Lectures 18 Physicochemical properties of Drug molecules-3 Salt Formation and Solubility For Class PDF
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Summary
This document provides lectures on medicinal chemistry, focusing on drug properties and behaviors, including functional groups, electronic effects, steric effects, acidity/basicity, chirality, and solubility in water or lipids. It explains the impact of these properties on a drug's administration, distribution, metabolism, and elimination. Various examples and diagrams are included.
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Medicinal Chemistry Drug Physicochemical Properties of Drugs - 1 Functional Group (FG) 1. Electronic Effects, 2. Steric Effects, 3. Acidity and Basicity of FG Physicochemical Properties of Drugs- 2, 3 4. Chirality...
Medicinal Chemistry Drug Physicochemical Properties of Drugs - 1 Functional Group (FG) 1. Electronic Effects, 2. Steric Effects, 3. Acidity and Basicity of FG Physicochemical Properties of Drugs- 2, 3 4. Chirality 5. Salt and Solubility Learning Objectives Identify water-soluble inorganic salts as well as water- soluble and lipid-soluble organic salts. Explain the therapeutic advantages that can be achieved by using water-soluble salts and lipid-soluble salts. Physicochemical properties of Drug molecules -1 Chemical Properties of Functional FG Groups FG is a part of a compound/drug which provides specific properties and behaviors that allow a compound/drug to produce biological response. Chemical Properties of FGs: (1) Electronic Effects: Resonance and Inductive Effect (2) Steric Effects (3) Acid-base Properties (4) Chirality (5) Solubility Effects: Water and Lipid Solubility, Salt Formation Lecture # 18 Chemical Properties of FGs 6. Solubility effects 5. Solubility Effects: The overall water and/or lipid solubility of a drug molecule affects its route(s) of administration, distribution within the body, metabolism, duration of action, and route(s) of elimination. This overall solubility is a composite sum of the contributions of each functional group present within the drug structure. Identify those functional groups that confer Water Solubility and those that confer Lipid Solubility. Chemical Properties of FGs Hydrogen Bond Acceptors 6. Solubility effects O O R1 R2 O F R1 R2 R1 O R1 R2 N R1 Ketone Ester Ether Heterocyclic nitrogens Fluorine Hydrogen Bond Donors (Pyridine ring shown) S R1 R1 H N H Thiol Heterocyclic nitrogens (Pyrrole ring shown) Hydrogen Bond Acceptors and Donors R1 O R2 O R2 R1 H H R1 N N O R1 H H Hydroxyl Phenol Amide Primary and secondary unionized amines O O O R1 R2 R1 R2 R1 OH O N N N Unionized H H H carboxylic acid Carbamate Urea Lipid Soluble Functional Groups Chemical Properties of FGs 6. Solubility effects FGs that lack the ability to either ionize or form hydrogen bonds tend to impart a measure of lipid solubility to a drug molecule. Common lipid soluble functional groups are shown below. R R C H3 R R F R C H3 R Cl R R C H3 R Br R n R I Aromatic rings Alkyl chains Alicylic rings Halogens and ring systems (Aliphatic chains) (Cyclopentyl and Cyclohexyl shown) R C H2 R C CH O R2 R1 O R2 C H3 R C C C H3 R1 O R Ester Ether Alkenes Alkynes What is a salt? A salt is an ionic compound that is produced when an acid reacts with a base. Salts consist of a positively charged cation and a negatively charged anion, and are electronically neutral. e.g. Sodium chloride. NaOH + HCl Na+ Cl- + H2O The product obtained from the following acid-base reaction: NH2 O NH3 Cl CH2 O CH2 one equivalent of HCl HO C N HO C N O O Acid & Base Chemistry: Salt Formation CH3 CH3.. N.. N N COOCH3 N COOCH3.. CH3 H.. CH3 H N N CH3 O CH3 O Imipramine (Tofranil) H Imipramine (Tofranil) H Cocaine O Cocaine O H+ H+ H CH3 H CH3.. N.. N N N COOCH3 COOCH3 H H CH3 H CH3 H N N CH3 O CH3 O H H O O Acid & Base Chemistry: Salt Formation CN CN N O N O H3 C S H3 C S NH H N N NH H N N S CH S CH H H H H N CH3 3 N CH3 H 3 H N CH3 N CH3 N O N O H Cimetidine H COOH Cimetidine H H COOH Penicillin G Penicillin G (Tagamet) (Tagamet) H+ Na+ OH- CN CN N O N O H3C S H3C N N S NH H N N NH H S H H CH3 CH3 S CH H N H H H N CH3 3 pKa ~ -1 N O N CH3 H H H COO Na pKa ~ -1 N CH3 NH O H H COO Na Acid & Base Chemistry: Salt Formation H O N O O N O HN H + HN O O Phenobarbital (Phenob) O N O HN O Different functional groups that behave as acids or bases A compound may contain multiple functional groups and therefore possess both acid and base properties depending upon the pH of the solution (or tissue). The molecule can be a base, acid, or amphoteric. Example: Because of the presence of three very polar functional groups (two of them being ionizable), one would expect tyrosine to be very soluble in water, yet its solubility is only 0.45 g/1,000 mL. The basic alkylamine (pKa 9.1 for the conjugate acid) and the carboxylic acid (pKa 2.2) are both ionized at physiologic pH, and a zwitterionic molecule results. These two charged groups are sufficiently close that a strong ion–ion interaction occurs, thereby keeping each group from participating in ion–dipole interactions with surrounding water molecules. Take Home Work A. From the following list, provide the best name of each functional group circled. B. Next to the name, write whether the functional group is acidic, neutral, or basic. Aliphatic amine, Nitro, Alcohol, Imide, Aldehyde, Amide, Cyano, Carboxylate ion, Phenolic alcohol, Aromatic amine, Carboxylic acid, Carbonyl, Ammonium ion, Ketone, Guanidine, Sulfonamide, Ester. From the following list, provide the best name of each functional group circled.. Next to the name, write whether the functional group is acidic, neutral, or basic. Aliphatic amine, Nitro, Alcohol, Imide, Aldehyde, Amide, Cyano, Carboxylate ion, Phenolic alcohol, Aromatic amine, Carboxylic acid, Carbonyl, Ammonium ion, Ketone, Guanidine, Sulfonamide, Ester. From the following list, provide the best name of each functional group circled.. Next to the name, write whether the functional group is acidic, neutral, or basic. Aliphatic amine, Nitro, Alcohol, Imide, Aldehyde, Amide, Cyano, Carboxylate ion, Phenolic alcohol, Aromatic amine, Carboxylic acid, Carbonyl, Ammonium ion, Ketone, Guanidine, Sulfonamide, Ester. From the following list, provide the best name of each functional group circled.. Next to the name, write whether the functional group is acidic, neutral, or basic. Aliphatic amine, Nitro, Alcohol, Imide, Aldehyde, Amide, Cyano, Carboxylate ion, Phenolic alcohol, Aromatic amine, Carboxylic acid, Carbonyl, Ammonium ion, Ketone, Guanidine, Sulfonamide, Ester Draw the structure of the products obtained from the following acid-base reactions. If they do not react write “No Reaction” or “NR”. Draw the structure of the products obtained from the following acid-base reactions. If they do not react write “No Reaction” or “NR”. Does salt form of a drug affect water solubility? Yes The solubility of a drug molecule in water greatly affects the routes of administration that are available, as well as its absorption, distribution, and elimination. Two key concepts to keep in mind for water solubility: – hydrogen bond formation – ionization of one or more functional groups within the molecule. Pharmacist Alert Water solubility of different salt forms of selective drugs Vistaril is better Atarax is for better for treating treating anxiety itching or difficulty sleeping Procaine is a local anesthetic to ease the pain of IM injection in penicillin. Low molecular weight (MWt) salts are water soluble and high MWt salts are water insoluble. Predicting Water Solubility: The Empirical Approach Water-solubilizing Potential of Organic Functional Groups in a Mono- or Polyfunctional Molecule If the solubilizing potential of the functional groups exceeds the total number of carbon atoms present, then the molecule is considered to be water soluble. H Amine hydrochloride 20-30 carbon atoms + Total 22 carbon 3x3=9 carbon from Anileridine hydrochloride FG (poly)..see Table HCl salt of Anileridine: alkylammonium Water insoluble contributes (20-30 carbon atoms). (26-36). (1g/10L) 0.2 g/mL (water soluble) Aspirin: 1 Carboxylic acid 3 carbons 1 Ester 3 carbons Total 6 carbons Insoluble (solubilizing potential less than carbon content, C9H8O4) Chlordiazepoxide: 1 Arylamidine ~3 carbons* 1 20 amine 3 carbons 1 N oxide ~2 carbons Total ~8 carbons Insoluble (solubilizing potential less than carbon content (C16H14ClN3O). *Estimate by counting number of potential hydrogen bonds with water for each group. Codeine phosphate: 1 30 amine salt 20-30 carbons 1 20 alcohol 3-4 carbons 2 Ethers 4 carbons Total 27-38 carbons Soluble (solubilizing potential is more than carbon content (C18H21NO3. H3PO4). Codeine 1 30 amine 3 carbons 1 20 alcohol 3-4 carbons 2 Ethers 4 carbons Total 10-11 carbons Insoluble (solubilizing potential is less than carbon content (C18H21NO3). Partition Coefficient (Experimental Approach) A reasonable model for passive transport to the site of action would be the ability to partition between a lipid membrane and water, expresses as P (or log P). 1-Octanol/Water The model would be solubility of the compound in 1-octanol, which simulates a lipid membrane, relative to that in water (the model for the cytoplasm). 1-Octanol has a long saturated alkyl chain and a hydroxyl group for hydrogen bonding. This combination of lipophilic chains, hydrophilic groups, and water molecule gives 1-octanol properties very close to those of natural membranes. Key Points Be able to analyze drug structure to find the number of chiral carbons and absolute configuration. Be able to analyze the structure of the drug for predicting salt formation and water solubility by calculating empirical Log P. Medicinal Chemistry Drug Physicochemical Properties of Drugs - 1 Functional Group (FG) 1. Electronic Effects, 2. Steric Effects, 3. Acidity and Basicity of FG Physicochemical Properties of Drugs- 2, 3 4. Chirality 5. Salt and Solubility