DRUG STABILITY KINETICS

The basic equations which describe the loss of drug from a dosage form on a shelf also apply to the loss of drug from the body. The ones given are the only ones you are likely to need to know. ZERO ORDER C = Co - kt k = zero order rate constant (Both Y and X axis are Slope = -k

Concentration vs. Tim e plot is linear. regular spacing; e.g., not logarithm ic.) The RATE of change is constant.

The RATE = -dA = k (concentration or am ount/tim e) dt The sam e AMOUNT of drug is lost per unit of tim e. In zero order, the half life increases as the concentration increases. FIRST ORDER C = (Co) (e -kt)

Concentration vs. Tim e plot is curved when using regular (e.g., linear) axes. The RATE of change is concentration dependent. The RATE = -dA = kA dt Therefore the sam e FRACTION (or percent) of drug is lost per unit of tim e; independent of concentration. For first order kinetics, the Concentration vs. Tim e plot is linear when logarithm ic Y axis is used and one plots the log of the concentration versus time. k = first order rate constant for elim ination (as fraction per unit of time; e.g., k = per unit of tim e) k = Clearance Vd Clearance = Volum e cleared Tim e Log C = Log Co kt 2.303 Slope of line is k 2.303

Vd = "Apparent" Volum e of Distribution

If you plot the natural log of Concentration versus Tim e, then Ln C = Ln Co kt. The slope of the line is then determ ined by k alone. HALF LIFE: Tim e required for elimination of one-half of a drug (by either zero or first order degradation). Half life is often used in dosing situations to m easure drug elim ination from the body. Zero order t 1/2 = Co = mg / m l = minutes 2K m g / m l / m in First order t
1/2

0.693 k

1 = minutes 1 / m in

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SHELF LIFE: The expiration date is based on the tim e required for the drug product to degrade below its USP established potency level. In the example below, this is assumed to be the tim e at which 90 percent of the drug rem ains (actual USP requirem ents range from 80% to 97% ). First order t 90 = C = Co 90 = 100 e -kt t 90 = 0.105 k 0.1 C o k

Zero order

C o - C = Kt C o - 0.9C o = Kt

t 90

TABLE 1. Stability of Drugs in Pharm aceutical Form ulations A. Factors W hich Decrease Drug Stability Heat (temperature) know storage guidelines Light (especially u/v) light resistant containers Moisture film coat tablets and do not store in bathroom (heat and m oisture) pH solution buffers Excipient incompatibility m odify formulation B. Oxidation can be Reduced by 1. Small am ounts of oxygen (O 2) - autoxidation 2. Nitrogen, Carbon Dioxide used to replace air in container 3. Temperature 0-5 degrees (1/2 rate) 4. Trace am ounts of heavy m etals (chrom ium , copper, iron) catalyze oxidation and cause destruction of: penicillin, epinephrine, phenylephrine, lincom ycin and procaine 5. Chelating agents - EDTA (ethylene diam ine tetraacetic acid), dihydroethylglycine, citric, tartaric, gluconic, and saccharic acid 6. Antioxidants For aqueous solutions: Sodium sulfite (hi pH range), Sodium Metabisulfite (low pH range), Sodium Bisulfite (interm ediate pH range), Acetone Metabisulfite, Ascorbic Acid, Thioglycerol, Sodium Thiosulfate, Cysteine Hydrochloride For non-aqueous solutions: Ascorbyl Palm itate, Hydroquinone, Propyl Gallate, Nordihydroguaiaretic, Butylated Hydroxytoluene, Butylated Hydroxyanisole and Alpha Tocopherol (vitam in E) C. Hydrolysis Rate can be Reduced by Temperature (0 - 5 degrees C.) Hum idity < 40% Dessicant in packaging Multi-layered tablets Film coating Buffers for solutions Suspensions for liquids Absorbent diluent in tablet or capsule (Kaolin, Mg Oxide, Ca carbonate)

EXAM PLES 1. At room tem perature the rate constant for loss of an antibiotic solution is k = 0.0357 days -1. W hat is the shelf life at room temperature? A. 0.0357 days ANS: Units are reciprocal tim e; so First order B. 3 days C. 14 days t 90 = 0.105 = 0.105 D. 3 hours K 0.0357 E. cannot determine order t 90 = 3 days at room temperature

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2. If refrigerated, the antibiotic solution has a rate constant for loss of k = .0075 days -1. W hat is the new shelf life? A. 0.0357 days ANS: t 90 = 0.105 = 14 days B. 3 days 0.0075 C. 14 days D. 3 hours E. cannot determine order 3. After reconstitution, an antibiotic suspension of 250m g per 5 m l has a stability rate constant of 1 m g/m l/day. W hat is the half life of this drug in suspension? A. 500 days B. 250 days ANS: K = concentration / tim e; loss from C. 100 days a suspension is a zero order process. D. 50 days E. 25 days t 50 = C o = 50 m g / m l = 25 days 2K 2 (1 m g / m l / day)

Questions 4 to 8. The stability of a reconstituted antibiotic solution was evaluated for stability at different tem peratures and in different pH solutions. The data from these experim ents is summarized in the graph to the right. Use this inform ation to answer questions 4 through 8. 4. From the graph it can be concluded that I. The rate constant for the antibiotic's degradation is the sam e for all solutions II. Stability of the solutions is not affected by temperature changes III. Stability of the solutions increases toward neutral pH A. I only B. III only I. No, if true only one line C. I and II only II. No, higher temperature D. II and III only m eans increased rate of loss E. I, II, and III only III. True, more stable at pH 7 than at pH 10 5. Based on the data shown, the marketed product should I. contain a buffer to control the pH at neutral II. be refrigerated after reconstitution III. be reconstituted with 8.4% Sodium Bicarbonate Solution A. I only B. III only I. Yes C. I and II only II. Yes D. II and III only III. No, pH of 8.4% Na Bicarb Solution would be alkaline (actually E. I, II, and III only about 8.5) and would increase rate of decom position 6. The data presented also indicate that I. the only formulation suitable for use after 8 hours is the pH 7, 4 C product II. if the reconstituted solution is refrigerated, pH control is not required III. if pH 7 is maintained, then refrigeration is not required for prolonged use A. I only B. III only I. True, only one above 90% at 8 hours C. I and II only II. False, pH control required regardless of temperature D. II and III only III. False, refrigeration required even at pH 4 E. I, II, and III only

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7. W hich of the following statements are accurate based on the graph? I. An increase in temperature slows the degradation process II. For the conditions studied the best stability is at pH 7 and 4 0 C III. This study indicates that stability is a function of pH A. I only B. III only I. No, it increases the degradation rate (universal truth) C. I and II only II. Yes, line stays above 90% for longest period of time D. II and III only III. Yes, it is a function of pH (and also of temperature) E. I, II, and III only 8. W hich of these statem ents may be concluded from the graph? I. The rate of loss of drug is independent of the concentration present. II. For the conditions studied the least stable solution is at pH 10 and 4 o C. III. The stability of the cephalosporin is only a function of pH. A. I only B. III only I. True, because this is first order degradation C. I and II only II. False, the least stable is pH 10 and 25 o C. D. II and III only III. False, it is a function of pH, but also of temperature E. I, II, and III only pH and BUFFER CALCULATIONS A. A buffer system consists of two com ponents: (1) a weak acid or weak base and (2) its corresponding salt form . An infinitely dilute solution contains <0.01M solute. In such system s, the pH to which the solution is buffered is determ ined by the ratio of base to acid (the Henderson-Hasselbach equation without making a correction for ionic strength). W hen the ratio of base to acid equals 1, the m olar concentration of the two com ponents is equal, then the buffer solution pH equals the pKa. The CAPACITY of a buffer is highest when the pH equals the pKa. If the ratio of components is the sam e for two different buffer systems, the system with the higher molar concentrations of buffer com ponents will have a higher buffer capacity. Henderson-Hasselbach General Guidelines: pH = pK a + log [Base] [Acid] or Base Salt or Salt Acid

B.

C.

D. E.

Other form s can include:

NH 3 NH 4+

or

A HA

A. B. C. D. E.

W hen pH equals pK a, the salt will be 50% ionized and 50% nonionized. W eak acids are nonionized at acid pH (any pH below the pKa). W eak bases are nonionized at basic pH (any pH above the pKa). W ithin two pH units; use Henderson-Hasselbach form ula to predict ratio. If pH is m ore than two full pH units away from the pKa (e.g., 3 vs 5), the salt will be 99% in the form predicted to dom inate by (B) and (C).

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Basic Facts about logarithm s and the num bers they represent Log 1 = 0.0 Log 2 = 0.3 Log 10 = 1.0 Log 100 = 2.0 K w = 1 x 10 -14 pH pH pH pH pK w = 14 = -Log [H +] = 14 when [H +] = 1 x 10 -14 = 7 when [H +] = 1 x 10 -7 = 2 when [H +] = 1 x 10 -2 pK w = pH + pOH

SALT TYPES 1. A strong acid (e.g., HCl) + strong base (e.g., NaOH) form s a salt (e.g., NaCl) that are strong electrolytes -- such salts are always 100% ionized in solution. 2. A weak acid (e.g., phenobarbital or penicillin G) + strong base (e.g., NaOH or KOH) will form salts (e.g., sodium phenobarbital or K Penicillin G) that are weak electrolytes -- the degree of ionization is a function of pH and pKa. nonionized pH << pKa << ionized pH pH = pKa + Log [Salt] [Acid] [ionized] [nonionized]

3. A weak base (e.g. atropine) + strong acid (e.g., sulfuric acid - H 2SO 4) will form salts (e.g., atropine sulfate) that are weak electrolytes -- they ionize the sam e as salts of weak acids. pH = pK a + log [Base] [Salt] [nonionized] [ionized] ionized pH << pK a << nonionized pH

4. A weak acid (e.g., gluconic acid) + weak base (e.g., quinidine) will form salts (e.g., quinidine gluconate) that are weak electrolytes and often have m ore than one pKa so their extent of ionization requires m ore calculations. EXAM PLES 1. W hat is the [H +] at pH 8 versus pH 10? A. 2x ANSW ER is D B. 10x C. 20x D. 100x E. 1000x

pH 8 = [H +] -8 pH 10 = [H +] -10 So; 10 - 8 = 2 and 2 is the log of 100.

2. Atropine Sulfate is 50% ionized at pH 9.65. W hat is the pKa of this drug? A. 9.65 ANSW ER is A Remember that at a ratio of 50/50 ionized to nonionized, B. 4.82 then pH = pKa. C. 2.41 D. 1.22 See Henderson-Hasselbach guideline (A). E. 13.45

3. A 0.1M ionized A. B. C. D. E.

solution of Sodium Phenobarbital (pKa = 4.2) is adjusted to pH 6.2. W hat is the ratio of to nonionized species? 1 to 1000 ANSW ER is C Na PB is salt of a strong base (Na) and a weak acid (PB) 1 to 100 so use form ula pH = pKa + log ionized 100 to 1 nonionized 1000 to 1 10 to 1 6.2 = 4.2 + log (Ionized/Nonionized) 2.0 = log (Ionized/Nonionized) and 2 = log of 100/1

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4. One hundred m Ls (100 m ls) of a buffer consisting of 0.01M Na 2HPO 4 (pka 4.6) and 0.01M NaH 2PO 4 is prepared. W hat is the pH of this buffer solution? A. 2.6 ANSW ER is C According to buffer guideline (C), if the ratio B. 6.6 of base (Na 2HPO 4) to acid (NaH 2PO 4) is 1, C. 4.6 then the pH of the buffer is equal to the pKa D. 9.2 E. 2.3 5. A drug is to be buffered in solution to a pH of 4.76. An acetate buffer is selected. If 0.05M Na Acetate (pKa 4.76) is used, what strength (in m oles) of Acetic Acid will be required? A. 4.76 ANSW ER is B Buffer guideline (C), as reviewed in Question 5, indicates B. 0.05 that the concentrations of Na Acetate and Acetic Acid C. 0.10 should be the sam e. D. 2.76 E. 1.00

6. W hat is the ratio of ionized to nonionized species present in 100 m Ls of 0.1M Clindinium Br (pKa = 6.5) at pH 6.2? A. 1 to 2 ANSW ER is D Salt of a weak base and strong acid B. 0.3 to 1 pH = pKa + log (Nonionized/Ionized) C. 10 to 1 6.2 = 6.5 + log (Nonionized/Ionized) D. 2 to 1 - 0.3 = log (Nonionized/Ionized) E. 1 to 10 10 - 0.3 = [Nonionized] [Ionized] Note that the question is the reverse of answer. 1 10 0.3 = [Nonionized] [Ionized] = 1 2

7. W hich of the following solutions has the highest buffer capacity? A. 0.1M HOAc + 0.1M NaCl ANSW ER is B Buffer guideline (E) says that if the ratios B. 0.1M HOAc + 0.1M NaOAc of two buffers are the sam e the system C. 0.01M HOAc + 0.01M NaOAc with the highest m olar concentrations D. (a) and (c) are equal will have the greatest buffer capacity. E. (b) and (c) are equal NOTE: System (a) is not a buffer system. 8. One hundred m Ls (100 m Ls) of 0.4M NaOH is added to 300 m Ls of 0.26M Acetic Acid (pKa 4.76). W hat is the pH of the final solution? A. 9.52 ANSW ER is D First, account for dilution that occurs by adding the two B. 3.84 solutions together (Steps 1 & 2). Then write out the chemical C. 2.38 reaction which would occur (Step 3). Note that the reaction D. 4.76 form s 0.1M of Na Acetate and leaves 0.1M of Acetic Acid. E. 7.04 Thus, the ratio between salt and base is 1 to 1; so pH = pKa. Step 1. (X Molar) (400 mLs) = (0.4 Molar) (100 m Ls) X = 0.1M NaOH

Step 2. (X Molar) (400 mLs) = (0.26 Molar) (300 m Ls) X = 0.2M Acetic Acid Step 3. Acetic Acid + NaOH = Na Acetate + H 2O + Acetic Acid 0.2 molar + 0.1M = 0.1M + 0.1M + 0.1M pH = pKa + log [Salt] [Acid] pH = 4.76 + log 0.1M 0.1M So, pH = 4.76

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TABLE 2: Classification of Em ulsifying Agents Type Synthetic (surface active agents) agents) Exam ples ANIONIC: Soaps Potassium laurate Triethanolam ine Stearate M echanism Coherent, flexible film form ed by surface active agents. These agents m arkedly lower interfacial tensions and this contributes to em ulsion stability. These are widely used, especially the nonionic type. Depending on the particular agent(s) chosen, can prepare O/W or W /O emulsions.

Monom olecular Film

Calcium oleate Prepare oil-in-water emulsions; oil-in-water emulsions are Sulfates easier to make than are water-in-oil emulsions. Sodium lauryl sulfate Sulfonates Dioctyl sodium sulfosuccinate (DOSS, DSS, Docusate) CATIONIC: Quarternary amm onium com pounds Cetyltrim ethylam m onium brom ide, Benzalkonium Chloride NONIONIC: Polyoxyethylene fatty alcohol ethers (Tweens), Sorbitan fatty acid (Spans)

Natural Multimolecular

Hydrophilic colloids Oil-in-W ater Em ulsions Acacia, Gelatin Tragacanth Colloidal clays Bentonite Veegum Metallic hydroxides Mg hydroxide

Strong, rigid film form ed; m ostly by hydrocolloids colloids which produce O/W emulsions. Interfacial tension is not reduced to any degree; stability is due m ainly to the strength of the interfacial film. Film form ed by solid particles that are sm all in size com pared to droplet of dispersed phase, The particles m ust be wetted by both phases to some extent in order to rem ain at the interface and form a stable film . Form either O/W or W /O emulsions, depending on method of preparation.

Finely Divided Solids

Solid Particle Film

BIOPHARMACEUTICS
Definitions Bioavailability. The extent of absorption and the rate of absorption from a dosage form as reflected by the time-concentration curve of the adm inistrated drug in the systemic circulation. Three parameters are used to establish bioavailability. Area under the Curve (AUC) C max (m axim um plasm a concentration) T max (tim e at which C m ax is reached) If there is no statistically significant difference between AUC, T max and C max then two drug products are considered to have equal bioavailability. Absolute bioavailability is the bioavailability of a specific drug form ulation given by any peripheral route com pared to IV administration of the sam e drug. Relative bioavailability is the bioavailability of one drug form ulation, of the sam e dosage form, com pared to another formulation, of the sam e dosage form, from a different manufacturer -orcomparision of the bioavailability of different dosage form s; i.e. suspension versus tablet. Bioequivalence. Chem ical equivalents which, when adm inistered to the sam e individuals in the same dosage regim en, will result in com parable bioavailability.

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Chem ical Equivalents. Drug products that contain the sam e am ounts of the sam e therapeutically active ingredients in the sam e dosage forms and that m eet present compendial standards. Deaggregation. The breaking up of granules or aggregates into fine particles in aqueous fluid. Disintegration. The breaking up of a tablet or capsule into granules or aggregates in aqueous fluid. Dissolution. The breaking down of fine particles into m olecules or ions hom ogenously dispersed in aqueous fluid. Excipient. An inert substance used to give a preparation a suitable form or consistency. Form ulation. A complex m ixture containing a selected chemical derivative of the drug compound, in proper physical form, together with excipients, diluents, stabilizers, preservatives, or a variety of other com ponents. General physical Characteristics Lipid Solubility; pKa (m ust be nonionized to be absorbed) Intram uscular Dissolution; Compliance assured; Blood flow, increases if injection site massaged; Advantage: larger volum e than SubQ; depot with suspension Disintegration; Dissolution; Gastric Acid Stability; Gastric Fluid Volum e; Gastric Em ptying Tim e; Meals; Gut Metabolism ; First Pass Metabolism ; Rate of GI Passage; Concurrent Drug Adm inistration

Oral Bioavailability

Pharm aceutical Equivalents. Drug products that contain the sam e am ounts of the same therapeutically active ingredients in the sam e dosage form and that m eet standards established on the basis of the best available technology. Pharm acodynam ics. The discipline that studies the biological and therapeutic effects of drugs. Pharm acokinetics. The discipline that treats the rates of m ovem ent and biotransform ation of a drug and its metabolites within the body. Rectal Disintegration; First Pass Metabolism ; som e vessels bypass liver; Dissolution - problem of availability if drug m ore oil soluble Dissolution (suspension = sustained release); Blood flow; Concurrent Drug Injection (e.g., Lidocaine with Epinephrine) Disintegration; Dissolution (Advantage: bypass liver; i.e. nitroglycerin, nifedipine)

Subcutaneous

Sublingual

Therapeutic Equivalents. Chem ical equivalents which, when adm inistered to the sam e individuals in the sam e dosage regim en, will provide essentially the sam e efficacy and/or toxicity. In order for a drug to act it m ust reach the site of action. Many factors stand in the way of achieving a therapeutic response. Intravenous adm inistration is not desirable as a route of chronic drug administration. W ith other routes we encounter absorption variables which alter the availability of drug to the system ic circulation. Factors influencing absorption by the various routes of adm inistration are listed below:

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1. Use the data presented to answer the question below.

t
Formulation A Formulation B

Cmax
(mcg/m l) 50 72 p < 0.05

Tmax
(hr) 0.5 0.6 NS

AUC
65 100 p < 0.05

(hr) 4.0 4.2 NS

I. Form ulation A and Form ulation B are not bioequivalent. II. Form ulation B has a greater T max than Form ulation A. III. There is no difference between the AUC of Form ulation A and Form ulation B. A. I only B. III only Answer: A C. I and II only I is true because of p < 0.05, so significant D. II and III only II is false because NS (not significant) E. I, II, and III only III is false because I is true 2. True statements about the graph to the left include I. Drug A has a faster onset than Drug B. II. Drug B has a greater C max than Drug C. III. Drug B has a longer half life than Drug C. A. I only B. III only C. I and II only D. II and III only E. I, II, and III only ANS: C I true due to shorter tim e to C max II true (you can see difference) III false, B = 3 hrs, C = 4 hrs Determine by finding C max for B is 70 at 5 hr, half of 70 is 35 at 8 hr so half-life is 3 hr (8 hrs minus 5 hrs = 3 hrs); repeat the sam e process for C

A Little Review of Some Pharmacy Math

W ith the advent of an electronic calculator for use during the NAPLEX, there is an increased interest in calculations problem s. This review provides refreshm ent in some areas. M oles and M illim oles Gram Molecular W eight the Molecular W eight of a substance expressed in Gram s Example: CaC1 2 = 111 Gm s, (Ca = 40, C1 = 35.5) NaCl = 58.5 Gm s (Na = 23, Cl = 35.5)

Gram Atom ic W eight is defined as the num ber of gram s num erically equal to the atom ic weight. Sulfur has an atomic weight of 32 atom ic mass units, so 32 gm s is 1 gram atom ic weight of sulfur. A mole (M) of any substance is the gram-atom ic or gram -m olecular weight. The term m illim ole (mMol) is used when the weight of the substance is expressed in m illigrams. Thus, 58.5 milligrams of sodium chloride will be one millim ole of sodium chloride. Moles and m illim oles are based solely on m olecular weight and the expression of that weight in gram s (moles) or m illigram s (millim oles). A confounding factor that often occurs in determining the molecular weight of drugs is water(s) of hydration. Many inorganic molecules will take up water from the air and are in a state of permanent hydration. Calcium chloride, for exam ple, exists as either the dihydrate (two waters of hydration) or the hexahydrate (six waters of hydration). The chemical form ulas are usually written as shown below (a period or asterisk is used to join the drug and the water):

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Calcium chloride CaC1 2 Molec W t 111

Calcium chloride dihydrate CaC1 2 * 2 H 2O Molec W t 147

(-2)

Calcium chloride hexahydrate CaC1 2 * 6 H 2O Molec W t 249

(-2)

1. W hat is the weight (in mg) of 3 mMol HP0 4

(Atom ic weight for HP0 4

= 95.98)

ANS: A millim ole of HPO 4 weighs 95.98 m g. Three tim es this am ount would be 287.94 mg.

2. How m any m M ol of P0 4-3 are present in 138 m illigrams of sodium phosphate, m onobasic, monohydrate? Molecular weight of NaH 2PO 4* H 20 = 138. Answ er: One m Mol of NaH 2PO 4*H 20 weighs 138 m g. Therefore, 138 m g of sodium phosphate, monobasic contains one m illim ole of phosphate since there is only one phosphate radical per molecule. The use of m Mol, rather than mEq, is suggested w hen calculations involving phosphorus (P) or phosphate (PO 4+3) are required. The mEq of phosphate present cannot be determ ined unless the pH of the solution is known. The pH determ ines the relative proportions of m onovalent (H 2PO 4) and divalent (HPO 4) phosphate present. The average valence of "phosphate" (between 1 and 2) in a particular solution can be calculated, only if the pH is known. The use of m Mol instead of mEq eliminates the ambiguities present when the pH of the solution has not been specified. M illiequivalents The Com bining Capacity of Electrolytes An equivalent weight is the weight of an atom or radical expressed in gram s, divided by the valence (number of positive or negative charges, holding power, etc). The prefix "milli" m eans "one 1,000th of." Therefore, a milliequivalent is 1/1000th of an equivalent. Perhaps the m ost confusing elem ent of m illiequivalent calculations involves recognizing that one mEq of sodium chloride contains one mEq of sodium and one m Eq of chloride. Sim ilarly, tw o mEq of calcium chloride contains two mEq of calcium and two m Eq of chloride. Nothing seem s to balance. W hat does balance is the fact that the net charge on both sides of the equation is equal to zero. For example, NaCl ionizes to give Na (positive 1) and Cl (negative 1), usually written in the form of NaCl = Na + and Cl-. On the NaCl side of the equation, the net charge is zero since the charge of the sodium and that of the chloride cancel each other. On the Na + + Cl - side of the equation, the charges also cancel out. Thus, the equation is in balance from the standpoint of milliequivalents (weights in milligram s divided by num ber of charges). Milliequivalent = W eight of Atom or Radical in m illigram s W eight (m Eq) Valence (num ber of charges) 1. Calculate the milliequivalent weight of Sodium (Na) given the atom ic weights: Na = 23, Cl = 35.5 Answer: milliequivalent weight = 23 m illigram s = 23 m illigram s per m illiequivalent 1 2. Calculate the milliequivalent weight (m Eq. wt.) for Sodium and for Sodium Chloride. Answer: Sodium mEq. W t. 23 m illigram s = 23 m illigram s/m Eq 1 NaCI m Eq. W t. = 23 m g + 35.5 mg = 58.5 mg/m Eq 1

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3. Calculate the milliequivalent weight (m Eq. wt.) for calcium . (Atom ic weight = 40) Answer: mEq. wt. = 40 m g = 20 m g/m Eq 2

4. How m any milliequivalents of calcium are there in 5 grams of anhydrous calcium chloride? Answer: CaC1 2 mEq. wt. = 40 m g + (2) * (35.5) m g = 55.5 m illigrams/mEq. 2 5 grams = 5000 mg, so 5000 mg = 90.09 mEq 55.5 m g/m Eq Rem ember, earlier we said that calcium chloride usually exists in the hydrated form . See Question Number 5 for how the waters of hydration change the answer to this problem . 5. How m any milliequivalents of calcium are there in 5 grams of CaC1 2 * 2 H 20? Answer: CaCl2 * 2 H 2O m Eq. wt. = 40 m g + (2) * (35.5) m g + (2) * (18) = 73.5 m g/m Eq 2 5000 mg = 68.03 mEq 73.5 mg /m Eq Osmoles and M illiosmoles W henever a sem iperm eable m em brane separates two solutions containing dissolved solids, as in biologic system s and body compartm ents, fluid from one com partm ent m oves across the m embrane to the other. Net movem ent of fluid is toward the com partment having a larger num ber of dissolved particles. The force created by this m ovem ent of fluid (solvent) is term ed osm otic pressure. In osm otic relationships the im portant factor is the total number of particles present, both ions and molecules dissolved in solution. The num ber of dissolved particles can be expressed as osmoles, (Osm ) or, usually in pharm acy, m illiosm oles (m 0sm ). An osmole is the weight of a chemical substance which, when dissolved in one liter of water, exerts an osm otic pressure equal to that exerted by a gram -m olecular weight of an unionized substance dissolved in one liter of water. One osm ole contains the sam e num ber of particles as one m ole of m olecules. (Avogadro's num ber of particles 6.023 x 10 23). Concentrations of nonelectrolytes are usually expressed in m illim oles. The concentration is the sam e when expressed in m illiosm oles. For exam ple, one m illim ole of glucose (dextrose) is the same as one m illiosmole of glucose since glucose does not ionize. However, for electrolytes, the particles formed by ionization m ust be considered in osm otic relationships. One m illim ole of sodium chloride ionizes into one m illim ole of sodium and one m illim ole of chloride, thus representing 2 m illiosmoles. 1. Dextrose 5% Injection, 1000 ml (MW = 198) (Dextrose as the m onohydrate) 1000 m l x 0.05 = 50 gm s/liter 50 gram s = 50,000 mg 50,000 m illigram s = 252 m illim oles per liter 198 m g (MW of dextrose * H 2O)

252 m Mol per liter (x) 1 m0sm per m Mol = 252 m Osm per liter (dextrose does not ionize) 2. 0.9% Sodium Choride Injection, 1000 m l (MW = 58.5) = 9 gram s (= 9000 m g) NaCl per liter 9000 mg 58.5 mg per mole = 154 m illim oles per liter (x) 2 m Osm per m MoI = 308 m Osm per liter

Blood plasm a has an osmotic pressure of about 280 m Osm per liter, so both these solutions are alm ost isotonic with plasm a. Norm al Saline is slightly hypertonic (308 mOsm /liter) and D-5-W is slightly hypotonic (252 mOsm/liter). Both are considered to be clinically isotonic with blood.

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Parenteral Nutrition
Who Needs It? Any patient unable to orally consum e the am ount of nutrition needed for their medical situation. Particularly, GI tract disease or surgery requiring bowel rest of >7 days, cannot tolerate enteral feeding, unconscious, severe infections, newborn infants, hyperem esis gravidarium, bulimia nervosa, burns, and other severe trauma. Contraindications. If oral intake will resum e in <5 days, enteral feeding is adequate (>75% of daily need), or there is a poor prognosis the patient does not warrant nutritional support Choice of Peripheral or Central Route. Peripheral: dextrose limited to 10% , phlebitis is an issue, days of therapy lim ited to 3 days at a single IV site, com pensate with IV fat Central: invasive procedure, increased possibility of infection, best for long term , can use up to 25% dextrose, reduces need for fat Calculating the Basal Energy Expenditure (BEE) Harris Benedict Equations are used to calculate specific energy requirem ents or do a round off of 20 to 25 kcal/kg/day BEE for m en (kcal per day) BEE for wom en (kcal per day) 66.47 + 13.75 (x) weight in kg + 5 (x) height in cm 6.76 (x) age in years

655.1 + 9.56 (x) weight in kg + 1.85 (x) height in cm 4.68 (x) age in years

The Total Energy Expenditure (TEE) in kcal/day = BEE plus Stress Factor -or- Activity Factor Stress or Injury Factor (% increase above BEE Activity Factors (% increase above BEE Major surgery 10 to 20 percent Confined to bed 20 percent Infection 20 percent Out of bed 30 percent Fracture 20 to 40 percent Alternatively No stress 28 kcal/kg/day Traum a 40 to 80 percent Mild stress 30 kcal/kg/day Sepsis 80 percent Moderate stress 35 kcal/kg/day Burns 80 to 100 percent Severe stress 40 kcal/kg/day Energy Requirem ents: Adults 150 kcal per gram of nitrogen (range 130-200). Energy is best supplied by one of the three choices below 1. Dextrose provides 3.4 kcal per gm, m etabolic rate lim it is 5 m g/kg/min, give 40-95% of nonprotein calories as dextrose; available as 50% and 70% for com pounding. 2. Fat (soybean oil emulsion) provides 9 kcal per gm , available as 10% (550 kcal/500 m l) and 20% (1000 kcal/500 m l); m aximum is 60% of daily calories, minim um is 5% to supply essential fatty acids (linoleic, arachidonic, linolenic). 3. Glycerin will provide 3.5 calories per gm and is popular in Europe (Procalam ine is a product that contains glycerin and amino acids for short term use, especially after surgery when tissue rebuilding is required.) Electrolyte Requirem ents (range per 24 hours) Sodium 60 - 150 mEq Potassium 70 - 180 mEq Magnesium 10 - 30 mEq Calcium 4 - 30 m Eq

Chloride 60 - 150 m Eq Bicarbonate 25 - 160 m Eq (as acetate or lactate salts) Phosphate 7 - 10 m Mol

Protein: is usually in the form of am ino acids, provides 4 kcal per gm , give 1 to 1.25 (range 0.6 to 1.76 gm s) per kg per day of a 50/50 m ixture of essential and non-essential am ino acids. Some situations require the use of specific am ino acid form ulations. All am ino acid form ulations contain som e cations (Na, K) and anions (acetate, som e phosphate).

Page 12

Renal failure only essential am ino acids (Nephram ine, Aminosyn-RF, RenAmin) Liver failure and traum a increase branched chain AA (isoleucine, leucine, valine) (Hepatam ine) Stress and traum a increase branched chain AA (isoleucine, leucine, valine) (FreAmine-HBC, Am inosyn-HBC, BranchAm ine for stress or trauma) Encephalopathy decrease arom atic AA (tryptophan, phenylalanine, tyrosine) (Fream ine-III is tyrosine free and lower in tryptophan and phenylalanine) Water minim um daily requirem ent is 1200 m ls of free water; usually give 1500 m ls/M 2 to assure adequate and dilute form ulation to total volum e of 2000-3000 mls per day. Vitamins several m ulti-vitam in m ixtures are available, the most com m on is MVI-12 that contains vitamins A, C (ascorbic acid), D (tachysterol), E (tocopherol), B-1 (thiam ine), B-2 (riboflavin), B-3 (niacin/nicotinic acid or niacinam ide/nicotinam de), B-5 (pantothenic acid), B-6 (pyridoxine), B-12 (cyanocobalam in), biotin and folic acid. Vitam in K (phytonadione) is also routinely added. Trace Elem ents (daily am ounts) Zinc, 2-6 mg Manganese, 0.15-0.8 m g

Copper, 0.5-1 m g Selenium , 20-60 m cg

Chrom ium , 10-15 mcg

Molecular W eights and Chemical Formulas Dextrose Monohydrate Injection, 70% Amino Acid Injection, 10% Na = 23, Cl = 35.5 C = 12, H = 1, O = 16 NaCl CH 3COONa NaHCO 3 K = 39, Cl = 35.5 KCl CH 3COOK Mg = 24.3, S = 32 P = 31 MgSO 4 . 7 H 2O Na 2HPO 4 / Na 3PO 4 / NaH 2PO 4 K 2HPO 4 / K 3PO 4 / KH 2PO 4 Ca = 40 CaCl 2 . 2 H 2O Dextrose = 180, W ater = 18 No m olecular weight Sodium Chloride Injection, 14.6% and 23.4% Sodium Acetate Injection, 16.4% Sod Bicarbonate Injection, 8.4% Potassium Chloride Injection, 14.9% Potassium Acetate Injection, 19.6% Magnesium Sulfate Injection, 50% Sod Phosphate Injection, 3 m M ol/m l Pot Phosphate Injection, 3 m M ol/m l Calcium Chloride Injection, 10%

MVI-12 = vitam ins A, C, D, E, B-1, 2, 3, 5, 6, 12, biotin and folic acid in 10 m ls Zn, Cu, Se, Cr and Mn Vitamin K Injection To m ake total final volum e 5 Trace Elem ents Injection, 5 m ls Phytonadione Injection, 1 m g/0.5 m l Sterile W ater for Injection Other Substances That Might be Added 1. Stom ach Acid Reduction with H-2 Blocking Agent Acid secretion reduction is indicated since no food into stom ach can lead to ulcers Zantac Injection, 25 m g/m l; Pepcid, 10 m g /m l or Tagam et, 300 m g/m l Proton pum p inhibitors often cannot be added since the parenteral form s are very unstable 2. Hum an Regular Insulin, 100 units/m l (Hum alog/Novalog not approved for IV use) Control of blood sugar is often required due to the high dextrose content 3. Iron only for very long term parenteral nutrition and best given separately

Page 13

4. Albumin raises serum protein levels quickly, but avoid routine use 5. Hydrocortisone can decrease phlebitis in peripherally adm inistered solutions 6. Heparin non-therapeutic dose can decrease phlebitis 7. Carnitine for renal patients on prolonged parenteral nutrition (required for proper utilization of long chain fatty acids) 8. Cysteine for neonates because the neonatal liver has not yet developed the ability to convert methionine to cysteine 9. Drugs for therapy of diseases (e.g., antibiotics, anticancer drugs) are best adm inistered separately, rather than mixed directly into the parenteral nutrition form ula, even though they may be piggy-backed into the parenteral nutrition solution IV line W hat follows is a formula for one 24-hour bag of parenteral nutrition solution. You should practice doing the calculations required, using the product list provided, to determine the quantity of each agent required to properly prepare this solution. Total Parenteral Nutrition (TPN) Calculations Prepare from the following parenteral products: Ingredient Dextrose Am ino Acids Sodium Chloride Potassium Chloride Sodium Acetate Magnesium Sulfate Sodium Phosphate Potassium Acetate Calcium Chloride Multivitam ins Trace Elem ents-5 Vitam in K-1 Ranitidine Hum an Reg Insulin Sterile W ater Flow Rate Daily Amount 420 gram s 120 gram s 100 m Eq 70 m Eq 40 m Eq 24 m Eq 18 m Mol 30 m Eq 4.65 m Eq 10 m ls 5 m ls 1 mg 150 m g 50 units qs ad 2400 m ls 100 m ls per hour Dextrose Injection, 70% in 1000 m l bags Am ino Acid Injection, 10% in 500 m l bottles Sodium Chloride Injection, 2.5 m Eq/m l Potassium Chloride Injection, 2 m Eq/m l Sodium Acetate Injection, 2 m Eq/m l Magnesium Sulfate Injection, 8 m Eq/2 m l Sodium Phosphate Injection, 3 m M ol/m l Potassium Acetate Injection, 2 m Eq/m l Calcium Chloride Injection, 0.465 m Eq/m l Multivitam ins Injection (M VI), 10 m ls 5 Trace Elem ents Injection, 5 m ls Phytonadione Injection, 1 m g/0.5 m l Zantac Injection, 25 m g/m l Hum an Regular Insulin, 100 units/m l Sterile W ater for Injection in 1000 m l bags 600 ml 1200 ml 40 ml 35 ml 20 ml 6 ml 6 ml 15 ml 10 ml 10 ml 5 ml 0.5 ml 6 ml 0.5 ml 446 ml

PHARMACOKINETICS
The challenge in treating the distribution of drugs and their elim ination from the body is that we cannot sample all body tissues. Basically we are lim ited to blood, urine, saliva, and CSF. Elim ination of drugs fits zero order or first order equations (first order is m ost com m on). k = elim ination rate constant t 1/2 = tim e required for a decline in concentration by one-half C = concentration of drug A = total am ount of drug in the body Parameters to enable us to estim ate actual physiological conditions from those param eters which we can experim entally m easure.

Page 14

Apparent Volum e of Distribution. The theoretical volume in which the total am ount of drug in the body would have to be dissolved if it were all present in the concentration m easured in the blood. Vd = Dose Co = mg mg/L = 1 C p = (C po) (e -kt) = Dose (e -kt) Vd

C o estim ated from intercept log C vs. Tim e plot Clearance. A measure of the volume of drug cleared per unit tim e. The total body clearance (TBC) is similarly the sum of the individual clearance rates for each elim ination pathway. T B C = Cl
urine

+ Cl

metab

+ Cl

lung

+ ...

Renal Clearance. The renal clearance rate provides a clue as to the m echanism of elim ination. The glom erular filtration rate in a normal individual is approxim ately 125 m l/m inute, therefore Cl = 125 m l/m in when drug is elim inated by glom erular filtration Cl < 125 m l/m in if glomerular filtration/tubular reabsorption Cl > 125 m l/m in if glomerular filtration/active secretion The clearance rate of creatinine is approxim ately 125 m l/m inute (sam e as glom erular filtration rate) in a norm al subject. It undergoes some excretion and reabsorption. Creatinine clearance is a good estimate of renal function. The creatinine clearance can be estim ated by the Cockroft-Gault Equation. Cl Cr (mls/m in) = (140 - age) x weight (kg) 72 x serum Cr (m g/dl) Multiply by 0.85 for wom en W eight is ideal body weight

Ideal Body Weight Formulas

IBW in kilogram s (males > 18 yrs) = 50 + (2.3 (x) height in inches over 5 feet) IBW in kgm s (fem ales > 18 yrs) = 45.5 + (2.3 (x) height in inches over 5 feet) Children, 1-18 yrs and < 5 feet tall IBW in kg = (height in cm ) (x) 1.65 1000 Males 1-18 yrs and > 5 ft tall IBW in kg = 39 + (2.27 (x) inches over 5 ft) Fem ales 1-18 yrs and > 5 ft tall IBW in kg = 42.2 + (2.27 (x) inches over 5 ft)
2

Elim ination Rate Constant. Drugs are elim inated from the body via several pathways; i.e. kidney, metabolism, lung m etabolism, etc. The total elim ination rate constant is the sum of the individual rate constants. K total = k urine + k metab + k lung + ...

Im portant First Order Equations A = A o e -Kt C = A Vd C = C o e -Kt Vd = Dose Co

t 1/2

0.693 K

T B C

Clu + Clm

K = ku + km

Cl = K Vd

Page 15

Pharmacokinetic Examples
1. After IV adm inistration of 500 mg of Drug A the initial plasm a concentration was 60 m cg/ml and the k = 0.0024 hr -1. W hat is the volum e of distribution and half life? Vd = Dose Co 0.693 k = 500 m g 60 g/m l = = 500 x 10 3 m cg 60 g/m l = 288 hours = 8333 m l = 8.3 liters

t 1/2 =

0.693 0.0024 hr -1

m g/L = mcg/m l = g/m l ln 2 = 0.693

2. Drug B has a half-life of 24 hours. The drug is 70% elim inated by the kidney and Vd = 20 liters. W hat is the renal clearance of this drug? K = 0.693 = t (24 hr) 0.0288 hr-1 Cl
renal

K = ku + km = k
renal

k u = 0.7 K = (.7) (.0288) = 0.0202 hr -1 Vd = (0.0202 hr -1) (20 L) = 0.4 liters/hour

3. Drug C has a half life of 6 hours. The drug is 60% elim inated via kidney excretion. A patient has lost 70% of her kidney function. W hat is the half life? K = 0.693 t 1/2 = 0.1155 k u = (0.6) (0.1155) = 0.0693 k m = K - k e = 0.1155 - 0.0693 = 0.0462

new k u = (0.3) (0.0693) = 0.0208 new K = new k u + k m = 0.0208 + 0.0462 = 0.067 t 1/2 = 0.693 0.067 = 10.3 hours in patient with 30% remaining kidney function

4.

Drug B produces a peak concentration of 10 m cg/m l two hours after oral adm inistration. This drug is elim inated by first order kinetics and has a biological half-life of 4 hours. How long will it take this drug to reach a drug level in the plasma of 1.25 mg/liter? m cg / m l = m g / L 10 mcg/m l at 2 hrs 5 m cg/m l at 6 hrs 2.5 mcg/m l at 10 hrs 1.25 m cg/m l at 14 hrs 12 hrs is wrong because drug level was 2 hrs after dose

5. Calculate a loading dose of phenytoin using the form ula below: Loading = (Vd/kg BW ) * (kg of Body W eight) * (Cp desired) Dose F Loading = (0.5 L/kg) * (60 kg) * (15 m g/L) = 450 m g Dose 1 DRUG METABOLISM Metabolism Biotransformation of a drug to 1. active products prodrug is adm inistered and converted to the active form (s), or 2. inactive products usually done to make a drug less toxic or inactive. This generally m akes the drug m ore water soluble (hydrophilic or lipophobic) which m akes it easier for the kidney to excrete the m etabolized form. Drugs that rem ain fat soluble (lipophilic or hydrophobic) are m ore readily reabsorbed and are less likely to be excreted. Drug m etabolism occurs to some extent in the lung, kidney, blood plasm a, brain, ovary, testes, placenta and the adrenal glands. The prim ary sites for drug m etabolism are the sm all intestine (ileum) and the liver. Drugs are not generally excreted into the small intestine so any drug that will be metabolized in the sm all intestine m ust be given orally. This is usually essential for prodrugs that will Given: Vd = 0.5 L/kg, F = 1, C p desired = 15 mcg/ml, W eight = 132 lb

Page 16

be converted to the active form . Exam ples of drugs that are converted to active form s, and remain in the GI tract, would include sulfasalazine (Azulfidine) that releases 5-am inosalicylic acid or mesalamine (Pentasa). Drugs that m ust undergo m etabolism in the GI tract for conversion to an active form are not likely to have any effect if given IV or by other parenteral routes. Liver m etabolism tends to be either high first pass (high intrinsic clearance) or low first pass (low intrinsic clearance; m ost drugs). For drugs that undergo high rates of clearance, the liver w ill metabolize as m uch drug as it receives and these are the drugs m ost affected by changes in liver function and liver enzym e induction or inhibition. For these drugs the IV and oral dose are likely to be quite different (propranolol, 1 m g IV vs 20 m g PO). Rem em ber that drugs absorbed from the GI tract will go through the liver on their way to the general circulation and these are the drugs that will likely need increased oral doses in some patients. Conversely, patients with hepatic disease may need to have doses of the sam e drugs decreased due to their inability to be m etabolized. Drugs that undergo low rates of liver m etabolism (low intrinsic clearance) do not have a lot of drug removed by the liver and so their oral and IV doses are likely to be about the sam e (a single dose of cimetidine is 300 m g IV or PO). Sim ilarly, these drugs are not very affected by induction or inhibition of liver enzym es by other other drugs. Sublingual adm inistration of drugs is a standard m ethod of avoiding first pass liver m etabolism. However, the sam e result occurs for drugs adm inistered as nose drops and eye drops. This is the reason that ophthalm ic beta blockers can cause systemic problems (beta blockers normally undergo significant first pass metabolism ). Drugs are m etabolized in the liver by one of four prim ary m echanisms: 1. Oxidation oxygen is added to the structure as a lipid soluble CH 3 becom es a water soluble CH 2OH 2. Reduction an exam ple would be addition of hydrogen to a lipophilic ketone =O to becom e a hydrophilic alcohol OH 3. Hydrolysis a molecule is broken into more than one part, such as when aspirin is broken into salicylic and acetic acids 4. Conjugation this involves adding a water soluble group to the molecule and can be attached to a water soluble site created by one of the first three reactions. W ater soluble groups com m only added include acetate, glycine, sulfate and glucuronate (m ost).

Pharmacokinetic Models
A. IV Bolus dose (single dose line A) C p = C po ( e -kt ) log C p = Cl = K V d - kt 2.303 + log C p o

Formulas

ln C p = - kt + ln C po

B.

IV Infusion m odel (continuous dose line B)

Formulas Cp = K o (1 - e -kt) (k) (Vd)

C p ss =

Ko = K Vd

Ko Cl

F S D T K Vd

Ko =

Dose Tim e

F = fraction absorbed (bioavailability) D = dose adm inistered C. Absorption model (single dose line C)

S = salt form percentage (e.g., theophylline)

T=

dosing interval (in hours) Form ula C p ss ave = Dose k Vd

Page 17

TRADE NAM E DOSAGE FORM S NAPLEX m ay ask you to identify a drugs dosing properties based on the dosage form of the drug. Som e drug products have specific nam es that are used to identify specific activity of the dosage form and these are listed below. 1. Coated Tablets, but not long acting Film tab, Film seals, W yseals 2. Long Acting Tablets or Capsules (sustained release, not enteric coated) Gradum et, Endurets, Duracaps, -DUR, Dospan, Sequels, EC pellets, -PM, -SR, -CD, -XL, Ten-Tab, Extentabs, Extencaps, Tim espan, Tim ecaps, Gyrocaps, Repetabs, -CR, Spansule, Tem bids, Plateau Caps, Del-Cap 3. Regular release tablets or capsules with fancy nam es Oralets, Perles, Pulvules, Gelseals, Gelcaps, Inlay-Tabs, Bayer-TR Caplets, Caplet, Kapseal, Infatab 4. Enteric coated tablets or capsules (not long acting) Enseals, ENtabs 5. Sustained release liquid form ulations Pennkinetic SR Microcapsule Suspension, T/SR 6. Injectable dosage form s in special packaging form ats Abboject, M ix-o-Vial, Tubex, Carpuject, Solu-, Depo7. Ophthalm ic dosage forms Liquifilm , C-Cap, SOP, Ocum eter 8. Products for inhalation adm inistration Rotacaps/Rotahaler, AeroBid, Respihaler; Turbinaire, Medihaler 9. Packages of tablets for therapy use Dosepak, Enpak (Medrol) Industrial Pharm acy and Dosage Form s A sam ple of questions with answers following. 1. W hich of the following IV drugs should be dispensed with light resistant covers? A. m etronidazole B. co-trim oxazole C. doxycycline D. am photericin B E. all of the above 2. Propofol, an agent for induction and m aintenance of anesthesia, is A. a solution for inhalation B. an emulsion for injection C. a solution for injection D. a gas for inhalation E. a suspension for injection 3. Once A. B. C. D. E. in solution, which of the following agents should not be refrigerated? fluorouracil m itom ycin cisplatin ceftazidim e cyclophospham ide

Page 18

4. W hich IV antiinfective is available already in solution and ready to use? A. erythrom ycin B. vancom ycin C. aztreonam D. am photericin B E. gentam icin 5. Neut (Sodium Bicarbonate Injection) can be used to increase pH and reduce phlebitis associated with the infusion of I. am inophylline II. m etronidazole III. erythromycin lactobionate A. I only B. III only C. I and III only D. II and III only E. I, II and III only 6. W hat dose of Dilantin (phenytoin) Suspension, 125 m g per 5 m l, is equivalent to a Dilantin (phenytoin sodium ) Capsule dose of 300 mg? Assum e equivalent bioavailability. Phenytoin is C 15H 12N 2O 2; mol wts are C = 12, H = 1, N = 14, O = 16, Na = 23 A. 5 m l B. 14 m l C. 11 m l D. 9 m l E. 12 ml 7. W hich is a sustained release nitroglycerin product? A. Nitrostat B. NitroBID C. Nitrol D. Tridil E. Nitrolingual 8. Microencapsulation of drugs may I. Provide release of drug over 12 hours II. Increase surface area to minim ize local irritation III. Release drug in alkaline pH of sm all intestine A. I only B. III only C. I and II only D. II and III only E. I, II and III only 9. After reconstitution Suprax suspension should be stored I. frozen II. refrigerated III. at room temperature A. I only B. III only C. I and II only D. II and III only E. I, II and III only

Page 19

10. For which of the following is "dispense in the original container" related to drug stability I. Cytotec II. Accutane III. Nitrostat A. I only B. III only C. I and II only D. II and III only E. I, II and III only 11. W hich of the following are alcoholic or hydro-alcoholic preparations? I. Syrup II. Tincture III. Elixir A. I only B. III only C. I and II only D. II and III only E. I, II, and III only 12. Enteric coated tablets will NOT A. Provide release of the drug over 12 hours. B. Protect the drug from light and m oisture. C. Release drug in alkaline pH of small intestine. D. Be affected by crushing for adm inistration E. Reduce irritation due to the drug in the stomach 13. Slow-K (Potassium Chloride) releases drug from a A. m icroencapsulation B. erosion core C. porous inert carrier D. m ultiple release rate granules E. m ultiple layer tablet 14. Suspending agents prim arily work by I. Increasing Viscosity II. Decreasing caking III. Neutralizing particle charges that form large flocculations A. I only B. III only C. I and II only D. II and III only E. I, II, and III only 15. Fifty m l of Calcium hydroxide Solution and 50 m l of cottonseed oil are shaken. W hich of the following statements are true about the em ulsion that is form ed? I. The em ulsion could also be m ade with m ineral oil II. An oil in water em ulsion is form ed III. The em ulsifier is Calcium Oleate A. I only B. III only C. I and II only D. II and III only E. I, II, and III only

Page 20

16. W hat A. B. C. D. E.

is a m ethod used to reduce particle size? levigation fusion geom etric dilution sublim ation incorporation

17. W hich are m ajor advantages of the hydrous absorption bases for sunscreen preparations? I. The base will not wash off in water II. W ater soluble ingredients can be incorporated III. The base is miscible with water on the skin A. I only B. III only C. I and II only D. II and III only E. I, II, and III only 18. IV solutions having more than 5 m g/m L of theophylline in PVC bags m ay precipitate due to A. drug degradation B. formation of an insoluble com plex C. decreased solubility due to hydrogen bonding D. decreased solubility due to a salting out effect E. com plexation between the theophylline and PVC plasticizers 19. A pharm acist in a hurry draws up two electrolyte solutions in the sam e syringe before making a large volum e I.V. Alm ost im m ediately, a white precipitate occurs in the syringe. The precipitate is the product of a reaction between A. calcium chloride and potassium chloride B. potassium chloride and a multivitam in infusion product C. calcium chloride and sodium phosphate D. m agnesium sulfate and potassium chloride E. sodium acetate and potassium phosphate 20. If unprotected, UV light will catalyze the degradation of must be discarded. I. norepinephrine II. nitroprusside III. nitroglycerin A. I only B. III only C. I and II only D. II and III only E. I, II, and III only such that the product

21. The prim ary plastic polym er responsible for drug loss due to adsorption to IV solution containers and adm inistration set tubing is A. PVP - polyvinylpyrrolidine B. PSF - polysulfone C. PVC - polvinylchloride D. PC - polycarbonate E. PS - polystyrene 22. W hich of the following filter sizes is a "sterilizing" filter? A. 0.22 m icron filter D. 4.5 micron screen filter B. 0.45 m icron filter E. 5 m icron filter C. 2.2 m icron filter

Page 21

23. W hich agent should NOT be adm inistered with a 0.22 m icron in-line filter IV set? I. am photericin B II. alteplase III. streptokinase A. I only B. III only C. I and II only D. II and III only E. I, II, and III only

Answers to the Questions 1. E The light sensitivity of tetracyclines and m etronidazole is well known. Som e antineoplastic agents require special light protection including carm ustine (BCNU), decarbazine (DTIC), daunorubicin, fluorouracil, m ethotrexate, m itom ycin, and vinblastine. Any drug that is sold in a brown am pule needs protection from light. Any drug with sulfur in its molecular structure and can cause photosensitivity reactions and needs protection from light. Diprivan (propolol) is a colloidal soybean oil oil-in-water em ulsion for intravenous injection. The emulsifier is egg lecithin. Bacterial contam ination comm only occurs. All emulsions for IV use are oil-in-water. Cisplatin m ay precipitate if refrigerated. Fluorouracil m ay precipitate during room temperature storage but m ay be used after warm ing to dissolve. Cyclophospham ide is stable after dilution in most solutions for 24 hours at room tem perature and 6 days when refrigerated. Mitom ycin stability varies with diluent and final solution concentration. Gentam icin Injection, in both vials and ready-to-use piggyback containers, is already a solution. All of the other drugs are provided in powders to be reconstituted prior to injection or addition to IV piggyback containers. Amphotericin B in the fat em ulsion is not a solution. Both metronidazole and erythrom ycin are highly acidic in solution. Neut a 4.2% sodium bicarbonate solution can be used to neutralize the pH. Flagyl ready-to-use bags are already pH adjusted. Am inophylline is an alkaline solution and would not require Neut. Each Dilantin (Phenytoin Sodium ) 100 m g Capsule contains 92 m g phenytoin. Dilantin Suspensions and Infatabs are prom pt release phenytoin free acid. The m olecular weight ratio between the free acid and its salt (0.92) can be used to adjust dose(s) when changing salt form s. Divided doses would also be required. The 30 m g/5 m l and 125 m g/5 m l suspensions are designed for children and are dosed by weight 5 m g/kg. NOTE: This is the sam e principal that applies to converting between doses of theophylline and am inophylline. Another form of the calculation is: MW phenytoin = 252, phenytoin Na = 275 Thus X mg of Phenytoin = 300 mg of Phenytoin Na 252 m g Phenytoin 275 m g Phenytoin Na = 275 m g Phenytoin

2. B

3. C

4. E

5. D

6. C

275 m g Phenytoin (div by) 125 m g Phenytoin per 5 m l (or 25 m g/m l) = 11 m l 7. B NitroBID is a controlled release capsule with a duration of action of approxim ately 8-12 hours. Nitrostat is a short onset and duration sublingual tablet. Nitrol is the original brand name for nitroglycerin ointment. Nitrolingual is a short onset and duration m etered spray for sublingual adm inistration. Tridil is nitroglycerin injection.

Page 22

8. C

Microencapsulation can alter degree and extent of drug release in the intestine. However, no presently m arketed form ulas act as a pH dependent enteric coating. Enteric coated products are pH dependent release. Suprax is stable for 14 days at RT (15 - 30 C). More im portantly refrigeration results in increased viscosity of the suspending agents and the ability to pour an accurate dose may be reduced. Cold storage includes freezer (- 20 to -10 C) and refrigerator (2 to 8 C). A cool place is 8 to 15 C. Excessive heat is any tem p above 40 C. The "dispense in the original tamper resistant container" cautions for Accutane and Cytotec pertain to their severe teratogenic potential and m anufacturer liability. Syrups are generally nonalcoholic. An exception is Phenergan Syrup with 7% alcohol. Tinctures are by definition alcoholic dilutions of fluid extracts. Elixirs most frequently contain alcohol. An exception, Tylenol with Codeine Liquid contains no alcohol. Enteric coating does not provide any sustained release effects, e.g. Ecotrin. Enteric coating does release drug in the pH of the sm all intestine. As with any other film coating, enteric coating with opacifying agents protects a drug from light and m oisture and improves palatability. Below are exam ples of various product form ulations. Microencapsulation Micro K Porous Inert Carrier/W ax Matrix Slow K, Klotrix, Klor-Con, Ferro-Grad Multiple Layer Tab Peritrate SA, Tedral SA Erosion Core Naldecon, Mestinon-Tim espan, Extentabs Mixed Release Rate Granules K-Dur, Theo-Dur Coated or Slow-Release Beads Spansules (Various), Sequels (Various)

9. B

10. B

11. D

12. A

13. C

14. A Suspending agents such as glycerin, propylene glycol, various polyethylene glycols increase viscosity and decrease rate of particle settling. Flocculated suspensions settle faster but have smaller surface area and do not form a solid cake so they readily resuspend. A colloid is the most stable suspension (e.g., m ilk). If this is not possible using the optim um com bination of suspending and/or flocculating agents give the longest shelf life. 15. B Anionic soaps such as calcium oleate form ed from fatty acids, e.g. oleic acid found in vegetable oils and a salt such as Ca ++ or Na + will form W /O em ulsions (see Table 1). Nonionic surfactants such as Tweens and Spans are very popular. In this problem m ineral oil does not contain fatty acids and no emulsion would be form ed unless a specific emulsifier were added to the form ula. Trituration, comm inution, levigation , and pulverization by intervention are all m ethods of particle size reduction. Incorporation and geom etric dilution relate to mixing of ingredients. Fusion is a process where waxes and petrolatum are m elted and m ixed to m ake ointments. Sublim ation is the heating of a powder until it vaporizes and then recrystalizes from the vapor form . For further details consult Rem ington's Practice of Pharmacy. All properties given are advantages of W /O absorption bases. W hile still oily to the touch there is prolonged sun protection com pared to O/W water washable lotion bases which must be reapplied frequently. NOTE: Water soluble drugs which cannot be incorporated into oleaginous bases can be dissolved in water and incorporated readily into absorption bases. (Rem em ber this for method of preparation questions and for both wet or dry practical labs.) In electrolyte solutions eg. norm al saline, the salt will com pete for water association and reduce the water available for solution of nonelectrolytes (e.g. am inophylline) resulting in precipitation or "salting out" of the less soluble am inophylline.

16. A

17. E

18. D

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19. C

Reaction of a divalent cation (Ca +2) and a divalent anion (HPO 4-2) in high concentration forms the insoluble precipitate CaHPO 4. This reaction is unlikely if the ions are well diluted before mixing. Norepinephrine (Levophed) which has darkened on exposure to air and ultraviolet (UV) light should not be used. It is very sensitive to alkaline pH and should not be mixed in saline alone. In Dextrose 5% (pH 5.6) it is stable at room temperature (RT) for 24 hours. UV light causes a color change of nitroprusside solutions from brown to blue due to a reduction of ferric to ferrous ion and 20% drug loss within 4 hours. W hen protected it is stable 24 hours. Nitroglycerin (TRIDIL) is stable at RT in clear glass bottles. Polyvinylchloride, a flexible plastic polym er readily adsorbs many drug m olecules. However, a m ore rigid polypropylene polym er bag shows no significant drug adsorption. Nitroglycerin could be dispensed in this plastic IV container. The 0.22 m icron filter pore diam eter will prevent any bacterial contam ination. It may not remove som e sm all viruses and pyrogens and requires aseptic manufacturing and handling procedures. Many new large m olecular weight protein drugs (e.g., Activase, or emulsions such as Intralipid) may not pass through a 0.22 m icron in-line filter. A 5 m icron filter can be used for possible particulate contam ination such as from am pule breakage ar stopper coring m issed by visual inspection. Som e Statistical Inform ation

20. C

21. C

22. A

23. E

1. Types of Statistics and Their Purpose Descriptive (param etric or norm al distribution) versus non-param etric (binom ial distribution describes the data through means, frequencies, m odes, m edians, variances or standard deviation (spread), range and correlation/covariances. Exam ple: How Y is affected by changes in X. Inferential the science of m aking decisions while attem pting to control or understand the uncertainty (or variance); Decision m aking through the probability of being correct. Testing a hypothesis about param eters. 2. Types of Measurem ents or Data Nom inal A number is used to designate a class or a category. An exam ple would be designating students by using 1 = Freshm en, 2 = Sophom ores, 3 = Juniors and 4 = Seniors. Ordinal In this case all m easurem ents (num bers, values) are arranged in rank (numerical) order from either highest to lowest or lowest to highest. Interval Interval measurem ents are those that are based on a scale with equal units of m easurem ent such as degrees of temperature on a thermom eter. Ratio Ratio scales differ from interval scales in that they have an absolute zero (0). This is seen when com paring the Kelvin scale of tem perature and the Centigrade scale. The Kelvin scale has an absolute zero (273 degrees Centigrade) where there is the com plete absence of heat. The Centigrade scale is a means of m easuring heat and, theoretically, has no absolute limits in either direction. 3. Distributions of Data Norm al Distribution Continuous distribution with m eans and variances of ratio or interval data such as the Z-test, T-test, F-test, analysis of variance (ANOVA) or regression analysis.

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Binom ial Distribution Discrete distribution (data takes the form of yes or no; live or dead; im proved or not im proved, etc). Tests performed include the Chi Square test, contingency tables, Fishers exactness test, sim ple probability, or frequency data. The data is either nominal or ordinal data. 4. Hypothesis testing It is easier to prove that som ething is NOT correct that it is to prove that som ething is ALW AYS correct. E.g., the hypothesis that Joe is a liar vs Joe always tells the truth. To prove that Joe is a liar, we only need one lie, but to prove Joe always tells the truth, we m ust study Joe for his entire life. But, it is also difficult to prove negativity; the fact that som ething does not exist (Joe never tells the truth). The Null Hypothesis (Ho) is a derived statem ent that is opposite to the research hypothesis. An exam ple would be the statem ent that the height of students in Marys class is the same as the height of students in Joes class (Marys = Joes). The Alternate Hypothesis (Ha) would be that the height of the students is different for the two classes. The Null Hypothesis (Ho) can be expressed as Ho: u1 = u2 (where u1 = the height of students in Marys class and u2 = the height of students in Joes class). The Alternate Hypothesis (Ha) can be expressed as Ha: u1 u2 (where u1 = the height of students in Marys class and u2 = the height of students in Joes class). There are four possible outcom es for any hypothesis test based on whether the Null hypothesis was accepted (correct or true) or rejected (not correct or false) and w hether or not the Null hypothesis was true or false. A Type I (alpha) error rejects Ho even though the statem ent is actually true. This error is controlled for by the statistical test. A Type II (beta) error accepts Ho even though the statem ent is actually false. This error is NOT controlled for by the statistical test. The POWER is the probability that the statistical test will reject the Null hypothesis when it is FALSE (1-beta). 5. Statistical Significance involves the likelihood (probability) of obtaining a given result by chance (it may, or m ay not, be true). This statistical significance is comm only represented by the letter p (for probability). The value of p can be between zero (0) and one (1). The p value. Think percentage when using the p value. This describes the likelihood that your data is, or is not, valid. If you convert the p value to a percent (p = 0.01 becom es 1 percent), this m eans that there is only a 1% chance that your data is inaccurate or does not support the conclusion you have drawn. The sm aller the p value (0.05 > 0.01 > 0.001), the m ore likely it is that your conclusions are accurate and your hypothesis is correct. That is, your conclusion is due to the data and is not sim ply an accidental finding. It is usually understood that a p value m ust be 0.05, or below, for data to be statistically valid. W ays of expressing statistical significance with a p value of 0.05 include: a. the finding is significant at the 0.05 level; b. the confidence level is 95% (I am 95% certain of m y findings); c. the Type I error rate is 0.05;

The Null Hypothesis (Ho) is: TRUE Accepted Ho Rejected Ho Correct Type I error (alpha) FALSE Type II error (beta) Correct

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d. the alpha level is 0.05; e. = 0.05; f. there is a 1 in 20 chance of obtaining a false result; g. the p value is 0.05; and h. p = 0.05 Averages and related values The Arithm etic M ean is the same as what we usually call the average of a set of values. The usual method to calculate the arithm etic mean (average) is to add up all of the values and divide that total by the num ber of values. This can be expressed in a formula as: X = 3 X N which is a shorter form of X = X1 + X2 + X3 + X4 + X5 * * * N

The M edian is defined as the point in the distribution of data that has 50% of the data points on each side. This is best done by arranging the various data values in num erical order and then counting the data points. For the data points 1, 3, 5, 7, 9 the m edian is 5 because there two points below and two points above five. This works when there is an odd num ber of data points. If there are an even num ber of data points, then some calculation is required. For the data points 2, 4, 6, 8 here the median is again 5 because there are two points above and two points below. This could be calculated by adding up the num bers and dividing by the num ber of observations: 20 div by 4 = 5. Consider the m ore complicated series of data 14, 15, 16, 17, 17, 17, 18, 19, 20, 21 the presence of the three 17's m eans we cannot chose either 16.5, 17, or 17.5 as our m edian. The three 17's are presumed to be equally distributed between 16.5 and 17.5. Since we have three points (14, 15 and 16) below the 17's, we only need two more points (2 out of 3) to find our median. Therefore, we take the 16.5 and add two-thirds (0.67) to determine a m edian of 17.2 for this case. The M ode is the value that occurs m ost frequently in a set of data. For the set of data in the paragraph above (14, 15, 16, 17, 17, 17, 18, 19, 20, 21), the mode is 17 because that value occurs three times and no other value occurs more than once.

Population Variance (sigma)

S2 = (x1 X)2 N

Sample S2 = (x1 X)2 Variance N-1

Population standard deviation = square root of population variance Sam ple standard deviation = square root of sam ple variance Degrees of freedom = m eans the freedom to vary. Suppose we have 44 data points. First, we com pute the mean, and then we take the deviation of each score from the m ean and com pute the standard deviation. W e had 44 degrees of freedom to begin with, but in the computations described, we used up one degree of freedom . Thus, we now have 43 (N 1) degrees of freedom . Degrees of freedom will be used in the t-test and Chi Square described below. W hen the num ber of measurem ents (sam ple size) is very sm all (e.g., < 25), then the t-test statistic is used to assess the difference between m eans. This is also caused the param etric test of m eans. Also known as the t-ratio or as Students t, the t-test statistic is calculated from the form ula: Population mean (X) Sam ple Mean (Xo) with N-1 degrees of freedom. Sam ple standard deviation the square root of the num ber of observations (%&N)

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The Chi Square (X 2) test of significance. This is m ost useful when the data are in frequencies such as the num ber of responses in different categories. Chi Square is a non-param etric test of m eans. Two illustrations can explain Chi Square. First case, when one tosses a coin 100 tim es, you would expect to get 50 heads and 50 tails. But when you actually tossed a coin 100 tim es, you got 40 heads and 60 tails. W e make the null hypothesis that the 40/60 split does not differ from the 50/50 split we would expect by chance. The general form ula for Chi Square is Thus, X 2 = (40 50) 2 + (60 50) 2 = 4.00 50 50 X 2 = 3 (Observed Expected)2 Expected

Now one needs to use a Chi Square table and refer to the one degree of freedom line (a coin can only com e up heads or tails; hence, one degree of freedom ). The table value for 4.00 lies between 0.05 and 0.02. Thus, we can be 5% confident that these results are different from those that would occur by chance alone. Second case, the null hypothesis (Ho) is that there is no relationship between the gender of a child and the childs favorite TV com m ercial. Data Table Group Boys Girls Totals A 30 (25.2) 12 (16.8) 42 B 29 (37.2) 33 (24.8) 62 C 16 (12.6) 5 (8.4) 21 Totals 75 50 125

The numbers in the parenthesis are calculated by using the totals in the colum ns and rows. The 25.2 in the Boys (A) group is calculated by taking the total num ber of boys (75) m ultiplied by the total number in Group A (42) and then divided by the total num ber of boys and girls (125). Thus, 25.2 is the expected value for this group. X 2 = (30 25.2)2 + (29 37.2)2 + ...... + ...... + ..... + ..... = 9.097 25.2 37.2 The degrees of freedom are calculated by the form ula: (No. of Rows 1) x (No. of Colum ns 1) = (2 1) x (3 1) = (1) x (2) = 2 degrees of freedom Going to a Chi Square table; 9.097 with two degrees of freedom falls between 0.02 and 0.01. Thus, at an alpha of 0.02, we would reject the null hypothesis that gender and favorite TV com m ercial are independent. That is, they are not associated. Sam ple from a Chi Square Table Degrees of Freedom 1 2 5 10 Probability 0.50 0.455 1.386 4.351 9.342 Probability 0.10 2.706 4.605 9.236 15.987 Probability 0.05 3.841 5.991 11.070 18.307 Probability 0.01 6.635 9.210 15.086 23.209 Probability 0.001 10.827 13.815 20.517 29.588

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