Physicochemical Properties of Drug Molecules PDF

Physicochemical Properties of Drug Molecules & Reactions Leading to Interconversion and Modification of Functional Groups By Charles O. Nnadi, PhD P hysicochemical properties...

Physicochemical Properties of Drug Molecules & Reactions Leading to Interconversion and Modification of Functional Groups By Charles O. Nnadi, PhD P hysicochemical properties play an important rotated is proportional to the path length through the role in product development including studies material and (for a solution) proportional to its on biological performance of drugs. A study of concentration. the physical properties of drug molecules is a prerequisite for product pre-formulation, formulation When the polarized light passes through the optically development and optimizing storage and usage active substance and rotates the plane of polarized light conditions. to the left side, or clockwise, then the compound is known as the dextrorotatory substance. If the rotation 1. Optical Rotation is observed in the right side, or anti-clockwise direction, then the compound is known as the Optical rotation also known as polarization rotation or laevorotatory substance. circular birefringence is the angle at which the plane of polarization is rotated when the polarized light passes The rotation of the plane polarized light is mainly through a layer of one liquid. Optically active based upon the asymmetric molecules and the steric substance is of dextro rotatory (rotation to the right) or configuration. The rotation is directly proportional to laevo rotatory (rotation to the left). Circular the concentration and the path length. The angle of birefringence and circular dichroism are the rotation is calculated by Biot's formula: manifestations of optical activity. [α] = (αo)/ (c x l) where Specific rotation is a rotation measured at the temperature, t and at the wavelength, λ given by a 1 dm [α] = specific rotation, in degrees thickness of liquid or solution containing 1 kg/m3 of αo = observed rotation, in degrees optically active substance. c = concentration, in g/mL Optical activity occurs only in chiral materials, those lacking microscopic mirror symmetry. Unlike other l = path length, in dm sources of birefringence which alter a beam's state of polarization, optical activity can be observed in fluids. Measurement of optical rotation This can include gases or solutions of chiral molecules Polarimeter is used to measure optical rotation of drug such as sugars, molecules with helical secondary molecules structure such as some proteins, and also chiral liquid crystals. It can also be observed in chiral solids such as certain crystals with a rotation between adjacent crystal planes (such as quartz) or metamaterials. The rotation of the plane of polarization may be either clockwise, to the right (dextrorotary — d-rotary), or to the left (laevorotary — l-rotary) depending on which stereoisomer is present (or dominant). For instance, sucrose and camphor are d-rotary whereas cholesterol is l-rotary. For a given substance, the angle by which the polarization of light of a specified wavelength is 1 Light Source: Generally, sodium vapour lamp is A bond dipole moment is a measure of the polarity of employed. This produces wavelengths above 450 nm. a chemical bond between two atoms in a molecule. It involves the concept of electric dipole moment, which Filter: Filter is mainly used to polychromatic light into is a measure of the separation of negative and positive monochromatic light by absorbing the undesired charges in a system. The bond dipole moment is a radiation. vector quantity since it has both magnitude and Sample Cell: Sample cells are long tubes which are direction. An illustration describing the dipole moment made up of glass. that arises in an HCl (hydrochloric acid) molecule is provided below. Analyzer: A Nicol prism is used for this purpose. This is mainly used to analyse the samples whether they rotate the plane of polarized light on the right or left side. Detector: The photomultiplier tube is commonly employed for the detection of the wavelength. It can be noted that the symbols 𝛿+ and 𝛿– represent The procedure followed is sample tube filled with the the two electric charges that arise in a molecule which sample solution which is placed between the polarizer are equal in magnitude but are of opposite signs. They and the analyser. Then, allow the source of light to pass are separated by a set distance, which is commonly through the radiation. This ordinary light is polarized denoted by ‘d’. by the polarizer and the polarized light is passed through the sample solution. The optically active The dipole moment of a single bond in a polyatomic substance present in the sample solution rotates the molecule is known as the bond dipole moment and it is plane polarized light into clockwise or in an anti- different from the dipole moment of the molecule as a clockwise direction. Then, the analyser measures the whole. It is a vector quantity, i.e. it has magnitude as angle of rotation and is detected by the detector. well as definite directions. Being a vector quantity, it can also be zero as the two oppositely acting bond Applications of optical rotation dipoles can cancel each other. By convention, it is denoted by a small arrow with its tail on the negative i. Identification and determination of optically centre and its head on the positive centre. In the case active compound of a polyatomic molecule, the dipole moment of the ii. Determination of quality of juice from molecule is the vector sum of the all present bond sugarcane and refined sucrose dipoles in the molecule. A dipole moment is the iii. In distinguishing chemicals product of the magnitude of the charge and the distance iv. Concentration and purity of steroids, diuretics, between the centres of the positive and negative antibiotics, narcotics, vitamins, analgesics charges. It is denoted by the Greek letter ‘μ’. v. Polarimetry is used in remote sensing Mathematically, Dipole Moment (μ) = Charge (Q) * applications distance of separation (r) 2. Dipole moment It is measured in Debye units denoted by ‘D’. 1 D = A dipole moment arises in any system in which there 3.33564 × 10-30 C. m, where C is Coulomb and m is a separation of charge. They can, therefore, arise in denotes a meter. The bond dipole moment that arises ionic bonds as well as in covalent bonds. Dipole in a chemical bond between two atoms of different moments occur due to the difference in electronegativities can be expressed as follows: electronegativity between two chemically bonded μ=𝛿xd atoms. 2 Where: μ is the bond dipole moment, 𝛿 is the is 1.5 D. The net dipole moment in a water molecule is magnitude of the partial charges 𝛿+ and 𝛿–, And d is found to be 1.84D. the distance between 𝛿+ and 𝛿–. The bond dipole moment (μ) is also a vector quantity, whose direction is parallel to the bond’s axis. In chemistry, the arrows that are drawn in order to represent dipole moments begin at the positive charge and end at the negative charge. When two atoms of varying electronegativities interact, the electrons tend to move from their initial positions to come closer to the more electronegative Measurement of dipole moment atom. This movement of electrons can be represented via the bond dipole moment. When a solution of polar molecules is placed between two plates having opposite charge, they align In a beryllium fluoride molecule, the bond angle themselves along the direction of field. between the two beryllium-fluorine bonds is 180o. Fluorine, being the more electronegative atom, shifts This process consumes energy that is returned to the the electron density towards itself. The individual bond electrical circuit when the field is switched off, an dipole moments in a BeF2 molecule are illustrated effect known as electrical capacitance below. From the illustration provided above, it can be Measurement of capacitance of gas or solution serves understood that the two individual bond dipole to determine magnitude of dipole moment of moments cancel each other out in a BeF2 molecule substance. because they are equal in magnitude but are opposite in direction. Therefore, the net dipole moment of a Dipole moment can be permanent, induced or BeF2 molecule is zero. instantaneous. Application of dipole moment i. Predicting nature of molecules (polar or non- polar) ii. Degree of polarity iii. Shape of molecules iv. Predict nature of bond v. The structure of the molecule can be confirmed from the dipole moment values, for example, chlorobenzene, benzene, carbon dioxide etc. In a water molecule, the electrons are localized around vi. The cis- and trans- isomers can be the oxygen atom since it is much more electronegative differentiated form dipole moment values, for than the hydrogen atom. However, the presence of a example, cis and trans dichloroethylene. lone pair of electrons in the oxygen atom causes the vii. Dipole moments can be used to determine water molecule to have a bent shape (as per the VSEPR percent ionic characteristic of bond of the theory). Therefore, the individual bond dipole molecule, e.g. H-Cl a covalent bond, ionic moments do not cancel each other out as is the case in characteristic is 17%. the BeF2 molecule. An illustration describing the viii. Permanent dipole moments can be correlated dipole moment in a water molecule is provided below. with the biological activities to obtain The bond angle in a water molecule is 104.5°. The information about the physical parameters of individual bond moment of an oxygen-hydrogen bond molecules. 3  ix. The more soluble the molecule the easier it the standard organic phase for experimental passes the lipoidal membrane of insects and determination, other solvents are applied to better attacks the insect’s nervous system. Therefore, mimic the special permeation of conditions such as the the lower is the dipole moment the greater is cyclohexane-water system for BBB permeation. the insecticidal action. x. For example, p, m and o isomers of DDT show Measurement of logP different insecticidal activities due to their Shake-flask method (in combination with UV differences in permanent dipole moment as p- spectroscopy) isomer shows μ=1.1 and has predominant toxicity, o-isomer shows μ = 1.5 with The method usually involves the following: intermediate toxicity while m-isomer shows μ solubilization of the compound in a mixture of = 1.9 with least toxicity. The variations in mutually pre-saturated buffered water and octanol, activities of different isomers are due to the separation of octanol and aqueous phases, and direct greater solubilities in non-polar solvents. measurement of the solute concentration in both phases) Dipole moments are often stated in Debyes. The SI unit is the coulomb meter. Potentiometric Method 3. Lipophilicity (Partition coefficient) The potentiometric method for log P determination has been correlated with the shake - flask method. The Lipophilicity is the measure of the partitioning of a potentiometric logP is characterized by comparing an compound between a lipidic and an aqueous phase. aqueous pKa to an apparent pKa measured in the two- Lipophilicity is one of the most informative phase system (generally octanol-water) using physicochemical properties in medicinal chemistry difference curve analysis. Therefore, the method is and since long successfully used in quantitative appropriate only for ionizable compounds with structure – activity relationship (QSAR) studies. Its accurately determined aqueous pKa values) important role in governing pharmacokinetic and pharmacodynamic events has been extensively Chromatographic methods documented. Lipophilicity can be determined by liquid Increased lipophilicity was shown to correlate with: chromatography, including reversed phase, thin- layer, micellar, reversed - phase (RP) – HPLC, RP - ion - pair i. poorer aqueous solubility, and counter-current chromatography, from TLC RF ii. increased plasma protein binding, values, respectively. RM of HPLC and GC P iii. increased storage in tissues calculated from the retention mes tM. iv. more rapid metabolism and elimination. v. increased rate of penetration through the skin, Electrophoretic methods sometimes with a shorter duration of action. Microemulsion electrokinetic chromatography Lipophilicity is also a highly important descriptor of (MEEKC), a variation of the capillary electrophoresis blood – brain barrier (BBB) permeability and plays a method. The method only suitable for estimating log P dominant role in toxicity prediction. of neutral compounds. Partition coefficient (logP), is defined as the ratio of 4. Solubility the concentrations of a neutral compound in organic and aqueous phases of a 2-compartment system under The solubility of drugs in water is important for oral equilibrium conditions. It is commonly used in its drug absorption. To simplify, a drug must be soluble in logarithmic form, log P. Whereas 1-octanol serves as the aqueous contents of the gastrointestinal lumen to be orally absorbed. 4 Solubility is the amount of a solute that can be temperature then it will decrease the solubility. Only a dissolved in a specific solvent under given conditions. few solid solutes are there which are less soluble in It depends on the nature of the solvent and temperature warm solutions. In case of gases, the solubility gets and the degrees of drug solubility is defined by decreased when temperature of solution is increased. European Pharmacopoeia 8th Edition. 4. Pressure: In case of solids and liquid solutes, there Water solubility can be increased by chemical is no effect of pressure on the solubility but in case of modification of the molecule by substitution with gaseous solutes, when the pressure is enhanced, there is an increase in the solubility and with the decrease in i. Neutral hydrophilic group pressure there is a decrease in solubility. ii. Ionizable organic acids or basis iii. Preparation of salts 5. Nature of solute and solvent: There is a lot of iv. Using appropriate solubilizers (benzoate, difference in the solubility of two or more different Sodium salicylate as solubilizers for purine substances on the basis of their natures. For example: alkaloids) In 100 grams of water at room temperature only 1 gram of Lead (II)chloride can be dissolved where 200 grams Water solubility can be reduced by of Zinc chloride can be dissolved in same amount of i. Modification of the structure water i.e. 100 grams of water at same room ii. Design the less soluble salt temperature. Increase the solubility lipids: 6. Polarity: The polarity of solute and the solvent molecules will affect the process of solubility. i. Blocking of hydrophilic groups (eg Generally, the polar solute molecules get dissolved in esterification) polar solvent system and nonpolar solute molecules get ii. The introduction of lipophilic substituents (eg dissolved in nonpolar solvent system. Thus, if the alkyl, halogens) solute molecule is polar in nature it must have both positive and negative ends and if the solvent is also of Factors influencing drug solubility polar nature then it also consists of both the ends, thus 1. Particle Size: The size of the solid particles affects the positive ends of solute molecule gets attracted the solubility because with the decrease in particle size, towards the negative ends of the solvent molecules. the surface area to volume ratio increases. The larger These types of attractions are known as dipole-dipole surface area of solute molecules allows more interactions which is a type of intermolecular force. interaction with the solvent. 7. Polymorphs: Solids have a rigid form and a definite 2. Molecular Size: The molecular size will affect the shape. The shape or crystal habit of a given solid may solubility of the drug as larger the molecule or higher vary but angles between the faces remains constant. A the molecular weight of the drug, less is the solubility crystal is made up of ions, atoms or molecules in a of that substance. In organic compounds, the amount lattice or in a regular geometric arrangement constantly of carbon branching increases the solubility because repeated in three dimensions. This repeating more branching will reduce the size of molecule and arrangement is known as the unit cell. The ability of a also make it easier for the solvent to solvate the substance to crystallize in more than one crystalline molecules. form is known as polymorphism. The polymorphs can vary in their melting points. As, the melting point of 3. Temperature: With the increase in temperature the any solid is related to its solubility, the polymorphs process of solution absorbs the energy and thus the will have different solubility. solubility will get increased but if the process of solution releases the energy with the increase in 8. Rate of solution: The rate of solution can be defined as the measure of how fast the substance dissolves in a 5 solvent. The various factors that affect the rate of absorbed by a tissue, organ or blood when they solution are: size of particles, temperature, amount of permeate its entire bulk or volume. solute already dissolved, stirring. Adsorption of material at solid interface may take 5. Permeability place from either liquid or gas phase. The adsorption of gases at solid interface can be applied in the removal The permeability of a particle is a measure of how of odours, the operation of gas masks, and the easily a fluid may flow through the pore channels in a measurement of the dimensions of particles as solid. It depends on the size, shape, and number of the powders. The adsorption of liquids at solid interface pore channels in the porous medium. Absolute can be applied in the decolorizing solutions, adsorption permeability is the permeability of the porous medium chromatography, detergency and wetting. if a single fluid is flowing. Effective permeability is the R permeability of a fluid if another fluid is present. eview of organic reactions leading to Relative permeability is the effective permeability interconversion and modification of functional divided by the absolute permeability. groups through nucleophilic and electrophilic substitution, elimination, addition and rearrangement 6. Polymorphism reactions. Utility of these reactions for isolation, Some elemental substance such as C and S, may exist characterisation, elucidation of structure and synthesis in more than one crystalline form and are said to be of medicinal products. allotropic, which is a special case of polymorphism. 1. Nucleophilic substitution Polymorphism is the ability of a substance to exist in more than one crystal structure. Alkyl halides undergo nucleophilic substitution reaction. The components required for nucleophilic Polymorphs: when two crystals have the same substitution are: substrate, nucleophile and solvent. chemical composition but different internal structure The substrate consists of two parts, alkyl group and (molecular packing –molecular conformation or / and leaving group. Some important nucleophilic inter or intra molecular interactions) modifications or substitution reactions are: polymorphs or forms. R-CH2-X + :OH R-OH + X- (alcohol) Pseudo polymorphs: different crystal forms have R-CH2-X + :CN R-CN + X- (nitrile) molecules of the same given substances and also R-CH2-X + :OH2 R-OH2+ + X- (alcohol) contain molecules of solvent incorporated into a R-CH2-X + :OR R-OR + X- (ether) unique structure (solvates or hydrates). R-CH2-X + :C≡CR R-C≡CR + X- (alkyne) The Principle of polymorphism: When the change R-CH2-X + RCOO: RCOOR + X- (ester) from one form to another is reversible, it is said to be R-CH2-X + :NH3 R-NH2 + X- (1° amine) enantiotropic. When the transition takes place in one R-CH2-X + :NH2R R-NHR + X- (2° amine) direction only—for example, from a metastable to a R-CH2-X + :NHRR R-NRR + X- (3° amine) stable form—the change is said to be monotropic. R-CH2-X + R-M R-R + X- (alkane) R-CH2-X + :SH R-SH + X- (thiol) 7. Adsorption R-CH2-X + :SR R-SR + X- (thioether) Adsorption is the accumulation of a substance at a Nucleophilic substitution reaction proceeds via two surface or interface. Absorption is the accumulation mechanisms: nucleophilic substitution unimolecular and distribution of a substance throughout a phase. (SN1) and nucleophilic substitution bimolecular (SN2). Drugs are adsorbed by a membrane, enzyme or cell wall when they are attached to its surface. They are 2. Elimination reaction 6 When alkyl halide is treated with a hot concentrated carbocation, +C6H6Y and (2) abstraction of a proton alcoholic solution of a strong base like KOH, there is from this carbocation by some base. In each case, there obtained alkene, potassium halide and water. This is an is a preliminary acid-base reaction which generates the example of dehydrohalogenation: 1,2-elimination of attacking particle; the actual substitution, however, is the elements of hydrogen halide. Dehydrohalogenation contained in these two steps. involves loss-elimination- of the halogen atom and of a hydrogen atom from a carbon adjacent to the one ArH + HONO2/H2SO4 Ar-NO2 + H2O losing the halogen. ArH + HOSO3H Ar-SO3H + H2O The reagent required is a base, whose function is to 4. Electrophilic addition reaction abstract the hydrogen as a proton. Halogenation or hydrohalogenation of alkenes yields alkane or haloalkane via electrophilic addition C C +B C C + H:B + :X reaction. Br2 (1,2 and 1,4 addition) Mechanism of reaction CH2=CH-CH=CH2 HCl (1,2 and 1,4 addition) Halogen leaves the molecule as halide ion, and hence must take its electron pair along. Hydrogen is H2 (1,2 and 1,4 addition) abstracted by the base as a proton and hence must leave In additions to conjugated dienes, a reagent may attach its electron pair behind; it is this electron pair that is itself not only to a pair of adjacent carbons (1,2- available to form the second bond – the π bond – addition), but also to the carbons at the two ends of the between the carbon atoms. conjugated system (1,4-addition). Very often the 1,4- X bH Hb addition product is the major one. C C C C + H:B + :X bC Ca Cb H X 5. Nucleophilic addition :B In some case, dehydrohalogenation The C=O group governs the chemistry of aldehydes yields a single alkene, and in other cases yields a and ketones by (i) providing a site for nucleophilic mixture. To predict which products can be formed in a addition and (ii) increasing the acidity of the hydrogen given reaction, we have only to examine the structure atoms attached to the alpha carbon. of the substrate. We can expect an alkene corresponding to the loss of any one of the β-hydrogens The C=O group contains a C-O double bond; since the – but no other alkenes. n-Butyl bromide, for example, mobile π-electrons are pulled strongly toward oxygen, can lose hydrogen only from C-2, carbonyl carbon is electron-deficient and carbonyl oxygen is electron-rich. Since the important step in 3. Electrophilic substitution these reactions is the formation of a bond to the electron-deficient (electrophilic) carbonyl carbon, the Electrophilic substitution reaction is common in carbonyl is most susceptible to attack by electron-rich, aromatic compounds where a hydrogen is replaced by nucleophilic reagents, that is by bases. The typical an electrophile. The reaction proceeds by a single reaction of aldehydes and ketones is nucleophilic mechanism. This can be summarized for the reagent addition. YZ as follows: 1. C6H6 + Y+ + C6H6Y Slow R :Z Z Z 2. +C6H6Y + :Z C6H5-Y + HZ Fast O C O: OH The essential steps involved: (1) attack by an R R R R R electrophilic reagent upon the ring to form a 7