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This chapter discusses the solubility phenomenon, focusing on molecular interactions and the factors influencing intermolecular forces. It explains the classification of solvents, methods of expressing concentration, and the solubility process, emphasizing the importance of solute-solvent interactions in pharmaceutical applications. Key concepts include the nature of solutions, types of solvents, and the role of intermolecular forces in determining solubility.

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9 views33 pages

Project D

This chapter discusses the solubility phenomenon, focusing on molecular interactions and the factors influencing intermolecular forces. It explains the classification of solvents, methods of expressing concentration, and the solubility process, emphasizing the importance of solute-solvent interactions in pharmaceutical applications. Key concepts include the nature of solutions, types of solvents, and the role of intermolecular forces in determining solubility.

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amityd7179
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fz Chapter ( 1 ) Solubility Phenomenon Molecular Interactions — Physical Forces Factors Influencing Intermolecular Forces © Classification of Solvents 5 Methods of Expressing Concentration LEARNING OBJECTIVES Id be able to:— After reading this chapter, the reader shoul solubility process and solubility ~ Understand the concepts of solutions, expressions. Explain the classification Appreciate the nature of intermolecular forces and their implications in the stabilization, physical and chemical properties of substances. FOO YS ee acne of solutions and solvents for predicting the solubility. Y ’ Solution is a homogeneous mixture in which one substance is said to dissolve in the other. The dissolved substance is present as individual entities, either ions or lecules. In solution, the substance that is present in a large proportion is termed as solvent. The component that is present in small proportion is known as solute. Based on the proportion of solute present in the solvent, he solution may be classified as dilute or concentrated solutions. The solutions are often referred to as molecular dispersions or true solutions, Le, i i : is pide in which one component (solute) is dispetsed as molecules eu the other component (solvent). A few examples : urea in water and sucrose i i ebibcull digs ae e in water. The properties of (1) The size of the parti i Particles (ions, atom: i of Angstroms, s or molecules) is of the order (2) i so (2) The particles are not visible even in the electron microscope. © 8 Ch-1_ SOLUBILITY PHENOMENON 3 le 4 rhe pharmaceutical solutions of solid in solid and solid in a gas are not possible, because the constituents eannot form a homogeneous mixture. As per the definition of solubility, it is essential to prepare a saturated le solution to express the concentration, Several of these are described in the individual chapters. The general principles are described in this chapter. Z cotain concepts of expressing the concentration of solutes are also explained. Solubility Expressions stive terms for the approximate solubilities of Pharma- ¥ The descrit 1 National Formulary substances are given by United States copeial and Pharmacopeia, USP.23 (Table 1-2). TABLE 1-2 Solubility Terms Given by USP 23 + cninnive | Parts ofsolvent | 4 in M=400 | M=40000 escriptive | required for 1 |” mol/L mol/L erm water ¥ ze iz of solute in water in water Very soluble <1 2 1000 22,5 20,025 1 to 10 1000 to 100] 2,5100.25 | 20,025 to 0,0025 Soluble 10 to 30 100 to 33 | 0,25t00,08 | 0,025 to 0,0008 Sparingly 30 to 100 33to10 | 08t00,025 | 0,0008 to soluble 0,00025 Slightly 100 to 1000 10to1 0,025 to | 0,00025 to soluble 0,0025 0,0000025 Very slightly | 1000 to 10,000 | 1 t00,1 0,0025 to | 0,000025 to soluble 0,00025 | _0,0000025 Practically insoluble or tuaslabie 2 10,000 <1 <0,00025 | < 00000025 Pharmacopeias express the concentration in terms of number parts of solute diss. cd in stated parts of solution. For example, from 10 to 30 ee =<" seeaeaulees do dispels cng part of the soli, This notation gan be usc! for solids-in-liquids, liquid-i i liquid (grams). terminology is approximate een ae ae : JP standards | not meant for testing for purity, but give primary keeping the allo 4 PHYSICAL PHARMACEUTIog ) Solubility (Dissolution) Process When a solid is placed in contact with a li ra with a liquid, particle Surface ofthe solid and pass into the liquid. Initial, the particlee ve of blocks of few molecules (solids), which ultimately breakdeys molecules and ions. The dissolved material diffuses through the jy all directions and some of them retu to the solid. This process ont until the equilibrium is established between the particles leaving then: and those returning to the solid. ice Drug molecules in solid <—* Drug molecules in sotution The solubility of a solute in a so consid in aa sob of solute na solvent may be considered as ccuning Substitution method: (a) The first step involves the removal of molecule from the solute phase, at a definite temperature. Work is done on the system in removing a molecule from the solute. As a result, bonds are broken from the adjacent molecules and one molecule becomes free, Such molecule moves into vapour state. This process involves work done on the system, The hole created due to the escape of one molecule is closed. ° ° 000——+000 o ea © Liberated a Closine solute molecules a ofhole| molecule oo °° (6) The second step involves the creation ofa hole in the solvent just ‘ept a solute molecule. This involves work done by the large enough to a system, °° oo °° Oren) oo oo Solvent Creating ofa hole molecules in the solvent (c) The last step involves placing the solute molecule in the hole (in the solvent). This step allows the work done by the system. °° (Xe) PRO! S45 @: ‘0-0 oo 20% Solvent Solute Solution molecules molecules eer ‘ch-t_ SOLUBILITY PHENOMENON. “The energy associated with the above 3 steps is accounted work done by the system is more, then solubil ‘work is done on the system {0 taneous. It isan endothermic srrition promotes the solubility) Good molecular effect : This criterion is satisfied by a few systems. Intersti b the size of solute is higher than the solvent, then size correction (Florey Higgins size correction) is applied Comment 1-1 : Explain the mechanistic behaviour of solubility of solids liquids. MOLECULAR INTERACTIONS-PHYSICAL FORCES: ‘The matter is considered as a collection of molecules. When molecules are brought together, they interact and exert repulsi attractive (physical) force. The attractive forces are two kinds. Co ‘forces indicate attraction between like-molecules and adhes indicate attraction between unlike-molecules. All these forces & to the existence of matter, Though attractive forces are im aggregation of molecules, repulsive forces are equally neck the molecules interpenetrating from one another. due to intramolecular bonding, which is mostly stronger, forces are comparatively weaker, An understanding of p important in the study of pharmaceutical sciences. The: forces are deseribed in Figure 1-1, hel SOLUBILITY PHENOMENON [ c ts with the organic solvent molecule and forms an organic solvate, imetuorocortisone-n-pentanol, If the solvent of erystallization is water, then drug hydrate is formed, e.g. theophylline hydrate, Substances can aren absorh moisture from the environment and may become hydestes A similar molecular association is possible through hydrogen bonding. Molecular association and solvation (organic) promote solubility, Solvation is a process in which solvent molecules (water or organic solvent) play a significant role in the interactions. The solvent can be a Single molecule (1:1) of more number of molecules (1:6). These have diferent physicochemical properties than the individual drug. Applications:— The structure of drugs can be anticipated. The nature of intermolecular forces can be understood. 3. Physical and chemical properties of drugs as well as solvents can be determined. Its possible to select a suitable solvent, cosolvent, buffer and surfactant based on structure. The prediction of solubility is based on the Ac-dissolves-like. Solvents are classified on this basis as: polar solvents. nonpolar solvents and semipolar solvents. Polar Solvents The solubility of a drug is due to the polarity of the solvents, ie. cipole moment. Polar solvents dissolve ionic solutes and polar solutes. Water dissolves phenols, alcohols, aldehydes, ketones, nitrogen-containing compounds through hydrogen bonding. The mechanisms of interaction may be described ags:-— 1 High dielectric constant, i.e. greater capacity of separating the “components bound in a molecule, . Break covalent bonds, ° Solvating the molecules, 4. The Brénstead-Lo yf i oe i wry type o} Protonation and Lewis electron other structural features such b ing 2 also influence the i 13° lutlty ofa substance also depends on the structural features, i. unctional groups (polar) i 28 PHYSICAL PHARMACEUTICS > Non-polar solvents il hen reduce the attractio 2 The solutes are kept in van det Waals forces. > Non-polar solvents are aprotic solvents, ie. they cannot form polar bridges with non-electrolytes. © Tonic compounds and polar substances are not soluble in nonpolar solvents Semipolar Solvents Semipolar solvents are intermediate between polar and nonpolar solvents ic. ketones and alcohols. These solvents induce a certain amount of polarity in the nonpolar solutes. For example, benzene is soluble in alcohol by this mechanism. On similar mechanisms, propylene glycol has been shown to increase the mutual solubility of water and peppermint oil Similarly, solutes (drugs) can be classified as polar, semipolar and ‘nonpolar solutes. METHODS OF EXPRESSING CONCENTRATION J The amount of solute present in a definite volume of solution i known as concentration, The concentration of a solution is generally expressed as molarity, molality, normality and mole fraction. In addition, several other terms arg used in pharmacy practice. These are in percentages, ie. % viv, % viv, %6 wiw and % w/v, These can also be applied to the liquid in liquids. The Plasma concentration may be expressed as mg/100 mL or g/mL. or ng/mL. Applications : Determination of concentration of the components is ‘essential for:— © Analytical work : The purity, percentage composition, extent of impurities, etc, are determined for drugs and excipients in a dosage form. Physical and chemical principles : Several laws can be derived based on the composition, e > Mass balancing work : In a chemical process, input and output balancing is obtained from concentration tern Summary Solution is a homogeneous mixture in which one substance is said to dissolve in the other. Since three diferent phases (gas, liquid and solid) exist, seven different types of solutions are possible. When solutions of liquid in liquids are considered, three different types are possible, ees SOLUNILITY PHENOMENON st iit, paraly mh aus a imi ids type Hquids are not a solution rie ese Sly an te tinsel iu wn ' hy qv (ef spr soluble) and quanta manner et saolaity Semi oe). The distin proces occur ony ithe inlay, molar salt a pe solute-solute and solventaolvent attractions. ; ihe ee ards aie carter ee adhesive forces, whict ib m to aera ee é ntribute to interfacial pronertet Nonna bynes psiebuley sevation of powder and subsequently, formation of tablets. The extent siibinding between the molecules depends on the distance between them, ‘hemieal mature ofthe molecules and spatial arangement. The d of about 0.3 to 0.4 nm is optimum for keeping a aaa state, The intermolecular interactions are possible only, ifthe molecules are properly oriented, dispersed and influence one another (induced forces), ‘though van der Waal forces are weaker. The cumulative amount of energy of such interactions is large that allows the material to exist in liquids and ses. The van der Waals forces are three types: - induced dipole and induced dipole-induced dipole. another type of interaction, based on electronegativity and | energy of 15-30 MW/kmol, Intra-molecular and bonding are possible. Hydrogen bonding is also cooperative nature of honey, the solubility of drugs in double helix structure of DNA and drug-receptor biological activity. Hydrophobic interactions are ob resulting from the water repulsion. Hydrophobic the stabilization of proteins and binding of monomers QUESTION BANK Each question carries one mark Note : Encircle the alphabet which corresponds to the singh 1 For various types of interactions, pick up the eo strength, A. Covalent < hydrogen bonding < dipole-dipole B, Dipole-dipole < covatent < hydrogen bonding C. Dipole-dipote < hydrogen bonding < covalent D. Hydrogen bonding < dipole-dipole < covalent How many categories are available in van der Waals forees? A. Four ©. Three 36 PHYSICAL PHARNACEIM gg ety in water decreases. The same structural feature is ect » AY drophili-tipothitic balance (HLB) and naned as surface Activity, Solubilization requirement of the surfactant is hydrophilic, then onh Surpactant can remain inthe aqueous fui, Nene, the HLB value gy Surfactant must be between 16 and 18 {hydrophilic region). These surge cal molecules self-assembie and form micelles in water, Several dr exhibit surface activity and also form micelles, which are Tesponsible fy higher aqueous solubility. Additionally, surface active agents (Tweens) ayy also added to further promote the micellar solubilization of OOTY Watey Soluble drugs. For example, the solubility of procaine is enhanced by 25 in Aqueous buffer, owing to the formation of surfactant micelles, sonLBILITY OF SOLIDS FF LIQUIDS cha nd al re of the same magnitude, (Wheel present any quid is formed, energy is necessary to liquefy ‘idered as equilibrium process between | ie iy vale ee Comment 2-8. What are the advantages of positive heat of solution? Comment 2-5. When an electrolyte is added to an aqueous solution of g nonelectrolyte, salting out phenomenon is observed. Explain. { Practice problem 2-1. Calculate the pH of preparation of the 2% solution of sodium phenobarbital in a hydroalcoholic solution. The solubili lity of phenobarbital in 15 % alcohol solution is 0.22%. The pK, of phenobarbital in this solution is 7.6. Solution : Data : $= 20; S, = 0.22: pK, = 7.6 Recall equation (1 ecall equation (1) er og DH, = BK, +1og 5% = 76+ tog “Gp age Lowe 055 6 + log 8.090 =7.6 + 0,908 = 8.508 The pH ofthe preparation of 2 % solution of phenobarbital = 8.508, THEORIES OF SOLUTIONS a Solubility involves solute-solvent interactions. Based on the nature of interactions, several theories are proposed. These are:— 1. Ideal solution, 2. Regular solution (nonideal solution), Ideal Solution X, Mole fraction solubilt am +x 10 Fig. 2-6 & Solubility versus reciprocal substance. Determination of molar heat deal solution of solid in a liquid is a dispersion in which unlike molecules A plot of the logarithm of the solubility hhave same affinities as they do for their own-kind absolute temperature (1/7) results in a straight line 2.303R, from which AH can be estimated (Fi Ideal solutions are analogous to perfect gases, but in perfect gases > re no intermolecular attractions. In ideal solutions, attractions af of fusion (AH) is also determined more conver 38 PHYSICAL PHARMACY, Scanning ca alorimetry (DSC), The heat of fusion values of some and drugs i chen a are given in Table 2-3 M TABLE 2 me C ion fo Heat of fusion, Heat opp emicals ‘imol Drugs sion, king) (-MsAmod) = (Msn Anthracene 28.857 | Caffeine 21.109 18.800 | Carbamazepine | 25.559 15.648 | Paracetamol 28.45] Methyl p-amino | 94 49 eairein ee 24.476 | Phenyt 47.279 Myristic acid 45.380 | Sulphadiazine 40.753 Naphtha 18573 | Sulphamethoxazole 30,945 Re disgmiciin |i hoon? | eager 22.133 Phenanthrene 18.644 | Theophylline 29,694 Steari acid 56584 | Tolbutamide 25.615 Sulphur 16.820 | Trimethoprim 46.550 ‘The ideal mole fraction solubility may altemativeh ly be expressed for solubility of solids in polar and nonpolar solvents as: (4) An ideal solution is a theoret nonpolar and/or low polar subst closely with the ideal solubility of ideal solutions is 0% solubility calculations, tical concept, but mixtures con: lances often have solubilities that agree The important contribution of the theory ction of the following parameters into the introdu + Melting point + Molar heat of fusion (or m, ‘lar entropy of fusion) Non-ideal Solution JF SOLIDS IN LIQUIDS sation (3). Therefore ideal solubility aceurately PY can be achieved by considering the ‘ration’ (or activity) of solute rather -v oh souuelltt cna 8 “concentration! sp atvity (2) 8 anal 9 rie els sides of eq Meret "ide = log X, + 108 Substituting equation (8) in equation (7) solubility. rot 2 ae 303 RT K Equation (9) is known as Scatchard-Hildebi solution to which the Scatchard-Hildebrand regular solution. Solutions showing deviation fro as non-regular solutions. Hildebrand regular solutions theory Predicting the solubilities of steroi —log X, =—log Xy'+ ‘The solubilities of testosterone esters straight and branched alkanes, eyclo= halogen derivatives. A 6 value of 9.5 to If Lestosterone propionate. In non-ideal predominant between unlike molect interaction leading to solvency) or deet Chapter (S) Drug Dissolution © Dissolution—Drug Absorption © Dissolution—Tablets and Capsules © Theories of Dissolution © Mathematical Treatment—Dissolution © Factors Influencing Dissolution © Dissolution Test Apparatus In Vitro-in Vivo Correlations of Dissolution © Powder Dissolution—The Hixson-Crowell Cube Root Law EARNING OBJECTIVES ‘ter reading this chapter, the reader should be able to:— ~ Describe the process of dissolution and its relevance to the performance of ugs and dosage forms. piain the dissolution rate, in terms of theories and relevant mathe-matical ysis. ~ Describe factors influencing the rate of dissolution, in terms of. ‘experimental, drug-related and dosage form-related. ~ Describe various apparatus used in the study of dissolution, of immediate release products. Dissolution is a process by which solid solute disolves in a solvent to eld a solution, \ drug is expected to be released from the solid dosage forms (granules, ». capsules, ete.) and immediately go into a molecular solution. Dissolution ‘itcal step for the performance of a drug as well as a dosage form, <1 1s a prerequisite for drug absorption, Release of a drag from a “osage form involves diverse factors as:— ~ Physical and chemical properties of the drug, ~ Physical and chemical The net effect of these factors is dissolution and diffusion, Such PHYSICAL PHARMACEUTICS he design of con applied in th a " ave oan Th following sectiong to lage extent Thee rt jon in pharmacenticay controlled and suai describe the principles * sciences. present in solution «ix possible onty when itis P Absorption of 2 drug i P° fern eee te entecles Fe itp and assume molecutay independent and assur eorbed independently through biological Jecule is absorbed ch mo Siar dispersion) is a prerequisite fop dispersion. Fash ny solution (molecular dispet ‘membranes. Thus diss drug absorption {sa serious problem for: aera water soluble drugs exhibit poor dissolution. aon er are absorbed from the gastric region, The delayed > Aca epibese drugs nay ead to decreased absorption Hence, scion focuses on these wo categories, Base drugs readily eo int sation in gastric fluids, but are absorbed from the small intestine, arenas tests are widely used in the pharmaceutical industry for a wide variety of applications 1. The dissolution testis used as a quality control tool to ensure wniformity and reproducibility of production batches. In this ‘ese, single point determination, ie. a certain percentage of the drug dissolved in a fixed time is usually sufficient (quality control parameter, The dissolution test is utilized as a esearch tool for optimizing ingredients and process parameters in a new formulation, stangss made in formulations or their manufacturing processes ( ‘marketing approval) re likely to affect the performance in the c Dissolution test hel best results in hee Dissolution test ‘Any after finie, ips in identifying the formulation producing the lini, before releasing products into the market. is Whethera generic ve Sometimes implemented for determining approved or not the dissolution 8 of bioabsomption. nal experimentation ch at different Stages ofits lifecycle, hi iij cht DRUG DISSOLUTION forms have been , additives (11), and aspirin tablets Hee patton ee cher a Baile t aa of aspirin from solution (1 1, The absorption solution (1) complete compared to as dissolution (the drug is 40) 3g & ee 2% 3 40 80 Time (min) Fig. 3-1 & Absorption of aspirin in man (dose 0.65 9 ‘olution, lI: Tablets containing alkaline additives, tk Aspirin has the least absorption from tablets ( products, obviously because of poor dissolution Comment 3-1. Dissolution is considered as the rat bio-absorption of drugs. Why? PHYSICAL PHARMACEUTICg 56 AND CAPSULES ‘Ss |-TABLET: DISSOLUTION: sess involving heterg, fa drug is @ multistep Fae and. solute-solveny The dissolution of ¢ ' >, solvent-se ‘ 7 Pause SA GURE solute-solute $0 Tieute an overall mass transfep geneous fac si ctions low. The effectiveness depends on two steps yencous interface. The heterogeneov ” lease of drugs from tablets is S! e relea drug for absorption process fe of a tablet in releasing the (Figure 3-2). Tablet 1 ws Gawd Copsute Lee, (m ion | Disintegration Dissolution (mater) Drug in Solution Granules or Drug in solutio Aggregates sot (in vitro or in vivo) sn Absorption ow (in vivo) Drug in blood Fine particles other fluids and tissues Fig. 3-2 © Different stages depicting the \ drug absorption from tablets and capsules. ee the drug gets absorbed from site of absorption. The above sequence suggi absorption i: dissolution rate-limited Process, Thee oa a i ened dissolution would alter the absonptigm: Ges ee antl to five-fold variation in the rate and mc by ly cheers f be dosage form extent of absorption, The release of drugs Gp abaopals oc Solutions > suspensions > ganay xe ao ss capsules > compress Comment 3-2. The time taken for dissolutiaas than that of the granules, Why? Chapter 4 Drug Diffusion © Methods and Procedures 0S aeearee ee on Cooled RelesseHiguc Esuaion eee Caiocs soe LEARNING OBJECTIVES After reading this chapter, the reader should be able to:— 7 Pesibetheprocessofdfusionanditsrelevancein pharmaceutical * Explain Fick's laws of diffusion and their applications. | et, ht PP sed or studyng the difuson along with the general method, sciences | * Explain the drug, diffusion across the ‘gastrointestinal tract, | J Pifsion is écfined as a process of ma sf of sagen defined as proce of mass transfer of individual molecul In general, molec Move more readily Le. concentratio Agitation), th of solute to les @ lower concentration, extemal forces, (such as tnt molecules measures the escapi In case of osmosis, 1 red, whereas in diff tendeney © escaping, lusion the ent molecule Of solute isn escaping tendency In pharmacy barrier may be S is: measu measured, mature" is important. This fra! membrane. The te 1 Tegion or regh a rane. The term of materials Tea ane ne ester oye 3)’ Medtoa lm separating the DRUG DIFFUSION cr DF sais The material that priate {transport is known 88 diffusant op phase ani or penetrant. ‘The material ransport across the fi ere calitated diffsion, im mey be by Panne membranes 1a) hata channels. oF ma y be ular diffusion ough non-porous media ude eotPorUs a Mation of the permeant in the bulk meng i Movement and channels involves passage though solvent fie oe Pormprane. This process is influenced bythe size ofthe moles a8 Mameter of the pores. ‘Applications of Diffusion i controlled release products, process. ‘The transport of drugs (absorption) from ei et an be understood diffusion. Some of these applications are vi chapters. The laws related to diffusion biological processes (drug absorption and following sections. STEADY STATE D Spontaneously from a region of hi concentration until diffusion eq The diffusion of molecules is est The permeant is dissolved in a vehicl compartment. The vehicle is placed the permeant gets transported. into Membrane. This diffusion is codified Steady state : A system is said 1b does not vary with time PHARMACELTI¢« PHYSICAL PHARMACEUTI¢g n wich ane tough wana tates ae Receptor artment compartment —Tiekness, de Fe, 44 ey heaton of args and poles sfer remains constant with time, j in case of diffusion, the mass transfer remain ig aoe east If the transport varies with time, the system jg fusion, the concentrations of solute in the donor and acceptoy ‘must be maintained constant. For this purpose, both connected to large reservoirs of solutions (maintained at trations) and recirculated. Therefore, the concentration 1s maintained constant. Thus, steady state diffusion does not mean that Fass transfers nil. Mass transfer takes place at a constant rate throughout the study. The diffusion process is not allowed to attain equilibrium, Sink condition : Its a state in which the concentration in the receptor compartment is maintained at a lower level compared to its concentration in the donor compartment. During diffusion study, the donor compartment acts as a source and the receptor compartment acts as a sink. This condition is maintained by connecting the receptor compartment to a large reservoir from which the solution is recirculated. Therefore, the concentration gradient is maintained nearly constant Ivis easy to maintain sink conditions rather than steady state, because recirculation in one compartment is sufficient. Further, maintaining constant concentration in the donor compartment is difficult. Therefore, sink condition is employed in practice and mass transfer is approximated as the steady state Fick’s First Law In diffusion, molecules (mass) get transported from one compartment to another over time, ie. rate of mass transfer (dM! flux, Flux is equal to the rate of mass transfer acr dt). This is expressed as a barrier. The flux, J can be mathematically exp OSS a unit surf ressed as: area of 1 dw peli di ) 4 DRUG DIFFUSION cn je dM = change inthe mass of materia, where “" $= barrier surface area, em? r= change in time, s , eee ‘The units for flux are [Link]-!, ae tilogram, meter">time'. Time may be given in min ted ag ‘The change in mass transfer also occurs simultanen sepa oF days, Drea asics ta bay = Fick’ first law states that the flux (the rate of vit furface area of the barrier) is directly propecia ne across a sradient. ‘Concentration, Fick’s law can be expressed as: en a ‘where dC = change in conc. of material, g/cm? D = diffusion coefficient of a penetrant, cm?/s dx = change in distance, em ‘The negative sign in the right-side term in equation (2) signifies a decrease in the concentration. However, fix aluaye shea quantity, because it increases continuously during the process. ‘The deg. perpendicular to the surface of the barrier. ‘Combining equations (1) and (2) gives: dM. dc ae The diffusion coefficient, D, may change in its value with high ‘ration, D is affected by temperature, pressure, solvent | chemical nature of diffusant, Therefore, itis nota constant, buté Equation (2) gives the flux in the steady state of first law is discussed with the help of two comps soncept can be used to understand available in one tment. Fick’s first law is ext further extended to make biomembranes. For this p included. (2) F Controlled release systems. Other 96 PHYSICAL PHARMACKy Fick’s Second Law Fick’: second law states that the change Particular region is proportional tothe change in the concent at that point of time. The second law of Fick's explains the change in concentration time ata definite location with respect tox, and = axes (or direction) general, this equation is not used in pharmaceutical problems of diffjy; since movement in one direction is sufficient to describe most caseq The diffusion equation is derived as follows. In particular volume element, the concentration, C, changes ag result of net flow of molecules into and outside the region, 4 Cis due to the difference in input and output. At the same time, dC also changes with time, ie. (ACIAA). The fy (or amount of diffusing molecules) changes with distance, (A//Ax) in tt | direction. This relationship can be expressed as: y we or ox fa) Partial derivative notation is used, because the concentration is y inction of both x and r. Similarly, flux is also a function of x and 1, Consider Fick’s first law expression, i.e. equation (2) comneenation With tng on edly In other wong, dc =D 2) Differentiating equation (2) with respect to x gives: a #c (5) ‘Substituting the (6C/ér) in equation (5) for (@J/éx), we get: x we GS Ot Be 4 Equation (6) represents diffusion in the x-direction only. Extending equation (6) in three coordinates, Fick's second law is written in the] general form as: .y Pe OS eae AD | o ax? ay?” az? ‘Thus, Fick's second law refers to change in concentration of diffusamt with time, at any distance, x, ic. non-steady state of flow. ; pA DRUG DIFFUSION cn ty state diffusion can be deseribed in Fiekts During emoved and replaced with fesh solvent i8 (oe of permeant in the receptor comy 2 : ferred to as a sink condition. Now, the oie es clement for siting Fig. 4-2 & A horizontal type of permeation system (Viles-Chien skin Vertical two-compartment cell is used for dif (Figure 4-3). The diffusion of drugs from oint delivery systems can be studied using these cell ‘The diffusion cells are made of glass, plexig cells are transparent, so that sti These are easy toassemble or clea in order to maintain thetemperature. If greater three compartment model ean be adopted. ee: PHYSICAL PHARMACE Up Ios i The study of diffusion is important to predict the drug absor “sign of controlled drug delivery system. The principles of soir Md \Cissolution) and diffusion (permeability) are combined for the absoy ly Process. This lead to the categorisation of drugs under biopharmaege® | classification, BIOPHARMACEUTICS CLASSIFICATION SYSTEM, Based on drug solubility and permeability cl cuties classification system (BCS) is developed as given in Figur Ption a Pham, 24.7, ] Class 1 ‘lass 2 | Low solubility and high | High solubility and high pemeabiiy(, He). | permeability (H9, HP) | Low solubility and Low | permeability (IS, LP) |r |. propanol eer ater 2 Class 4 Class 3 é High solubility and low permeability (HS, LP) E., hydrochlorthiazide | £9. ranitidine, atenolol fuenide | Solubility —> Fig. 4-7 + Biopharmaceutics classification system with examples. Solubility Criteria A drug is considered highly soluble, wh en the highest d A drug ighly soluble, when the highest dose is soluble in 250 mL or less of aqueous medium over the pH range, 1-8 The ratio of dose/solubility m t be | 5 too lubility must be less than or equal to 250 mL. ire sume (250 ml.) is derived ffom the minimum volume anticipated ia faeted ace auivalent to a glass of water taken with the dosage form, Eee a {The volun Is taken from typical bioequivalence study Gas ei of the solution is fixed, the dose of drug in) is also taken into account for predictions A sufficient number of Ee T Of PH conditions sh uld be evalt el Pe s should be evaluated to accurately edie? ee peti based on the ionization characteristics of Be rctiocs: 18in the range of 3-5, solubility is determined volume PH = px PH = px’ pH pH=1 pH=7.5 pRuG DIFFUSION buffers are not suitable (for physical op lutions can be used. EEE 19g chemical reasons) “a cn If these 1 bulfer so jons : Calculation of the dose solubility ram ae th dose oft new dag ns ney 82 MAY ne iiMyelopment. Drugs with low doses may be i ety stages of dev (eg digoxin). Inthe calculation, only pH and vel set 2 class dered. Some compounds may be i rately chee sonst few substances have solubility > 109 giclee Zrsotuion problems in vivo, lity Criteria jgh permeability drugs are generally those hay soc greater than 90%, in the absence of documented the gastrointestinal tract). ‘The permeability of a drug can be determined experi a is Pears ‘one of the methods used in Perea However, these methods have to be calibrated with known compounds. A few of these methods are:— : 1. In vivo intestinal perfusion studies in humans. : 2. In vivo or insite intestinal perfusion studies in animals, 3. In vitro permeation experiments using excised h intestinal tissue. a 4. In vitro permeation experiments across mono-layers human intestinal cells. ee The experimental permeability data need to be eoreated known extent of absorption data in humans. In many cases, method may be sufficient, when the absolute BA is 90 % or! othe Limitati reliable, are nto class $e, 90% or more of the administered drug is recovered in urine. method fails to conclusively demonstrate the b two different methods may be advisable. Chemical physicochemical attributes of a drug substance (e.g. a suitable system, n-octanol-water) ean provide usefi the permeability characteristics. | Applications of BCS Design of dosage forms (Optimiz applied in order to modify the formulatio Class 1 (High solubility and high Class of drugs are rapidly absorbed, the big Provided these drugs do not form insoluble et fluids or undergo presystemic metabolism. for immediate release dosage forms PNSICAL PHARMACE 7 rugs: Since thig rmoability) arUS' dified t Clay a gh me mes ye 2 Law mt NN prove an . of drags as lw seal biota ove 7 he dstation rat i es: Itis impor, the disahsion 1 pilin) dru on wrelations between low permea: aximize the ce cay and mc axe te a the drug available (disso tidine a) saris tion window, ¢.g. Fa eat Now permesbili) drags These dny lew have Fo oa WT rute, Hence, these drugs should be hat it cannot be given by ora eee sed am to the systemic circulation, Bests accel es pdtang ltbood of achivngsucesfl in vive saath (VIVO. oat atthe a iy and high permeability) drugs : The required $5 % in (0.1 N hydrochloric acid solution in 15 minutes. nt athe saat fh drugs wo limited by pra t 10 revolutions per minute (or Apparatus Il c)is specified. The volume is 900 mL. (3 lution media, y dissolution, at $0 revolutions ) or less, in each of (1) ONS without enzyme 2) pH4S butter ydrochloric acid solution or simulated gastric fluid USP (G) PH 6.8 or simulated intestinal flu For the class 1 id USP without enzymes. ‘erate limitng sep would be gastric empying (for the drug absorption tie esiece (emptying time is 15 to 20 minutes, : rad board conservative estimate, ‘oso, @NSures Poems i luon ad hereto ch Problems. If dissolution ig lower than gastric empt ‘ Profile with mult. Point is reg it lass 2 (Low sot the rate dissolution pod this category Given drug solution “ommended, in several media. ep for drag it POPMeabiliy) drugs : Dra lea, ordre absorption and IVI may be e ile in multiple ‘pnuG DIFFUSION 4 and low veabilit «3 thigh solubility and low permeability) dr ‘ tas ntrolling step for drug al ion. Hence, md ihe rate je. It depends on the felative rates Of dissolution ang me be pos aes 4 (low solubility and low permeabtiy) dry rece i, Hence, bioequivalence sles of hse dus at ove rosette regulations. i me fe ientfcation of dup fo imei eles Taratastiee Cori for whieh Aspnes) incu oy. Ti TPPronch senses fat 06 otha eemmea thee ty mulation affects the membrane andlor gastrointestinal tract summary — ei aera ‘ ifsion sa process of mass transfer of individual mole. hig sss vats the ecaping tendencies of ules and this transport the bares, natural or synthetic. Dison i eberved tare gt pees ofthe drug (fom the dosage form), absoron aces Gite ky eS Cnto tissues) and even excretion rough soli Ths telationship between the rte of diffusion of drug across the bilogi- calcined oveauatia pale A. directly proportional : C. inversely proportional D. log linear Which one of these drugs diffuses easly through ssiric region? A. Aspirin C. Morphine ‘Which one of these: ‘inal portion of the: A. Aspirin ©. Paracetamol Chapter & solubility of Gases Im a 01 ses in Liquids encing Soibity of Gases in Lig Fae tent coefcent ©. ostwalds Solubili LEARNING OBJECTIVES: } be able to:— fir x, the reader should eosin Henry's law of solubility of gases in iquids > a a ken testy of asesin igus gas in a ligud is expressed as the concentration of pee ne cenilium with the pure gas above the in water Iforgaic mater polltes water fishes die, because the supply of oxygen may be depleted Applications Preparation of reagents : Concentrated re: passing the gases into water, e.g, hydrochloric ac acid and liquid ammonia, nts are prepared by |, sulphuric acid, nite Prepar: of carbonated beverages : Solubility of carbon dioxide in water is necessary forthe preparation of soda water Solubility of oxygen in blood : The respiratory function of the lungs is to add oxygen to the blood and to remove carbon dioxide from it. The Solubility of oxygen in the blood is dependent upon the concentration of haemoglobin Transportation of anesth Such as ether has higher bl Jungs more rapidly than hal etic gas through blood : Anesthetic 288 lood solubility and transported away from the lothane. QUUBILITY OF GASES IN LIQUIDS ns i ‘ic t — 1 solubility of anesthetic pases : The angen = ONS solubility are Well correlated, “Tyee potency op ite ity is effective at a low alveolar "Thus, oil solubility of 109, tas 5 with i one anesthetic ga in ettom aNd as a eh evant in pharmacy {a The solubility of gases (includin water and water for injection," “") SMO¥ld be nil in distiieg ‘The solubility of a gas such as oxy, s © cause it enhances the Oxidation af dn ere ‘Athigher temperatures, explosion abd Ascorbic acid, OF teas produces high pressure in the Toit, Fon bese while opening the botle of ammonia soliton, te we os FACTORS INFLUENCING soup; i f OF GASES IN LIQUIDS Pett : ‘ ‘The solubility of a gas in a liquid depends on: > Pressure: > Temperature a cil sol oteny pisadvantages: aibiioci oii to the partial pressure of the gas above the sok dilute solution at a constant temperature Mathematically, Henry’ law can be e > % p or Cy= op concentration of dissolved gas, ml partial pressure of the gas abovell solubility coefficient, mol/L KPa Mole fraction solubility may be appropli tions, molarity may be used. According 16 of gas increases as the pressure of the gas Ont be concluded that when the pressure is do dissolves in the same volume of solvent. Co where C, no PHYSICAL PHARMACE Ic) decreases and the excess gas escape, when the pressure above the sot i is decreased a When a mixture of gases isin contact with liquid, the partial preg of individual gases determine the solubility of each gas. In such casey!" solubility of each gas is proportional to its partial pressure. the Explanation : Ifa bottle containing a liquid and a as is shaken equilibrium, the gas can be regarded as distributed between the liquig jit space above it. When the bole is opened, the partial pressure aboye nl solution decreases and carbon dioxide gas bubbles out. This behaviogt® Our observed when the cap of a coca cola bottle is removed. is Let concentration of the gas (present above the solution) = C, Let concentration of the gas in the liquid phase = C. Applying the distribution law concentration of gas in the liquid phase AQ) The molar concentration of gas (C,) is proportional to its partial pressure. Hence, equation (2) may be written as: < = a (a proportionality constant) ater This is Henry's equation. Based on the extent and nature of solubility of gases in water, itis possible to classify the gaseous solution into three ‘groups. I. First group : These gases are sparingly soluble in water, eg ‘oxygen and nitrogen. These obey Henry’s law. IL. Second group : These gases are slightly soluble in water, e& carbon dioxide and chlorine. These show considerable deviation from Henry’s law. ILL. Third group : These gases are highly soluble in water, €& hydrogen chloride and ammonia. These do not obey Henry's lav because of a specific interaction between gas and water. Applications : The influence of pressure on solubility is utilised making carbonated beverages, such as beer, champagne and many suet drinks. Henry’s law is used to estimate the solubility. Bunsen absorption ‘method can be used to determine the solubility of gases in liquids. «goLUBILITY OF GASES IN LIQUIDS: nS pation in wae, When ep carbon diets is observed due to decrease in pressure cfferver nee ‘cess dissolved gail isteleased. All pues liq’ dertain extent: (a) tendency of gases to clevated temperatures, Applications : Dissol Distilled water is maintained use, because gases cannot i and carbon dioxide. Dissolve example, oxygen can be remove different gas, nitrogen, through Yapour pressure of oxygen, whi is employed, while handling solver Disadvantages : The pharmacist the factor of warm conditions, while h PHYSICAL PHARMACR nie OF Cold yy ey be ir . lr of the gas before gt hy jpressure of the B Pe {bromine and chic ainers should These containers should! Pe the temperature on, liquid sna sotutio some time to reduc Effects of Salts sowers the solubility OF Bas in so) Additios Ipstances udded to a ¢ b cof salt isa Hit ‘Arbon fution. This phenomenon is kyoy ll + from the sol ; ‘ es sca olution, aration between the Bns ond sol yay ve. When the electro Kens gas-solvent interactions. The, h water molecules. This weakens & = se citer electrolytes such as sodium chtog ase cavcrose. This effect is of great indirect imponga = such ations of vitamin A. High sugar conceng sidbeegs so that substances liable to oxi tion idatiog protected ical Reaction ae erica Bee chloride, ammonia and carbon dioxide result of a chemical reaction between gas and solvent systems, Henry's law is not applicable. In fact, due to chem tion, the solubility of the gases is higher. For example, hydrog Jes about 10,000 times more soluble in water than in liquid oxygag Fog Applications : These principles are used forthe preparation of reagen concentrated solutions, namely, hydrochloric acid, sulphuric agi OSTWALD’S SOLUBILITY COEFFICIENT aid’s solubility coefficient is also known as Bunsen absorption ¥ coefficient is defined as the volums dissolves in unit volume of the liquid 1 of gas that at the given temperature. fathematically, Ostwald’s solubility coefficient is expressed as at temperature 7 and pressure P : ‘lume of the solvent 4 op The advantage of ¢ independent of req. O8¥Ald'S solubility coefficient is that itl Prenat Of pressure. It is applied to anest) et MPreasion are absorption coeficien wp The other terms of aa sation of Solubility of Gases ue Ui rena be eg Mn The coin. Such met a we i ig eee Pee in eal © methods ae wel ee several gases are soluble in liquids and such solutions are weds ‘Be, reparation of reagents, carbonated beverages (soda water), soba of oxygen in blood, transportation of anesthetic gaser teu ft, and oil solubility of sacs Cs The solubility of a gas in a Tiguid nds on the pressure (pressurized systems), temperature, present os (electrolytes or non-clectrolytes) and the chemical interaction a liquid. The effect of pressure is explained by Henry's law, which stacy thatthe concentration of the dissolved gas is proportional is the panel vapour pressure ofthe gas above the solution at equilibrium in very dias solution at a constant temperature. chemical interaction promotes the solubility of gases in a liquid, for example, hydrogen chloride gas dissolved in water to obtain concentrated hydrochloric acid and (gas) is dissolved in water. ‘ammonia Restricted response type of questions. Each question carries 2 marks 1, Explain two applications and two disadvantages of solubility phenome- non of gases in liquids. 2. Describe the effect of temperature and added substances on the solubility of gases in liquids, Each question carries § marks: | State and explain Henry's law solubility of gases in liquids. Write its applications. : Ostwald's solubility coefficient Applications >) Cont OF GASE Chapter (6) Solubility of Liquids in Liquids ice ids © Ideal Solutions-Raoult’s Law {© Non-ideal Solutions or Real Solutions After reading this chapter, the reader should be able to:-— Describe the miscibility of liquids, classification of liquid-liquid solutions > State and explain the properties of idea solutions and laws, R Dalton’s law. LEARNING OBJECTIVES: | 20ult’s law and) Define the concept of real solutions, deviations from ideal properties and theirimplications. Solution is © homogeneous mixture in which one substance is said to dissolve in the other, Solutions are also known as true solutions or molecular The dissolved substance is present molecules. Ina solution, the subst is termed. known as solutions dispersions, as individual entities, either ions or ance that is present in a larg 8 asolvent, The component that is present in small solute. Based on the proportion of ay be classified as dilute Liquid-tiquid mixtures 1. Miscibte liquids alcohol and water © proportion, proportion is ‘solute present in the solvent, and concentrated. are of three types These are miscible in all proportions, ethyl 2. Partially miscible liquids proportion, 8. Phenol in w Immiscible liquids relative amount of ¢ water These are miscible only at a certain ater These are tot ally immiscible r ardless of the ach component carbon tetrachloride and ouuBILITY OF LIQUIDS IN LiQuIDg cro & utions are also rele ts “ iquid-1iquid solutions are also relevant fom point of : va jal solutions (obeys Raoult’ law) ya al solutions (vations fom Raoul tauy A is chapter, liquid-liquid solutions of miscible nature ; ‘The eres of iqud-iguid solutions are explained insepae eT: . Non: 5 MISCIBLE LIQUIDS ible liquids are those liquids that are xanple sey alcohol in water. These liquids. Applications 1. ‘The principles of solutions are applied in the aerosol products (spray systems) and solution dosage 2, Distillation isa process of separating and {na liquid mixture. The vapout-liquid used in distillation. The higher the vapour more volatile itis. Such liquids have a binary mixture is heated, the vapour is, volatile constituent. Distillation ‘more volatile liquid from the less volatile distillation methods are developed based on a Dag rinse a Meme a IDEAL SOLUTIONS-RAO Ideal solution is defined as the one in whieh properties of the components other than dilution, form a solution, ate miscible in all quis are also known as binary Heat is neither evolved nor abs Volume of the solution represents an constituents. There is no shrinkage or expa AA few examples of ideal solution are gi Liquid mixture These liquids have similar p Complete uniformity. It means for the same type as those present b theory provides a model system to whieh 16 PHYSICAL PHARMACEY P Meg, ql xl by a physicoch compared. Ideal solutions are cha of a liquid, namely, the vapour pressure. Raoult’s Law ‘The vapour pressure of a liquid serves as a qu describing thy 's of molecules m (OF LIQUIDS IN LIQUIDS Prope, sounitY yy each gas, sures exerted b} ‘olume the Bs von’ ta is mathematically expressed as: ib «ral pressure = partial vapour pressure of A+ partial vapour pressure titative expression Raoult’ law states that the partial vapour pressure of each yo) P= Dy tPp til 2) constituent is equal tothe vapo seo the pure constituent male seating equations (1) and 2) in equation ()g by its mole fraction in the solution, at a given temperature. Substituting ©9 P= eX, +09 %y ead Since the solution is homogeneous by definition, the relative num, jes are additive, i.e. total vapour pressure of the mixture cof components onthe surface reflect the numbers of these component a These agin Bo areas cna be expressed on na iste eghted average al vapour pe vio scale. Thus, Raoults law is appropriately suited to describe an ideal solution i in Figure 614. The following conssions cn be dew fom A mixture of miscible liquids A and B are considered. In this mixture; Let partial vapour pressure exerted by liquid A =p, kilopascals (pay Let partial vapour pressure exerted by liquid B =p, kPa Let vapour pressure exerted by pure liquid A = p,” kPa Let vapour pressure exerted by pure liquid B =p,” kPa Let mole fraction concentration of A in liquid = X, Let mole fraction concentration of B in liquid =X’, Raoult’s law may be mathematically expressed as: Partial vapour pressure vapour pressure mole fraction, ofa liquid = ofpure liquid “ of liquid P= BEX, (i) Py = Ps Xy Q) a When two liquids are mixed, the vapour pressure of each is reduced by : the presence of other to the extent of dilution of each phase. 3 Jdeal solution may be defined as the one that obeys Raoult’s law. Raoult’s a Jaw is obeyed by a few solutions of liquid in liquid. The components of g these solutions have similar structures. E.g. benzene and toluene, n-hexane = and n-heptane, ethyl bromide and ethyl iodide. The individual components 12k Composition 00% A do not have interaction of any kind or complete uniformity of attractive mB forces is observed. Fig. 6-1 & Vapour ya diagrams for different Ww piers gpa me a Applications Dalton s law of partial pressures states that the total pressure ex ‘Accordin, : ‘ 1 10 ideal solution concep by a mixture of ideal gases may be considered as the sum of the parti Yolatile component, i.e, one having This principle is used in simple distillatio PHYSICAL PHARMACE Teg q An aerosol preparation contains the drug dispersion (iN 8 solveng) ayy a propellant mixture of proper vapour characteristics. A Few exanyyl Of propellants are nittogen, unsbsttutedydroea#0ONs, propellant (trichloromonoffueromethane)andpeopellant12(dichloroditluoromethan The propellant mixture (fluorinated hydrocarbons) approximately bel as an ideal solution and hence, the total pressure exerted by the mixture gp be easily calculated, using Raoult's and Dalton’s laws NONG-IDEAL SOLUTIONS OR REAL SOLUTIONS x degree of deviation from Raoul Most liquid mixtures show varying degree of deviation from Raoyy solutions are known as rea solutions. Se “The deviations are observed because solute-solute, solute-solvey waeachlosds and eyelohexane, chloroform and acetone. In thee achlonde and roneid by replacing the term “concentration Z ‘term “effective concentration” indicating activity 1 Equations (1) and (2) may be modified as ‘equations (1) and (2) by (thermodynamic activity’ Pa = Pay AS) Pa Paty (6) ere a, and a, are activities of components A and B, respectively uations (5) and (6 are applicable for both ideal and non-ideal solution, Ideal solution: a=X a Non-ideal solution: a 4X i) The ratio of activity/concentration is termed as the activity coefficient and it provides a measure of deviations from ideality (ratio= 1). In general, an increase in temperature brings the system closer to ideal behavior, whilst 4 fall in temperature increases the deviations. Mutual interactions lead to either lowering or enhancing of the vapour pressure of the mixture with respect to ideal behaviour (Figure 6-1 and c). Based on these properties, deviations are described Positive Deviation from Raoult’s Law In some liquid systems, the vapour pressure is greater than the sum of the partial pressures of the individual components, (i.e. ideal solution) Such systems are said to exhibit positive deviation from Raoult’ law A few examples are carbon tetrachloride and cyclohexane, benzene and ethanol, water and ethanol. ‘The typical behaviour of such a system is shown in Figure 10-16. This type of behaviour occurs when the components differ in their polarity, length of hydrocarbon chain and degree of association (Figure The total vapour pressure shows @ owt OF LIQUIDS IN LIQ e 22S nn m at one particular composition (Figure 6.15), ie g 5 : | nu owe seltions ate KROWn 8 maximum yop > Xe and 1147 MH poaing point solutions, The degree of deviation fom Reng, mini” Png temperatute increases, since the diferences eats desrenes peratures. Conversely, a decrease in temperture magucstat crag components, resulting in phage se meats Posies the Weakening the cohesive forces i etn aol at ; Semipolr ad eet | Weakening te cohesive forces “inser a 0 0 Maen eee eee As a result, the vapour pressure of each respect to the ideal behaviour (Figure shows a mit These solutions are known as: boiling point solutions. (Weak attractions in tig Hydrogen bondi cH — La Chloroform sure of a mixture, nega or PHYSICAL PHAR) Un, IDEAL GAS EQUATION ig The general gas laws may be stated as follows, Boyle's la Pressure (P) is inversely proportional to the volume (I) 1 v PY = constant + For a given mass of gas at constant temperaty ture Boyle’s law Px Charles’ law : For a given mass of gas at const wt 42) fant pressure (py volume (V) is directly proportional to the absolute ma temperature (7) te Charles’ aw Ver . vir Combining equations (2) and (3) gives: %) PI SE = constant, k a 3 PY = ir a Although P. Vand 7 change, the ratio remains constnt, Equi (4) is valid for one set of conditions and may be experimental conditions. Ay _ Bh ae extended to two sep 6) Avogadro's law : It states that one-kilogram mole of all gases und the same conditions of temperature and pressure occupies the same volume The volume of | kmol of an ideal gas at 105 pascal and 300 K (26350) is 24.944 m’. The value of k will be the same for all gases, if one kilogram mole of the gas is taken. This value is designated as R. Replacing the constant by R in equation (5) gives: PV = RT 0) Equation (7) is known as gas equation and R is known as gas consta Equation (7) is applicable for | kilogram mole of the gas. For n numberof kilomoles of gas, the general form is: PV = aRT 8) Equation (8) is termed as an ideal gas equation. tis also known combined gas law. Ideal gas law is related to specific conditions or ae (pressure, volume and temperature of a given mass of gas). Theref equation (8) is called the equation of the state. svar os chose which Obey ideal gas equation (PY = nt egy res and pressures src also known as perfect gases. At ordinary seg ane nitrogen and hydrogen. “A majority of pases ng) tarts equation at ordinary temperature and pressure, Rest 1 ideal gas equation, eg. carbon dioxide, oxygen, wc, ste dono O10 ges do not follow precisely, ideal gas equation con te Thou act in engineering calculations, anaes (a) Ideal gas equation helps to convert the volume of sure and pressure to another temperature and, ; ot kilomole of gas under definite conditions (of temperature or pressure) always occupies a definite volume, regardless ofthe ante of gases. This volume is called molar volume. tis useful in the calculation of recovery from a chemical process (© I ving gases eg. production of ammonia by Haber process, (ati used forthe determination of the molecular mass of gases. ) deal gas equation provides the value of R, which has profound (© (pplications in many areas in physical pharmacy. (p) The study and development of thermodynamics are based on ideal gas equation and other gas laws, cae, (b) Ideal Gas Constant (A) ‘The R has different numerieg Jorits calculation. In SI system, JmoLK. SI units make calcul values need not be remembered) notation, Bee ra Applications : R value 206 PHYSICAL Pian Actin, LIQUID CRYSTAL (MESO) PHAsy Solids wh ; hen heated do not directly be converted into Phase, but assume an crystal is am liquid erystat mermediate phase resophase between liquid and solid \ Phage. ig phases (Figure ¢, hi (@) Wem ments | (6) Smectc liquid erystals, © Cotester Layered arrangement i tiga ement is restricted Pere freryran least in one act eae | orca tina Fig. 10-7, Types of liquid crystal phases Nematic (thread- in parallel arran used in develo, to electri about ke) liquid crystal phase : The molecules ae jgement and the rotation is restricted, “The these Ping display systems, because mobile in three direction fields. These are are sensitive ns, but rotate ic (coap-like or grease-like) liquid crystal phase molecules are arranged in layer rater inceh PINE Of layers. It is used for solubility camulsion Ke drugs. ‘Smectic type is frequently observed aah sions and imparts enhanced physical stability, owing othe, ith viscous nature. These are mobilen two directions eurees The S with their axis. essentially o ‘Cholesterie liquid crystal phase : It is ‘and smectic types, i.¢, these are arran; lime layered. Therefore, the fluid is th arrangement is rey Cholesterol is involve combination of nematic din parallel and atthe same hicker. A helical and twist ed, which is slow to change the direction 'd and is observed in Properties of Liquid Crystal The liquid erystals ex are of that of solids. atherosclerosis, hibit some of the properties of liquids and some 2 Liquid crystals are mobile (low Properties of liquids), > Liquid crystals exhibit bi ine fring (like the property of solids), 27 1 colour change with temperature, It is useful for | onl? sion ‘and detection. 2 ace Tmpuications ly aqueous in nature. Many lipids are He int stems Passes and exhibit biological functions ait te ae al liquid crystal and liquid phases, see 7 is present in the bile are cholesterol (in large Oe and wited 1 hese ae resent in incorrect MM ane cis Gaespite, which ra Se to be gall hese exist 88 ubilized, gallstone can be dissolved. ‘Sodium Seneca age Soaernionof the liquid ciysatice phase of si sade 80 Pe Nae chlasteral rapidly dissolved from the is prevented le all tones j steno sis, cholesterol and lipids are incorporated into human Sete iageaiithis ata thc fortatic oe ueoio, sas, which ultimately turn into plaque. Thus, coronary blood ‘auido ardened leading to atherosclerosis. a structures that are believed to be similar to those i crystals have st b baad ioranes. Thus, these can be useful as biophysical models for the ed ing of cell membranes, LIQUID COMPLEXES Liquid complexes i ions in whi ible solids mid | those interactions in which poorly soa thi eae solubility, when dissolved in a liquid (water). i it ute Crain substances form intermolecular complexes with the sol ‘lt na particular liquid (water). This phenomenon is exploited to enhance ‘he aguous solubility of poorly water soluble drugs. The term apparent ‘olbiliy is used, because these systems exhibit higher concentrations: ae About 70 % ofn ‘cube. Solubility sone ofthe’ sponse, lat Solubilization, lecular complexes. Chapter 2) Physicochemical Properties of Drug Molecules Group Contribution Methods Dielectric Constant Dipole Moment induced Polarizability—Induced Dipole Moment Refractive Index and Molar Refraction Optical Rotation Dissociation and Dissociation Constant Determining Dissociation Constant LEARNING OBJECTIVES, ‘After reading this chapter, the reader should be able to:— > Appreciate the nature of physical properties of drugs, liquids and hel applications. > Understand the methods of calculating the physical properties by gua contribution methods or fragmental constants > Explain the principles of dielectric constant and its applications > Explain the principles of dipole moment with relevant. mathemic treatment, applications and chemical structural elucidation. Describe the interaction of ight with liquids, applications and deter of refractive index and molar refraction Describe the concept of polarization of light, applications and determi af optical rotation Understand the concept of dissociation constant and applications Describe Ostwal's dilution law and ts applications | Derive equations for the determination of dissociation constants fore) acids and weak bases and pH of their solutions in water. | Describe the methods of estimation of dissociation constants PP) procedures and advantages. J Physical properties are properties that can be measured of oa without changing the chemical composition of the substance- gical PROT ee ae oct , gperties are the properties of a substance, which ont mice Pe use of animal or isolated organs phsiod HN properties involves the specific interaction ont gy of PhYSES 4a well-defined form of energy or external re 0 ost oncept of weight uses the free of gravity as an eit exe pare the mass ofthe objects. Ideally, the physical inte uence 10 essjly measured OF calculated. Such measurements eral i ” Refractive index > Surface tension applications in the pharmaceutical sciences in These eee ‘A few examples of physicochemical properties are variety Of WAYS: icsociation constant, dielectric constant, dipole partition bility, ete. These are implicated in understanding the drug sama Rito proceres. Some ofthese ae dscunod in tis lve chap. ‘Applications . a 1. Identification of drugs : Physical properties are used for qualitative dnalysis of drugs, E.g. molar refraction and optical rotatory dispersion (ORD). 2. Percentage composition of drugs : Methods are developed for the quantitative analysis of drugs. These methods are used in the ‘quality control of dosage forms and a few of them are official. Eg refractive index, optical rotation and viscosity. Drug synthesis : The physical properties of reactants help in planning the chemical reaction and experimental conditions. The properties of produets decide the isolation and purification steps. For example, distillation method depends on the boiling point (or Vapour pressure) of liquid and contaminants. Elucidation of the chemical structure : Physical properties provide information regarding the spatial arrangement of drug molecules, Eg, dipole moment and molar refraction- From the chemical structure, itis ‘to predict the physical properties. a a Formulation of dosage olecular relationship helps forms such as liquid orals 284 Colligative Property Coltgative number of mok PC my Property is a physical property lecules present in a solution th pends The colligative pro is perty does not depend on the n : ee {nse0us Volume. One mole of any gas at NTP with He il 10 24.944 m’, whether iti onyeense hydrogen or APY aya “iHsatve properties cannot be calculated by up contrban et A few physical properties of drug mols, inne sequent sections, PISS OF drug molecules arg Sica stn DIELECTRIC CONSTANT The dielectric constant is a ‘ i is a physical prope, i asance y EMOLCUF acto pe fs & substance is a measure of its effie = Ac molecule. An elec pieces Of dielectric constant, Voltage source Example: Water molecule, Sipolar nature, € >» 4 Example: Carbon tetrachloride, non-polar naturee > 1 Fig. 12-4 ® Parallel plate condenser. Condenser is one ‘of two parallel plates sep: an store electricity. A simple condenser consis arated by an insulating medium (Figure 12-1), If ap. >> OF DRUG MOLECULES 285 ried across the plates, electricity wll be stored isa perenc® of the medium. i ae rat nbs of electricity that a condenser can store is id er Of COUN ential difference in vols applied across the portional 1 te re expressed a ra ser (coulombs) 2 potential difference (vols) dense constant * potential difference, v ‘i cll Pato je el ae neo ee Oc condense. 4 slectricitY" designated as capacitance, which may be written as: is desis Theeansa ene ~) defined pieleetric constant is pielectric constant __ capacitance of liquid () ‘The dielectric cons relating to the amount charged regions in the separate the same in Vi Diclectrie constant (a) If the conden: is considered of vacuum is substance whic dielectric const is water or ber Dielectric Dielect aa constant Liquid constant UE Sy ag aes] 5 227 Ethylene glycol 3120 Recs 7 naa Carbon tetrachloride 2.23 | Acetone 20.70. Methanol 32.60 | Glycerin 42.50 Methanol 32.60] Hydrochloric acid 4.60 | 1-Octanol ne eS

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