Physical-Chemical & Formulation Properties PDF

PHYSICAL-CHEMICAL & FORMULATION PROPERTIES Prof. Dr. Fatima A. Tawfiq 1 Physical-Chemical Factors Affecting Oral Absorption ❑ pH-partition theory ❑ Lipid solubility of drugs ❑ Dissolution ❑ Drug stability and hydrolysis in GIT ❑ Complexation ❑ Adsorption...

PHYSICAL-CHEMICAL & FORMULATION PROPERTIES Prof. Dr. Fatima A. Tawfiq 1 Physical-Chemical Factors Affecting Oral Absorption ❑ pH-partition theory ❑ Lipid solubility of drugs ❑ Dissolution ❑ Drug stability and hydrolysis in GIT ❑ Complexation ❑ Adsorption 2 1- pH-partition theory ❑ According to the pH-partition hypothesis, the gastrointestinal epithelia acts as a lipid barrier towards drugs which are absorbed by passive diffusion, and those that are lipid soluble will pass across the barrier. ❑ As most drugs are weak electrolytes, the unionized form of weakly acidic or basic drugs (the lipid-soluble form) will pass across the gastrointestinal epithelia, whereas the gastrointestinal epithelia is impermeable to the ionized (poorly-lipid soluble) form of such drugs. ❑ Consequently, the absorption of a weak electrolyte will be determined by the extent to which the drug exists in its unionized form at the site of absorption 3 Gastrointestinal tract Lipoprotein Plasma membrane Unionized drug Unionized drug Ionized drug Ionized drug Removed in bloodstream 4  The extent to which a weakly acidic or basic drug ionizes in solution in the gastrointestinal fluid may be calculated using Henderson - Hasselbach equation. For a weakly acidic drug having a single ionizable group (e.g. aspirin, phenylbutazone, salicylic acid) the equation takes the form of: pH = pKa + log [ ionized] / [unionized ] For a weakly basic drug possessing a single ionizable group (e.g. chlorpromazine) the analogous equation is: pH = pKa + log [unionized] / [ionized ] 5  According to these equations a weakly acidic drug, pKa 3.0, will be predominantly unionized in gastric fluid at pH 1.2 (98.4%) and almost totally ionized in intestinal fluid at pH 6.8 (99.98%), whereas a weakly basic drug, pKa 5, will be almost entirely ionized (99.98%) at gastric pH of 1.2 and predominantly unionized at intestinal pH of 6.8 (98.4%) This means that, according to the pH-partition hypothesis, a weakly acidic drug is more likely to be absorbed from the stomach where it is unionized, and a weakly basic drug from the intestine where it is predominantly unionized. However, in practice, other factors need to be taken into consideration 6 Limitations of the pH-partition hypothesis: Despite their high degree of ionization, weak acids are highly absorbed from the small intestine and this may be due to: – The large surface area that is available for absorption in the small intestine. – A longer small intestine residence time. The pH-partition hypothesis cannot explain the fact that certain drugs (e.g. quaternary ammonium compounds and tetracyclines) are readily absorbed despite being ionized over the entire pH range of the gastrointestinal tract 7 2- Lipid solubility of drugs: The lipophilicity of a drug is critical in the drug discovery process Some drugs are poorly absorbed after oral administration even though they are non- ionized in small intestine. Low lipid solubility of them may be the reason. Polar molecules, i.e. those that are poorly lipid soluble (log P < 0) and relatively large, such as gentamicin, ceftriaxone, heparin and streptokinase, are poorly absorbed after oral administration and therefore have to be given by injection The best parameter to correlate between water and lipid solubility is partition coefficient. Partition coefficient (p) = [ L] conc / [W] conc where, [L] conc is the concentration of the drug in lipid phase. [W] conc is the concentration of the drug in aqueous phase. The higher p value, the more absorption is observed. 8 3-Drug Dissolution Many drugs are given in solid dosage forms and therefore must dissolve before absorption can take place. Disintegration Dissolution Absorption Drug in the blood and the body Steps : (1) Disintegration (2) Dissolution (3) Absorption In the process of drug disintegration, dissolution, and absorption, the rate at which drug reaches the circulatory system is determined by the slowest step in the sequence. The slowest step in a series of kinetic processes is called the rate-limiting step. 9 10  Various models/theories which explain dissolution – 1.Diffusion layer model/Film theory – 2.Dankwert’s Model (Penetration or Surface renewal theory) – 3.Interfacial barrier model (Double Barrier Mechanism OR Limited Solvation Theory) Types of Models of Mechanism of Drug Release – Zero order – First order – Higuchi model – Korsemeyer Peppas Model – Hixon Crowel plot 11 Official dissolution Apparatus According to BP – 1.Basket apparatus – 2.Paddle apparatus – 3.Flow Through Cell Apparatus According to USP – 1.Basket apparatus/Rotating basket – 2.Paddle apparatus – 3.Reciprocating Cylinder – 4.Flow through cell apparatus – 5.Paddle over disk apparatus – 6.Cylinder apparatus – 7.Reciprocating holder apparatus 12 Apparatusa Name Drug Product Apparatus 1 Rotating basket Tablets Apparatus 2 Paddle Tablets, capsules, modified drug products, suspensions Apparatus 3 Reciprocating cylinder Extended-release drug products Apparatus 4 Flow cell Drug products containing low-water-soluble drugs Apparatus 5 Paddle over disk Transdermal drug products Apparatus 6 Cylinder Transdermal drug products Apparatus 7 Reciprocating disk Transdermal drug products Rotating bottle (Non-USP-NF) Extended-release drug products (beads) Diffusion cell (Franz) (Non-USP-NF) Ointments, creams, transdermal drug products Apparatus 1–7 refer to compendial dissolution apparatus in USP-NF (United States Pharmacopeia) 13 Rotating basket (Apparatus 1) 14 Rotating Paddle (Apparatus 2) 15 Reciprocating cylinder (Apparatus 3) 16 Flow cell (Apparatus 4) 17 Paddle over disk (Apparatus 5) 18 Cylinder (Apparatus 6) 19 Reciprocating Disk Method (Apparatus 7) 20 − Drug dissolution is considered to be diffusion controlled process through a stagnant layer surrounding each solid particle − The dissolution of drugs can be described by the Noyes-Whitney equation: Where D is the diffusion coefficient, A the surface area, Cs the solubility of the drug, Cb the concentration of drug in the bulk solution, and h the thickness of the stagnant layer. If Cb is much smaller than Cs then we have so-called "Sink Conditions" and the equation reduces to 21  Factors affecting drug dissolution in the GIT: I. Physiological factors affecting the dissolution rate of drugs: − The environmentof the GITcan afect the parametersof the Noyes-Whitneyequationand hencethe dissolutionrateofadrug. A- Diffusion coefficient, D: – Presence of food in the GIT increase the viscosity of the gastrointestinal fluids reducing the rate of diffusion of the drug molecules away from the diffusion layer surrounding each undissolved drug particles (↓D) decrease in dissolution rate of a drug. B- Drug surface area, A: – Surfactants ingastric juice and bile salts increase the wettability of the drug increase the drug solubility via micellization. 22  C. The thickness of diffusion layer, h: – An increase in gastric and/or intestinal motility decrease the thickness of diffusion layer around each drug particle increase the dissolution rate of a drug D. The concentration, C, of drug in solution in the bulk of the gastrointestinal fluids: – Increasing the rate of removal of dissolved drug by absorption through the gastrointestinal-blood barrier and increasing the intake of fluid in the diet will decrease in C rapid dissolution of the drug. 23 II Physicochemical factors affecting the dissolution rate of drugs: A- Surface area, A: The smaller the particle size the greater the effective surface area of drug particle the higher the dissolution rate. Methods of particle size reduction include: mortar and pestle, mechanical grinders, mills, solid dispersions in readily soluble materials (PEG's). However very small particles can clump together. Therefore a wetting agent such as Tween 80 can have a beneficial effect on the overall absorption. 24  B-Diffusion coefficient, D The value of D depends on the size of the molecule and the viscosity of the dissolution medium. C- Solubility in the diffusion layer, Cs: The dissolution rate of a drug is directly proportional to its intrinsic solubility in the diffusion layer surrounding each dissolving drug particle. D- Salts: Salts of weak acids and weak bases generally have much higher aqueous solubility than the free acid or base. 25  The pH of the diffusion layer would be increased if the chemical nature of the weakly acidic drug was changed from that of the free acid to a basic salt (the sodium or potassium form of the free acid. The pH of the diffusion layer would be higher (5-6) than the low bulk pH (1-3.5) of the gastric fluids because of the neutralizing action of the strong (Na+, K+ ) ions present in the diffusion layer. The drug particles will dissolve at a faster rate and diffuse out of the diffusion layer into the bulk of the gastric fluid, where a lower bulk pH. Thus the free acid form of the drug in solution, will precipitate out , leaving a saturated solution of free acid in gastric fluid. 26  Dissolution process of a salt form of a weakly acidic drug in gastric fluid. 27  E- Crystal form Polymorphism: – Some drugs exist in a number of crystal forms or polymorphs. These different forms may have different solubility properties and thus different dissolution characteristics. – Chloramphenicol palmitate is one example which exists in three crystalline forms A, B and C. A is the stable polymorph B is the metastable polymorph (more soluble) C is the unstable polymorph 28  Amorphous solid: – The amorphous form dissolves more rapidly than the corresponding crystalline form. – the possibility exists that there will be significant differences in the bioavailabilities exhibited by the amorphous and crystalline forms of drugs that show dissolution rate limited bioavailability 29  Solvates – Solvates: If the drug is able to associate with solvent molecules to produce crystalline forms known as solvates. – Hydrates: drug associates with water molecules (i.e When water is the solvent, the solvate formed is called a hydrate) – The greater the solvation of the crystal, the lower are the solubility and dissolution rate in a solvent identical to the solvation molecules. – As the solvated and nonsolvated forms usually exhibit differences in dissolution rates, they may also exhibit differences in bioavailability 30 4- Drug stability and hydrolysis in GIT: Drugs that are susceptible to acidic or enzymatic hydrolysis in the GIT, suffer from reduced bioavailability. The aqueous solubility of weak electrolytes is dependent on pH Hence in the case of an orally administered solid dosage form containing a weak electrolyte drug, the dissolution rate of the drug will be influenced by its solubility and the pH in the diffusion layer surrounding each dissolving drug particle differences in dissolution rate will be expected in different regions of the gastrointestinal tract 31  How to protect drugs (erythromycin) from degradation in gastric fluid ?? – Preparing enteric coated tablets containing the free base of erythromycin. The enteric coating resists gastric fluid but disrupts or dissolves at the less acid pH range of the small intestine. – The administration of chemical derivatives of the parent drug. These prodrugs (erythromycin stearate) exhibit limited solubility in gastric fluid, but liberate the drug in the small intestine to be absorbed. 32 5- Complexation: Complexation of a drug may occur within the dosage form and/or in the gastrointestinal fluids, and can be beneficial or detrimental to absorption. Complexation may occur between the drug and: 1. Component of gastrointestinal fluids 2. Dietary components 3. Excipients within the dosage forms – Intestinal mucosa (mucin) + Streptomycin = poorly absorbed complex – Calcium + Tetracycline = poorly absorbed complex (Food-drug interaction) – Carboxyl methylcellulose (CMC) + Amphetamine = poorly absorbed complex (tablet additive – drug interaction) – Lipid soluble drug + water soluble complexing agent = well-absorbed water soluble complex ( cyclodextrin) 33 6-Adsorption Certain insoluble substances may adsorbed co- administrated drugs leading to poor absorption. Decrease in the effective concentration of the drug in solution available for absorption – Charcoal (antidote in drug intoxication). – Kaolin (antidiarrheal mixtures) 34 Formulation Factors Affecting Oral Absorption The role of the drug formulation in the delivery of drug to the site of action is important drugs must be in solution in the gastrointestinal fluids before absorption can occur, the bioavailability of a given drug tends to decrease in the following order of types of dosage form: aqueous solutions > aqueous suspensions> solid dosage forms Excipients are added to a formulation to provide certain functional properties to the drug and dosage form. Some of these functional properties of the excipients are used to improve the compressibility of the active drug, stabilize the drug against degradation, decrease gastric irritation, control the rate of drug absorption from the absorption site, increase drug bioavailability, etc. 35 36  Solution dosage forms – In most cases absorption from an oral solution is rapid and complete, compared with administration in any other oral dosage form. Suspension dosage forms – A well formulated suspension is second to a solution in terms of superior bioavailability – A suspension of a finely divided powder will maximize the potential for rapid dissolution. – A good correlation can be seen for particle size and absorption rate. – The addition of a surface active agent will improve the absorption of very fine particle size suspensions. 37  Capsule dosage forms – The hard gelatin shell should disrupt rapidly and allow the contents to be mixed with the G-I tract contents. – If a drug is hydrophobic a dispersing agent should be added to the capsule formulation. These diluents will work to disperse the powder, minimize aggregation and maximize the surface area of the powder. – Tightly packed capsules may have reduced dissolution and bioavailability. Tablet dosage forms – The tablet is the most commonly used oral dosage form – It is also quite complex in nature Drug : may be poorly soluble, hydrophobic Lubricant : usually quite hydrophobic Granulating agent : tends to stick the ingredients together Filler: may interact with the drug,etc.,should be water soluble Wetting agent : helps the penetration of water into the tablet Disintegration agent: helps to break the tablet apart 38 Biopharmaceutical Classification System (BCS) Class I High soluble and High Permeable Class II Low soluble and High permeable Class III High soluble and Low permeable Class IV Low soluble Low permeable 39  permeability dissolution solubility solubility, dissolution and permeability are the 3 major factors controlling the oral absorption of drug substances from oral medicinal products 40