Physicochemical factors influencing Drug Absorption PDF

Physicochemical factors influencing bioavailability Prof. Mohammad Issa Saleh 1 Overview of rate limiting step in drug absorption 2 Rate-limiting steps in oral drug absorption For drugs orally dosed in solid...

Physicochemical factors influencing bioavailability Prof. Mohammad Issa Saleh 1 Overview of rate limiting step in drug absorption 2 Rate-limiting steps in oral drug absorption For drugs orally dosed in solid dosage forms such as tablets or capsules, there are two distinctive processes during absorption: dissolution of solid drug particles to drug molecules in the GI fluid and permeation of the drug molecules across intestinal membranes Depending on the relative magnitude of the rates of these two processes, one of them can be rate-limiting in overall drug absorption 3 Dissolution Rate-Limited Absorption For oral absorption, a drug must be in aqueous solution, except in cases of pinocytosis or lymphatic absorption Solid dosage forms like tablets must disintegrate into small particles before dissolution Disintegration generally occurs faster than dissolution For highly lipophilic drugs, the absorption rate is primarily governed by the dissolution rate Permeation Disintegration Dissolution (slowest step) Tablets 4 Membrane Permeation Rate-Limited Absorption If the dissolution process is very rapid, the absorption rate of a drug could be dependent primarily on its ability to transport across the intestinal membrane For highly water-soluble compounds, the membrane permeation can become critical in overall absorption owing to their limited ability to partition into the lipid bilayers of the enterocyte membranes Permeation (Slowest step) Disintegration Dissolution Tablets 5 Drug Dissolution 6 Drug Dissolution Dissolution rate equation Physiological factors affecting the dissolution rate Drug factors affecting dissolution rate Surface area and particle size Wetting agents / wettability Solubility in the diffusion layer Crystal form Solvate/Hydrate Degree of Ionization 7 Dissolution rate equation 8 Dissolution rate equation Orally administered solid drugs need to dissolve before 𝑑𝑚ൗ = 𝐷𝐴(𝐶𝑆 − 𝐶) absorption. 𝑑𝑡 ℎ The dissolution rate can be Where: 𝑑𝑚Τ = rate of dissolution described by the Noyes-Whitney 𝑑𝑡 equation, which accounts for D = Diffusion coefficient the rate of diffusion of a solute A = effective surface area of through the boundary layers the drug particles surrounding a dissolving h = thickness of the diffusion spherical particle layer Cs = saturation solubility of the drug C = drug concentration in GI fluids 9 Physiological factors affecting the dissolution The diffusion coefficient (D) of a drug in gastrointestinal fluids can be decreased by substances that increase fluid viscosity, such as food, which can reduce the drug's dissolution rate Surfactants in gastric juice and bile salts affect drug wettability and its effective surface area (A), enhancing solubility through micellization (Cs) The thickness of the diffusion layer (h) is influenced by the agitation experienced by drug particles; increased gastric or intestinal motility can reduce this thickness, thus increasing the dissolution rate of sparingly soluble drugs 10 Physiological factors affecting the dissolution The concentration of the drug in gastrointestinal fluids (C) is influenced by the absorption rate and the volume of available fluid, which depend on the drug's location in the GI tract and the timing of food and fluid intake. The stomach fluid volume is directly affected by fluid intake. 11 Drug factors affecting dissolution rate 12 Drug factors affecting dissolution rate Drug factors that can influence the dissolution rate are the particle size, the wettability, the solubility and the form of the drug (including polymorphs, solvates and whether the drug is a salt or a free form) 13 Surface area and particle size According to the Noyes-Whitney equation, increasing the total surface area of the drug in contact with gastrointestinal fluids increases the dissolution rate If each drug particle is properly wetted by the GI fluids, the effective surface area is inversely related to particle size Therefore, smaller particles provide a greater surface area and dissolve faster Reducing particle size can enhance bioavailability when the absorption of the drug is dissolution-rate limited. 14 Surface area and particle size A classic example of particle size effects on the bioavailability of poorly soluble compounds is griseofulvin. Reducing its mean particle size from about 10 mm to 2.7 mm nearly doubled the drug absorption in humans. Around 50 smaller spheres with a diameter of 2.7 mm can be made from one larger sphere with a diameter of 10 mm (Chatgpt calculations) The size reduction is associated with 365% increase in the total surface area Consequently, many poorly water- soluble, slowly dissolving drugs are routinely micronized to increase their surface area. 15 Controlling particle size The following are examples of drugs where reducing particle size increases oral absorption and bioavailability This can lead to plasma concentrations above the minimum safe level, raising the risk of adverse effects For poorly water-soluble drugs, controlling particle size is crucial; thus, a particle size limit is included in the specifications of licensed medicinal products 16 Sometimes particle size reduction lowers dissolution For hydrophobic drugs, micronization and other dry particle size reduction techniques can cause material aggregation due to increased surface area and cohesion This reduces the drug's 'effective' surface area exposed to gastrointestinal fluids, lowering its dissolution rate and bioavailability Wet milling with stabilizers (often surfactants) is used to overcome aggregation and achieve particle sizes in the small micrometre or nanometre range 17 Enhancing Drug Delivery and Bioavailability in Solid Dosage Forms Specialized drug delivery companies produce solid dosage forms with drugs stabilized in the nanometre size range for greater bioavailability Sirolimus, initially a poorly soluble liquid, was transformed using Nanocrystal technology into tablets with 27% greater bioavailability and improved taste Megace ES, a nanosuspension of megestrol acetate, treats appetite loss in AIDS patients. This reformulation enhances dissolution, absorption, and bioavailability, reduces viscosity, and requires a smaller dose, aiding patient adherence 18 Wetting agents / wettability In addition to milling with wetting agents, the effective surface area of hydrophobic drugs can be increased by adding a wetting agent to the formulation, such as surfactants like polysorbate 80 or sodium lauryl sulfate This increases the microscopic contact area between the powder surface and the gastrointestinal fluid 19 Wetting agents / wettability For example, the presence of polysorbate 80 in a fine suspension of phenacetin (with an average particle size of less than 75 micrometers) significantly increased the rate and extent of phenacetin absorption in human volunteers compared to a similar suspension without a wetting agent Polysorbate 80 enhances the wetting and solvent penetration of drug particles, preventing aggregation and maintaining a large effective surface area If increasing the effective surface area of a drug does not improve its absorption rate, it is likely that the dissolution process is not the rate-limiting step in drug absorption. 20 Solubility in the diffusion layer, Cs Aqueous drug solubility is crucial for determining the dissolution rate, which affects oral drug bioavailability Poor solubility often results in slow dissolution and poor bioavailability According to the Noyes-Whitney equation, the dissolution rate is directly proportional to the drug's solubility in the surrounding diffusion layer (Cs) 21 Solubility in the diffusion layer, Cs Nearly two-thirds of drugs in development have poor aqueous solubility, posing formulation challenges. Solubility depends on: 1. interactions within the crystal lattice (crystallinity), indicated by melting point 2. drug molecule-solvent interactions (hydrophilicity/lipophilicity) High melting points indicate strong crystal lattices, making dissolution difficult Drugs with limited solubility due to solid- state properties are called "brick-dust" molecules High log P values indicate lipophilic molecules with poor water interactions, known as "grease-ball" molecules 22 Solubility in the diffusion layer, Cs Identifying solubility issues helps develop specific formulation strategies to improve absorption. Crystal form, solvates, and ionization are key properties affecting solubility 23 Improving the solubility in the diffusion layer by salts Formation of drug salts can significantly enhance drug solubility and dissolution, since the ionized form of the drug has much higher solubility. For instance, the sodium salt of a weak acid will dissociate as follows: NaA A-+Na+ where A- is the drug ion and Na+ is its counterion 24 the dissolution process of a salt form of a weakly acidic drug in gastric fluid Diffusion layer Gastric fluid (pH 5-6) (pH 1-3) A- + Na Na+ A- A- Drug Redissolution NaA HAdissolved Blood Na+ diffusion Na+ A- - Na+ A Fine Absorption precipitate of the free acid (HA) 25 NaA: sodium salt of acidic drug Salts In the pharmaceutical industry, salt formation is commonly used for ionizable drugs to increase solubility and dissolution rates The counter ion in the salt changes the pH at the dissolving surface of the salt particle in the diffusion layer, resulting in a higher dissolution rate compared to the free form According to the Henderson-Hasselbalch equations, pH changes highly influence the aqueous solubility of an ionizable drug 26 Salts For weak acidic drugs, solubility increases exponentially with increasing pH within the range between their pKa and pHmax (the pH of maximum solubility in the pH-solubility profile) This increased saturation solubility on the dissolving surface contributes to a higher dissolution rate For example, celecoxib, a poorly water- soluble weak acidic drug, showed enhanced dissolution rate and oral bioavailability with Na salt formation and the use of a precipitation inhibitor compared to the free acid form. 27 Salts For weak basic drugs, solubility increases exponentially with decreasing pH within the range between their pKa and pHmax (the pH of maximum solubility in the pH-solubility profile) The oral administration of a salt form of a weakly basic drug in a solid oral dosage form generally ensures that dissolution occurs in the gastric fluid before the drug passes into the small intestine, where pH conditions are unfavourable for dissolution Thus the drug should be delivered in solution to the major absorption site, the small intestine 28 Salts Strongly acidic salt forms of weakly Diffusion layer basic drugs (e.g. chlorpromazine hydrochloride) dissolve more rapidly Cl- in gastric and intestinal fluids than BH+ BH+ do the free bases (e.g. Cl- chlorpromazine). BHCl Cl- The presence of strongly acidic BH+ BH+ anions (e.g. Cl- ions) in the diffusion Cl- layer around each drug particle BH+ Cl- ensures that the pH in that layer is lower than the bulk pH in either the gastric fluid or the intestinal fluid This lower pH will increase the solubility of the drug in the diffusion layer. 29 Salt The solubility and dissolution rate of a salt Solid Solution are influenced by the counter ion For example, the solubility of haloperidol BH+Cl- BH++Cl- mesylate is significantly higher than its hydrochloride salt at a lower pH range The presence of Cl- in the gastric The aqueous solubility of a moderately fluids shifts the equilibrium toward soluble hydrochloride salt for a basic drug can be reduced in solutions containing solid phase: chloride ions, such as gastric fluids (common-ion effects) BH+Cl- BH++Cl-↑↑ An appropriate salt form should be developed considering both physicochemical and biopharmaceutical properties, especially for poorly water- soluble drugs. 30 Salts: example The non-steroidal anti- inflammatory drug naproxen was originally marketed as the free acid for the treatment of rheumatoid and osteoarthritis However, the sodium salt (naproxen sodium) is absorbed faster and is more effective in newer indications, such as mild to moderate pain 31 Salt The sodium salts of acidic drugs and the hydrochloride salts of basic drugs are the most common However, other salt forms are increasingly used A limitation of salt formation is that the solubility enhancement may be insufficient for drugs with very poor aqueous solubility, like itraconazole Some salts, such as aluminum salts of weak acids and pamoate salts of weak bases, have lower solubility and dissolution rates than the free form In these cases, insoluble films of aluminum hydroxide or pamoic acid can coat the dissolving solids when exposed to basic or acidic environments, respectively 32 Salt Poorly soluble salts delay absorption and can be used to sustain drug release, often in suspension dosage forms For example, the antipsychotic drug olanzapine is available as the poorly soluble salt olanzapine pamoate This prolonged-release suspension, administered via intramuscular injection every two to four weeks, improves adherence in patients with schizophrenia 33 Salt: Considerations and Strategies While salt forms are often chosen to increase bioavailability, other factors like chemical stability, hygroscopicity, manufacturability, and crystallinity are also considered and may limit the selection For example, the sodium salt of aspirin, sodium acetylsalicylate, is more prone to hydrolysis than aspirin itself To address such issues, salts can be formed in situ, or basic/acidic excipients (pH modifiers) can be added to formulations to improve solubility and dissolution rates 34 Salt: Considerations and Strategies Acidifiers like citric acid, succinic acid, and tartaric acid are used for weakly basic drugs, while alkalizers like calcium phosphate, magnesium hydroxide, and sodium carbonate are used for weakly acidic drugs 35 Crystal form: Polymorphism Polymorphism in the context of pharmaceuticals refers to the ability of a drug substance to exist in more than one crystalline form Each crystalline form is known as a polymorph A metastable polymorph usually exhibits a faster dissolution rate than the corresponding stable polymorph Consequently, the metastable polymorphic form of a poorly soluble drug may exhibit an increased bioavailability compared to the stable polymorphic form 36 Crystal form A classic example of the influence of polymorphism on drug bioavailability is provided by chloramphenicol palmitate This drug exists in three crystalline forms designated A, B and C At normal temperature and pressure, form A is the stable polymorph, form B is the metastable polymorph and form C is the unstable polymorph Polymorph C is too unstable to be included in a dosage form, but polymorph B, the metastable form, Chloramphenicol palmitate suspensions is sufficiently stable containing varying ratios of A and B polymorphs ( Percentage polymorph B in the suspension ) 37 Crystal form The extent of absorption of chloramphenicol increased as the proportion of polymorphic formB of chloramphenicol palmitate was increased in each suspension This was attributed to the more rapid in vivo dissolution rate of the metastable polymorphic form (form B) Following dissolution, chloramphenicol palmitate is hydrolysed to give free chloramphenicol in solution, which is then absorbed The stable polymorphic form of chloramphenicol palmitate (form A) dissolves so slowly and consequently is hydrolysed so slowly to chloramphenicol in vivo that this polymorph is virtually Chloramphenicol palmitate suspensions clinically ineffective containing varying ratios of A and B polymorphs ( Percentage polymorph B in the suspension ) 38 Crystal form The importance of polymorphism for the gastrointestinal bioavailability of chloramphenicol palmitate is reflected by a limit being placed on the content of the inactive polymorphic form, A, in a chloramphenicol palmitate mixture. Chloramphenicol palmitate suspensions containing varying ratios of A and B polymorphs ( Percentage polymorph B in the suspension ) 39 Amorphous Form Drugs may exist in amorphous forms which have higher apparent solubility and faster dissolution compared to their crystalline counterparts There may therefore be significant differences in the bioavailabilities exhibited by the amorphous and crystalline forms of drugs that show dissolution rate-limited bioavailability A classic example of the influence on bioavailability of amorphous and crystalline forms of a drug is provided by the antibiotic novobiocin The more soluble and rapidly dissolving amorphous form of novobiocin was readily absorbed following oral administration of an aqueous suspension 40 Amorphous Form The less soluble and more slowly dissolving crystalline novobiocin form was not absorbed to any significant extent. The crystalline form was thus therapeutically ineffective A further important observation was made for aqueous suspensions of novobiocin. The amorphous form slowly converts to the more thermodynamically stable crystalline form, with an accompanying loss of therapeutic effectiveness Thus unless adequate precautions are taken to ensure the stability of the less stable, more therapeutically effective amorphous form of a drug in a dosage form, unacceptable variations in therapeutic effectiveness may occur Several delivery technologies for poorly soluble drugs rely on stabilizing the drug in its amorphous form to increase the drug’s solubility, dissolution and absorption. 41 Insulin: amorphous vs. crystalline The polypeptide hormone insulin, used for regulating carbohydrate, fat, and protein metabolism, shows varying activity levels based on its crystalline form In acetate buffer, zinc combines with insulin to form an insoluble complex, either amorphous or crystalline, depending on the pH The amorphous form, with particles smaller than 2 mm, is quickly absorbed after injection and has a short duration of action The crystalline form, with larger rhombohedral crystals (10-40 mm), is absorbed more slowly and has a longer duration of action Intermediate-acting insulin preparations are made by mixing these two forms. 42 Polymorphic transitions Polymorphic transitions can occur during milling, granulating, drying, and compacting operations, such as with digoxin and spironolactone Granulation can lead to solvate formation, and drying can result in the loss of solvent or water molecules, creating anhydrous materials These transformations can negatively impact product performance, often undetectable by routine chemical analyses Over time, metastable forms may revert to stable forms, affecting the consistency, shelf life, and stability of suspensions 43 Amorphous solid dispersions (ASDs), In amorphous solid dispersions (ASDs), the drug is in an amorphous form within an inert carrier, usually a polymer or a mix of surfactant and polymer The polymeric carrier enhances drug dissolution and solid-state stability While ASDs significantly improve drug dissolution rate and solubility, amorphous drugs are inherently unstable due to their disordered structure and higher free energy 44 Amorphous solid dispersions (ASDs), Fewer than 20 marketed products using solid dispersions (as of 2021) These products show up to 20- fold increases in drug-plasma AUC compared to crystalline forms The amorphous drug form generates higher supersaturated concentrations in gastrointestinal fluids, maintained by the polymer for a sustained period 45 Amorphous solid dispersions (ASDs), ASDs are prepared by solvent evaporation or melt cooling, commonly using spray drying, lyophilization, or hot-melt extrusion Ideally, ASDs form a one-phase system with the drug molecules mixed with the carrier, creating a 'solid solution' or 'molecular-level dispersion’ The drug and polymer carrier are dissolved in a common solvent to form a solution, which is rapidly evaporated by spray drying For heat-unstable drugs, the solution may be frozen, and the solvent removed by lyophilization 46 Amorphous solid dispersions (ASDs), The solid dispersion, with the drug embedded in the carrier, is collected as a dry powder Rapid solvent removal prevents the drug molecules from forming crystals, resulting in an amorphous form Sporanox (itraconazole) is made by spray drying the drug-polymer solution onto sugar beads The main challenge with solvent evaporation methods is finding a common solvent in which both the drug and polymer are soluble Surfactants are sometimes used to improve polymer dissolution in the solvent. 47 Mechanisms of Improved Drug Absorption through Solid Dispersions 1. Increased Surface Area: The drug is dispersed in a carrier, often as tiny particles, which increases the surface area exposed to the dissolution medium 2. Improved Wettability: Carriers in solid dispersions can enhance the wettability of the drug particles 3. Supersaturation: The amorphous form of the drug in solid dispersions can create a supersaturated solution in the gastrointestinal fluids, leading to higher concentrations than those achieved with crystalline forms 4. Enhanced Solubility: The drug in an amorphous state generally has higher solubility compared to its crystalline counterpart, which can lead to better absorption 5. Prevention of Crystallization: The carrier matrix prevents the drug from crystallizing, maintaining it in a high-energy, more soluble amorphous form48 Solvates Materials can crystallize and trap solvent molecules within their lattice If the solvent is water, the material is called a hydrate This entrapment often occurs in a specific molar ratio; for example, a monohydrate has one water molecule per molecule Different levels of hydration are possible, such as monohydrate, dihydrate, and trihydrate, with one, two, and three water molecules, respectively 49 Solvates If solvents other than water are present in a crystal lattice, the material is called a solvate, such as an ethanolate if ethanol is present Solvates are generally undesirable for pharmaceuticals due to retained organic material being considered an impurity, unless deemed safe and beneficial Toxic solvents are obviously Indinavir Sulfate Ethanolate inappropriate for pharmaceutical solvates. Therefore, this lecture will focus on hydrates. 50 Hydrate and dissolution rate Hydrates often have very different properties from their anhydrous forms, similar to how different polymorphs vary. This difference is sometimes called pseudopolymorphism Unlike polymorphs, where the stable form has the highest melting point and slowest dissolution rate, hydrates can have either faster or slower dissolution rates than anhydrous forms The dissolution of theophylline monohydrate compared with that for anhydrous theophylline 51 Hydrate and dissolution rate Typically, anhydrous forms dissolve faster, as seen with theophylline In hydrates, water can form hydrogen bonds between drug molecules, creating a stronger lattice and slower dissolution rate Initially, anhydrous theophylline shows a higher concentration in solution, which then decreases to match the hydrate's equilibrium solubility, as the anhydrous form initially creates a supersaturated The dissolution of theophylline solution monohydrate compared with that for anhydrous theophylline 52 Hydrate and dissolution rate The faster dissolving anhydrous form of ampicillin is absorbed to a greater extent from both hard capsules and an aqueous suspension than the more slowly dissolving trihydrate form As the hydrate and nonhydrate forms usually exhibit differences in dissolution rates, they may also exhibit differences in bioavailability, particularly in the case of poorly soluble drugs that exhibit dissolution-rate-limited bioavailability. 53 Hydrate and dissolution rate Although anhydrous forms usually dissolve faster than hydrates, there are exceptions. In some cases, water acts like a wedge, pushing molecules apart and weakening the lattice, leading to a faster dissolution rate An example of the hydrate form speeding up dissolution is shown in the Figure for erythromycin The dissolution behaviour for erythromycin as the anhydrate, monohydrate and dihydrate, showing a progressively faster dissolution rate as the level54of hydrate is increased Degree of ionization For weak electrolyte drugs, their aqueous solubility depends on the pH of the dissolving fluid Thus, for orally administered solid dosage forms, the dissolution rate is influenced by the drug's solubility and the pH in the diffusion layer around each drug particle This microclimate pH is affected by the drug's pKa and solubility, as well as the pKa and solubility of the gastrointestinal buffers Therefore, dissolution rates will vary in different regions of the gastrointestinal tract as the pH changes 55 Degree of ionization The solubility of weakly acidic drugs increases with higher pH, so as they move from the stomach to the intestine, their solubility improves Conversely, weakly basic drugs are more soluble in the acidic stomach than in the small intestine Therefore, poorly water-soluble weak bases must dissolve quickly in the stomach, as their pH-solubility profile of dipyridamole dissolution rate in the small (weakly basic drug with pKa 6.4) intestine will be much slower 56 Degree of ionization For weakly basic drugs, two species exist in solution, with proportions depending on pH. At low pH (such as in the fasted stomach with pH ~2), the ionized form (BH⁺) predominates At higher pH (lower in the intestine), the free base (B), which has lower solubility, predominates. 57 Degree of ionization Increasing the pH of gastric fluid reduces the ionization and solubility of weakly basic drugs in the stomach Proton pump inhibitors (PPIs) raise gastric pH to about 5.5, affecting the dissolution rates of triazole antifungals like ketoconazole, itraconazole, and posaconazole For example, dosing posaconazole after the PPI omeprazole decreases absorption by 40%, while taking it with Coca-Cola (pH 2.5) increases systemic exposure by 70% compared to water 58 Degree of ionization The un-ionized form of a drug is primarily absorbed, but it must be in solution first The un-ionized form (B) permeates the lipophilic gastrointestinal membrane more easily than its charged ions As (BH⁺) and (B) are in equilibrium, (B) is replenished when absorbed 59 Factors affecting the concentration of drug in solution in gastrointestinal fluids 60 Introduction The rate and extent of absorption of a drug depend on the effective concentration of that drug, i.e. the concentration of the drug in solution in the gastrointestinal fluids, which is in an absorbable form Complexation, micellar solubilization, adsorption and chemical stability are the principal physicochemical properties that can influence the effective drug concentration in the gastrointestinal fluids 61 Complexation Complexation, involving covalent or noncovalent interactions with another compound, can occur in the dosage form or gastrointestinal fluids and can be beneficial or detrimental to drug absorption In general, this only becomes a problem (with respect to bioavailability) where an irreversible or an insoluble complex is formed 62 Examples: Mucin Complexation Mucin, present in gastrointestinal fluids, can form complexes with certain drugs For example, streptomycin binds to mucin, reducing the drug's available concentration for absorption This complexation is thought to contribute to streptomycin’s poor bioavailability 63 Insoluble Complexes Tetracyclines can form insoluble complexes with calcium, which decreases their solubility and bioavailability This is significant when tetracyclines are taken with calcium-rich foods or supplements. Bisphosphonates form insoluble complexes with food components, similarly reducing their bioavailability 64 Complexation with excipients The presence of calcium in certain excipients, such as dicalcium phosphate used as a diluent, can lead to the formation of poorly soluble complexes with drugs like tetracycline, thereby reducing their bioavailability. Other examples include the formation of complexes between amphetamine and sodium carboxymethylcellulose, and phenobarbital with polyethylene glycol (PEG) 400. These interactions reduce the drugs' bioavailability 65 Complexation to improve absorption: Cyclodextrins Cyclodextrins (CDs) are natural cyclical oligosaccharides made by enzymatic modification of starch, consisting of glucopyranose units forming rings of six (α-CD), seven (β- CD), or eight (γ-CD) units The outer ring surface is hydrophilic, and the inner cavity is hydrophobic, resembling ‘bucket-like’ structures Lipophilic molecules can fit into the cavity, forming soluble inclusion complexes in aqueous solutions without forming covalent bonds 66 Cyclodextrins CD complexes enhance the apparent solubility β-CD and γ-CD are most commonly used due to their larger hydrophobic cavities (approximately 6 Å and 8 Å, respectively) Typically, one drug molecule associates with one cyclodextrin molecule to form reversible complexes, with drug molecules in the CD cavity in dynamic equilibrium with free drug molecules in solution However, not all drugs can form CD complexes, and enhancement in absorption is not always achieved 67 Hydrophobic Hydrophilic cavity exterior ` + Free Cyclodextrin Hydrophobic drug: Cyclodextrin-drug complex: poor solubility Improved solubility 68 Cyclodextrins Cyclodextrins enhance solubility in tablets, oral and parenteral solutions, eye drops, and nasal sprays For example, voriconazole, poorly soluble in water, forms a complex with sulfobutyl ether β-cyclodextrin (SBEβCD), improving its solubility and allowing a lyophilized formulation for intravenous use at 10 mg/mL (VFEND) Compare previous number with Voriconazole aqueous solubility without cyclodextrin of 0.5 mg/ml 69 Cyclodextrins Itraconazole is available as a hydroxypropyl-β-cyclodextrin (HPβCD) complex for oral and intravenous use (Sporanox) Cetirizine-βCD complexes are used in chewable tablets in some European countries to mask the drug’s bitter taste, improving palatability 70 Cyclodextrin-Drug complex preparation There are several methods for preparing drug-CD complexes A common method is the kneading or slurry technique, where water is added to CD powder under high-shear mixing to form a viscous paste The drug is then mixed into the paste, equilibrated for 24 hours, dried, filtered, and milled into a powder Once in the gastrointestinal fluids, the drug is rapidly released from the complex mainly by dilution. Cyclodextrins have low oral bioavailability ( 0 are usually well absorbed orally Highly lipid-soluble drugs (log P > 3) are well absorbed but may be more susceptible to metabolism and biliary clearance Generally, within a homologous series, drug absorption increases with lipophilicity. 96 Improve lipid solubility: Prodrugs If a compound's structure cannot be modified to increase lipid solubility without losing pharmacological activity, medicinal chemists may create a lipid-soluble prodrug A prodrug is a chemically modified version, often an ester, that converts back to the parent compound through metabolism It has no pharmacological activity on its own. Examples of prodrugs used to enhance lipid solubility and absorption are shown in Table 20.4. 97 Molecular size and hydrogen bonding Two drug properties that are important in determining permeability are the molecular size and the number of hydrogen bonds within the molecule For paracellular absorption, the molecular mass should ideally be less than 200 Da; however, there are examples where larger molecules (with molecular masses up to 400 Da) have been absorbed via this route Molecular shape is also an important factor for paracellular absorption. 98 Molecular size and hydrogen bonding In general, for transcellular passive diffusion, a molecular mass of less than 500 Da is preferable Drugs with molecular masses greater than this are absorbed less efficiently There are few examples of drugs with molecular masses greater than 700 Da being well absorbed 99 Molecular size and hydrogen bonding Excess hydrogen bonds in a molecule hinder its absorption Generally, a molecule should have no more than five hydrogen- bond donors and ten hydrogen- bond acceptors (often estimated by counting nitrogen and oxygen atoms) for optimal absorption Peptides, which have many hydrogen bonds, are poorly absorbed for this reason. 100 Lipinski’s Rule of Five In general, for oral absorption, a molecule should not violate more than one of the rules known as Lipinski’s Rule of Five, which are based on the aforementioned considerations The molecule should have no more than five hydrogen bond donors, no more than 10 hydrogen bond acceptors, a molecular mass less than 500 Da and an octanol-water partition coefficient, log P, of not more than 5 101