Physicochemical Properties of Drug

The ability of a chemical compound to elicit a pharmacological/ therapeutic effect is related to the influence of various physical and chemical (physicochemical) properties of the chemical substance on the bio molecule that it interacts with.
1)Physical Properties : Physical property of drug is responsible for its action
2)Chemical Properties :The drug react extracellularly according to simple chemical reactions like neutralization, chelation, oxidation etc.

1. Lecture by- Priyanka Bindlish GGSCOP- Ymaunanagar Physicochemical Properties of Drug

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3. DEFINITION: The ability of a chemical compound to elicit a pharmacological/ therapeutic effect is related to the influence of various physical and chemical ( physicochemical) properties of the chemical substance on the bio molecule that it interacts with. 1) Physical Properties : Physical property of drug is responsible for its action 2) Chemical Properties : The drug react extracellularly according to simple chemical reactions like neutralization, chelation, oxidation etc .

4. Various Physico-Chemical Properties are, Ionization Solubility Partition Coefficient Hydrogen Bonding C helation Protein binding Bioi sosterism Optical and geometrical isomerism

5. Ionization of drug 5 Most of the drugs are either weak acids or base and can exist in either ionised or unionised state. Ionization = Protonation or deprotonation resulting in charged molecules. The ionization of the drug depends on its pKa & pH. The rate of drug absorption is directly proportional to the concentration of the drug at absorbable form but not the concentration of the drug at the absorption site.

6. Ionization form imparts good water solubility to the drug which is required of binding of drug and receptor interaction Unionized form helps the drug to cross the cell membrane . Unionized form- nonpolar -----can cross capillary wall + cell membrane 6

7. pKa --------- transport,distribution,absorption pKa < 2 strong acids pKa = 4-6 weak acids pKa = 8-10 very weak acids pKa > 12 no acidic proerty Acidic drug basic drug pKa = 4-5 pKa = 9-10 Non ionic in stomach non ionic in intestine Partly Absorb in stomach absorb in intestine Partly in intestine

8. ♣ hydrophilic ..............waterloving ♣ lipophobic ............... L ipid hating ♣ lipophilic ................... L ipid loving ♣ hydrophobic ............... water hating 7

9. SOL U BIL I T Y O F OR G A NI C ME D I C I NA L AGENTS Importance of solubility: Formulation of the drug in an appropriate dosage form and Bio- disposition: Disposition of drugs in the living system after administration (absorption, distrib ution, metabolism , and excretion).

10. Solubility: The solubility of a substance at a given temperature is defined as the concentration of the dissolved solute, which is in equillibrium with the solid solute . Solubility depends on the nature of solute and solvent as well as temperature , pH & pressure . The solubility of drug may be expressed in terms of its affinity/philicity or repulsion/phobicity for either an aqueous or organic solvent. The atoms and molecules of all organic substances are held together by various types of bonds (e.g. hydrogen bond, dipole –dipole, ionic bond etc.) These forces are involved in solubility because it is the solvent- solvent, solute-solute, solvent-solute interactions that governs solubility.

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12. Solubility of organic medicinal agents In order for a chemical compound to dissolve in a particular solvent/ medium the compound must establish attractive forces between itself and molecules of the solvent. Polar drug non polar drug Hydrophilic lipophilic The most important intermolecular attractive forces (bonds) that are involved in the solubilization process are: 10

13. Solubility Prediction 13 The relative solubility of a drug is a function of the presence of both lipophilic and hydrophilic features within its structure, which serve to determine the extent of interaction with lipid and/or aqueous phases. T he relative solubility of a drug can be determined in the laboratory , i.e. the partition coefficient [ P ; the ratio of the solubility of the compound in an organic solvent to the solubility of the same compound in an aqueous environment (i.e., P=[Drug]lipid/ [Drug]aqueous). P is often expressed as a log value.

14. Solubility Prediction For example, the relative solubility of a drug is the sum of the contributions of each group and substituent to overall solubility. Example: Examination of the structure of chloramphenicol (indicates the presence of both lipophilic (nonpolar) and hydrophilic (polar) groups and substituents . 14

15. 15 Solubility Prediction L i p o ph ili c Hydrophilic Hydrophilic L i p o ph ili c O 2 N CHCl 2 OH O C H C H N H C CH 2 OH Chloramphenicol Hydrophilic The presence of oxygen and nitrogen containing functional groups usually enhances water solubility. While lipid solubility is enhanced by nonionizable hydrocarbon chains and ring systems .

16. Partition Co-efficient Partition co-efficient is one of the Physicochemical parameter which influencing the drug transport & drug distribution., the way in which the drug reaches the site of action from the site of application Partition co-efficient is defined as equilibrium constant of drug concentration for unionized molecule in two phases.

17. For ionized ( acids, bases and salts) Partition coefficient responsible to cross the cell membrane The contribution of each functional group & structural arrangement help to determine the lipophilic or hydrophilic character of drug molecules. It is widely used in QSAR . P = conc of drug in non aqueous/ conc of drug in aqueous phase

18. Factors affecting Partition Coefficient pH Co solvents Surfactant Complexation Partition Co-efficient are difficult to measure in living system. They are usually determined in vitro 1-octanol as a lipid phase and phosphate buffer of pH 7.4 as the aqueous phase .

19. Hydrogen Bond The hydrogen bond is a special dipole-dipole interaction between the hydrogen atom in a polar bond such as N-H, O-H or F-H & electronegative atom O, N, F atom. Dipoles result from unequal sharing of electrons between atoms within a covalent bond. These are weak bonds and denoted as dotted lines. O-H…….O, HN-H…….O, The compounds that are capable, of forming hydrogen bonding is only soluble in water. hydrogen bonding is classified into 2 types: Intermolecular Intramolecular

20. 1) Intermolecular hydrogen bonding It occur s between two or more than two molecules of the same or different compound. Due to this increase the boiling point of the compound & increase the molecular weight of compound hence more energy is required to dissociate the molecular for vaporization.

21. 2) Intramolecular Hydrogen bonding H- bonding occurs within two atoms of the same molecules. This type of bonding is known as chelation and frequently occurs in organic compounds. Sometimes h-bond develop six or five member rings Due to decrease the boiling point salicylic acid o-nitrophenol O H C O O H O H N O O

22. Hydrogen Bonding and biological action N N CH 3 H 3 C O Eg. 1) Antipyrin i.e. 1- phenyl 2,3- dimethyl 5- pyrazolone has analgesic activity. C 6 H 5 H N H 3 C O 1-phenyl-3-methyl-5-pyrazolone is inactive. C 6 H 5 H N H N H 3 C O Active form Can’t form H- bonding Freely soluble in non-polar Solvents so easily cross BBB So have analgesic activity Inactive form Intermolecular H-bond Less soluble in non polar solvents

23. O H O C OH Salicylic acid (O-Hydroxy Benzoic acid) has antebacterial activity O H C O H O H O C O OH Para and meta Hydroxy Benzoic acids are inactive. Ortho Active form Intramolecular H bonding Less soluble 300 times more partition coefficient para Inactive form Intermolecular H bonding More soluble less partition coefficient

24. Effect of H-bonding All physical properties affected by H-bonding, Boiling and Melting point Water solubility Strength of acids Spectroscopic properties On surface tension and viscosity Drug-receptor interaction

25. Chelation /Complexation Complex of drug molecules can’t cross the natural membrane barriers, they render the drug biological ineffectivity. The rate of absorption is proportional to the concentration of the free drug molecules i.e. the diffusion of drug. Due to reversibility of the Complexation, equillibrium between free drug and drug complex Drug + complexing agent Drug complex Complexation reduce the rate of absorption of drug but not affect the availability of drug Natural complexing agents= Hb and cyanocobalamin

26. Importance of chelates in medicine: 1.Dimercaprol (BAL) is a chelating agent make complex with mercury , gold , arsenic a)Antidote for metal poisoning 2.Penicillamine - make complex with copper

27. 8-Hydroxyquinoline and its analogs acts as antibacterial and anti fungal agent by complexing with iron or copper. Phenobarbital forms a non-absorbable complex with polyethylene glycol-4000. Calcium with EDTA form complex which is increase the permeability of membrane . Tetracyclin - make complex with Ca, Mg, Al ions Sequestration process- Water soluble chelating agents

28. Protein binding The reversible binding of protein with non-specific and non- functional site on the body protein without showing any biological effect is called as protein binding. Protein + drug ⇌ Protein-drug complex Depending on the whether the drug is a weak or strong acid , base or is neutral, it can bind to single blood proteins to multiple proteins (sereum albumin, acid-gycoprotien or lipoproteins).The most significant protein involved in the binding of drug is albumin, which comprises more than half of blood proteins.

29. protein binding values are normally given as the percentage of total plasma concentration of drug that is bound to all plasma protein. Free drug ( D f ) + Free protein ( P f ) Drug / protein complex ( D p ) Total plasma concentration Protein drug complex- act as a reservoir Protein binding affects- solubility, half life, biotransformation, interaction with other drugs. Placenta- significance of placenta in protein binding Advantage & disadvantage of protein binding

30. Stereochemistry involve the study of three dimensional nature of molecules . It is study of the chiral molecules. Stereochemistry plays a major role in the pharmacological properties because; Any change in stereo specificity of the drug will affect its pharmacological activity The isomeric pairs have different physical properties ( pKa etc.) and thus differ in pharmacological activity. The isomer which have same bond connectivity but different arrangement of groups or atoms in the space are termed stereoisomer . Stereochemistry of drugs

31. Conformational Isomers Different arrangement of atoms that can be converted into one another by rotation about single bonds are called conformations. Rotation about bonds allows inter conversion of conformers.

32. A classical example is of acetylcholine which can exist in different conformations. H H OCOCH3 Staggered H H N + H N + H H H OCOCH3 Eclipsed H 3 COCO H N H H H G A U C H E OCOCH 3 N H H H H Fully Eclipsed

33. Optical Isomers Stereochemistry , enantiomers, symmetry and chirality are impotant concept in therapeutic and toxic effect of drug. A chiral compound containing one asymmetric centre has two enantiomers. Although each enantiomer has identical chemical & physical properties, they may have different physiological activity like interaction with receptor, metabolism & protein binding. A optical isomers in biological action is due to one isomer being able to achieve a three point attachment with its receptor molecule while its enantiomer would only be able to achieve a two point attachment with the same molecule.

34. Different examples of stereospecificity (-)Adrenalin (+)Adrenalin More active less active Warfarin - anticoagulant drug used as racemate S (-) warfarin is 2-5 times more active than R (+) (-) hyoscyamine (+) hyoscyamine 15-20 times more active mydriatic drug

35. Examples where two enantiomers have different pharmacogical Activities- L- Thyroxine with S configuration- thyroid activity D- Thyroxine with R configuration- hypocholesterolemic D- Penicillamine (S) - antiarthritic drug L- Penicillamine (R) - extremely toxic D- Asparagine - sweet taste L- Asparagine - tasteless

36. (-)-Adrenaline (+)- Adrenaline

37. E.g. Ephedrine & Psuedoephedrine MP = 37-39 MP = 118-120 Ep h ed ri n e ( E rythro) CH 3 NHCH 3 OH H H P s e ud o ep h ed ri n e ( T hreo) CH 3 NHCH 3 H H H O

38. The category of drugs where the two isomers have qualitatively similar pharmacological activity but have different quantitative potencies. O O O H O ( s ) - (- ) w arf ar i n O O H O O (R)-(+)warfarin

39. Geometric Isomerism Geometric isomerism is represented by cis / trans isomerism resulting from restricted rotation due to carbon-carbon double bond or in rigid ring system. OH HO OH HO t r a n s - d i e t h y l s t i b es t e r ol Estrogenic activity E - isomer c i s - d i e t h y l s t i b es t e r ol Only 7% activity of the trans isomer Z-isomer

40. Geometric isomers have different physical and chemical properties . so receptor binding is in structurally specific manner.

41. I. L a ngmuir introduced the term isosterism in 1919 . Isosteres are the compounds or group of atoms having the same number and arrangement of electrons. Same total charge- same no of electrons – same physical properties N₂ = CO = 14 electrons Isosteres should be isoelectric i.e. they should possess same total charge. ISOSTERISM Example Carboxylate and sulphonamido (SO₂NR) Chloro and trifluoromethyl (- CF₃) Amine and methylene (-CH₂-)

42. Bioisosterism is defined as compounds or groups that possess near or equal molecular shapes and volumes, approximately the same distribution of electron and which exhibit similar physical properties. They are classified into two types . i ) Classical biososteres or essential ii ) Non classical bioisosters or non essential BIOISOSTERISM

43. Classical Bioisosteres They have similarities of shape and electronic configuration of atoms, groups and molecules which they replace. The classical bioisosteres may be, Univalent atoms and groups Cl, Br, I ii ) CH ₂ , NH ₂ , -OH, -SH Bivalent atoms and groups R-O-R,R-NH-R, R-S-R, RCH 2 R –CONHR, -COOR, -COSR

44. Trivalent atoms and groups i)-CH=, -N= ii) –p=, -AS= Tetravalent atoms and groups =c=, =N=, =P= Ring equivalent -CH=CH-, -S-, -O-, -NH, -CH 2 -

45. Application of Classical Bioisosteres in in drug design i ) Replacement of – NH ₂ group by – CH ₃ group. Car b u t am i d e Tolbutamide R= NH2 R= CH3 ii ) Replacement of –OH & -SH Guanine= -OH 6-Thioguanine = -SH R SO 2 NH CONH(CH 2 ) 3 CH 3 N H N N H 2 N H N x

46. Non classical Bioisosteres They do not obey the stearic and electronic definition of classical isosteres. Non-classical biosteres are functional groups with dissimilar valence electron configuration. Specific characteristics: Electronic properties Physicochemical property of molecule Spatical arrangement Functional moiety for biological activity

47. Examples Ether -S-, -O- Carbonyl group Hydroxyl group – OH , CH ₂ OH Halogens Cl , F, Br, CN Catechol HO HO Catechol O S O O

48. A classical e.g. of ring Vs. noncycclic structure is Diethylstilbosterol & 17-ß oestradiol. O H H H H HO 17-ß oestradiol. OH H O trans -diethylstibesterol

49. THANKY OU