Lecture 8 - Absorption of molecules 1 PDF

Absorption of molecules 1 – Part 1 Normal Function of the GI Tract Dr David Breen Learning outcomes (what you need to know) Define solubility Describe the factors that affect drug solubility Define LogP Explain the importance of LogP in terms of drug absorption Describe the pharmaceut...

Absorption of molecules 1 – Part 1 Normal Function of the GI Tract Dr David Breen Learning outcomes (what you need to know) Define solubility Describe the factors that affect drug solubility Define LogP Explain the importance of LogP in terms of drug absorption Describe the pharmaceutical implications of polymorphism Previously: Steps in drug absorption Dissolution – drug in solution - absorption Drug can be absorbed and enter the blood stream Key Factors in dissolution dm CS  C DA dt h Drug Solubility Solubility of a substance: the amount that goes into a solution when equilibrium is established between the solute in solution and the excess (undissolved) substance. The solution process Can be considered in 3 stages: 1. A drug molecule is ‘removed’ from its crystal + 2. A cavity from the molecule is created in the solvent 3. The drug molecule inserts into this cavity  Solubility & saturation When a solution contains a drug at the limit of its solubility at any given temperature and pressure it is described as saturated. If the solubility limit is exceeded, solid particles of solute may be present.  Remember The rate something dissolves (the dissolution rate) and the amount that can be dissolved (the solubility) are not the same. Factors influencing solubility Factors that affect solubility of drugs in solution 1. Temperature 2. Molecular structure of the drug a) Its shape and surface area b) Its hydrophobicity and degree of ionisation (and the influence of pH) 3. Nature of the solvent a) Including pH & cosolvents, solubilising agents.  Temperature The solubility of a drug typically depends on temperature For many solids dissolved in water, the solubility increases with temp up to 100oC. You tube (for homework): https:// www.youtube.com/watch?v=VTOmQ9jEf Ak The boiling point and melting point These both reflect the strengths of interactions between the molecules (step 1 and step 2) In general Aqueous solubility decreases with increasing boiling and melting points. Surface Area of the drug molecule: the surface area of the drug molecule affects solubility because placing the solute molecule in the solvent cavity requires a number of solute-solvent contacts. Substituents/drug polarity/structure Polar groups such as –OH capable of hydrogen bonding with water molecules give higher solubility Non-polar groups such as –CH3, -Cl are hydrophobic and impart low solubility Ionisation increases solubility – e.g. COOH and NH2 are slightly hydrophobic – COO- and NH3+ are very hydrophilic. Solute-Solvent interactions Functional groups can be classified as relatively hydrophilic or hydrophobic: hydrophobic -CH3 -CH2- -Cl/-Br/-I -SCH3 slightly hydrophilic -OCH3 -OCH2CH2- hydrophilic -CHO -COOH -NH2 -OH -NO2 - + very hydrophilic -COO -NH3 Note: The addition of hydrophilic elements does not necessarily make it hydrophilic e.g. –OCH3 - Consider surface area Ionisation causes increased hydrophilicity  Question time 1 Which of the following molecular characteristics will be expected to decrease the solubility of a drug in an aqueous solution. A. A high melting point B. The presence of an ionised group C. A low molecular surface area D. The presence of a polar group E. A low boiling point.  Learning outcomes Discussed formation of a solution as a three step process. Dissolution is the rate limiting step of absorbtion and drug solubility is a key factor. Started to consider the factors affecting solubility at the molecular level. Absorption of molecules 1 – Part 2 Normal Function of the GI Tract Dr. David Breen Learning outcomes (what you need to know) Define solubility Describe the factors that affect drug solubility Define LogP Explain the importance of LogP in terms of drug absorption Describe the pharmaceutical implications of polymorphism The solvent  Molecular properties – Solvent Consider the solubility of citric acid… Citric acid in water Citric acid in hexane Key properties: 1) Polarity; 2) Surface area  Solute-Solvent interactions key properties of the solute surface: Polarity Many drug molecules contain both: Polar, hydrophilic functional groups favour solubility in polar solvents e.g. -O-H, -NH2, -COOH Non-polar, hydrophobic groups favour solubility in non-polar solvents, not water. e.g. -CH2CH2CH2-, or -C6H5 e.g. omeprazole Partitioning of drugs between immiscible solvents Due to difference in the solubility in different phases, drugs will partition between solvents. What do we mean by this? – Drugs going between aqueous and lipid phases (e.g. across cell walls) – Antibiotics partitioning into micro-organisms – Drugs partitioning into plastics Molecular properties – Log P Log P – partition coefficient measure of lipophilicity/hydrophilicity - Unionised Drugs needs to cross lipid membranes Can we put a number to this?? Molecular properties – Log P [𝐶𝑜] 𝑃= Partition Coefficient: [𝐶𝑤] [𝐶𝑜 ] 𝐿𝑜𝑔 𝑃 =𝐿𝑜𝑔 Oil [𝐶𝑤 ] Log P > 0; lipophilic Water Log P < 0; hydrophilic  Molecular properties – Log P Aliphati Aromati Aliphati Aromati c c c c -F -0.38 0.37 C 4H 4S 1.8 1.8 CH3 -Cl 0.06 0.94 -H 0.23 0.23 -Br 0.20 1.09 -NH- -2.15 -1.03 O -I 0.59 1.35 -OH -1.64 -0.44 -NO2 -1.16 -0.03 -NH2 -1.54 -1.00 Log P = 1.7 -O- -1.82 -0.61 -SH -0.23 0.62 -S- -0.79 0.03 -CONH- -2.71 -1.81 Therefore:P = 101.7 -CH3 0.89 0.89 -COOH -1.11 -0.03 P = 50.2 -CH2- 0.66 0.66 -CONH2 -2.18 -1.26 50.2 -CH< 0.43 0.43 -CN -1.27 -0.34 P= 1 >C< 0.20 0.20 -CO -1.90 -1.09 C 6H 5 1.90 1.90 -CO2- -1.49 -0.56 Lipophilic C 6H 4 1.67 1.67 -N- -1.51 -0.75 More examples in Florence and Attwood 4th Ed., Ch 5, Table 5.18  Question time 2 Indicate which of the following statements are correct A. The partition coefficient P is usually defined as the ratio of solubility in the aqueous phase to that in the non-aqueous phase B. The lower the value of log P, the higher the lipid solubility of the drug C. Ionised solutes will readily partition into the non- aqueous phase D. Log P > 0 means the drug is lipophilic  Learning outcomes Reinforced the concept of complementarity of solute and solvent interaction. We have introduced the concept of log P, its importance to absorption and how we can calculate and predict it for a wide range of molecules. Log P is a good predictor of membrane permeability. Absorption of molecules 1 – Part 3 Normal Function of the GI Tract Dr. David Breen Learning outcomes (what you need to know) Define solubility Describe the factors that affect drug solubility Define LogP Explain the importance of LogP in terms of drug absorption Describe the pharmaceutical implications of polymorphism The solid state of the drug particle Crystal structure and form Crystals contain highly ordered arras of molecules and atoms held together by non- covalent interactions. The crystals of a give substance may vary in size, number of and kind of faces Homework: Florence and Attwood, Physicochemical principles of pharmacy, 4th edition pages 8 to 22. 1.What types Ionic solids e.g. of solid are there? i. aluminium hydroxide Al(OH)3, ii. magnesium carbonate (MgCO3), iii. magnesium trisilicate Mg2(Si3O8) 2. Molecular solids e.g. omeprazole 3. Molecular salts e.g loperamide hydrogen bond hydrochloride Polymorphism Compounds can crystallise out of solution in a variety of different habits depending on the conditions of crystallisation. These crystal habits usually have the same internal structure. However compounds can also crystallise with different internal structures  Polymorphism Polymorphism: molecules arrange themselves in different ways in the crystal These different polymorphs are normally referred to a Forms.  Polymorphism The ability of a compound to adopt more than one three dimensional structure Let’s look at Lego…. See Florence and Attwood, Ch1.; Aulton, Ch. 8  Polymorphism The ability of a compound to adopt more than one three dimensional structure Let’s look at Lego…. Unit Cell – smallest repeating unit  Polymorphism - Properties Solubility Bioavailability higher Cs C faster slower lower Cs t Compaction properties, Not all solids are have order…. melting points, colour!!... ?? Crystalli Amorpho The good, the bad and the ugly The Good Polymorphs/amorphous forms Alter the physical properties The Bad Beware the hydrate/solvate (Florence and Attwood Ch 1.) Solubility of pure: Caffeine 22.9 g/dm3; Theophylline 10.5 g/dm3 Solubility of hydrate : Caffeine 22.8 g/dm3; Theophylline 5.6 g/dm3 The Ugly Ritonavir manufacturing and batch release problems with the capsule formulation caused by unexpected appearance of a new ritonavir  Summary Define solubility List the factors that affect drug solubility Define LogP  Summary cont. Explain the importance of LogP in terms of drug absorption Describe the pharmaceutical implications of polymorphism