solubility.ppt

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,Dosage Forms Design,III Preformulation,Preformulation involves the application of biopharmaceutical principles to the physico-chemical 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.,Following studies are conducted as basic preformulation studies,special studies are conducted depending on the type of dosage form and the type of drug molecule,Physicochemical properties,:,structure;melting point;boiling point;solubility;dissolution rate;crystal properties and polymorphism;pKa;partition coefficient;stability,Properties related with dosage forms,:,hygroscopic;micromeritics(particle size,shape,and surface area,density,flowability;porosity);interaction;,Biological properties,:,membrane permeability;pharmacokinetics parameters,1.Solubility,Preformulation,The solubility of drug is an important physicochemical property because it affects the rate of drug release into the dissolution medium,and the bioavailability of the drug,consequently,the therapeutic efficacy of the pharmaceutical product.,Background(1)Formulation challenges with poor soluble compound,Background(2),Factors causing poor solubility,Background(3),Solubility criteria(1),Dependent on the dose and permeability,how soluble is soluble enough,Biopharmaceutics Classification System(BCS),Solubility criteria(2),Minimum acceptable solubility,Solubility and Bioavailability,Solubility,系指在一定温度下（气体在一定压力下），溶质在溶剂中达到溶解平衡时所形成的饱和溶液的浓度。,表示方法:一定温度下100g溶剂(100g溶液/100ml溶液）中溶解溶质的最大质量值（g），亦可用质量摩尔浓度mol/kg或物质的量浓度mol/L来表示(一般化学手册和溶解度手册),Solubility Concept,极易溶,溶质1g(ml)能在溶剂不到1ml中溶解；,易溶,溶解,略溶,微溶,极微溶解,几乎不溶或不溶,溶质1g(ml)能在溶剂1不到10ml中溶解；,溶质1g(ml)能在溶剂10不到30ml中溶解；,溶质1g(ml)能在溶剂30不到100ml中溶解；,溶质1g(ml)能在溶剂100不到1000ml中溶解；,溶质1g(ml)能在溶剂1000不到10000ml中溶解；,溶质1g(ml)在溶剂10000ml中不能完全溶解；,药典:药物的溶解程度分类,Solubility Concept,The solubility of a molecule,in various solvents,is determined as a first step.,Solubility is usually determined in a variety of commonly used solvents and some oils if the molecule is lipophilic.,This information is valuable in developing a formulation.,Solubility Determination(1),Common solvents for solubility determination,Water Castor Oil,Buffers at various pHs,Peanut Oil,Polyethylene Glycols Sesame Oil,Propylene Glycol,Glycerin,Sorbitol,Ethyl AlcoholMethanol,Benzyl Alcohol,Isopropyl Alcohol,Tweens,Solubility Determination(1),Solubility Determination(1),The solubility of a material is usually determined by the,equilibrium solubility method,which employs a saturated solution of the material,obtained by stirring an excess of material in the solvent for a prolonged period until equilibrium is achieved.,time-consuming;drug degradation;polymorphism transformation,Solubility Determination(2),Intrinsic solubility,1解离、复合物、杂质增溶；,2纯物质，无相互作用；3同离子效应（盐析）抑制,Solubility Determination(3),Influencing factors of the solubility(1),Solvent and solubility,In general,polar solutes are dissolved by polar solvents,and non-polar solutes are dissolved by non-polar solvents.,NH,4,Cl:Water=11.1mol%,Methanol=2.07mol%,Ethanol=0.578mol%,n-propanol,=0.252mol%,Chloroform=0.00mol%,Temperature and solubility,ln,S,=-,H,s,/RT+C,S,为溶解度；,H,s,为摩尔溶解焓；,R,为摩尔气体常数；,T,为热力学温度；,C为常数。,如果溶解过程是吸热的，即,H,s,为正值，则溶解度随温度升高而增加；,反之，如果溶解是放热过程，即,H,s,为负值，则溶解度随温度升高而降低。,Influencing factors of the solubility(2),Polymorphism and solubility,化学结构相同而晶型不同称之为多晶现象,(polymorphism),。由于同一药物的不同晶型具有不同的晶格能，因而其溶解度及溶解速度可能不同,.,Influencing factors of the solubility(3),Particle size and solubility,难溶性药物的溶解度与粒子大小有关，当粒子半径在,10,-9,10,-7,m,时有影响，当粒子半径超过,210,-6,m,时则无影响。粒径大小与溶解度的关系可用下式表示：,log,S,2,/S,1,=,（,1/r,2,-1/r,1,）,2,M/,RT,其中，,S,1,和,S,2,分别为半径为,r,1,、,r,2,的药物的溶解度，,为界面张力，,M,为药物的摩尔质量；,为固体药物的密度；,R,为气体常数，,T,为绝对温度。在一定温度下，粒子越小，溶解度越大。,Influencing factors of the solubility(4),When the solubility of a material is less than desired,it can usually be increased through a solubilization process:,-pH,-Co-solvents,-Surfactants,-Complexing agents,Solubilization,Cosolvency,using co-solvents for increasing the solubility,Solubilization(1),Effect of co-solvents on the solubility of fluasterone,Solubilization,make a substance with lipid soluble more soluble,especially in water,by the action of surfactants,Solubilization(2),Effect of surfactant on the solubility of fluasterone,Complexing,agents,Solubilization(3),Effect of cyclodextrins on the solubility of fluasterone,2.pKa,Preformulation:,30,The,pK,a,or,Dissociation Constant,is a measure of the strength of an acid or a base,Strong acids and bases-defined as completely ionized in pH range 0-14,Weak acids and bases-defined as incompletely ionized in pH range 0-14,Concept of pKa,For acidic compounds,HA,H,+,+A,-,K,a,=H,+,A,-,/HA,For basic compounds,BH,+,H,+,+B,K,a,=H,+,B/BH,+,pKa,is the pH at which a substance is 50%ionized,Henderson-Hasselbalch equation,Preformulation,HU,30.01.02,32,Acid with pK,a,=8,Base with pK,a,=8,Determination of the dissociation constant for a drug capable of ionization within a pH range of 1 to 10 is important since solubility,and consequently absorption,can be altered by orders of magnitude with changing pH.,The importance of pKa,pKa and solubility,溶液中药物的总浓度为,S,，分子型药物的浓度为,So,，离子型药物的浓度为,SSo,Weak basic,Weak acid,溶解度方程,Hypothetical example of pH/solubility,Amino acid:carboxylic acid group(pKa4)and basic guanidino group(pKa12),pKa and absorption,药物多是弱酸性或弱碱性有机化合物，其离子化程度受其pKa及其所在溶液的 pH而定，这是影响药物跨膜被动转运，吸收分布排泄的一个可变因素。,非离子型(分子型)药物可以自由穿透，而离子型药物就被限制在膜的一侧，这种现象称为离子障。例如弱酸性药物在胃液中非离子型多，在胃中即可被吸收。弱碱性药物在酸性胃液中离子型多，主要在小肠吸收。,Aspirin(pKa 3.5),Stomach pH=1.5,HA/A,-,=100,Quinine (pKa 8.4),Stomach pH1.5,BH,+,/B=8.0,10,6,Intestine pH6.0,BH,+,/B=250,分子型/离子型药物的平衡转化,有膜孔途径,小肠吸收表面积大,What is the solubility of Aspartic acid?,Aspartic acid has many ionic states,pKa=2.28,pKa=3.90,pKa=9.95,In abundance at different pHs,Which pH?,Stomach,1.4-2.1,3-7,Ileum,6.8-8.0,6.8-8.0,Colon,5-8,5-8,pH,fasted state,fed state,Jejunum,4.4-6.6,5.2-6.2,3.,Partition Coefficient,Preformulation:,Concept of Partition Coefficient,Partition coefficient(oil/water)is a measure of a drugs lipophilicity and an indication of its ability to cross cell membranes.It is defined as the ratio of un-ionized drug distributed between the organic and aqueous phases at equilibrium.,P,o/w,=(C,oil,/C,water,),equilibrium,44,Log P=log(Partition Coefficient),NOTE:,Log P=1 means 10:1 Organic:Aqueous,Log P=0 means 1:1 Organic:Aqueous,Log P=-1 means 1:10 Organic:Aqueous,Drugs having values of logP much greater than 1 are classified as lipophilic,whereas those with partition coefficients much less than 1 are indicative of a hydrophilic drug.,Concept of Partition Coefficient,45,Log P,is for,neutral compounds(un-ionized).,In practice the Log P will vary according to the conditions under which it is measured and the choice of partitioning solvent.,The distribution coefficient(,log D,)is the ratio of the sum of the concentrations of all forms of the compound(,ionized plus un-ionized,)in each of the two phases,Concept of Partition Coefficient,log D is pH dependent,hence one must specify the pH at which the log D was measured.,Of particular interest is the log D at pH=7.4(the physiological pH of blood serum).,For un-ionizable compounds,log P=log D at any pH,Concept of Partition Coefficient,The classical and most reliable method of log,P,determination is the,shake-flask method,which consists of dissolving some of the solute in a volume of octanol and water,then measuring the concentration of the solute in each solvent.,Measurement of logP,Application of logP,(1),分配系数可预测药物在混合溶剂中的溶解度,例如，有些药物在水中的溶解度较小，须使用潜溶剂增加溶解度，可利用下式初步估计所需的潜溶剂。,log,C,s,=F(log,P,)+log,C,w,其中，,P,为药物在该潜溶剂与水中的分配系数；,C,s,为药物在混合溶剂中的溶解度；,C,w,为药物在水中的溶解度；F为潜溶剂所占的体积百分数。,Application of logP,(2),药物被包装材料的吸附,例如，硝酸甘油是挥发性药物在氯仿-水中的分配系数为109，它从片剂扩散入塑料瓶壁，扩散入包装片剂的塑料衬垫。若在片剂处方设计时加入一种能与药物络合的物质，则可防止这种分配，因而可增大硝酸甘油在片剂中的亲和力。若硝酸甘油以浸剂剂型在塑料输液袋中给药时，则甚至有50%的药物被塑料吸附，因此必须使用超常大剂量,Application of logP,(3),For series of compounds,the partition coefficient can provide an empiric handle in,screening,for some biologic properties.,Log1/C=a(logP),2,+b(logP)+q,+,E+常数,为电性参数，E为立体参数，a、b、q、为各因素的系数，其正、负值取决于化合物的类型和作用方式。,C为药物产生效应的浓度，C值越小，活性越大，故用log1/C表示药物的生物活性。,Log1/C与logP有一最佳适宜值，此时的活性最大。,Application of logP,(4),Lipinskis Rule of Five,Lipinskis rule says that,in general,an orally active drug has no more than one violation of the following criteria,Application of logP,(5),pH7.4时的logP对于药物开发的启示,0,有肠和中枢神经系统透过性问题；易受肾清除影响,如果MW5,较低的溶解度和较差的口服生物利用度；吸收不稳定；虽然药效可能仍然很高，但有较高的代谢倾向；碱性胺的分布容积可能高或很高,Although it appears that the partition coefficient may be the best predictor of absorption rate,the effect of dissolution rate,pKa,and solubility on absorption must not be neglected.,55,56,