Pharmaceutics (Part I) – Spring 2005 Prof. C. Thompson (SB 383; 243-4643; charles.thompson@umontana.

edu

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Pharmaceutics Class
This document contains lecture notes for Part I of the class (about 4 weeks). These lecture notes are intended as an aid for your note taking and are not comprehensive. Additional/clarifying information, select resources, and practice problems will also be provided in the classroom. Although the notes have been scanned and checked for errors, mistakes are possible so feel free to drop me a line with any corrections.

Helpful Hints (really).
• Relocate your general chemistry book. Briefly review sections on equilibrium, acids & bases. Answer a few calculations of pH problems. It helps to get the feel for the numbers. • Relocate your organic and biochemistry chemistry books. Familiarize yourself with organic functional groups, particularly carboxylic acids and amines. Amines (organic bases) are synonymous with pharmaceuticals and a brief review of their structure and properties will be helpful in this class and beyond. Carboxylic acids will be the subject of a majority of calculations in this class and worth a quick review. Your biochemistry book will have examples and problems in the area of pKa, HendersonHasselbalch, buffers, and ionization. Please review these sections. • Do not ignore the first two helpful hints. Right about now you’re thinking, “Where are those chem. books? Oh yeah, I sold them for a case of Lunch Noodles, I don’t really need them.” • Check those seldom used calculator keys! You will need to calculate log and antilog so find those fun keys on your calculator and reacquaint yourself with them (it may have been a while). Remember that: log (100) = 2, and log (10) = 1. So, when you solve for x in the equation “log(x) = 1.7” does it makes sense that x = 50? Just for fun, push the antilog key about 50 times and let it know who is boss. • Web Assistance: The internet can be an excellent source of information, but beware. In the area of pH, pKa, buffers, etc., about half of them very useful, one-fourth OK and one-fourth had many incorrect statements. I am not responsible for the content in these web sites, or the vast resource of the internet but do encourage you to find instructional materials on the web that complement our topics. One example is an interactive website that allows you to visualize how the Henderson-Hasselbalch equation is graphed. You simply put in the pKa and pH boundaries, and voila, a nice S-shaped titration. Check out the following website and follow the link to Henderson-Hasselbalch weak acid or weak base. http://www.cpb.uokhsc.edu/cc/ • Stay Current. Try to keep up with the assigned problems. This section is short and once you fall behind, it is difficult to catch up. I encourage workgroups but I wish to emphasize the importance of being confident in your own calculations and understanding. At the end of this document is a copy of last year’s exam. Answers will be provided in a few weeks.

C Thompson

Pharmaceutics (Part I) – Spring 2005 Prof. C. Thompson (SB 383; 243-4643; charles.thompson@umontana.edu

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Acids, bases, pH/pKa calculations and the Henderson Hasselbalch equation
Introductory questions: 1. What is the difference between an organic compound that is described as an acid (proton donor) and a compound described as capable of hydrogen bonding? 2. The alkaloid natural product, cocaine is a “nitrogenous base” typically isolated as the hydrochloride salt. a. What is a nitrogenous base? b. What is a hydrochloride salt? c. What benefits if any would result from forming an alternate salt (e.g., HBr, HI, benzoate, maleate, and succinate) with cocaine? 3. Three common classifications of organic compounds are polar non-protic, polar protic and non polar. a. Which class is more likely to penetrate skin? Why? b. Which class is more likely to dissolve in saliva? Why? c. What is DMSO and which class does it belong? d. One compound class that is not included is non-polar protic. Can a molecule with these properties exist? e. How do these “chemical” properties relate to lipophilic/hydrophobic or lipophobic/hydrophilic? 4. Almost all modern drugs are “organic,” that is, they contain one or more carbon atoms. Name some inorganic drugs that pharmacists MUST be knowledgeable of. 5. What percentage of drugs currently prescribed is likely to be in use in 5 yrs, 10 yrs, and 25 yrs from now? How will an understanding of basic molecular properties enable you to withstand this change?

Pharmaceutics (Part I) – Spring 2005 Prof. C. Thompson (SB 383; 243-4643; charles.thompson@umontana.edu

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Acids & bases
Keywords: acid base buffer Henderson-Hasselbalch equation Objective(s): • • • • Restore understanding of fundamental acid-base ionization equilibria. Relate acidity and basicity of organic compounds to that of water. Conduct and gain confidence in ionization calculations. Gain a basic understanding of the physiologic importance/implication of drug ionization – specifically in relation to absorption, transport, and excretion. pH ‘salt’ pKa ionization equilibria

Definitions and descriptions: Hydrogen ions (H+): Hydrogen ions (H+), or protons, do not have electrons, but can bond to nitrogen or oxygen containing molecules because nitrogen and oxygen have “non-bonding” pairs of electrons. Hydrogen ions cannot bond to carbon since carbon does not have “non-bonding” electrons. Acids: According to the Bronsted-Lowry theory of acids and bases, an acid is a substance capable of donating a proton, or hydrogen ion (H+) to a base. Bases: A base is a substance that is capable of accepting a proton from an acid. pH: A method of expressing the hydrogen ion concentration [H+], or more correctly, hydronium ion [H3O+] concentration in solution. pH is equal to the negative log of the molar hydrogen ion concentration. pH = -log[H+] pOH: A method of expressing hydroxyl ion (OH-) concentration in solution. pOH is equal to the negative log of the molar hydroxyl ion concentration. pOH = -log[OH-]

pOH 2. [OH-] = 10-7 and therefore [H+] = [OH-] and pH = pOH. the OH. This is neutral pH (pH = 7).thompson@umontana. the H+ concentration b. C. 243-4643. you chlorinate your hottub on a regular basis and find the pH = 5. As a successful pharmacist.000001 M solution of hydroiodic acid (HI) what are: a.edu Page 4 IONIZATION OF WATER Kw and pKw: Water ionizes (dissociates) slightly to yield hydronium and hydroxyl ions: H2O + H2O H3O+ + OH- The dissociation constant for water is Kw: Kw = [H3O+] x [OH-] . For a 0. charles. how do pH and pOH correlate? Some pH examples: [H+] 10-1 10-5 10-7 10-10 10-14 1 pH 1 5 7 10 14 0 [OH-] 10-13 10-9 10-7 10-4 1 10-14 pOH 13 9 7 4 0 14 Kw 10-14 10-14 10-14 10-14 10-14 10-14 pKw 14 14 14 14 14 14 Note: At [H+] = 10-7. the pH c.Pharmaceutics (Part I) – Spring 2005 Prof. Thompson (SB 383. 1.concentration d. Questions: 1. What is the concentration of H+ and molarity of HCl? .0 x 10-14 pKw is equal to the negative log of the dissociation constant of water: pKw = -logKw = pH + pOH = 14 So.

the forward and reverse reaction rates are the same.Pharmaceutics (Part I) – Spring 2005 Prof. and the relative concentrations of reactants and products and remain constant. In comparison to HCl. 243-4643. This is an attribute of many strong acids – the conjugate base is stable while bearing a negative charge..thompson@umontana. Thompson (SB 383. C. phenol has a weaker tendency to ionize and the conjugate base.is ‘stable’ just the way it is. In the laboratory phenol is used to lyse cells! Anti-bacterial activity was increased by increasing the waxy chain to enhance membrane infiltration. This means the conjugate base happily accepts the extra electron.). As a result. etc. methyl. charles. This further indicates that Cl.g.HCl is considered a strong acid because it has a strong tendency to ionize resulting in a large [H3O+] and the reverse reaction occurs only to a small amount. phenoxide ion. At equilibrium. . what effect on the ionization might they have? One example of how the phenol structure has been altered to achieve the desired pharmacologic property is the anti-bacterials: Fun fact: Phenol causes some of the most serious and damaging chemical burns to the skin. What this means is that Cl. OH + H2O H3O+ + O- Question: When substituents are added to the aromatic ring (e. That means that there is a forward reaction and a reverse reaction. Strong acids are completely ionized at all pH values (pH independent ionization). HCl + H2O H3O+ + Cl- Weak Acid – Phenol is a good example of a weak acid. nitro. the equilibrium shifts further to the left and the acid (protonated) form of phenol predominates. is moderately strong. Strong and weak acids: Strong acid .edu Page 5 ACID-BASE EQUILIBRIA AND IONIZATION OF ELECTROLYTES Acid-Base Reactions: Acid-base reactions are equilibrium reactions.is very weak as a conjugate base and not likely to accept a proton. Hexylresorcinol and hexachlorophene are used in hospital sterilization methods.

charles.8 17. An equilibrium constant (K) can be defined that is equal to the forward rate constant (kf) divided by the reverse rate constant (kr).thompson@umontana. Explain the increasing trend in pKa values (table at right) for the alcohols and the “unusual” drop in pKa for phenol relative to the other alcohols. the “switch” of an H for a Me. C. Et.edu Page 6 In general.4 16. It is also equal to the product concentrations divided by the reactant concentrations: K = kf kr = [A-][H3O+] [HA][H2O] since water is constant @ 55 M Ka = 55M = [A-][H3O+] [HA] Ka is a measure of (weak) acid strength as expressed by the concentration of ionized molecules divided by the concentration of unionized molecules.8 16. for a weak acid: HA + H2O kf kr H3O+ + A(conj base) Note that the product (A-) is designated as the conjugate base. Thompson (SB 383. Question: Alcohol are organic ‘analogs of water meaning they share the identical functional group (OH) but vary in one component. etc. R-OH H-OH (water) MeOH (methanol) Et-OH (ethanol) iPr-OH (isopropanol) t-Bu-OH (tert-butanol) Ph-OH pKa 15.Pharmaceutics (Part I) – Spring 2005 Prof. 243-4643. The conjugate base is also known as the salt of the acid when combined with a counterion such as Na+ to give Na+A-.2 18 10 .

1/2(logC) or .log C) pH = 1/2(pKa) . pKa = -log(Ka) As the acid strength increases. so does the Ka. Because the scale is log-based. which relates the strength of weak acids on logarithmic scale.log C) pH = 1/2 (-logKa . Thompson (SB 383. the ionization in water is: HA H+ + A(conj base) Which can be expressed as: Ka = [A-][H+] [HA] Ka = [H+][H+] = [H+]2 [HA] [HA] [H+] = With no other ions in solution. 243-4643. the pKa decreases as the acid strength increases. the concentration of H+ and A. charles.Pharmaceutics (Part I) – Spring 2005 Prof. It provides a means to compare the acidity of a class of compounds or across classes of compounds in whole numbers.edu Page 7 Trends to consider based on the Ka equation: As acid strength increases (8): Ka increases [A-] increases [H3O+] increases [HA] decreases A helpful utility is pKa. therefore: and [H+]2 = Ka[HA] Ka[HA] KaC Rearrange and substitute to: [H+] = This equation in bold is useful for calculating the pH of a weak acid in water when you know the molar concentration and the pKa of the weak acid or drug (usually found in tables). if you take the -log of each side: -log[H+] = 1/2 (-log Ka .thompson@umontana.should be equal and. which is fine for most comparisons. comparisons are typically based on ten-fold increments. C. For weak acids. However.

Ka and pKa are generally used for both acids and bases because pKa uses the same scale and goes in the same direction as pH. For bases. which reacts with water to form ammonium hydroxide (NH4OH or NH4 + / OH-). B: + H2O BH+ (conj acid) + OH- Note that the product (BH+) is designated as the conjugate acid.thompson@umontana. C. as base strength increases: Ka decreases pKa increases . Weak Bases. Ka and Kb are related: pKa and pKb are also related: Ka x Kb = Kw = 1. Kb is mostly unused and has been replaced by Ka. if the Ka and pKa terms are used.0 x 10-14 pKa + pKb = pKw = 14 So. BH+.Pharmaceutics (Part I) – Spring 2005 Prof. 243-4643.to give BH+Cl-. The basicity constant is defined as Kb (expressed similarly to the Ka) and is a measure of base strength. Ka and pKa indicate the strength of the conjugate acid. One example of a weak base is ammonia (NH3). When base strength is increased the equilibrium is moved to the right.edu Page 8 Question: Calculate the pH of a 0.76 at 25 oC. The conjugate acid is also known as the salt of the base when combined with a counterion such as Cl. Ammonia has a weak tendency to ionize and the conjugate acid is strong: the equilibrium favors the left side of the equation.1 M solution of a drug at 25 oC. Weak bases react with water to take up hydrogen atoms to form a conjugate acid resulting in hydroxyl ions that turn the solution alkaline (basic). charles. Thompson (SB 383. The pKa of the acid is 4.

N + H2O NH+ + OH- Question: Amines rarely give up a proton and behave like an acid.06 x 10-3. Why does the proton on phenobarbital (above) act like an acid? . pKa = 5.9 x 10-8. pKa = 7.76 O OH + H O 2 O O.edu Page 9 Examples of pKa Acids and bases: Acetic acid: Ka = 1.41 O Et Ph O H N O N H + H2O O Et Ph O H N O N+ H3O+ Pyridine: Ka = 7. Ka = 4. charles.1 x 10-6.15 (the pyridinium or protonated form is the acid). 243-4643.thompson@umontana. C.+ H O+ 3 H3C C H3C C Salicylic acid: Ka = 1.75 x 10-5.Pharmaceutics (Part I) – Spring 2005 Prof.97 CO2H + H2O OH salicyclic acid CO2 OH + H3O+ Phenobarbital: Ka = 3. Thompson (SB 383. Ka = 2.

pKa and/or the relative amounts of acid and base in a solution. Also important to consider is that the ionized form of a drug. It can be used for both weak acids and weak bases and primarily for the following: calculating the ratio of base to acid when the pKa and pH of the solution are known. may not bind the receptor or target whereas the neutral form of the drug does. C. charles. Most drugs are weak acids or bases.…please note the range in pKa. calculating the pH of a solution if the ratio of base to acid and the pKa are known.2 8.5 to 11 Compound RNH3+ (protonated primary amines) HCO3RSH (sulfides) water ROH (alcohols) RC(O)NH2 (amides) alkanes pKa 10 to 11 10. phenobarbital. calculating the pKa if the ratio of base to acid and pH of the solution are known.3 10 to 11 15. One of the more important features of the HH equation in Pharmacy is the ability to predict the proportions of ionized and unionized forms of a drug at a given pH. . 243-4643. metabolism. and excretion. net effect.4 4 to 5 6. and pyridine are examples of weak acids and bases. may permit better prediction of the physiologic effect. small changes in the local environment can have a dramatic effect on uptake.edu Page 10 Some pKa’s of interest.thompson@umontana. Acetic acid. for example. [This information can be used to prepare buffer solutions]. Careful use of the HH equation.Pharmaceutics (Part I) – Spring 2005 Prof. Henderson-Hasselbalch Equation . therefore. correlation with water Compound sulfuric acid hydrochloric acid nitric acid RCOOH (carboxylic acids) H2CO3 NH4+ phenol pKa -9 -7 -1. Since pH varies in vivo depending on the system/location and a one (1) pKa unit difference results in a ten-fold change in the ionization (log scale). Thompson (SB 383.3 9.7 15 to 18 17 to 18 48-50 Weak acids and bases are weak electrolytes meaning that they are only ionized to a small extent (less than 1%) in solution. Weak acids have Ka values which are << 1 and positive pKa values. distribution..Utility The Henderson-Hasselbalch equation can be used to determine pH.

C. pH = pKa + log [conj base] [acid] .thompson@umontana.logKa + log [A-] [HA] or pH = pKa + log [A-] [HA] finally. in descriptive terms.edu Page 11 From the equilibrium and Ka equation: HA + H2O H3O+ + A(conj base) Ka = [A-][H3O+] [HA] [A-] [HA] the following equation can be derived: Ka which in log form is converted to: = [H3O+] log or Ka [H3O+] = log [A-] [HA] = logKa . charles.Pharmaceutics (Part I) – Spring 2005 Prof. Thompson (SB 383.log[H3O+] log [A-] [HA] log[H3O+] = . 243-4643.

alcohol.99 99. Question: Which form of a carboxylic acid (carboxylic acid or carboxylate anion) is more likely to traverse cell membranes? . 243-4643.edu Page 12 Key points: One important thing to keep in mind is that the weak acid is the proton donor. However.5).pKa = log [conj base] [acid] In this instance.1 0.9 99. the drug would remain in the protonated.8-7.01 0. sulfide or even amine hydrochloride. Thompson (SB 383. 6. base 99.thompson@umontana.000 % acid 0.Pharmaceutics (Part I) – Spring 2005 Prof.1 1 9 50 91 99 99.1 0. one could get a “sense” for the amount of acid and base forms. That means the “form” or “structure” of the acid may vary as a carboxylic acid.01 0. but the real issue is to keep “trends” and ratios at the forefront. for example.000/1 1000/1 100/1 10/1 1/1 1/10 1/100 1/1000 1/10. Using the table above. You can rearrange the equation to solve a number of calculations.01 % unionized 0.pKa 4 3 2 1 0 -1 -2 -3 -4 [base] [acid] 10.2.9 99 91 50 9 1 0. acid form.1 1 9 50 91 99 99. C. there will be an equal amount of ionized and ionized (because the log of zero = 1).99 % conj.01 Note that when the pKa = pH. That is.99 % ionized 99.9 99 91 50 9 1 0. For example.99 99. in the stomach.9 99. at pH 1. So. one could determine that the drug was deprotonated at physiologic pH (approx. the difference between the pH and the pKa (typically defined for the drug in question) can tell you how much of one form the drug is in (ionized or unionized). rearrange the equation to get an understanding of the acid to base ratio as follows: pH . Important: this difference is logarithmic! pH . if a drug contained a carboxylic acid group that had a pKa of 4. the carboxylic acid group lost its proton to form the ionized carboxylate. charles.

Pharmaceutics (Part I) – Spring 2005 Prof. Talk about high doses! Contrast agents are administered as 100 mL of a 60% solution. Osmotoxicity! Examples of other drugs that are salts of weak acids and their counterions: 1.” And. Fun fact: There are five radiologic x-ray densities: air. the contrast agent is cleared rapidly from the body (t ½ = 2 h). Certain compounds increase the radiographic contrast b/c they have x-ray absorption characteristics that afford a ‘bone-like’ or metal-like’ density. spleen. intestines. fluid. as many know. 243-4643. charles. all of which show up differently on “film.g.edu Page 13 Salts of Weak Acids In chemistry classes we learn that metals like sodium. Penicillin G potassium K+ . bladder. the formation of the sodium salt adds significant water solubility. imide or other ionizable group.thompson@umontana. C. Compounds that fall into this class are iodinated aromatic compounds (bone-like density) and barium salts (metal like density). potassium and calcium are common counterions for salts of drugs that are weak acids. fat. Thompson (SB 383. phenol. There is no significant penetration into intracellular matrices and moreover. which allows the contrast agent to distribute evenly throughout extracellular space. Warfarin sodium Na+ 3. many organs and tissues do not show up well on traditional x-ray. Salts of weak acids have the general form R-M+ where R is a carboxylic acid. e. R O OH O OH R N H O R Question: Why is lithium not used as a countercation for drugs that are weak acids in salt formation? Example of drug salt formation: O Et Ph O Phenobarbital NH O NH NaOH Et Ph O O NH O N Na Phenobarbital sodium CO2 Na I CO2H I H3C(OC)HN I NaOH I H3C(OC)HN radiologic contrast agent C(O)NHCH3 I Iothalamate C(O)NHCH3 I Iothalamate sodium In the case of the radiologic (x-ray) contrast agent. Fenoprofen calcium Ca+2 2. iothalamate. liver. and abdominal muscles (all have similar density and ‘shadow’ each other). bone and metallic.. kidneys.

charles. Both classes are capable of being protonated by an acid to form an amine or aniline salt.Pharmaceutics (Part I) – Spring 2005 Prof.thompson@umontana. 243-4643.edu Page 14 Salts of Weak Bases Most of the weak bases of interest to pharmacists are the amines and anilines. Question: Why are the pKa values so different for amines and anilines? Another example of a base is the aromatic heterocycle pyridine.g. The acid used to do the protonation contains a conjugate anion that forms the anion after the amine has been protonated. primary amine R1 NH2 HA R1 NH3 A R1 H secondary amine R1 N H R2 tertiary amine R1 R N 2 R3 HA R1 R2 N H A R3 NH3 A where R1. C. Its structure appears in many drugs and it readily forms salts with mineral and weak acids. Thompson (SB 383. R2 and R3 are various alkyl/aryl groups and A is the conjugate base. Br. N pyridine HCl N H Cl pyridine hydrochloride Examples of drugs that are salts of weak bases and their counterions: Meperidine hydrochloride Dextromethorphan hydrobromide Atropine sulfate Codeine phosphate Biperiden lactate Ergotamine tartrate Chlorpheniramine maleate Benztropine mesylate ClBrSO4-2 PO4-3 CH3CHOHCOO-OOCCHOHCHOHCOO-OOCCH=CHCOOCH3SO3- . etc.. aniline NH2 HA HA N R2 H A Amines have a pKa ranging from 9-11 and anilines have a pKa 4 to 5. Cl. e.

.edu Page 15 Lets examine the “organic” salts a little closer. Some other important considerations in the use of these acids include: (a) low cost. Amines comprise one of the largest classes of organic molecules used as pharmaceutically important drugs. 243-4643. The amine and one of these acids (for example) combine to form an amine salt. OH H3C CO2H HO2C OH tartaric acid from $10-100/kg maleic acid OH CO2H HO2C CO2H lactic acid These carboxylic acids serve as proton donors to weakly basic amines.Pharmaceutics (Part I) – Spring 2005 Prof. (c) high stereochemical purity.thompson@umontana. Maleic acid is the cis isomer – the trans isomer is called succinic acid (succinate). and (d) potential to serve as ‘dual’ or as a twofold proton donor (e. . charles. (b) high chemical purity. You are likely to see all of these acids in advertisements for pharmaceuticals. which improves its water solubility. tartaric acid and maleic acid). C.g. Thompson (SB 383.

Thompson (SB 383. buffer equation buffer capacity Definitions and descriptions: Buffer – A buffer is a solution that resists pH changes when acids or bases are added to the solution.edu Page 16 BUFFERS Keywords/Concepts: buffer Objective(s): • • • • Restore understanding of buffer systems and establish importance for use. tris(hydroxymethyl)aminomethane "Tris" OH tris(hydroxymethyl)aminomethane hydrochloride "Tris HCl" OH HO NH2 OH HO NH3 OH Cl . Most buffer solutions consist of a weak acid and its conjugate base (salt of the weak acid). 243-4643. Common Examples of Weak Acid Buffer Systems. Define preliminary physiologic buffer systems.thompson@umontana. C.Pharmaceutics (Part I) – Spring 2005 Prof. Gain confidence in selecting pharmaceutical buffers. Acetic acid Boric acid Citric acid Phosphoric acid Sodium acetate Sodium borate Sodium citrate Potassium phosphate Examples of Weak Acid Buffer System. charles. Develop the physicochemical relationship between weak acids and bases and buffer systems.

pH (room temp) 3. Thompson (SB 383.5 6.ratio. the assumption here is that the concentration of buffer salts exceeds that of the acid being introduced to the solution and therefore.6 2. C. the pH change is relatively small.6 3. which is converted to the conjugate base (A-). Added bases are neutralized by the acid (HA).edu Page 17 The pH of some ‘well known’ liquids containing buffer systems: Product Apple juice Club Soda (Schwepps) Coffee (instant) Diphenhydramine Distilled Vinegar Gatorade Ipecac Listerine Pepsi Robitussin DM Saline USP Visine Buffer Properties and Function: When acids or bases are added to pure water.8 6.ratio will also change the pH. charles.7 3. 243-4643.thompson@umontana. the pH change is related to the log of the change in the HA/Aratio. . Therefore.7 5. there is a large number of “solvation ions” (halleluiah) to handle. Added acids are neutralized by the conjugate base (A-) which is converted to the acid (HA).1 4.system (equilibrium). However…… we know that from the Henderson-Hasselbalch (buffer) equation. Addition of acids or bases therefore change the HA/A.9 2. respectively. changes in the HA/A.7 5. they immediately produce H3O+ or OH. Buffer systems resist large pH changes because added acids or bases are neutralized by the existing HA/A.ions that decrease or increase the pH.Pharmaceutics (Part I) – Spring 2005 Prof.0 2. However.0 1.3 Also.

the pH change which results from the addition of an acid or base to a buffer solution In most cases. you will need to know the pKa of the weak acid to conduct these calculations. 243-4643.170 M HCl and diluting to 100 mL with water. the smaller the change in pH from the addition of a given amount of strong acid or base.03 moles of NaOH was added to an acetate buffer system prepared at 0. [Tris: mw 121 g/mol and pKa = 8. The buffer equation can be used to calculate: • • • the pH of a buffer solution when the HA/A. charles. Thompson (SB 383. when 0. The buffer index number is generally experimentally derived in a manner like a titration (see Table below).11 .Pharmaceutics (Part I) – Spring 2005 Prof. the pH expectedly increased from 4.1 M. C.27 = 1/9 = 0.03/0.edu Page 18 The Buffer Equation(s): The buffer equation is the Henderson-Hasselbalch equation adapted to consider acids and their conjugate bases leading to solutions that are resistant to pH change. a change of 0. the HA/A. Buffer capacity is dependent on the total concentration of the buffer system and on the HA/A. The following forms of the buffer equation are useful for buffer calculations: pH = pKa + log B/A (useful to calculate the pH of the buffer solution) pH . the equation β = δB/∆pH = 0.thompson@umontana.27 pH units.ratio.ratio is known.pKa = log B/A (useful to calculate the ratio of base to acid ) pKa = pH + log A/B (useful to calculate the pKa of a buffer at a known pH) pKa . Therefore.03.08 for the conjugate acid] Buffer Capacity: The ability of a buffer system to resist pH changes is its buffer capacity and indicated by the buffer index (β): β = ∆B/∆pH where: B = strong base (in molarity) ∆ = change (delta) Buffer capacity is defined as the number of equivalents of strong base (∆B) required to cause a one-unit change in pH (∆pH ) in 1 L of solution. For example. The greater the buffer capacity.ratio required to give a buffer of a given pH.pH = log A/B (useful to calculate the ratio of acid to base) Question: Calculate the pH of a buffer solution prepared by dissolving 242 mg of Tris in 10 mL of 0.76 to 5.

High or low pH can cause tissue irritation. Also. charles. doubling the total molar concentration of the buffer system will double the buffer capacity at a given pH).The unionized form of a drug is more lipid soluble than the ionized form. Buffer capacity is increased by the following factors: increasing the concentration of the buffer system components (e. Absorption . ester drugs are very susceptible to hydrolytic reactions.using equimolar concentrations of the acid (HA) and its conjugate base (A-). Ophthalmic products are least irritating at pH 7-9.Pharmaceutics (Part I) – Spring 2005 Prof.The ionized form of a drug is more water soluble than the unionized form.edu Page 19 Note that the buffer capacity is highest when the smallest number of moles of NaOH are added. The unionized form therefore penetrates biological membranes much more efficiently than the ionized form. Buffer capacity is maximal when pH = pKa ([HA]=[A-]).thompson@umontana. Buffering formulations at low pH (pH 3-5) can reduce the rate of hydrolysis. buffers can also be used to maintain the drug in its unionized form. C. Tissue irritation . Stability . except the pH would decrease in these experiments.g. . Why use buffers in pharmacy? Solubility . Buffers can be used to maintain a drug in its ionized (salt) form for aqueous solutions.pH can affect the stability of a drug in an aqueous solution. For example. the buffer equation can be adapted for the addition of acids. Thompson (SB 383. 243-4643. Buffering a formulation to near neutral pH can reduce tissue irritation. .

Choosing the Right Pharmaceutical Buffer : • • • • • Choose a weak acid with pH » pKa. Use buffer equation to calculate ratio of acid/base needed to give required pH.9 or pH > 7. Important endogenous (natural) buffer systems include carbonic acid/sodium bicarbonate and sodium phosphate in the plasma and hemoglobin. at least. Choose available ingredients considering sterility.8 can be life threatening. charles. Use pH meter or. Pharmaceutical solutions generally have a low buffer capacity in order to prevent overwhelming the bodies own buffer systems and significantly changing the pH of the body fluids. Buffer concentrations of between 0. 243-4643.thompson@umontana.5 M and buffer capacities between 0. toxicity. An in vivo value of pH < 6. stability. Choose concentration needed to give suitable buffer capacity. pH indicator paper.4. cost. C. .edu Page 20 Buffers and the Body: Body fluids contain buffering agents and buffer systems that maintain pH at or near pH=7.05 and 0.1 are usually sufficient for pharmaceutical solutions.01 to 0. and potassium phosphate in the cells.Pharmaceutics (Part I) – Spring 2005 Prof. Thompson (SB 383.

charles.8 to 5.6 . citrate): Buffer System Acetic acid/sodium acetate Phosphoric acid/sodium phosphate H3PO4/NaH2PO4 NaH2PO4/Na2HPO4 Na2HPO4/Na3PO4 Citric acid/sodium citrate pKa 4.8-10. C.6 5 to 8 1.edu Page 21 PHARMACEUTICAL BUFFER EXAMPLES The following are some buffer systems that are used in the formulation of pharmaceuticals.8(pK2) 9.2 7. Thompson (SB 383.thompson@umontana.3(pK3) 3. phosphate.6 Boric acid/sodium borate 9.Pharmaceutics (Part I) – Spring 2005 Prof.g. Most pharmaceutical buffers are composed of ingredients that are found in the body (e.2 to 6.2(pK3) buffer pH range 3.76 2. acetate.1(pK1) 4. 243-4643.1(pK1) 7.2(pK2) 12.

depending on the relative charges. lysine. Ionic Bonds – a. Thompson (SB 383. opposite charges hold ions together. charles.edu Page 22 BONDING Bonding and molecular interactions: Understanding the basic forces that hold molecules together is important for understanding how molecules interact with each other. in part. C. worth anywhere from -40 to -110 kcal/mol in stability.by virtue of varied electronegativity values when compared to carbon certain groups have an asymmetric distribution of electrons that produce dipoles. For ionic bonds. Bonds in the molecule at right are all covalent even though some are single. The dipoles in a drug molecule.. These interactions affect solubility. Although most drug interactions are non-covalent. at physiologic pH basic side chains of certain amino acids like arginine. If an ionic attraction is reinforced by other interactions (H-bonding.0 kcal/mol. the interaction is generally weaker (G ranges from -1 to -7 but is usually -1 to -2). can find complementary dipole interactions in the receptor. since the net charge on a dipole is less than on a full ion. A simple ionic attraction can provide as much as -5. Dipoles exist where one atom (X) is more electronegative than another (H). As an example.the strongest bond (arrows).Pharmaceutics (Part I) – Spring 2005 Prof. etc) is can provide up to -10. However. cationic drug with anionic receptor site. Electrons are not shared. alkylation of DNA for example in cancer chemotherapy is an example of covalent bond formation by drugs.g. e. Ion-dipole and dipole-dipole Interactions . stability and other properties of drugs. therefore.0 kcal/mol and declines as the square of the distance between the charged sites. but are transferred. Dipolar interactions refer to unequal distribution of charge within a bond or a molecule. Like charges repel each other and opposite charges attract. 243-4643. and. δ- O + δ + δδδ+ δ δδ+ δ F O. Electrostatic interactions can be attractive or repulsive.H δ+ δ . Therefore.a. Acidic groups like aspartic and glutamic acid are deprotonated to give negatively charged groups. drugs and their target receptors can be mutually attracted by opposite charges on their surfaces.thompson@umontana. Not shown are the carbon-hydrogen bonds that are also covalent. double or triple bonds.k. histidine are protonated and therefore provided a cationic environment. BOND TYPES Covalent Bonds .

1 to -2. alkyne.0 kcal/mol. It is important to consider in this interaction that each receptor and drug molecule aliphatic chain is surrounded by water molecules. methoxy. 243-4643. Hydrogen bonds for example.Some atoms on mostly non polar molecules experience or exert a temporary non-symmetric distribution of electrons to cause a dipole. charles. cyano. Charge Transfer Complexes .simply a variation of a dipole-dipole interaction formed between the proton of one group and an electronegative atom of another group.thompson@umontana. aromatic moiety) that bears a good electron donating group (alkyl. S. Hydrophobic Interactions . carbonyl. drug molecule R1 R2 δ O + O R4HN δ− δ+ NHR δ− R3 receptor target . The interaction is rare and most likely found with the tyrosine residue on certain receptors (as the donor).involve a non-polar/non-polar interaction between receptor and drug.Pharmaceutics (Part I) – Spring 2005 Prof. Usually alkyl chains are found to stack as in the lipid bilayer except this is for a single interaction. Further. Van der Waals or London Forces . The G for hydrogen bonding ranges from -1 to -7 kcal/mol but in biosystems is usually between -3 and -5 kcal/mol.). N N H N NH2 There are two forms of hydrogen bonds . SR. The interaction involves transfer of charge from donor to acceptor. and as the chains approach each the water molecules are squeezed out to permit the non-polar chains to align with each other in a "side by side" position. C. Electron donor groups or molecules usually contain a -bond (alkene. etc. In molecules of biological interest the hydrogen bonds most widely experienced are when X = O.).1 to -2.this attraction comes about when molecules containing a good electron donor group (on an aromatic ring) interact with a molecule that contains an electron-withdrawing (acceptor) group.g. are important in maintaining the structural integrity of peptides and proteins . This orienting results in a drop in the free energy of about 0. Thompson (SB 383. OR. etc.. halogen.-helical structure and -sheets derive their structure from hydrogen bonds. Hydrogen bonds are usually denoted by a dashed or dotted line as in the case of the DNA bases at right sharing two hydrogen bonds: O O N H O H N NH What makes hydrogen bonds so unique is that hydrogen is the only atom that can carry a positive charge at physiologic pH while remaining covalently attached to a molecule. N.edu Page 23 Hydrogen Bonds . The G varies greatly and values from -0.intramolecular (within a single molecule) and intermolecular (between two molecules). The G for charge-transfer complexes range from -1 to -7 kcal/mol. the opposite dipoles attract forming an interaction. Acceptor groups or molecules usually contain a π-bond with electron withdrawing groups attached (e. As these atoms approach each other in different molecules.0 are reasonable. hydrogen is small enough to permit close approach by another electronegative atom or molecule to accept the hydrogen bond.

A saturated solution is one in which the solvent has dissolved all of the solute that it can. dipole-dipole (van der Waals) and hydrogen-bonding forces may be involved in solutesolvent interactions. When excess solute is added to a saturated solution. and addition of further solute will not increase the concentration of the solute in the solvent. the intermolecular attractive forces between solute molecules and between solvent molecules must be overcome and replaced with solutesolvent attractive forces. an equilibrium will exist between the solid solute and the solute in solution. Electrostatic. Thompson (SB 383. charles. Solutions are the result of intermolecular attractive forces between solutes and solvents. . In order for a solute to dissolve in a solvent. 243-4643. C.thompson@umontana.Pharmaceutics (Part I) – Spring 2005 Prof.edu Page 24 SOLUBILITY Solubility is the maximum concentration that can be attained by a solute in a specific solvent.

Solubility (water as a solvent): In part. Aggregates of water form easily based upon hydrogen bonding." Compare this phenomena to a truly ionic compound in solution that is fully ionized. so pH is very important for the solubility of weak electrolytes. Packets of water exist in flux.. • temperature: Increasing temperature generally increases solubility. delivery agent. water has a very high dielectric constant (Debeye = D = 80) as compared to the organic solvents acetone (D = 21) or hexane (D = 1 to 2).and extracellular domains. 243-4643. nucleophile. Think of a microscopic droplet of oil surrounded by water (as represented by an organic compound). a vibrating. the compound dissolves (e. the structure of the water cluster also is altered to form an envelope or "breaker" in the structure. some basic properties of water are illustrated: bond angles. Therefore. • pH: Weak acids and bases are more soluble in their ionized (conjugate base or conjugate acid) forms than their unionized forms. different polymorphic forms. the flux adds to the "solvent" properties of water. pH. Ice takes on a tetrahedral geometry and although the structure of ice does not play a significant role in vivo. Why is water important toward an understanding of drug action? It is the universal solvent. Also. As a result of solvation. When the heat of solvation is favored over the energy stored in the stability of the crystal lattice." for example. For some neutral organic molecules a different physicochemical process is involved. It also is responsible for certain aspects of protein structure (conformation). Thompson (SB 383. rotating. C. Recall that certain organic compounds forms "ions. and the physical form of the solute. and primary source of H+ and OH. Charged species are generally more soluble in water and neutral compounds. To effect a spectrum of solubility characteristics.in vivo. solvates and hydrates will have different solubilities. a few solutes have a negative heat of solution which means that they give off heat during dissolution and solubility decreases with increasing temperature. Within this description. rapidly reorganizing environment. Due to a high dipole. and other phenomena where H-bonding plays a role. we ask the following question: . some organic molecules have an ionic character and fall somewhere in between an "inclusion" complex and solvation. the structure of water does vary depending on its environment and local temperature.Pharmaceutics (Part I) – Spring 2005 Prof. • physical form: Non-crystalline (amorphous) solids are generally more soluble than crystalline solids.thompson@umontana. [Note: highly polarized solvents favor "polarized" transition states. Water as solvent. the formation and structure of the lipid bilayer and other important intra. carboxylic acids (oxyanions) and amines (nitrogen cations). NaCl). In comparison. water is capable of breaking the electrostatic attraction of ions (crystal lattices) to favor hydration. Such complexes between a solvated species and the water are called "clathrates. Most solutes absorb heat upon dissolution and have a positive heat of solutions.edu Page 25 Solubility can be affected by temperature. In the figure below. charles. These terms will be discussed later. dispersing agent. The water exerts a solvation effect on the compound and the compound exerts a "disturbance" on the H-bonded water environment.] With a high dielectric constant. The water molecule is not linear. H-bonded and intermingled.g. water is not inert. charge distribution and H-bonding.

fat phase loving. Non-polar solvents: • Ionic and polar solutes are poorly or not soluble in non-polar solvents because the solvent cannot reduce the attractive forces between the solute molecules (ionic or dipolar or hydrogen bonding). but tissues (e. Some trends for organic molecule solubility in water: a.. aqueous phase hating Hydrophilic. fat phase hating Amphiphilic. • Non-polar solvents can dissolve non-polar solutes through induced dipolar interactions (non-polar solutes are held together weakly unlike polar solutes) .g.thompson@umontana.a lipophilic). charles. aldehydes.. aqueous phase loving. C.g. Water can also dissolve (to some extent) other O. Where will the drug go? Why is this important? This question is important because all biochemistry processes are based upon small amounts of organic molecules dispersed in the aqueous or lipid (organic) phase or both. Water can also dissolve the salt (ionic) forms of weak acids and weak bases (the conjugate base and conjugate acid forms of weak acids and weak bases).k. tissue membranes) and the cavities of certain proteins have an organic environment. serum) and fat (organic layer). Water is miscible with other liquids such as ethanol and methanol meaning that they can be mixed in any (unlimited) proportion to form a homogeneous liquid. molecule with branched chains are more soluble than linear chain c. Polar solvents • Polar solvents (e. amines. Circulating fluids (blood) have aqueous characteristics. up to five carbons with one functional group are usually soluble.and N-containing compounds including alcohols.Pharmaceutics (Part I) – Spring 2005 Prof. b. phenols. water solubility deceases with increase in molecular weight Some nomenclature used to describe solubility that you should be familiar with: o o o Hydrophobic (a. filled with water (aqueous layer.g. water. 243-4643.edu Page 26 To what extent are organic molecules soluble in water? Consider the body as a huge separatory funnel. has atomic characteristics to permit solubility in both phases Solvent-solute interactions: As a general rule: like dissolves like so polar solvents dissolve polar solutes and non-polar solvents dissolve non-polar solutes. ketones. methanol) readily dissolve polar solutes such as salts (ionic compounds). These compounds contain polar groups which can hydrogen bond with water. sugars and other polyhydroxy compounds. e. Thompson (SB 383.

243-4643. Thompson (SB 383.edu Page 27 acetone = ketone solvent.thompson@umontana.Pharmaceutics (Part I) – Spring 2005 Prof. Solubility Terms: . C. charles.

Lipid solubility for crossing biological membranes and aqueous solubility for distribution into the systemic circulation and other biological fluids. • Lipid vs. 243-4643.Pharmaceutics (Part I) – Spring 2005 Prof. aqueous solubility: Drug substances must exhibit some degree of both lipid and aqueous solubility.edu Page 28 THINGS TO NOTE IN TABLE 6.2. C. Substances that are relatively insoluble in water may exhibit poor absorption characteristics such as erratic or incomplete absorption. Thompson (SB 383.thompson@umontana. we’ll get to this later) and drug effect. charles. The salt of a drug is more soluble in water than in ethanol The “neutral” form of a drug is usually more soluble in ethanol than in water. • • “Alcohol” is synonymous with ethanol. The graph below shows the correlation between lipid/aqueous solubility (log P. .

↑A-.Pharmaceutics (Part I) – Spring 2005 Prof. and ↑ST Correlation with Henderson Hasselbalch: Maximum aqueous solubility for weak acids is attained at pH-pKa » 2. C. pH.edu Page 29 Modification of aqueous solubility: • • • • salt formation or structural modification adjust pH if a liquid formulation use co-solvent complexation Rate of solution: While solubility is constant at a given temperature and pressure. charles. pKa and solubility: Solubility is influenced by the degree of ionization of the substance. 243-4643. Total aqueous solubility of an ionizable substance can be expressed as: ST = [HA] + [A-] S = [B] + [BH+] or ST = SHA + [A-] S = S + [BH+] T T T for a weak acid for a weak base for a weak acid for a weak base where ST is the total solubility and SHA and SB are the solubilities of the unionized weak acid or weak base. rate of solution can vary depending on the particle size of the solute and the agitation rate of the solution. where 99% is in the ionized (A-) form. For a non-ionizable substance.thompson@umontana. The logarithmic form can be used to predict the pH (pHp) below which the unionized weak acid would precipitate from solution: pHp = pKa + log ST-SHA SHA . Minimum solubility is at pH-pKa » -2 where 99% is in the unionized (HA) form. Thompson (SB 383. the following equation can be derived: ST = SHA + KaSHA [H3O+] which indicates that solubility of a weak acid increases with increasing pH (decreasing H3O+ concentration): so as ↑ pH then ↓HA. a non-electrolyte: ST = SNE For a weak acid.

• • . The solubilities of a weak base and its conjugate acid are also different in water for a similar reason. The pH of the buffer solution determines the B/A ratio and the solubility will be the same for either form (weak acid or conjugate base). where 99% is in the ionized (BH+) form. and ↑ST Maximum aqueous solubility for weak bases is attained at pH-pKa » -2. Addition of the weak base makes the water basic so there is more of the unionized weak base form present and solubility is low.pKa » 2 where 99% is in the unionized (B) form.thompson@umontana.Pharmaceutics (Part I) – Spring 2005 Prof. water: • The solubilities of a weak acid and its conjugate base are identical in a buffer solution. C. The logarithmic form can be used to predict the pH (pHp)above which the weak base would precipitate from solution: pHp = pKa + log SB ST-SB Solubility of weak acids and weak bases in buffers vs. The same is true for a weak base and its conjugate acid. charles. Minimum solubility is at pH. Addition of the conjugate base makes the water basic so there is more of the ionized form present and solubility is high. ↑BH+. The solubilities of a weak acid and its conjugate base are different in water. Thompson (SB 383. Addition of the conjugate acid makes the water acidic so there is more of the ionized form present and solubility is high. Addition of the weak acid makes the water acidic so there is more of the unionized weak acid form present and solubility is low.edu Page 30 For a weak base. 243-4643. the following equation can be derived: ST = SB + [H3O+]SB Ka which indicates that solubility of a weak base increases with decreasing pH (increasing H3O+ concentration): as the ↓ pH then the ↓B.

Pharmaceutics (Part I) – Spring 2005 Prof. C. 243-4643. Thompson (SB 383. The expression can then be written: K = CO [HA]W The apparent distribution coefficient (K’) is the experimentally observed ratio. The true distribution coefficient (K) is the concentration of a substance in an oil phase ([HA]O). if ionizable. and it includes the ionized fraction of the substance in the water phase. divided by the concentration of unionized substance (e. Higher P or K values indicate higher lipid solubility relative to aqueous solubility. Its ability to do this depends on its lipophilicity/hydrophilicity balance and. charles. a drug molecule must cross a mostly lipid biological membrane. Distribution coefficients: The partition coefficient (P.edu Page 31 PARTITION COEFFICIENTS Distribution/partition coefficients: In order to produce a biological response.g. its degree of ionization. K) is also known as the distribution coefficient or distribution ratio.thompson@umontana. K’ = [CO] [HA]W + [ A ]W The total concentration in the aqueous phase (CW) is: CW = [HA]W + [A-]W - so the apparent distribution coefficient can be expressed: K’ = CO/CW . weak acid or weak base) in the aqueous phase ([HA]W): K = [HA]O [HA]W Since substances do not ionize significantly in the oil phase: [HA]O = CO (where CO is the total concentration in the oil phase). such as octanol.

Pharmaceutics (Part I) – Spring 2005 Prof. Thompson (SB 383. charles. C. 243-4643.edu Page 32 Degree of ionization: The degree of ionization is the fraction ionized (α) in solution and is equal to: α = [A-]W [HA]W + [A-]W The degree of ionization depends on the pH of the aqueous phase and the pKa of the substance. The fraction unionized (1-α) is equal to: 1.thompson@umontana.α = [HA]W [HA]W+[A-]W The true distribution coefficient for non-ionizable substances may be expressed: K = Co/CW (since K and K’ are the same for non-ionizable substances) .

Methods for increasing dissolution rates: • Decrease particle size.] • Increase solubility in the diffusion layer. penicillin V potassium will dissolve faster than penicillin V itself). effervescent. The ionized form of the drug (salt of the weak acid or salt of the weak base) will have greater solubility in the diffusion layer than the unionized weak acid or weak base.Pharmaceutics (Part I) – Spring 2005 Prof. This increases the available surface area to the dissolving fluid. (e. agglomeration of the particles may occur leading to decreased dissolution rates. buffered aspirin). Noyes-Whitney equation: The Noyes-Whitney equation shows how factors such as solubility and surface area can affect dissolution rate: dM dt where: dM/dt = the dissolution rate D = the diffusion coefficient of the solute in the solution S = the surface area of the exposed solid h = the thickness of the diffusion layer CS = the concentration of the drug in the diffusion layer (solubility of the drug since diffusion layer is assumed to be saturated) C = the drug concentration in the bulk solution at time t. Dissolution is therefore driven by surface area (S) and the concentration gradient (CS-C). Thompson (SB 383. • Alter pH of dissolution medium (e. [Note: In rare cases.thompson@umontana. 243-4643.g. Dissolution is important for the bioavailability of solid dosage forms including oral capsules. = DS(CS-C) h .g. • Increase agitation of dissolution medium (e.edu Page 33 DISSOLUTION The dissolution rate is the time required for a drug substance to dissolve in the fluids at the absorption site. tablets and suspensions and intramuscular suspensions. C. charles. Dissolution rate is often the rate-limiting step in the absorption process and can control the overall bioavailability of the drug from the dosage form.g. buffered aspirin).

A Brief Survey.edu Page 34 Dissolution Equations. Thompson (SB 383. Noyes-Whitney Equation: The rate of dissolution (dM/dt)…. C. dM dt where: M = amount of drug (material) dissolved (usually mg or mmol) t = time (seconds) D = diffusion coefficient of the drug (cm2/s) S = surface area (cm2) H = thickness of the liquid film Cs & Cb = concentrations of the drug at the surface of the particle (surface = Cs) and the bulk medium (bulk medium = Cb) Drug Particle Diffusion Layer Cs Bulk Solution = DS(CS-Cb) h Cb h Scheme 1. The current version of the equation is slightly modified from the original but remains based on a diffusion layer model of dissolution (Scheme 1) of drug from a particle into a large excess bulk medium. 243-4643.thompson@umontana. Dissolution of drug particles according to diffusion layer model. In 1897. Calculations and Relationships .Pharmaceutics (Part I) – Spring 2005 Prof. Noyes and Whitney described the quantitative analysis that correlated the amount of time it took to dissolve a drug from solid particles. . charles.

edu Page 35 Problem 1: Calculate the dissolution rate of a hydrophobic drug having the following physicochemical characteristics: surface area = 2.5 x 103 cm2 saturated solubility = 0. .35 mg/mL (at room temperature) diffusion coefficient = 1.5 x 103)( 0.2 = 21 mg/sec (approx).75 x 10-7)(2.75 x 10-7 cm2/s thickness of diffusion layer = 1. multiply the rate 1. C. Therefore.22 mg/sec x 17.00021 mg/mL).22 mg/sec NOTE!!!! The concentration in bulk solution is generally much lower than the saturated solubility.5 x 103)( 0.5 x 103 cm2).3 x 104 cm2 is a 17.25 x 10-4 cm] conc of drug in bulk = 2. Thompson (SB 383. and the Cb term can sometimes be ignored.25 x 10 -4 = = = = 1.2-fold increase over the prior surface area (2.25 x 10-4 1.35 mg/mL .2.75 x 10-7)(2. charles.75 x 10-7)(2.25 x 10-4 (1.3 x 104 cm2? Answer: 4.thompson@umontana. (0. 243-4643.Pharmaceutics (Part I) – Spring 2005 Prof.349 mg/mL) 1.2. so 1 µm = 1 x 10-4 cm and 1.1 x 10-4 mg/mL) 1.35mg/mL – 0. Or you can recalculate the rate by substituting all the values into the equation. Problem 2: What would the rate of dissolution be in Problem 1 if the surface area was increased to 4.5 x 103)( 0.53 x 10-4 1.1 x 10-4 mg/mL dM dt dM dt dM dt dM dt dM dt = = DS(CS-Cb) h (1.35 mg/mL . See for example above.25 x 10-4 (1.1 x 10-4 mg/mL) 1.25 µm [Note: need to convert to cm.

we consider a cell membrane that is composed of phospholipids and proteins. Cd C1 receptor compartment (low drug conc) donor compartment (high drug conc) C2 Cr h Scheme 2.C2 = concentration gradient where C1 is the concentration of drug at donor side of membrane and C2 is the concentration of drug in the membrane at receptor side. 243-4643. Transport through porous membranes occurs by diffusion and convection (not covered here). . For our purposes. The Integrated Studies uses C1 and C2 where Cd and Cr should be used. C1 and C2 are not measured since these are values within the membrane. Typically. Skin is another great example of a membrane for the entry of drugs.Cr. However. the gradient is measured as Cd .thompson@umontana. The transport of drug molecules through a non-porous membrane occurs by diffusion.edu Page 36 Diffusion . Thompson (SB 383. C. Absorption of drugs across the stomach lining/mucosa and the blood/brain barrier are two representative examples and important for understanding drug transport into the circulation and CNS. Diffusion model for Fick’s Law. Similar to dissolution. respectively. representing the partition at each phase. but it doesn’t really matter for the calculation so long as you know what the gradient is. Notes: The rate of drug transport into diffusional system is predominantly dependent upon the magnitude of the concentration gradient – the other parameters are constant. the diffusion equation is… dM dt = DAK(C1-C2) h M = amount of drug (material) dissolved (usually mg or mmol) t = time (seconds) D = diffusion coefficient of the drug (cm2/s) A = surface area of membrane (cm2) K = oil/water partition coefficient h = thickness of the liquid film C1 . charles.Through a Membrane: A membrane is defined as a physical barrier that separates two or more regions.Pharmaceutics (Part I) – Spring 2005 Prof. namely Ko/w = C1/Cd and Ko/w = C2/Cr.

edu Page 37 Pharmaceutics 331 Exam 1 (February 2004) Read each question carefully and for choice questions. For a thiol-containing drug (weak acid donor).4 16. when the pH of the solution is adjusted to equal the pKa.2 18 10 .8 17.” List three possible advantages to using tartaric acid rather than a mineral acid (e.g. If strong electron withdrawing substituents (e. nitro) were added to the phenyl ring of phenol. Thompson (SB 383. H2SO4. there will be (4): (a) precipitation of the drug (b) a greater amount of the ionized form of the drug (c) an equal amount of ionized and ionized (d) a greater amount of the unionized form of the drug 5. R-OH H-OH (water) MeOH (methanol) Et-OH (ethanol) iPr-OH (isopropanol) t-Bu-OH (tert-butanol) Ph-OH 2. etc. Choose one of the underlined words (4). C. As the strength of a weak acid increases the (4): (a) Ka increases (b) [A-] increases (c) [HA] increases (d) answers (a) and (b) (e) answers (b) and (c) 4. etc. Point value in parentheses. and their pKa values are dramatically lower than alcohols (table above). Et.Pharmaceutics (Part I) – Spring 2005 Prof. HCl. the pKa value of the substituted phenol would: INCREASE (LESS ACIDIC) / DECREASE (MORE ACIDIC). 1. 3.g. Good luck.. the increasing trend in pKa values (table at right) for the alcohols (5).) form amine salts. Double check your calculations and write out all formulae used to answer a question. circle only one answer.8 16.. charles. 243-4643. Explain in one or two statements. Phenols are aromatic analogs of alcohols. Alcohols are organic ‘analogs’ of water meaning they share the identical functional group (OH) but vary in one component. Relevant equations are provided on page 4. the “switch” of an H for a Me.thompson@umontana. The structure of tartaric acid is (6): OH HO2C OH tartaric acid CO2H pKa 15. Tartaric acid is frequently used to react with an amine to form a “tartrate salt.

etc. Thompson (SB 383. Calculate the buffer capacity for a 0. 10. 8. Plausible reasons that buffers resist change in pH upon addition of acids or bases are (4): (a) added acids and bases are too dilute to effect change (a) the buffer anions (conjugate bases) are typically bigger and neutralize acids quickly (b) added acid/base change the pH but the change is logarithmically related (c) answers (a) and (b) (d) answers (b) and (c) 7. Three classifications of organic compounds are polar non-protic.g.) (d) all of the above . C. maleate.Pharmaceutics (Part I) – Spring 2005 Prof. sulfate. polar protic and non polar (6). The solubility of amine salts in aqueous systems is effected by the (4): (a) temperature (b) buffer/pH (c) structure of the anion (e. An example of a chemical bond that uses the principle of dipole-dipole interaction is (4): (a) covalent bonding (b) hydrogen-bonding (c) van der Waals bonding (d) answers a and b (e) answers b and c 12.edu Page 38 6. charles.3 M phosphoric acid/sodium phosphate buffer that has an initial pH 2.1 and changes to pH 2.thompson@umontana.2 upon the addition of 50 mmoles of NaOH (5). (a) Which class is most likely to cross membranes? _____________________ (b) Which class is most likely to dissolve in saliva and serum? ___________________ (c) Do these “classifications” directly correlate with lipophilic/hydrophobic properties? Briefly explain. Deleted 11. Why is the molarity of the buffer system not found in the calculation of buffer capacity? Is it unimportant (5)? 9. Cl-.. 243-4643.

0005 M) at pH 3. If sulfadiazine is sparingly soluble in water. it completely dissolved in the mixture. (d) answers (a) and (b) (e) answers (a) and (c) 14. Calculate the dissolution rate of cimetidine having the physicochemical characteristics (6): surface area = 2. The maximum aqueous solubility for weak acids is attained when (4): (a) the pH value exceeds the pKa value by more than 2 (b) the pH = pKa (c) the pH value is less than the pKa by more than 2 16. (morphine pKa = 7. Ka 1. If the drug is a weak acid and the pKa is more than the pH. 243-4643.0 g of loratidine was added to a separatory funnel containing 50 mL of water and 50 mL of octanol. (4).87.edu Page 39 13. When 1. The unionized form of a drug (4): (a) is less water soluble (b) is less able to traverse membranes (c) has a Ko/w > 1. charles.thompson@umontana. sulfadiazine sodium is likely to be ____________ in water (4): (a) insoluble (b) slightly soluble (c) freely soluble (d) sparingly soluble 15. Analysis of the octanol solution showed a concentration of loratidine = 16 mg/mL.1 x 10-4 mg/mL saturated solubility = 0. Calculate the partition coefficient (K) for loratidine (5): 17.60 mg/mL (at room temperature) thickness of diffusion layer = 1.25 x 10-4 cm) 18.25 µm (1. C.Pharmaceutics (Part I) – Spring 2005 Prof.5 x 104 cm2 diffusion coefficient = 2. the ionized species is more / less than 50% 19. Calculate the theoretical solubility S of morphine (S0 = 0.35 x 10-8) (6): . Thompson (SB 383.5 x 10-7 cm2/s conc of drug in bulk = 2.

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