上海交通大学：《药剂学》教学资源（课件讲义）2Preformulation_full page

preformulation Xiaohui Wei xhwei@sjtu.edu.cn 2008.9

preformulation preformulation Xiaohui Wei xhwei@sjtu.edu.cn 2008.9

Preformulation Objective: Preformulation involves the application of biopharmaceutical principles to the physicochemical parameters of a drug with the goal of designing an optimum drug delivery system.Characterization of drug molecule is a very important step at the preformulation phase of product development. From www.pharmquest.com

Preformulation Objective: Objective: Preformulation Preformulation involves the application of involves the application of biopharmaceutical principles biopharmaceutical principles to the physicochemical physicochemical parameters parameters of a drug with the goal of designing an of a drug with the goal of designing an optimum drug delivery system. optimum drug delivery system. Characterization of drug Characterization of drug molecule is a very important step at the molecule is a very important step at the preformulation preformulation phase of product development. phase of product development. From www.pharmquest.com

Preformulation Studies:contents Physicochemical properties of the drug 。Solubility 。pKa .Partition Coefficient (lipophilic vs.hydrophilic) .Crystal Properties and Polymorphism Particle size,shape and surface area 。Hygroscopicity Stability 。Chemical stability In solid state In solution phase Compatibility Stability in the presence of excipient Biopharmaceutics research

Preformulation Preformulation Studies: contents Studies: contents ™ Physicochemical properties of the drug Physicochemical properties of the drug z Solubility z pKa z Partition Coefficient ( Partition Coefficient (lipophilic lipophilic vs. hydrophilic) vs. hydrophilic) z Crystal Properties and Polymorphism z Particle size, shape and surface area z Hygroscopicity ™ Stability Stability z Chemical stability Chemical stability z In solid state & In solution phase In solid state & In solution phase ™ Compatibility Compatibility z Stability in the presence of excipient ™ Biopharmaceutics Biopharmaceutics research research

1.Physicochemical properties of the drug 1.1.SOLUBILITY 1.Significance Intrinsic solubility (Co dissociation constant(pKa) Co will immediately indicate need and pKa possibility of making more soluble form (salt)of the drug to eliminate solubility-related poor bioavailability,particularly with solid dosage form. Kaplan(1972):37 C,pH1-7,solubility<1%(10mq/ml). absorption problem,dissolution-limited absorption

1. Physicochemical properties of the drug Physicochemical properties of the drug 1.1. SOLUBILITY 1.1. SOLUBILITY 1.Significance 1.Significance z Intrinsic solubility (C0) z dissociation constant (pKa) C0 will immediately indicate will immediately indicate need and pKa possibility possibility of making more soluble form (salt) of the drug to eliminate making more soluble form (salt) of the drug to eliminate solubility solubility-related poor bioavailability, particularly with related poor bioavailability, particularly with solid dosage form solid dosage form. Kaplan(1972): 37 Kaplan(1972): 37℃, pH1-7, solubility<1%(10mg/ml), solubility<1%(10mg/ml), absorption problem, dissolution absorption problem, dissolution-limited absorption limited absorption

Solubility Definition: Solubility is generally expressed as the maximum amount of solute that dissolves in a given volume of solvent. As water is the most used solvent in pharmacy and biological fluids are aqueous solutions,we will focus on solubility in water. Saturated Solution: A solution where the dissolved solute is in equilibrium with the undissolved solute( the solid phase) Solubility(Cs上z The concentration of a solute in saturated solution at a given temperature and pressure

Solubility Definition: Solubility is generally expressed as the maximum amount of solute that dissolves in a given volume of solvent. As water is the most used solvent in pharmacy and biological fluids are aqueous solutions, we will focus on solubility in water. Saturated Solution: A solution where the dissolved solute is in equilibrium with the undissolved solute( the solid phase) Solubility(Cs): The concentration of a solute in saturated solution at a given temperature and pressure

Parameters affecting solubility: Molecular Structure:like dissolves like" Crystal Characteristics: polymorphism,amorphous and solvates Temperature:endothemic and exoehtmic △Hsolution=△Hcrystal lattice+△Hsolvation Solubility Vs pH:Stotal=Sunionized+Sionized

Parameters affecting solubility: Molecular Structure: “ like dissolves like” Crystal Characteristics: polymorphism, amorphous and solvates Temperature: endothemic and exoehtmic  Hsolution =  Hcrystal lattice +  Hsolvation Solubility vs pH: Stotal=Sunionized+ Sionized

Parameters affecting solubility: Molecular structure: The general rule is that"like dissolves like".A polar solvent, like water,is able to dissolve ionic solutes and other polar substances.High dipole moment,the ability to form hydrogen bonds,and the acidic or basic nature (electron donor-acceptor ability)are important characteristics to increase solubility in water. Water is a good solvent for a numerous substances: It has a high dielectric constant(that reduces the attractive forces between the atoms into a crystalline structure) It is an amphiprotic substance,acting as an acid or as a base It can solvate substances by means of dipole-dipole,ion- dipole and hyrogen bonding interactions

Parameters affecting solubility: Crystal characteristics: Polymorphism:Polimorphs are different crystalline forms of the same substance.Each form has a different crystalline lattice and different lattice enthalpies.This results in different dissolution enthalpies(Hsol).As a general rule,the less stable polimorphs have higher aqueous solubilities and hence faster dissolution rate. Amorphous:Amorphous forms(without crystalline structure)are usually more soluble compared with the crystalline form of the same substance. Solvates:Crystalline forms that include solvent molecules into the crystalline lattice.Generally the solvate has lower solubility and dissolution rate into the solvating solvent

Parameters affecting solubility: Temperature: To dissolve a crystalline solid it is neccesary to break down the crystal lattice and to solvate the formed ions.From a thermodynamic point of view this can be expressed as: △Hsolution=△Hcr+△Hsolvation △Hsolution dissolution enthalpy △HCr crystal lattice enthalpy AHsolvation solvation enthalpy AHsolvation is always 0

Parameters affecting solubility: Considering the relative magnitudes of the enthalpies, If △Hcr>△solvation then△solution>O Heat is absorbed when dissolution occurs and the dissolution is called endothermic If △Hcr<△Hsolvation then△Hsolution<O Heat is produced when dissolution occurs and the dissolution is called exothermic Cs(T1) △solution(Ti-T2) In- Cs(T2) R Ti.T2 If AHsolution 0,solubility will increase when temperature is raised If AHsolution 0.solubility will decrease when temperature is raised