magnesium silicate having the elements illustrated by the formula represented above. The actual composition of talc is somewhat variable, containing from 28.1 to 31.2% MgO, 57 to 61.7% SiO ₂, and 3 to 7% H₂O. As a magnesium polysilicate, it is unreactive to acids and bases, and inert to most other reagents. Talc can be used as:  lubricating, protective dusting powder. It can be used to prevent irritation due to friction, and to protect areas from further irritation.  Talc is used in preparations which may be perfumed for cosmetic purposes, or medicated with antimicrobial agents, such as boric acid. 2 Inorganic Pharmaceutical Chemistry: Topical Agents 2- Zinc Oxide (ZnO; Mol. Wt. 81.37) Zinc Oxide is a very fine, odorless, amorphous, white or yellowish white powder, free from gritty particles. It gradually absorbs carbon dioxide from the air. When heated to 400° or 500°C, the oxide develops a yellow color that disappears on cooling. Zinc Oxide is insoluble in water and alcohol and will gradually absorb carbon dioxide from the air to form a basic zinc carbonate [Zn₂(OH)₂CO₃]. Chemically, zinc oxide reacts with dilute acids and aqueous solutions of ammonium compounds to form water-soluble products. When treated with dilute hydrochloric acid, the oxide forms the Lewis acid, zinc chloride. ZnO + 2HCl → ZnCl₂ + H₂O Zinc oxide can be used as:  Mild astringent and a weak antimicrobial compound. The antimicrobial- astringent action is due to the release of a small amount of zinc ion from hydrolysis in the acidic moisture on the skin  Astringent and topical protective in ointments in the treatment of skin ulcerations and other dermatological problems.  Zinc oxide is the primary ingredient in Calamine. 3- Calamine (ZnO Fe₂O₃) Calamine is zinc oxide with a small proportion of ferric oxide. The presence of the ferric oxide (Fe₂O₃) gives the substance a pink color. The material is a fine powder, odorless, and practically tasteless. It is insoluble in water, but almost completely soluble in mineral acids. 3 Inorganic Pharmaceutical Chemistry: Topical Agents The term calamine, besides being applied to the official product, is also used to describe the impure, naturally occurring zinc carbonate. The official Calamine is obtained by calcination (powdered by heating) of the natural ore. The calcined product is then passed through a 100-mesh sieve to obtain the finely powdered material necessary for good cohesive and adhesive (adhering to skin) properties.  Thermal Decomposition of Zinc Carbonate: ZnCO₃ → heat ZnO + CO₂  Calamine Formation: ZnO + Fe₂O₃ → ZnO⋅xFe₂O₃ (Calamine) Calamine is a topical protective. It is used in dusting powders, ointments, and lotions (Calamine Lotion, U.S.P.) where it is applied to the skin for its soothing, adsorbent, protective properties. Antimicrobial Agents These are the chemicals, and their preparations used for the prevention and/or reduction of infection caused by microorganisms. The terminology of antimicrobial agents include:  Antiseptic: A substance that kills or inhibits the growth of microorganisms, usually applied to living tissues (e.g., skin) to prevent infection.  Germicide: A substance that kills microorganisms outright. This term includes agents like bactericides (kills bacteria), fungicides (kills fungi), and amebicides (kills protozoa).  -stat (e.g., bacteriostat): Refers to agents that do not kill microorganisms but inhibit their growth. For example, a bacteriostat stops bacteria from multiplying. 4 Inorganic Pharmaceutical Chemistry: Topical Agents  Disinfectant: A chemical used to kill microorganisms on inanimate objects, such as instruments or surfaces, but not safe for use on living tissue.  Sterilization: A process (often using heat or chemicals) that completely removes or kills all microorganisms from an object, making it free of any life. The mechanisms of action of inorganic antimicrobial agents can be divided into three general categories: oxidation, halogenation, and protein precipitation. I- Oxidation: those compounds are generally nonmetals and certain types of anions. Most common among these are hydrogen peroxide, metal peroxides, permanganates, halogens (i.e., chlorine and iodine), and certain oxo-halogen anions. The effective oxidative action of these compounds involves the reducing groups present in most proteins, e.g., the sulfhydryl (-SH) group in cysteine. An illustration of the reaction between the oxidizing antiseptic and a sulfhydryl- containing protein is shown in Fig1. Based on the concept that the protein has a specific function in the microorganism, e.g., enzyme, the formation of the disulfide bridge (Fig1-B) will alter the conformation (shape) of the protein and thereby alter its function. II- Halogenation: This is a reaction occurring with antiseptics of the hypohalite type and hypochlorite, OCl⁻. It is expected that a similar reaction can take place 5 Inorganic Pharmaceutical Chemistry: Topical Agents under appropriate conditions with the peptide linkage between the amino acid groups comprising the protein molecule. This reaction is ultimately destructive to the function of specific proteins because the substitution of the chlorine atom for the hydrogen produces changes in the forces (hydrogen bonding) responsible for the proper conformation of the protein molecule. III- Protein Precipitation: This type of mechanism involves the interaction of proteins with metallic ions having large charge/radius ratios or strong electrostatic fields. This property is available in transition metal cations, e.g., Cu(II), Ag(I), and Zn(II). Aluminum(III), due to its charge and small ionic radius, is also an effective protein precipitant. The nature of the interaction is one of complexation in which the various polar groups on the protein act as ligands (see Fig2). The complexation of the metal results in a radical change in the properties of the protein or protein precipitant. The interaction of metal ions with protein is nonspecific, and at sufficient concentration will react with host as well as microbial protein. The presence of the metal "ties up" important functional groups at the active site on the enzyme. 6 Inorganic Pharmaceutical Chemistry: Topical Agents 1- Hydrogen Peroxide Solution (H₂O₂; Mol. Wt. 34.02) Hydrogen Peroxide Solution is a clear, colorless liquid which may be odorless or may have an odor resembling that of ozone. The solution will usually deteriorate upon standing or upon agitation, and rapidly decomposes when in contact with many oxidizing or reducing substances. It is unstable on prolonged exposure to light and may decompose suddenly when rapidly heated. Chemically, hydrogen peroxide may be stable in solutions of high purity; however, small amounts of contaminants, e.g., divalent and polyvalent ions of chromium, iron, copper, mercury, etc., will catalyze the decomposition of unstabilized solutions. Hydrogen peroxide solutions may be stabilized with acids, complexing agents, or adsorbents. Depending upon the chemical environment, hydrogen peroxide will react as either an oxidizing or reducing agent. The oxidation state of oxygen in the peroxide ion, (O-O)²⁻, is -1. When hydrogen peroxide functions as an oxidizing agent it forms two oxide ions, O²⁻, requiring two electrons, and resulting in a change of the oxidation state of the oxygen to -2. (O2) −2 ⟶ 2O −2 + 2e− 7 Inorganic Pharmaceutical Chemistry: Topical Agents This type of reaction is most efficient in acidic media to produce water H2O2 + 2H+ + 2e− ⟶ 2H2O The reducing actions of hydrogen peroxide result in the evolution of molecular oxygen. This involves the release of two electrons and a change from the peroxide ion to an oxidation state of zero. (O2)−2 ⟶ O2 + 2e− The primary use of Hydrogen Peroxide Solution is:  As a mild oxidizing antiseptic. This action is produced when the solution encounters open or abraded tissue, exposing the chemical to the enzyme, catalase. This enzyme catalyzes the decomposition of H₂O₂ to water and oxygen.  When diluted with one part of water, it can be used as a gargle or mouthwash in the treatment of bacterial infections of the throat and mouth.  Half-strength solutions may also be used as a vaginal douche. 2- Sodium hypochlorite Solution It is a clear, pale greenish-yellow liquid having an odor of chlorine. The solution is affected by light. Common household bleach is usually a 4.5 to 5.0% solution of sodium hypochlorite. The Diluted Sodium Hypochlorite Solution is prepared by diluting the original sodium hypochlorite solution with five times its volume of purified water. The pH is then adjusted to 8.3 or lower using a 5% sodium bicarbonate solution until no color change occurs with phenolphthalein. This adjusted solution is recognized as the only hypochlorite preparation approved for use as an antibacterial on tissues. 8 Inorganic Pharmaceutical Chemistry: Topical Agents The alkalinity and oxidizing action of this solution is too strong for use on tissues. In addition, the solution dissolves blood clots and delays healing. Solutions of sodium hypochlorite are strong oxidizing agents, as can be shown by the liberation of free iodine from solutions of potassium iodide. 2KI + NaClO + H2O ⟶ 2KOH + NaCl + I2 The antibacterial properties of sodium hypochlorite solutions are due in part to the liberation of chlorine and to the oxidizing action produced by the liberation of oxygen by forming hypochlorous acid when reacted with water. NaOCl + H2O ⟶ HOCl + NaOH In Diluted Sodium Hypochlorite Solution, the pH is reduced through the addition of sodium bicarbonate solution. This has the effect of reducing the caustic action of the highly alkaline solution on tissues and of increasing the effective concentration of hypochlorous acid. The bicarbonate acts to reduce the hydroxide ion concentration according to the reaction shown: HCO3− + OH− ⟷ CO32− + H2O The primary uses for hypochlorite solutions:  Sodium Hypochlorite Solution is useful as a disinfectant and laundry bleach.  Diluted Sodium Hypochlorite Solution, N.F. XIII, has been used in the past as an antiseptic on pus-forming (suppurating) wounds. It has the disadvantages of dissolving certain types of sutures, and of dissolving blood clots and prolonging clotting time.  The solution may also be used as a foot bath in the prevention of various fungal infections (athlete’s foot, etc.). 9 Inorganic Pharmaceutical Chemistry: Topical Agents  The antibacterial effectiveness may be increased by acidifying the solution at the time of use, thereby further increasing the concentration of HOCl. 3- Iodine Solution Both Iodine Solution and Iodine Tincture contain the same concentrations of ingredients, they differ only in the nature of the solvent, i.e., Iodine Solution is aqueous, having been prepared with purified water, and Iodine Tincture contains approximately 50% alcohol as the final solvent. Both solutions are transparent, have a reddish-brown color, and have the characteristic odor of iodine. Iodine Tincture also has the odor of alcohol. The active antimicrobial agent common to both preparations is iodine. The most notable chemical property of iodine in aqueous solution is that of a mild oxidizing agent. It is believed that the oxidizing action is mediated through the formation of hypoiodous acid [HIO]. I2 + H2O ⇌ HI + HIO ⟶ HI + (O) It will oxidize iron to form ferrous iodide. Fe + I2 ⟶ FeI2 For this reason, metal spatulas should not be used to handle iodine, and balance pans should be protected against pitting by using weighing papers. Iodine is a very active element and is, therefore, easily inactivated by organic materials in the gastrointestinal tract. Most of the toxicity due to the ingestion of large quantities of iodine is a result of the corrosive action of the element on the gastrointestinal tract, producing abdominal pain, gastroenteritis, and possibly bloody diarrhea. The treatment usually involves gastric lavage with a soluble starch solution or administration of a 5% sodium thiosulfate solution. The starch 10 Inorganic Pharmaceutical Chemistry: Topical Agents solution forms a complex with the iodine (purple color), thus aiding in its removal from the stomach. 2Na2S2O3 + I2 ⟶ Na2S4O6 + 2NaI The primary uses of iodine solutions:  Iodine Tincture and Iodine Solution are probably the most effective topical antiseptic agents available. There is some indication that Iodine Tincture may be more suitable for this purpose, since the alcohol seems to improve the penetration of the iodine.  Iodine Solution is preferred for application to wounds because the alcohol in the Tincture is very irritating to open tissue.  Iodine Tincture may be used to disinfect drinking water.  Povidone-Iodine is a member of a class of compounds referred to as Iodophors, these are complexes of iodine, with carrier organic molecules serving as a solubilizing agent. These complexes slowly liberate iodine in solution. The major advantage to their use is the lack of tissue irritation, which makes them useful for application to sensitive areas and mucous membranes. 4- Silver Nitrate (AgNO₃; Mol. Wt. 169.87) Silver Nitrate occurs as colorless or white crystals which become gray or grayish black on exposure to light in the presence of organic matter. It is very soluble in water, sparingly soluble in alcohol, and freely soluble in boiling alcohol. Solutions of silver nitrate in concentrations between 0.5 and 1.0% are used as antibacterial agents. The chemistry and pharmacological action of these preparations are essentially those of the silver ion. The only salts of silver are those 11 Inorganic Pharmaceutical Chemistry: Topical Agents of the monovalent cation [Ag(I)]. This ion is readily obtained from metallic silver through treatment with an oxidizing acid, e.g., cold dilute nitric acid. 3Ag + 4HNO₃ → 3AgNO₃ + NO↑ + 2H₂O The protein precipitant action of silver ion is not selective; it will precipitate both bacterial and human protein. The range of activity available includes antibacterial, astringent, irritant, and corrosive, depending upon the concentration applied. Silver ion precipitation of protein involves interactions between the cation and various polar groups on the protein molecule, e.g., –SH, –NH₂, –COOH, and heterocyclic residues, e.g., histidine. When applied to tissue in a concentration of 0.1% Ag ⁺ the activity is rapidly bactericidal. Extended use of silver preparations is likely to cause a darkening of the skin due to the deposition of free silver below the epidermis. This condition is termed argyria and is essentially irreversible. The primary uses of silver nitrate products:  It is employed as an antibacterial in solutions ranging in concentration from 0.01 to 10%, recognizing that the higher concentrations present astringent and irritant properties to the tissues.  Silver Nitrate Ophthalmic Solution is a 1% solution for instillation into the eyes of newborn babies. Silver salts are quite effective against gonococcal organisms, and two drops of this solution are placed in each eye as a prophylactic measure against (ophthalmia neonatorum).  Silver nitrate is applied as of 0.5% aqueous solution in the form of a wet dressing on burned areas of patients suffering from third-degree burns. Astringents Agents 12 Inorganic Pharmaceutical Chemistry: Topical Agents Astringents are compounds that cause protein precipitation on the surface of cells, resulting in the coagulation of proteins and tissue constriction without causing deep damage. They typically act on small blood vessels (smooth muscle) and are applied topically. Astringents have limited penetration, causing a mild antimicrobial effect and restricting blood flow, but they don't result in the death of cells. Uses of Astringents:  Styptic action: Stops bleeding from small cuts by promoting blood coagulation and constricting capillaries.  Antiperspirant: Decreases the secretion of sweat.  Constricts mucous membranes: Reduces inflammation by limiting blood flow to the surface.  Topical actions: Removes unwanted tissue or restricts protein action, often used at higher concentrations as a corrosive agent. Common astringent products include aluminum, zinc, and zirconium salts. 1- Aluminum Chloride (AlCl₃·6H₂O): It acts as a Lewis acid and is very soluble in water, alcohol, and glycerin, producing an acidic solution. It is used in aqueous solutions as an astringent and mild antiseptic, with concentrations ranging from 10% to 25%. It can cause irritation to tissue due to the hydrolysis of the aluminum chloride forming hydrochloric acid (HCl). This compound was initially used as an antiperspirant but was too irritating and could damage clothing. 2- Aluminum Hydroxy chloride: This term refers to two possible compounds: monohydroxy chloride and dihydroxy chloride, which are both acidic but less soluble in water than aluminum chloride. 13 Inorganic Pharmaceutical Chemistry: Topical Agents These compounds are less irritating and are commonly used in commercial antiperspirants. They replace the more irritating aluminum chloride in products such as deodorant sprays, creams, and solutions, used in concentrations around 20%. 3- Zinc Chloride Zinc chloride solutions are acidic due to hydrolysis, which forms hydrochloric acid (HCl) and basic zinc chloride, as shown in the equation: ZnCl2 + H2O ⇌ Zn(OH)Cl +H+ + Cl− It is important to filter zinc chloride solutions through asbestos or glass wool as they can dissolve materials like paper and cotton. Zinc chloride is used to form zinc oxychloride when mixed with zinc oxide. This creates a hard mass, which is used in some dental cements. Uses of Zinc Chloride:  Astringent & Antiseptic: Zinc chloride acts as a powerful protein precipitant, making it a strong astringent and mild antiseptic.  Escharotic Action: The compound also acts as an escharotic, aiding in tissue sloughing and scar tissue formation, which helps in healing.  Nasal Spray & Sinus Treatment: In lower concentrations (0.5 to 2%), zinc chloride solutions are applied to mucous membranes or used as nasal sprays to aid sinus drainage.  Dentin Desensitizer: A 10% solution of zinc chloride is applied to teeth to act as a desensitizer of dentin. 14